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Journal of Lipid Research Volume 54, 2013 2325
Copyright © 2013 by the American Society for Biochemistry and Molecular Biology, Inc.
of the metabolic syndrome, the exact mechanisms under-
lying the different comorbidities are not yet completely
known. Recently, dietary fi bers have raised much interest,
as they exert benefi cial effects on body weight, food intake,
glucose homeostasis, and insulin sensitivity ( 2–4 ). Epidemio-
logical studies show an association between a higher fi ber
intake and a reduced risk of irritable bowel syndrome, in-
fl ammatory bowel disease, cardiovascular disease, diabetes,
and colon cancer ( 1 ).
Humans lack the enzymes to degrade the bulk of dietary
fi bers. Therefore these nondigestible carbohydrates pass
the upper gastrointestinal tract unaffected and are fer-
mented in the cecum and the large intestine by the an-
aerobic cecal and colonic microbiota. Fermentation results
in multiple groups of metabolites [elegantly reviewed by
Nicholson et al. ( 5 )] of which short-chain fatty acids (SCFAs)
are the major group ( 6 ). To the microbial community
SCFAs are a necessary waste product, required to bal-
ance redox equivalent production in the anaerobic en-
vironment of the gut ( 7 ). SCFAs are saturated aliphatic
organic acids that consist of one to six carbons of which
acetate (C2), propionate (C3), and butyrate (C4) are
the most abundant ( 95%) ( 8 ). Acetate, propionate, and
butyrate are present in an approximate molar ratio of
60:20:20 in the colon and stool ( 9–11 ). Depending on the
diet, the total concentration of SCFAs decreases from 70
to 140 mM in the proximal colon to 20 to 70 mM in the
distal colon ( 12 ). A unique series of measurements in
Abstract Short-chain fatty acids (SCFAs), the end products
of fermentation of dietary fi bers by the anaerobic intestinal
microbiota, have been shown to exert multiple benefi cial
effects on mammalian energy metabolism. The mechanisms
underlying these effects are the subject of intensive research
and encompass the complex interplay between diet, gut mi-
crobiota, and host energy metabolism. This review summa-
rizes the role of SCFAs in host energy metabolism, starting
from the production by the gut microbiota to the uptake by
the host and ending with the effects on host metabolism.
There are interesting leads on the underlying molecular
mechanisms, but there are also many apparently contradic-
tory results . A coherent understanding of the multilevel net-
work in which SCFAs exert their effects is hampered by the
lack of quantitative data on actual fl uxes of SCFAs and met-
abolic processes regulated by SCFAs.
In this review we ad-
dress questions that, when answered, will bring us a great
step forward in elucidating the role of SCFAs in mammalian
energy metabolism. —den Besten, G., K. van Eunen, A. K.
Groen, K. Venema, D-J. Reijngoud, and B. M. Bakker. The
role of short-chain fatty acids in the interplay between diet,
gut microbiota, and host energy metabolism. J. Lipid Res.
2013. 54: 2325–2340.
Supplementary key words nutritional fi ber • bacterial short-chain fatty
acid metabolism • short-chain fatty acid fl uxes and concentrations
The decrease in physical exercise and increase in en-
ergy intake, especially seen in the Western world, disrupts
the energy balance in humans and can lead to a complex
of symptoms collectively denoted as the metabolic syn-
drome. The key characteristics of the metabolic syndrome
are obesity, loss of glycemic control, dyslipidemia, and hy-
pertension ( 1 ). Due to the complex multifactorial etiology
This work was funded by the Netherlands Genomics Initiative via the Nether-
lands Consortium for Systems Biology.
Manuscript received 18 January 2013 and in revised form 21 June 2013.
Published, JLR Papers in Press, July 2, 2013
DOI 10.1194/jlr.R036012
The role of short-chain fatty acids in the interplay
between diet, gut microbiota, and host energy
metabolism
Gijs den Besten , *
,†
Karen van Eunen , *
,†
Albert K. Groen , *
,†,§
Koen Venema ,
†,
**
Dirk-Jan Reijngoud , *
,†,§
and Barbara M. Bakker
1,
*
,†
Center for Liver, Digestive, and Metabolic Diseases, Department of Pediatrics* and Department of
Laboratory Medicine,
§
University of Groningen, University Medical Center Groningen , Groningen, The
Netherlands ; Netherlands Consortium for Systems Biology ,
†
Amsterdam, The Netherlands ; and TNO ,**
Zeist, The Netherlands
Abbreviations: AMPK, AMP-activated protein kinase; Ffar, free
fatty acid receptor; GLP-1, glucagon-like peptide-1; GPR, G protein-
coupled receptor; HSL, hormone-sensitive lipase; MCT, monocar-
boxylate transporter; PEP, phosphoenolpyruvate; PGC, peroxisome
proliferator-activated receptor gamma coactivator; PKA, protein kinase
A; PPAR, peroxisome proliferator-activated receptor; PYY, peptide YY;
SCFA, short-chain fatty acid; SMCT, sodium-dependent monocarboxy-
late transporter.
1
To whom correspondence should be addressed.
e-mail: B.M.Bakker@med.umcg.nl
review
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2326 Journal of Lipid Research Volume 54, 2013
intake. There is no linear correlation between fi ber in-
take and SCFA concentration in the cecum ( 32 ). Cecal
SCFA concentrations increased when 10% of dietary wheat
starch was replaced by inulin, but decreased again when
fi ber content was increased to 20% inulin ( Table 1 ). In
contrast to other fi bers, inulin shifted the relative produc-
tion of SCFAs from acetate to propionate and butyrate
( 32, 33 ). In pigs, compared with rats a better model for the
human gastrointestinal tract, the increase in daily fi ber in-
take is less refl ected in the cecal SCFA concentrations
( Table 1 ) ( 34, 35 ). However, in studies with pigs, the
increase in daily fi ber intake per kg body weight is much
less compared with the rat studies described above. Indeed,
by increasing the daily fi ber intake even more, the cecal
SCFA concentrations were also increased in pigs ( Table 1 )
( 36, 37 ).
In humans the effect of dietary fi ber intake has been
studied mainly by measuring the SCFA concentrations in
feces followed by calculating the total rate of SCFA excre-
tion. Fecal secretion rates for SCFA are in the range of
10–30 mmol/day for diets with high fi ber content com-
pared with 5–15 mmol/day for control diets ( 38–42 ). In
most studies, acetate is the predominant SCFA in the
feces, followed by propionate and butyrate. It is important
to note that fecal SCFA concentrations do not refl ect their
concentration and production rate in the intestine as most
SCFAs are taken up by the host and therefore fecal SCFA
excretion provides little information about actual intesti-
nal SCFA metabolism.
Production fl uxes of SCFAs
Because SCFA production is diffi cult to measure in vivo,
most experiments have been done in vitro with intestinal
or fecal microbiota as inoculum ( Table 2 ). In vitro fermenta-
tion, however, differs from the in vivo situation because: i )
during isolation of microbiota the diversity alters dramati-
cally, and ii ) products accumulate during fermentation.
Using microbiota obtained from pig intestine, studies
showed pronounced differences in SCFA production rates
from different fi bers ( Table 2 ) ( 43, 44 ). In addition, in vitro
SCFA production by inocula derived from swine ileum were
higher when the swine were put on galactooligosaccharide
diets for 6 weeks compared with production rates before
adaptation ( Table 2 ) ( 44 ). Studies using human feces as in-
oculum show less pronounced effects of fi ber type ( 45, 46 ).
It is unclear if this is due to the type of fi ber or the origin
of the microbiota. Titration with lactulose yielded an opti-
mum SCFA production rate at 7.5 mg/ml ( Table 2 ), remi-
niscent of the in vivo effect of inulin supply on the cecal
SCFA concentrations ( Table 1 ).
As far as we know, Bergman et al. ( 47 ) performed the
most accurate in vivo determination of SCFA production
rates. In three separate experiments they infused radiola-
beled acetate, propionate, or butyrate into the rumen of
continuously dried grass-fed sheep. Combining the data of
the radioactivity of the SCFAs in the rumen they found
production rates of 2.9, 0.8, and 0.5 mmol kg body weight
1
h
1
for acetate, propionate, and butyrate, respectively.
These values cannot be translated to humans, because
sudden-death victims (n = 6) showed that the acetate:
propionate:butyrate ratio in humans was similar in the
proximal and distal regions of the large intestine ( 11 ). In
the cecum and large intestine, 95% of the produced SCFAs
are rapidly absorbed by the colonocytes while the remain-
ing 5% are secreted in the feces ( 12–15 ).
In the last few decades, it became apparent that SCFAs
might play a key role in the prevention and treatment
of the metabolic syndrome, bowel disorders, and certain
types of cancer ( 16–22 ). In clinical studies SCFA adminis-
tration positively infl uenced the treatment of ulcerative
colitis, Crohn’s disease, and antibiotic-associated diarrhea
( 10, 23–27 ). The molecular mechanisms by which SCFAs
induce these effects are an active fi eld of research. In this
review we will discuss the role of SCFAs in the interplay
between diet, gut microbiota, and regulation of host en-
ergy metabolism. We will argue that an integrated under-
standing will require more quantitative data on the SCFA
fl ux across the intestinal wall and the impact this has on
host metabolism.
THE DIET
Gut bacteria in the cecum and large intestine produce
SCFAs mainly from nondigestible carbohydrates that pass
the small intestine unaffected. The different types and
amounts of nondigestible carbohydrates that reach the ce-
cum and large intestine depend on the daily intake and
type of food. The major components of fi ber that pass the
upper gut are plant cell-wall polysaccharides, oligosaccha-
rides, and resistant starches ( 28 ). The average human diet
in Western societies contains approximately 20–25 g fi ber/
day ( 29 ). In diets that are high in fruit and vegetables, the
fi ber content may reach 60 g/day ( 30 ). Fermentation of
the carbohydrates reaching the cecum yield 400–600 mmol
SCFAs/day, which amounts to a production of SCFAs of
0.24–0.38 kg body weight
1
h
1
, equivalent to ⵑ 10% of the
human caloric requirements ( 31 ).
The amount and type of fi ber consumed has dramatic
effects on the composition of the intestinal microbiota and
consequently on the type and amount of SCFAs produced.
For the host, the in vivo SCFA production rates as well as the
intestinal SCFA concentrations on different fi bers are most
relevant. As we discuss in the next sections, information on
the cecal SCFA content is available in model organisms, but
there is limited information about in vivo production rates.
In contrast, in humans measurement of the cecal SCFA con-
centration is almost impossible and in most cases conclu-
sions about cecal and colonic metabolism are deduced from
fecal content and in vitro studies.
Concentrations of SCFAs as a function of diet
In Table 1 we list the effect of fi bers on intestinal SCFA
concentrations in various studies. Although units and in-
formation on dietary composition differ, this overview
allows a number of conclusions. In the rat, the addition
of fi ber resulted in increased cecal SCFA concentrations
compared with control diets. The cecal concentrations de-
pend on the type of fi ber used but also on the daily fi ber
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Short-chain fatty acids and host energy metabolism 2327
THE PRODUCTION OF SCFAs BY GUT
MICROBIOTA
Changes in dietary fi bers drive changes in the composition
of gut microbiota. Although diet is a major determinant of
the colonic microbiome, the host genetic background and
the colonic milieu also exert a strong infl uence on the mi-
crobial composition in the large intestine ( 51–54 ). The
microbial activity in turn also affects the colonic milieu.
Together, this causes a strong variation of the microbial
population between individuals. In this section we will
discuss this variation, the mechanisms of microbial SCFA
production, and the interaction between microbial composi-
tion, microbial SCFA production, and the colonic milieu.
The composition of gut microbiota
Infants are born without gut microbiota, but rapidly
after birth the infant’s gut is conventionalized by bacteria
coming from the mother and the surrounding environ-
ment. The composition of the microbiota stays unstable
until the age of approximately 3–4 years, when it becomes
mature. Colonization of the gut has two major benefi ts.
First, the microbiota educate the immune system and in-
crease the tolerance to microbial immunodeterminants
( 55 ). Second, the microbiota act as a metabolic organ that
fiber fermentation in ruminants has a more prom inent
role than it has in nonruminants ( 31 ), yet this methodol-
ogy is well-suited to be applied more widely in labora-
tory animals. Alternative techniques to measure intestinal
SCFA fl uxes are indirect and subject to controversy. In
these studies isotope dilution of intravenously infused
13
C-labeled SCFAs was monitored ( 48, 49 ). The obtained
values refl ect the rate of appearance of SCFAs in the
peripheral circulation after fi rst-pass extraction by the
splanchnic bed, and thereby underestimate SCFA pro-
duction by gut microbiota. Pouteau et al. ( 48 ) performed
whole-body stable-isotope-dilution studies in fasted humans
before and after giving them 20 g of pure lactulose. From
the difference in whole-body production between both
situations, they estimated the colonic acetate production
rate to be 0.2 mmol kg body weight
1
h
1
. Isotope studies
in children, who are unable to metabolize propionate due
to a nonfunctional propionyl-CoA carboxylase, showed
that gut microbiota produce approximately 0.05 mmol kg
body weight
1
h
1
propionate ( 50 ). This estimated propi-
onate production rate is 4-fold lower than the reported
acetate production rate. Although we are aware that these
studies cannot be compared directly, we note that this
ratio is similar to the average acetate:propionate ratio in
cecal concentration ( Table 1 ).
TABLE 1. Total and molar percentage SCFAs after dietary intervention with various types of fi bers in different
organisms
Diet
Daily Fiber
Intake (g/day)
Concentration
SCFAs
Molar Percentage
(Acetate:Propionate:Butyrate) Reference
Rat cecum
mmol/L
( 76 )
Control 0 41 72:14:14
Cellulose 1 36 72:14:14
Oligofructose 1 50 71:10:19
Fructooligosaccharides 1 61 74:9:17
Xylooligosaccharides 1 46 76:11:13
mmol/L
( 32 )
Control 0 85 65:23:12
5% inulin 1 143 45:34:21
10% inulin 2 156 43:37:20
20% inulin 4 107 40:34:26
mol/g
( 33 )
Control 0 47 77:8:15
Cellulose 2 48 83:6:11
Pectin 3 71 84:11:5
Inulin 2 57 63:18:19
Resistant starch 5 92 76:7:17
Barley hulls 2 62 78:5:17
Pig cecum
mmol/L
( 34 )
White rice (control) 20 80 64:25:11
Brown rice 43 75 66:27:7
Rice bran 36 68 67:25:8
Rice bran plus rice oil 43 76 68:22:10
mmol/L
( 35 )
White rice 33 69 68:26:6
Pan-boiled brown rice 33 63 62:32:6
mmol/L
( 37 )
Control 14 70 67:22:11
Wheat bran 42 131 60:31:9
Oat bran 44 92 59:32:9
Baked beans 45 124 65:30:5
mmol/L
( 36 )
Control Not reported 100 73:20:6
Resistant starch Not reported 140 73:22:5
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2328 Journal of Lipid Research Volume 54, 2013
propionate, whereas the Firmicutes phylum has butyrate
as its primary metabolic end product ( 58 ). Most bacterial
activity occurs in the proximal colon where substrate avail-
ability is highest. Toward the distal colon, the availability
of substrate declines and the extraction of free water re-
duces diffusion of substrates and microbial products. This
makes the proximal part of the colon the principal site
of fermentation. Particularly, nondigestible carbohydrates
are fermented in the proximal colon by saccharolytic bac-
teria, mainly primary fermenters like Bacteroidetes. This
fermentation results in SCFAs together with the gases CO
2
and H
2
( 12 ). The Bacteroidetes are part of a community,
stabilized by mutual cross-feeding, where other members
of the community consume these gasses. For instance,
Archaea produce CH
4
from CO
2
and H
2
, while acetogens
convert CO
2
into acetate.
Nitrogen is essential for bacterial growth, and the hy-
drolysis of host-derived urea to NH
3
is a major nitrogen
source. Almost 50% of the urea produced by the host is
hydrolyzed in the lumen of the large intestine ( 59 ). Fer-
mentation of bacterial proteins and amino acids derived
from primary fermenters like Bacteroidetes occurs in the
can break down otherwise indigestible food components,
degrade potentially toxic food compounds like oxalate,
and synthesize certain vitamins and amino acids ( 55 ).
Each individual has a unique microbiome of which the
composition is infl uenced by the host genotype and phys-
iology, the colonization history, environmental factors,
food, and drugs (e.g., antibiotics) ( 56 ). A recent metabolic
reconstruction based on the data of the Human Micro-
biome Consortium clearly showed, however, that meta-
bolic functionality was rather constant over a group of
studied individuals because many biochemical pathways
are redundant between alternative members of the micro-
biome ( 57 ).
Bacteria constitute, with 10
14
citizens, the most domi-
nant and most diverse group of microorganisms present in
the human colon. Based on variation in 16S rRNA genes,
it was assessed that there may be between 500 and 1,000
different species present, which belong to more than
70 genera ( 55 ). The three phyla Bacteroidetes (gram-
negative), Firmicutes (gram-positive), and Actinobacteria
(gram-positive) are the most abundant in the intestine.
The Bacteroidetes phylum mainly produces acetate and
TABLE 2. In vitro SCFA production rates from different organisms
Substrate Inoculum Origin
SCFA Production Rate
ReferenceAcetate Propionate Butyrate Total SCFAs
Pig colon mmol/L reaction volume/h ( 43 )
Cellulose 1.7 2.5 0.8 5.0
Wheat bran 5.8 4.2 3.1 13.1
Ispaghula husk 8.3 8.3 1.0 17.6
Gum arabic 5.8 5.8 0.4 12.0
Swine ileum mmol/g substrate/h ( 44 )
Raffi nose + stachyose 0.17 0.08 0.08 0.33
Non-oligosaccharides soy solubles 0.17 0.05 0.05 0.27
Soy solubles 0.12 0.02 0.03 0.17
Non-oligosaccharide tGOS 0.15 0.05 0.05 0.25
Transgalactooligosaccharides 0.07 0.02 0.02 0.10
After 6 week adaptation
Raffi nose + stachyose 0.30 0.20 0.07 0.57
Non-oligosaccharides soy solubles 0.17 0.07 0.03 0.25
Soy solubles 0.12 0.05 0.02 0.18
Non-oligosaccharide tGOS 0.18 0.13 0.03 0.35
Transgalactooligosaccharides 0.07 0.05 0.02 0.13
Human feces mmol/L reaction volume/h ( 45 )
Glucose 21.2 5.0 2.2 28.3
Soy oligosaccharide 12.3 6.6 5.8 24.6
Fructooligosaccharide 15.8 5.5 2.8 24.1
Inulin 13.5 7.8 5.3 26.6
Hydrolyzed inulin 15.1 6.4 3.9 25.4
Cellulose 9.3 11.8 1.6 22.7
Powdered cellulose 7.6 8.3 3.5 19.5
Methyl cellulose 15.3 5.8 5.0 26.2
Hydrolyzed guar gum 13.3 11.1 7.3 31.8
Psyllium husk 8.7 8.0 7.9 24.7
Human feces mmol/g substrate/h ( 46 )
Corn fi ber 0.178 0.070 0.058 0.306
Oat bran 0.546 0.187 0.125 0.858
Wheat bran 0.285 0.082 0.063 0.430
Human feces mmol/L reaction volume/h ( 166 )
Lactulose 2.5 mg/ml — — — 3.8
Lactulose 5.0 mg/ml — — — 7.5
Lactulose 7.5 mg/ml — — — 10.0
Lactulose 10.0 mg/ml — — — 6.3
tGOS, transgalactooligosaccharides.
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Short-chain fatty acids and host energy metabolism 2329
Lactate-utilizing bacteria can produce butyrate by first
producing acetyl-CoA from lactate ( 67 ). In the so-called
classical pathway the enzymes phosphotransbutyrylase and
butyrate kinase convert butyryl-CoA to butyrate and CoASH
with the concomitant formation of ATP ( 68 ). However,
recently an alternative pathway was discovered in which
butyryl-CoA is converted by butyryl-CoA:acetate CoA-
transferase to butyrate ( 69 ). The conversion utilizes ex-
ogenously derived acetate and generates butyrate and
acetyl-CoA. This fi nding was supported by labeling studies,
which showed that there was cross-feeding between ace-
tate-producing and butyrate-producing bacteria ( 70, 71 ).
The alternative pathway appears to dominate over the clas-
sical pathway in human gut microbiota ( 69 ).
For the production of SCFAs, it is important that the gut
microbiota work as a community, but also that the gut
microbiota have symbiotic associations with the host. The
molecular H
2
that is produced during acetate formation
must be used by other bacteria in the community to avoid
accumulation of H
2
which would inhibit the ability of pri-
mary fermenters to oxidize NADH. The CO
2
that is needed
in the primitive electron transfer chain is partly provided
by the host. Humans produce on average about 0.7 kg of
CO
2
per day ( 72 ). Part of that production is excreted into
the lumen of the gut as HCO
3
in exchange for SCFA an-
ions (see below and Fig. 2 ). Most likely this is an important
pH regulatory mechanism because protons in the lumen
of the gut, formed during the production of SCFAs, are
neutralized by bicarbonate under the formation of CO
2
.
Although much is known about the biochemistry of the
conversion of carbohydrates into SCFAs by the bacteria
composing the microbial community, there is a paucity of
data on the production rates of SCFAs by the gut microbial
community as a whole. This is largely due to the inability
to sample the large intestine of man. Therefore, and as
discussed in the previous section, the supply rate of SCFAs
to the host remains enigmatic. There is a pressing need for
measurement of true production rates of SCFAs, and the
degree by which specifi c carbohydrates and microbiota in-
fl uence the mass and composition of SCFAs.
The mutual relationship between microbial composition,
microbial SCFA production, and the colonic milieu
The diet and the intestinal milieu interact in a complex
way with the bacterial population in the gut. Fibers that
lead to high amounts of SCFAs, lower the pH in the colon,
which in turn affects the composition of the colonic mi-
crobiota and thereby the SCFA production.
Because most SCFAs are absorbed by the host in ex-
change for bicarbonate, the luminal pH is the result of the
microbial SCFA production and the neutralizing capacity
of bicarbonate. As the concentration of SCFAs decline
from the proximal to the distal colon, the pH increases
from cecum to rectum ( 11, 73–75 ). The drop in pH from
the ileum to the cecum due to the higher SCFA concentra-
tions has two effects. First, both in vitro and animal studies
show that lower pH values change gut microbiota compo-
sition and second, it prevents overgrowth by pH-sensitive
pathogenic bacteria like Enterobacteriaceae and Clostridia
more distal part of the colon by secondary fermenters: the
proteolytic bacteria. Degradation of proteins and amino
acids results in branched-chain fatty acids, accompanied
by potentially toxic metabolites such as amines, phenolic
compounds, and volatile sulfur compounds ( 60 ).
The bacterial pathways of anaerobic SCFA production
The microbiota hydrolyze nondigestible carbohydrates
into oligosaccharides and then monosaccharides, which
they ferment in the anaerobic environment of the gut.
Major bacterial metabolic routes are the Embden-Meyerhof-
Parnas pathway (glycolysis, for six-carbon sugars) and the
pentose-phosphate pathway (for fi ve-carbon sugars), which
convert monosaccharides into phosphoenolpyruvate (PEP)
( 61 ). Subsequently, PEP is converted into fermentation
products such as organic acids or alcohols.
At the level of glyceraldehyde-3-phosphate dehydroge-
nase (GAPDH) the electron carrier NADH is formed. An-
aerobically, there are three types of pathways to get rid of
excess reducing equivalents ( Fig. 1A ). The fi rst is the clas-
sical fermentation pathway where pyruvate is reduced to
lactate or ethanol, thereby oxidizing NADH . Second, many
primary fermenters sink their excess of reducing equiv-
alents into molecular H
2
( 62 ). Two major routes are used
to generate H
2
: 1 ) an exergonic ( G
o
′ < 0) route via
pyruvate:ferredoxin oxidoreductase and ferredoxin hy-
drogenase; and 2 ) an endergonic ( G
o
′ > 0) route via NADH:
ferredoxin oxidoreductase and ferredoxin hydrogenase.
The latter proceeds only at a low H
2
pressure in the lumen
of the large intestine. Consequently, H
2
-consuming bacte-
ria drive the metabolism of primary fermenters by de-
pleting H
2
( 58 ). The third type of pathway is a primitive
anaerobic electron transport chain ( 63, 64 ). It starts with
the carboxylation of PEP and the resulting oxaloacetate is
reduced to fumarate. Subsequently fumarate accepts elec-
trons from NADH via a simple electron-transfer chain be-
tween NADH and fumarate. Two enzymes constitute this
chain: NADH dehydrogenase and fumarate reductase. Pro-
tons are transported across the cell membrane by the NADH
dehydrogenase, which are then used for chemiosmotic ATP
synthesis. When the partial pressure of CO
2
is low, succi-
nate, the product of fumarate reductase, is converted into
methylmalonate, which is cleaved into propionate and CO
2
.
The latter can be recycled into PEP via carboxylation to
form oxaloacetate.
Major end products of the described fermentation path-
ways are the SCFAs. A major part of pyruvate is converted
to acetyl-CoA with the concomitant formation of H
2
and
CO
2
. Acetate is either formed by hydrolysis of acetyl-CoA
or from CO
2
via the Wood-Ljungdahl pathway ( Fig. 1B ), in
which CO
2
is reduced to CO and converted with a methyl
group and CoASH to acetyl-CoA ( 65, 66 ). Propionate can
be formed via the primitive electron transfer chain using
PEP as described above or by the reduction of lactate to
propionate, the latter being called the acrylate pathway
( 61 ). Both pathways reduce additional NADH compared
with the fermentation to lactate ( Fig. 1B ). Formation of
butyrate starts from condensation of two molecules of acetyl-
CoA and subsequent reduction to butyryl-CoA ( Fig. 1C ).
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2330 Journal of Lipid Research Volume 54, 2013
cecum content differed in SCFA concentration, pH, and
microbiota composition in the different fi ber groups ( 76 ).
After 14 days of diet, the rats fed oligosaccharide-containing
diets showed higher cecal SCFA pools while pH was lower
compared with control or cellulose diets. The oligosaccha-
ride-containing diets resulted also in altered microbiota
compositions as cecal bifi dobacteria and total amounts of
anaerobes were higher, whereas total aerobes were lower
compared with rats fed the control diet. In addition, in vitro
SCFA production rates from swine ileum were higher when
the swine were put on galactooligosaccharide diets for 6
weeks compared with production rates before adaptation
( 51, 52, 54 ). Studies of human fecal microbial communi-
ties showed that at pH 5.5 the butyrate-producing bacteria
such as Roseburia spp. and Faecalibacterium prausnitzii , both
belonging to the Firmicutes phylum, comprised 20% of
the total population ( 53 ). When fermentable dietary fi bers
become limiting in the more distal parts of the large intes-
tine, the luminal pH increases to 6.5, the butyrate-producing
bacteria almost completely disappear, and the acetate- and
propionate-producing Bacteroides-related bacteria become
dominant ( 53 ).
The interplay between diet, gut microbiota, and SCFA
production was also found in rats fed different fi bers. The
Fig. 1. Schematic overview of the three pathways that gut microbes use to get rid of excess reducing equivalents A: Pyruvate reduced to
lactate thereby reducing NADH (1), pyruvate:ferredoxin oxidoreductase and hydrogenase (2a) or NADH:ferredoxin oxidoreductase and
hydrogenase to sink reducing equivalents into molecular H
2
(2b), and primitive anaerobic electron transport chain for reducing NADH
(3). B, C: Schematic overview of the production of acetate, propionate, and butyrate from carbohydrates. B: Acetate is either formed di-
rectly from acetyl CoA or via the Wood-Ljungdahl pathway using formate. Propionate can be formed from PEP through the succinate de-
carboxylation pathway or through the acrylate pathway in which lactate is reduced to propionate. C: Condensation of two molecules of
acetyl CoA results in butyrate by the enzyme butyrate-kinase or by utilizing exogenously derived acetate using the enzyme butyryl-
CoA:acetate-CoA-transferase.
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Short-chain fatty acids and host energy metabolism 2331
around 6.0 (pH 5.5–6.5), only a very small part of the
SCFAs is present in the undissociated form ( 84 ). Thus it is
unlikely that passive diffusion of the undissociated form
plays a major role.
Three mechanisms have been described for the trans-
port of the SCFA anions across the apical membrane of the
epithelial cells lining the gut. The fi rst type of transporter
couples the import of SCFA anions to HCO
3
secretion
into the intestinal lumen ( Fig. 2 ). Conclusive evidence for
the existence of SCFA-HCO
3
exchange was obtained
from vesicle studies in which it was shown that SCFA-
HCO
3
exchange was independent of Cl
-HCO
3
ex-
change and Na
+
transport ( 85–88 ). The identity of the
transporter, however, remains unknown. Second, members
of the family of monocarboxylate transporters (MCTs)
catalyze SCFA anion cotransport with cations ( 85, 89 ).
MCT1 ( SLC16A1 ) was found in the apical membranes of
enterocytes, and it transports SCFAs in an H
+
-dependent
electroneutral manner, but it can also transport lactate
and pyruvate ( Fig. 2 ) ( 90 ). Finally, the electrogenic so-
dium-dependent monocarboxylate transporter (SMCT)1
( SLC5A8 ) is expressed along the entire length of the large
intestine and is located in the apical membrane ( 91 ).
SCFA anion transport by SMCT1 is coupled to Na
+
trans-
port in a 1:2 stoichiometry and stimulates Cl
and water
absorption ( Fig. 2 ) ( 92 ). SMCT1 transports butyrate faster
than propionate and acetate. Recently, it was shown that
SCFA anion transport by MCT dominates over transport
by SMCT1 ( 93 ). An increased transport of SCFA anions
across the apical membrane enhances the activity and ex-
pression of NHE3, an apical Na
+
/H
+
exchanger, and
thereby stimulates sodium and water absorption as well
as deacidification of the cell ( 94 ).
The part of SCFAs that is not consumed by the colono-
cytes is transported across the basolateral membrane.
SCFA anion transport across the basolateral membrane is
probably mediated via the SCFA
-HCO
3
antiport and
the cation-SCFA anion symport ( Fig. 2 ). The basolateral
SCFA
-HCO
3
antiporter is distinct from the apical SCFA
-
HCO
3
antiporter as indicated by their different K
m
values
for butyrate, which are 1.5 mM and 17.5 mM for the apical
and the basolateral exchanger, respectively ( 87, 95 ). Im-
munoblotting revealed that MCT4 ( SLC16A3 ) and MCT5
( SLC16A4 ) were localized to the basolateral membrane
( 96 ). MCT4 transports SCFA anions in an H
+
-dependent
electroneutral manner, but has a lower substrate affi nity
compared with MCT1 ( 97 ). Whether MCT5 is capable of
transporting SCFAs is not known, as MCT5 has not been
functionally characterized yet. Because the intracellular
pH is higher than the pH in the intestinal lumen, all intra-
cellular SCFAs are present in the dissociated form, imply-
ing that transport at the basolateral side should be via
transporters only because no diffusion can occur.
The transporters for the uptake of SCFAs from the
blood into the tissues remain largely unknown. Recently,
the organic anion transporters OAT2 and OAT7 were
found to transport propionate and butyrate, respectively,
across the sinusoidal membrane of hepatocytes ( 98, 99 ).
For a better understanding of the role of SCFAs in various
( Table 2 ) ( 44 ). Microbiota analysis showed that fecal bifi -
dobacteria and lactobacilli were increased after adapta-
tion. The changes in the intestinal lumen pH also affects
the transport of SCFAs from the lumen to the colono-
cytes ( 8 ), which we will discuss more extensively below in
the section about SCFA metabolism by the host.
THE EFFECTS OF SCFAs ON HOST METABOLISM
SCFAs produced by the microbiota in the cecum and
the colon can be found in hepatic, portal, and peripheral
blood ( 11, 77 ). These SCFAs affect lipid, glucose, and cho-
lesterol metabolism in various tissues ( 17, 78–80 ). These
results indicate that SCFAs are transported from the intes-
tinal lumen into the blood compartment of the host and
are taken up by organs where they act as substrates or sig-
nal molecules. SCFA transport has been studied mostly in
colonocytes, the fi rst host cells that take up SCFAs and
which depend largely on butyrate for their energy supply
( 10 ). SCFA receptors constitute a new and rapidly growing
fi eld of research as more functions of these receptors are
discovered ( 81–83 ). In this section we will discuss the trans-
port and metabolism of SCFAs by the host as well as their
regulatory role in energy metabolism of the host.
Transport of SCFAs across host cell membranes
Most SCFA transport studies have been performed in
colonocytes, which form the cecal and colonic epithelium
and are exposed to the highest SCFA concentrations. SCFAs
are transported across the apical and the basolateral mem-
branes of colonocytes ( Fig. 2 ). For the apical uptake of
SCFAs two mechanisms have been proposed, namely pas-
sive diffusion of undissociated SCFAs and active transport
of dissociated SCFA anions mediated by a number of dif-
ferent transporters. With a p K
a
of ⵑ 4.8 and a luminal pH
Fig. 2. Schematic overview of the proposed transport mecha-
nisms of SCFAs in colonocytes. Across the apical membrane the
major part of SCFAs is transported in the dissociated form by an
HCO
3
exchanger of unknown identity (?) or by one of the known
symporters, MCT1 or SMCT1 . A small part may be transported via
passive diffusion (spiral). The part of SCFAs that is not oxidized by
the colonocytes is transported across the basolateral membrane.
The basolateral transport can be mediated by an unknown HCO
3
exchanger, MCT4, or MCT5.
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2332 Journal of Lipid Research Volume 54, 2013
methylmalonyl-CoA epimerase, and methylmalonyl-CoA
mutase. Succinyl-CoA enters the tricarboxylic acid (TCA)
cycle and is converted to oxaloacetate, the precursor of
gluconeogenesis ( 107 ). In humans the extent to which
propionate contributes to energy metabolism is unknown
due to the lack of data on true production rates of pro-
pionate. Concentrations of propionate in portal blood
and hepatic venous blood suggest that around 30% of
propionate is taken up by the liver ( 11, 105 ). Peripheral
tissues take up the remainder of propionate because pe-
ripheral venous blood levels were 23% lower compared
with hepatic venous blood levels. In another study it was
estimated that humans use 50% of the propionate as a
substrate for hepatic gluconeogenesis ( 108 ). The general
view is that the liver clears a large fraction of propionate
from the portal circulation, but absolute values are still
unknown.
As discussed above, the major part of butyrate is used as
fuel for colonocytes. The remainder is mostly oxidized by
hepatocytes, which prevents toxic systemic concentrations
( 107 ).
Receptors of SCFAs
Next to the role as substrates, SCFA concentrations
are also sensed by specifi c G protein-coupled receptors
(GPRs), which are involved in the regulation of lipid and
glucose metabolism. GPR41 and GPR43 were identifi ed
as SCFA receptors ( 109, 110 ), and two other GPRs of the
same subfamily, GPR40 and GPR42, were found to be
receptors for medium- and long-chain fatty acids and an
open reading frame pseudogene of GPR41, respectively
( 81 ). After the discovery of the SCFA receptors, GPR41
was renamed free fatty acid receptor (Ffar)3 and GPR43
became Ffar2. Ffar2 and Ffar3 only share 33% amino acid
identity and they differ in affi nity for SCFAs, tissue distri-
bution, and physiological roles. The distinct chain length:
activity relationship for Ffar2 is acetate = propionate > bu-
tyrate, and for Ffar3, butyrate = propionate > acetate ( 109,
110 ). The two receptors have distinct G protein-coupling
specifi cities: Ffar2 couples to both pertussis toxin-sensitive
(G
i/o
) and -insensitive (G
q
) G proteins and Ffar3 only to
G
i/o
proteins ( 109, 110 ). Nilsson et al. ( 111 ) showed by a
[Ca
2+
] mobilization assay in the presence of pertussis toxin
that Ffar2 signals approximately for 70% through the G
i/o
pathway.
The highest mRNA expression of Ffar2 was found in im-
mune cells such as monocytes, B-lymphocytes, and poly-
morphonuclear cells ( 109–111 ). In addition, considerable
mRNA expression was found in white and brown adipose
tissue, bone marrow, spleen, pancreas, and large intestine
( 112 ). Ffar3 has a more widespread expression pattern
than Ffar2, with the highest expression in adipose tissue.
High mRNA expression was also found in the spleen, pan-
creas, lymph nodes, bone marrow, and polymorphonu-
clear cells ( 109–111 ). It is not known whether Ffar2 and
Ffar3 reside on apical or basolateral membranes.
As discussed below, SCFA-Ffar pathways turn out to be
involved in regulation of lipid and glucose metabolism
( 113–120 ).
tissues, the uptake by the different organs should be inves-
tigated further.
SCFAs as a source of energy
When taken up, a large part of the SCFAs is used as a
source of energy. In humans, SCFAs provide ⵑ 10% of
the daily caloric requirements ( 31 ). CO
2
production
measurements in isolated colonocytes showed that colono-
cytes derive 60–70% of their energy supply from SCFA oxi-
dation ( 100 ). The general idea is that colonocytes prefer
butyrate to acetate and propionate, and oxidize it to ketone
bodies and CO
2
( 100 ). This is based on the relatively high
affi nity of the colonocytes for butyrate. However, isolated
colonocytes from humans and rats showed a maximum
fl ux of 0.6, 0.2, and 0.4 mol/min/g cell weight and a K
0.5
of approximately 0.6, 0.4, and 0.1 mM for acetate, propi-
onate, and butyrate, respectively ( 101, 102 ). This indicates
that under physiological conditions, with a relative high
colonic concentration of acetate compared with butyrate,
acetate is at least as important as butyrate for the energy
supply in colonocytes. In sudden death victims (n = 6),
molar fractions of SCFAs in the hepatic portal vein were
found to be 69:23:8 for acetate:propionate:butyrate, as
compared with 57:22:21 in the large intestine ( 11 ). This is
generally attributed to consumption of a large part of bu-
tyrate by colonocytes. Donohoe et al. ( 18 ) showed that
colonocytes of germ-free mice exhibit a defi cit in mito-
chondrial respiration and undergo autophagy. By intro-
ducing the butyrate-producing strain Butyrivibrio fi brisolvens
into germ-free mice or by adding butyrate to isolated
colonocytes of germ-free mice, they rescued the colono-
cytes from both the defi cit in mitochondrial respiration
and from autophagy. In the presence of an inhibitor for
fatty acid oxidation, butyrate was unable to suppress au-
tophagy. From this it was concluded that the rescue was
due to butyrate acting as an energy source rather than as a
regulator.
Exogenous acetate formed by colonic bacterial fermen-
tation enters the blood compartment and is mixed with
endogenous acetate released by tissues and organs ( 103,
104 ). Up to 70% of the acetate is taken up by the liver
( 105 ), where it is not only used as an energy source, but is
also used as a substrate for the synthesis of cholesterol and
long-chain fatty acids and as a cosubstrate for glutamine
and glutamate synthesis. Other tissues including heart,
adipose tissue, kidney, and muscle metabolize the remain-
der of acetate ( 104 ).
To prevent high SCFA concentrations in blood, the liver
clears the major part of propionate and butyrate from the
portal circulation ( 105 ). Propionate acts as a precursor for
gluconeogenesis in the liver ( 6 ). In ruminants, with iso-
tope dilution techniques, the contribution of propionate
to glucose synthesis was calculated to vary between 45 and
60% ( 106 ). It is unclear if this is similar in nonruminants,
because ruminants depend on SCFAs for 80% of their main-
tenance energy ( 31 ). After conversion of propionate into
propionyl-CoA by propanoate:CoA ligase (AMP-forming),
propionyl-CoA is converted to succinyl-CoA in three con-
secutive steps catalyzed by propionyl-CoA carboxylase,
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Short-chain fatty acids and host energy metabolism 2333
fatty acid oxidation is enhanced in both tissues and de novo
fatty acid synthesis in the liver is decreased. In addition,
SCFAs have been shown to increase protein expression of
PGC-1 and uncoupling protein (UCP)-1 in brown adipose
tissue, thereby increasing thermogenesis and fatty acid oxi-
dation ( 17 ). If AMPK is involved in this effect of SCFAs,
however, is still unknown. SCFAs activate AMPK either di-
rectly by increasing the AMP/ATP ratio or indirectly via the
Ffar2-leptin pathway. In vitro studies showed that SCFAs in-
creased the AMP/ATP ratio and AMPK activity in both mus-
cle and liver cells in a leptin-independent manner ( 17, 123 ),
but the mechanism is still unknown. In vitro and in vivo ex-
periments showed that SCFAs increase leptin expression via
a Ffar2-dependent pathway ( 113, 118, 119 ). Leptin, an adi-
pokine that regulates energy expenditure and food intake,
stimulates fatty acid oxidation by increasing the AMP/ATP
ratio and AMPK activity in liver and muscle tissue ( 128,
129 ). To what extent the AMPK-activated effect of SCFAs in
vivo is regulated via leptin or via the leptin-independent
mechanism is still unknown.
Regulation of fatty acid metabolism by SCFAs
SCFAs regulate the balance between fatty acid synthesis,
fatty acid oxidation, and lipolysis in the body. Fatty acid
oxidation is activated by SCFAs, while de novo synthesis
and lipolysis are inhibited. The net result is a reduction of
the concentrations of free fatty acids in plasma ( 114 ) and
a decrease in body weight ( 17, 121–124 ). In this section we
discuss the signaling pathways that mediate this regula-
tion. Besides the receptors Ffar2 and Ffar3 that we dis-
cussed above, AMP-activated protein kinase (AMPK) plays
an important role in this regulation, as summarized in Fig. 3 .
SCFAs have been shown to increase the AMPK activity in
liver and muscle tissue ( 17, 121, 125 ). Activation of AMPK
triggers peroxisome proliferator-activated receptor gamma
coactivator (PGC)-1 expression, which is known to control
the transcriptional activity of several transcription factors
such as peroxisome proliferator-activated receptor (PPAR) ,
PPAR , PPAR , liver X receptor (LXR), and farnesoid X
receptor (FXR) , all important in regulation of cholesterol,
lipid, and glucose metabolism ( 126, 127 ). As a consequence,
Fig. 3. Schematic overview of the proposed mechanisms by which SCFAs increase fatty acid oxidation in liver,
muscle, and brown adipose tissue. In muscle and liver, SCFAs phosphorylate and activate AMPK (pAMPK)
directly by increasing the AMP/ATP ratio and indirectly via the Ffar2-leptin pathway in white adipose tissue.
In white adipose tissue, SCFAs decrease insulin sensitivity via Ffar2 and thereby decrease fat storage. In addi-
tion, binding of SCFAs to Ffar2 leads to the release of the G
i/o
protein, the subsequent inhibition of adeny-
late cyclase (AC), and an increase of the ATP/cAMP ratio. This, in turn, leads to the inhibition of PKA and
the subsequent inhibition of HSL, leading to a decreased lipolysis and reduced plasma free fatty acids .
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2334 Journal of Lipid Research Volume 54, 2013
In addition, the gut hormones peptide YY (PYY) and glu-
cagon-like peptide-1 (GLP-1) play an important role in the
communication between tissues.
Oral administration of acetate and propionate reduced
glycemia in diabetic hyperglycemic KK-A(y) mice and nor-
mal rats ( 137, 138 ). There is indirect evidence for a reduced
gluconeogenesis by the liver. Activation of the hepatic
AMPK pathway decreased gene expression of the gluconeo-
genic enzymes glucose 6-phosphatase (G6Pase) and phos-
phoenolpyruvate carboxykinase (PEPCK). Unfortunately,
the gluconeogenic fl ux was not measured, but fasting plasma
glucose and insulin levels were decreased together with an
increased glucose tolerance ( 137 ).
SCFAs may also affect plasma glucose levels by increas-
ing the gut hormones PYY and GLP-1 via activation of the
receptors Ffar2 and Ffar3. PYY is known as a satiety hor-
mone, but it also reinforces the insulin action on glucose
disposal in muscle and adipose tissue ( 139–141 ). In human
and rat colon samples, the SCFA receptors Ffar2 and Ffar3
colocalize with enteroendocrine L cells containing PYY
( 142–144 ). In addition, Ffar2 and Ffar3 knockout mice
showed reduced colonic PYY expression and whole-body
glucose tolerance ( 145 ). Intracolonic infusions of SCFAs
in rats and pigs increased blood concentrations of PYY,
but unfortunately no data on glucose metabolism was re-
ported ( 146, 147 ). GLP-1 indirectly regulates blood glu-
cose levels by increasing the secretion of insulin and
decreasing the secretion of glucagon by the pancreas
( 148 ). Intracolonic infusions of SCFAs and intake of fi bers
both increased plasma GLP-1 concentrations and glucose
uptake by adipose tissue ( 147, 149–151 ). In addition, mice
lacking Ffar2 or Ffar3 exhibited reduced SCFA-triggered
GLP-1 secretion in vitro and in vivo, and a parallel impair-
ment of glucose tolerance ( 145 ).
In summary, SCFAs seem to benefi cially affect glucose
metabolism by normalizing plasma glucose levels and in-
creasing glucose handling. To what extent these effects oc-
cur directly via a hepatic AMPK regulation pathway, or
indirectly via the gut derived hormones PYY and GLP-1, is
not clear.
Regulation of cholesterol metabolism by SCFAs
SCFAs have been shown to reduce plasma concentra-
tions of cholesterol in rodents and humans ( 78, 79, 124 ).
Cholesterol is synthesized from its precursor unit, acetyl-
CoA, via a complex metabolic pathway in which 3-hydroxy-
3-methylglutaryl-CoA reductase is the rate-limiting enzyme
( 152 ).
In vitro studies showed that propionate lowered choles-
terol synthesis rate by decreasing the enzyme activity of
hepatic 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS)
and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR)
( 152, 153 ). In addition, in vivo experiments using
3
H
2
O as
a tracer showed that total cholesterol synthesis rate was
decreased in rat livers upon addition of dietary propionate
( 154, 155 ). The role of acetate in cholesterol homeostasis
has received less attention, but Fushimi et al. ( 78 ) showed
that serum cholesterol levels are affected by acetate. Rats
receiving a diet containing 1% (w/w) cholesterol showed
Hepatic fatty acid lipolysis seems to be unaffected by SC-
FAs, but lipolysis in adipose tissue is strongly reduced by
SCFAs ( 113, 114, 121, 130 ). In isolated adipocytes, acetate
and propionate were found to inhibit lipolysis via Ffar2
activation ( 113, 114 ). A reduction of lipolysis is consistent
with data from human studies where intravenous adminis-
tration of acetate and propionate reduced plasma free
fatty acids and glycerol ( 131, 132 ). Ffar2 mediated inhibi-
tion of lipolysis is most likely through inactivation of the
hormone-sensitive lipase (HSL), which hydrolyzes triglyc-
erides and is one of the key molecules controlling lipoly-
sis in adipose tissue ( 133 ). Binding of SCFAs to Ffar2 leads
to the dissociation and thereby the activation of the G
i/o
protein. The G
i/o
protein inhibits adenylate cyclase and
thereby reduces the production of cAMP from ATP, which
subsequently decreases the activity of protein kinase A
(PKA) ( 134 ). A decrease of PKA activity leads to dephos-
phorylation and deactivation of HSL in adipose tissue
( 133 ). Consistently, administration of high resistant starch
to humans resulted in higher plasma SCFA concentrations
and lower HSL activity in adipose tissue ( 130 ).
Ffar2 also plays an important role in storage of fat in
white adipose tissue as shown recently by Kimura et al.
( 135 ). Ffar2-defi cient mice are obese on a normal diet,
whereas mice overexpressing Ffar2 specifi cally in adipose
tissue are protected against dietary-induced obesity. The
authors concluded that SCFA activation of adipose-specifi c
Ffar2 suppresses insulin signaling by inhibition of Akt
phosphorylation, which inhibits fat storage in adipose tis-
sue and promotes the metabolism of lipids and glucose in
other tissues. Indeed, liver triglycerides were decreased
and mRNA levels of genes involved in fatty acid oxidation
in muscle tissue were increased in mice overexpressing
adipose-specifi c Ffar2 compared with wild-type controls. In
addition, total body energy expenditure was also increased
together with a decreased respiratory exchange ratio value,
indicating increased fatty acid oxidation. Unfortunately, no
data was provided on the AMP/ATP ratio, AMPK activity,
and actual organ-specifi c fatty acid oxidation fl uxes. Sur-
prisingly, plasma leptin levels in adult mice overexpressing
adipose-specifi c Ffar2 were lower than in wild-type mice.
Although SCFAs have been shown to increase leptin ex-
pression via a Ffar2-dependent pathway, it is possible that
the decreased leptin levels are simply a result of decreased
adipose tissue ( 136 ).
In conclusion, it has been shown convincingly that the
prevention of dietary-induced obesity by SCFAs can be at-
tributed to an increase of fatty acid oxidation in multiple
tissues and a decrease of fat storage in white adipose tissue.
However, our understanding of the molecular mechanisms
is still incomplete.
Regulation of glucose metabolism by SCFAs
The scarce data available on the effect of SCFAs on glu-
cose metabolism reveal a decrease of plasma glucose levels
possibly via multiple mechanisms. The plasma glucose level
is determined by uptake via the food, gluconeogenesis,
and uptake by multiple organs. Again, the Ffars and AMPK
are involved in transduction of the effects of SCFAs ( Fig. 4 ).
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Short-chain fatty acids and host energy metabolism 2335
enough to compensate for an adverse diet or genetic
predisposition.
Another puzzling result is that despite very low SCFA
levels, germ-free mice and rats are protected from diet-in-
duced obesity ( 162, 163 ). In this respect it is important to
note that the type of microbiota is of key importance. A
conventionalization study of adult germ-free mice with mi-
crobiota from obese mice ( ob / ob ) exhibited a signifi cantly
greater percentage increase in total body fat than coloni-
zation with microbiota from lean (+/+) donors ( 159 ). The
obese animals in this study showed a 50% reduction in
relative abundance of the Bacteroidetes (i.e., acetate and
propionate producers), whereas the Firmicutes (i.e., bu-
tyrate producers) were proportionally increased compared
with the lean counterparts. Comparative metagenomic
analysis predicted that the microbiota from ob / ob mice
had an increased fermentation capacity, which was also
shown in increased cecal concentrations of SCFAs. From
this, it was hypothesized that the effi ciency of energy
harvesting from the diet is increased by a change in gut
microbiota, which then might lead to obesity. To test this
hypothesis, Murphy et al. ( 160 ) fed wild-type mice and
ob / ob mice either a high-fat or a low-fat diet and investi-
gated the relationship between the microbial composition
and energy harvesting capacity (deduced from the cecal
SCFA concentrations). The decrease of Bacteroidetes and
the increase of Firmicutes were confi rmed, but they did
not see a direct association between changes in the micro-
biota and markers of energy harvesting. This and other
studies are, however, limited by a lack of fl ux data. A pri-
ori, there is no reason why cecal SCFA concentrations
signifi cantly less increased serum cholesterol levels when
the diet was supplemented with 0.3% (w/w) acetate. In
the liver, the protein concentration of HMGCS was reduced
and the mRNA level of cholesterol 7 -hydroxylase (CYP7A1)
was increased upon addition of acetate. CYP7A1 is involved
in the conversion of cholesterol to bile acid, and acts as
a sink for cholesterol. In line with this observation, ace-
tate supplementation decreased hypercholesterolemia in
humans ( 124 ).
Because AMPK activation has also been reported to in-
hibit HMGCR activity and reduce cholesterol levels in iso-
lated rat hepatocytes ( 156–158 ), it is not unlikely that the
cholesterol-lowering effects described are mediated through
AMPK activation by SCFAs, just like the effects of SCFAs on
fatty acid and glucose metabolism.
THE INTERPLAY BETWEEN GUT MICROBIOTA,
SCFA CONCENTRATIONS, AND HOST ENERGY
METABOLISM
The complexity of the interactions between gut micro-
biota, SCFA concentrations, and host energy metabo-
lism is illustrated by contradictory reports in obese and
germ-free subjects. Dietary administration of SCFAs pro-
tected mice from diet-induced obesity and insulin resis-
tance ( 17, 121, 122 ). Yet, genetically obese ob/ob mice and
obese human subjects have increased amounts of cecal
and fecal SCFAs ( 159–161 ). It is unclear whether the
benefi cial effect of SCFAs is somehow compromised in
obese subjects, or whether the effect is simply not strong
Fig. 4. Schematic overview of the proposed mechanisms by which SCFAs effect glucose metabolism. In the
colon SCFAs can increase PYY and GLP-1 expression via Ffar2 and Ffar3. PYY has been shown to increase
glucose uptake in muscle and adipose tissue, whereas GLP-1 increases insulin and decreases glucagon pro-
duction in the pancreas. In addition, SCFAs have been shown to decrease hepatic gluconeogenesis by in-
creasing the AMPK phosphorylation and activity.
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2336 Journal of Lipid Research Volume 54, 2013
7 . van Hoek , M. J. , and R. M. Merks . 2012 . Redox balance is key to
explaining full vs. partial switching to low-yield metabolism. BMC
Syst. Biol. 6 : 22 .
8 . Cook , S. I. , and J. H. Sellin . 1998 . Review article: short chain fatty
acids in health and disease. Aliment. Pharmacol. Ther. 12 : 499 – 507 .
9 . Hijova , E. , and A. Chmelarova . 2007 . Short chain fatty acids and
colonic health. Bratisl. Lek. Listy . 108 : 354 – 358 .
10 . Binder , H. J. 2010 . Role of colonic short-chain fatty acid transport
in diarrhea. Annu. Rev. Physiol. 72 : 297 – 313 .
11 . Cummings , J. H. , E. W. Pomare , W. J. Branch , C. P. Naylor , and
G. T. Macfarlane . 1987 . Short chain fatty acids in human large
intestine, portal, hepatic and venous blood. Gut . 28 : 1221 – 1227 .
12 . Topping , D. L. , and P. M. Clifton . 2001 . Short-chain fatty acids
and human colonic function: roles of resistant starch and non-
starch polysaccharides. Physiol. Rev. 81 : 1031 – 1064 .
13 . Ruppin , H. , S. Bar-Meir , K. H. Soergel , C. M. Wood , and M. G. J.
Schmitt . 1980 . Absorption of short-chain fatty acids by the colon.
Gastroenterology . 78 : 1500 – 1507 .
14 . Dawson , A. M. , C. D. Holdsworth , and J. Webb . 1964 . Absorption
of short chain fatty acids in man. Proc. Soc. Exp. Biol. Med. 117 :
97 – 100 .
15 . Rechkemmer , G. , K. Rönnau , and W. V. Engelhardt . 1988 .
Fermentation of polysaccharides and absorption of short chain
fatty acids in the mammalian hindgut. Comp. Biochem. Physiol. A .
90 : 563 – 568 .
16 . Hu , G. X. , G. R. Chen , H. Xu , R. S. Ge , and J. Lin . 2010 . Activation
of the AMP activated protein kinase by short-chain fatty acids is the
main mechanism underlying the benefi cial effect of a high fi ber
diet on the metabolic syndrome. Med. Hypotheses . 74 : 123 – 126 .
17 . Gao , Z. , J. Yin , J. Zhang , R. E. Ward , R. J. Martin , M. Lefevre , W. T.
Cefalu , and J. Ye . 2009 . Butyrate improves insulin sensitivity and
increases energy expenditure in mice. Diabetes . 58 : 1509 – 1517 .
18 . Donohoe , D. R. , N. Garge , X. Zhang , W. Sun , T. M. O’Connell , M.
K. Bunger , and S. J. Bultman . 2011 . The microbiome and butyrate
regulate energy metabolism and autophagy in the mammalian
colon. Cell Metab. 13 : 517 – 526 .
19 . Blouin , J. M. , G. Penot , M. Collinet , M. Nacfer , C. Forest , P.
Laurent-Puig , X. Coumoul , R. Barouki , C. Benelli , and S. Bortoli .
2011 . Butyrate elicits a metabolic switch in human colon cancer
cells by targeting the pyruvate dehydrogenase complex. Int. J.
Cancer . 128 : 2591 – 2601 .
20 . Scharlau , D. , A. Borowicki , N. Habermann , T. Hofmann , S.
Klenow , C. Miene , U. Munjal , K. Stein , and M. Glei . 2009 .
Mechanisms of primary cancer prevention by butyrate and other
products formed during gut fl ora-mediated fermentation of di-
etary fi bre. Mutat. Res. 682 : 39 – 53 .
21 . Tang , Y. , Y. Chen , H. Jiang , G. T. Robbins , and D. Nie . 2011 .
G-protein-coupled receptor for short-chain fatty acids suppresses
colon cancer. Int. J. Cancer . 128 : 847 – 856 .
22 . Hamer , H. M. , D. Jonkers , K. Venema , S. Vanhoutvin , F. J. Troost ,
and R. J. Brummer. 2008 . Review article: the role of butyrate on
colonic function. Aliment. Pharmacol. Ther. 27 : 104 – 119 .
23 . Harig , J. M. , K. H. Soergel , R. A. Komorowski , and C. M. Wood .
1989 . Treatment of diversion colitis with short-chain-fatty acid ir-
rigation. N. Engl. J. Med. 320 : 23 – 28 .
24 . Breuer , R. I. , S. K. Buto , M. L. Christ , J. Bean , P. Vernia , P. Paoluzi ,
M. C. Di Paolo , and R. Caprilli . 1991 . Rectal irrigation with short-
chain fatty acids for distal ulcerative colitis. Preliminary report.
Dig. Dis. Sci. 36 : 185 – 187 .
25 . Vernia , P. , A. Marcheggiano , R. Caprilli , G. Frieri , G. Corrao ,
D. Valpiani , M. C. Di Paolo , P. Paoluzi , and A. Torsoli . 1995 .
Short-chain fatty acid topical treatment in distal ulcerative colitis.
Aliment. Pharmacol. Ther. 9 : 309 – 313 .
26 . Scheppach , W. 1996 . Treatment of distal ulcerative colitis with
short-chain fatty acid enemas. A placebo-controlled trial. German-
Austrian SCFA Study Group. Dig. Dis. Sci. 41 : 2254 – 2259 .
27 . Di Sabatino , A. , R. Morera , R. Ciccocioppo , P. Cazzola , S. Gotti , F.
P. Tinozzi , S. Tinozzi , and G. R. Corazza . 2005 . Oral butyrate for
mildly to moderately active Crohn’s disease. Aliment. Pharmacol.
Ther. 22 : 789 – 794 .
28 . Flint , H. J. , E. A. Bayer , M. T. Rincon , R. Lamed , and B. A. White .
2008 . Polysaccharide utilization by gut bacteria potential for new
insights from genomic analysis. Nat. Rev. Microbiol. 6 : 121 – 131 .
29 . Bingham , S. A. , N. E. Day , R. Luben , P. Ferrari , N. Slimani , T.
Norat , F. Clavel-Chapelon , E. Kesse , A. Nieters , H. Boeing , et al.;
European Prospective Investigation into Cancer and Nutrition.
2003 . Dietary fi bre in food and protection against colorectal
refl ect the SCFA fl ux to the host and thereby the addi-
tional energy harvest.
In humans the distinct relation between the Firmi-
cutes:Bacteroidetes ratio and obesity is less clear. Multiple
studies found a higher Firmicutes:Bacteroidetes ratio and
an increased amount of SCFAs in the stool samples of
obese people compared with lean people ( 159, 164, 165 ).
In contrast, Schwiertz et al. ( 161 ) found no changes in
Firmicutes but an increase in Bacteroidetes in obese hu-
mans compared with lean humans. In agreement with ear-
lier studies, the latter also reported an increase in total
fecal SCFA concentrations in obese humans.
OUTLOOK
SCFAs have unambiguously been shown to exert mul-
tiple benefi cial effects on various aspects of mammalian
energy metabolism. An ever increasing detail in our un-
derstanding of the underlying molecular mechanisms,
however, does not yet allow us to understand paradoxical
results in physiological studies . Partly this is caused by the
lack of human data, because not all results obtained in ro-
dents can be directly translated to humans. More funda-
mentally, the fi eld is severely hampered by the lack of data
on actual fl uxes of SCFAs and metabolic processes regu-
lated by SCFAs. Most studies report concentrations of me-
tabolites (fatty acids, glucose, cholesterol, etc.) or transcript
levels, but these do not necessarily refl ect fl ux changes. A
number of questions need to be addressed: 1 ) What are
the in vivo SCFA production and uptake fl uxes under dif-
ferent conditions (i.e., with different fi bers, with different
microbiota, or in different disease models)? 2 ) How do
these SCFAs then affect glucose and lipid fl uxes via their
dual role as substrates and regulators? 3 ) Can we quantify
the role of different tissues and hormones? 4 ) Does the
demand of the host for specifi c SCFAs drive a change in
microbial metabolism? 5 ) At which timescales are differ-
ent, apparently contradictory effects working?
A quantitative and time-resolved approach to these ques-
tions should bring us a great step forward to elucidate the
role of SCFAs in mammalian energy metabolism.
REFERENCES
1 . Galisteo , M. , J. Duarte , and A. Zarzuelo . 2008 . Effects of dietary fi -
bers on disturbances clustered in the metabolic syndrome. J. Nutr.
Biochem. 19 : 71 – 84 .
2 . Venn , B. J. , and J. I. Mann . 2004 . Cereal grains, legumes and dia-
betes. Eur. J. Clin. Nutr. 58 : 1443 – 1461 .
3 . Delzenne , N. M. , and P. D. Cani . 2005 . A place for dietary fi bre
in the management of the metabolic syndrome. Curr. Opin. Clin.
Nutr. Metab. Care . 8 : 636 – 640 .
4 . Marlett , J. A. , M. I. McBurney , and J. L. Slavin . 2002 . Position of
the American Dietetic Association: health implications of dietary
fi ber. J. Am. Diet. Assoc. 102 : 993 – 1000 .
5 . Nicholson , J. K. , E. Holmes , J. Kinross , R. Burcelin , G. Gibson , W.
Jia , and S. Pettersson . 2012 . Host-gut microbiota metabolic inter-
actions. Science . 336 : 1262 – 1267 .
6 . Roy , C. C. , C. L. Kien , L. Bouthillier , and E. Levy . 2006 . Short-
chain fatty acids: ready for prime time? Nutr. Clin. Pract. 21 :
351 – 366 .
at University of Groningen, on January 9, 2014www.jlr.orgDownloaded from
Short-chain fatty acids and host energy metabolism 2337
colon and whole body using stable isotopes. Proc. Nutr. Soc. 62 :
87 – 93 .
50 . Thompson , G. N. , J. H. Walter , J. L. Bresson, G. C. Ford, S. L.
Lyonnet, R. A. Chalmers, J. M. Saudubray, J. V. Leonard, and D.
Halliday. 1990 . Sources of propionate in inborn errors of propi-
onate metabolism. Metabolism . 39 : 1133 – 1137 .
51 . Cherrington , C. A. , M. Hinton , G. R. Pearson , and I. Chopra .
1991 . Short-chain organic acids at ph 5.0 kill Escherichia coli and
Salmonella spp. without causing membrane perturbation. J. Appl.
Bacteriol. 70 : 161 – 165 .
52 . Prohászka , L. , B. M. Jayarao , A. Fábián , and S. Kovács . 1990 . The
role of intestinal volatile fatty acids in the Salmonella shedding of
pigs. Zentralbl. Veterinarmed. B . 37 : 570 – 574 .
53 . Walker , A. W. , S. H. Duncan , E. C. McWilliam Leitch , M. W.
Child , and H. J. Flint . 2005 . pH and peptide supply can radically
alter bacterial populations and short-chain fatty acid ratios within
microbial communities from the human colon. Appl. Environ.
Microbiol. 71 : 3692 – 3700 .
54 . Duncan , S. H. , P. Louis , J. M. Thomson , and H. J. Flint . 2009 . The
role of pH in determining the species composition of the human
colonic microbiota. Environ. Microbiol. 11 : 2112 – 2122 .
55 . Xu , J. , and J. I. Gordon . 2003 . Honor thy symbionts. Proc. Natl.
Acad. Sci. USA . 100 : 10452 – 10459 .
56 . Zoetendal , E. G. , A. D. L. Akkermans , W. M. Akkermans-van Vliet ,
J. A. G. M. de Visser , and W. M. de Vos . 2001 . The host genotype
affects the bacterial community in the human gastrointestinal
tract. Microb. Ecol. Health Dis. 13 : 129 – 134 .
57 . Abubucker , S. , N. Segata , J. Goll , A. M. Schubert , and J. Izard . 2012 .
Metabolic reconstruction for metagenomic data and its application
to the human microbiome. PLOS Comput. Biol. 8 : e1002358 .
58 . Macfarlane , S. , and G. T. Macfarlane . 2003 . Regulation of short-
chain fatty acid production. Proc. Nutr. Soc. 62 : 67 – 72 .
59 . Veeneman , J. M. , H. A. Kingma , F. Stellaard , P. E. de Jong , D.
Reijngoud , and R. M. Huisman . 2004 . Comparison of amino acid
oxidation and urea metabolism in haemodialysis patients during
fasting and meal intake. Nephrol. Dial. Transplant. 19 : 1533 – 1541 .
60 . Millet , S. , M. J. Van Oeckel , M. Aluwé , E. Delezie , and D. L. De
Brabander . 2010 . Prediction of in vivo short-chain fatty acid pro-
duction in hindgut fermenting mammals: problems and pitfalls.
Crit. Rev. Food Sci. Nutr. 50 : 605 – 619 .
61 . Miller , T. L. , and M. J. Wolin . 1996 . Pathways of acetate, propi-
onate, and butyrate formation by the human fecal microbial fl ora.
Appl. Environ. Microbiol. 62 : 1589 – 1592 .
62 . Fischbach , M. A. , and J. L. Sonnenburg . 2011 . Eating for two: how
metabolism establishes interspecies interactions in the gut. Cell
Host Microbe . 10 : 336 – 347 .
63 . Macy , J. M. , L. G. Ljungdahl , and G. Gottschalk . 1978 . Pathway
of succinate and propionate formation in Bacteroides fragilis. J.
Bacteriol. 134 : 84 – 91 .
64 . Macy , J. M. , and I. Probst . 1979 . The biology of gastrointestinal
bacteroides. Annu. Rev. Microbiol. 33 : 561 – 594 .
65 . Pryde , S. E. , S. H. Duncan , G. L. Hold , C. S. Stewart , and H. J.
Flint . 2002 . The microbiology of butyrate formation in the human
colon. FEMS Microbiol. Lett. 217 : 133 – 139 .
66 . Ragsdale , S. W. , and E. Pierce . 2008 . Acetogenesis and the Wood-
Ljungdahl pathway of CO(2) fi xation. Biochim. Biophys. Acta . 1784 :
1873 – 1898 .
67 . Duncan , S. H. , P. Louis , and H. J. Flint . 2004 . Lactate-utilizing bac-
teria, isolated from human feces, that produce butyrate as a major
fermentation product. Appl. Environ. Microbiol. 70 : 5810 – 5817 .
68 . Louis , P. , and H. J. Flint . 2009 . Diversity, metabolism and micro-
bial ecology of butyrate-producing bacteria from the human large
intestine. FEMS Microbiol. Lett. 294 : 1 – 8 .
69 . Duncan , S. H. , A. Barcenilla , C. S. Stewart , S. E. Pryde , and
H. J. Flint . 2002 . Acetate Utilization and butyryl coenzyme A
(CoA):acetate-CoA transferase in butyrate-producing bacte-
ria from the human large intestine. Appl. Environ. Microbiol. 68 :
5186 – 5190 .
70 . Venema , K. 2010 . Role of gut microbiota in the control of energy
and carbohydrate metabolism. Curr. Opin. Clin. Nutr. Metab. Care .
13 : 432 – 438 .
71 . Duncan , S. H. , G. Holtrop , G. E. Lobley , A. G. Calder , C. S.
Stewart , and H. J. Flint . 2004 . Contribution of acetate to butyrate
formation by human faecal bacteria. Br. J. Nutr. 91 : 915 – 923 .
72 . el-Khoury , A. E. , M. Sánchez , N. K. Fukagawa , R. E. Gleason , and
V. R. Young . 1994 . Similar 24-h pattern and rate of carbon dioxide
production, by indirect calorimetry vs. stable isotope dilution, in
cancer in the European Prospective Investigation into Cancer
and Nutrition (EPIC): an observational study. Lancet . 361 :
1496 – 1501 .
30 . Musso , G. , R. Gambino , and M. Cassader . 2011 . Interactions be-
tween gut microbiota and host metabolism predisposing to obe-
sity and diabetes. Annu. Rev. Med. 62 : 361 – 380 .
31 . Bergman , E. N. 1990 . Energy contributions of volatile fatty acids
from the gastrointestinal tract in various species. Physiol. Rev. 70 :
567 – 590 .
32 . Levrat , M. A. , C. Rémésy , and C. Demigné . 1991 . High propionic
acid fermentations and mineral accumulation in the cecum of
rats adapted to different levels of inulin. J. Nutr. 121 : 1730 – 1737 .
33 . Hedemann , M. S. , P. K. Theil , and K. E. Bach Knudsen . 2009 . The
thickness of the intestinal mucous layer in the colon of rats fed various
sources of non-digestible carbohydrates. Br. J. Nutr. 102 : 117 – 125 .
34 . Marsono , Y. , R. J. Illman , J. M. Clarke , R. P. Trimble , and D. L.
Topping . 1993 . Plasma lipids and large bowel volatile fatty acids
in pigs fed on white rice, brown rice and rice bran. Br. J. Nutr. 70 :
503 – 513 .
35 . Bird , A. R. , T. Hayakawa , Y. Marsono , J. M. Gooden , I. R. Record ,
R. L. Correll , and D. L. Topping . 2000 . Coarse brown rice increases
fecal and large bowel short-chain fatty acids and starch but lowers
calcium in the large bowel of pigs. J. Nutr. 130 : 1780 – 1787 .
36 . Haenen , D. , J. Zhang , C. Souza da Silva , G. Bosch , I. M. van der
Meer , J. van Arkel , J. J. van den Borne , O. Pérez Gutiérrez , H.
Smidt , B. Kemp , et al . 2013 . A diet high in resistant starch modu-
lates microbiota composition, SCFA concentrations, and gene ex-
pression in pig intestine. J. Nutr. 143 : 274 – 283 .
37 . Topping , D. L. , R. J. Illman , J. M. Clarke , R. P. Trimble , K. A.
Jackson , and Y. Marsono . 1993 . Dietary fat and fi ber alter large
bowel and portal venous volatile fatty acids and plasma choles-
terol but not biliary steroids in pigs. J. Nutr. 123 : 133 – 143 .
38 . Cummings , J. H. , E. R. Beatty , S. M. Kingman , S. A. Bingham ,
and H. N. Englyst . 1996 . Digestion and physiological proper-
ties of resistant starch in the human large bowel. Br. J. Nutr. 75 :
733 – 747 .
39 . van Munster , I. P. , A. Tangerman , and F. M. Nagengast . 1994 .
Effect of resistant starch on colonic fermentation, bile acid me-
tabolism, and mucosal proliferation. Dig. Dis. Sci. 39 : 834 – 842 .
40 . Holt , P. R. , E. Atillasoy , J. Lindenbaum , S. B. Ho , J. R. Lupton ,
D. McMahon , and S. F. Moss . 1996 . Effects of acarbose on fecal
nutrients, colonic pH, and short-chain fatty acids and rectal pro-
liferative indices. Metabolism . 45 : 1179 – 1187 .
41 . Fleming , S. E. , A. U. O’Donnell , and J. A. Perman . 1985 . Infl uence
of frequent and long-term bean consumption on colonic function
and fermentation. Am. J. Clin. Nutr. 41 : 909 – 918 .
42 . Jenkins , D. J. A. , V. Vuksan , C. W. C. Kendall , P. Wursch , R.
Jeffcoat , S. Waring , C. C. Mehling , E. Vidgen , L. S. A. Augustin ,
and E. Wong . 1998 . Physiological effects of resistant starches on
fecal bulk, short chain fatty acids, blood lipids and glycemic index.
J. Am. Coll. Nutr. 17 : 609 – 616 .
43 . Holtug , K. , H. S. Rasmussen , and P. B. Mortensen . 1992 . An in
vitro study of short-chain fatty acid concentrations, production
and absorption in pig (Sus scrofa) colon. Comp. Biochem. Physiol.
Comp. Physiol. 103 : 189 – 197 .
44 . Smiricky-Tjardes , M. R. , C. M. Grieshop , E. A. Flickinger , L. L.
Bauer , and G. C. Fahey . 2003 . Dietary galactooligosaccharides
affect ileal and total-tract nutrient digestibility, ileal and fecal
bacterial concentrations, and ileal fermentative characteristics of
growing pigs. J. Anim. Sci. 81 : 2535 – 2545 .
45 . Velázquez , M. , C. Davies , R. Marett , J. L. Slavin , and J. M. Feirtag .
2000 . Effect of oligosaccharides and fi bre substitutes on short-
chain fatty acid production by human faecal microfl ora. Anaerobe .
6 : 87 – 92 .
46 . Bourquin , L. D. , E. C. Titgemeyer , K. A. Garleb , and G. C. Fahey .
1992 . Short-chain fatty acid production and fi ber degradation by
human colonic bacteria: effects of substrate and cell wall fraction-
ation procedures. J. Nutr. 122 : 1508 – 1520 .
47 . Bergman , E. N. , R. S. Reid , M. G. Murray , J. M. Brockway , and F.
G. Whitelaw . 1965 . Interconversions and production of volatile
fatty acids in the sheep rumen. Biochem. J. 97 : 53 – 58 .
48 . Pouteau , E. , K. Vahedi , B. Messing , B. Flourie , P. Nguyen , D.
Darmaun , and M. Krempf . 1998 . Production rate of acetate dur-
ing colonic fermentation of lactulose: a stable-isotope study in
humans. Am. J. Clin. Nutr. 68 : 1276 – 1283 .
49 . Pouteau , E. , P. Nguyen , O. Ballevre , and M. Krempf . 2003 .
Production rates and metabolism of short-chain fatty acids in the
at University of Groningen, on January 9, 2014www.jlr.orgDownloaded from
2338 Journal of Lipid Research Volume 54, 2013
94 . Musch , M. W. , C. Bookstein , Y. Xie , J. H. Sellin , and E. B. Chang .
2001 . SCFA increase intestinal Na absorption by induction of
NHE3 in rat colon and human intestinal C2/bbe cells. Am. J.
Physiol. Gastrointest. Liver Physiol. 280 : G687 – G693 .
95 . Tyagi , S. , J. Venugopalakrishnan , K. Ramaswamy , and P. K. Dudeja .
2002 . Mechanism of n-butyrate uptake in the human proximal
colonic basolateral membranes. Am. J. Physiol. Gastrointest. Liver
Physiol. 282 : G676 – G682 .
96 . Gill , R. K. , S. Saksena , W. A. Alrefai , Z. Sarwar , J. L. Goldstein ,
R. E. Carroll , K. Ramaswamy , and P. K. Dudeja . 2005 .
Expression and membrane localization of MCT isoforms along
the length of the human intestine. Am. J. Physiol. Cell Physiol.
289 : C846 – C852 .
97 . Halestrap , A. P. , and D. Meredith . 2004 . The SLC16 gene family-
from monocarboxylate transporters (MCTs) to aromatic amino
acid transporters and beyond. Pfl ugers Arch. 447 : 619 – 628 .
98 . Islam , R. , N. Anzai , N. Ahmed , B. Ellapan , C. J. Jin , S. Srivastava ,
D. Miura , T. Fukutomi , Y. Kanai , and H. Endou . 2008 . Mouse
organic anion transporter 2 (mOat2) mediates the transport
of short chain fatty acid propionate. J. Pharmacol. Sci. 106 :
525 – 528 .
99 . Shin , H. J. , N. Anzai , A. Enomoto , X. He , D. K. Kim , H. Endou ,
and Y. Kanai . 2007 . Novel liver-specifi c organic anion transporter
OAT7 that operates the exchange of sulfate conjugates for short
chain fatty acid butyrate. Hepatology . 45 : 1046 – 1055 .
100 . Roediger , W. E. 1982 . Utilization of nutrients by isolated epithe-
lial cells of the rat colon. Gastroenterology . 83 : 424 – 429 .
101 . Clausen , M. R. , and P. B. Mortensen . 1995 . Kinetic studies on
colonocyte metabolism of short chain fatty acids and glucose in
ulcerative colitis. Gut . 37 : 684 – 689 .
102 . Jørgensen , J. R. , M. R. Clausen , and P. B. Mortensen . 1997 .
Oxidation of short and medium chain C2-C8 fatty acids in
Sprague-Dawley rat colonocytes. Gut . 40 : 400 – 405 .
103 . Ballard , F. J. 1972 . Supply and utilization of acetate in mammals.
Am. J. Clin. Nutr. 25 : 773 – 779 .
104 . Knowles , S. E. , I. G. Jarrett , O. H. Filsell , and F. J. Ballard . 1974 .
Production and utilization of acetate in mammals. Biochem. J. 142 :
401 – 411 .
105 . Bloemen , J. G. , K. Venema , M. C. van de Poll , S. W. Olde Damink ,
W. A. Buurman , and C. H. Dejong . 2009 . Short chain fatty acids
exchange across the gut and liver in humans measured at surgery.
Clin. Nutr. 28 : 657 – 661 .
106 . Wiltrout , D. W. , and L. D. Satter . 1972 . Contribution of propi-
onate to glucose synthesis in the lactating and nonlactating cow. J.
Dairy Sci. 55 : 307 – 317 .
107 . Bloemen , J. G. , S. W. M. Olde Damink , K. Venema , W. A.
Buurman , R. Jalan , and C. H. C. Dejong . 2010 . Short chain fatty
acids exchange: is the cirrhotic, dysfunctional liver still able to
clear them? Clin. Nutr. 29 : 365 – 369 .
108 . Reilly , K. J. , and J. L. Rombeau . 1993 . Metabolism and poten-
tial clinical applications of short-chain fatty acids. Clin. Nutr. 12
(Suppl. 1): S97 – S105 .
109 . Brown , A. J. , S. M. Goldsworthy , A. A. Barnes , M. M. Eilert , L.
Tcheang , D. Daniels , A. I. Muir , M. J. Wigglesworth , I. Kinghorn ,
N. J. Fraser , et al . 2003 . The orphan G protein-coupled receptors
GPR41 and GPR43 are activated by propionate and other short
chain carboxylic acids. J. Biol. Chem. 278 : 11312 – 11319 .
110 . Le Poul , E. , C. Loison , S. Struyf , J. Y. Springael , V. Lannoy , M. E.
Decobecq , S. Brezillon , V. Dupriez , G. Vassart , J. Van Damme ,
et al . 2003 . Functional characterization of human receptors for
short chain fatty acids and their role in polymorphonuclear cell
activation. J. Biol. Chem. 278 : 25481 – 25489 .
111 . Nilsson , N. E. , K. Kotarsky , C. Owman , and B. Olde . 2003 .
Identifi cation of a free fatty acid receptor, FFA2R, expressed
on leukocytes and activated by short-chain fatty acids. Biochem.
Biophys. Res. Commun. 303 : 1047 – 1052 .
112 . Regard , J. B. , I. T. Sato , and S. R. Coughlin . 2008 . Anatomical
profi ling of G protein-coupled receptor expression. Cell . 135 :
561 – 571 .
113 . Hong , Y. H. , Y. Nishimura , D. Hishikawa , H. Tsuzuki , H. Miyahara ,
C. Gotoh , K. C. Choi , D. D. Feng , C. Chen , H. Lee , et al . 2005 .
Acetate and propionate short chain fatty acids stimulate adipo-
genesis via GPCR43. Endocrinology . 146 : 5092 – 5099 .
114 . Ge , H. , X. Li , J. Weiszmann , P. Wang , H. Baribault , J. Chen , H.
Tian , and Y. Li . 2008 . Activation of G protein-coupled receptor
43 in adipocytes leads to inhibition of lipolysis and suppression of
plasma free fatty acids. Endocrinology . 149 : 4519 – 4526 .
healthy adults under standardized metabolic conditions. J. Nutr.
124 : 1615 – 1627 .
73 . Annison , G. , R. J. Illman , and D. L. Topping . 2003 . Acetylated,
propionylated or butyrylated starches raise large bowel short-
chain fatty acids preferentially when fed to rats. J. Nutr. 133 :
3523 – 3528 .
74 . Jacobs , L. R. , and J. R. Lupton . 1986 . Relationship between co-
lonic luminal pH, cell proliferation, and colon carcinogenesis in
1,2-dimethylhydrazine treated rats fed high fi ber diets. Cancer Res.
46 : 1727 – 1734 .
75 . Ward , F. W. , and M. E. Coates . 1987 . Gastrointestinal pH measure-
ment in rats: infl uence of the microbial fl ora, diet and fasting.
Lab. Anim. 21 : 216 – 222 .
76 . Campbell , J. M. , G. C. Fahey , and B. W. Wolf . 1997 . Selected in-
digestible oligosaccharides affect large bowel mass, cecal and fe-
cal short-chain fatty acids, pH and microfl ora in rats. J. Nutr. 127 :
130 – 136 .
77 . Murase , M. , Y. Kimura , and Y. Nagata . 1995 . Determination of
portal short-chain fatty acids in rats fed various dietary fi bers by
capillary gas chromatography. J. Chromatogr. B Biomed. Appl. 664 :
415 – 420 .
78 . Fushimi , T. , K. Suruga , Y. Oshima , M. Fukiharu , Y. Tsukamoto ,
and T. Goda . 2006 . Dietary acetic acid reduces serum cholesterol
and triacylglycerols in rats fed a cholesterol-rich diet. Br. J. Nutr.
95 : 916 – 924 .
79 . Demigné , C. , C. Morand , M. A. Levrat , C. Besson , C. Moundras ,
and C. Rémésy . 1995 . Effect of propionate on fatty acid and cho-
lesterol synthesis and on acetate metabolism in isolated rat hepa-
tocytes. Br. J. Nutr. 74 : 209 – 219 .
80 . Todesco , T. , A. V. Rao , O. Bosello , and D. J. Jenkins . 1991 .
Propionate lowers blood glucose and alters lipid metabolism in
healthy subjects. Am. J. Clin. Nutr. 54 : 860 – 865 .
81 . Stoddart , L. A. , N. J. Smith , and G. Milligan . 2008 . International
Union of Pharmacology. LXXI. Free fatty acid receptors FFA1, -2,
and -3: pharmacology and pathophysiological functions. Pharmacol.
Rev. 60 : 405 – 417 .
82 . Ulven , T. 2012 . Short-chain free fatty acid receptors FFA2/GPR43
and FFA3/GPR41 as new potential therapeutic targets. Front.
Endocrinol. (Lausanne) . 3 : 111 .
83 . Tazoe , H. , Y. Otomo , I. Kaji , R. Tanaka , S. I. Karaki , and A.
Kuwahara . 2008 . Roles of short-chain fatty acids receptors,
GPR41 and GPR43 on colonic functions. J. Physiol. Pharmacol. 59 :
251 – 262 .
84 . Sellin , J. H. 1999 . SCFAs: the enigma of weak electrolyte transport
in the colon. News Physiol. Sci. 14 : 58 – 64 .
85 . Vidyasagar , S. , C. Barmeyer , J. Geibel , H. J. Binder , and V.
M. Rajendran . 2005 . Role of short-chain fatty acids in colonic
HCO(3) secretion. Am. J. Physiol. Gastrointest. Liver Physiol. 288 :
G1217 – G1226 .
86 . Mascolo , N. , V. M. Rajendran , and H. J. Binder . 1991 . Mechanism
of short-chain fatty acid uptake by apical membrane vesicles of rat
distal colon. Gastroenterology . 101 : 331 – 338 .
87 . Harig , J. M. , E. K. Ng , P. K. Dudeja , T. A. Brasitus , and K.
Ramaswamy . 1996 . Transport of n-butyrate into human colonic
luminal membrane vesicles. Am. J. Physiol. 271 : G415 – G422 .
88 . Harig , J. M. , K. H. Soergel , J. A. Barry , and K. Ramaswamy . 1991 .
Transport of propionate by human ileal brush-border membrane
vesicles. Am. J. Physiol. 260 : G776 – G782 .
89 . Hadjiagapiou , C. , L. Schmidt , P. K. Dudeja , T. J. Layden , and
K. Ramaswamy . 2000 . Mechanism(s) of butyrate transport in
Caco-2 cells: role of monocarboxylate transporter 1. Am. J. Physiol.
Gastrointest. Liver Physiol. 279 : G775 – G780 .
90 . Teramae , H. , T. Yoshikawa , R. Inoue , K. Ushida , K. Takebe , J.
Nio-Kobayashi , and T. Iwanaga . 2010 . The cellular expression of
SMCT2 and its comparison with other transporters for monocar-
boxylates in the mouse digestive tract. Biomed. Res. 31 : 239 – 249 .
91 . Takebe , K. , J. Nio , M. Morimatsu , S. Karaki , A. Kuwahara , I. Kato ,
and T. Iwanaga . 2005 . Histochemical demonstration of a Na(+)-
coupled transporter for short-chain fatty acids (slc5a8) in the in-
testine and kidney of the mouse. Biomed. Res. 26 : 213 – 221 .
92 . Gupta , N. , P. M. Martin , P. D. Prasad , and V. Ganapathy . 2006 .
SLC5A8 (SMCT1)-mediated transport of butyrate forms the basis
for the tumor suppressive function of the transporter. Life Sci. 78 :
2419 – 2425 .
93 . Gonçalves , P. , J. R. Araújo , and F. Martel . 2011 . Characterization
of butyrate uptake by nontransformed intestinal epithelial cell
lines. J. Membr. Biol. 240 : 35 – 46 .
at University of Groningen, on January 9, 2014www.jlr.orgDownloaded from
Short-chain fatty acids and host energy metabolism 2339
133 . Carmen , G. Y. , and S. M. Víctor . 2006 . Signalling mechanisms
regulating lipolysis. Cell. Signal. 18 : 401 – 408 .
134 . Houslay , M. D. , and G. Milligan . 1997 . Tailoring cAMP-signalling
responses through isoform multiplicity. Trends Biochem. Sci. 22 :
217 – 224 .
135 . Kimura , I. , K. Ozawa , D. Inoue , T. Imamura , K. Kimura , T.
Maeda , K. Terasawa , D. Kashihara , K. Hirano , T. Tani , et al .
2013 . The gut microbiota suppresses insulin-mediated fat ac-
cumulation via the short-chain fatty acid receptor GPR43. Nat.
Commun. 4 : 1829 .
136 . Friedman , J. M. , and J. L. Halaas . 1998 . Leptin and the regulation
of body weight in mammals. Nature . 395 : 763 – 770 .
137 . Sakakibara , S. , T. Yamauchi , Y. Oshima , Y. Tsukamoto , and T.
Kadowaki . 2006 . Acetic acid activates hepatic AMPK and reduces
hyperglycemia in diabetic KK-A(y) mice. Biochem. Biophys. Res.
Commun. 344 : 597 – 604 .
138 . Boillot , J. , C. Alamowitch , A. M. Berger , J. Luo , F. Bruzzo , F. R.
Bornet , and G. Slama . 1995 . Effects of dietary propionate on
hepatic glucose production, whole-body glucose utilization, car-
bohydrate and lipid metabolism in normal rats. Br. J. Nutr. 73 :
241 – 251 .
139 . Batterham , R. L. , M. A. Cowley , C. J. Small , H. Herzog , M. A.
Cohen , C. L. Dakin , A. M. Wren , A. E. Brynes , M. J. Low , M. A.
Ghatei , et al . 2002 . Gut hormone PYY(3-36) physiologically inhib-
its food intake. Nature . 418 : 650 – 654 .
140 . van den Hoek , A. M. , A. C. Heijboer , E. P. M. Corssmit , P. J.
Voshol , J. A. Romijn , L. M. Havekes , and H. Pijl . 2004 . PYY3-36
reinforces insulin action on glucose disposal in mice fed a high-fat
diet. Diabetes . 53 : 1949 – 1952 .
141 . Boey , D. , S. Lin , T. Karl , P. Baldock , N. Lee , R. Enriquez , M.
Couzens , K. Slack , R. Dallmann , A. Sainsbury , et al . 2006 . Peptide
YY ablation in mice leads to the development of hyperinsulinae-
mia and obesity. Diabetologia . 49 : 1360 – 1370 .
142 . Karaki , S. , H. Tazoe , H. Hayashi , H. Kashiwabara , K. Tooyama ,
Y. Suzuki , and A. Kuwahara . 2008 . Expression of the short-chain
fatty acid receptor, GPR43, in the human colon. J. Mol. Histol. 39 :
135 – 142 .
143 . Karaki , S. , R. Mitsui , H. Hayashi , I. Kato , H. Sugiya , T. Iwanaga , J.
B. Furness , and A. Kuwahara . 2006 . Short-chain fatty acid recep-
tor, GPR43, is expressed by enteroendocrine cells and mucosal
mast cells in rat intestine. Cell Tissue Res. 324 : 353 – 360 .
144 . Tazoe , H. , Y. Otomo , S. Karaki , I. Kato , Y. Fukami , M. Terasaki ,
and A. Kuwahara . 2009 . Expression of short-chain fatty acid recep-
tor in the human colon. Biomed Res . 30 : 149 – 156 .
145 . Tolhurst , G. , H. Heffron , Y. S. Lam , H. E. Parker , A. M. Habib ,
E. Diakogiannaki , J. Cameron , J. Grosse , F. Reimann , and F. M.
Gribble . 2012 . Short-chain fatty acids stimulate glucagon-like
peptide-1 secretion via the G-protein–coupled receptor FFAR2.
Diabetes . 61 : 364 – 371 .
146 . Cherbut , C. , L. Ferrier , C. Rozé , Y. Anini , H. Blottière , G. Lecannu ,
and J. Galmiche . 1998 . Short-chain fatty acids modify colonic mo-
tility through nerves and polypeptide YY release in the rat. Am. J.
Physiol. 275 : G1415 – G1422 .
147 . Cuche , G. , J. C. Cuber , and C. H. Malbert . 2000 . Ileal short-chain
fatty acids inhibit gastric motility by a humoral pathway. Am. J.
Physiol. Gastrointest. Liver Physiol. 279 : G925 – G930 .
148 . Barrera , J. G. , D. A. Sandoval , D. A. D’Alessio , and R. J. Seele .
2011 . GLP-1 and energy balance: an integrated model of short-
term and long-term control. Nat. Rev. Endocrinol. 7 : 507 – 516 .
149 . Zhou , J. , R. J. Martin , R. T. Tulley , A. M. Raggio , K. L. McCutcheon ,
L. Shen , S. C. Danna , S. Tripathy , M. Hegsted , and M. J. Keenan .
2008 . Dietary resistant starch upregulates total GLP-1 and PYY in a
sustained day-long manner through fermentation in rodents. Am.
J. Physiol. Endocrinol. Metab. 295 : E1160 – E1166 .
150 . Hooda , S. , J. J. Matte , T. Vasanthan , and R. T. Zijlstra . 2010 .
Dietary oat beta-glucan reduces peak net glucose fl ux and insulin
production and modulates plasma incretin in portal-vein cath-
eterized grower pigs. J. Nutr. 140 : 1564 – 1569 .
151 . Freeland , K. R. , and T. M. Wolever . 2010 . Acute effects of intra-
venous and rectal acetate on glucagon-like peptide-1, peptide YY,
ghrelin, adiponectin and tumour necrosis factor-alpha. Br. J. Nutr.
103 : 460 – 466 .
152 . Rodwell , V. W. , J. L. Nordstrom , and J. J. Mitschelen . 1976 .
Regulation of HMG-CoA reductase. Adv. Lipid Res. 14 : 1 – 74 .
153 . Bush , R. S. , and L. P. Milligan . 1971 . Study of the mechanism of
inhibition of ketogenesis by propionate in bovine liver. Can. J.
Anim. Sci. 51 : 121 – 127 .
115 . Samuel , B. S. , A. Shaito , T. Motoike , F. E. Rey , F. Backhed , J.
K. Manchester , R. E. Hammer , S. C. Williams , J. Crowley , M.
Yanagisawa , et al . 2008 . Effects of the gut microbiota on host
adiposity are modulated by the short-chain fatty-acid binding G
protein-coupled receptor, Gpr41. Proc. Natl. Acad. Sci. USA . 105 :
16767 – 16772 .
116 . Sleeth , M. L. , E. L. Thompson , H. E. Ford , S. E. K. Zac-Varghese ,
and G. Frost . 2010 . Free fatty acid receptor 2 and nutrient sens-
ing a proposed role for fi bre, fermentable carbohydrates and
short-chain fatty acids in appetite regulation. Nutr. Res. Rev. 23 :
135 – 145 .
117 . Bjursell , M. , T. Admyre , M. Goransson , A. E. Marley , D. M. Smith ,
J. Oscarsson , and M. Bohlooly-Y. 2011 . Improved glucose control
and reduced body fat mass in free fatty acid receptor 2-defi cient
mice fed a high-fat diet. Am. J. Physiol. Endocrinol. Metab. 300 :
E211 – E220 .
118 . Zaibi , M. S. , C. J. Stocker , J. O’Dowd , A. Davies , M. Bellahcene , M.
A. Cawthorne , A. J. H. Brown , D. M. Smith , and J. R. S. Arch . 2010 .
Roles of GPR41 and GPR43 in leptin secretory responses of murine
adipocytes to short chain fatty acids. FEBS Lett. 584 : 2381 – 2386 .
119 . Xiong , Y. , N. Miyamoto , K. Shibata , M. A. Valasek , T. Motoike ,
R. M. Kedzierski , and M. Yanagisawa . 2004 . Short-chain fatty
acids stimulate leptin production in adipocytes through the G
protein-coupled receptor GPR41. Proc. Natl. Acad. Sci. USA . 101 :
1045 – 1050 .
120 . Covington , D. K. , C. A. Briscoe , A. J. Brown , and C. K.
Jayawickreme . 2006 . The G-protein-coupled receptor 40 family
(GPR40-GPR43) and its role in nutrient sensing. Biochem. Soc.
Trans. 34 : 770 – 773 .
121 . Yamashita , H. , K. Fujisawa , E. Ito , S. Idei , N. Kawaguchi , M.
Kimoto , M. Hiemori , and H. Tsuji . 2007 . Improvement of obesity
and glucose tolerance by acetate in type 2 diabetic Otsuka Long-
Evans Tokushima fatty (OLETF) rats. Biosci. Biotechnol. Biochem.
71 : 1236 – 1243 .
122 . Lin , H. V. , A. Frassetto , E. J. J. Kowalik , A. R. Nawrocki , M. M. Lu ,
J. R. Kosinski , J. A. Hubert , D. Szeto , X. Yao , G. Forrest , et al . 2012 .
Butyrate and propionate protect against diet-induced obesity and
regulate gut hormones via free fatty acid receptor 3-independent
mechanisms. PLoS ONE . 7 : e35240 .
123 . Kondo , T. , M. Kishi , T. Fushimi , and T. Kaga . 2009 . Acetic acid
upregulates the expression of genes for fatty acid oxidation en-
zymes in liver to suppress body fat accumulation. J. Agric. Food
Chem. 57 : 5982 – 5986 .
124 . Kondo , T. , M. Kishi , T. Fushimi , S. Ugajin , and T. Kaga . 2009 .
Vinegar intake reduces body weight, body fat mass, and serum
triglyceride levels in obese Japanese subjects. Biosci. Biotechnol.
Biochem. 73 : 1837 – 1843 .
125 . Zydowo , M. M. , R. T. Smolen´ski , and J. Swierczyn´ski . 1993 .
Acetate-induced changes of adenine nucleotide levels in rat liver.
Metabolism . 42 : 644 – 648 .
126 . Lin , J. , C. Handschin , and B. M. Spiegelman . 2005 . Metabolic con-
trol through the PGC-1 family of transcription coactivators. Cell
Metab. 1 : 361 – 370 .
127 . Jäger , S. , C. Handschin , J. St.-Pierre , and B. M. Spiegelman . 2007 .
AMP-activated protein kinase (AMPK) action in skeletal muscle
via direct phosphorylation of PGC-1 . Proc. Natl. Acad. Sci. USA .
104 : 12017 – 12022 .
128 . Minokoshi , Y. , Y. B. Kim , O. D. Peroni , L. G. Fryer , C. Müller , D.
Carling , and B. B. Kahn . 2002 . Leptin stimulates fatty-acid oxi-
dation by activating AMP-activated protein kinase. Nature . 415 :
339 – 343 .
129 . Yu , X. , S. McCorkle , M. Wang , Y. Lee , J. Li , A. K. Saha , R. H.
Unger , and N. B. Ruderman . 2004 . Leptinomimetic effects of
the AMP kinase activator AICAR in leptin-resistant rats: preven-
tion of diabetes and ectopic lipid deposition. Diabetologia . 47 :
2012 – 2021 .
130 . Robertson , M. D. , A. S. Bickerton , A. L. Dennis , H. Vidal , and
K. N. Frayn . 2005 . Insulin-sensitizing effects of dietary resistant
starch and effects on skeletal muscle and adipose tissue metabo-
lism. Am. J. Clin. Nutr. 82 : 559 – 567 .
131 . Suokas , A. , M. Kupari , J. Heikkilä , K. Lindros , and R. Ylikahri .
1988 . Acute cardiovascular and metabolic effects of acetate in
men. Alcohol. Clin. Exp. Res. 12 : 52 – 58 .
132 . Al-Lahham , S. H. , M. P. Peppelenbosch , H. Roelofsen , R. J. Vonk ,
and K. Venema . 2010 . Biological effects of propionic acid in hu-
mans; metabolism, potential applications and underlying mecha-
nisms. Biochim. Biophys. Acta . 1801 : 1175 – 1183 .
at University of Groningen, on January 9, 2014www.jlr.orgDownloaded from
2340 Journal of Lipid Research Volume 54, 2013
154 . Wright , R. S. , J. W. Anderson , and S. R. Bridges . 1990 . Propionate
inhibits hepatocyte lipid synthesis. Proc. Soc. Exp. Biol. Med. 195 :
26 – 29 .
155 . Hara , H. , S. Haga , Y. Aoyama , and S. Kiriyama . 1999 . Short-chain
fatty acids suppress cholesterol synthesis in rat liver and intestine.
J. Nutr. 129 : 942 – 948 .
156 . Carling , D. , P. R. Clarke , V. A. Zammit , and D. G. Hardie . 1989 .
Purifi cation and characterization of the AMP-activated protein ki-
nase. Eur. J. Biochem. 186 : 129 – 136 .
157 . Corton , J. M. , J. G. Gillespie , and D. G. Hardie . 1994 . Role of the
AMP-activated protein kinase in the cellular stress response. Curr.
Biol. 4 : 315 – 324 .
158 . Henin , N. , M. F. Vincent , H. E. Gruber , and G. Van den Berghe .
1995 . Inhibition of fatty acid and cholesterol synthesis by stimula-
tion of AMP-activated protein kinase. FASEB J. 9 : 541 – 546 .
159 . Turnbaugh , P. J. , R. E. Ley , M. A. Mahowald , V. Magrini , E. R.
Mardis , and J. I. Gordon . 2006 . An obesity-associated gut micro-
biome with increased capacity for energy harvest. Nature . 444 :
1027 – 1031 .
160 . Murphy , E. F. , P. D. Cotter , S. Healy , T. M. Marques , O. O’Sullivan ,
F. Fouhy , S. F. Clarke , P. W. O’Toole , E. M. Quigley , C. Stanton ,
et al . 2010 . Composition and energy harvesting capacity of the
gut microbiota: relationship to diet, obesity and time in mouse
models. Gut . 59 : 1635 – 1642 .
161 . Schwiertz , A. , D. Taras , K. Schäfer , S. Beijer , N. A. Bos , C. Donus ,
and P. D. Hardt . 2010 . Microbiota and SCFA in lean and over-
weight healthy subjects. Obesity (Silver Spring) . 18 : 190 – 195 .
162 . Bäckhed , F. , J. K. Manchester , C. F. Semenkovich , and J. I.
Gordon . 2007 . Mechanisms underlying the resistance to diet-in-
duced obesity in germ-free mice. Proc. Natl. Acad. Sci. USA . 104 :
979 – 984 .
163 . Høverstad , T. , and T. Midtvedt . 1986 . Short-chain fatty acids in
germfree mice and rats. J. Nutr. 116 : 1772 – 1776 .
164 . Ley , R. E. , F. B. Ãckhed , P. Turnbaugh , C. A. Lozupone , R. D.
Knight , and J. I. Gordon . 2005 . Obesity alters gut microbial ecol-
ogy. Proc. Natl. Acad. Sci. USA . 102 : 11070 – 11075 .
165 . Ley , R. E. , P. J. Turnbaugh , S. Klein , and J. I. Gordon . 2006 .
Microbial ecology: human gut microbes associated with obesity.
Nature . 444 : 1022 – 1023 .
166 . Khan , K. M. , and C. A. Edwards . 2002 . Effect of substrate concen-
tration on short chain fatty acid production in in vitro cultures of
human faeces. Microb Ecol Health Dis . 14 : 160 – 164 .
at University of Groningen, on January 9, 2014www.jlr.orgDownloaded from
