New hypotheses for the health-protective mechanisms of whole-grain cereals: What is beyond fibre?

Abstract

Epidemiological studies have clearly shown that whole-grain cereals can protect against obesity, diabetes, CVD and cancers. The specific effects of food structure (increased satiety, reduced transit time and glycaemic response), fibre (improved faecal bulking and satiety, viscosity and SCFA production, and/or reduced glycaemic response) and Mg (better glycaemic homeostasis through increased insulin secretion), together with the antioxidant and anti-carcinogenic properties of numerous bioactive compounds, especially those in the bran and germ (minerals, trace elements, vitamins, carotenoids, polyphenols and alkylresorcinols), are today well-recognised mechanisms in this protection. Recent findings, the exhaustive listing of bioactive compounds found in whole-grain wheat, their content in whole-grain, bran and germ fractions and their estimated bioavailability, have led to new hypotheses. The involvement of polyphenols in cell signalling and gene regulation, and of sulfur compounds, lignin and phytic acid should be considered in antioxidant protection. Whole-grain wheat is also a rich source of methyl donors and lipotropes (methionine, betaine, choline, inositol and folates) that may be involved in cardiovascular and/or hepatic protection, lipid metabolism and DNA methylation. Potential protective effects of bound phenolic acids within the colon, of the B-complex vitamins on the nervous system and mental health, of oligosaccharides as prebiotics, of compounds associated with skeleton health, and of other compounds such as alpha-linolenic acid, policosanol, melatonin, phytosterols and para-aminobenzoic acid also deserve to be studied in more depth. Finally, benefits of nutrigenomics to study complex physiological effects of the 'whole-grain package', and the most promising ways for improving the nutritional quality of cereal products are discussed.

Full text

New hypotheses for the health-protective mechanisms
of whole-grain cereals: what is beyond fibre?
Anthony Fardet
1,2
1
INRA, UMR 1019 Nutrition Humaine, F-63122 Saint-Gene
`s-Champanelle, France
2
Clermont Universite
´, UFR Me
´decine, UMR 1019 Nutrition Humaine, F-63000 Clermont-Ferrand, France
Epidemiological studies have clearly shown that whole-grain cereals can protect against obesity,
diabetes, CVD and cancers. The specific effects of food structure (increased satiety, reduced transit
time and glycaemic response), fibre (improved faecal bulking and satiety, viscosity and SCFA
production, and/or reduced glycaemic response) and Mg (better glycaemic homeostasis through
increased insulin secretion), together with the antioxidant and anti-carcinogenic properties of
numerous bioactive compounds, especially those in the bran and germ (minerals, trace elements,
vitamins, carotenoids, polyphenols and alkylresorcinols), are today well-recognised mechanisms
in this protection. Recent findings, the exhaustive listing of bioactive compounds found in
whole-grain wheat, their content in whole-grain, bran and germ fractions and their estimated
bioavailability, have led to new hypotheses. The involvement of polyphenols in cell signalling and
gene regulation, and of sulfur compounds, lignin and phytic acid should be considered in
antioxidant protection. Whole-grain wheat is also a rich source of methyl donors and lipotropes
(methionine, betaine, choline, inositol and folates) that may be involved in cardiovascular and/or
hepatic protection, lipid metabolism and DNA methylation. Potential protective effects of bound
phenolic acids within the colon, of the B-complex vitamins on the nervous system and mental
health, of oligosaccharides as prebiotics, of compounds associated with skeleton health, and
of other compounds such as a-linolenic acid, policosanol, melatonin, phytosterols and
para-aminobenzoic acid also deserve to be studied in more depth. Finally, benefits of
nutrigenomics to study complex physiological effects of the ‘whole-grain package’, and the most
promising ways for improving the nutritional quality of cereal products are discussed.
Whole-grain wheat: Bioactive compounds: Physiological mechanisms: Health
Introduction
There is growing evidence that whole-grain cereal products
protect against the development of chronic diseases. The
most important of these in terms of public health are
obesity
(1,2)
, the metabolic syndrome
(3,4)
, type 2 diabetes
(5,6)
,
CVD
(7)
and cancers
(8 – 12)
. Whole-grain cereal consumption
has also been shown to be protective against mortality, as
was shown with inflammation-related death (i.e. non-
cardiovascular and non-cancer inflammatory diseases such
as, for example, respiratory system diseases)
(13)
and with
cancer and CVD
(4,14,15)
. These conclusions are supported by
the effects of consuming refined cereal products (bread,
pasta and rice), as these have been associated with an
increased risk of digestive tract, pharynx, larynx and thyroid
cancers in northern Italians
(16)
. However, an association
between a lower risk of developing a chronic disease and a
high whole-grain cereal consumption does not mean a direct
causal relationship and provides no information about the
physiological mechanisms involved.
These metabolic diseases are related to our daily lifestyle,
notably an unbalanced energy-rich diet lacking fibre and
protective bioactive compounds such as micronutrients and
phytochemicals. Today, it is agreed to advance that this is the
synergistic action of the compounds, mainly contained in the
bran and germ fractions of cereals, which is protective
(17,18)
.
Some specific mechanisms are today well recognised. For
example, food structure influences satiety and the slow
release of sugars recommended for type 2 diabetes. Dietary
fibre improves gut health, and the antioxidant and anti-
inflammatory properties of most phytochemicals can help
Abbreviations: AACC, American Association of Cereal Chemists; DW, dry weight; FRAP, ferric-reducing ability of plasma; GI, glycaemic
index; GSH, reduced glutathione; GSSG, oxidised glutathione; RS, resistant starch; USDA, US Department of Agriculture.
Corresponding author: Dr Anthony Fardet, fax þ33 473624638, email anthony.fardet@clermont.inra.fr
Nutrition Research Reviews (2010), 23, 65–134
qThe Author 2010
doi:10.1017/S0954422410000041
Nutrition Research Reviews

prevent cancer and CVD. However, the precise physiological
mechanisms involved are far from being elucidated.
The main whole-grain cereals consumed worldwide are
wheat, rice and maize, followed by oats, rye, barley,
triticale, millet and sorghum. Whole-grain wheat, which is
the focus of the present review, is composed of 10– 14 %
bran, 2·5– 3·0 % germ and 80 –85 % endosperm, depending
on the intensity of the milling process. The bioactive
compounds are unevenly distributed within these parts
(Fig. 1), and this distribution also varies according to the
type of cereal considered. Whole-grain cereals are a rich
source of fibre and bioactive compounds. For example,
whole-grain wheat contains about 13 % dietary fibre and at
least 2 % bioactive compounds other than fibre (Table 1),
which accounts for at least 15 % of the whole grain. In the
bran and germ fractions, still higher proportions are
reached: about 45 and 18 % of dietary fibre, and about
7 % and at least 6 % of bioactive compounds, respectively;
which represents about 52 % and at least 24 % of these
fractions. These proportions obviously depend on the cereal
type. It is therefore easy to understand that refined cereal
products that lack the bran and germ fractions have lost most
of their protective compounds. For example, refining whole-
grain wheat may lead to the loss of about 58 % of fibre, 83 %
of Mg, 79 % of Zn, 92 % of Se, 70 % of nicotinic acid, 61 %
of folates and 79 % of vitamin E
(19)
.
However, the exact nature of the positive physiological
effects exerted by whole-grain cereal products remains
unresolved because of the huge number of phytochemicals
and biological effects involved (Tables 2 and 3). The most
significant of them in wheat, besides fibre, are n-3 fatty
acids, sulfur amino acids, oligosaccharides (stachyose,
raffinose and fructans), lignin, minerals, trace elements,
vitamins B and E, carotenoids, polyphenols (especially
phenolic acids such as ferulic acid and smaller amounts of
flavonoids and lignans), alkylresorcinols, phytic acid,
betaine, total choline-containing compounds, inositols,
phytosterols, policosanol and melatonin. Each one of these
compounds has numerous physiological functions and
recognised health benefits (Tables 3 and 4). While studying
each compound separately, the main approach used to date,
may well be unavoidable, it also involves considerable risk.
This is because it ignores two important factors. One is the
importance of synergy between the actions of compounds
which is poorly characterised and more difficult to assess
than the biological action of an isolated compound. The
second is the importance of the cereal matrix and its
influence on the accessibility of compounds in the digestive
tract and hence on their availability within the organism.
Indeed, little is often known of the bioavailability of many
bioactive compounds derived from complex cereal products
(Table 2). Thus, the amount of a particular compound in
Testa (1 %)
• Alkylresorcinols
Aleurone
layer
(6–9 %)
Starchy endosperm
(80–85 %)
• Starch and proteins
(sulfur amino-acids)
•β-Glucans, arabinoxylans
• Carotenoids
•Se
• Thiamin (B1) and vitamin E
• Flavonoids (anthocyanins)
• Lipids (α-linolenic acid)
• Sucrose and
monosaccharides
• Sulfur amino acids
• Glutathione
• Insoluble and soluble
fibre, raffinose
• Flavonoids
• Vitamin E
• B vitamins
• Minerals and trace
elements
• Phytosterols
• Betaine and choline
• Policosanol
• Enzymes
Soluble and insoluble
dietary fibre (xylans,
β-glucans, raffinose,
stachyose, fructans)
•
•
Proteins (sulfur amino
acids and glutathione)
•Antioxidants
(phenolic acids,
carotenoids, lignans,
anthocyanins,
isoflavonoids)
• Vitamin E
•B vitamins
• Minerals and trace
elements
•Phytic acid
•Betaine and choline
•Enzymes
Germ (3 %)
•Insoluble dietary
fibre (xylans,
cellulose, lignin)
•Antioxidants bound
to cell walls
(phenolic acids)
Crease
Brush
Inner -
and
outer
pericarp
(4–5 %)
Bran*
• Policosanol
• Phytosterols
Scutellum
Embryonic axis
Hyaline layer
•
Myo
-inositol
Fig. 1. The three wheat fraction (bran, germ and endosperm) with their main bioactive compounds as obtained from Tables 1 and 2. Whole-grain
wheat has an heterogeneous struture with bioactive compounds unevenly distributed within its different parts (with permission from Surget &
Barron for original image
(476)
, and adapted from the brochure ‘Progress in HEALTHGRAIN 2008’, HealthGrain Project, European Community’s
Sixth Framework Programme, FOOD-CT-2005-514008, 2005– 2010).* No published data on the precise locations of policosanol and phytosterols
in a specific layer of the wheat bran fraction.
A. Fardet66
Nutrition Research Reviews

whole-grain cereals is rarely the same as the amount that is
available to exert a given physiological action, in contrast to
the result of consuming the free compound.
There may be many protective physiological mechanisms
associated with consuming whole-grain cereal because of
the high number of protective compounds. They may be
mechanical within the digestive tract (insoluble fibre can
increase transit time and faecal bulking), hormonal (Zn, Se
and nicotinic acid participating in hormone activation and
synthesis), antioxidative (almost all micronutrients), anti-
inflammatory (for example, n-3 a-linolenic acid, Cu and
ferulic acid), anti-carcinogenic (almost all micronutrients),
or linked to gene regulation (for example, flavonoids), cell
signalling (for example, polyphenols and redox status),
energy metabolism (for example, the B-complex vitamins)
and effects on enzymes (for example, some minerals and
trace elements) (Table 3).
The main objective of the present paper is to propose new
hypotheses for exploring the mechanisms behind the
protective actions of whole-grain cereals using wheat as
the main example. I have therefore exhaustively itemised all
the bioactive compounds in whole-grain wheat and in the
two fractions that are usually removed during refining: bran
and germ. I have also listed their contents (range) in wheat,
their bioavailability when obtained from complex whole-
grain wheat products, their potential physiological effect(s)
and the resulting health outcomes, with particular attention
to some compounds that are specific to cereals other than
wheat. The proposed new hypotheses are based on the
action of compounds that are all bioactive when tested alone
in their free form, such as the B vitamins, lignin, phytic acid,
betaine, choline-containing compounds, inositols, policosa-
nol, melatonin, para-aminobenzoic acid, sulfur amino acids,
a-linolenic acid, phytosterols and some oligosaccharides.
First, I define the term ‘whole-grain cereal products’ and
then examine the presently accepted mechanisms for
explaining the role played by whole-grain cereals in
preventing chronic diseases, as identified by studies on
human subjects (for example, the importance of food
structure and antioxidants), on rats (for example, the anti-
carcinogenic property of many phytochemicals) and in vitro
(cell-associated mechanisms). I then discuss my new
hypotheses that are based on recent findings and on the
potential physiological effects of whole-grain cereal
compounds. I develop a broader view of the well-known
antioxidant hypothesis that takes into account the actions of
polyphenols on cell signalling and gene regulation in
relation to the redox status. I review recent publications that
have also revealed the great potential of the nutrigenomic
approach for extending our knowledge of the protective
mechanisms associated with complex foods. Finally,
I briefly review the ways by which the nutritional quality of
cereal products can be improved so as to optimally preserve
the protective properties of whole-grain cereals.
What are whole-grain cereal products?
Definition
The American Association of Cereal Chemists (AACC)
gave the following scientific and botanical definition in
1999: ‘Whole grains shall consist of the intact, ground,
cracked or flaked caryopsis, whose principal anatomical
Table 1. Average content of the major bioactive compounds in whole-grain wheat and wheat bran and germ fractions (%)*
Bioactive compound Whole-grain wheat† Wheat bran† Wheat germ†
a-Linolenic acid (18 : 3n-3) –‡ 0·16 0·53
Sulfur compounds 0·5 0·7 1·2
Total free glutathione§ 0·007 0·038 0·270
Dietary fibrek13·2 44·6 17·7
Lignins 1·9 5·6 1·5
Oligosaccharides{1·9 3·7 10·1
Phytic acid 0·9 4·2 1·8
Minerals and trace elements 1·12 3·39 2·51
Vitamins 0·0138 0·0398 0·0394
B vitamins 0·0091 0·0303 0·0123
Vitamin E (tocopherols and tocotrienols) 0·0047 0·0095 0·0271
Carotenoids 0·00 034 0·00 072 –‡
Polyphenols 0·15 1·10 .0·37
Phenolic acids 0·11 1·07 .0·07
Flavonoids 0·037 0·028 0·300
Lignans 0·0004 0·0050 0·0005
Alkylresorcinol 0·07 0·27 –‡
Betaine 0·16 0·87 0·85
Total choline 0·12 0·17 0·24
Total free inositols (myo- and total chiro-inositols) 0·022 0·025 .0·011
Phytosterols 0·08 0·16 0·43
Policosanol þmelatonin þpara-aminobenzoic acid 0·00 341 0·00 290 .0·00 186
Total .15·4 51·5 .23·9
Subtotal (without dietary fibre) .2·2 6·9 .6·2
* Mean percentages of bioactive compounds found in wheat bran, whole-grain wheat and wheat germ are calculated from Table 2 as follows:
%¼(minimum value þmaximum value)/2.
† Expressed as g/100 g food.
‡ No data found.
§ Total free glutathione is given as glutathione equivalents ¼reduced glutathione þ(oxidised glutathione £2).
kDietary fibre content is measured according to the AOAC method as such or modified (for details, see American Association of Cereal Chemists
(53)
).
{Oligosaccharides include fructans, raffinose and stachyose.
Hypotheses for whole-grain cereal protection 67
Nutrition Research Reviews

Table 2. Content, apparent absorption and fermentability of bioactive compounds and fibre from whole-grain wheat and wheat bran and germ fractions*
Bioactive compound
Content in whole
grain (per 100 g)†
Apparent absorption or degree
of fermentation in crude or processed
whole-grain wheat (%)
Content in bran
(per 100 g)†
Apparent absorption or degree
of fermentation in crude or
processed wheat bran (%)
Content
in germ
(per 100 g)†
n-3 Fatty acids (g/100 g)
a-Linolenic acid (18 : 3n-3) – ‡ –‡ 0·16 –‡ 0·47–0·59
Sulfur compounds
Reduced glutathione (mg/100 g)§ 1·04–5·74 Negligible in humans when free‡ 1·7– 19·4 Negligible in humans when free‡ 19·4– 245·7
Oxidised glutathione (mg/100 g)§ 0·86 –2·88 – 6·1 –21·4 – 15·3 –122·4
Methionine (g/100 g) 0·17 – 0·24 – 0·20 – 0·29 – 0·39– 0·58
Cystine (g/100 g) 0·19 –0·40 – 0·32 –0·45 – 0·35 –0·61
Sugars (g/100 g)
Monosaccharides 0·26– 1·30 – 0·14–0·63 – 0·6– 1·5
Sucrose 0·60–1·39 – 1·8–3·4 – 7·7– 16·0
Fibre (g/100 g)
Total 9·0–17·3 34 in humansk35·7– 53·4 34 – 56 in humans; 37–49
in rats; 42–65 in pigsk
10·6–24·7
Insoluble 9·5–11·4 – 32·4–41·6 42 in ratsk8·5– 18·6
Soluble 1·1–3·2 – 1·3–5·8 73 in ratsk2·1– 6·1
Cellulose 2·1–2·8 20 in humansk6·5– 9·9 6 – 23 in humans; 14 – 24
in pigs and ratsk
7·5
Hemicellulose 8·6 46 in humansk20·8 –33·0 50– 54 in humans; 47 – 74
in pigs and ratsk
6·8
Lignins 0·9–2·8 4 in humansk2·2–9·0 0 in humans‡; 0 – 4 in ratsk1·3 –1·6
Fructans 0·6–2·3 – 0·6– 4·0 – 1·7–2·5
Raffinose 0·13–0·59 97–99 in dogs fed a soyabean meal‡ 1·08–1·32 Almost completely fermented
when free‡
5·0–10·9
Stachyose 0·05–0·17 97–99 in dogs fed a soyabean meal‡ 0·04–0·36 Almost completely fermented
when free‡
–
Arabinoxylans 1·2– 6·8 – 5·0 – 26·9 49 arabinose in humans;
71 xylose in humans
5·6– 9·1
Water-extractable 0·2– 1·2 – 0·1 – 1·4 – 0·4
b-Glucans 0·2 – 4·7 – 1·1 – 2·6 – –
Phytic acid
(hexakisphosphate; g/100 g)
0·3–1·5 Poorly absorbed in humans; 54–79
degraded in human
subjects fed whole bread; 79 %
absorbed as free compound in rats‡{
2·3–6·0 58 – 60 degraded into lower
inositol phosphates in
ileostomates fed raw wheat bran
1·4– 2·2
Minerals (mg/100 g)
Fe 1·0–14·2 1–20 in human or usual diets‡ 2·5 – 19·0 3·8 in human subjects fed
wheat bran rolls
3·9–10·3
Mg 17 –191 21 – 28 in human subjects fed brown
bread diet; 70 in rats
390– 640 – 200–290
Zn 0·8–8·9 17–20 in humans; 19 – 95 in rats 2·5–14·1 – 10– 18
Mn 0·9 – 7·8 Very low‡ 4–14 Very low‡ 9– 18
Cu 0·09–1·21 62–85 in humans; 16
as free compound in rats
0·84– 2·20 – 0·70 – 1·42
Se 0·0003 – 3 81 –85 in rats 0·002– 0·078 60 – 80 in rats/free sodiumselenite 0·001–0·079
P 218– 792 41–55 in humans fed brown bread diet 900– 1500 41 – 56 in human subjects fed
sodium phytate‡
770–1337
Ca 7–70 82 % in humans; 43 – 93 in rats 24– 150 22 % in humans 36–84
Na 2–16 – 2–41 – 2 –37
K 209– 635 – 1182– 1900 – 788–1300
Vitamins (mg/100 g)
Thiamin (B
1
) 0·13–0·99 91 in rats/free thiamin mononitrate 0·51 – 0·80 – 0·8 – 2·7
A. Fardet68
Nutrition Research Reviews

Riboflavin (B
2
) 0·04– 0·31 95 as oral supplement in human subjects‡ 0·21–0·80 – 0·50 – 0·80
Nicotinic acid (B
3
) 1·9–11·1 Low, since mostly bound‡ 13·6–35·9 27– 38 in humans (nicotinic acid
concentrate)
4·0– 8·5
Pantothenic acid (B
5
) 0·7– 2·0 About 50 in human/average American diet‡ 2·2–4·1 – 1 – 2·7
Pyridoxine (B
6
) 0·09–0·66 71–79 in human/average American diet
as compared with free compound‡
0·70–1·30 Unavailable in humans 0·49 – 1·98
Biotin (B
8
) 0·002–0·011 Very low‡ 0·0440 Very low‡ 0·0172
Folate (B
9
) 0·014–0·087 – 0·088– 0·373 Low 0·14–0·70
Tocopherols þtocotrienols (E) 2·3– 7·1 – 9·5 Not readily available 23·1–31
Total tocopherols 1·06 –2·89 – 2·4 – 21·5 – 30·6
a-Tocopherol 0·34– 3·49 70 in humans as free compound 0·13–2·84 – 3·1 – 22
Total tocotrienols 1·09 – 4·49 – 7·10 – 1·3 – 1·6
Phylloquinone (K) 0·002 – 0·020 – 0·002– 0·083 – 0·003 – 0·350
Carotenoids (mg/100 g)
Total 0·044–0·626 – 0·25– 1·18 – –
b-Carotene 0·005– 0·025 – 0·003– 0·010 – 0·062
Lutein 0·026–0·383 – 0·050–0·180 – –
Zeaxanthin 0·009 – 0·039 – 0·025– 0·219 – –
b-Cryptoxanthin 0·001–0·013 – 0·018– 0·064 – –
Polyphenols
Phenolic acids (mg/100 g)**
Total 16– 102 See free/soluble-conjugated and bound‡ 761 – 1384 See free/soluble-conjugated
and bound‡
–
Extractable (free and conjugated) 5– 39 Probably high 46– 63†† Probably high 51
Bound 14–78 See wheat bran‡ 148– 340†† 33 in pig; partially/slowly
solubilised within human
model colon
–
Ferulic acid (mg/100 g)
Total 16– 213 Low: 3·4 % urinary excretion in rats 138– 631 Low: 2·0 –5·7 % urinary
excretion in humans and
3·9 % urinary excretion in rats
7–124
Extractable (free and conjugated) 0·7– 4·9 High in rat small intestine 1·3 – 23·1 High: 27·8– 78·9 % urinary
excretion in humans; high
in rat small intestine
18
Bound 14–64 Low: action of small intestine esterases 122 – 286 Low: action of small intestine
esterases
–
Dehydrodiferulic acid 1·5 – 76·0 See wheat bran‡ 13 – 230 Undetectable in human plasma;
free diferulic acid can be
absorbed from the gut in rats
9
Dehydrotrimer ferulic acid 2·6 – 3·5 – 15 – 25 – –
Flavonoids (mg/100 g) 30 –43‡‡ – 15 –41 – 300§§
Free (mg/100 g) 2·2 –4·9‡‡ – – – –
Bound (mg/100 g) 28 –40‡‡ – – – –
Anthocyanins (mg/100 g) 0·5 – 52·4 – 0·9 –48·0 – –
Isoflavonoids (mg/100 g) 14·8kk – 3·8 – 10·4 – –
Lignans (mg/100 g) 0·2 –0·6 – 2·8 –6·7 – 0·49
Others
Alkylresorcinols (mg/100 g) 12 –129 60 – 79 in pig small intestine fed
whole-grain rye bread
215– 323 45– 71 % from ileostomy effluents
in humans fed rye bran
soft/crisp bread
–
Betaine (mg/100 g) 22– 291 – 230 –1506 – 306 – 1395
Total choline{{ (mg/100 g) 27 – 195 – 74 – 270 – 152
***
–330
Phytosterols (mg/100 g) 57 –98 Weakly absorbed from the gut‡ 121 –195 Weakly absorbed from the gut‡ 410– 450
Inositols
Total chiro-inositol††† (mg/100 g) 17 Apparently high in humans/free compound nd – –
Free myo-inositol (mg/100 g)‡‡‡ 1·9– 7·5 Apparently high in rat as free compound 14·0 –36·4 – 8·5 –13·3
Hypotheses for whole-grain cereal protection 69
Nutrition Research Reviews

components – the starchy endosperm, germ and bran – are
present in the same relative proportions as they exist in the
intact caryopsis’
(20)
. The definition given by the Whole
Grains Council in May 2004 includes processed food
products: ‘Whole grains or foods made from them contain all
the essential parts and naturally-occurring nutrients of the
entire grain seed. If the grain has been processed (e.g.
cracked, crushed, rolled, extruded, and/or cooked), the food
product should deliver approximately the same rich balance
of nutrients that are found in the original grain seed’
(21)
. The
US Food and Drug Administration published a Draft
Guidance on Whole-grain Label Statements in 2006 that
adopted the international AACC definition and included
amaranth, barley, buckwheat, bulgur, maize (including
popcorn), millet, quinoa, rice, rye, oats, sorghum, teff,
triticale, wheat and wild rice; pearled barley was not included
because some outer layers of the bran fraction are
removed
(22)
. Pseudocereals such as amaranth, buckwheat
and quinoa have similar macronutrient compositions
(carbohydrates, proteins and lipids), and are used in the
same traditional ways as cereals
(23,24)
. The response to the US
Food and Drug Administration Draft Guidance by the AACC
International recommended that some traditional cereals
such as ‘lightly pearled barley, grano (lightly pearled wheat),
nixtimalized corn and bulgur that has been minimally
processed be also classified as whole grains’
(23)
, making
allowance for small losses of components that occur through
traditional processing. The Whole Grain Task Force stated in
2008 that it ‘supports the use of the term whole-grain for
products of milling operations that divide the grain into germ,
bran and endosperm, but then recombine the parts into their
original proportions before the flour leaves the mill’
(24)
.
However, as I will explain later, most of the products defined
as whole-grain foods in studies showing the health benefits of
whole-grain cereals are made of recombined whole-grain
flours
(24)
, which rarely contain the same proportions of bran,
germ and endosperm as the intact grain before milling. Thus,
the germ fraction is almost always removed because its high
lipid content (about 9 %) may go rancid upon storage
(25)
.
Processing whole-grain cereals also leads to losses of
bioactive compounds so they cannot really deliver ‘approxi-
mately the same rich balance of nutrients that are found in the
original grain seed’
(21)
. Thus, if researchers had referred
strictly to the definitions given above, few studies could have
concluded that whole-grain cereal foods protect human
health. Alternative definitions have therefore been proposed
by the Whole Grain Task Force in which ‘as they exist in the
intact caryopsis’ in the AACC definition is replaced by ‘as
found in the least-processed, traditional forms of the edible
grain kernels’ or completed by adding ‘as they exist in the
intact caryopsis to the extent feasible by the best modern
milling technology’
(24)
. This last definition is probably the
best adapted to our Western country technologies. But none
of these alternative definitions has been adopted to date and
there is still no official international definition of whole-grain
cereal products in Europe.
What proportions?
Finally, the proportion of whole grains that must be present
in a cereal product needs to be defined for it to be considered
Table 2. Continued
Bioactive compound
Content in whole
grain (per 100 g)†
Apparent absorption or degree
of fermentation in crude or processed
whole-grain wheat (%)
Content in bran
(per 100 g)†
Apparent absorption or degree
of fermentation in crude or
processed wheat bran (%)
Content
in germ
(per 100 g)†
Policosanol (mg/100 g) 0·30 – 5·62 – 0·11 –3·00 – 1·01
Melatonin (mg/100 g) 0·2 –0·4 – – – –
p-Aminobenzoic acid (mg/100 g) 0·34 –0·55 – 1·34 – 0·85
nd, Not detected.
* All data are based on international references unless specified (see references in Appendices); for bioavailability data, methods used for determining percentage apparent absorption, the subject status and the model
used (animals v. humans) differ from one study to another which may explain the sometimes very large range of values given: data remain therefore indicative and should be taken cautiously.
† When expressed on a DM basis in references, results were converted on a wet matter basis considering that whole grain, bran and germ contain 13, 10 and 11·4 g water/100 g food, respectively.
‡ No data found as regard with whole-grain wheat, and wheat bran and germ.
§ Total glutathione equivalents ¼reduced glutathione þ(oxidised glutathione £2).
kDegree of fermentation.
{Small-intestinal phytases (high activity in rats and very much lower in humans and pigs) are able to hydrolyse phytic acid.
** High ranges are likely to result from the different types of extraction procedure used.
†† Expressed in gallic acid equivalents/100 g.
‡‡ Expressed in catechin equivalents.
§§ Expressed as rutin equivalents.
kk Sum of genistein and daidzein (whole-wheat flour type not specified).
{{ Total choline refers to the sum of free choline, glycerophosphocholine, phosphatidylcholine and sphingomyelin.
*** Toasted wheat germ
(477)
.
††† Chiro-inositol refers to the sum of free D-chiro-inositol and chiro-inositol moieties mainly derived from pinitol (i.e. methyl chiro-inositol) and glycosylated pinitol.
‡‡‡ Evaluation based on the fact that about 95 % of total myo-inositol would come almost exclusively from phytic acid
(250)
.
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Table 3. Main physiological functions, potential protective mechanisms and health benefits of isolated bioactive compounds found in whole-grain wheat, rice and oat*
Bioactive compounds (degree of
significance) Main physiological functions and potential protective mechanisms Potential health protection
n-3 Fatty acids
a-Linolenic acid (18 : 3n-3) (þþ) Beneficial effects on blood clotting, thrombosis, blood pressure and inflammation: for
example, anti-atherosclerotic effect via inhibition of oxidative stress-mediated
CD40L (protein with inflammatory and prothrombotic property) up-regulation,
suppresses levels of arachidonic acid (20 : 4n-6) and eicosanoids in tissues (such as
lung) and plasma phospholipids and the synthesis of pro-thrombotic cyclo-
oxygenase-derived products (thromboxane A2 and B2, PGE2), reduces plasma
TAG, inhibits synthesis of cytokines and mitogens; essential constituent of neuronal
cells and retina; precursor in vivo of potentially protective DHA (22 : 6n-3) and EPA
(20 : 5n-3); stimulates immune system via cell signalling and gene expression
CVD; retinal and brain development; inflammatory bowel
disease (Crohn’s); breast and colon cancers; mild
hypertension; mental health (for example, depression
and anxiety); rheumatoid arthritis
Sulfur compounds
Reduced glutathione GSH (þ) Strong antioxidant; detoxification of toxic electrolytic metabolites of xenobiotics and of
reactive oxygen intermediates generated intracellularly and at sites of inflammation;
binding with cellular mutagens; important role in cellular immune function and as
source of cysteine for various organs
Some cancers (for example, oral); diseases associated
with imbalance of glutathione (for example, HIV, ageing,
hepatic cirrhosis, cystic fibrosis and lung and neurode-
generative disorders)
Methionine (þþ) Precursor of S-adenosyl methionine, the universal methyl donor, and of glutathione;
intermediate in the biosynthesis of cysteine, carnitine, taurine, lecithin, phospha-
tidylcholine, and other phospholipids; methyl donor; may possess antioxidant
activity; lipotrope
Neural tube defects; cognitive impairment; atherosclerosis;
muscular wasting
Cystine (þ) Reduced to two cysteine residues upon absorption; cell signalling through reactive
cysteine residues in proteins; antioxidant; precursor of glutathione; constituent of the
antioxidant metallothionein; many metal cofactors in enzymes are bound to the
thiolate substituent of cysteinyl residues; precursor to Fe– S clusters (role in
the oxidation–reduction reactions of mitochondrial electron transport); increases
protein stability in the harsh extracellular environment
Muscular wasting; normal hair and nail development
Undigestible carbohydrates
Insoluble fibre (þþþ)†
(cellulose, hemicellulose)
Delivers antioxidant-bound phenolics to the colon; carcinogen binding and/or diluting;
increases gut transit and faecal bulking; satiating effect
Gut health; colon cancer; obesity and weight regulation
Soluble fibre (þþ)†
(for example, b-glucans,
arabinoxylans)
Decreases glycaemia through a delayed gastric emptying and glucose absorption rate;
reduces cholesterolaemia through a possible effect of propionate (yielded by fibre
fermentation) upon hepatocyte cholesterol and NEFA synthesis; improves insulin
response; reduces bile acid reabsorption; produces SCFA
Type 2 diabetes; CVD; gut health; colon cancer
Resistant starch (þþþ)† Produces high levels of butyrate, a tumour-growth suppressor; decreases glycaemia,
cholesterolaemia and energy intake; promotes lipid oxidation and metabolism;
prebiotic effect
Type 2 diabetes; CVD; colon health and cancer; body
weight; gallstones
Oligosaccharides (þþ)
(fructans, raffinose, stachyose)
Prebiotic (effect on bacterial metabolism: for example, bifidogenic); cholesterol-
lowering through SCFA production, especially propionate; decrease glycaemia
(through reduced hepatic gluconeogenesis by propionate) and triacylglycerolaemia;
limit TAG accumulation in liver: effect on lipogenesis through exposure to propionate
and reduced insulin/glucagon levels; produce butyrate, a tumour-growth suppres-
sor; increase the absorption of minerals within colon; stimulate the immune system;
control blood ammonia levels
Gut health; colon cancer; CVD; lifespan; weight reduction;
hepatic encephalopathy (nervous troubles) and steatosis
Phytic acid (þþþ) (also named
myo-inositol hexakisphosphate)
Antioxidant: chelates various metals (for example, suppresses damaging Fe-catalysed
redox reactions), inhibits xanthine oxidase, suppresses oxidant damage to the
intestinal epithelium, and interferes with the formation of ADP-Fe-oxygen complexes
that initiate lipid peroxidation; prevents the formation of carcinogens and blocks the
interaction of carcinogens with cells; controls cell division and reduces cell
proliferation rate; increases the immune response by enhancing the activity of
natural killer cells; may be involved in cellular and nuclear signalling pathways;
important source of P; inhibitor for renal stone development; hypoglycaemic (for
example, by chelating Ca, an a-amylase cofactor) and cholesterol-lowering (by
Various cancers (for example, colon and breast cancers);
type 2 diabetes; CVD (for example, age-related aorta
calcification); kidney health (renal stone development);
hypercalciura; acute Pb poisoning; dental caries
Hypotheses for whole-grain cereal protection 71
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Table 3. Continued
Bioactive compounds (degree of
significance) Main physiological functions and potential protective mechanisms Potential health protection
binding Zn and decreasing Zn:Cu ratio) effects; affects the metabolic and
detoxification capacity of the liver; reduces blood glucose and lipid, and hepatic
lipid levels; inhibits calcification of cardiovascular system (lower level of Ca in aorta);
prevention of platelet aggregation; high affinity for hydroxyapatite; adsorption onto
Ca-based crystals; in vitro effect on gene expression through chromatin remodelling
Lignins (þþþ) Antioxidant due to phenolic hydroxyl groups; adsorb dietary carcinogens and reduce
carcinogen exposure; reduce bile acid reabsorption as a bile salt-sequestrating
agent: possibly reduce fat absorption and the formation of carcinogenic metabolites
from bile salts, and increase cholesterol turnover; source of enterolactone, a phyto-
oestrogenic mammalian lignan
Colon cancer; large bowel health; type 2 diabetes; CVD
Minerals and trace elements
Fe (þþ)† Cofactor with several enzymes involved in energy metabolism and thermoregulation:
for example, catalase cofactor in the production of O
2
þ2H
2
O from H
2
O
2
,
involvement in the Krebs cycle, oxygen transport as Hb and myoglobin constituent,
and electron carrier within cytochromes; close association between the activities of
Fe-containing oxidase pathways in muscle and endurance; role in collagen
synthesis, and bone formation and resorption (for example, bone mineral density in
post-menopause); role in cell-mediated immunity and phagocytosis; role in vitamin
metabolism; improves developmental scores in Fe-deficient infants; might reduce
increase in lipid peroxides and liver/serum TAG, cholesterol and phospholipids;
deficiency associated with obesity
Mental health (fatigue, concentration, cognitive develop-
ment and reduced intellectual performances); physical
health (anaemia, reduced effort and resistance to
infections); bone health
Mg (þþþ)† Second most abundant intracellular cation; constituent of several metalloenzymes with
a role in cellular functions: glycolysis, DNA transcription, protein synthesis and
oxidative phosphorylation; essential for all ATPase activity; necessary for coenzyme
A reaction (for example, increases enzyme activity in the liver: lipotrope-like effect);
role in neurotransmission, gut transit/cardiac rhythm/blood pressure regulation,
platelet aggregability and insulin sensitivity; improved glucose uptake, glucose
metabolic clearance rate, and oxidative glucose metabolism; cholesterol-lowering
and may reduce hypertriacylglycerolaemia; antioxidant (for example, against lipid
peroxidation); favours Ca fixation in bones and muscle relaxing; activates alkaline
phosphatase; psycho-relaxing; anti-inflammatory and anti-allergic effects; favours
thermoregulation; important role in inducing some angiogenesis-related mechan-
isms; direct inhibition of calcium oxalate crystallisation in the urine
Mental health (fatigue, stress and anxiety); type 2 diabetes;
CVD (for example, atherosclerosis and hypertension);
bone health (skeletal growth and osteoporosis); nervous
and muscular equilibrium; renal stones
Zn (þþ)† Superoxide dismutase and alkaline phosphatase cofactor; antioxidant; chemical
inactivator: inhibits the formation of active carcinogenic compounds (for example,
conversion of nitrosamines from nitrite in the stomach and Zn-binding compounds);
lymphocyte T and hormone activator; participates in numerous enzymic reactions
(more than 200 enzymes) in relation to carbohydrate, lipid and protein metabolism;
role in neurotransmission; DNA stabilisation; markedly modulates mechanisms of
the pathology of inflammatory disease s; influences gene expression, cell
development and replication; role in cell signalling within salivary gland, prostate,
immune system, intestine and endothelial cells (for example, NF-kB and activator
protein-1); key factor in reproductive organ growth; role of Zn homeostasis in insulin
secretion/responsiveness; may stimulate food intake via orexigenic peptides
coupled to the afferent vagal stimulation
Immunoprotection; brain and mental health; atherosclero-
sis; cancers (for example, oesophagus); skeletal growth
and maturation; olfaction (anosmia); type 2 diabetes;
weight regulation (for example, anorexia)
Mn (þþ) Constituent of several metalloenzymes (for example, superoxide dismutase cofactor);
role in amino acid, lipid and carbohydrate metabolism, insulin secretion and
cholesterol synthesis; favours fat and sugar assimilation; improves cartilage
elasticity and membrane quality of small blood vessels; protects vitamins (thiamin,
biotin and vitamin E); role in synovial liquid formation; essential for growth and
Anti-ageing; vascular sclerosis; bone formation (for
example, osteoporosis); cancers
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reproduction; anti-carcinogenic: manganese superoxide dismutase plays a role in
regulating tumour cell growth and its over-expression suppresses NF-kB activation
in carcinogenic process
Cu (þ) Component of numerous metalloenzymes acting as oxidases to achieve the reduction
of molecular oxygen (for example, superoxide dismutase cofactor, lysyl oxidase
or cytochrome coxidase); anti-inflammatory and anti-infectious effects; role in
neurotransmission, and Hb and collagen fibre synthesis; reverses cardiomyocyte
hypertrophy; anti-cancer effect of Cu– DNA complexes (for example, with guanine).
Role in well-balanced cholesterolaemia and glucose tolerance; antioxidant effect
mainly as superoxide dismutase cofactor; low Zn:Cu ratio associated with reduced
risk of CHD
Brain and mental health (central nervous system dysfunc-
tion); bone, tendon and cartilage health (for example,
osteoarthritis); cardiovascular health (for example, IHD);
cancers
Se (þþ)† Glutathione peroxidase/thioredoxin reductase cofactor: protects cell membranes from
lipid oxidation damage; role at the catalytic site of multiple selenoproteins; tumour
growth suppressor (selective apoptotic activity according to the tissue considered);
reduces susceptibility to experimental carcinogens; immune system stimulation and
role in anti-infective mechanisms; helps liver to eliminate toxins; role thyroid
hormone synthesis; may improve insulin resistance and protect vascular
endothelium; insulin-like actions; prevents platelet aggregation
Anti-ageing; CVD; immunoprotection; breast, prostate,
gastrointestinal, liver, brain, skin and lung cancers; liver
health; type 2 diabetes
P(þþ)† Most abundant mineral after Ca within organism (80 % is in skeleton, 10 % in muscles
and 10 % in nervous tissues and blood); supports tissue growth through temporary
storage and transfer of energy (for example, ATP/ADP), helps in maintaining normal
pH (acidity regulation through buffering effect) and activation of many catalytic
proteins by phosphorylation; limits Ca escape and its metabolism; DNA/RNA, myelin
and hydroxyapatite constituent; occurs structurally as phospholipids (for example,
lecithin), a major component of most biological membranes; stimulates B-complex
vitamins; may reduce the risk of colorectal tumours
Bone (for example, osteoporosis), teeth, mental
(for example, fatigue, spasmophily, stress, memory,
vigilance) and brain health; heart and kidney health;
digestion and growth; cancers (for example, colorectal)
Ca (þ)† Most abundant mineral within organism (about 98% in bones as hydroxyapatite); role
in bone and teeth formation, cellular exchanges, nerve transmission, blood
coagulation, muscle contraction (for example, in heart), pH regulation, P retention
and glandular secretion; essential signal transduction element (for example, cell
cycle progression regulation); intracellular Ca is vital for regulation of cell
proliferation and growth; may reduce systolic blood pressure; enzyme activation;
role in vitamin B
12
assimilation, blood acid– base equilibrium and clotting, Fe
metabolism and immune system maintenance; inversely associated with type 2
diabetes; would regulate fat metabolism in adipocytes
Bone (for example, osteoporosis and rachitis) and teeth
health; colorectal cancer; heart health (for example,
hypertension and stroke); nervous system; mental
health (for example, insomnia and stress); diabetes;
weight regulation
Na (þ)† 50% of Na is in extracellular liquids; generally associated with chlorine (NaCl); role in
nervous and muscular impulse transmission, in control of arterial pressure and
acidity regulation; role in water repartition within organism: essential in hydroelectric
equilibrium by yielding most part of extracellular liquid osmotic pressure
CVD (for example, blood pressure); nervous system;
hydration state
K(þþ)† Cation essentially intracellular; role in acid– base equilibrium; favours Na excretion;
inhibition of neuromuscular excitability; role in regulation of aldosterone excretion
within glomerular zone; role in action of numerous enzymes; role in gastric acid and
insulin secretion, and in blood pressure regulation; improves ventricular arrhythmia;
may have inhibitory effects on free radical formation from macrophages and
endothelial cells and on LDL oxidation, vascular smooth muscle cell proliferation (for
example, neointima formation) and arterial thrombosis; reduces platelet sensitivity to
thrombin; may reduce macrophage adherence to vascular wall; role in glucose
control
Muscular contraction (for example, cramps); hydration
state; cardiovascular protection and nervous system
functioning; mental health (for example, vigilance and
fatigue); oedema; hypercalciura; osteoarthritis/porosis;
arterial hypertension;kidney health (for example, stones);
cerebro/cardiovascular diseases; type 2 diabetes
Vitamins
Thiamin: B
1
(þþ) Involved in glucose metabolism and Krebs cycle through thiamin-dependent enzymes,
and in branched-chain amino acid metabolism; works to promote healthy nerves
(for example, neuromodulation of chlorine canals in brain and involvement in
neurotransmitter synthesis); improves mood; strengthens the heart and may restore
peripheral vascular resistance; improves heartburn; antioxidant
Mental (for example, Korsakoff syndrome and dry Beri
Beri), neuronal (for example, neuropathy) and heart
(for example, wet Beri Beri) health
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Table 3. Continued
Bioactive compounds (degree of
significance) Main physiological functions and potential protective mechanisms Potential health protection
Riboflavin: B
2
(þþ)† Participates as a coenzyme in numerous redox reactions in metabolic pathways and
energy production via the respiratory chain; assists fat, protein and carbohydrate
metabolism; role in haematological status (erythrocyte formation) and gastrointes-
tinal development; modulator of plasma homocysteine level; protects from heart
tissue damage; improves skin blemishes and migraines; influence dark adaptation
through riboflavin-dependent photoreceptors; participates in antioxidant defences;
possibly anti-carcinogenic (for example, reduction in DNA damage)
CVD; cancers; vision (for example, corneal opacity and
cataract); mental health (for example, neurodegenera-
tion and peripheral neuropathy); skin health
Nicotinic acid: B
3
(þþ)† Precursor of nicotinamide, NAD þ, NAD, NADP, NADH, and NADPH: functions in
many redox reactions; lowers cholesterol, LDL and NEFA levels and increases HDL
level; inhibits catecholamine stimulation of lypolysis in adipose tissue (via the same
post-receptor pathway as catecholamines); involved in DNA replication and repair,
in cell differentiation and the production of steroid hormones in the adrenal gland
Skin health (for example, dermatitis in pellagra); lipid
disorders and CVD; cancers; HIV; mental health (for
example, schizophrenia, depression, insomnia); osteo-
arthritis
Pantothenic acid: B
5
(þþ)† Ubiquitous vitamin; critical in the metabolism and synthesis of carbohydrates, proteins,
and fats; used in the synthesis of coenzyme A, a way to transport carbon atoms
within the cell (cellular respiration); involved in metabolism of fatty acids
(biosynthesis), cholesterol and acetylcholine; would enhance the activity of the
immune system
Cure of wounds, minor burns, irritations and cutaneous
hurts; mental health (for example, insomnia, depression,
irritability and stress); healthy digestive tract
Pyridoxine: B
6
(þþ)† Needed for almost every function in the body, working as a coenzyme for numerous
enzymes, notably in protein, glycogen, sphingoid bases, amino acid and fat/fatty
acid metabolism; plays a major role in forming erythrocytes, neurotransmitters (such
as serotonin, melatonin, dopamine and g-aminobutyric acid) and in antibody
synthesis; stabilises homocysteine levels; allows production of nicotinic acid from
tryptophan; role in vitamin B
12
absorption; role in humoral and cellular immunity; role
in maintenance and synthesis of DNA
Heart health; mental and brain health (for example,
depression, fatigue, insomnia and epileptiform convul-
sions); colorectal cancer; asthma attacks; microcytic
anaemia; occlusive arterial disease; seborrhoeic der-
matitis
Biotin: B
8
(þþ)† Functions as a coenzyme in bicarbonate-dependent carboxylation reactions (i.e. for
four carboxylase enzymes such as the acetyl-CoA carboxylase): catalysis for CO
2
fixation on different substrates fundamentally involved in lipid, protein and
carbohydrate assimilation; necessary for cell growth and the production of fatty
acids; role in the citric acid cycle; helps to maintain a steady blood sugar level;
regulation of gene expression; role in normal immune function and cell proliferation
(oncogene-dependent metabolic pathways)
Mental and central nervous system health (neurological
disorders); growth; skin health (for example, dermatitis);
hair health (for example, alopecia)
Folate: B
9
(þ)† Functions as a coenzyme in single-carbon transfers in the metabolism of nucleic and
amino acids: stabilises homocysteine levels, needed to synthesise DNA bases and
for DNA replication; anti-carcinogenic; prevents depletion of brain membrane
phosphatidylcholine; lipotrope; effect on altered methylation and related epigenetic
effects on gene expression
Neural tube defects; CVD; cancers (for example, colon);
fertility; megaloblastic anaemia; mental health (cognitive
impairment and depression)
Tocols: E (þþ)† Strong intracellular antioxidant that protects from oxidative damages of PUFA within
cell membranes and in lipoproteins, DNA nucleotidic bases and proteins;
complementary effect with Se to maintain cell integrity and immune function;
induction of apoptosis (anti-proliferative effect); anti-atherogenic action through, for
example, reduction of oxidised LDL and of monocytes adhesion or inhibition of
smooth muscle cell proliferation
–
Tocopherols Antioxidant; act directly to inhibit the formation of active carcinogenic compounds or
their activation to more potent forms; possible protection of pancreatic b-cells
against glucose toxicity; various non-antioxidant molecular mechanisms: inhibit
protein kinase C (correlation with cell proliferation inhibition), produce a decrease in
monocyte superoxide anion and IL-1 release and in adhesion to endothelium, effect
on gene expression (possible direct action on cell signalling), and remove the
suspected carcinogens peroxynitrite-derived nitrating species
Cancers (for example, pancreas); CVD; type 2 diabetes
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Tocotrioenols Stronger antioxidant than tocopherols; role in immune response induction and bone
calcification; prevent the formation of carcinogens (anti-proliferative and apoptotic
inducer); cholesterol-lowering; anti-hypertensive; anti-inflammatory; anti-athero-
genic; may increase bone Ca content
Neurodegeneration; cancers; CVD; type 2 diabetes;
osteoporosis; obesity
Phylloquinone: K (þ) Functions as a coenzyme involved in the post-translational formation of
g-carboxyglutamate residues, essential for the activity of all known g-carboxy-
glutamate proteins, which plays a role in coagulation (for example, vitamin
K-dependent clotting factors such as prothrombin – factor II and factors VII, IX and
X), bone metabolism (probable role in Ca uptake) and vascular biology; in the
intestines, assists in converting glucose to glycogen; anti-haemorrhagic factor
Bone health (osteoporosis and bone loss); atherosclerosis;
haemorrhagic event and haematuria (reflects tumours or
kidney stones?)
Carotenoids
b-Carotene (þ)† Antioxidant; precursor of vitamin A; tumour growth suppressor (i.e. apoptosis inducer) Colon cancer; lung cancer in non-smokers; coronary artery
disease
Lutein (þþ) Antioxidant by quenching single oxygen, neutralising photosensitisers and inhibiting
lipid peroxidation; inhibits progression of aberrant crypt foci; protects ocular
functions as antioxidant/optical filter and by increasing macular pigment density;
reduces the skin inflammatory response; can inhibit thickening of the carotid artery
walls and LDL-induced migration of monocytes to artery cell walls
Visual function protection (for example, age-related
macular degeneration, cataract and glaucoma); stroke
and atherosclerosis; lung and colon cancer; skin health
Zeaxanthin (þ) Antioxidant by quenching single oxygen, neutralising photosensitisers and inhibiting
lipid peroxidation; reduces the skin inflammatory response; protects ocular functions
as antioxidant/optical filter and by increasing macular pigment density
CVD (for example, stroke); visual function protection (for
example, cataract); skin health; lung cancer
b-Cryptoxanthin (þ) Antioxidant; induces anabolic effects on bone components by increasing Ca content
and alkaline phosphatase activity; possible protector against carcinogenesis (for
example, bioregulatory function in the control of cell differentiation and apoptosis);
precursor of vitamin A, retinal and retinoic acid
Bone loss; lung cancer; visual function
Polyphenols
Phenolic acid (þþþ) (for ex-
ample, ferulic acid)
Antioxidant (for example, scavenges superoxide anion radical and reduces oxidative
stress caused during diabetes, for example, lipid peroxidation); anti-apoptotic; anti-
microbial; anti-inflammatory; blood cholesterol- and glucose-lowering; UV absorber;
interferes with intracellular signalling pathways; hypotensive effect by reducing
blood pressure (vascular relaxation); tumour growth suppressor; enzyme modulator;
may increase b-cell mass; may decrease adipose tissues, serum lipid profiles,
insulin and leptin
Cancer; CVD (for example, thrombosis and atherosclero-
sis); neurodegenerative disorders (for example,
Alzheimer’s and Parkinson’s diseases); type 2 diabetes;
skin health; anti-ageing; hepatoprotective; pulmonary
protective; hypertension; obesity
Flavonoids (þ) (for example,
anthocyanins, isoflavonoids)
Antioxidant (for example, against LDL-cholesterol oxidation); tumour growth
suppressor; enzyme modulator; role in redox cell signalling, glutathione synthesis
regulation and gene regulation; modulate angiogenesis; anti-microbial and anti-
inflammatory; inhibition of platelet aggregation (for example, may affect arachidonic
acid metabolism through inhibition of lipoxygenase activity); stimulation of uric acid
production; role in fat oxidation and decreased adipose tissues; may decrease
serum lipid profiles, insulin and leptin; hypoglycaemic effect; daidzein and/or
genistein may improve trabecular connectivity and trabecular thickness
Cancer; CVD; body-weight regulation/obesity; type 2
diabetes; bone development and osteoporosis
Lignans (þþ) Antioxidant: may reduce fatty acid oxidation; precursors of enterolactone and
enterodiol; anti-carcinogenic activity: inhibit cell proliferation by competing with
oestradiol for nuclear type II oestrogen-binding sites, stimulation of differentiation,
may inhibit the tyrosine-specific protein kinase (associated with cellular receptors for
several growth factors) and DNA topoisomerase, prevent the production of oestrone
from androstenedione, and influence cholesterol homeostasis (for example,
deoxycholic acid is correlated with increased colon cancer); anti-atherosclerotic;
hypolipidaemic effect (improves blood lipid profile); diuretic action and antagonistic
action of platelet-activating factor receptor; priming action on superoxide production
on human neutrophiles; anti-bacterial and anti-fungal; may inhibit bone resorption
Colon cancer; hormonally mediated diseases (for example,
breast and prostate cancers); CVD (for example,
stroke); osteoporosis and rheumatoid arthritis; gastric
and duodenal ulcers; skin health
Other compounds
Alkylresorcinols (þþþ) Antioxidant (for example, modulator of lipid oxidation); anti-microbial, anti-parasitic and
anti-carcinogenic properties; inhibitors of 3-phosphoglycerate dehydrogenase (key
enzyme of TAG synthesis in adipocytes); direct effect on structure and metabolism
of nucleic acids; can be incorporated into biological membranes (for example,
Cancer; tuberculosis; tropical diseases
Hypotheses for whole-grain cereal protection 75
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Table 3. Continued
Bioactive compounds (degree of
significance) Main physiological functions and potential protective mechanisms Potential health protection
modulate phospholipid bilayer properties by inhibiting the activity of some
membrane-bound enzymes); cholesterol-lowering in liver
Betaine (þþþ) Osmoprotectant; methyl donor: increases DNA methylation and decreases hyperho-
mocysteinaemia; role in sulfur amino acid homeostasis; antioxidant; able to reverse
insulin resistance; inversely associated with serum non-HDL-cholesterol, TAG, BMI,
percentage body fat, systolic and diastolic blood pressure, and positively associated
with HDL-cholesterol; inversely associated with inflammatory markers related to
atherosclerosis (C-reactive protein and TNF-a); inverse association with colorectal
adenoma; lipotrope
CVD; liver and kidney health; colorectal cancer; athletic
performances; type 2 diabetes; metabolic syndrome
Choline (þþ) Precursor of betaine, acetylcholine (neurotransmitter), membrane phospholipids
(phosphatidylcholine and sphingomyelin: role in intracellular signalling) and platelet-
activating factor (potent messenger molecule); methyl donor (for example, DNA
methylation and reduced hyperhomocysteinaemia); epigenetic regulator of gene
expression; promotes carnitine conservation (for example, accretion in skeletal
muscle); antioxidant-type action; lipotrope: role in lipid metabolism (for example,
increases fatty acid oxidation), and in integrity and signalling functions of cell
membranes; accelerates the synthesis and release of acetylcholine
Brain development and normal learning and memory
functions; weight regulation; fetal development (for
example, neural tube); liver dysfunctions (for example,
fatty liver); cancer; CVD
Phytosterols (þþ) (for
example, b-sitosterol)
Lower serum total and LDL-cholesterol: compete with cholesterol for micelle formation
in the intestinal lumen (and increase its excretion) and inhibit dietary and biliary
cholesterol absorption; anti-inflammatory; may protect from vascular smooth muscle
cell hyperproliferation; effect on immune system (for example, may prevent
immunosuppression associated with excessive physical stress, i.e. immune-
modulatory activity on human lymphocytes); b-sitosterol inhibits carcinogen-induced
neoplasia (suppressing agent) and might mediate apoptosis through caspase
activation; hypoglycaemic; anti-pyretic
CVD; colon, breast and benign prostate cancer; type 2
diabetes
Inositols (þþ)(forexample,
myo- and chiro-inositol, pinitol)
Involved in several biological processes as secondary messenger molecules: in insulin
signal transduction, cytoskeleton assembly, nerve guidance, intracellular Ca
concentration control, gene expression and breakdown of fat and reducing of
blood cholesterol; myo-inositol may be converted into chiro-inositol in vivo
(epimerisation) and is precursor for several phospholipids (for example,
phosphatidylinositol 4-phosphate) playing a role in membrane structure and
function; chiro-inositol improves insulin resistance and helps in controlling blood
glucose, ovulatory functions (i.e. increased ovulation), decreases serum androgen
and plasma TAG concentrations, and reduces blood pressure; myo-inositol
depresses the rise in TAG and total lipid liver, hepatic activities of glucose-6-
phosphate dehydrogenase, malic enzyme, fatty acid synthetase and citrate
cleavage enzyme; free inositol is involved in volume regulation during persistent
osmotic stress; reduces myelinolysis after rapid correction of chronic hyponatrae-
mia; may reduce mammary and colon carcinoma; impaired myo-inositol metabolism
would be linked to altered nerve conduction impairment in diabetics; prevents
impaired sciatic nerve Na-K ATP
Type 2 diabetes (for example, diabetic polyneuropathy);
polycystic ovary syndrome or compromised fertility (for
example, insulin resistance hyperandrogenism and
oligo-amenorrhoea); neural tube defects; CVD; neuro-
logical and psychiatric diseases (for example, bipolar
depression, panic attacks and obsessive–compulsive
disorders); severity of osmotic demyelination syndrome;
cancers; intestinal lipodystrophy
Policosanol (þþ) (for example,
octacosanol)
Antioxidant by reducing LDL and membrane lipid peroxidation; decreases platelet
aggregation, endothelial damage and foam cell formation; vasodilatating effect;
cholesterol-lowering by inhibiting cholesterol synthesis at the earliest step of the
biosynthetic pathway (through down-regulating 3-hydroxy-3-methyl-glutaryl CoA
reductase); lowers plasma LDL-cholesterol and increases plasma HDL-cholesterol
level; affects lipid metabolism; prevents smooth muscle cell proliferation; role in
cytoprotection; active energy-releasing factor; affects the nervous system (for
example, anti-fatigue and improves reaction time to a visual stimulus)
CVD (for example, atherosclerosis and hypertension);
gastric ulcer; athletic performances; mental health
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Melatonin (þ) Antioxidant (but irreversibly oxidised), the most potent physiological scavenger of OH
z
:
for example, reverses massive DNA degradation, stimulates glutathione peroxidase
activity, increases gene expression for antioxidant or may protect against lenticular
protein oxidation enzymes; effects on mood, happiness, sleep–wake period
regulation and brain neuromodulation; promotes mitochondrial respiration; anti-
carcinogenic, anti-proliferative and oncostatic effects through antioxidant, immu-
nostimulating and apoptotic properties (for example, increase of natural killer cell
activity as well as the stimulation of cytokine production), and also effects on gene
expression; regulates the glucocorticoid receptor and blocks the activation of
oestrogen receptor for DNA binding
Mental and brain health (for example, Alzheimer’s disease,
depression and sleep troubles); anti-ageing; cancers
(for example, colorectal, breast and prostate); cataract
para-Aminobenzoic acid Role in folate formation: for example, stimulates bacterial growth within intestines,
enabling them to produce folates; cholesterol-lowering; anti-carcinogenic through
down-regulation of N-acetyltransferase which may activate human carcinogens;
acetylation in blood, notably by platelets: arachidonic acid is a main acetyl donor,
suggesting the involvement of peroxisomal b-oxidation; anti-aggregatory effect:
inhibits the production of thromboxane, which participates in increased arterial
pressure through vasoconstriction and in blood coagulation, in human platelets;
chromotrichial effect on grey hair
CVD (for example, atherosclerosis and hypertension); skin
(for example, UV absorber and vitiligo) and hair health;
collagen diseases; leukaemia; rheumatic fever and
rickettsial diseases
Specific cereal compounds
g-Oryzanol in rice Antioxidant (for example, decreases serum lipid peroxides); lowers total and LDL-
cholesterol and increases HDL-cholesterol through its tocotrienol and fibre contents;
improves glycaemia control through its lipoic acid content: increases glucose uptake
by insulin-resistant muscle to produce energy; anti-ulcerogenic; inhibition of platelet
aggregation; stimulates hypothalamus (link between nervous and endocrine
system), for example, change in serum growth hormone level
Climacteric disturbances (i.e. menopausal troubles) and
autonomic nervous imbalance (autonomic ataxia); type
2 diabetes; CVD; gut health (for example, gastric ulcer);
mental health (for example, anxiety)
Avenanthramides in oats Antioxidant, anti-inflammatory and anti-atherogenic: inhibit smooth muscle cell
proliferation and increase NO production, inhibit aortic endothelial cell expression
of adhesion molecules and their adhesion to monocytes, and reduce production of
several pro-inflammatory cytokines and chemokines
Atherosclerosis
Saponins in oats‡ Antioxidant (for example, activate transcriptional activity of Cu, Zn-superoxide
dismutase gene, scavenge superoxides and reduce lipid peroxidation); cause
hypoglycaemia and hypoinsulinaemia; reduce non-enzymic protein glycation (i.e.
HbA
1c
level); partially reverse hypercholesterolaemia (by binding with cholesterol
and impairing its absorption and/or by binding bile acids, by interfering with their
enterohepatic circulation and by increasing their faecal excretion) and hypertria-
cylglycerolaemia; anti-fungal and anti-viral; immunostimulant and anti-carcinogenic
(tumour growth suppressor and binding of primary bile acids); effects on nervous
system functioning (for example, induce NO production in the brain and inhibit gap
junction communication)
Colon, breast, prostate and skin cancers; CHD; skin health;
nervous system health (for example, harmful stress on
organs); liver health; type 2 diabetes
b-Glucans in oats and barley Plasma cholesterol- and glucose-lowering; may indirectly affect the metabolism of bile
acids (i.e. formation of secondary bile acids) and neutral sterols in intestine and liver;
anti-mutagenic; anti-microbial; anti-parasitic; stimulate immune functions (for
example, may stimulate proliferation and activation of peripheral blood monocytes)
Cancers; CVD; type 2 diabetes; gut health
* All data concerning physiological mechanisms and health effects are based on international references (in vitro studies on culture cells and in vivo studies in animals and human subjects; see references in Appendices).
† For these compounds, the intensity of the symbol in brackets (þ,þþ or þþþ) refers to the importance of the compound as supplied by a predominantly cereal-based diet, based on British data collected by
Truswell
(19)
; for other compounds, the intensity of the symbol in brackets was estimated based on the compound content in whole-grain wheat compared with other food sources.
‡ Mechanisms and health outcomes are associated with plant saponins in general, not exclusively cereal saponins.
Hypotheses for whole-grain cereal protection 77
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a whole-grain product. The issue is still debated. The
definition given by the American Food and Drug
Administration
(26)
in 1999 was: ‘For purposes of bearing
the prospective claim, the notification defined ‘whole grain
foods’ as foods that contain 51 percent of total weight or
more whole grain ingredient(s) by weight’ (extract). This
definition was debated and contested by the European
Whole Grain Task Force in 2008. They explained that:
‘Using total weight gives advantage to products sold by dry
weight such as crackers and ready-to-eat cereal. Because
foods like breads have a proportionally high water content,
even some breads made with all whole grain flours but
containing significant amounts of nuts, seeds and fruit
would fail to meet the 51 % by weight rule’
(24)
. Apparently,
there is still no international consensus as to the right
proportion of whole grain by dry weight (DW) in a product
in order for it to be called a whole-grain product. Each
country has its own definition and standards
(21)
. However,
most research and observational studies, particularly those
on breakfast cereals, estimate the whole-grain intake from
products containing at least 25 % whole grains or bran by
weight
(5,14,27,28)
. Thus, a study on young individuals aged
4– 18 years found that using a 51 %-based definition
underestimated the whole-grain intake by 28 %, breakfast
cereals (56 %) and bread (25 %) being the major sources of
whole-grain cereals
(29)
. In another study on adiposity among
two cohorts of British adults, the same research team
assumed that whole-grain foods contained $10 % whole
grains and found little or no association between the whole-
grain intake and anthropometric indices
(30)
. This suggests
that the threshold of 10 % is probably too low and
emphasises the need to harmonise how the whole-grain
cereal food intake is calculated. In these studies, generally
carried out in Western countries, whole-grain cereal foods
considered are, for the most cited, whole-grain breads (for
example, dark, brown, wholemeal and rye bread), whole-
grain breakfast cereals (for example, muesli), popcorn,
cooked porridges (oatmeal or whole wheat), wheat germ,
brown rice, bran, cooked grains (for example, wheat, millet
and roasted buckwheat) and other grain-based foods such as
bulgur and couscous. A complete list of food ingredients
classified as whole grains in the US Department of
Agriculture (USDA) pyramid servings database is reported
by Cleveland et al.
(31)
. Refined grain foods generally
include white breads (for example, French baguette), sweet
rolls, noodles, pasta, cakes, biscuits, viennoiseries, muffins,
refined grain breakfast cereals, white rice, pancakes, waffles
and pizza.
The importance of whole-grain cereal product consumption
There are far fewer whole-grain cereal products on the
market than there are refined products, at least in Western
countries. The major sources of whole-grain cereals are
breads, breakfast cereals and whole-grain cereals consumed
as such (for example, brown rice or quick-cooking whole-
grain barley and wheat). Epidemiological data show that the
consumption of two to three servings of whole-grain cereal
per d is sufficient to get beneficial health effects
(32)
. The
recommended consumption of whole-grain cereal products
differs from one country to another, but most recommend
increased whole-grain cereal product consumption
(21,32)
.
For example, at least three servings daily are recommended
in the USA, that is, about 48 g of whole-grain cereals
(33)
;
between six and twelve servings daily are recommended
in Australia and four servings daily in Denmark
(21)
.
Table 4. Whole-grain cereal bioactive compounds potentially involved in the prevention of major health outcomes and in antioxidant protection*
Major health outcome Bioactive compound
Body-weight regulation and obesity Insoluble fibre, fructans, resistant starch, Zn, Ca, tocotrienols, phenolic acids, flavonoids,
choline, p-aminobenzoic acid
CVD and heart health a-Linolenic acid, methionine, oligosaccharides, soluble fibre, resistant starch,
phytic acid, Mg, Mn, Cu, Se, K, thiamin, riboflavin, nicotinic acid, pyridoxine, folates,
tocopherols, tocotrienols, phylloquinone, b-carotene, lutein, zeaxanthin,
phenolic acids, flavonoids, lignans, phytosterols, betaine, choline, inositols,
policosanol, p-aminobenzoic acid, g-oryzanol, avenanthramides, saponins
Type 2 diabetes Soluble fibre, resistant starch, phytic acid, Mg, Zn, Se, K, Ca, tocopherols, tocotrienols,
phenolic acids, flavonoids, betaine, inositols, phytosterols, g-oryzanol, saponins
Cancers a-Linolenic acid, oligosaccharides, soluble fibre, insoluble fibre, resistant starch, lignin,
phytic acid, Zn, Mn, Cu, Se, P, Ca, riboflavin, nicotinic acid, pyridoxine, folates,
tocopherols, tocotrienols, b-carotene, b-cryptoxanthin, phenolic acids, flavonoids,
lignans, alkylresorcinols, betaine, choline, inositols, phytosterols, melatonin,
p-aminobenzoic acid, saponins
Gut health a-Linolenic acid, oligosaccharides, soluble fibre, insoluble fibre, resistant starch,
riboflavin, pantothenic acid, phenolic acids, policosanol, g-oryzanol
Mental/brain/nervous system health and
neurodegenerative disorders
a-Linolenic acid, methionine, oligosaccharides, Fe, Mg, Zn, Cu, P, Ca, Na, K,
thiamin, riboflavin, nicotinic acid, pantothenic acid, pyridoxine, biotin, folates,
tocotrienols, phenolic acids, choline, inositols, policosanol, melatonin,
g-oryzanol, saponins
Skeleton health (i.e. bone, tendon, cartilage,
collagen, articulation and teeth)
a-Linolenic acid, Fe, Mg, Zn, Mn, Cu, P, Ca, K, nicotinic acid, tocotrienols, phylloquinone,
b-cryptoxanthin, flavonoids, lignans, p-aminobenzoic acid
Antioxidant protection (development of diseases
in relation to increased oxidative stress)
Reduced glutathione, methionine, cystine, lignins, phytic acid, Mg, Fe, Zn, Mn, Cu,
Se, thiamin, riboflavin, tocopherols, tocotrienols, b-carotene, lutein,
zeaxanthin, b-cryptoxanthin, phenolic acids, flavonoids, lignans,
alkylresorcinols, betaine, choline, policosanol, melatonin, g-oryzanol,
avenanthramides, saponins
* Prepared from data in Table 3.
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Other countries such as Canada, UK, Greece, Germany,
Austria and Switzerland are not so precise and generally
recommend an increase in cereal consumption with
emphasis on whole-grain products
(21)
. Surveys carried out
in the USA and the UK showed that most individuals
consume less than one serving per d and about 30 % any, and
that only 0·8 to 8 % of those surveyed in the USA consumed
the recommended three servings per d
(31,32,34)
. The situation
is quite different in Scandinavian countries, where
individuals consume more whole-grain cereal products,
particularly rye-based
(32)
. For example, Norwegians con-
sume an estimated four times more whole-grain products
than do Americans
(35)
, but less than the Finns, 40 % of
whom may consume four or more slices of dark bread
per d
(36)
. Why is consumption so low in other Western
countries? There are probably several reasons. First, unlike
fruits and vegetables, individuals do not know about the
benefits of whole-grain cereal products. Second, individuals
tend to think that whole-grain cereal products are not very
tasty. And third, whole-grain cereal products are less
common and many are difficult to identify as being whole-
grain (problem of labelling). Last, time and money have
been cited as obstacles to eating more nutritiously
(37)
.
Whole-grain and wholemeal
The terms ‘whole-grain’ and ‘wholemeal’ are mostly used
synonymously. It is generally believed that whole-grain
products are made with wholemeal flour, and that they may
secondarily also contain intact grains. But the form in which
grain is incorporated into food, intact or milled, is
nutritionally significant. Thus ‘wholemeal’ (made of milled
whole-grain flour) and ‘whole-grain’ (made with intact
cereal grains) breads have different effects on postprandial
glycaemia. The whole-grain breads produce a significantly
lower glycaemic response than the wholemeal breads
(38)
.
This underlines the importance of food structure on
physiology. Thus, for clarity, the term ‘whole-grain’ should
be used for cereal products containing more or less intact
cereal kernels, and ‘wholemeal’ for cereal products made of
more or less refined flour, in which bran, germ and
endosperm are first separated, and then reassembled, in
proportions that rarely correspond to those of intact grains,
as the germ fraction is generally removed.
Current hypotheses and mechanisms for the
protective action of whole-grain cereals
The mechanisms underlying the health benefits of whole-
grain cereals are undoubtedly multi-factorial. A recent
cross-sectional study on 938 healthy men and women
showed that a higher consumption of whole grains, bran and
germ was associated with a significant decrease in plasma
homocysteine (hyperhomocysteinaemia is a risk factor for
CVD) and of some markers of blood glucose control,
inflammation and lipid status
(17)
. Other studies have linked
the consumption of high-whole-grain diets with improved
BMI and insulin sensitivity, lower concentrations of serum
TAG, total and LDL-cholesterol and inflammation markers,
and higher plasma or serum enterolactone
(2,39 – 42)
. Except
for enterolactone, for which high serum levels are associated
with reduced risk of CVD
(43)
, all of the other biomarkers,
when outside a normal healthy range, are all risk factors
associated with the development of diabetes and CVD.
There is the same kind of significant negative association
between whole-grain consumption and the risk of digestive
cancer
(44,45)
. Other mechanisms are involved in this,
including the capacity of several whole-grain compounds
to suppress tumour growth
(46)
. The next section describes
the main known mechanisms by which whole-grain cereals
help protect the gut and prevent the development of obesity,
diabetes, CVD and cancers.
Food structure
The structure of food has long been recognised as an
important parameter governing the health benefit of whole-
grain cereal products. The first study was performed in 1977
by Haber et al. on the influence of apple structure (intact
apples v. apple pure
´ev. fibre-free apple juice) on satiety,
plasma glucose and serum insulin. The removal of fibre
and/or the disruption of the physical food structure was
accompanied by reduced satiety, disturbed glucose homeo-
stasis and an inappropriate insulin response
(47)
. Almost
10 years later, it was shown that simply swallowing
carbohydrate-rich foods (rice, apple, potato and sweetcorn)
without chewing was sufficient to significantly decrease
postprandial glycaemia
(48)
. This was the simplest way to
emphasise the importance of food structure (chewing v. no
chewing) on digestion. Then, Jenkins et al. studied the
effects of wholemeal and wholegrain breads and showed
that the glycaemic index (GI) of wholemeal breads (wheat
or barley flour-based) without intact grains was the same as
that of white bread made of refined flour (.90), and that
increasing the intact barley kernel or cracked wheat grain
content of the bread (50 and 75 %) resulted in a significantly
large decrease in the GI from 92 – 96 to 39
(38)
. Thus, an
intact botanical food structure is more important than the
composition of the food (the presence of fibre in wholemeal
bread and absence from white bread) for influencing
physiological responses like those related to satiety and
glucose metabolism. Many later studies have confirmed
these results, emphasising the importance of preserving the
natural initial fibrous network, particularly in more or less
intact wheat, barley, rye and oat kernels
(49 – 52)
.
Whole-grain cereals as a rich source of fibre
Dietary fibre is defined by the AACC as ‘the edible parts of
plants or analogous carbohydrates that are resistant to
digestion and absorption in the human small intestine with
complete or partial fermentation in the large intestine.
Dietary fibre includes polysaccharides, oligosaccharides,
lignin and associated plant substances. It promotes
beneficial physiological effects including laxation and/or
blood cholesterol attenuation and/or blood glucose attenu-
ation’
(53)
. This definition includes that fraction of starch not
digested in the small intestine, resistant starch (RS). Whole-
grain wheat may contain from 9 to 17 g total fibre per 100 g
edible portion (Table 2), which is more than in most
vegetables (generally ,6 g/100 g edible portion). Thus,
consuming whole-grain cereal products is undoubtedly
Hypotheses for whole-grain cereal protection 79
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a good way of increasing the fibre intake from the 10 –15 g/d
eaten by most Western populations to the recommended
level of about 30 – 35 g/d.
Wheat is relatively poor in soluble fibre. It has been found
that the soluble:insoluble fibre ratio is about 1:5 for whole-
grain wheat, 1:10 for wheat bran and 1:3 for wheat germ
(Table 2). Whole-grain wheat therefore provides large
quantities of insoluble fibre (up to 11 g/100 g) and RS (up to
22 % for certain high-amylose barley varieties
(54)
). Cereal
fibre is now recognised to be beneficial for bowel health.
Wheat has a great diversity of fermentable carbohydrates.
Except for lignin, whose nutritional benefits are not really
known, all the types of fibre compounds, including soluble
and insoluble fibre, oligosaccharides and RS, have important
physiological properties and provide significant health
benefits
(18,55)
. For example, soluble fibre increases viscosity,
which delays gastric emptying and limits glucose diffusion
towards the enterocytes for absorption. This leads to a lower
glucose response when sufficient quantities are ingested
(56)
.
Cereal fibres also increase satiety and help control body
weight
(57)
. The mechanisms by which dietary fibre positively
affect body weight have been previously described: briefly,
they involve hormonal effects via reduction of the insulin
secretion, metabolic effects via increased fat oxidation and
decreased fat storage due to greater satiety, and colonic
effects via SCFA production
(58)
. Thus, the consumption of
highly viscous fibre such as b-glucans, found mainly in
barley and oats, is now recommended for the management of
glucose homeostasis in type 2 diabetic subjects
(59)
. Soluble
fibre has also been shown to reduce cholesterolaemia in
ileostomy subjects
(60)
by probably favouring an increase in
bile acid excretion as shown in ileostomates following oat
b-glucans consumption
(61)
. Increased bile acid excretion
stimulates bile acid synthesis from serum cholesterol, so
reducing cholesterolaemia
(61)
.
The fermentation of fibre and RS within the colon
produces SCFA that are associated with a lower risk of
cancer
(62,63)
, favouring the development of a healthy colonic
microbiota (i.e. prebiotic effect)
(64)
. These SCFA also
reduce the proliferation of human colon cancer cell lines
in vitro
(62,63)
. RS is known to produce large quantities of
butyrate
(65)
. The increased butyrate production by rats fed
wheat bran is negatively associated with the proliferation of
colon crypt cells that are involved in the development of
colorectal cancer
(66)
. RS also significantly increases fat
oxidation in humans, probably by increased SCFA
production that inhibits glycolysis in the liver, so rendering
it more dependent on fat-derived acetyl CoA as fuel, this
effect being associated with a concomitant decrease in
carbohydrate oxidation and fat storage
(67)
.
In contrast, insoluble fibre, which is poorly fermented in
the colon, favours an increased transit time and greater
faecal bulking
(68)
, two parameters that probably prevent
colon cancer by diluting carcinogens and reducing their
time in contact with epithelial cells
(69)
. The fermentation of
some fibre also increases mineral absorption in rats, mainly
by increasing the surface area available for absorption
(epithelial cell hypertrophy) and/or by favouring better
hydrolysis of phytic acid via enhanced fermentation, as
was shown with RS
(70,71)
and inulin (a fructan-type
compound)
(72,73)
.
Whole-grain cereals and butyrate production
Whole-grain cereal products are an important indirect
source of butyrate, produced notably through RS fermenta-
tion
(65)
. Butyrate has cancer-preventing properties in rats by
inducing apoptosis
(74)
or reducing tumour mass
(75)
. But its
positive physiological action may not be restricted to these
two effects. The precise mechanisms involved in the anti-
colon cancer effect of butyrate have been reviewed from
in vitro, animal and human studies and they mainly include
a combination of several physiological modifications in
relation to abnormal cell growth inhibition, immune system
stimulation and modulation of DNA repair and synthesis
(65)
.
Butyrate might also protect against breast and prostate
cancers, as shown by in vitro studies on mammary
(76)
and
prostate
(77)
cancer cell lines
(65)
. The RS content of whole-
grain cereal products depends on the proportion of the
different types of RS: RS1 which is physically inaccessible
to a-amylase, RS2 which is raw starch granules, and RS3
which is recrystallised/retrograded amylose that is formed
when cooked food cools. It is therefore difficult to obtain
precise data on the RS content of whole-grain cereal
products, but some products are enriched in RS by selecting
high-amylose varieties of cereal. Nevertheless, products
containing whole grains or made from high-amylose cereal
varieties will have proportionally higher RS contents and
produce more butyrate, as was shown in human subjects fed
various breads, breakfast cereals and crackers
(78,79)
. Whole-
grain cereal products with an intact botanical structure, that
is with intact kernels, will have a higher RS1 content, since
it is inaccessible to a-amylase, and butyrate production. The
relationship between the consumption of whole-grain
cereals and/or their bran and germ fractions, butyrate
production and long-term health effects deserve to be
studied more thoroughly in human subjects, particularly
because of the effects in rats of butyrate on fat oxidation and
of total SCFA production on cholesterol synthesis
reduction
(80)
.
The ‘second-meal effect’
The ‘second-meal effect’ is characterised by an improved
carbohydrate tolerance at a meal (either lunch or breakfast,
called the ‘second meal’) about 4 – 5 or 10 –12 h after the
consumption of a low-GI meal (i.e. the ‘first meal’), an
effect which may contribute to the long-term metabolic
benefits of low-GI diets. It was first described by Jenkins
et al. who used viscous guar gum
(81)
, and thereafter for low-
GI carbohydrate foods such as lentils
(82)
. Recently,
mechanisms have been proposed to explain the sustained
positive effect of low-GI whole-grain products composed of
intact barley or rye kernels consumed at diner or breakfast
on the glycaemic response at the following meal, breakfast
or lunch
(52,54,83)
.
The physiological mechanisms involved appear to differ
according to the interval between the two meals, dinner to
breakfast (about 10 – 12 h) or breakfast to lunch (about
4– 5 h). The shorter period seems to be sufficient for the
low-GI feature of the cereal product consumed at breakfast
to reduce the glucose response at lunch, probably by
improving blood sugar regulation and insulin sensitivity
(54)
.
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The longer interval between dinner and breakfast involved
the fermentation of indigestible carbohydrates in the colon,
reduced plasma NEFA and modified glucose metabolism.
This indicates that the presence of specific dietary fibre
(soluble or insoluble or RS) in boiled barley kernels is more
significant in this ‘second-meal effect’ than is its low GI.
SCFA produced during the fermentation of fibre in the
colon might be particularly involved
(83)
through at least
three potential processes: a possible decrease of the gastric
emptying rate by SCFA as reviewed in rats and humans
(84)
,
notably through an increased level of the polypeptide YY in
blood by SCFA, that may lead to a reduced rate of glucose
entry into the bloodstream; the ability of propionate and
acetate to reduce serum NEFA in humans
(85)
, circulating
fatty acids being able to induce peripheral and hepatic
insulin resistance in humans
(86)
; and, finally, the possible
specific action of propionate on glucose metabolism by
increasing hepatic glycolysis and decreasing hepatic
glucose production as shown in isolated rat hepatocytes
(87)
.
A later study on healthy subjects
(54)
confirmed that the low-
GI feature of the products consumed in the evening meal
was not per se involved in the improved glucose response at
breakfast, and that the lower plasma NEFA concentration
combined with the high plasma propionate content (from
fermentation in the colon) contributed to the overnight
benefits in terms of glucose tolerance
(83)
. The quantity and
quality of the indigestible carbohydrates (for example,
barley fibre and RS) are most important. There is also an
important relationship between gut microbial metabolism
and insulin resistance
(54)
.
These results suggest that the influence of carbohydrates
on glucose tolerance over a longer time (semi-acute) is
optimal when the food structure is preserved (i.e. a low-GI
feature) and content of RS and/or fibre is high (i.e.
production of specific SCFA). Eating barley or rye kernels
for breakfast resulted in lower cumulative postprandial
increases in blood glucose after breakfast, lunch and dinner
(a total of 9·5 h) than did a breakfast of white-wheat
bread
(52)
. From a technological point of view, the quantity
and quality of the indigestible carbohydrates is therefore
particularly important, in addition to preserving a more or
less intact botanical food structure, for a better control of
glucose metabolism, especially to prevent type 2 diabetes.
Whole-grain cereals as rich sources of
anti-carcinogenic compounds
A survey of 61 433 women found that a high consumption of
whole grains (hard whole-grain rye bread, soft whole-grain
bread, porridge, and cold breakfast cereals) was associated
with a lower risk of colon cancer
(11)
. An inverse association
between cereal fibre and whole-grain cereal consumption
and small-intestinal cancer incidence has also been
reported
(12)
. The roles played by dietary fibre and phyto-
chemicals in preventing intestinal cancer in humans and
animals have been reviewed and discussed for both human
intervention and animal studies
(45,69,88)
. The positive action
of the wheat bran oil on colon tumour incidence in rats
(azoxymethane-induced cancer)
(89)
and mice (Min cancer
model)
(90)
has also been demonstrated. This anti-carcinogenic
effect is mainly attributed to the antioxidant and anti-inflammatory
properties of several bioactive compounds, as increased
oxidative stress and inflammation are involved in cancer
aetiology
(91)
. Phenolic acids, flavonoids, carotenoids,
vitamin E, n-3 fatty acids, lignan phyto-oestrogens, steroid
saponins (found mainly in oats), phytic acid and Se are all
potential suppressors of tumour growth, but human, animal
and/or in vitro cell studies indicate that their mechanisms of
action may differ (Tables 3 and 4)
(46,69,92 – 95)
. For example,
cereal lignans are converted by fermentation into mamma-
lian lignans or phyto-oestrogens (enterodiol and enterolac-
tone). These may have a weak oestrogenic activity, and may
protect against hormone-dependent cancers (prostate and
breast cancers) and/or colon cancer
(96)
. Studies on
postmenopausal women, ovariectomised rats and liver and
breast cancer cell cultures indicate that phyto-oestrogens
inhibit cell proliferation by competing with oestradiol for
type II oestrogen binding sites
(97,98)
. Phytic acid would help
reduce the rate of cell proliferation during the initiation and
post-initiation stages (for example, decreased incidence of
aberrant colon crypt foci) by complex mechanisms that
involve its antioxidant properties, signal transduction
pathways, gene regulation and immune response through
enhancing the activity of natural killer cells
(99)
, and its anti-
carcinogenic effect seems to be dose-dependent
(100)
. The
high phytic acid content of whole-grain cereals (up to 6 % in
wheat bran) has led to questions about whether the anti-
cancer activity of wheat bran should be attributed more to
phytic acid than to dietary fibre
(69,92)
. Indeed, pure phytic
acid is more efficient at reducing the incidence and
multiplicity of mammary tumours in rats than is the bran
fraction (All Bran; Kellogg
w
)
(101)
. The many anti-carcino-
genic actions of flavonoids include their ability to inhibit
various stages of tumour development in animals
(102)
and to
reduce the mutagenicity of several dietary carcinogens in
Salmonella typhimurium TA98NR
(103)
. The anti-carcino-
genic activity of ferulic acid is mainly attributed to its
antioxidant capacity; it scavenges the free oxidative radicals
that are involved in the aetiology of cancer, and to its ability
to stimulate cytoprotective enzymes
(104,105)
. Studies on
azoxymethane-treated rats indicate that vitamin E and
b-carotene inhibit the progression of aberrant crypt foci to
colon cancer, especially the later stages of carcinogenesis,
while wheat bran is better at inhibiting earlier stages
(106)
.
Lignins, by hydrophobically binding bile salts, might reduce
the formation of carcinogens from them
(107,108)
. Their
adsorptive ability would increase with increased methylation
of the hydroxyl moieties on the phenyl-propane units
(107,108)
.
Lignins also reduce DNA lesions in rat testicular cells and
lymphocytes both in vitro and ex vivo
(109)
. Se inhibits the
occurrence of neoplasia in rats and mice, suggesting that an
Se-poor diet is associated with an increased prevalence of
neoplasia in specific human populations
(110)
. This probably
depends on the activity of the selenoprotein glutathione
peroxidase, which is involved in the development of
cancers
(111)
. Cereal bioactive compounds act via several
other anti-mutagenic and anti-carcinogenic mechan-
isms
(112)
. Important ones are the adsorption and dilution of
carcinogens by insoluble dietary fibre and lig-
nins
(69,106,113,114)
, and the action of SCFA produced by
fibre fermentation
(115)
. Butyrate is a major factor, as more is
produced in the presence of RS, and favours apoptosis in
Hypotheses for whole-grain cereal protection 81
Nutrition Research Reviews

human cancer cell lines
(62)
and DNA repair in rats
(116)
.
Interestingly, contrary to what was believed since the works
of Burkitt emphasising the preponderant role of fibre in the
prevention of Western diseases, notably colon cancer
observed in Western countries and not in African rural
population consuming high levels of dietary fibre
(117)
,itis
more and more believed today that the effect against colon
cancer development might be before all attributed to RS
(118)
,
since a lower risk of colon cancer was recently observed in
populations with a low level of fibre consumption but with a
high intake of RS
(119,120)
. This reinforces the idea that
specific products of RS fermentation within the colon, such
as butyric acid, are the active components. Betaine
(121)
may
be added to the list of anti-carcinogenic compounds, as its
concentration can reach 0·3 % in whole-grain wheat and
1·5 % in wheat bran (Table 2).
To summarise, the anti-carcinogenic effects of insoluble
fibre (including lignin), phytochemicals and wheat bran oil
can be distinguished. Insoluble fibre may act directly by
adsorbing or diluting carcinogens (through increased faecal
bulk by water absorption), or indirectly by decreasing colon
pH (through SCFA production) and increasing butyrate
production. The role of phytochemicals is complex and
multi-factorial, and notably involves their antioxidant
properties since increased oxidative stress is a major factor
in the aetiology of cancers
(91,122)
. The exact components of
wheat bran oil that reduce the development of colon tumours
are still to be identified
(89,90)
. However, animal experiments
indicate that dietary fibre, particularly soluble fibre, may not
protect against or even enhance carcinogenesis. This may be
due to the abrasive property of insoluble fibre, a too low pH
(,6·5) reached within the colon following soluble fibre and
RS fermentation, the enhanced colon glucuronidase activity
(that converts conjugated carcinogens to free carcinogens)
and the increased production of secondary bile acids
(tumour promoters) within the colon due to the increased
viscosity of some soluble fibre which reduces the
reabsorption of bile salt in the small intestine
(123)
.
Whole-grain cereals as a rich source of antioxidants
Whole-grain cereals can protect the body against the
increased oxidative stress that is involved and/or
associated with all the major chronic diseases: metabolic
syndrome
(124)
, obesity
(125,126)
, diabetes
(127,128)
, cancers
(91)
and CVD
(129,130)
. Whole-grain cereals are good sources of
antioxidants (thirty-one compounds or groups of compounds
are listed in Table 4), as shown by measurements made
in vitro of the antioxidant capacity of whole-grain, bran and
germ fractions
(131 – 135)
. However, this may not be the same
in vivo
(136)
, and up to today, to my knowledge, the number
of studies exploring the in vivo antioxidant effect of whole-
grain cereals and/or their fractions in human subjects does
not exceed eleven
(137 – 147)
. The antioxidants in cereals differ
in their structure and mode of action
(46,136)
. There are
indirect antioxidants, such as Fe, Zn, Cu and Se, which act as
cofactors of antioxidant enzymes, and direct radical
scavengers such as ferulic acid, other polyphenols (lignans,
anthocyanins and alkylresorcinols), carotenoids, vitamin E
and compounds specific to cereals other than wheat, such as
g-oryzanol in rice and avenanthramides in oats. These can
neutralise free radicals and/or stop the chain reactions that
lead to the production of oxidative radical compounds (for
example, the lipid chain peroxidation stopped by vitamin E
within cell membranes). Another antioxidant mechanism
involves phytic acid, which can chelate Fe and thus stop the
Fenton reaction producing the highly oxidative and
damaging free radical OH
z
, ultimately reducing lipid
peroxidation
(148)
. Lignins are also considered to be
antioxidants in vitro (radical-scavenging activity)
(149)
, but
precisely how they act in vivo is not known: they may adsorb
oxidative damaging compounds within the digestive tract in
a way similar to bile salts adsorption
(107,108)
. While the
action of cereal antioxidants is not well characterised once
the epithelial barrier has been crossed, there is a growing
belief that cereal antioxidants protect the intestinal
epithelium cells from oxygen-derived free radicals
(136,150)
,
particularly those produced by bacteria that may help form
active carcinogens by oxidising procarcinogens or those that
may result from increased stool Fe content (Fenton reaction)
due to a diet high in red meat
(151)
. The concept of ‘dietary
fibre-bound phytochemicals/phenolic compounds’ was
proposed recently
(18,150)
. The authors suggest that the
antioxidant polyphenols survive digestion in the small
intestine because most of them are bound to fibre (for
example, esterification of phenolic acids to arabinoxylans) in
the cereal food matrix. They reach the colon where the fibre
is fermented and some of the antioxidants are released
(150)
.
Vitaglione et al. hypothesised ‘the slow and continuous
release in the gut of the dietary fibre bound antioxidants’,
such as that of ferulic acid, which will determine the effects
of these antioxidants, and considered dietary fibre to be a
‘natural functional ingredient to deliver phenolic compounds
into the gut’
(150)
. For example, only 0·5– 5 % of the ferulic
acid is absorbed within the small intestine, mainly the
soluble free fraction
(152 – 154)
, and this typical whole-grain
wheat phenolic acid (about 90 % of total phenolic acids)
would probably exert a major action in the protection of the
colon from cancer. Thus, bound antioxidant phenolic acids
might act along the whole length of the digestive tract by
trapping oxidative compounds. This fraction of bound
polyphenols has often led to an important underestimation of
the real antioxidant capacity of whole-grain cereals – and of
their fractions – as measured in vitro and generally based
on the measurement of the easily extractable polyphenol
fraction
(133,155)
.In vivo studies are now needed to examine
this hypothesis, and to characterise and quantify this
potential antioxidant effect within the digestive tract.
The antioxidants in whole-grain cereals act via different,
complex, and synergetic mechanisms in vivo. However, the
antioxidant action of whole-grain cereals has not yet been
convincingly validated in human subjects and requires
further exploration.
Whole-grain cereals as rich sources of magnesium
Among plant-based foods, whole-grain cereals, together
with legumes, nuts and seeds, are one of the best sources of
Mg: whole-grain wheat contains 104 mg Mg/100 g, wheat
bran 515 mg, and wheat germ 245 mg (Table 2). The high
Mg content of whole-grain cereals may explain its
favourable impact on insulin sensitivity and diabetes risk
A. Fardet82
Nutrition Research Reviews

(Fig. 2)
(156)
, diabetes being otherwise frequently associated
with Mg deficiency
(157)
. Mg can increase insulin secretion
and the rate of glucose clearance from the blood in
humans
(158,159)
. This was also proposed to explain the lower
insulin response in obese and overweight adults following
the consumption of a whole-grain-based diet as compared
with those on a refined cereal-based diet
(160)
. High-Mg diets
reduce insulin resistance in rats fed a high-fructose diet
(161)
;
they also reduce the development of spontaneous diabetes in
obese Zucker rats, a model of non-insulin-dependent
diabetes mellitus, but these rats had to be given Mg before
the onset of diabetes to obtain protection
(162)
.Most
explanations of the prevention of type 2 diabetes by Mg
are based on the finding that Mg stimulates insulin-
dependent glucose uptake in elderly subjects
(158,163)
. It also
protects Mg-deficient animals from the production of
reactive oxygen species
(164)
. Reactive oxygen species are
partly responsible for the increased hyperglycaemia-
mediated oxidative stress in diabetic subjects
(165,166)
.Mg
also acts as a mild physiological Ca antagonist
(167)
. Obese
and diabetic patients with insulin resistance have excess free
intracellular Ca and these two clinical conditions are
associated with hypertension
(168)
. In addition, Mg helps
keep the concentration of intracellular Ca optimal through
various complex cellular mechanisms involving Ca
channels, Ca sequestration/extrusion by the endoplasmic
reticulum and Ca binding sites on proteins and mem-
branes
(156)
. Finally, low serum plasma Mg has been
positively associated with a higher risk of coronary
atherosclerosis or acute thrombosis
(169)
, suggesting that
whole-grain cereal Mg might also contribute to the
prevention of CVD. This may also involve the inhibition
of platelet-dependent thrombosis by Mg supplementation in
patients with coronary artery disease
(170)
and the positive
effect of Mg upon blood pressure regulation in hypertensive
patients
(171)
. The capacity of a regular prolonged consump-
tion of whole-grain cereals to sustain a high plasma Mg
concentration therefore deserves to be investigated in the
context of type 2 diabetes prevention.
The action of some anti-nutrients on starch hydrolysis
and glycaemia
Whole-grain cereals are also a source of antinutrients with
both adverse and positive health effects. The most important
are phytic acid, lectins, tannins, saponins and inhibitors of
enzymes such as proteases and a-amylases. Their main
negative effect is their ability to reduce the bioavailability
and the absorption of some nutrients (for example, the
chelation of minerals by phytic acid and tannins), the binding
of lectins to epithelial cells that damages the intestinal
microvillae, and inhibition of digestive enzymes by tannins,
which inhibits growth in animals
(172,173)
. Cereal products in
the human diet are cooked; this leads to losses of antinutrients
such as lectins and enzyme inhibitors, and the major health
outcome appears to be the low dietary Fe bioavailability
in African populations that consume sorghum or finger
millet-based beverages, gruels and porridges, both cereals
containing phytic acid and a high tannin content
(174,175)
.For
example, the phytate and Fe-binding phenolic compounds in
whole-grain millet flour may reach 0·6 g/100 g (DW)
(176)
.
This is one of the key factors responsible for Fe-deficiency
anaemia in developing countries
(175)
. On the other hand,
the use of traditional processing such as germination,
soaking, pre-fermentation and cooking may help to decrease
the tannin and phytic acid contents, so improving Fe
bioavailability
(177 – 180)
.
However, phytic acid, lectins, protease inhibitors and
tannins also contribute to the low-GI property of whole-
grain foods
(181,182)
. In wheat and derived whole-grain food
Insulin sensitivity
Dietary fibre (phytic acid)
Whole grain intake
Blood lipids
Bioactive components
Cardiovascular diseasesType 2 diabetes
(Betaine)
Antioxidant/
anti-
inflammatory
status
(Mg)
Homocysteine
GI
and/or II
Colonic
fermentation
(Viscosity/food structure)
Cancers
Tumour
growth
Obesity
Satiety
Fig. 2. Currentaccepted mechanisms for how whole grain protects againstmajor chronic diseases (modified with permission from ProfessorI. Bjo
¨rck
(University of Lund, Sweden); see the HealthGrain brochure for original diagram: ‘Progress in HEALTHGRAIN 2008’, a project from the European
Community’s Sixth Framework Programme, FOOD-CT-2005-514008, 2005– 2010; see Poutanen et al.
(478)
for more details about the Project).
GI, glycaemic index; II, insulinaemic index.
Hypotheses for whole-grain cereal protection 83
Nutrition Research Reviews

products, since lectins and enzyme inhibitors are inactivated
by cooking processes, this is primarily phytic acid which
would reduce glycaemia through several potential mechan-
isms: thus, binding with proteins closely associated with
starch, association with digestive enzymes, chelation of Ca
required for a-amylase activity, direct binding with starch,
effect on starch gelatinisation during cooking processes and
slowing of gastric emptying rate might be involved
(181)
.
Conclusion
The proposed mechanisms by which whole-grain cereals
may protect the body are shown in Fig. 2. The most
important ones are the preservation of food structure, fibre
fermentation in the colon, the hypoglycaemic and
hypoinsulinaemic, antioxidant, anti-inflammatory and anti-
carcinogenic properties of several bioactive compounds,
improved insulin sensitivity by Mg and reduced hyperho-
mocysteinaemia by betaine, a significant CVD risk factor
(for details about betaine, see the ‘New hypotheses’ section
below). However, an extensive list of all the bioactive
compounds in whole-grain wheat and its fractions (Table 2),
the ways they act and their health effects as isolated free
compounds (Tables 3 and 4) makes it possible to formulate
new hypotheses to explain the protective role of whole-grain
cereals. Whole-grain cereals, particularly wheat and/or
wheat bran and germ, are also a source of n-3 fatty acids
(especially a-linolenic acid), sulfur compounds (reduced
glutathione (GSH), oxidised glutathione (GSSG), methion-
ine and cystine), oligosaccharides (fructans, raffinose and
stachyose), P, Ca, Na, K, B vitamins, flavonoids (for
example, anthocyanins and isoflavonoids), alkylresorcinols,
betaine, choline, phytosterols, inositols, policosanol and
melatonin. The actions of these compounds will be
described in the next ‘New hypotheses’ section. The
antioxidant hypothesis will be discussed with a broader
perspective, as well as the health benefits of active
compounds from whole-grain cereals that are less often
studied, such as B vitamins, sulfur compounds, methyl
donors and lipotropes, a-linolenic acid, lignins, oligosac-
charides, policosanol and melatonin.
New hypotheses: a broader perspective for the
protective action of whole-grain cereals
The antioxidant hypothesis must not be reduced to free
radical scavenging and antioxidant enzyme activation
There is more and more evidence that the primary effect of
antioxidants from whole-grain cereals is in the digestive
tract, where they protect intestinal epithelial cells from
attack by free radicals
(136,150)
. However, the mechanisms by
which antioxidants that cross the intestinal barrier protect
the body remain uncertain. Published studies on animals and
human subjects fed the free compounds give rise to new
explanations of the antioxidant protection by whole-grain
cereals. The antioxidant action of whole-grain cereals might
be multi-factorial and much more complex than it first
appears. There are at least four new mechanisms to be
studied in the context of whole-grain cereals: the action of
polyphenols on cell signalling and gene regulation
modifying the redox status of tissues and cells, the action
of sulfur amino acids on glutathione synthesis, the possible
stimulation of endogenous antioxidants by whole-grain
cereal bioactive compounds, and the underestimated
antioxidant properties of phytic acid and lignin.
Whole-grain cereals as a source of polyphenols involved
in cell signalling. The polyphenols in complex foods are
generally not readily absorbed in the small intestine: 2 –5 %
for whole-grain cereal phenolic acids (Table 2), and 30–
40 % for flavonoids from vegetables, beverages and fruits,
depending on the food
(183)
. The resulting plasma concen-
trations of these absorbed compounds are generally in the
nanomolar (nM) or micromolar (mM) range, lower than that
of endogenous antioxidant compounds such as GSH and
vitamin C (millimolar). However, this does not mean that
they have no antioxidant action. Some quite recent studies on
isolated compounds have shown that flavonoids
(184,185)
and
phenolic acids
(186,187)
act on cell signalling pathways, so
modifying gene regulation and/or cell redox status, as has
been discussed in several recent reviews
(188 – 191)
. However,
most of the studies were performed with flavonoids, not
phenolic acids which are more abundant in whole-grain
wheat (up to 100 mg/100 g) than are flavonoids (30 –
43 mg/100 g) (Table 2). Results obtained with isolated
flavonoids, mainly in in vitro cell cultures, may be
extrapolated to flavonoids found in whole-grain wheat
once they have entered the bloodstream and then reached
cells. Little work has been done to precisely identify wheat
flavonoids. Nevertheless, some of them are catechin and
proanthocyanidins
(192)
, tricine
(69)
, apigenin glycosides
(193)
,
and vicenin and schaftosides
(194)
. These flavonoids may act
as signals within cells. The main mechanisms probably
involve the redox status and antioxidant and pro-inflamma-
tory genes activated by increased oxidative stress, i.e. a
modified redox state of the cell, through signalling pathways
that may be up- and down-regulated by polyphenols via
activation or inactivation of transcription factors such as
NF-kB
(189,187)
or activator protein-1 (AP-1)
(186)
. Thus,
flavonoids can increase GSH synthesis through the
transcription factor Nrf2 (nuclear factor-erythroid 2-related
factor 2) which binds to specific antioxidant/electrophile
response element (AREs/EpRE)-containing gene promo-
ters
(188)
. For example, oxidised quercetin (quinone) can react
with thiols in the Keap1 protein (Kelch-like ECH-associated
protein 1 bound to the cytoskeleton), releasing Nrf2 and then
activating specific genes via ARE/EpRE involved in GSH
synthesis
(188)
. Here, more than the antioxidant property of
the flavonoids, it is its activated or metabolised form which
would be active within cells. Kaempferol and quercetin, two
flavonoids, also modulate the production of g-glutamylcys-
teine synthetase
(195)
, an important enzyme in the synthesis of
GSH. The authors conclude that flavonoids are important for
regulating the intracellular concentration of GSH
(195)
. There
is therefore a strong link between the intra- and/or extra-
cellular actions of polyphenols, redox cell status and gene
regulation, broadening the notion of antioxidant polyphenols
to activities other than just free radical scavenging. However,
most studies have used higher polyphenol concentrations
(.10 mM) than those found in vivo. For example, the
postprandial plasma ferulic acid concentrations following
A. Fardet84
Nutrition Research Reviews

wheat bran consumption in rats were about 1 mM
(154)
and
about 0·2 mMin human subjects
(196)
. However, a study
conducted in vitro on cell cultures with six wine phenolic
acids in the 20 nM–20mMrange showed that ferulic, sinapic,
p-coumaric and caffeic acids (all found in whole-grain
wheat) are able to inhibit the action of pro-inflammatory
transcription factor AP-1 as low as 20 nMin a range of
5 –15 %
(186)
. Besides, it may reasonably be supposed that the
true plasma polyphenol concentration is higher than the
0·2 – 1 mMreached with ferulic acid due to the presence of
other polyphenols such as sinapic acid and, to a lesser extent
flavonoids, as recently reported in human subjects where
aþ5mMincrease in plasma total polyphenols has been
observed 1 h after boiled wheat bran consumption
(146)
. Most
of the sinapic acid in whole-grain wheat is free or in a soluble
conjugated form (approximately equal to 70 %), and may
reach a total concentration of 4 –18 mg/100 g whole-grain
wheat
(197)
. However, whether the low plasma polyphenol
concentrations obtained following a whole-grain cereal
meal are compatible with cell signalling activity remains to
be explored.
Whole-grain cereals are a rich source of sulfur com-
pounds. The sulfur amino acid contents (methionine and
cystine) of whole-grain wheat, wheat bran and germ are 0·5,
0·6 and 1·0 % (Table 2), and may be higher in some cereal
varieties (see ranges in Table 2). Methionine and cystine are
both precursors of GSH, an intracellular antioxidant, and as
such contribute to the control of the cell oxidative status by
participating in gene expression through modification of the
thiol redox status, as has been recently reviewed
(198,199)
.
Thus, rats fed a 0·6 % free methionine diet had a higher
hepatic GSH content than rats fed a control 10 % casein-
based diet without methionine supplementation
(200)
. It has
also been shown in rat gut mucosa and plasma that an
inadequate intake of sulfur amino acids leads to the oxidation
of the thiol/disulfide redox status (expressed by the ratios
cysteine:cystine and GSH:GSSG), i.e. a less reductive
potential, that in the end increases oxidative stress
(201)
.
Methionine also generates cysteine via the cystathionine
pathway
(202)
, cysteine being oxidised to cystine (two
cysteine moieties linked by a disulfide bond).
For humans, average daily intakes of 305 –2770 mg
methionine and 197– 1561 mg cystine have been reported
for a usual diet
(203)
. The estimated daily requirements of
methionine þcysteine are 910 – 2100 mg/d for a 70 kg
adult
(204)
. Based on the methionine and cystine content of
commercially prepared whole-wheat bread (USDA data-
base, 155 and 214 mg/100 g)
(205)
and on a daily consumption
of one serving of whole-grain cereal products (i.e. about 30 g
for a slice of bread)
(206)
, whole-grain cereals provide an
average 47 mg methionine and 64 mg cystine per d. This
suggests that whole-grain cereals contribute little to
methionine and cystine intakes, at least for low consumers.
However, quite significant amounts of at least 280 mg
methionine and 380 mg cystine per d can be obtained by
following the USDA food guide pyramid that recommends
between six and eleven daily servings of whole-grain
cereal products. This would significantly contribute either to
the average daily intakes as previously reported
(203)
or to
the daily recommendations
(204)
. However, it is not known
how a regular daily consumption of between six and eleven
servings of whole-grain cereal products would contribute to
GSH synthesis and/or an improved antioxidant status in
humans.
GSH can be hydrolysed in the small intestine by g-
glutamyltransferase and/or absorbed intact, mainly in the
upper jejunum
(207)
. It is therefore available to cells where it
may exert its physiological effects as an antioxidant, anti-
carcinogenic and/or immunostimulating
(208)
agent and also
as detoxifier of xenobiotics. Human subjects given a solution
of 46 mg GSH/kg body weight (a single oral dose of 3 g)
showed no significant increase in postprandial plasma
GSH
(209)
. Dietary GSH, but also its dietary precursors
methionine and cystine, are therefore not major determinants
of circulating GSH
(203)
, probably because GSH is rapidly
hydrolysed in the small intestine
(209)
; however, it might help
detoxify reactive electrophiles in the diet within the
intestinal lumen
(207)
or protect epithelial cells against attack
by free radicals. The human daily total GSH consumption is
13 –110 mg (mean 35 mg)
(203)
. Using the GSH highest
content in whole-grain wheat (Table 2), that is about 5·7 mg/
100 g, and eating 30 g whole-grain cereal per d as bread
(about 38 % water), it may be calculated that whole-grain
bread provides less than 1·3 mg GSH per d. Increasing the
consumption of whole-grain cereal products to between six
and eleven servings daily as recommended by the USDA
food pyramid (epidemiological data show that an average 2·7
servings of whole-grain foods have beneficial health effects),
especially servings containing wheat germ since this fraction
may have 246 mg GSH/100 g – and probably more if total
glutathione equivalents (GSH þ(2 £GSSG) þprotein-
bound glutathione) are considered – might therefore provide
a substantial supply of GSH. Thus, the total GSH content of
high-grade extraction wheat flours (1·44 –1·73 g ash/100 g)
is 11·6 –17·6 mg/100 g (with a water content for whole-grain
wheat flour of 13·0 %), which is about three times the total
GSH content of low-grade extraction wheat flours
(0·54– 0·59 g ash/100 g and 4·7 –5·0 mg total GSH/100 g
flour with an 11·9 % water content for white wheat flour),
clearly showing that GSH is mainly in the bran
(210)
.
However, a higher total glutathione content of 15·8 mg/100 g
(thirty-six wheat varieties) was evaluated from data by
Li et al. for white wheat flours
(211,212)
. The contribution of
total whole-grain wheat GSH to the antioxidant defence, either
within the gut lumen or as a substrate supplying cysteine for
endogenous GSH synthesis in the liver, might be explored by
comparing low-methionine and whole-grain-rich diets.
The possible action of whole-grain cereal compounds on
plasma uric acid level. A recent study on human subjects
consuming apples demonstrated that the elevated plasma
postprandial antioxidant level (þ55 mMtrolox equivalents
after 1 h and stabilisation at about þ20 mMtrolox
equivalents between 2 and 6 h; ferric-reducing ability of
plasma (FRAP) assay) was due to increased uric acid and
not to a significant increase in plasma vitamin C or
polyphenols
(213)
. Fructose was thought to stimulate adenine
nucleotide degradation leading to uric acid synthesis
(214)
.
The authors proposed that the increased plasma antioxidant
level following consumption of flavonoid-rich diets is due to
an increase in uric acid, while sucrose, sorbitol, lactate
Hypotheses for whole-grain cereal protection 85
Nutrition Research Reviews

and/or methylxanthines are also candidates for endogenous
uric acid synthesis
(214)
. Uric acid is a powerful antioxidant
whose concentration in human plasma can reach 160–
450 mM, and can account for as much as 40 – 90 % of the
plasma antioxidant capacity
(214)
. A recent study on human
subjects has shown that there is little or no correlation
between changes in plasma total phenolic acids and
antioxidant capacity (FRAP assay) following the consump-
tion of wheat bran, indicating that compounds other than
phenolic acids contribute to the postprandial increase in
plasma antioxidants to about þ50 mMof FRAP between 1
and 3 h
(146)
. This increase is in the same range as that found
by Lotito & Frei with apples
(213)
and with other values
reported by Price et al. with tea, red wine, spinach and
strawberries, from þ15 to þ100 mMincrease in plasma
FRAP
(146)
. This cannot be explained by the low fructose
content of wheat bran (about 50 mg/100 g), much lower than
that of apples (about 5·7 g/100 g)
(215)
. However, whole-grain
cereals contain an important package of bioactive
compounds other than fructose or polyphenols whose effect
upon endogenous antioxidant synthesis has not been
explored. It would be therefore relevant to confirm this
increase in plasma antioxidant level following wheat bran
consumption, and to identify the mechanisms underlying
such an increase, which is apparently not due to the increase
in circulating plasma polyphenols alone
(146)
. Work is also
needed to determine whether the consumption of whole-
grain cereals and/or bran and germ fractions can
significantly increase the plasma uric acid concentration to
those produced by coffee (þ5 %) or tea (þ7%)
(216)
.
Whole-grain cereals as a source of phytic acid and
lignins. Phytic acid from whole-grain cereals has long
been considered to be nutritionally negative, since it
chelates minerals such as Zn, Fe, Ca and/or Mg, thus
limiting their intestinal bioavailability
(217)
. This has been
used as an argument for using refined flours instead of
wholemeal wheat flours. However, phytic acid is also a
strong antioxidant in vitro
(218)
, and may reach 6 % in the
bran of certain wheat varieties (Table 2). It therefore needs
to be determined whether the negative effect of phytic acid
on mineral assimilation can be offset by its antioxidant
activity and the high content in minerals of whole-grain
wheat. Today, the answer to this is undoubtedly ‘yes’.
First, the quantity of mineral chelated by phytic acid is
apparently not high enough compared with the much greater
quantity in whole-grain cereals compared with refined ones.
Rats fed whole-wheat flour absorbed more minerals than
rats fed white wheat flour
(219)
. Besides, baking bread
according to a sourdough procedure can activate endogen-
ous phytases and lower the pH, thus limiting the chelation of
minerals by phytic acid
(220)
. Second, it is now known that
phytic acid can chelate Fe, thus limiting the damage due to
the Fenton reaction leading to the production of the very
reactive free radical OH
z
. Third, the phytate in whole grain is
accompanied by other bioactive compounds that are lost
during refining. Phytic acid is therefore a serious candidate
as a whole-grain cereal antioxidant acting in vivo.
Unfortunately, I know of no studies that have explored the
antioxidant effect of this compound from whole-grain
cereals in vivo.
The concentration of lignins in whole-grain wheat is
1·9 %: 5·6 % in wheat bran and 1·5 % in germ (Table 1).
Lignins are absent from refined flour and are generally
considered to be nutritionally inert. However, some studies
have demonstrated its potential positive physiological
effects. Studies on rats showed that lignin may account for
26 –32 % of the enterolactone (a mammalian lignan) formed
from cereal bran
(221)
. Mammalian lignans are antioxidants
in vitro at the concentrations (10 –100 mM) achievable
in vivo
(222)
, particularly in the colon
(223)
. A study on rats fed
a diet containing 8 % lignin for 21d showed that lignins can
have antioxidant effects on ex vivo fresh lymphocytes by
significantly decreasing the peroxide-induced DNA strand
breaks and visible light-induced oxidative DNA lesions
under the form of oxidised bases via singlet oxygen –
1
O
2
–
production
(224)
. But I know of no studies on human subjects
that have examined the physiological effects of lignins.
However, if lignins are partially metabolised to mammalian
lignans in humans, as they are in rats, they might add to the
protection by lignans observed in human subjects against
some cancers
(96)
. Again, studies are needed to explore the
antioxidant effect of whole-grain cereal lignins in vivo.
Whole-grain cereals as a source of bioactive compounds
with underestimated physiological effects
Whole-grain cereals as a source of lipotropes and methyl
donors: betaine, choline, folates, methionine and myo-
inositol. Betaine and choline are now recognised as
important in human nutrition: betaine improves the health
of the heart, liver and kidneys, while choline is important for
lipid metabolism, brain development, the integrity and
signalling function of cell membranes, and as a precursor
of phosphatidylcholine, acetylcholine and betaine
(Table 3)
(225,226)
. The nutritional role of folates (vitamin
B
9
) is also well recognised, particularly in the prevention of
neural tube defects and CVD (Table 3). What is more
surprising is that their contribution to the health benefits of
whole-grain cereals, particularly wheat bran and wheat
germ, has not been recognised until very recently
(Fig. 2)
(136,227)
. Whole-grain wheat, wheat bran and wheat
germ, respectively, contain about 0·28, 1·04 and 1·09 %
betaine and choline and about 51, 231 and 420 mg
folates/100 g (Tables 1 and 2). However, whole-grain cereals
are not very good sources of folates as compared with
legumes or vegetables, notably when based on a 100 kcal
(420 kJ) content
(228)
. The bioavailability of choline and
betaine from whole-grain cereal products and fractions is not
known. However, its presence as a free soluble osmolyte
(225)
in cells of the aleurone layer suggests that betaine is readily
available, especially compared with fibre-bound antioxidant
polyphenols. To my knowledge, only two studies, using the
metabonomic approach, have underlined the importance of
betaine from whole-grain cereals by showing an increased
hepatic, urinary and plasma betaine levels in rats and pigs fed
whole-grain wheat flour and high-fibre rye bread
(229,230)
.
This suggests that betaine from whole-grain cereals is quite
available. It has also been recently shown that free betaine
can reverse insulin resistance and liver injury in mice fed a
high-fat diet, an animal model of non-alcoholic fatty liver
disease
(231)
. Thus, the probably high bioavailability of
A. Fardet86
Nutrition Research Reviews

betaine from cereals
(229,230)
combined with its many
described health effects
(225)
suggest that whole-grain cereal
betaine may have multivariate health benefits.
Betaine, choline and folates are all methyl donors, able
per se to transform homocysteine into methionine, thereby
decreasing hyperhomocysteinaemia
(232)
, a known risk
factor for CVD
(233)
, and also for neural tube defects
(234)
and cancers
(235)
. The dietary intake of whole-grain and bran,
but not germ, is significantly and negatively associated with
the plasma homocysteine concentration: 217·4 and
210·9 % when comparing the highest and lowest quintiles
of whole-grain and bran cereal intake, respectively
(17)
.The
wide variety of micronutrients may interact in synergy in
this effect
(17)
. More precisely, one may hypothesise that
folates, betaine and choline would be primarily involved.
Besides, since hyperhomocysteinaemia is associated with
increased oxidative stress
(236,237)
, betaine and choline may
act as indirect antioxidants.
Betaine, choline and folates are also lipotropic
compounds, together with methionine and myo-inositol,
that are essential for lipid metabolism, DNA methy-
lation and the production of nucleoproteins and mem-
branes
(225,226,238– 240)
. By definition, a lipotrope is a
substance that specifically prevents excess fat deposition
in the liver by hastening fat removal or by limiting lipid
synthesis. However, using this definition sensu strictu, very
few studies on human subjects have been published; most
have been performed on animals. It is estimated that whole-
grain wheat, wheat bran and wheat germ can supply 0·51,
1·31 and 1·59 g lipotropes/100 g, respectively (Table 2).
These values could be higher if other compounds with
indirect lipotrope-like effects are included (those that
indirectly prevent fat accumulation) such as Mg, niacin,
pantothenic acid, RS, some flavonoids, PUFA, phytic acid,
lignans, some oligosaccharides and fibre. Among lipotropes,
as for choline, myo-inositol (a carbocyclic polyol) is derived
from several myo-inositol-derived compounds that are
essentially free myo-inositol and conjugated myo-inositol,
either with glycosylated (for example, galactinol and
di-galactosyl myo-inositol) or phosphorylated (for example,
phytate or hexakisphosphate) groups. However, the
lipotropic effect of phytate has not yet been demonstrated
in human subjects and is probably low since human phytases
are much less active than those in the rat small intestine
(241)
.
In addition, among the nine isomers of inositol, only
myo-inositol has been shown to be lipotropic, not
chiro-inositol
(242)
, which is abundant in the pseudo-cereal
buckwheat
(243,244)
and is mainly known for its action against
insulin resistance and its ability to help controlling blood
glucose
(245)
.Exceptformyo-inositol phosphate (from
hexakisphosphate to monophosphate) contents, there are
few data on the free myo-inositol content of whole-grain
cereals and their bran and germ fractions before processing.
To my knowledge, the only published values are 86·7 mg/
100 g for whole-grain amaranth
(246)
,8·5mg/100gfor
oats
(247)
, 30·8– 35·4 mg/100 g for whole-grain quinoa
(248)
and 52·5 mg/100 g for dry mature wheat embryo
(249)
, which
is quite similar to the germ fraction. The same authors also
reported that dry mature wheat embryo contained about
56 mg galactinol/100 g
(249)
.Myo-inositol is therefore mainly
present in phytate in cereal grains, about 95 % in wheat
(250)
.
I have used this percentage and the phytic acid content of
whole-grain wheat to estimate the free myo-inositol contents
of whole-grain wheat, wheat bran and wheat germ (Table 2).
The total myo-inositol content of 487 foods was published in
1980, forty-seven of which were processed cereal-based
products (twenty-four types of bread, fifteen breakfast
cereals and eight kinds of pasta). The total myo-inositol/
100 g was 25 –1150 mg for wheat breads and 7 –35 mg/
100 g for wheat-derived breakfast cereals
(251)
. Considering
all cereal foods, the values given were then within the range
6– 1150 mg/100 g for breads and 2–274 mg/100 g for other
cereal foods (pasta and breakfast cereals)
(251)
. But these
values are for total myo-inositol after acid hydrolysis for
40 h at 1208C, which releases myo-inositol from phytate in
addition to free myo-inositol
(251)
. Nevertheless, hydrolysis
of phytic acid within lower inositol phosphate esters (from
inositol pentaphosphate to inositol monophosphate and free
myo-inositol) by activated endogenous food phytases,
through, for example, sourdough baking with natural
leaven
(220)
and/or simple fermentation with yeast
(252)
and/
or germination
(247,252,253)
, may lead to free myo-inositol
formation
(247,254)
, as was shown by using different
hydrothermal processes with lactic acid and whole barley
kernels
(255)
. Free myo-inositol may then become available
for absorption depending on the quantity not degraded by
microflora, either during pre-fermentation or in the colon.
Thus, the total free myo-inositol content of wheat products is
difficult to ascertain precisely and probably depends on the
processing parameters (which would explain the high value
ranges found for breads). But it is not insignificant. Once
ingested, except for folates whose bioavailability would be
low when originating from cereal products, other cereal
lipotropic compounds are quite readily available in the
digestive tract (Table 2), myo-inositol being likely to be
further partly converted into chiro-inositol after absorption,
as shown in rats
(256)
.
Wheat bran and germ are rich in choline, which is
important in lipid metabolism and DNA methylation.
Choline, as choline bitartrate, is often used as a lipotrope
in animal diets
(257)
, and rats fed a choline-free diet for
14 months develop severe hepatic lesions, hepatic DNA
undermethylation and cellular carcinomas
(258)
, DNA under-
methylation being related to carcinogenesis develop-
ment
(259)
, as demonstrated for benign and malignant
human colon neoplasms
(260)
. The extent to which lipotropes
from whole-grain wheat such as choline help improve lipid
status, by preventing fat deposition in the liver, and in
balancing DNA methylation in the liver and colon deserve
to be explored in prolonged trials with a whole-grain cereal-
based diet. In addition to the well-known anti-carcinogenic
property of several whole-grain cereal compounds (Table 4),
that of choline
(260)
and betaine
(121)
should be studied more
thoroughly, more particularly at the colorectal level.
The specific actions of bound and free ferulic acid. The
physiological action of ferulic acid from whole grain has
undoubtedly been underestimated because it is poorly
absorbed by the small intestine (,5 %; Table 2), and
because most studies have been conducted with the free
compound at high and often unrealistic nutritional levels.
These studies have nevertheless underlined the potential
Hypotheses for whole-grain cereal protection 87
Nutrition Research Reviews

role of ferulic acid as an antioxidant, anti-microbial, anti-
apoptotic, anti-ageing, anti-inflammatory, neuroprotective,
hypotensive, pulmonary-protective and cholesterol-
lowering agent in metabolic diseases such as thrombosis,
atherosclerosis, cancer and diabetes (Tables 3
and 4)
(104,261,262)
. However, there have been few studies
on the capacity of ferulic acid from cereal products to
improve some physiological functions in human sub-
jects
(104)
. Ferulic acid may reach up to 0·2 % of whole-grain
wheat and over 0·6 % of wheat bran (Table 2), which is quite
significant; and 80 % of ferulic acid is in the bran
fraction
(263)
. Since no more than 5 % of ferulic acid is
absorbed by the intestine
(153)
, about 95 % reaches the colon
bound to fibre where it may act as a natural antioxidant on
epithelial cells
(150)
. Thus, both free and metabolised ferulic
acid (mainly sulfated and glucuronated) may have a
signalling function within cells, and the bound compound
might be a strong protective antioxidant and anti-
inflammatory agent within the colon. The bacterial esterases
in the colon will also partially and relatively slowly
solubilise bound ferulic acid, as shown in vitro in a human
model colon
(264)
. The possible absorption of ferulic acid
within the colon and the physiological effects of its
metabolites produced by the colon microbiota remain
therefore to be quantified and qualified.
The specific actions of lignins. I have discussed the
potential role of lignin as an antioxidant. However, lignin is
one of the main non-energy-producing compounds in whole
grain (about 1·9 % of whole-grain wheat, 5·6 % of wheat
bran and 1·5 % of wheat germ) (Table 1). Although
generally considered to be nutritionally inert, such a high
concentration should have physiological effects, such as
protecting the gut epithelium against oxidative damage and
protecting other cell wall compounds against fermentation,
so increasing faecal bulk and the associated positive health
effects (dilution of carcinogens). Some studies support the
hypothesis that lignins are not nutritionally inert. For
example, bioactive lignophenol derivatives from bamboo
lignin are anti-carcinogenic in human neuroblastoma SH-
SY5Y cells, where they suppress oxidative stress-induced
apoptosis
(265)
. It has also been shown that cell walls
containing lignins (hydrophobic polymers) favour the
adsorption of hydrophobic carcinogens and their release in
the faeces
(266)
. Lignins from wheat bran also adsorb bile
salts (i.e. bile salt-sequestering agent) such as deoxycholate
in vitro, but a link between cholesterol lowering and wheat
bran consumption was not demonstrated
(267)
. Lignin may
reduce bile salt reabsorption in vivo by adsorbing them
(268)
,
and may further reduce the formation of carcinogenic
metabolites from bile salts by colon bacteria
(269)
. The lignin
nordihydroguairetic acid is also able to prevent changes in
renal morphology, by reducing oxidative stress, in rats with
diabetic nephropathy for which reactive oxygen species play
an important role in its development as a result of chronic
hyperglycaemia
(270)
. Finally, lignins from fractionated
hardwood hydrolysate, when consumed during 3 weeks
from an 8 % lignin-based diet, are able to decrease H
2
O
2
-
and visible light-induced DNA damage in ex vivo fresh
rat blood lymphocytes
(224)
and in testicular cells
(109)
.
This suggests that lignin compounds or some of their
metabolites have crossed the epithelial barrier, or at least
have been able to induce antioxidant defences in blood by
unknown mechanisms. More recently, studies using a liquid
chromatography– MS-based metabonomic approach
showed that lignins appear not to be metabolised by rats
for 2 d, but that they probably had some effects on
endogenous metabolism
(271)
. To summarise, lignins might
act in many ways: they are metabolised to enterolactone in
rats
(221)
, their antioxidant capacity may protect the gut
epithelium, they may act on endogenous metabolism, they
may reduce DNA damage in blood or cells via their
antioxidant capacity and they may adsorb carcinogens. All
these potential physiological effects should be taken into
consideration in further in vivo studies, especially towards
cancer prevention. Lignins are therefore far from being inert
and researchers in nutrition and cereal technology should
ask more questions about the nutritional effects of lignins.
The combined effects of B vitamins. Whole-grain wheat,
and especially its bran and germ fractions, contains almost
all the B-group vitamins, vitamins B
1
(thiamin), B
2
(riboflavin), B
3
(niacin), B
5
(panthothenic acid), B
6
(pyridoxine), B
8
(biotin) and B
9
(folates). Whole wheat
contains about 9·1 mg B vitamins/100 g, bran about 30·3 mg
and germ about 12·3 mg (Table 1). Whole-grain cereals are
particularly significant sources of thiamin, niacin, pantothe-
nic acid and biotin compared with other food sources, and
wheat germ is rich in nicotinic acid, pantothenic acid and
pyridoxine. Cereal products are not a particularly rich
source of folates unless fortified with folic acid (the
synthetic form of folate), as it is often the case, especially
for breakfast cereals. One key issue is the bioavailability of
these vitamins in whole-grain cereals, but data are scarce:
the few studies on the subject show that the bioavailability
of each B vitamin seems to vary greatly, and that it is far
from 100 % (Table 2). Thiamin and pyridoxine are the most
bioavailable (Table 2). The specific action of each of these
vitamins is described in Table 3. Their actions are complex
and multi-factorial. The B vitamins are also called the
‘B-complex vitamins’ and they play an important role in
maintaining muscle tone in the gastrointestinal tract and
promoting the health of the nervous system, skin, hair and
liver. Thiamin, nicotinic acid, pyridoxine, pantothenic acid
and folates play a positive role in mental health (Tables 3
and 4). For example, folates and pyridoxine are coenzymes
in the one-carbon metabolism pathways and are involved in
the synthesis of serotonin and other neurotransmitters,
deficits of which are implicated in deficient mental
health
(272)
. Folates also reduce the risk of neural tube
defects in babies when consumed during the periconcep-
tional period
(273)
. It was recently suggested that they could
be used to treat depression
(274,275)
, as a low folate status is
associated with depression
(276)
. Although difficult to
demonstrate, it would be particularly interesting to explore
the effect of whole-grain cereals on the nervous system and
mental health, particularly disorders such as depression,
insomnia, cognitive impairment or more generally psychic
equilibrium. Other bioactive compounds, such as choline,
ferulic acid, Mg, Zn, Cu, inositols, policosanol and
melatonin, are also potential candidates for mental health
protection and equilibrium (Tables 3 and 4).
A. Fardet88
Nutrition Research Reviews

The effects of whole-grain cereals on bone, teeth,
articulation and tendon health. Whole-grain cereals and
their fractions might contribute to the good health of bones,
cartilages, teeth, collagen, joints and tendons (Table 3),
which are all constituents of the skeleton, by the combined
actions of a-linolenic acid, Fe, Zn, Mg, Mn, Cu, P, Ca, K,
nicotinic acid, tocotrienols, phylloquinone (vitamin K) and
b-cryptoxanthin (Table 4). While P and Ca are components
of hydroxyapatite, a major constituent of bones and teeth,
the Ca:P ratio in cereals, notably wheat (about 0·08;
Table 2), is below the ratio of 0·5– 0·8 recommended for a
satisfactory Ca use by the body. Ca from whole-grain
cereals is therefore unlikely to contribute significantly to the
health of bones and teeth. However, the addition of calcium
carbonate (CaCO
3
) to cereal food recipes before processing
might be a simple way to achieve the desirable Ca:P ratio
without altering product palatability
(277)
. Whole-grain
wheat also contains Ca absorption enhancers such as
fructans and/or RS, which increase the apparent
absorption of Ca from 20 to 50 % in rats
(71 – 73)
. Similarly,
inulin increases Ca absorption by about 12 % in human
subjects
(71 – 73)
. However, although whole-grain wheat does
not contain inulin, it may contain up to 2·3 g fructans/100 g
(Table 2) that might also increase Ca absorption upon
fermentation. The effect of indigestible oligosaccharides
such as fructans on Ca absorption and metabolism, and bone
health (as measured by indices such as bone mineral
content and density, and/or bone resorption rate/osteopenia)
is more and more recognised today, both in rats and
humans
(278 – 280)
.
The results for P are less conclusive; some studies have
shown increased P in bone following fructo-oligosaccharide
consumption in rats
(278,280)
, while others have found no
effect
(280)
. P is mainly supplied by phytic acid (.85 % of
the total P in grain), which has a high affinity for
hydroxyapatite
(281)
. Indeed, the incidence of dental caries
has been hypothesised to be concomitant with the change
towards dietary habits of Western societies, as was shown
with African Bantu acquiring susceptibility to dental decay
as they adopted the European diet, through increased
consumption of cariogenic refined foods such as refined
sugar and white wheat bread in which a dominant caries-
preventing factor would be removed during the refining
process
(282 – 284)
. P, which is abundant in less refined wheat
flour, is involved in this effect
(285)
. Thereafter, several
studies on rats using organic and inorganic phosphates and
different Ca:P ratios also showed the cariostatic effect of
phytic acid
(282,286 – 289)
, possibly through its ability to affect
organic materials and the adsorption of bacteria to tooth
surfaces
(281)
, and also through its ability to be rapidly
adsorbed onto hydroxyapatite, forming a natural barrier
resistant to acid attacks
(290)
and thus to protect teeth from
demineralisation and the formation of cavities by causing
the desorption of salivary proteins from hydroxyapatite, the
first step in plaque formation
(281,291)
. But, later, Cole &
Bowen failed to show a significant effect of feeding
monkeys with phytic acid for 2 weeks on the physical
properties of plaques (such as dry and wet weights), or their
chemical properties (protein, carbohydrate, Ca, Mg and P
contents), or the microbial composition
(292)
. Further studies
in human subjects are therefore needed to ascertain the
cariostatic role of phytic acid, and perhaps of other cereal
bioactive compounds, in subjects on a regular whole-grain
cereal diet.
Whole-grain wheat also contains mammalian lignans
(0·2– 0·6 mg/100 g; Table 2) that seem to protect against
osteoporosis (Table 3), notably in the postmenopausal
period. Japanese women consuming high concentrations of
phyto-oestrogens were found to have fewer hip fractures
than women in the USA or Europe
(293)
. However, the effect
of lignans on bone health remains to be confirmed. To my
knowledge, no research has answered this particular issue of
the role of long-term whole-grain cereal consumption on
skeletal health and bone physiology.
Whole-grain cereals as a source of oligosaccharides.It
has previously been seen that whole-grain cereals are rich in
fibre (including RS) and oligosaccharides that may have
both a prebiotic effect by favouring the development of a
healthy microbiota
(294,295)
and that enhance mineral
absorption through hypertrophy of the gut epithelium
(70,71)
.
Thus, whole-grain wheat contains 1·9 %, its bran has 3·7 %
and the germ fraction 10·1 % of fructans (fructo-
oligosaccharide), raffinose and stachyose (Table 1). The
average wheat germ raffinose content is about 8 % and may
reach 10·9 %, which is quite high (Table 2). Whole-grain
wheat contains about 0·4 % of raffinose and wheat bran has
1·2 % (Table 2). The stachyose content is lower: 0·1 % in
whole-grain wheat, 0·2 % in wheat bran and no data are
available for wheat germ (Table 2). Raffinose is a
trisaccharide composed of galactose, glucose and fructose.
Stachyose is a tetrasaccharide formed with two galactose
molecules, one glucose and one fructose. To my knowledge,
there are no published data on the health effects of these
whole-grain cereal oligosaccharides, apart from the fact that
they are both considered to reinforce the fibre effect of
whole-grain cereals, by producing SCFA generally
favourable to large-bowel health. They are completely
fermented in vitro within 48 h in the presence of a piglet
faecal inoculum
(296)
. Rats fed a 3 % raffinose-based diet
for 21 d have a significantly reduced weight gain,
more lactobacilli and fewer streptococci, greater SCFA
production, and, interestingly, a lower plasma TAG
concentration with no effect on plasma cholesterol
(297)
.
However, it must be noted that fermented products (notably
breads) constitute an important part of the whole-grain
cereal food consumption of humans; and fermentation
may lead to the partial breakdown of fructans, raffinose and
stachyose by bacteria.
The specific action of phytosterol and of little studied
bioactive whole-grain cereal compounds:
a
-linolenic acid,
policosanol, melatonin and para-aminobenzoic acid. The
concentration of a-linolenic acid, an n-3 fatty acid (18 : 3)
with many positive health effects (Table 3), may reach 0·5 %
of wheat germ and almost 0·2 % of wheat bran (Table 1).
A diet containing about 2·7 g a-linolenic acid-rich wheat
germ oil per d has an anti-atherosclerotic effect in mildly
hypercholesterolaemic subjects; it acts by inhibiting
oxidative stress-mediated synthesis of CD40L (protein
involved in the progression of atherosclerosis with
inflammatory and prothrombotic properties)
(298)
. Wheat
Hypotheses for whole-grain cereal protection 89
Nutrition Research Reviews

germ contains 0·53 % a-linolenic acid, so one should
consume about 500 g/d to reach the 2·7 g tested in the present
study, which is not really realistic. However, a regular
consumption of wheat germ as a nutritional complement
and/or of wheat germ oil is nutritionally relevant.
Phytosterols, policosanol and melatonin, although present
at lower concentrations, also possess numerous positive
health effects (Table 3). Phytosterols, known for their
cholesterol-lowering effect in humans
(299,300)
, are particu-
larly high in wheat germ (430 mg/100 g) (Table 2) but their
health effects are not known when they come from whole-
grain cereals. Policosanol is a natural mixture of high-
molecular-weight aliphatic primary alcohols (C24 to C34)
in which octacosanol is the main compound
(301,302)
.
Although less nutritionally studied, policosanol is also a
lipid-lowering agent (for example, total and LDL-choles-
terol) in both human subjects and animals at levels of about
10 –20 mg daily, and it can also increase HDL-cholesterol
up to þ30 %
(303,304)
, making it a promising agent in CVD
prevention and treatment
(304)
. Whole-grain wheat contains
about 3 mg policosanol/100 g (Table 2). One recent study
has shown that eating chocolate pellets supplemented with
wheat germ policosanol (20 mg/d) for 4 weeks does not
reduce blood cholesterol or modify the blood lipid profile of
healthy human subjects
(305)
. A diet containing about 100 mg
policosanol/d eaten for 30 d reduced the increase in plasma
LDL-cholesterol in hypercholesterolaemic rabbits by
reducing cholesterol synthesis in the liver through increased
LDL catabolism
(306)
. Feeding policosanol to rats for up to
4 weeks (250 and 500 mg/kg per d) significantly renders the
lipoprotein fractions (VLVL þLDL) resistant to ex vivo
Cu-mediated oxidation
(307)
. In view of these results, the
policosanol content of whole-grain wheat seems too low
(about 3 mg/100 g) to significantly improve the blood lipid
profile in humans. Rather, it is probably the combined action
of the different cholesterol-lowering compounds of wheat
(for example, SCFA produced by undigestible carbo-
hydrates, soluble fibre, tocotrienols, phytosterols and
policosanol) that contributes to improve the blood lipid
profile to its optimum.
The concentration of the mammalian pineal hormone
melatonin, which can be extracted from numerous plants,
is about 0·3 mg/100 g in whole-grain wheat (Table 2)
(308)
.
This compound has a positive effect on human mood,
cognitive functions, prolonged sleep period and brain
neuromodulation
(309,310)
, but it may also be an antiox-
idant
(310)
and anti-carcinogen
(311,312)
(Table 3). The health
effects of melatonin in humans when originating from
whole-grain cereals are not known: as for policosanol and
other cholesterol-lowering compounds, due to the low
melatonin content of whole-grain wheat (Table 4), this is
probably the combined action of melatonin and of other
compounds acting positively on mental and brain health
that has to be considered first.
Para-aminobenzoic acid has also been detected in cereals.
Values are scarce and not recent: reported values are
0·34– 0·55, 1·34 and 0·852 mg/100 g for whole-grain
wheat, bran and germ fractions, respectively
(313,314)
.Para-
aminobenzoic acid is best known as a sunscreen agent
that protects the skin from UV radiation
(315)
, but it also
stimulates bacterial growth in the intestine and is an
intermediate in the bacterial synthesis of folates. Besides its
role in folate formation, para-aminobenzoic acid has long
been used to treat rickettsial infections and may lead to a
11·5 % decrease in serum cholesterol in man, when
consumed at 8 mg/d in the form of its Na salt
(316,317)
.Para-
aminobenzoic acid down-regulates N-acetyltransferase in
human cell cultures (peripheral blood mononuclear
cells)
(318)
– acetylation plays an important role in the
activation of several potential human carcinogens
(319,320)
,
and inhibits the production of thromboxane which partici-
pates in blood coagulation (anti-aggregatory effect) and in
increased arterial pressure through vasoconstriction
(321)
.
However, these studies used para-aminobenzoic acid
concentrations of 30 – 100 mM, about 4 –137 mg/l, which
is far higher than the quantity that can be obtained from
eating whole-grain cereal products, as whole-grain wheat
containing only 0·34– 0·55 mg para-aminobenzoic acid/
100 g (Table 2). Thus, like the other bioactive compounds
present at low concentrations in whole-grain wheat
(for example, policosanol and melatonin), the health benefit
of cereal para-aminobenzoic acid has to be considered
complementary to that of other cholesterol-lowering,
anti-carcinogenic and anti-aggregatory compounds.
The nutrigenomic approach
Nutrigenomics in nutrition is devoted to the study of the
influence of dietary interventions on gene transcription
(transcriptome), protein synthesis (proteome) and metab-
olites (metabolome, the whole set of metabolites) in cells,
body fluids and tissues
(322 – 326)
. One of the most important
objectives of nutrigenomics is to detect and identify early
metabolic disturbances and their regulation (for example, in
relation to oxidative stress or inflammation) that can lead to
more serious chronic diseases. The possibility of detecting
some diseases early could change clinical nutrition and
public health practices
(326)
. This implies studying the effects
of bioactive compounds in whole-grain cereals on gene
expression, protein synthesis and the metabolome. In the
field of nutritional studies, besides the measurement of usual
biomarkers such as plasma glucose (for example, GI) or
urinary lipid peroxides (oxidative stress index), it seems
particularly important to focus on the metabolome, which
reflects both the endproducts of metabolism and the changes
over time of metabolism following food consumption.
While many metabolomic studies have been done with
isolated compounds, notably in pharmacology for drug
toxicity
(327)
, very few have been done with complex food
products. In metabolomics and nutrition, only a few studies
have been performed
(328)
: to characterise the metabolic
effect of energy restriction
(329)
, vitamin deficiency
(330)
or of
intake of PUFA-rich oils
(331)
, antioxidant-rich foods such as
soya
(332)
, chamomile
(333)
and tea
(334)
, or of pure dietary
antioxidants such as epicatechin
(335)
, catechin
(336)
or ferulic
and sinapic acids and lignins
(271)
. Studies on rats have been
carried out using the metabolomic approach to explore the
metabolic fate and the effect on endogenous metabolism of
whole-grain and refined wheat flours
(230)
and of lignin-
enriched wheat bran lignins
(271)
. It has thus been shown that
whole-grain wheat flour consumption leads to significant
increases in liver betaine and GSH and decreases in some
A. Fardet90
Nutrition Research Reviews

liver lipids, but has no effect on conventional lipid and
oxidative stress biomarkers. It also causes a greater urinary
excretion of tricarboxylic acid cycle intermediates, aromatic
amino acids and hippurate (from phenolic acid degradation
in the colon). When the diet was changed to refined wheat
flour, a new metabolic balance was reached within 48 h, and
conversely from refined to whole-grain flour (Fig. 3)
(230)
.
The metabolomic approach also showed that rats did not
appear to metabolise lignins from wheat bran within 2 d of
the regimen, but they are likely to affect endogenous
metabolism through mechanisms which need to be
elucidated
(271)
. Results are convincing in that new metabolic
effects have been unravelled using this new open approach,
for example, the role of symbiotic microbiota in triggering
diet-induced mechanisms of steatosis
(337)
or some specific
metabolic pathway disturbances in diabetic rats
(338)
, thus
improving our understanding of diseases and the mechan-
isms responsible for them. However, more significant
conclusions could be drawn once the databases for
compound identification are completed and distributed. To
my knowledge, few if any studies have investigated the
effect of consuming complex whole-grain cereals and their
fractions on gene expression. The tools are now available to
study this, which would provide important information
about which gene-regulated metabolic pathways are
stimulated by the synergetic action of the bioactive
compounds in whole-grain cereals, not the restricted action
of isolated compounds. Thus, nutrigenomics should enable
us to better characterise the metabolic pathways affected
in vivo by the antioxidants in whole-grain cereals.
Conclusion
The metabolic fate and health effects of major compounds
such as lignin (up to 9 % in wheat bran), ferulic acid (up to
0·6 % in wheat bran), phytic acid (up to 6 % in wheat bran)
and betaine (up to 1·5 % in wheat bran) (Table 2) have been
little studied when originating from whole-grain cereals.
Yet, these three compounds may account for about 11 % of
wheat bran (Table 1), and therefore deserve to be studied
more. Wheat germ also merits greater attention since it
contains quite significant levels of bioactive compounds
such as a-linolenic acid (about 530 mg/100 g), GSH (about
133 mg/100 g), GSSG (about 69 mg/100 g), thiamin (about
1·75 mg/100 g), vitamin E (about 27·1 mg total tocols/
100 g), flavonoids (about 300 mg/100 g), betaine (about
851 mg/100 g), choline (about 223 mg/100 g), myo-inositol
(.11 mg/100 g) and phytosterols (about 430 mg/100 g)
(Table 2). It thus contains 2·5 % of vitamins and minerals,
at least 1·6 % of lipotropic compounds and 1·2 % of sulfur
compounds. All these compounds are involved in the new
hypotheses proposed here and their corresponding physio-
logical mechanisms. Based on past and new hypotheses, a
synthetic view of the mechanisms underlying the health
benefits of whole-grain cereals and their fractions can be
proposed (Fig. 4). The diagram purposefully illustrates the
complexity of the mechanisms involved and their obvious
synergy and interconnection in vivo. Due to this complexity,
whole-grain cereal bioactive compounds are listed in
Table 4, ranking according to the five major health outcomes
generally considered in the literature: body-weight regu-
lation, CVD, diabetes, cancers, and gut health; mental, brain
–10 0 10
–10
–5
0
5
10
14
15
16 17
19
21
25
27
13
14
15
16 17
19
21
23
25
27
14
15
16 19
21
23
25
27
28
13
15
16
17
19
21
25
27
17
14
23
28
23
LD1 (30·2 %)
LD2 (13·8 %)
RF diet
WGF diet
PP urine
PA urine
RF-WGF group
RF-WGF group
WGF-RF group
WGF-RF group
Fig. 3. Linear discriminant (LD) analysis score plot of the
1
H NMR urinary spectra highlighting the separation before, between and after the diet
change (days 14 –15) and between the urine sampling times (postprandial (PP) and post-absorptive (PA)). (- - - -), Refined flour followed by whole-
grain flour consumption (RF-WGF) group; (—), whole-grain flour followed by refined flour consumption (WGF-RF) group. Each polygon represents
the limits of the metabolic profile obtained for the ten rats of a given group at a given day and urine sampling time. Urine samples were collected
from days 13 to 28 (for details, see Fardet et al.
(230)
).
Hypotheses for whole-grain cereal protection 91
Nutrition Research Reviews

Fig. 4. Current and new proposed physiological mechanisms involved in protection by whole-grain cereals (adapted from Table 3). The dotted thin arrows ( >) indicate the link between whole-
grain bioactive compounds and protective physiological mechanisms, while the plain arrows (→) indicate the relationship between physiological mechanisms and health outcomes.
Whole-grain cereals
(bran, germ and endosperm)
Fermentable carbohydrates Lignin
Oligosaccharides
(fructans, raffinose,
stachyose, etc)
Cell wall
polysaccharides
(soluble, insoluble)
Resistant
starch
(RS1)
Bioactive compounds
Vitamins, minerals
and trace elements
(vitamins B and E, Zn,
Mg, Se, etc)
Phytochemicals
(polyphenols, carotenoids,
alkylresorcinols, phytic acid, γ-oryzanol,
phytosterols, melatonin, policosanol, etc)
Sulfur
compounds
and
α-linolenic
acid
Methyl donors
and lipotropes
(betaine, choline,
folates, inositols)
↑ Antioxidant and ↓
inflammatory status
↓ Homocysteinaemia
Large-bowel
health
↓ Cholesterolaemia
and/or
triacylglycerolaemia
and/or glycaemia
and/or insulinaemia
↑ Satiety and
gut transit
Cell signalling and/or
gene regulation
Body-weight
regulation
Type 2
diabetes
Cardiovascular diseases
Cancers
↓ Tumour growth and
↑ carcinogen
adsorption or dilution
Skeleton health Mental and/or
brain health
↑ Prebiotic
effect
↑ Immune
system
stimulation
Other specific mechanisms
↑ SCFA
(butyrate)
More or less intact
food structure
↑ Plasma
enterolactone
A. Fardet92
Nutrition Research Reviews

and skeleton health being new proposed ways to explore.
One important question remains: do bioactive compounds
exert the same effects when they are free compounds and
when they are in whole-grain cereals? This is notable,
because their bioavailability in whole-grain cereals is
probably lower than the free compounds (Table 2) and
because the quantities in whole-grain cereal products do not
match the daily human needs. Again, it is probably the
summed and combined action of all the bioactive
compounds on a particular physiological function (as
illustrated in Fig. 4 and Table 4) which leads to improved
specific physiological functions such as antioxidant status
and glucose homeostasis, especially when whole-grain
products are consumed daily, generating long-term health
benefits. This is why it is urgent to carry out further in vivo
studies both in rats and human subjects, to unravel the
complex mechanisms activated by the consumption of
highly complex foods such as whole-grain cereal products.
Intervention studies on human subjects consuming whole-
grain cereals are so rare that they should be carried out first.
The non-invasive characteristic and high potential of the
metabolomic approach for unravelling new metabolites and
metabolic pathways affected by a given diet and its ability to
explore the complexity inherent in metabolism means that it
should accompany the measurement of the usual biomarkers
in order to describe the metabolic actions of whole-grain
cereals in all their complexity. The mechanisms described in
Fig. 4 are complex, but are above all interconnected as in
the whole organism. Metabolomics therefore seems to be
the most appropriate tool for studying such an interconnect-
edness, and so provide a more realistic view of how whole-
grain cereal bioactive compounds act in synergy. For
example, inflammation, oxidative stress and immune
system-related metabolic pathways are generally all
involved in cancers, as is the case for other metabolic
diseases in which there is a progressive metabolic imbalance
following an unhealthy diet. Finally, genomic studies are
needed on the action of whole-grain cereals on gene
regulation, as bioactive compounds really exert their
physiological effects within the cell. While isolated free
bioactive compounds may be used for in vitro studies on cell
cultures, studies in animals and human subjects should use
an integrated ‘complex food approach’.
Cereals other than wheat
The present review discusses whole-grain wheat, since it is
one of the most widely consumed cereals, especially in
Western Europe. However, most of the bioactive compounds
in wheat are also present in other major cereals such as rice,
maize, oats, barley, sorghum and millet. The main
differences lie in the relative contents of each of these
compounds, their distribution in bran, germ and endosperm
and the proportions of the bran and germ fractions.
Nevertheless, compounds such as g-oryzanol, avenanthra-
mides and saponins are specific to cereals other than wheat.
The bran fraction
The proportion of the bran fraction varies with the cereal
type: for wheat, rice and maize, it is 10 – 16 % of the whole
grain. The bran fraction in rice contains about 15 –20 %
oil
(215,339)
. This oil is rich in bioactive compounds and
contains more than 100 different antioxidants, such as
lipoic acid, a powerful antioxidant
(340,341)
that helps
prevent cognitive deficits, is beneficial in the treatment of
Alzheimer’s disease
(342)
, and may protect against risk
factors of CVD
(343)
. Rice bran contains tocotrienols
(10·6 mg/100 g)
(344)
,g-oryzanol (281 mg/100 g)
(344)
and up
to 1·2 % phytosterols
(345)
such as b-sitosterol, all of which
may help improve the blood lipid profile and reduce the risk
of CVD
(346 – 348)
. Rice bran also contains up to 21 % dietary
fibres
(345)
. Maize bran has more dietary fibre than wheat and
rice bran, about 74– 79 %
(215,349,350)
. It contains about 4 %
phenolic acids, about 50 % heteroxylans and about 20 %
cellulose, and is almost devoid of lignins
(350)
.Itis
particularly rich in ferulic acid (up to 3 %), mainly in a
very resistant (to enzymes) bound form
(351)
. And, contrary
to wheat for which phytate is essentially in the bran fraction,
90 % of maize phytate is in the germ fraction
(352)
.
Some specific compounds
Some bioactive compounds are quite specific to certain
cereals: g-oryzanol in rice, avenanthramides and saponins in
oats, and, although present in other cereals such as wheat,
b(1 !3)(1 !4)-glucans in oats and barley, and alkylre-
sorcinols in rye. Their mechanisms of action and health
effects are shown in Table 3.
g
-Oryzanol in rice.g-Oryzanol is derived from rice bran
oil and is a mixture of substances including sterols and
ferulic acid, and at least ten phytosteryl ferulates (for
example, methylsterols esterified to ferulic acid). Its content
in whole-grain rice is 18 –63 mg/100 g (DW)
(339,353)
and in
rice bran 185– 421 mg/100 g, depending on the rice variety,
milling time, stabilisation process and extraction
methods
(344,354 – 356)
. Its antioxidant activity has been
demonstrated in vitro
(357)
. Its health effects are diversified,
with positive actions against CVD and hyperlipidaemia,
as shown in animal models through cholesterol-lowering,
lipid peroxidation reduction and anti-atherogenic
effects
(348,358 – 360)
and in human subjects
(361)
.
Avenanthramides and saponins in oats. Aventhramides
are specific polyphenols from oats. They are substituted
cinnamic acid amides of anthranilic acids and there are at
least twenty-five distinct entities
(362)
. Total avenanthramide
content in five oat cultivars (husked and naked) ranges
from 4·2 to 9·1 mg/100 g
(363)
, while the oat grain contains
4 –13 mg avenanthramide 1/100 g (the major avenanthramide),
again depending on the oat cultivar
(364)
. The avenanthramide
content in oat bran is 1·3–12·5 mg/100 g according to the
type of avenanthramide considered
(364,365)
. As polyphenols,
they are strong antioxidants both in vitro
(366,367)
and
in vivo
(140)
. They play a particular role in the prevention of
CVD due to their anti-inflammatory and anti-atherogenic
effects
(368)
, and by protecting LDL from oxidation, in
synergy with vitamin C, as shown on human LDL
(369)
.
Saponins are glycosides with a steroid or triterpenoid
aglycone
(370)
. They are especially found in oats,
which synthesise two families of saponins, the steroidal
Hypotheses for whole-grain cereal protection 93
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avenacosides and the triterpenoid avenacins
(371)
.The
saponin content, depending on the oat cultivar, seems to
be situated mainly within the endosperm and has been
shown to vary from 0·02 to 0·13 % (DW)
(372,373)
. Saponins
have a wide range of biological activities (about fifty are
listed by Gu
¨c¸lu
¨-U
¨stu
¨ndag & Mazza
(370)
), such as anti-
carcinogenic and hypocholesterolaemic
(374)
, stimulation of
the immune system
(375,376)
and cholesterol-lowering
(377)
.
However, it is not known whether all these properties could
be ascribed to cereal saponins. Saponins are also poorly
absorbed by the gut
(267)
.
b
(1 !3)(1 !4)-Glucan in barley and oats.Theb(1
!3)(1 !4)-glucan content of oats and barley is especially
high. Total, insoluble and soluble barley b-glucan contents
vary widely with the variety, the presence of hull (i.e. hulled
v. hull-less) and the amylose content
(378)
. Thus, the water-
soluble b-glucan content of barley is 0·5– 8·3 % (w/w,
DW)
(378 – 385)
, the insoluble fraction is 1·2–21·7 % (w/w,
DW)
(379 – 381)
and the total b-glucan content is 3·0– 27·17 %
(w/w, DW)
(379 – 381,383)
.Totalb-glucans contents vary
widely and might be attributable, in addition to variety
variability, to the method of extraction and possible
confusion in some studies where the soluble b-glucan
fraction seems to be confounded with the total b-glucans.
The soluble b-glucans content of naked oat grains is
3·9– 7·5 %, and in hulled oat grains it is 2·0– 7·5 % (w/w,
DW); the insoluble content of naked oat grains is
5·2– 10·8 % and that of hulled oat grains is 13·8– 33·7 %
(w/w, DW)
(381,386)
. Much work has already been done on the
health effects of b-glucans, particularly their glycaemia-
and cholesterol-lowering properties, having implications for
type 2 diabetes
(387)
and CVD
(56,388,389)
. As soluble viscous
fibre
(383)
, they slow the rate of gastric emptying, and the
diffusion of glucose and NEFA into epithelial cells for
absorption in both animals and humans
(56,389)
.However,a
recent study conducted on healthy subjects demonstrated
that muesli enriched with oat b-glucans had no more effect
on gastric emptying rate than did cornflake-based muesli,
despite its plasma glucose-lowering effect
(390)
.b-Glucans
are also positively involved in the protection against
cancers, especially through reactions with mutagenic agents
to prevent them interacting with DNA as shown in rodent
and human cell lines
(391)
.
Alkylresorcinols in rye. Alkylresorcinols are plant-derived
phenolic lipids, especially found in whole-grain cereals. Rye
contains the highest concentration of alkylresorcinols, which
can be twice that of wheat (up to 320 mg/100 g DW)
(392)
.
They are 1,3-dihydroxybenzene derivatives with an alkyl
chain at position 5 of the benzene ring, which gives them an
amphiphilic feature. They are apparently relatively well
absorbed within the small intestine (about 58 %; Table 2) of
ileostomates following the consumption of soft bread
enriched with rye bran and whole-grain rye crispbread
(393)
,
making them (either intact in plasma or as metabolites in
urine) potential biomarkers of whole-grain rye and wheat
intake
(394 – 396)
, especially for epidemiological research and
observational studies
(396,397)
. Their biological activity is
multifactorial
(396)
, from interacting with metabolic enzymes
(for example, inhibiting 3-phosphoglycerate dehydrogenase,
the key enzyme in TAG synthesis in adipocytes)
(398)
to
decreasing cholesterol in the rat liver
(399)
, to anticancer/
cytotoxic effects but almost exclusively in vitro
(400,401)
.
New bases for improving the nutritional
properties of cereal products
The elucidation of the mechanisms by which whole-grain
cereals protect our bodies, together with a better under-
standing of how bioactive compounds are released from the
cereal food matrix and delivered to the bloodstream, will
provide important information for the industrial develop-
ment of cereal products with improved nutritional qualities.
Surprisingly, the present supply of cereal products of a good
nutritional quality is still limited. I believe that the best way
to improve the nutritional quality of cereal products is to
combine the preservation of a relatively intact botanical
food structure (as far as the recipe allows it), a low-GI
feature and a high nutritional density of fibre and bioactive
compounds, by using less refined flour with a higher
extraction rate. These factors are important but probably not
sufficient to ensure that the right macro- or micronutrient
reaches the right site of absorption for an optimal
physiological effect. This is why more and more private
and public research is aimed at modelling the fate of
nutrients from complex foods within the intestine so as to
predict their bioaccessibility and thus control their delivery
for a specific physiological effect
(402 – 404)
.
Optimising and controlling the delivery of bioactive
compounds for improving health
There are great differences between the food content in a
defined nutrient and the percentage really metabolised, or
even absorbed. This is especially true for cereal products
where numerous factors linked to the food matrix may limit
the release of macro- and micronutrients. There is
increasing evidence that the physical structure of natural
cereal food matrices (for example, intact cereal kernels) or
the artificial microstructure of processed cereal products
may either favour or limit the bioavailability of nutrients,
and thus their nutritional effects. However, differences in
bioaccessibility – bioavailability of nutrients, particularly
micronutrients, at present cannot be correlated with
differences in long-term health effects, except for the
positive health effects of starch and its so-called slowly
digestible fraction
(405,406)
. The question is therefore: is there
a positive correlation between increased or decreased
bioaccessibility of a given nutrient and its health effect?
This probably depends on the nutrient considered and on the
health status of the subject. For example, the rapid release of
glucose from starch digestion into the bloodstream is
advantageous in some situations (for example, the urgent
need for glucose for brain or muscles to function, as for
immediate intellectual and physical efforts), and harmful in
other situations (for example, type 2 diabetes). The same
approach is now being developed for proteins (slow v. rapid
proteins) and lipids for which their physical state and/or
their physico-chemical properties may influence the release
of amino acids and fatty acids, respectively, into the
bloodstream. The resulting significant metabolic impact
A. Fardet94
Nutrition Research Reviews

could be used in some situations such as diabetic
subjects
(407)
, the elderly
(408)
and for patients on enteral
nutrition suffering from pancreatic insufficiency to ade-
quately hydrolyse lipids
(409)
.
In vitro bioaccessibility and in vivo bioavailability studies
with vegetables and whole-grain cereals and/or their
fractions have clearly shown that food structure affects the
bioavailability of polyphenols, carotenoids, minerals, trace
elements and vitamins (Table 2)
(403)
. Table 2 shows the
results of bioavailability studies on whole-grain wheat
products and wheat bran. Much data are still lacking: studies
exploring the bioavailability of compounds in whole-grain
cereals are scarce and the products are often consumed as
part of a complex diet that also supplies the same bioactive
compounds from other foods. For example, studies on
mineral or trace element bioavailability in rats often included
mineral mixtures that made it difficult to determine the exact
apparent absorption of the mineral supplied by the cereals.
Thus, radiolabelled cereal products should be used more
frequently to answer such questions. The few data obtained
show that bioactive compounds are far from being 100 %
bioavailable within the small intestine. No more than 5 % of
the ferulic acid in wheat bran is released into the small
intestine, so that most reaches the colon where it can exert an
antioxidant protective action on the gut epithelium. On the
other hand, there is convincing evidence that the small
proportion absorbed in the small intestine can affect cell
signalling and the activation or repression of some genes.
Thus, in a way similarly to starch, it seems that two fractions
of ferulic acid can be defined: the rapidly available ferulic
acid released and absorbed in the small intestine (i.e. free and
soluble-conjugated), and slowly available ferulic acid
gradually released mainly in the colon (i.e. ester-linked)
(264)
,
each fraction having its own health benefits.
Betaine (about 0·9 % of wheat bran; Table 1), unlike
ferulic acid, is probably much more bioavailable since it is
not bound to other constituents: is there a need to slow down
its release and to favour a fraction reaching the colon, for
example, for improving its anticancer effect
(410)
? The same
issue, that is the optimal bioavailability to reach, might be
questioned for polyphenols such as lignans and alkylre-
sorcinols, vitamins and minerals, and phytosterols. The
problem for phytic acid is slightly different; we need to
know the extent to which it is reasonable to pre-hydrolyse it
in order to combine a maximum mineral bioavailability with
its antioxidant effect in the gut against free radicals
produced by microbiota, and from its potential hypogly-
caemic effect as well.
Otherwise, the case of fibre is not yet resolved for whole-
grain wheat which contains more insoluble fibre than soluble
fibre (soluble:total fibre ratio is about 0·16; calculated from
Table 2): what would be the optimum ratio of soluble:total
fibre to reach? It is not known to what extent it would be
beneficial to increase the soluble fibre content, for example,
by pre-hydrolysing insoluble arabinoxylans to soluble
arabinoxylans (soluble:total arabinoxylans ratio is about
0·18; calculated from Table 2). Soluble fibres may be
beneficial to health by reducing the postprandial glucose
response through increased viscosity
(411)
(see Tables 3 and
4), but they may also be harmful, by, for example, increasing
the risk of colon cancer
(412)
.
Provided it has positive health benefits, the range by which
industrial processes can improve the bioaccessibility and
bioavailability of cereal bioactive compounds is therefore
large. This approach has been applied to starch with
success
(413)
, by controlling its delivery in the gut by
rendering it more slowly hydrolysed (i.e. slowly digestible
starch) within the small intestine, or by making it
inaccessible to a-amylase (i.e. RS), so that a fraction of
starch reaches the colon where it is fermented to the anti-
carcinogenic molecule butyrate, the preferred fuel for
colonocytes (see Whole-grain cereals and butyrate pro-
duction section). Technologists know how to modulate the
proportions of these three fractions in cereal products, i.e.
rapidly, slowly and indigestible starch. RS is representative
of the different ways it can be used by breeders and
technologists to control the delivering of a compound, i.e.
starch, within the digestive tract. It has been seen that the RS
content of whole-grain products may be very high, up to
12 % in ordinary barley kernels and even 22 % by combining
intact botanical structure with a high-amylose barley
variety
(54)
. The formation of RS can be technologically
favoured through starch encapsulation within the cereal food
matrix by protein or fibre networks (RS1), restricting starch
granule gelatinisation (RS2), the use of high-amylose cereal
varieties with a high content of retrograded starch (RS3) and/
or chemical modification such as acylation (RS4). RS is now
considered to be a prebiotic compound that can positively
modify microbiota growth in quality and quantity within the
colon
(414,415)
. If technologists may be able to modify
processing parameters such as temperature, extrusion
pressure, retrogradation and/or chemical modification to
increase the RS content, breeders can select high-amylose
cereal varieties
(294,416)
, amylose being more slowly digested
than amylopectin
(417,418)
.
The traditional use of fermentation and the
development of new technologies
Fig. 5 shows the ways in which the nutritional quality of
whole-grain cereals can be improved. There are mainly
three: the growing conditions, the genetic approach and
through technological processes.
Growing conditions. The growing conditions, for
example, the use of adequate fertilisers, can increase the
cereal content of Se, Mg, Fe and Zn
(419 – 421)
with possible
modified physiological effects in humans
(422)
. An increase
in environmental stress, for example, water stress, cold or
exposure to micro-organisms, may favour the synthesis of
antioxidants by the plant to combat this stress. This has
been shown with a-tocopherols, carotenoids and betaine in
wheat seedlings and sugarbeet roots under temperature- and
salt-stressed environments
(423,424)
.
Genetic approach. The genetic approach
(425)
using
conventional tools (indirect action on genes) such as
cross-breeding and hybridisation to combine varieties high
in some bioactive compounds, for example, Zn, Fe and
pro-vitamin A
(426,427)
, and/or low in others, for example,
phytic acid
(428,429)
, and non-conventional tools (direct
action on genes) such as genetic engineering to modify
Hypotheses for whole-grain cereal protection 95
Nutrition Research Reviews

Fig. 5. Ways for improving cereal product nutritional quality. RS, resistant starch.
Growing conditions Genetics Technological processes
• Se/Zn-
containing
fertilisers (e.g.
sodium
selenate)
• Organic
v.
conventional
farming
• N, P and K
fertilisers
Soil
composition/
fertilisation
Meteoro-
logical
conditions
Cross-
breeding and
hybridisation
Genetic
engineering
Milling Food shaping and cooking procedures
Effect on Se,
Mg, Fe, Zn,
vitamins
B1/B2 and
phytate
contents, etc
Variability in the bioactive compound contents according to
cereal varieties and genotypes selected (e.g. see ranges in
Table 2 for wheat)
Selection, combination and addition of specific traits:
– High amylose content → increases RS content
– Increase in mineral and/or vitamin contents (provitamin A)
– Increase in arabinoxylan or β-glucan contents
– Protein/amino-acid contents of the aleurone layer
– Low-phytic acid mutants → improve mineral bioavailability
– High phytase varieties or over-expression of phytase
– Low-protease inhibitor variety
• Whole grain
• Brans of different particle size
• Germ
• Shorts and middlings
• More or less refined flours
• Aleurone flour
• Germination
• Enzymic pre-
treatments
• Fermentation
(yeast
v.
leaven,
duration)
• Water content
• Temperature
• Pressure (e.g.
during extrusion)
More or less removal of bioactive compounds and fibre during
milling → isolation of the aleurone layer, bran and germ
fractions
More or less intact botanical structure and compact processed
food matrix → compound bioavailability
Increase in bioactive compound and soluble fibre contents, and
decrease in phytate content by activating enzymes
(sourdough)
Variation in RS content
Partial losses of bioactive compounds during food shaping and
cooking procedures
• Water
availability
(e.g.
irrigation)
• Solar
radiation
(intensity and
duration)
• Temperature
• Micro-
organisms
Dry fractionation
processes on whole
grain (roller
v.
stone
milling) or bran
(macromolecular
fractionation)
Effect of
stress
(drought,
cold, salt,
micro-
organisms,
etc) on
bioactive
compound
content (e.g.
antioxidant
levels)
Micronutrient-
dense species
selection
Different species,
e.g.
• Wild and primitive
wheats
• Durum
v.
soft
wheats
• Pigmented wheat
• Diploid
v.
tetraploids
Combining
different strains
of a species or
members of
different
species
GM species:
• Gene silencing
through RNA
interference
• Gene splicing
through
recombinant
DNA carrying
reporter gene
A. Fardet96
Nutrition Research Reviews

gene expression in relation to the nutrient synthesis and/or
metabolism can be used to improve the nutritional
quality of whole-grain cereals. By these means, the
amylose
(294,430,431)
,RS
(416)
, arabinoxylan
(432)
and miner-
al/vitamin
(419,433)
contents can be modified (i.e. increased in
most cases).
Development of new technologies. Besides growing
conditions and genetics, the third way of improving the
nutritional quality of cereal products is through technologi-
cal processes. The literature about them is plethoric, but it is
not an objective of the present paper to review them.
However, some key issues may be emphasised since they
allow optimising the health benefits of cereal by preserving
their nutritional density and food structure.
Increasing nutritional density in bioactive compounds
through germination, soaking and pre-fermentation of
whole-grain cereals and/or their fractions. Cereals are
usually processed in two main ways. The first is dry
fractionation followed by cooking under different con-
ditions of water content, temperature and pressure, as for
pasta, biscuits, breakfast cereals and other cereal products
widely consumed in Western countries. The second is
fermentation. This is generally used for whole-grain cereals
in more traditional procedures used for the many whole-
grain foods consumed in developed countries and several
alcoholic beverages (for example, beer, sake, whisky, etc)
consumed around the world
(434,435)
. A fermentative step
stimulates enzyme activities, which generally increases the
content of free bioactive compounds. Bread products
combine both approaches by using dry milling, fermentation
and cooking.
Due to the plasma cholesterol- and glucose-lowering
properties of soluble fibre and to its low content in wheat, due
to the numerous health effects of free ferulic acid
(261,262)
, and
due to the relative negative effect of phytic acid upon mineral
bioavailability
(217)
, different ways to pre-hydrolyse insolu-
ble fibre (for example, insoluble b-glucans or arabinoxylans)
into soluble fibre with endohydrolases
(150,436)
, ester-bound
ferulic acid into free ferulic acid with feruloyl-
esterases
(437,438)
, and phytic acid with exogenous or
endogenous phytases (i.e. through adding degrading fungal
and microbial enzymes, genetic engineering to over-express
phytase activity and food processes to activate endogenous
phytases
(217)
) have been considered with the objective of
increasing the bioactive potential of whole-grain cereal
foods, and in the end their nutritional value.
Practically, this could be also partly achieved by using
traditional and natural processes such as germination,
soaking and/or fermentation in a highly hydrated medium.
The fermentation of whole-grain cereals such as wheat,
maize, rice, sorghum and millet, either germinated or not,
often in combination with leguminous seeds (for example,
soyabean and chickpea), is widespread in developed
countries and the Orient for whole-grain cereal-based
beverages, gruels and porridges (for example, koko,doro,
ogi,akasa,tuo zaafi and togwa in Africa; idli in India; shoyu
in the Orient; chicha in South America; or kishk in Arabian
countries). It increases the nutritional density of the
products, protects against diarrhoea, is easy to apply, allows
a good preservation of the products (useful, for example, for
long displacements), may improve sensory quality and is
inexpensive
(439 – 441)
. Before fermentation, whole-grain
cereals are generally soaked, germinated, dried and coarsely
ground with a grinding stone
(440)
. Fermentation, by
activating enzymes, can release bound bioactive com-
pounds, synthetise new bioactive compounds, degrade anti-
nutrients and increase protein and starch digestibility
(439)
.
This is accompanied by numerous potential positive health
effects as recently reviewed, for example, improved gut
health or reduction of the rate of starch degradation
(442)
.
Thus, germination and fermentation have been used for
whole-grain wheat, rye, maize, sorghum and millet in order
to decrease the tannin and phytic acid contents, as both
compounds impair mineral bioavailability – leading to Fe-
deficiency anaemia in developing countries – and also in
order to increase the protein/gluten and starch digestibility
and the concentration of free amino acids by enhanced
proteolytic and a-amylolytic activities
(177,178,180,443 – 449)
.
Sourdough pre-fermentation (incubation for 24 h at 308C
with lactic acid bacteria) for whole-wheat flour degrades
about 60– 70 % of the phytic acid in bread dough (compared
with the initial flour content) in 4 h, so increasing Mg
bioaccessibility in vitro
(220,450)
and in vivo in rats
(451)
.In
another study, the type of starter for sourdough fermentation
and the type of raw material (native v. malted or germinated
rye) was shown to influence the content in bioactive
compounds of the resulting wholemeal rye flour. The
combination of germination and fermentation increased the
levels of folates (7-fold), free phenolic acids (10-fold), total
phenolic compounds (4-fold), lignans (3-fold) and alkylre-
sorcinols, but, to a lesser extent (,1·5-fold) the metabolic
activities of microbes together with the breakdown and
hydrolysis of some cereal cell walls were involved in this
effect
(452)
. Conversely, a 4 h sourdough fermentation of
whole-wheat flour leads to losses of alkylresorcinol
(453)
.
The fermentation of rye bran also enhances the free ferulic
acid and the solubilisation of pentosans through xylanase
activation
(454)
. Recently, an increased level of free ferulic
acid (about a 2-fold increase) has been reported within
whole-wheat dough pizza upon 18 and 48 h of fermenta-
tion
(455)
, as well as an increase in pentosan solubilisation
and prolamin hydrolysis in germinated rye sourdough
(446)
.
This could have practical nutritional implications as
discussed earlier with free ferulic acid, and also since the
soluble fraction of arabinoxylans has been shown to reduce
the glycaemic response in either healthy subjects
(411)
or in
those with impaired glucose tolerance
(456)
. On the other
hand, prolamin proteins are known to trigger coeliac disease
(autoimmune disorder due to gluten intolerance) and their
intensive pre-hydrolysis during germination and fermenta-
tion might render cereal products from these technologies
coeliac-safe
(446)
. Lastly, fermentation of whole-grain
cereals has been reported in several studies to increase the
content of available methionine and B vitamins, such as
thiamin, riboflavin, niacin, folates and pantothenic acid,
through the action of micro-organisms
(439)
. Despite all these
convincing results, the health benefits of hydrolysis and/or
the release of free bioactive compounds from whole-grain
cereal products through germination and/or fermentation
have not been sufficiently explored in human subjects.
Hypotheses for whole-grain cereal protection 97
Nutrition Research Reviews

The addition of a pre-fermentation step before processing
other cereal products, such as those usually widely
consumed in our Western societies (for example, breakfast
cereals or crackers), should also be studied more. A recent
study showed that adding a pre-fermentation step while
omitting steam cooking before wheat flake processing
preserved a satisfactorily nutritional quality by improving
the management of the feeling of hunger in the morning and
by moderately improving insulin economy, which could be
of interest for type 2 diabetic subjects
(457)
.
Whole-grain and wholemeal breads are generally made of
flours with an extraction rate of 85 – 90 % (type 80 flours).
Baking these flours does not sufficiently degrade phytic acid
or hydrate the fibre fraction. These flours also do not
generally contain the germ fraction, leading to a loss of B
vitamins. One alternative would be to add 20 to 30 % whole-
grain flour (with an extraction rate of 100 %) to white wheat
flour
(441)
. The whole-grain flour could be pre-fermented in a
strongly hydrated medium with leaven, and then reincorpo-
rated into white flour for baking to avoid hydration
competing with gluten and fibre. This adds the germ fraction
together with a significant increase in bioactive compounds
while partially degrading phytic acid
(441)
.Sourdough
whole-grain barley and wheat breads also reduce the
glycaemic response in healthy subjects through delayed
gastric emptying and possibly through a higher content of
RS, thus prolonging satiety with potential benefits in weight
control
(458,459)
.
Reinforcing the food structure cohesiveness in processed
cereal products. As preserving intact the botanical
structure in whole-grain cereal products and favouring
compactness of processed cereal products such as pasta
reduces the glycaemic and insulinaemic responses and
increases satiety, both of which are useful in the management
of type 2 diabetes and weight regulation, processed cereal
products with greater cohesiveness need to be identified. This
can be achieved artificially by creating protein and/or fibrous
networks in the food matrix to hinder enzyme accessibility to
its substrate within the small intestine
(460)
, by using intact
cereal kernels with a natural fibrous network
(51,54)
, and/or by
altering kneading intensities and proving time during baking
to obtain breads with a more dense crumb texture
(461)
. Some
have also tried, with relative success, to increase the
thickness of breakfast cereal flakes to reduce their glycaemic
and insulinaemic indices in healthy subjects
(462)
. The more
frequent use of more or less intact whole-grain cereal
kernels in food recipes seems the most promising, easiest
and cheapest way to explore by technologists.
Isolating the aleurone layer from the wheat bran
fraction. Since most of the bioactive compounds are in
the aleurone layer of the bran
(463)
and since the pericarp
(especially the outer fraction composed of cellulose,
penstosans and lignins is poorly digestible) may contain
contaminants (pesticides, mycotoxins and heavy metals),
antinutrient compounds, irritants for the digestive epithelium
(for example, lignins and insoluble fibre) and may limit the
bioavailability of bioactive compounds, different processes
for isolating the aleurone layer from wheat bran have been
investigated
(464 – 466)
, with the objective of reincorporating it
in cereal food recipes. This appears to be a new way of
enhancing the nutrition value of cereal products
(464,466)
. The
aleurone layer represents approximately 6 – 9 % of the
whole-grain wheat (Fig. 1). Some researchers have studied
the nutritional quality of aleurone flour, and shown that the
aleurone layer is a rich source of bioavailable folate in
humans
(467)
, that it lowers plasma homocysteine
(468)
,
increases SCFA production
(469)
, reduces colon adenoma in
azoxymethane-treated rats
(470)
, and that it is more digestible
(þ17 %) and fermentable (þ30 %) than wheat bran, so
yielding more butyrate
(471)
. It also has a higher antioxidant
activity than wheat bran (1·5-fold) and whole-grain wheat
(2-fold) in vitro
(132,464)
. However, isolating the aleurone
layer from the bran fraction means losing the health benefits
of lignins (mainly in the outer pericarp and testa layers of the
bran fraction), which seem to be significant and remain
largely unknown (see above). The long-term benefit of
consuming bran and aleurone fractions on several physio-
logical parameters and major health problems is therefore an
important issue that should be explored in order to assess the
real nutritional value of lignins and decide whether the few
negative physiological effects generally associated with
lignins are outweighed by their positive effects. The issue is
close to that of phytic acid, which also has both negative and
positive physiological effects. However, the issue of
preserving the lignin would be the most meaningful in the
case of organic whole-grain cereals which should not contain
pesticides in their outer pericarp.
Conclusions
The nutritional quality of cereal products may therefore be
improved by agricultural conditions, genetics and techno-
logical processes. Organic agriculture, genetics, the use of a
pre-fermentation step and of a more or less intact grain
structure are probably the most promising ways to preserve
and enhance the nutritional density of whole-grain foods.
Sourdough pre-fermentation could also be used for other
whole-grain cereal foods such as breakfast cereals. The first
parameter described in Fig. 5 is the milling process, and the
best way to preserve a high nutritional density in bioactive
compounds is to use flours with high extraction rates. It must
be remembered that whole-grain wheat, wheat bran and
wheat germ contain, respectively, at least 15, 52 and at least
24 % bioactive compounds and dietary fibre (Table 1).
Removing the bran fraction during milling and using it to
feed animals is therefore an issue to consider more seriously.
General conclusions
The importance of preserving bran and germ fractions
The bioactive compounds in whole-grain cereals are
unevenly distributed (Fig. 1). Some (mainly soluble fibre,
Se, some B vitamins, carotenoids and flavonoids) are
present in significant quantities in the endosperm, but most
are in the bran (especially the aleurone layer) and germ
fractions. This fact alone shows the importance of
preserving these fractions in cereal products, at least in
the most currently consumed forms of breads and breakfast
cereals, and to a lesser extent pasta, crackers and biscuits.
A. Fardet98
Nutrition Research Reviews

Some products consumed on special occasions (i.e.
generally not at breakfast, lunch or dinner), such as cakes,
pastries and viennoiseries, use very refined flours (extraction
rate of 70 –82 %), and it is probably not meaningful to use
less refined flours. To preserve the bran and germ fractions
means either reincorporating fractions later in the recipe or
using the whole-grain cereal so as to maintain its botanical
structure relatively intact during processing. However,
reincorporation of the bran and germ fractions implies
destroying the botanical structure with the loss of its health
benefits (for example, increased satiety or RS content),
unless technological processes can yield a cereal product
with an artificial compact food structure as for pasta
(472)
or
breads with decreased loaf volume
(461)
.
The concept of the ‘whole-grain package’
The content of individual bioactive compounds in whole
grain often seems too low for them to have any significant or
lasting physiological effects. It is becoming more and more
evident that the synergetic action of several bioactive
compounds contributes to health protection and/or the
maintenance of one physiological function, not just one
compound. Fig. 1 and Table 4 illustrate this concept of the
‘whole-grain package’: thus, obesity/body-weight regu-
lation, CVD, type 2 diabetes, cancers, gut, mental/nervous
system and skeleton health may be potentially protected by
at least, respectively, ten, thirty-four, seventeen, thirty-two,
ten, twenty-six and sixteen different bioactive compounds
and/or groups of compounds (i.e. oligosaccharides, tocols,
phenolic acids, flavonoids, saponins, inositols, g-oryzanol,
lignans and alkylresorcinols). Because of their many
protective bioactive compounds (at least twenty-six),
whole-grain cereals are particularly suitable for protecting
the body from CVD, cancers and mental/nervous system
disorders. The long-term protection against mental or
nervous system disorders by consuming whole-grain cereal
products therefore deserves to be studied in human subjects,
notably because depression ranks among the major causes
of mortality and disability with an overall prevalence of
5–8%
(274)
. It is also remarkable that at least thirty
compounds and/or groups of compounds may participate
in antioxidant protection through different mechanisms
(Tables 3 and 4), which approximately corresponds to a total
of at least 3·9, 13·4 and 6·3% of the whole-grain wheat,
wheat bran and germ fractions (Tables 1 and 2). As most
age-related and chronic diseases are associated with
increased oxidative stress, the regular consumption of
whole-grain cereal products should benefit all of us, but
particularly the elderly.
The importance of pesticides and mycotoxins
Since whole-grain cereals include by definition the outer
parts of the grain, they may contain pesticides and
mycotoxins (for example, zearalenone and deoxynivalenol
in wheat or fumonisin in maize). Their presence should not
decrease the benefits of bioactive compounds also mainly
contained in the outer layers. For example, there may be a
relationship between the consumption of fumonisin-
contaminated maize in some regions of the world
(for example, China and South Africa) and the occurrence
of oesophageal cancers
(473,474)
. However, more generally, the
consequences of long-term consumption of high quantities
of mycotoxin-contaminated cereal grains for human health
(i.e. toxicological effects) are not well known. The link
between some cancers and exposure to pesticides has been
well established, particularly among farmers
(475)
.Itis
therefore particularly relevant that recommendations for
the consumption of more whole-grain cereal products
should be accompanied by the production of less
contaminated cereals, such as those from organic agriculture
devoid of pesticides.
Perspectives
It is surprising to note that, although numerous epidemio-
logical surveys have shown a significant and positive
association between whole-grain cereal consumption and
the prevention of several chronic diseases, fewer studies
have been performed on the mechanisms involved. For
example, to my knowledge, no more than eleven studies
have examined the antioxidant hypothesis by postprandial
or intervention studies in human subjects to investigate the
antioxidant effect of whole-grain cereals, bran or germ
(136)
,
with only a recent postprandial study on human subjects
consuming wheat bran
(146)
. Therefore, there is a real gap
between observational studies and the elucidation of the
mechanisms involved. The mechanisms are certainly
complex, as has been seen. But more data are needed on
the mechanisms involved so as to prepare strong, convincing
arguments for an increased consumption of whole-grain
cereal products by the public, to better inform health
professionals about their health benefits, to favour their
marketing by the food industry and to develop new health
claims in the near future.
Acknowledgements
I thank Dr Christian Re
´me
´sy for his constructive criticism of
the manuscript and Professor Inger Bjo
¨rck (Department of
Applied Nutrition and Food Chemistry, Chemical Centre,
Lund University, Sweden) for allowing me to use her
original diagram (from the HealthGrain Project, European
Community’s Sixth Framework Programme, FOOD-CT-
2005-514008, 2005– 2010) that I have adapted for Fig. 2 of
the paper (see original diagram in the brochure ‘Progress in
HEALTHGRAIN 2008’ at http://www.healthgrain.org/pub/).
The English text of the manuscript has been checked by Dr
Owen Parkes.
There are no conflicts of interest and the present review
received no specific grant from any funding agency in the
public, commercial or not-for-profit sectors.
Colour versions of Figs. 1, 2 and 4 can be seen in the
online version of the paper.
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1025. Liu WK, Xu SX & Che CT (2000) Anti-proliferative effect
of ginseng saponins on human prostate cancer cell line.
Life Sci 67, 1297–1306.
1026. Mujoo K, Haridas V, Hoffmann JJ, et al. (2001)
Triterpenoid saponins from Acacia victoriae (Bentham)
decrease tumor cell proliferation and induce apoptosis.
Cancer Res 61, 5486–5490.
1027. Podolak I, Elas M & Cieszka K (1998) In vitro antifungal
and cytotoxic activity of triterpene saponosides and
quinoid pigments from Lysimachia vulgaris L. Phytother
Res 12, S70–S73.
1028. Zhang YW, Dou DQ, Zhang L, et al. (2001) Effects
of ginsenosides from Pana x g ins e ng on cell-to-cell
communication function mediated by gap junctions.
Planta Med 67, 417–422.
1029. Peng JP, Chen H, Qiao YQ, et al. (1996) Two new steroidal
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A. Fardet126
Nutrition Research Reviews

Appendix 1
References cited for evaluating the range (minimum and
maximum values) of bioactive compound contents in
whole-grain wheat, and wheat bran and germ fractions
(data for Tables 1 and 2)*
* All wheat varieties are included, i.e. durum, soft, hard,
spring, winter and pigmented wheats; all data are
expressed for 100 g of food. When data are expressed
on a DM basis within a reference with no indication of the
water content, results are converted on a fresh matter
basis considering a mean water content of 13 % for
whole-grain wheat, 10 % for wheat bran and 11·4 % for
wheat germ (means calculated from US Department of
Agriculture database for cereal grains and pasta
(479)
).
Whole-grain wheat
Reduced glutathione: 1·04– 5·74 mg/100 g
(210,480)
Oxidised glutathione: 0·86– 2·88 mg/100 g
(480)
Sulfur amino acids:
Methionine: 0·17– 0·24 g/100 g
(479,481 – 483)
Cystine: 0·19– 0·40 g/100 g
(479,482,483)
Sugars:
Monosaccharides: 0·26– 1·30 g/100 g
(484,485)
Sucrose: 0·60– 1·39 g/100 g
(482,484,485)
Total fibre (lignin, oligosaccharides, resistant starch and
phytic acid included): 9·0– 17·3 g/100 g
(482,486 – 492)
Insoluble fibre (lignin included): 9·5– 11·4 g/100 g
(482,488,490,493)
Soluble fibre: 1·1– 3·2 g/100 g
(482,488,490,491,493)
Cellulose: 2·1– 2·8 g/100 g
(479,482,494)
Hemicellulose: 8·6 g/100 g
(485)
Lignins: 0·9– 2·8 g/100 g
(485 – 487)
Fructans: 0·6– 2·3 g/100 g
(485,487,495 – 497)
Raffinose: 0·13– 0·59 g/100 g
(482,484,485,495,496)
Stachyose: 0·05– 0·17 g/100 g
(484,485)
Total arabinoxylans: 1·2 –6·8 g/100 g
(482,486,487,491,498,499)
Water-extractable arabinoxylans: 0·2 –1·2 g/100 g
(486,491)
b-Glucans: 0·2– 4·7 g/100 g
(485,486,491,492,498,500)
Phytic acid: 0·28– 1·50 g/100 g
(482,501 – 506)
Fe: 1·0– 14·2 mg/100 g
(426,427,479,482,483,502,504,507 – 511)
Mg: 17 –191 mg/100 g
(479,482,483,504,507,511,512)
Zn: 0·8–8·9 mg/100 g
(426,427,479,482,483,504,507,509,511 – 513)
Mn: 0·9– 7·8 mg/100 g
(479,482,483,504,507,509,511,512)
Cu: 0·09– 1·21 mg/100 g
(479,482,483,504,507,509,511 – 513)
Se: 0·0003– 3·0000 mg/100 g
(479,482,483,507,512,514,515)
P: 218 –792 mg/100 g
(479,482,483,507,511)
Ca: 7 –70 mg/100 g
(479,482,483,504,507,511)
Na: 2 –16 mg/100 g
(479,482,483)
K: 209 –635 mg/100 g
(479,482,483,504,507,511)
Thiamin (vitamin B
1
): 0·13 –0·99 mg/100 g
(314,479,482,483,516 – 519)
Riboflavin (vitamin B
2
): 0·04 –0·31 mg/100 g
(314,479,482,483,516– 518)
Niacin (vitamin B
3
): 1·9– 11·1 mg/100 g
(314,479,482,483,517,518)
Pantothenic acid (vitamin B
5
): 0·72– 1·99 mg/100 g
(314,479,482,483,518)
Pyridoxine (vitamin B
6
): 0·09– 0·66 mg/100 g
(314,479,482,483,516– 518)
Biotin (vitamin B
8
): 0·002– 0·011 mg/100 g
(314,482)
Folates (vitamin B
9
): 0·014– 0·087 mg/100 g
(314,482,518,520 – 522)
Tocols (vitamin E) ¼tocopherols þtocotrienols:
2·3– 7·1 mg/100 g
(482,492,523 – 526)
Total tocopherols: 1·06– 2·89 mg/100 g
(482,523 – 526)
a-Tocopherol: 0·34 –3·49 mg/100 g
(479,482,483,518,523 – 527)
Total tocotrienols: 1·09– 4·49 mg/100 g
(482,523 – 526)
Phylloquinone (vitamin K): 0·002 –0·020 mg/100 g
(479,482)
Total carotenoids: 0·044– 0·626 mg/100 g
(479,493,528 – 530)
b-Carotene: 0·005 –0·025 mg/100 g
(479,482,527,528)
Lutein: 0·026– 0·383 mg/100 g
(14,527 – 531)
Zeaxanthin: 0·009– 0·039 mg/100 g
(14,527,529 – 531)
b-Cryptoxanthin: 1·12 –13·28 mg/100 g
(14)
Total phenolic acids: 16 – 102 mg/100 g
(197,492)
Extractable (free and conjugated) phenolic acids:
5 –39 mg/100 g
(197,492)
Bound phenolic acids: 14 –78 mg/100 g
(197,492)
Total ferulic acid: 16– 213 mg/100g
(197,499,527,532 – 535)
Free/soluble-conjugated ferulic acid:
0·7– 4·9 mg/100 g
(527,532)
Bound ferulic acid: 14 – 64 mg/100 g
(197,527,532)
Total dehydrodiferulic acid:
1·5– 76·0 mg/100 g
(197,533,534)
Total dehydrotrimer ferulic acid: 2·6– 3·5 mg/100 g
(501,533)
Total flavonoids: 30– 43 mg catechin equivalents/100g
(14,532)
Free flavonoids: 2·15 –4·86 mg catechin equivalents/100 g
(14,532)
Bound flavonoids: 28 –40 mg catechin equivalents/100 g
(14,532)
Anthocyanins: 0·45– 52·60 mg/100 g
(308,493,536,537)
Isoflavonoids:
Daidzein: 2·1 mg/100 g
(538)
Genistein: 12·7 mg/100 g
(538)
Lignans: 0·199– 0·619 mg/100 g
(293,539,540)
Alkylresorcinols: 11·6– 128·8 mg/100 g
(392,393,396,399,492,501,541)
Betaine: 22 –291 mg/100 g
(227,483,542)
Total choline: 27– 195 mg/100g
(227,313,314,483,542)
Phytosterols: 57 –98 mg/100 g
(482,489,492,543 – 546)
Total D-chiro-inositol: 17 mg/100 g
(245)
Policosanol: 0·30– 5·62 mg/100 g
(547)
Melatonin: 0·2– 0·4 mg/100 g
(308)
p-Aminobenzoic acid (PABA): 0·34– 0·55mg/100 g
(313,314)
Wheat bran
a-Linolenic acid (18 : 3n-3): 0·16 g/100 g
(548)
Reduced glutathione: about 1·7 –19·4 mg/100 g
(549)
Oxidised glutathione: about 6·1 –21·4 mg/100 g
(549)
Sulfur amino acids:
Methionine: 0·20– 0·29 g/100 g
(479,482,483)
Cystine: 0·32– 0·45 g/100 g
(479,482,483)
Sugars:
Monosaccharides: 0·14 –0·63 g/100 g
(482,485)
Sucrose: 1·8– 3·4 g/100 g
(482,485,550,551)
Hypotheses for whole-grain cereal protection 127
Nutrition Research Reviews

Total fibre (lignin, oligosaccharides, resistant starch and
phytic acid included):
35·7– 52·8 g/100 g
(221,471,482,487 – 489,552 – 554)
Insoluble fibre (lignin included):
32·4– 41·6 g/100 g
(482,485,488,493,552,555 – 557)
Soluble fibre: 1·3– 5·8 g/100 g
(482,485,488,493,552,555)
Cellulose: 6·5– 9·9 g/100 g
(471,479,482,485,556,558 – 561)
Hemicellulose: 20·8 –33·0 g/100 g
(485,550,558 – 561)
Lignins: 2·2– 9 g/100 g
(221,485,487,552,556,558 – 562)
Fructans: 0·6– 4·0 g/100 g
(485,487,551)
Raffinose: 1·08– 1·32 g/100 g
(482,485,550,551)
Stachyose: 0·04– 0·36 g/100 g
(482,485,551)
Total arabinoxylans: 5·0 –26·9 g/100 g
(471,486,487,492,554,562,563)
Water-extractable arabinoxylans: 0·1– 1·4 g/100 g
(486,492,562,563)
b-Glucans: 1·1– 2·6 g/100 g
(471,485,562)
Phytic acid: 2·3– 6·0 g/100 g
(471,482,505,553,556,557,559,564– 566)
Fe: 2·5– 19·0 mg/100 g
(70,479,482,483,510,511,556,557,567)
Mg: 390 –640 mg/100 g
(70,479,482,483,511,559,568)
Zn: 2·5– 14·1 mg/100 g
(70,479,482,483,510,511,557,559,567,568)
Mn: 4 –14 mg/100 g
(70,479,482,483,511)
Cu: 0·84– 2·20 mg/100 g
(70,479,482,483,511)
Se: 2 –78 mg/100 g
(479,482,483)
P: 900 –1500 mg/100 g
(70,479,482,483,511,559,568)
Ca: 24 –150 mg/100 g
(70,479,482,483,511,559,568)
Na: 2 –41 mg/100 g
(70,479,482,483)
K: 1182 –1900 mg/100 g
(70,479,482,483,511)
Thiamin (vitamin B
1
): 0·506– 0·800 mg/100 g
(314,479,482,483)
Riboflavin (vitamin B
2
): 0·210– 0·800 mg/100 g
(314,479,482,483)
Niacin (vitamin B
3
): 13·6– 35·9 mg/100 g
(314,479,482,483)
Pantothenic acid (vitamin B
5
): 2·2 –4·1 mg/100 g
(314,479,482,483)
Pyridoxine (vitamin B
6
): 0·704 – 1·303 mg/100 g
(479,482,483,569)
Biotin (vitamin B
8
): 0·044 mg/100 g
(314,482)
Folates (vitamin B
9
): 0·088– 0·373 mg/100 g
(314,482,521,570)
Tocols (vitamin E) ¼tocopherols þtocotrienols:
9·5 mg/100 g
(482)
Total tocopherols: 2·4 mg/100 g
(482)
a-Tocopherol: 0·13 –2·84 mg/100 g
(479,482,483,571,572)
Total tocotrienols: 7·1 mg/100 g
(482)
Phylloquinone (vitamin K): 0·002 –0·083 mg/100 g
(479,482)
Total carotenoids: 0·25– 1·18 mg/100 g
(479,493)
b-Carotene: 0·003– 0·010 mg/100 g
(479,482,572)
Lutein: 0·050– 0·180 mg/100 g
(571,572)
Zeaxanthin: 0·025– 0·219 mg/100 g
(571,572)
b-Cryptoxanthin: 0·018 –0·064 mg/100 g
(571,572)
Total phenolic acids: 761 – 1384 mg/100 g
(533,573)
Extractable (free and conjugated) phenolic acids:
46 –63 mg gallic acid equivalents/100 g
(574,575)
Bound phenolic acids: 148– 340 mg gallic acid
equivalents/100 g
(574,575)
Total ferulic acid:
138–631 mg/100 g
(154,194,263,264,365,499,533,573,575,576)
Free/soluble-conjugated ferulic acid:
1·34– 23·05 mg/100 g
(154,194,571,572,574,575,577 – 579)
Bound ferulic acid: 122 –286 mg/100 g
(154,574,575)
Total dehydrodiferulic acid: 13 – 230 mg/100 g
(194,533,534,573)
Total dehydrotrimer ferulic acid: 15 –25 mg/100 g
(533)
Total flavonoids: 14·9 –40·6 mg/100 g
(193)
Anthocyanins: 0·9– 48·0 mg/100 g
(493,536,537,580)
Isoflavonoids:
Daidzein: 3·5 mg/100 g
(293)
Genistein: 3·8– 6·9 mg/100 g
(293,538)
Lignans: 2·8– 6·7 mg/100 g
(221,581)
Alkylresorcinols: 215 –323 mg/100 g
(365,392,582)
Betaine: 230 –1506 mg/100 g
(227,477,483,583,584)
Total choline: 74 – 270 mg/100 g
(227,314,477,483,583)
Phytosterols: 121 –195 mg/100 g
(482,543,546,585)
Total D-chiro-inositol: not detected
(245)
Policosanol: 0·11– 3·00 mg/100 g
(574,586)
PABA: 1·34 mg/100 g
(314)
Wheat germ
a-Linolenic acid (18 : 3n-3): 0·47– 0·59 mg/100 g
(25,548,587)
Reduced glutathione: about 19·4 –245·7 mg/100 g
(549)
Oxidised glutathione: about 15·3– 122·4 mg/100 g
(549)
Sulfur amino acids:
Methionine: 0·39– 0·58 g/100 g
(479,482,483)
Cystine: 0·35– 0·61 g/100 g
(479,482,483)
Sugars:
Glucose: ,390 –700 mg/100 g
(482,588 – 590)
Fructose: ,200 –801 mg/100 g
(482,588 – 590)
Sucrose: 7·7– 16·0 g/100 g
(482,550,588 – 592)
Total fibre (lignins, oligosaccharides, resistant starch and
phytic acid included): 10·6– 24·7 g/100 g
(482,487 – 489)
Insoluble fibre: 8·5– 18·6 g/100 g
(25,482,488)
Soluble fibre: 2·1– 6·1 g/100 g
(25,482,488)
Cellulose: 7·5 g/100 g
(550)
Hemicellulose: 6·8 g/100 g
(550)
Lignins: 1·3– 1·6 g/100 g
(487)
Fructans: 1·7– 2·5 g/100 g
(487)
Raffinose: 5·0– 10·9 g/100 g
(550,588 – 592)
Total arabinoxylans: 5·6– 9·1 g/100 g
(487,563)
Water-extractable arabinoxylans: 0·37 g/100 g
(563)
Phytic acid: 1·3– 2·2 g/100 g
(482,565,593)
Fe: 3·9– 10·3 mg/100 g
(479,482,483,589,594)
Mg: 200 –340 mg/100 g
(479,482,483,589,594)
Zn: 10 –18 mg/100 g
(479,482,483,589,594)
Mn: 9 –18 mg/100 g
(479,482,483,594)
Cu: 0·70– 1·42 mg/100 g
(479,482,483,589,594)
Se: 1 –79 mg/100 g
(479,482,483)
P: 770 –1337 mg/100 g
(479,482,483,589,594)
Ca: 36 –84 mg/100 g
(479,482,483,589,594)
Na: 2 –37 mg/100 g
(479,482,483,589,594)
K: 842 –1300 mg/100 g
(479,482,483,589,594)
Thiamin (vitamin B
1
): 0·8– 2·7 mg/100 g
(314,479,482,483)
Riboflavin (vitamin B
2
): 0·49– 0·80 mg/100 g
(314,479,482,483)
A. Fardet128
Nutrition Research Reviews

Niacin (vitamin B
3
): 4·0– 8·5 mg/100 g
(314,479,482,483)
Pantothenic acid (vitamin B
5
): 1 –2·7 mg/100 g
(314,479,482,483)
Pyridoxine (vitamin B
6
): 0·49– 1·98 mg/100 g
(479,482,483)
Biotin (vitamin B
8
): 17·0– 17·4 mg/100 g
(314,482)
Folates (vitamin B
9
): 0·14– 0·70 mg/100 g
(314,482,483,521)
Tocols (vitamin E) ¼tocopherols þtocotrienols:
23·1– 31 mg/100 g
(482,524)
Total tocopherols: 21·5– 30·6 mg/100 g
(482,524)
a-Tocopherol: 3·1 –22 mg/100 g
(482,483,524,525,591)
Total tocotrienols: 1·3– 1·6 mg/100 g
(482,524)
Phylloquinone (vitamin K): 0·003– 0·350 mg/100 g
(482)
b-Carotene: 0·062 mg/100 g
(482)
Extractable (free and conjugated) phenolic acids: about
51 mg/100 g
(194)
Total ferulic acid: 7– 124 mg/100 g
(194,499)
Free/conjugated soluble ferulic acid: about 18 mg/100 g
(194)
Total dehydrodiferulic acid: about 9 mg/100 g
(194)
Total flavonoids: 300 mg rutin equivalents/100g
(595)
Lignans: 0·490 mg/100 g
(596)
Betaine: 306 –1395 mg/100 g
(227,477,483)
1395 mg/100 g
(477)
: toasted
Total choline: 152 – 330 mg/100 g
(227,314,483)
152 mg/100 g
(477)
: toasted
Phytosterols: 410 –450 mg/100 g
(489,546,597)
Policosanol: 1·0 mg/100 g
(586)
PABA: 0·852 mg/100 g
(314)
Appendix 2
References for evaluating the range of compound bioavail-
ability and degree of fibre-type compounds fermentation
from whole-grain wheat, wheat bran and/or derived
products (data for Table 2).
Whole-grain wheat and derived products
Reduced glutathione: negligible in humans as free compound
(209)
Stachyose and raffinose:
Completely fermented in vitro within 48 h as free compound
(296)
97 –99 % in dogs
(598)
Total fibre: 34% in human subjects fed wholemeal bread
(599)
Cellulose: 20 % in human subjects fed wholemeal bread
(599)
Hemicellulose: 46 % in human subjects fed wholemeal
bread
(599)
Lignins: 4 % in human subjects fed wholemeal bread
(599)
Phytic acid: 54–79 % apparently degraded (faeces
recovery) in human subjects fed Hovis bread (whole
bread)
(600)
Rapidly and almost fully absorbed (about 79 %) in upper part of
the gastrointestinal tract of rats fed free compound
(601)
Small-intestinal phytases have high activity in rats and very
much lower activity in human subjects and pigs
(217)
Fe: 1– 20 % in human subjects fed usual diets
(204)
Mg:
70 % in rats fed whole-wheat flour
(219)
21 –28 % in human subjects fed brown bread diet
(602)
50 % in human subjects fed a typical diet
(603)
57·6 % in human subjects fed a standard diet
(604)
Zn:
16·6 % in human subjects consuming wholemeal bread
(605)
20 % in adult women consuming whole-wheat tortillas
(606)
35 % in rats fed whole-wheat flour
(219)
88·9– 94·6 % in rats fed whole-wheat flour
(607)
18·5 % in rats fed wheatmeal
(608)
60 –82 % in rats fed whole-grain wheat
(609)
30 –37 % in rats fed whole-wheat flour chapatti
(610)
Cu:
62 –85 % in human subjects fed whole-wheat bread
(611)
16·3– 16·5 % in rats fed free compound
(71,73)
Se:
81·1– 84·5 % in rats fed whole-wheat flour
(607)
73 –86 % in rats fed whole wheat as compared with sodium
selenite
(612)
100 % in rats fed whole-wheat flour as compared with
sodium selenite
(613)
P: 41– 55 % in human subjects fed brown bread diet
(602)
Ca:
81·7 % in human subjects fed whole-wheat bread
(614)
43 –44 % in rats fed whole-wheat flour chapatti
(610)
85·7– 92·8 % in rats fed whole-wheat flour
(607)
Thiamin (vitamin B
1
): 91 % in rats fed whole-wheat bread
compared with free thiamine mononitrate (100 %)
(519)
Riboflavin (vitamin B
2
): 95 % as oral supplement in human
subjects
(615)
Niacin (vitamin B
3
): low
(19)
Pantothenic acid (vitamin B
5
): about 50 % in human
subjects for average American diet
(616)
Pyridoxine (vitamin B
6
): 71– 79 % for an average American
diet compared with free compound
(616)
a-Tocopherol: 70 % in human subjects fed free
compound
(617)
Total ferulic acid: 3·2– 3·6 % urinary excretion in rats
(152)
Free/soluble-conjugated ferulic acid: at least that of wheat
bran in rat small intestine
(154)
Bound ferulic acid: a small fraction released within small
intestine by intestinal esterases
(618)
Alkylresorcinols: 60– 79 % from ileal samples in pigs fed
whole-grain rye bread
(619)
Phytosterols: weakly absorbed from the gut
(620)
Total free inositols (myo- and chiro-inositol):
Apparently high in rats fed free compounds for
myo-inositol
(256)
Apparently high in women fed free compounds for
chiro-inositol
(621)
Apparently high in old human subjects fed free compounds
for pinitol
(622)
Hypotheses for whole-grain cereal protection 129
Nutrition Research Reviews

Wheat bran
Total fibre:
55·6 % neutral sugars in human subjects fed wheat bran
(552)
34 % neutral sugars in human subjects fed wheat bran
(623)
35 –42 % neutral-detergent fibre in human subjects fed
coarse and fine bran
(561)
36·9 and 41·1 % in rats fed coarse and fine brans
(624)
39 % in rats fed wheat bran
(623)
49·1 % NSP in rats fed wheat bran
(625)
58·8– 65·0 % in pigs fed coarse and fine bran cell walls
(626)
41·5 % in pigs fed wheat bran-based diet
(627)
Insoluble fibre:
42·3 % in rats fed wheat bran
(625)
Cellulose:
6 –23 % in human subjects fed coarse and fine bran
(561)
7 % in human subjects fed wheat bran
(623)
13·8– 21·9 % in rats fed coarse and fine brans
(624)
24·1 % in pigs fed wheat bran-based diet
(627)
18·2– 23·7 % in pigs fed coarse and fine brans
(626)
Hemicellulose:
50 –54 % in human subjects fed coarse and fine brans
(561)
69·4– 74·4 % in pigs fed coarse and fine brans
(626)
46·5 % non-cellulosic neutral sugar residues in pigs fed
wheat bran-based diet
(627)
Lignins:
Undigested in humans
(561)
0 % in rats fed wheat bran
(623)
0 –4 % in rats fed processed wheat bran
(628)
Soluble fibre: 72·9 % in rats fed wheat bran fibre
(625)
Total arabinoxylans: 49·2% arabinose and 71·1 % xylose in
human subjects fed wheat bran
(552)
Phytic acid:
Phytate from wheat bran without phytase is almost not
absorbed at the intestinal level in humans
(629)
58 –60 % degraded into lower myo-inositol phosphates in
ileostomates fed raw wheat bran
(629,630)
and only 5 %
with phytase-deactivated wheat bran
(629,630)
58 % degraded in ileostomates and 25 % hydrolysed for
extruded wheat bran (loss of phytase activity)
(630)
Fe:
3·8 % in human subjects fed rolls made of wheat bran and
white wheat flour
(631)
Negative effect of bran on Fe absorption is not observed in
rats
(632)
Se:
About 60 % in rats fed wheat bran compared with sodium
selenite and selenomethionine biological value
(633)
80 % in rats fed wheat bran as compared with sodium selenite
(613)
P: 41– 56 % in human subjects fed sodium phytate þwhite
bread
(602)
Ca: 22·3 % in human subjects fed extruded wheat bran
cereals
(614)
Niacin (vitamin B
3
):
27– 38 % in human subjects fed a concentrate of bound
niacin from wheat bran
(634)
17 % in rats fed a concentrate of bound niacin from wheat
bran (cited in Carter & Carpenter
(634)
)
Pyridoxine (vitamin B
6
): unavailable in human subjects fed
wheat bran
(635)
Folates (vitamin B
9
): low in human subjects fed wheat
bran
(467)
Tocopherols/tocotrienols (vitamin E): not available in rats
fed wheat bran
(636)
Bound phenolic acids:
32·7 % in pigs fed a wheat bran diet
(627)
Partially and slowly solubilised from wheat bran within a
human model colon
(264)
Total ferulic acid:
,5 % in small intestine of rats fed wheat bran-based
diet
(154)
3·9 % urinary excretion in rats fed wheat bran
(152)
1·99– 5·65 % urinary excretion in human subjects fed high-
bran cereal
(196)
Free/soluble-conjugated ferulic acid:
High in rat small intestine fed wheat bran
(154)
27·77– 78·92 % urinary excretion in human subjects fed
high-bran cereal
(196)
Bound ferulic acid: a small fraction (%?) released within rat
small intestine by intestinal esterases following wheat
bran consumption
(618)
Dehydrodiferulic acid:
Undetectable in plasma of human subjects fed high-bran
cereal
(196)
Free diferulic acid can be absorbed from the gut in rats fed
wheat bran
(637)
Alkylresorcinols: 45– 71 % from ileostomy effluents in
human subjects fed rye bran soft/crisp bread
(393)
Phytosterols: weakly absorbed from the gut in human
subjects
(620)
Appendix 3
References for the physiological mechanisms and health
effects of bioactive compounds from whole-grain wheat,
and wheat bran and germ fractions (data for Tables 3 and 4)*
* Keywords relative to the physiological mechanisms
involved, health outcomes associated with bioactive
compounds and the corresponding reference(s) are given;
the models used, i.e. human, animals or in vitro cultured
cells, may be found in references cited.
a-Linolenic acid (18 : 3n-3):
Health and diseases
(638)
;CVD
(548,638 – 641)
; anti-athero-
sclerotic
(298)
; depression and anxiety
(642,643)
; plasma
TAG
(644)
; blood clotting, thrombosis, plasma lipid profile,
blood pressure and inflammation
(638)
; colon
(645)
and
breast
(646)
cancers; synthesis of cytokines and mito-
gens
(638)
; arachidonic acid (20 : 4n-6) and eicosanoids in
tissues (such as lung) and plasma phospholipids, and
A. Fardet130
Nutrition Research Reviews

synthesis of pro-thrombotic cyclo-oxygenase-derived
products (thromboxane A2 and B2, PGE2)
(647)
; immune
system, cell signalling and gene expression
(648,649)
Glutathione (reduced, GSH):
Health and diseases
(650)
; source of cysteine
(651)
; oral cancer,
anti-carcinogen, antioxidant effect, binding with cellular
mutagens and GSH transferase activity
(110)
; detoxifica-
tion of toxic electrolytic metabolites, xenobiotics and
reactive oxygen intermediates
(652)
; cellular immune
function
(208)
Sulfur amino acids:
Methionine:
Precursor of glutathione
(200)
; precursor of S-adenosyl
methionine
(653)
; neural tube defects
(654)
; colon can-
cer
(410)
; cognitive impairment in situation of folate
deficiency
(653)
; antioxidant activity
(655)
; lipotrope
(239)
Cystine:
Hair and nail development
(656,657)
; muscle wasting
(658)
;
antioxidant and cell signalling through reactive cysteine
residues in proteins
(659)
Total fibre
(18,46,58,266,660,661)
:
Type 2 diabetes risk
(662)
; risk of weight and fat gains; large
bowel cancer
(66,75,106,266)
; satiating effect; cholesterol,
bile acids, hormonal activity; immune system, toxicant
transit; production of SCFA in the colon
(663)
; SCFA,
growth of tumour cells, glutathione-S-transferase and
genotoxic activity of 4-hydroxynonenal
(664)
; dilution of
gut substances; energy content and glycaemic index of
foods; insulin response; free radicals
(93)
Insoluble fibre
(63)
: antioxidant-bound phenolics and
colon
(150)
; faecal wet and dry weight and faecal bulking
effect
(660)
; intestinal transit
(660)
Soluble fibre
(63)
: cholesterol; glucose and insulin
responses
(412)
; bowel health
(412)
Lignins:
Antioxidant
(112,149,224)
; dietary carcinogens adsorp-
tion
(69,266)
; bile acid reabsorption
(268)
; bile-salt seques-
trating agent
(107,108)
; fat absorption
(665)
; bile salt pool
size
(666)
; cholesterol turnover
(667)
; formation of carcino-
genic metabolites from bile salts
(269)
; precursor of
lignans
(221)
; anti-carcinogenic
(265)
Oligosaccharides (raffinose, stachyose and fructans)
(295)
:
Serum cholesterol
(46,80)
; gut modifier, enzyme modulator
and binding scavenger
(46)
Fructans
(668,669)
:
Lifespan and weight gain reduction
(670)
;prebiotic
(18)
;
microbiota
(671)
; growth of harmful bacteria, immune
system, absorption of minerals and synthesis of B
vitamins
(18)
; absorption of Ca, Mg and Fe
(18,72,73)
;
butyrate with cancer-preventing properties in the
colon
(672)
; growth of cancer cells
(672 – 674)
; glycaemia
and insulinaemia
(668)
; plasma TAG and total/LDL-
cholesterol
(675,676)
; lipid metabolism
(677)
; hepatic gluco-
neogenesis and glycolysis
(669)
Raffinose: weight gain
(297)
Arabinoxylans
(664)
:
Colon cancer growth and progression
(678)
;glucose
response
(411)
; chemoprotection and fermentation
products
(664)
; bile acids
(664)
; anti-proliferative properties
of butyrate
(679)
b-Glucans
(56)
:
Satiety
(54)
; blood sugar and gastric emptying rate
(18)
; blood
cholesterol
(18)
; hypoglycaemic and hypoinsulinae-
mic
(680 – 682)
; hypocholesterolaemic
(56,683)
;propionate,
hepatocyte lipid synthesis and cholesterolaemia
(684)
;
anti-carcinogenic
(391)
; immune system
(391)
; peripheral
blood monocytes and breast cancer
(685)
; anti-bacterial,
anti-parasitic, anti-fungal and anti-viral
(391)
Phytic acid:
Risk of colon
(100)
and breast
(101)
cancers; anti-cancer
agent
(95,99,106,686)
; antioxidant activity
(148)
; chelation
with various metals and Fenton reaction
(95)
; oxidative
damage to the intestinal epithelium and neighbouring
cells (cited in Slavin
(63)
); lipid peroxidation (cited in
Ferguson & Harris
(69)
); formation of ADP-iron-oxygen
complexes that initiate lipid peroxidation
(687)
; cellular
and nuclear signalling pathways
(95)
; plasma glucose
(cited in Yoon et al.
(182)
); insulin and/or plasma
cholesterol and TAG
(688 – 690)
; lipid levels in liver and
serum
(691)
; detoxification capacity of liver and levels of
GSH transferase and cytochrome P-450
(692)
; immune
response
(99)
; renal stones
(693)
; calcification of cardiovas-
cular system
(694)
; dental caries and platelet aggregation,
treatment of hypercalciura and kidney stones, and Pb
poisoning
(218)
; gene expression
(695,696)
Resistant starch
(697)
:
Physically inaccessible within small intestine
(18)
; prebio-
tic
(415)
; glycaemic response
(52)
; glucose metabolism and
plasma NEFA
(54)
; energy intake; SCFA, butyrate and
colon health, and SCFA and serum cholesterol
(65,80)
; lipid
oxidation and metabolism
(67)
; gallstones
(698)
Fe:
Neural functioning
(699)
; catalase cofactor
(700)
; lipid peroxi-
dation
(701)
; cofactor, enzymes and energy metab-
olism
(702)
; cellular energy metabolism
(703)
; infection
and mental function
(704)
; cognitive development and
intellectual performance
(705,706)
; collagen synthesis
(707)
;
bone health
(708)
; aerobic endurance exercise
(709)
; immu-
nity and infection
(710)
; vitamin metabolism
(711)
; serum
and liver TAG, phospholipid, and cholesterol
(701)
;
obesity
(712)
Mg
(204,603)
:
Metalloenzymes
(569)
; alkaline phosphatase (bone
health)
(713)
; antioxidant
(714)
; lipid peroxidation
(715)
;
hypertriacylglycerolaemia
(716)
and insulin resist-
ance
(156,159,715,717,718)
;diabetes
(157,719 – 722)
;glucose
uptake
(158)
, glucose metabolic clearance rate and insulin
response
(158,159)
, and oxidative glucose metabolism
(723)
;
platelet aggregability
(170)
; blood pressure regulation
(171)
;
coronary atherosclerosis and acute thrombosis
(169)
;
vascular function
(724)
; blood pressure
(725)
; cardiovascular
Hypotheses for whole-grain cereal protection 131
Nutrition Research Reviews

death rate
(726)
;osteoporosis
(727)
; angiogenesis and
inflammation
(728)
; stone formation
(729)
Zn
(204,700)
:
Alkaline phosphatase cofactor; antioxidant and superoxide
dismutase (SOD) cofactor
(730,731)
; skeletal growth and
maturation, and bone metabolism
(732)
; chemical inacti-
vator
(46)
; formation of active carcinogenic com-
pounds
(93)
; Zn-binding compounds and cancer cell
death
(733)
; oesophagus cancer
(734)
; Zn sensing receptor
and cell signalling
(735)
; immune functions
(736)
; inflam-
matory diseases and cell signalling mechanisms
(737)
; type
2 diabetes
(738)
; food intake
(739)
Mn
(569,700)
:
Antioxidant
(740)
; metalloenzyme constituent and enzyme
activation
(569)
; bone health
(732,741)
; manganese-SOD, NF-
kB activation and carcinogenic process
(742)
; manganese-
SOD and tumour growth
(743)
Cu
(204,700)
:
Antioxidant
(744)
; Cu-containing/binding proteins
(569)
; bone
health
(732,745)
; central nervous system dysfunction
(700)
;
immune and cardiac dysfunctions
(700,746,747)
;heart
health
(748,749)
; anti-cancer effect and DNA binding
(750)
;
risk of CHD
(751,752)
Se
(204)
:
Glutathione peroxidase and thioredoxin reductase cofactor;
antioxidant
(46,93,753)
; constituent of selenoproteins
(754)
;
tumour growth
(46,110,754,755)
; prostate and colon cancer
(cited in Reeves et al.
(633)
); susceptibility to carcino-
gens
(756,757)
; apoptotic effects
(758)
; anti-carcinogenic
(759)
;
cell membranes and oxidation damage
(760)
; anti-infec-
tive
(761,762)
; plasma, liver and erythrocyte GSH peroxi-
dase activity
(763)
; insulin resistance and vascular
endothelium
(764,765)
; platelet aggregation
(753)
P
(204,603,766)
:
Kidney health
(766,767)
; colorectal adenoma
(768)
; tooth devel-
opment
(769)
Ca
(204,603)
:
Colorectal cancer
(770,771)
; signal transduction element
(772)
;
cell signalling
(773)
; mitotic events and cell cycle
(774)
;
hypertension
(603,775,776)
;strokerisk
(777)
; diabetes
risk
(718)
; tooth development
(769)
; energy balance and
obesity
(778,779)
Na
(204)
:
Fluid balance
(780)
; blood pressure
(781)
; CVD
(782)
; osteo-
porosis and bone health
(783)
K
(204,784,785)
:
Diabetes risk
(718)
; insulin secretion
(157,786)
; blood pressure
(787)
;
CVD
(788 – 790)
; cardiac arrhythmias
(791)
; kidney health
(792)
and
stones
(793)
; bone health
(794)
; hypercalciura
(795)
Thiamin (vitamin B
1
)
(204,796,797)
:
Antioxidant
(798)
; glucose metabolism and Krebs cycle
(799)
;
mental and neuronal health
(800)
Riboflavin (vitamin B
2
)
(204,796)
:
Haematopoiesis
(801,802)
; gastrointestinal development
(803)
;
mental health
(804)
; vision
(805)
; cardiovascular protec-
tion
(806,807)
; cancer
(808,809)
Niacin (vitamin B
3
)
(204,796)
:
Hypolipidaemic and cardiovascular protection
(810,811)
;
cancers
(812)
;AIDS
(813)
; arthritis
(814)
; catecholamine
stimulation of lipolysis
(815,816)
(citedinMarcus
et al.
(817)
and Figge et al.
(810)
)
Pantothenic acid (vitamin B
5
)
(204,796)
Pyridoxine (vitamin B
6
)
(204,796)
:
Colorectal cancer
(818)
; asthma and CVD
(819)
; impaired
homocysteine metabolism and occlusive arterial
disease
(820)
Biotin (vitamin B
8
)
(204,796,821 – 823)
:
Regulation of gene expression
(824)
; cell proliferation
(825)
;
dermatological abnormalities; immune response
(826,827)
Folates (vitamin B
9
)
(204,796,828)
:
Plasma homocysteinaemia
(829,830)
;neuraltube
defects
(273,831)
; biochemistry of nucleic acid
(828)
; colon
cancer risk
(410,832)
; anti-carcinogenic
(833,834)
; megalo-
blastic anaemia
(835)
; depression
(274–276)
; fertility
(836)
;
lipotrope
(239)
; methylation and related epigenetic effects
on gene expression
(837)
Tocopherols and tocotrienols (vitamin E)
(204)
:
Cardiovascular risk
(838,839)
; antioxidant
(840 – 842)
; Se and
reduced state (cited in Slavin
(63)
); formation of
nitrosamines (cited in Slavin
(63)
); formation of carcino-
gens (cited in Slavin et al.
(663)
); apoptosis
(843)
Tocopherols:
Non-antioxidant effects
(844)
; chemical inactivator (cited in
Kohlmeier et al.
(93)
); protein kinase C regulation
(844,845)
;
monocyte superoxide anion and IL-1
(846)
;gene
expression and cell signalling
(844,847,848)
; peroxynitrite-
derived nitrating species
(849,850)
; cell proliferation
(851)
;
pancreatic carcinogenesis
(852)
; type 2 diabetes-induced
oxidative stress
(853)
Tocotrienols
(347)
:
Neurodegeneration and immune responses
(347)
;
cancer
(94,347,851)
; cholesterol
(347)
; risk of heart disease;
obesity and osteoporosis/bone calcification
(854,855)
Phylloquinone (vitamin K)
(204,700,856)
:
Coenzyme and formation of g-carboxyglutamate resi-
dues
(857)
; osteoporosis
(858)
; atherosclerosis
(859)
b-Carotene:
Cancer
(860)
; colon cancer
(106,861)
; lung cancer
(862 – 864)
;
tumour growth suppressor
(824,865)
; apoptosis
(866)
;
immune function
(867)
; antioxidant
(868)
; coronary artery
disease risk
(869)
Lutein (xanthophyll family)
(870,871)
:
A. Fardet132
Nutrition Research Reviews

Ocular function
(872)
; age-related macular degeneration
(873)
;
cataract
(874)
; macular pigment density
(875)
;antioxi-
dant
(871,876,877)
; CVD, stroke and lung cancer
(862,863)
;
skin protection
(878)
; colon cancer
(879)
; atherosclerosis
(880)
Zeaxanthin (xanthophyll family):
Age-related macular degeneration
(873)
; cataract
(881)
; macu-
lar pigment density
(875)
; antioxidant
(871,876,877)
; CVD and
stroke (cited in Anonymous
(876)
); skin protection
(878)
;
lung cancer
(862)
b-Cryptoxanthin:
Anabolic effects on bone components and bone loss/resorp-
tion
(882,883)
; anti-proliferative/chemopreventive agent and
lung cancer
(863,884 – 886)
; carcinogenesis
(887)
; control of
differentiation and apoptosis
(888)
; antioxidant (cited in
Castelao & Olmedilla
(889)
)
Phenolic acids:
Antioxidant
(890)
; insulin secretion
(891)
; plasma glucose,
insulin, cholesterol and TAG (cited in Slavin et al.
(46)
);
cancer and action as blocking compounds
(892)
;
carcinogens binding to targets and release of phenolic-
bound antioxidant
(150,893)
; tumour growth suppressor
(cited in Slavin et al.
(46)
and Thompson
(173)
); enzyme
modulators (cited in Slavin et al.
(46)
); dyslipidaemia,
hepatosteatosis and oxidative stress
(894)
; cell signal-
ling
(186,189)
Ferulic acid
(104,261,262)
:
Antioxidant
(895)
; HDL-cholesterol
(896)
; hyperlipidae-
mia
(897)
; anti-carcinogenic
(69)
, for example, tongue
cancer
(892)
; hypotensive and vascular relaxation
(898)
;
hypoglycaemia
(899)
; neurodegenerative disorders (cited
in Barone et al.
(104)
)
Flavonoids:
Antioxidant
(69,890)
; enzyme modulator, antioxidant and
tumour growth suppressor (cited in Kohlmeier et al.
(93)
);
anti-carcinogenic (cited in Ferguson & Harris
(69)
and
Thompson
(173)
); CVD
(900)
; signalling molecules
(188,189,191)
;
cell signalling, gene regulation, angiogenesis and other
biological processes
(214)
; inflammation
(189)
; platelet aggre-
gation
(901)
; anti-microbial
(902)
; production of urate
(214)
;
bone resorption
(903)
; dyslipidaemia, hepatosteatosis and
oxidative stress
(894)
Anthocyanins:
Antioxidants
(904 – 906)
; anti-inflammatory
(907,908)
;
anti-carcinogenic
(909,910)
; hypoglycaemic
(911)
Isoflavonoids:
Hormone-like diphenolic phyto-oestrogens
(293)
; cancer and
atherosclerosis
(293)
; osteoporosis
(293)
; trabecular connec-
tivity and thickness
(912)
Lignans:
Hormone-like diphenolic phyto-oestrogens
(293)
; antioxi-
dant
(18,45,69,96)
; hormonally mediated diseases
(293)
;
cell proliferation
(97)
; tumour growth suppressor
(913)
;
precursors of enterolactone and enterodiol
(96,914,915)
;
cancers
(96)
; osteoporosis
(293)
; rheumatoid arthritis, gastric
and duodenal ulcers, skin health, diuretic, antagonistic
action of platelet-activating factor receptor and action on
superoxide production (cited in Thompson
(173)
)
Alkylresorcinols
(396)
:
Antioxidant
(916,917)
; anti-carcinogenic, anti-microbial, anti-
parasitic and cytotoxic, structure and metabolism of
nucleic acids, phospholipid bilayer properties
(400)
; anti-
mutagenic
(918)
; 3-phosphoglycerate dehydrogenase (key
enzyme of TAG synthesis in adipocytes)
(398)
; liver
cholesterol
(399)
Betaine:
Fatty deposits in the liver and hyperhomocysteinaemia
(919)
;
osmoprotectant, performance (for example, athletic)
(225)
;
organic osmolyte
(920)
;CVD
(921)
; homocysteine and
inflammatory markers related to atherosclerosis
(C-reactive protein and TNF-a)
(922,923)
; sulfur amino
acid homeostasis
(924)
; colorectal adenoma
(121)
; antiox-
idant and non-alcoholic fatty liver diseases
(925)
Choline
(226,796)
:
Brain development and normal memory function
(926–928)
;
plasma homocysteine level
(929)
; antioxidant
(930)
; carnitine
conservation
(931)
; body fat and fatty acid oxidation
(932,933)
;
precursor for the cell membrane phospholipids phosphatidyl-
choline
(934)
, sphingomyelin
(226,935)
, brain acetylcholine
(936)
and for platelet-activating-factor formation
(937)
; synthesis and
release of acetylcholine
(936,938)
; lipid metabolism, hepatic
secretion of VLDL, nerve function and integrity of cell
membranes
(226)
;neuraltubedevelopment
(939)
; lipotrope and
methyl donor
(240)
; DNA hypomethylation and tumour
development in the liver
(226,239,258,940)
; epigenetic regulator
of gene expression
(941)
Phytosterols
(18,942,943)
:
Total and LDL serum cholesterol
(942,944 – 947)
;micelle
formation, dietary and biliary cholesterol absorption and
LDL-cholesterol
(948)
; vascular smooth muscle cell
hyperproliferation
(949)
; immunosuppression associated
with excessive physical stress
(950)
; anti-inflammatory,
anti-pyretic, immunomodulator and anti-diabetic (cited in
Brufau et al.
(942)
); anti-diabetic and hypoglycaemic
(951)
b-Sitosterol:
Growth of colon cancer line
(952,953)
; prostate cancer
(954)
;
carcinogen-induced neoplasia (cited in Wattenberg
(110)
);
apoptosis
(955)
through caspase activation
(956)
Inositols:
Chiro-inositol:
Insulin, signal transduction and mimetic of insulin
action
(957)
; type 2 diabetes
(245,958 – 961)
; ovulatory func-
tions and serum androgen concentrations, blood pressure
and plasma TAG
(621)
; folate-resistant neural tube
defects
(962)
; pinitol and glucose metabolism
(622)
Myo-inositol:
Metabolism
(963)
; TAG and total lipid liver, hepatic activities
of glucose-6-phosphate dehydrogenase, malic enzyme,
fatty acid synthetase and citrate cleavage enzyme
(242,964)
;
Hypotheses for whole-grain cereal protection 133
Nutrition Research Reviews

conversion into chiro-inositol and precursor for several
phospholipids (cited in Larner
(957)
, Novak et al.
(965)
and
Pak et al.
(256)
); mental health
(966,967)
; osmotic demyeli-
nation syndrome
(968)
; volume regulation during persistent
osmotic stress
(969)
; cancer
(686)
; diabetic polyneuropathy
and nerve conduction
(970)
; intestinal lipodystrophy
(963)
Policosanol:
Octacosanol in human health
(302)
;CVD
(304)
; lipid, cholesterol
and LDL
(303,306,971 – 973)
; cholesterol biosynthesis and LDL
catabolism
(973)
; hydroxymethylglutaryl-coenzyme A (HMG-
CoA) reductase
(974)
; LDL peroxidation
(307)
;membranelipid
peroxidation
(975)
; lipid metabolism
(301)
; platelet aggregation
and thromboxane generation, endothelial damage and foam
cell formation
(976,977)
; cytoprotection in gastric ulcer
(978)
;
athletic performances
(979)
; cardiac events, and cholesterol and
anti-aggregatory effects (cited in Taylor et al.
(302)
); smooth
muscle cell proliferation
(980)
; anti-fatigue drug
(302)
Melatonin
(981)
:
Mood, happiness, sleep and brain neuromodulation in
Alzheimer’s disease
(309,310)
; antioxidant
(982,983)
; corticoid
receptor
(984)
; scavenger of hydroxyl radicals
(985)
; brain
GSH peroxidase activity
(986)
; gene expression for
antioxidant enzyme
(987)
; sleep– wake regulation
(309,988)
;
DNA damage
(989)
; lifespan
(990)
; oncostatic role and anti-
proliferative effect
(311,312)
; cancers
(991)
para-Aminobenzoic acid (PABA):
Acetylation in blood and other tissues
(315,321,992,993)
; peroxisomal
b-oxidation and PABA acetylation
(316)
;N-acetyltransferase
regulation
(994)
; acetylation
(319,320)
; rickettsial infections
and collagen diseases
(995)
; serum cholesterol
(995)
;folate
formation
(316)
; treatment of vitiligo, leukaemia, rheumatic
fever and in rickettsial diseases(cited in Barbieri et al.
(316)
);
production of thromboxane
(321)
;anti-aggregatory
(996)
;
UV protection of the skin (cited in Barbieri et al.
(996)
and Wang et al.
(315)
); liver folic acid metabolism (cited
in Russell et al.
(997)
)
g-Oryzanol
(361)
:
Cholesterol and rice bran oil
(998)
; cholesterol absorption
and aortic fatty streaks
(348,358)
; lipid metabolism
(999)
;
autonomic nervous unbalance and menopausal troubles
(climacteric disturbance)
(999,1000)
; anti-ulcerogenic
(1001)
;
antioxidant
(357,360,1002)
; gene expression and oxidative
stress
(1003)
; glycaemia control
(1004,1005)
; platelet aggrega-
tion
(1006)
; anxiety and stress ulcer
(1001,1007 – 1009)
Avenanthramides:
Anti-inflammatory and anti-atherogenic
(368)
;smooth
muscle cell proliferation and NO production
(1010,1011)
;
antioxidant
(140,367,369)
Saponins
(370,1012,1013)
:
Hypercholesterolaemia
(173,374,377,1014)
; lipase activity and fat
absorption
(1015)
; transcriptional activity of Cu,Zn-SOD
gene
(1016)
; scavenger and superoxides
(1017)
; hypoglycae-
mia
(1018,1019)
; gastric emptying rate and glucose transport
across the brush border of the small intestine
(1018,1020)
;anti-
fungal
(374)
; anti-viral
(1021)
;diabetes
(1022)
; anti-inflamma-
tory
(1019)
; anti-carcinogenic
(374)
; tumour growth and cytostatic
effect
(1013,1023 – 1027)
; bile acid binding (cited in Mimaki
et al.
(1013)
); cell-mediated immune system and antibody
production
(375)
; nervous system functioning
(1012,1028)
;blood
coagulation
(1029)
A. Fardet134
Nutrition Research Reviews