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