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There is now an abundance of evidence to show that short-chain fatty acids (SCFAs) play an important role in the maintenance of health and the development of disease. SCFAs are a subset of fatty acids that are produced by the gut microbiota during the fermentation of partially and nondigestible polysaccharides. The highest levels of SCFAs are found in the proximal colon, where they are used locally by enterocytes or transported across the gut epithelium into the bloodstream. Two major SCFA signaling mechanisms have been identified, inhibition of histone deacetylases (HDACs) and activation of G-protein-coupled receptors (GPCRs). Since HDACs regulate gene expression, inhibition of HDACs has a vast array of downstream consequences. Our understanding of SCFA-mediated inhibition of HDACs is still in its infancy. GPCRs, particularly GPR43, GPR41, and GPR109A, have been identified as receptors for SCFAs. Studies have implicated a major role for these GPCRs in the regulation of metabolism, inflammation, and disease. SCFAs have been shown to alter chemotaxis and phagocytosis; induce reactive oxygen species (ROS); change cell proliferation and function; have anti-inflammatory, antitumorigenic, and antimicrobial effects; and alter gut integrity. These findings highlight the role of SCFAs as a major player in maintenance of gut and immune homeostasis. Given the vast effects of SCFAs, and that their levels are regulated by diet, they provide a new basis to explain the increased prevalence of inflammatory disease in Westernized countries, as highlighted in this chapter.
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CHAPTER THREE
The Role of Short-Chain Fatty
Acids in Health and Disease
Jian Tan, Craig McKenzie, Maria Potamitis, Alison N. Thorburn,
Charles R. Mackay
1
, Laurence Macia
1
Department of Immunology, Monash University, Clayton, Victoria, Australia
1
Corresponding authors: e-mail address: charles.mackay@monash.edu; laurence.macia@monash.edu
Contents
1. Introduction 92
1.1 The production of SCFAs 92
1.2 Transport of SCFAs 96
2. SCFA Sensing and Signal Transduction 97
2.1 HDAC inhibitors 97
2.2 G-protein-coupled receptors 99
3. Varied Functions of SCFAs 103
3.1 Anti-inflammatory and antitumorigenic roles 103
3.2 SCFAs and antimicrobial activities 106
3.3 SCFAs and gut integrity 107
4. Integrative View of the Gut Microbiota, SCFAs, and Disease 109
5. Perspective 112
References 112
Abstract
There is now an abundance of evidence to show that short-chain fatty acids (SCFAs) play
an important role in the maintenance of health and the development of disease. SCFAs
are a subset of fatty acids that are produced by the gut microbiota during the fermen-
tation of partially and nondigestible polysaccharides. The highest levels of SCFAs are
found in the proximal colon, where they are used locally by enterocytes or transported
across the gut epithelium into the bloodstream. Two major SCFA signaling mechanisms
have been identified, inhibition of histone deacetylases (HDACs) and activation of
G-protein-coupled receptors (GPCRs). Since HDACs regulate gene expression, inhibition
of HDACs has a vast array of downstream consequences. Our understanding of SCFA-
mediated inhibition of HDACs is still in its infancy. GPCRs, particularly GPR43, GPR41, and
GPR109A, have been identified as receptors for SCFAs. Studies have implicated a major
role for these GPCRs in the regulation of metabolism, inflammation, and disease. SCFAs
have been shown to alter chemotaxis and phagocytosis; induce reactive oxygen species
(ROS); change cell proliferation and function; have anti-inflammatory, antitumorigenic,
and antimicrobial effects; and alter gut integrity. These findings highlight the role of
Advances in Immunology, Volume 121 #2014 Elsevier Inc.
ISSN 0065-2776 All rights reserved.
http://dx.doi.org/10.1016/B978-0-12-800100-4.00003-9
91
SCFAs as a major player in maintenance of gut and immune homeostasis. Given the vast
effects of SCFAs, and that their levels are regulated by diet, they provide a new basis to
explain the increased prevalence of inflammatory disease in Westernized countries, as
highlighted in this chapter.
1. INTRODUCTION
There is increasing evidence implicating the gut microbiota as critical
contributors to host health and gut/immune homeostasis. This may be
achieved, at least in part, through the release of short-chain fatty acids
(SCFAs), which are the main bacterial metabolites produced following
the fermentation of dietary fiber and resistant starches by specific colonic
anaerobic bacteria. SCFAs are a subset of saturated fatty acids containing
six or less carbon molecules that include acetate, propionate, butyrate, pen-
tanoic (valeric) acid, and hexanoic (caproic) acid. Recent advances in the
study of SCFAs, especially acetate, propionate, and butyrate, have
highlighted their effects on various systems both at cellular and molecular
levels. Indeed SCFAs or their deficiency may affect the pathogenesis of a
diverse range of diseases, from allergies and asthma to cancers, autoimmune
diseases, metabolic diseases, and neurological diseases.
1.1. The production of SCFAs
SCFAs are carboxylic acids defined by the presence of an aliphatic tail of two to
six carbons. Although SCFAs can be produced naturally through host meta-
bolic pathways particularly in the liver, the major site of production is the colon
which requires the presenceof specific colonicbacteria explaining their absence
in germ-free mice (Hoverstad & Midtvedt, 1986). Acetate (C2), propionate
(C3), and butyrate (C4), beingthe major SCFA released through fermentation
of fiber and resistant starches, are mostly released in the proximal colon in very
high concentrations (70–140 mM) while their concentrations are lower in the
distal colon (20–70 mM) and in thedistal ileum (20–40 mM) (Wong, de Souza,
Kendall, Emam, & Jenkins, 2006). The molar ratio of acetate, propionate, and
butyrate production in the colon is 60:25:15, respectively (Tazoe et al., 2008),
although proportions can vary depending on factors such as diet, microbiota
composition, site of fermentation, and host genotype (Hamer et al., 2008).
Butyrate is mostly utilized by colonocytes while acetate and propionate reach
the liver through the portal vein. Propionate is subsequently metabolized by
hepatocytes while acetate either remains in the liver or is released systemically
92 Jian Tan et al.
to the peripheral venous system (Pomare, Branch, & Cummings, 1985). Thus,
only acetate is usually detectable in peripheral blood. Extensive research has
highlighted the beneficial effects of SCFAs on health, detailed below in this
chapter. Health authorities have thus established a recommended daily intake
of fiber, which according to the World Health Organization is 20 g per
1000 kcal consumed (in adults) and this quantity is reached through the daily
consumption of grains as well as 400 g per day of fresh fruits and vegetables
(www.who.int). Notably, the typical consumption of fiber in most Western
countries is much less than this (King, Mainous, & Lambourne, 2012)and
consumption of fiber is inversely related to premature death from all causes
of disease (Park, Subar, Hollenbeck, & Schatzkin, 2011)
1.1.1 Substrates for SCFA production
Indigestible saccharides are the major substrates leading to SCFA produc-
tion. Polysaccharides are subdivided into three categories: starch, starch-like,
and nonstarch polysaccharides (NSPs). Starch, such as amylose, and starch-
like polysaccharides, such as glycogen, consist of polymers of glucose linked
by alpha 1–4 and alpha 1–6 glycosidic bonds. These bonds are broken down
by salivary, pancreatic, and intestinal brush barrier enzymes and are thus
digestible by mammals. Under healthy conditions, starch and starch-like
polysaccharides are fully digested in the small intestine yielding glucose.
Polysaccharides that are undigested or partially digested in the small intestine
are able to undergo a process of fermentation by specific colonic anaerobic
bacteria leading to the release of SCFAs in addition to gases and heat. These
polysaccharides are called fermentable polysaccharides and are subclassified
as NSPs, or dietary fibers, and resistant starch (RS). Depending on their
degree of solubility, fibers are subclassified into insoluble or soluble fibers
and in both cases are found in plant cell walls. Cellulose and lignin are exam-
ples of insoluble fibers while pectin substances or gums forming a gel in
water are classified as soluble fibers. Insoluble fibers are highly fermentable
and hence generate greater quantities of SCFA in the colon while soluble
fibers have a rather low fermentability but increase fecal bulking and
decrease colonic transit time. RS can be subdivided into four types: physi-
cally trapped starch (in coarse grains), RS granules naturally rich in amylose
(i.e., raw potato flour), retrograded starch (i.e., cooked and cooled potato),
and chemically modified starch (i.e., processed foods) (Englyst, Kingman, &
Cummings, 1992). RS is considered as the most powerful butyrogenic
substrate where fermentation of RS in vitro as well as in vivo generally results
in a significant higher level of butyrate production compared to NSP
93The Role of Short-Chain Fatty Acids in Health and Disease
(Englyst et al., 1992). Oligosaccharides, defined by a short chain of mono-
saccharide units, such as galactooligosaccharides, fructooligosaccharides,
mannanoligosaccharides, and chitooligosaccharides are also substrates for
SCFAs (Pan, Chen, Wu, Tang, & Zhao, 2009). Finally, to a lesser extent,
some SCFAs such as isobutyrate and isovalerate are produced during the
catabolism of branched chain amino acids valine, leucine, and isoleucine
and intermediate of fermentation in the microbiota such as lactate or ethanol
can also be metabolized into SCFA (Macfarlane & Macfarlane, 2003).
1.1.2 Mechanism of SCFA production
The process involved in the production of SCFAs from fiber involves com-
plex enzymatic pathways that are active in an extensive number of bacterial
species. The most general pathway of SCFA production in bacteria is via the
glycolytic pathway, although certain groups of bacteria such as the
Bifidobacteria can utilize the pentose phosphate pathway to produce
the same metabolites (Cronin, Ventura, Fitzgerald, & van Sinderen, 2011;
Macfarlane & Macfarlane, 2003). Other pathways utilizing a variety of sub-
strates are also able to produce SCFAs. Radioisotope analysis by Miller and
Wolin (1996) demonstrated that a major pathway of acetate production by
bacteria was via the oxygen-sensitive Wood–Ljungdahl pathway and is reg-
arded as the most efficient pathway of acetate production (Fast &
Papoutsakis, 2012). Using similar methods they show that propionate was
generally generated by a carbon dioxide fixation pathway while butyrate
was most commonly formed by conventional acetyl-Scoenzyme
A condensation (Miller & Wolin, 1996). Other pathways, such as the
Bifidobacterium pathway (fructose-6-phosphate phosphoketolase pathway)
found in the Bifidobacterium genus are able to utilize monosaccharides in a
unique manner to ultimately generate SCFAs (Pokusaeva, Fitzgerald, & van
Sinderen, 2011). These results suggest that different species possessing spe-
cific enzymes are involved in the production of the various SCFAs. Indeed,
the Wood–Ljungdahl pathway is typically found in acetate-producing bac-
teria (known as acetogens) where the majority are of the Firmicutes phylum
(Ragsdale & Pierce, 2008). On the other hand, the major groups involved in
the production of butyrate are of the Cytophaga and Flavobacterium group
belonging to the Bacteroidetes phylum (Guilloteau et al., 2010). Specific
species of bacteria characterized by their high levels of butyrate production
include Clostridium leptum,Roseburia species, Faecalibacterium prausnitzii, and
Coprococcus species belonging to both the Firmicutes and Bacteroidetes phyla
(Guilloteau et al., 2010).
94 Jian Tan et al.
The production of SCFAs is a highly complex and dynamic process. For
example, butyrate and propionate may be degraded into the smaller two car-
bon chain acetate by sulfate- or nitrate-reducing acetogenic bacteria such as
Acetobacterium,Acetogenium,Eubacterium,andClostridium species (Westermann,
Ahring, & Mah, 1989). However, increased proportion of butyrate-
producing or -consuming species such as F. prausnitzii and Roseburia species
can reverse this process (Duncan et al., 2004). Such interactions can involve
the mutualistic production of SCFAs asdemonstrated by the cocolonization of
Bacteroides thetaiotaomicron and Eubacterium rectale where acetate produced by
B. thetaiotaomicron acted as a substrate for butyrate generation by E. rectale
(Mahowald et al., 2009).
In addition to enzymatic requirements, expression of protein transporters
is also imperative for SCFA production. For example, the presence of ATP-
binding cassette (ABC) transporters in Bifidobacterium longum is crucial for the
uptake and transport of substrates, such as fructose, required for acetate pro-
duction (Davidson & Chen, 2004; Fukuda et al., 2011). Another trans-
porter, the PEP translocation group or the phosphotransferase system
(PTS) is able to transport carbohydrates which can be subsequently metab-
olized to produce SCFAs (Postma, Lengeler, & Jacobson, 1993; Zoetendal
et al., 2012). Genomic analysis revealed that Bacteroidetes possesses more
polysaccharide-degrading enzymes but less ABC transporters and fewer
PTS than the Firmicutes (Mahowald et al., 2009) suggesting that despite
having the machinery to produce SCFAs they might not efficiently uptake
the substrate necessary for their production. However, Firmicutes may be
excellent scavenger of acetate through their ABC transporters and can
uptake acetate to produce butyrate and propionate as fermentative
by-products. It has therefore been hypothesized that the two predominant
phyla could exist in a balance whereby acetate from Bacteroidetes is used to
produce butyrate and propionate by Firmicutes (Mahowald et al., 2009).
Therefore, the complex and delicate interaction within the microbiota
may also control the proportion and levels of SCFAs in the gut lumen.
Accordingly, prebiotics (agents favoring the growth of beneficial bacteria)
or probiotic (introduction of beneficial bacteria) agents altering such balance
may modulate the production of SCFAs.
1.1.3 Manipulation of SCFA production via modulation of microbiota
Dietary changes can alter the composition of the gut microbiota in as little as
a day (Wanders, Graff, & Judd, 2012) and even minute alteration of dietary
factors such as fiber content could shape microbial communities (Donohoe
95The Role of Short-Chain Fatty Acids in Health and Disease
et al., 2011). The biggest issue presented by a Western diet typically high in
fat and digestible saccharides is that nutrients are mostly absorbed in the duo-
denum leaving very few substrates for the colonic bacteria. Consequently,
this results in dysbiosis, the impairment of microbiota composition and
increased susceptibility to inflammatory diseases such as inflammatory bowel
diseases (IBDs) or colon cancer. On the other hand, in rural areas where the
diet is closer to the Paleolithic diet comprising of fruit and vegetables
enriched in fibers and RS, the prevalence of these inflammatory diseases
is low while SCFA and presence of SCFA-producing bacteria are signifi-
cantly more elevated (De Filippo et al., 2010). These data aligns with a “diet
hypothesis” which suggests that adequate intake of fiber promotes a healthy
microbiota that significantly reduces the prevalence of inflammatory dis-
eases, notably through the release of SCFA (Macia et al., 2012;
Maslowski & Mackay, 2011). Despite intense public health efforts to pro-
mote the beneficial effects of a healthy diet in Western countries, the inci-
dence of obesity and inflammatory diseases are still increasing suggesting that
other approaches must be explored. One alternative could be to provide
food supplements such as the prebiotic inulin-type fructans, which have
been shown to promote Bifidobacteria at the expense of Roseburia species
and of Clostridium cluster XIVa in mice (Dewulf et al., 2011). The other
alternative would be to directly introduce a cocktail of beneficial bacteria
including the SCFA producer Bifidobacteria into solution, such as yogurt,
similar to how some currently available probiotics products are consumed.
One study has shown that gavage of mice with B. longum increased the pro-
duction of acetate (Xiong et al., 2004) and reduced their susceptibility to
infection. Another study showed that mice inoculated with VSL#3 (com-
mercial formula containing eight naturally occurring probiotic strains of
bacteria) showed protection against acute DSS-induced colitis (Mennigen
et al., 2009). This suggests that even if all the mechanisms behind the use
of probiotics are not fully understood, such as their rate of survival or site
of action, they remain to be a very promising therapeutic strategy.
1.2. Transport of SCFAs
As discussed, while the majority of SCFAs are generated and utilized within
the vicinity of the gut, a small proportion of propionate and acetate reaches
the liver where they can be used as substrates for the energy-producing tri-
carboxylic acid cycle and efficiently metabolized to produce glucose. A small
percent of SCFAs in the gut exists as unionized forms and can directly cross
96 Jian Tan et al.
the epithelial barrier. However, most exists in an ionized state and requires
specialized transporters for their uptake. Therefore, the passage of the major-
ity of SCFAs across the mucosa involves active transport mediated by two
main receptors: the monocarboxylate transporter 1 (MCT-1) and the
sodium-coupled monocarboxylate transporter 1 (SMCT-1) receptors. Both
MCT-1 and SMCT-1 are highly expressed on colonocytes and also along
the entire gastrointestinal tract including the small intestine and the cecum
(Iwanaga, Takebe, Kato, Karaki, & Kuwahara, 2006). Additionally, MCT-1
is also highly expressed on lymphocytes suggesting the importance of intra-
cellular SCFA uptake by these cells (Halestrap & Wilson, 2012). Addition-
ally, SMCT-1 is expressed on the kidney and thyroid gland. SMCT-1 binds
SCFAs in order of affinity butyrate >propionate >acetate (Ganapathy,
Gopal, Miyauchi, & Prasad, 2005). Unabsorbed SCFAs are excreted.
2. SCFA SENSING AND SIGNAL TRANSDUCTION
The ability of SCFAs to modulate biological responses of the host
depends on two major mechanisms. The first involves the direct inhibition
of histone deacetylases HDACs to directly regulate gene expression. Intrin-
sic HDAC inhibitor (HDACi) activity is particularly characteristic of the
SCFAs butyrate and propionate. The second mechanism for SCFA effects
is signaling through G-protein-coupled receptors (GPCRs). The major
GPCRs activated by SCFAs are GPR41, GPR43, and GPR109A.
2.1. HDAC inhibitors
Acetylation of lysine residues within histones induces gene activation by facil-
itating the access of transcription factors to promoter regions (MacDonald &
Howe, 2009). HDACs remove acetyl groups from histones (Kim & Bae,
2011); as such, inhibition of HDAC activity or expression can increase gene
transcription by increasing histone acetylation. SCFAs inhibit HDAC activity,
and may therefore alter gene expression in a wide variety of cells.
Of all the SCFAs, butyrate is considered to be the most potent inhibitor of
HDAC activity. Indeed, butyrate exhibits a stronger HDAC inhibitory activity
than propionate as demonstrated in both HeLa (Boffa, Vidali, Mann, & Allfrey,
1978) and colon cancer cell lines whereas acetate appeared to have very little or
no or effect (Hinnebusch, Meng, Wu, Archer,& Hodin, 2002; Kiefer, Beyer-
Sehlmeyer, & Pool-Zobel, 2006; Waldecker, Kautenburger, Daumann,
Busch, & Schrenk, 2008). However, this lack of effect on HDACs by acetate
may be tissue dependent, since others have shown that acetate can inhibit
97The Role of Short-Chain Fatty Acids in Health and Disease
HDACs. In one study, treatment of hepatoma tissue (Sealy & Chalkley, 1978)
with acetate, propionate, or butyrate leads to a global increase in histone acet-
ylation. In the same vein,orally administered acetate has been shown to inhibit
both HDAC2 activity and protein expression in the rodent brain (Soliman &
Rosenberger, 2011). Thus, HDAC inhibition by SCFAs depends not only on
the type of SCFA but also on which tissue or cell type they are acting.
2.1.1 Mechanism behind SCFA-mediated HDAC inhibition
While the exact mechanism behind SCFA inhibition of HDACs is not
known, SCFAs might either act directly on HDACs by entering into the
cells via transporters or indirectly through the activation of GPCRs (see
below). Transporters such as SMCT-1 could be good candidates. Indeed,
expression of SMCT-1 was required for butyrate- and propionate-induced
blockade of murine dendritic cell development, which correlated with a
global increase in HDAC inhibition and DNA acetylation (Singh et al.,
2010). Thus, the transport of SCFAs into cells via SMCT-1 may account
for the observed global inhibition of HDACs by propionate and butyrate
and the subsequent blockade of enzymatic activity. Direct inhibitory activity
of SCFAs on HDACs has been highlighted by the fact that while one buty-
rate molecule is a noncompetitive inhibitor that does not interfere with the
binding of HDACs to their substrates, two molecules of butyrate may com-
petitively occupy the hydrophobic cleft of the active site of HDACs
(Cousens, Gallwitz, & Alberts, 1979). This is similar to the action of the
well-characterized HDACi trichostatin A (TSA) (Davie, 2003).
Apart from a direct effect of SCFAs on HDACs, another interesting
hypothesis is that they may have an indirect effect through GPCRs. Indeed,
activation of GPR41 in Chinese hamster ovary cell lines suppressed histone
acetylation possibly through the inhibition of HDACs (Wu, Zhou, Hu, &
Dong, 2012). Thus, GPR41 but also GPR43 or GPR109 might contribute
to HDAC inhibition mediated by SCFAs. Whether the SCFAs directly or
indirectly block HDAC activation remains elusive and extensive research
will be necessary to clarify these points.
2.1.2 Immunological relevance of SCFA-mediated HDAC inhibition
When SCFA-mediated HDAC inhibition can be established or associated, the
overwhelming result is an anti-inflammatory immune phenotype (Table 3.1).
Indeed, treatment of human macrophages with 1 mM of acetate in vitro signif-
icantly reduced their global HDAC activity and increased global histone acet-
ylation correlating with decreased production of inflammatory cytokines IL-6,
98 Jian Tan et al.
IL-8, and TNFa(Kendrick et al., 2010). Similarly, butyrate and propionate
decreased LPS-induced TNFaproduction in vitro from human peripheral
blood mononuclear cells (PMBCs) in a similar manner to TSA (Usami et al.,
2008). These results suggest an active control of the release of proinflammatory
cytokines by SCFAs through HDAC inhibition in both rodents and humans.
Activation of NF-kB is one of the major pathways involved in the release of
inflammatory cytokines (Hayden, West, & Ghosh, 2006). Butyrate and propi-
onate were shown to reduce NF-kB activity in PBMCs in a similar manner to
TSA (Usami et al., 2008) suggesting that the anti-inflammatory effect of SCFAs
might be mediated through the modulation of NF-kB via HDAC inhibition.
However, a direct effect of these SCFAs on histone acetylation in PMBCs has
not been shown. Finally, global inhibition of HDAC activity was also observed
in rodent neutrophils after addition of acetate, propionate, or butyrate in vitro
with increasing strength, respectively (Vinolo et al., 2011). In monocytes, buty-
rate and propionate, but not acetate, decreased LPS-induced TNFaexpression
and NOS expression in rodent neutrophils (Vinolo et al., 2011). This suggests
that acetate might not mediate its anti-inflammatory effects through HDAC
inhibition but rather through GPCR activation, as we have reported
(Maslowski et al., 2009). Finally, HDAC inhibition by SCFAs is not restricted
to cells of the innate immune system. Lymphocytes, in particular regulatory
T cells (Tregs), may also be affected by HDAC inhibition. Indeed, HDACinhi-
bition, particularly HDAC9, increased expression of the forkhead box P3
(Foxp3) transcription factor in mice, which subsequently increased prolifera-
tive and functional capabilities of Tregs (Lucas et al., 2009; Tao et al., 2007).
In vitro, addition of butyrate on human Treg was shown to moderately diminish
their proliferation while increased their inhibitory capacities on T cell prolifer-
ation through a CTLA-4-mediated mechanism (Akimova et al., 2010). Fur-
thermore, effector CD4
þ
T cells could be anergized via the HDACi
activities of butyrate, which occurred independently of Treg (Fontenelle &
Gilbert, 2012). Although global HDAC activity is often associated with
SCFA-mediated immunomodulation, specific HDAC inhibition or expres-
sion is rarely investigated and provides an avenue for further research.
2.2. G-protein-coupled receptors
2.2.1 GPR43
GPR43, also known as free fatty acid receptor 2 (FFA2/FFAR2), is the pri-
mary receptor for the SCFA acetate. GPR43 recognizes an extensive range of
SCFAs including propionate, butyrate, caproate, and valerate and while pro-
pionate was reported to be the most potent activator of GPR43, acetate is the
99The Role of Short-Chain Fatty Acids in Health and Disease
Table 3.1 HDAC specific immunomodulation of the immune system
HDAC No. Immunological function References
HDAC1 Reduces TNF-induced NF-kB-dependent reporter gene expression via direct
interaction with corepressor p65 and p50
Repression of IL-12 expression
Increases expression of NF-kB-independent genes
Ashburner, Westerheide, and
Baldwin (2001), Zhong, May, Jimi,
and Ghosh (2002), Viatour et al.
(2003), and Lu et al. (2005)
HDAC2 Reduces TNF-induced NF-kB-dependent reporter gene expression inde-
pendent of interaction with p65
Repression of major histocompatibility class II transactivator (CIITA) activity
and subsequent repression of activation in macrophages
Ashburner et al. (2001) and Kong,
Fang, Li, Fang, and Xu (2009)
HDAC3 Repression of NF-kB signaling by sequestration of NF-kB to the cytoplasm
Increases expression of NF-kB-independent genes
Required for inflammatory gene expression in macrophages
Increased HDAC3 is associated with reduced apoptotic T lymphocytes from a
reduction in p53 expression (tumor suppressor)
Chen, Fischle, Verdin, and Greene
(2001), Viatour et al. (2003), and
Zhang, Shi, Wang, and Sriram
(2011)
HDAC7 Transcriptionally represses macrophage genes during B cell development
Enhances Foxp3 function
Histone deacetylation of the Foxp3 promoter
Bruna Barneda-Zahonero et al.
(2013), Li et al. (2007), and Lal and
Bromberg (2009)
HDAC8 Induces apoptosis of T cell lymphoma dependent on phospholipase C-g1
signaling
Balasubramanian et al. (2008)
HDAC9 Inhibits proliferation and suppressive function of Tregs and is downregulated
during TCR stimulation of Tregs
HDAC9 knock-out mice have increased numbers of Tregs compared to WT.
Tao et al. (2007)
HDAC11 Regulates IL-10 expression from APCs
Increasing HDAC11 caused an increase in IL-10 and promoted the restoration
of responsiveness in tolerant CD4
þ
T cells
Reducing HDAC11 increased IL-10 expression in APCs and impaired antigen-
specific T cell responses
Villagra et al. (2009)
most selective (Le Poul et al., 2003). GPR43 expression has been identified
along the entire gastrointestinal tract, including cells of both the immune
and nervous system. In the intestinal tract, GPR43 is highly expressed on
intestinal peptide YY (PYY) and glucagon-like peptide 1 (GLP-1)
(Tolhurst et al., 2012) producing endocrine L-cells of the ileum and colon
(Vangaveti, Shashidhar, Jarrod, Baune, & Kennedy, 2010) as well as on col-
onocytes and enterocytes of the small and large intestine. Direct infusion of
SCFAs in the colon of rats and rabbits induced the release of PYY, possibly
through their binding on GPR43, that exerted anorexigenic effects
(Roelofsen, Priebe, & Vonk, 2010) and GPR43 knock-out (Gpr43
/
) mice
have decreased SCFA-induced release of GLP-1, a key hormone controlling
insulin release (Tolhurst et al., 2012). While SCFAs might modulate body
weight via central effects by reducing food intake through secretion of
PYY and GLP-1, they can also directly act in periphery on the adipose tissue.
Indeed, high fat diet has been shown to upregulate GPR43 expression in sub-
cutaneous adipose tissue in parallel with increased fatstorage in adipocytes. On
the other hand, supplementation of the diet with inulin-type fructans, fer-
mentable carbohydrates, blunted the weight gain and the overexpression of
GPR43 due to high fat feeding, suggesting that SCFAs might modulate adi-
posity (Dewulf et al., 2011). Moreover, inhibition of GPR43 expression in
the adipocyte cell line 3T3-L1 using small interfering RNA inhibited their
differentiation suggesting a possible role of GPR43 in adipocyte development
(Dewulf et al., 2013). While RS consumption in rats leads to activation of the
hypothalamic anorexigenic pathway shown by the increased expression of
proopiomelanocortin in the arcuate nucleus, GPR43 does not seem to be
expressed in the arcuate nucleus or other region of the hypothalamus
(Sleeth, Thompson, Ford, Zac-Varghese, & Frost, 2010). More broadly, to
our knowledge, there is no report of GPR43 expression in the central or
peripheral nervous system.
In the immune system, GPR43 is expressed on eosinophils, basophils
(Le Poul et al., 2003), neutrophils, monocytes, dendritic cells (Cox et al.,
2009; Le Poul et al., 2003), and mucosal mast cells (Karaki et al., 2008)
suggesting a broad role of SCFAs in immune responses. It is highly expressed
in murine hemopoietic tissues such as the bone marrow and spleen suggesting
the potential role for GPR43 in modulating the development or differentia-
tion of immune cells (Maslowski et al., 2009; Senga et al., 2003).
Finally, a recent study has shown the expression of GPR43 in
myometrium and fetal membranes after the onset of labor and a significant
upregulation of GPR43 in preterm fetal membranes with evidence of
101The Role of Short-Chain Fatty Acids in Health and Disease
infection. This study also suggests an anti-inflammatory role of SCFAs
through GPR43 that may reduce the risk of preterm labor induced by path-
ogens (Voltolini et al., 2012). This anti-inflammatory role of GPR43 is in
accordance with our findings on the exacerbated inflammatory phenotypes
of Gpr43
/
mice in colitis and arthritis models (Maslowski et al., 2009).
2.2.2 GPR41
Identified at the same time as GPR43, GPR41, also known as free fatty acid
receptor 3 (FFA3/FFAR3), is a receptor for acetate and propionate and to a
lesser degree butyrate. Like GPR43, it also recognizes other SCFAs includ-
ing caproate and valerate, but to a lesser degree. GPR41 is expressed in the
colonic mucosa in PYY but not GPR43-expressing cells. GPR41 is also
expressed in the colonic smooth muscle and SCFAs induce phasic contrac-
tion of these muscles in a GPR41-dependent manner with the following
order of potency: propionate butyrate >acetate (Tazoe et al., 2009).
SCFAs stimulate sympathetic activation through GPR41 activation by
acting on the sympathetic ganglion. This effect is abolished under fasted
conditions by ketone bodies (Kimura et al., 2011). Based on these results,
GPR41 agonists could be used as potential antiobesity therapeutics.
Moreover, the expression of GPR41 in adipose tissue and its potency to
induce the release of the anorexigenic hormone leptin when activated by SCFAs
confirms its beneficial effects on body weight (Xiong et al., 2004). The former
findings are still controversial as Hong and colleagues did not find GPR41 expres-
sion on adipocytes and suggest that this effect on leptin release is mediated
through GPR43. Langerhans cells in the pancreas also express GPR41 but its
functional role in these cells is unknown. Finally, GPR41 is expressed in spleen
and in PBMC but its role on immune cells remains uninvestigated.
2.2.3 GPR109A
GPR109a, also known as Niacin receptor 1, is a high affinity niacin (Vitamin
B3) receptor and related to its low affinity analog GPR109B, which is only
expressed in humans. Although niacin is the primary ligand of GPR109A,
physiological concentrations of niacin do not reach a threshold required to
activate the receptor (Wanders et al., 2012). However, butyrate is a suitable
candidate ligand with the ability to bind GPR109A with low affinity in mil-
limolar concentration (Thangaraju et al., 2009). GPR109A transcript is highly
expressed in adipocytes but declines with age (Thangaraju et al., 2009). To a
lesser extent, GPR109A is also expressed on immune cells such as dermal den-
dritic cells, monocytes, macrophages, and neutrophils (Wanders et al., 2012).
102 Jian Tan et al.
Activation of GPR109A in adipocytes has been shown to suppress lipolysis
and lowering of plasma-free fatty acid levels (Kang,Kim,&Youn,2011).
The role of GPR109A in immune responses, and gut homeostasis, is yet to
be reported. A summary of the major SCFA receptors, associated ligand,
and their functions is presented in Table 3.2.
3. VARIED FUNCTIONS OF SCFAs
SCFAs, particularly butyrate, are key promoters of colonic heath and
integrity. Butyrate is the major and preferred metabolic substrate for colo-
nocytes providing at least 60–70% of their energy requirements necessary for
their proliferation and differentiation (Suzuki et al., 2008). As such, colo-
nocytes of germ-free mice, deficient in SCFAs, are highly energy deprived,
as indicated by decreased expression of key enzymes involved in fatty acid
metabolism in mitochondria (Tazoe et al., 2008). Consequently, these cells
have a marked deficit of mitochondrial respiration, as shown by a decreased
NADH/NAD
þ
ratio, in ATP production as well as of oxidative phosphor-
ylation, which can lead to autophagy. Addition of butyrate to colonocytes
isolated from germ-free mice normalized this deficit (Donohoe et al., 2011).
Apart from being a major energy source for colonocytes, SCFAs in the gut
perform various physiological functions including dictating colonic mobility,
colonic blood flow, and gastrointestinal pH, which can influence uptake and
absorption of electrolytes and nutrients (Tazoe et al., 2008). These effects
could be mediated through the activation of GPCRs as discussed earlier.
Finally, the physiological roles of SCFAs are broader than a local effect on
the gut on enterocytes and on digestive function; they indeed play major
immunological roles both systemically and locally in the gut that will be fur-
ther expanded in the following sections.
3.1. Anti-inflammatory and antitumorigenic roles
SCFAs are well known for their anti-inflammatory functions by modulating
immune cell chemotaxis, reactive oxygen species (ROS) release as well as
cytokine release. Butyrate elicits anti-inflammatory effects via inhibition
of IL-12 and upregulation of IL-10 production in human monocytes
(Saemann et al., 2000), repressing production of proinflammatory molecules
TNFa, IL-1b, nitric oxide (Ni et al., 2010), and reduction of NF-ĸB activity
(Ni et al., 2010; Segain et al., 2000). The active suppression of NF-ĸB activ-
ity was shown by all three major SCFAs in order of potency being
butyrate >propionate >acetate in Colo320DM cells (Tedelind, Westberg,
103The Role of Short-Chain Fatty Acids in Health and Disease
Table 3.2 Summary of the major short-chain fatty acids-activated GPCR including its ligand, expression, and function
GPCR Ligands Expression Roles Reference(s)
GPR41 SCFA (C2–C7)
Formate, acetate,
propionate, butyrate,
and pentanoate
Adipocytes, various immune
cells, and enteroendocrine
L cells
Leptin production,
sympathetic activation
Kimura et al. (2011) and Xiong
et al. (2004)
GPR43 SCFA (C2–C7)
Formate, acetate,
propionate, butyrate,
and pentanoate
Adipocytes, various Immune
cells, enteroendocrine L cells,
gut epithelium, fetal membrane
Anorexigenic effects via
secretion of PYY and GLP-1,
anti-inflammatory, and
antitumorigenic
Cherbut et al. (1998),
Maslowski et al. (2009), Tang,
Chen, Jiang, Robbins, and Nie
(2011), Suzuki, Yoshida, and
Hara (2008), Tazoe et al. (2008),
Le Poul et al. (2003), Cox et al.
(2009), and Voltolini et al.
(2012)
GPR109a SCFAs (C4–C8),
particularly butyrate
Nicotinate
Adipocytes, various immune
cells, intestinal epithelial cells,
upregulated in hepatocytes
during inflammation, epidermis
in squamous carcinoma
High-density lipoprotein
metabolism, cAMP reduction
in adipocytes, DC trafficking,
anti-inflammatory, and
antitumorigenic
Li, Hatch, et al. 2010, Li, Millar,
Brownell, Briand, and Rader
(2010),Bermudez et al. (2011),
Ingersoll et al. (2012),
Thangaraju et al. (2009), and
Wanders et al. (2012)
Kjerrulf, & Vidal, 2007). Suppression of NF-ĸB activity and also TNFapro-
duction by SCFAs is also commonly observed in LPS-activated PMBCs
such as neutrophils (Aoyama, Kotani, & Usami, 2010). This is consistent
with the findings that butyrate could inhibit high mobility group box-1
(Aoyama et al., 2010), a nuclear transcription factor downstream of
NF-ĸB signaling involved in eliciting inflammatory roles and promoting cel-
lular proliferation that could promote cancer (Tang, Kang, Zeh Iii, & Lotze,
2010). Furthermore, butyrate (and also propionate) could induce apoptosis
of neutrophils in nonactivated and LPS- or TNFa-activated neutrophil apo-
ptosis by caspase-8 and caspase-9 pathways (Aoyama et al., 2010).
Under inflammatory conditions, addition of acetate has been shown to
inhibit human neutrophil migration toward C5a or fMLP in a GPR43-
dependent manner as phenylacetamide, a human GPR43 agonist mimicked
these effects (Vinolo et al., 2011). In vivo, migration of neutrophils toward the
peritoneum was exacerbated in Gpr43
/
mice when mice were challenged
with C5a or fMLP, confirming the critical role of GPR43 as regulator of cell
chemotaxis. It is, however, puzzling that under noninflammatory conditions,
SCFAs attract both mouse and human neutrophils through a mechanism
involving GPR43 activation (Le Poul et al., 2003; Maslowski et al., 2009;
Vinolo et al., 2009). This illustrates the dual effects of SCFAs on chemotaxis
and the phenomenon that SCFAs might attract inflammatory cells under basal
conditions requires further investigation. SCFAs can enforce the epithelial
barrier by affecting the mucus layer, epithelial cell survival, as well as tight
junction proteins, and will be discussed in a later section of this chapter. SCFAs
might enforce this epithelial barrier by increasing the infiltration of immune
cells in the lamina propria. Themost common immune mechanism known to
induce content leakage from the gut is through the release of neutralizing IgA;
however, the increase in phagocytes in the lamina propria might also be an
important unexplored mechanism. Other than suppressing neutrophil func-
tions, butyrate (and to a degree acetate and propionate) can inhibit IL-2 pro-
duction and lymphocyte proliferation in culture (Cavaglieri et al., 2003).
SCFAs not only modulate cell migration but also their activity. As dis-
cussed earlier SCFAs are potent anti-inflammatory mediators, by inhibiting
the release of proinflammatory cytokines from macrophages and neutro-
phils. Acetate was shown to promote the release of ROS when added on
mouse neutrophils by activating GPR43 (Maslowski et al., 2009). ROS
are efficient bactericidal factors involved in the clearance of pathogens.
Thus, SCFAs might be key regulators of inflammatory diseases by tightly
controlling the migration of immune cells toward inflammatory sites as well
105The Role of Short-Chain Fatty Acids in Health and Disease
as modulating their activation state, enabling accelerated pathogen clearance
through ROS activation. As discussed earlier, all these processes would
decrease host injury, which would not only allow for the survival of the host
but also for survival of the SCFA-producing bacteria.
Butyrate has been associated with anticancer activity on a variety of human
cancer cell lines. Treatment of human hepatoma cells in vitro increased expres-
sion of cell cycle inhibitory genes and appeared to reverse malignant pheno-
type, which has been associated with a reduction in telomerase activity via
HDAC inhibition (Nakamura et al., 2001; Wakabayashi et al., 2005). Telo-
merase activity can maintain cancer cellproliferation, therebyproviding a pos-
sible target for butyrate-induced antitumor effects. Furthermore, activation of
GPR109a on human colon cancer cells by butyrate has been associated with
increased apoptosis independent of HDAC inhibition and increased expres-
sion of the butyrate transporter MCT-1 (Borthakur et al., 2012; Thangaraju
et al., 2009). Butyrate-induced GPR109a activation may directly inhibit
colon cancer growth by inducing apoptosis or may act indirectly via increased
MCT-1 expression and subsequent increase of butyrate transport into the cell.
Expression of the butyrate transporter SMCT-1 on colon cancer cells is essen-
tial for its antitumorigenic function and correlates with global increases to his-
tone acetylation (Gupta, Martin, Prasad, & Ganapathy, 2006). In addition,
SMCT-1 is downregulated in human colon cancer cells, further accentuating
the role of SMCT-1 in colon cancer (Miyauchi, Gopal, Fei, & Ganapathy,
2004). SMCT-1 may therefore transport butyrate into colonic cells and pre-
vent development of a cancerous phenotype, though the involvement of
HDAC inhibition remains largely unknown. Even if the mechanisms behind
the beneficial role of SCFAs on cancer are not fully understood, it is widely
accepted that intake of fiber lowers risk of cancer, especially colorectal cancer.
The analysis of 25 studies demonstrated that cereals and whole grain intake
was associated with reduced risk of colorectal cancer supporting the potential
beneficial role of SCFAs in cancer (Aune et al., 2011).
3.2. SCFAs and antimicrobial activities
Free fatty acids (such as medium- and short-chain fatty acids) exhibit intrin-
sic broad-spectrum antimicrobial activity and are used as such in the agricul-
ture industry. For example, propionate is routinely used as an antimicrobial
additive in food (Arora, Sharma, & Frost, 2011) while in vivo administration
of butyrate is used to control Salmonella infections (Fernandez-Rubio et al.,
2009). Several key mechanisms were attributed to the antimicrobial
106 Jian Tan et al.
activities of free fatty acids including disruption of osmotic and pH balance,
nutrient uptake, and energy generation and their working concentrations
were well below the toxicity threshold to host cells (Dewulf et al., 2011).
This was shown in a study by Hong et al. (2005) demonstrating that formic
acid, acetate, propionate, butyrate, and hexanoic acid exerted various bio-
cidal (lethal) or biostatic (growth inhibitory) effects on oral microorganisms
at concentrations as low as micromolar. Propionate and hexanoic acid can
also exert antimicrobial activities by promoting host antimicrobial peptide
expression (Alva-Murillo, Ochoa-Zarzosa, & Lopez-Meza, 2012). Simi-
larly, host defense peptides of the innate immune system were potently
induced by oral treatment of butyrate and were responsible for the clearance
of Salmonella enteritidis without triggering a proinflammatory response indi-
cated by a lack of IL-1bproduction (Sunkara, Jiang, & Zhang, 2012). In
humans, the activity of cathelicidin, an antimicrobial agent released by poly-
morphonuclear leukocytes was induced by butyrate, possibly via its HDAC
inhibitory activities (Kida, Shimizu, & Kuwano, 2006). A recent study has
shown that the antimicrobial activities of individual SCFAs were relatively
inert toward species of bacteria that produced them but were otherwise
potent toward other microorganisms (Alva-Murillo et al., 2012). Therefore,
the production of SCFAs themselves may play a significant role in the shap-
ing of the gut microbial ecology; however, the precise effects of SCFAs on
bacterial selection require further investigation.
3.3. SCFAs and gut integrity
Gut integrity is an essential factor in maintaining mucosal homeostasis. It is
ensured by an efficient separation between the gut luminal contents and the
host, which is partly due to an effective epithelial barrier. Disruption of gut
integrity has been attributed to various intestinal diseases such as inflamma-
tory bowel disease, celiac diseases, irritable bowel syndrome (Voltolini et al.,
2012), and colorectal cancer (Tolhurst et al., 2012). It is interesting to note
that alteration of gut integrity seems to have much broader health implica-
tions than locally in the gut. Indeed, a phenomenon called “leaky gut,” char-
acterized by increased gut permeability, is associated with diseases such as
asthma or type 1 diabetes (T1D) showing that an effective physical separa-
tion of host tissues from the gut microbiota is critical for general health.
A layer of mucus forms a physical barrier that separates the epithelium
from the luminal environment, and this contributes to gut integrity by lim-
iting physical access of bacteria to the epithelium, thus limiting prospects for
107The Role of Short-Chain Fatty Acids in Health and Disease
breach and inflammation (Tolhurst et al., 2012). Mucus is comprised of
secretory (MUC2, MUC5A/B, MUC6) and epithelial membrane-bound
(MUC1, MUC3A/B, MUC4, MUC12, MUC13, MUC15, MUC16,
and MUC17) mucin glycoproteins (Cherbut et al., 1998; Tolhurst et al.,
2012). Deficiencies in mucins exacerbate various intestinal diseases such
as mucositis but can be remediated via oral supplementation of butyrate,
which modulates gut permeability (Ferreira et al., 2012). Consistent with
this, supplementation of either butyrate or propionate could induce both
MUC2 mRNA expression and MUC2 secretion in human goblet-like cell
line LS174T (Burger-van Paassen et al., 2009) suggesting that SCFAs might
be critical bacterial products promoting gut integrity. However, whether the
mechanisms behind these effects are through HDAC inhibition or via the
stimulation of GPR41, GPR43, or GPR109 has not been elucidated.
Functional tight junction proteins, such as ZO-1 and occludin between
epithelial cells, are also required for maintaining gut integrity by limiting gut
permeability (Balda & Matter, 2008). As mentioned earlier, increased gut
permeability is a common feature in diseases such as food allergy and asthma
(Hijazi et al., 2004; Perrier & Corthesy, 2011), however, whether it is the
cause or the consequence of these diseases remains largely unresolved.
In vitro, butyrate supplementation to Caco-2 cell monolayers enhances
the transepithelial resistance (TER), which is a marker of gut integrity, by
accelerating the assembly of tight junction proteins ZO-1 and occludin
dependent on AMPK activation without altering their expression levels
(Tolhurst et al., 2012). In vivo, mice treated with B. longum, a probiotic strain
of bacteria that releases large amounts of acetate, decreased the translocation
of Shiga toxin from enterohemorrhagic Escherichia coli O157:H7 toward the
bloodstream and thus increased survival (Xiong et al., 2004). In vitro, this
study shows that while acetate per se did not affect the TER of Caco-2 cells,
it did increase their survival when they were coinfected with this pathogen
resulting in increased gut integrity.
Finally, it has been shown in numerous studies that obesity or inflamma-
tory bowel disease, that dysbiosis is associated with increased gut permeabil-
ity. These conditions are probably associated with much lower concentrations
of SCFAs in both the GI tract and the blood. Apart from acting on the epi-
thelial layer, SCFAs might promote gut integrity by maintaining symbiosis.
Indeed, by lowering the luminal pH, SCFAs can directly promote the growth
of symbionts, and on the other hand inhibit growth of pathobionts (Roy,
Kien, Bouthillier, & Levy, 2006). However, some opportunistic pathobionts
have evolved to take advantage of the presence of SCFAs. Indeed it has been
108 Jian Tan et al.
shown that butyrate promotes virulence gene factor expression in pathogenic
E. coli and thus, colonize the colon where levels of butyrate are the highest
(Nakanishietal.,2009). Furthermore, SCFAs (particularly butyrate) could
also induce the production of flagella and regulate its motility function in
enterohemorrhagic E. coli (Herold, Paton, Srimanote, & Paton, 2009;
Tobe, Nakanishi, & Sugimoto, 2011).
From an evolutionary point of view, it is not surprising that beneficial
bacteria protect the host, notably by maintaining gut homeostasis to ensure
their own survival. Our view is that vertebrates have evolved systems that
allow bacterial metabolites such as SCFAs to regulate immunity and gut
physiology. Expression of GPR43 on innate/inflammatory immune cells
and the gut epithelium is an excellent example of this relationship. In
Western countries where consumption of dietary fiber is low, boosting
the levels of SCFAs appears as a promising new approach to promote gut
integrity and homeostasis. SCFAs or HDAC/GPR43 agonists might find
uses to treat or prevent a broad range of diseases from cancers to allergies
and autoimmune diseases.
4. INTEGRATIVE VIEW OF THE GUT MICROBIOTA,
SCFAs, AND DISEASE
The incidence of both inflammatory and autoimmune diseases has
increased dramatically in Westernized countries over the past several
decades. While both genetic and environmental factors influence the induc-
tion of such diseases, the contribution of diet and the relevance of SCFAs
have only been appreciated recently. The effect of SCFAs on various inflam-
matory and autoimmune diseases will be discussed below.
IBDs such as Crohn’s disease (CD) and ulcerative colitis (UC) are char-
acterized by inflammation of the gastrointestinal tract and colonic mucosa.
The induction of IBDs is multifactorial with genetic, environmental, and
microbial components. The increased incidence of IBD in developed coun-
tries over the last 20 years is too rapid to be explained by genetic changes.
However, what has dramatically changed over the last 20 years is the life-
style, particularly the introduction of Western style diets, which are gener-
ally low in fiber, and rich in fat and digestible sugars. Thus, “Western” diets
could be driving this increase of IBD in Western countries (Shapira,
Agmon-Levin, & Shoenfeld, 2010).
As mentioned previously, changes in diet can lead to rapid changes in the
composition of gut microbiota, which in turn could influence the relative
109The Role of Short-Chain Fatty Acids in Health and Disease
amounts of the different SCFAs produced. Observations in both mice and
humans support the link between diet, SCFA production via the gut micro-
biota, and IBDs. Indeed, metagenomic analyses of fecal bacteria have shown
significant dysbiosis in patients suffering from CD or UC, where there is a
lower representation of Bacteroidetes and Firmicutes, typical commensal
bacterial species, especially Clostridial clusters IV (C. leptum subgroup)
and XIVa (Clostridium coccoides subgroup) compared to healthy individuals
(Frank et al., 2007). Whether this dysbiosis is causative or a consequence
of IBD is unknown, however, targeting the microbiota through antibiotic
treatments has shown promising results by decreasing bacterial infiltration to
tissues. Combined treatment with probiotics and prebiotics also appears
beneficial in IBD, however, the use of anti-, pro-, and prebiotics as treat-
ments for IBD is yet to be fully established (Sartor, 2004). An emerging
and promising therapeutic approach is fecal transplantation, which has been
highly successful in some Clostridium difficile-infected patients (Borody,
Brandt, Paramsothy, & Agrawal, 2013; Brandt, 2012), as well as some
UC patients (Damman, Miller, Surawicz, & Zisman, 2012).
In mouse models, the role of the microbiota in the development of
DSS-induced colitis, a mouse model of ulcerative colitis, has been demon-
strated. While under SPF conditions, IL-10-deficient mice developed exac-
erbated colitis, whereas they were protected under germ-free conditions
(Sellon et al., 1998). These results suggest that IL-10-deficient mice have
a colitogenic microbiota. Although it has not been shown in humans, we
can speculate that patients with IBD may also house a colitogenic microbiota
that if transmitted from mother to child at birth may confer susceptibility to
CD (Akolkar et al., 1997).
Interestingly, in parallel with the dysbiosis, two studies have shown that
IBD was correlated with lower levels of SCFAs in feces by nuclear magnetic
resonance spectroscopy (Marchesi et al., 2007) and by HPLC with acetate
(162.0 mM/g), propionate (65.6 mM/g), and butyrate (86.9 mM/g) in the
feces of IBD patients compared to healthy individuals (209.7, 93.3, and
176.0 mM/g, respectively) (Huda-Faujan et al., 2010). Given these differ-
ences, SCFAs may play an important role in the pathogenesis of IBD. How-
ever, the stage of these diseases at which SCFAs are lowered, before the first
signs of inflammation, early signs, or once the diseases are clearly established,
remains unknown. Sabatino et al. (2005) explored the therapeutic effect of
administering butyrate orally to patients with CD. Administration of 4 g of
butyrate per day for 8 weeks via an enteric-coated tablet induced clinical
improvement and remission in 53% of patients where butyrate successfully
110 Jian Tan et al.
downregulated mucosal levels of NF-kB and IL-1b. Mouse studies have also
shown that SCFAs were beneficial in colitis as mice treated with butyrate
had reduced inflammation in their colonic mucosa with reduced neutrophil
infiltration (Vieira et al., 2012) and treatment with acetate had similar ben-
eficial effects (Maslowski et al., 2009). Moreover, lack of SCFA signaling
through GPR43 in Gpr43
/
mice exacerbated the development of colitis
(Maslowski et al., 2009). Thus, normalizing levels of SCFAs as well as
remediating dysbiosis may have synergistic and beneficial effects in the treat-
ment of IBD.
The beneficial anti-inflammatory effects of SCFAs extend beyond the
gut. Indeed, Brown et al. (2011) completed a metagenomic analysis of the
gut microbiome of T1D matched case–control subjects. 16S rRNA
sequencing revealed a larger proportion of bacterial species producing
butyrate in controls compared to individuals suffering from T1D. This
confirms the notion that in healthy individuals, the presence of
butyrate-producing bacteria might maintain gut integrity, while in T1D
patients, nonbutyrate-producing bacteria impede the synthesis of mucin,
which could lead to increased gut permeability. In rats, oral treatment with
butyrate during the preweaning period tended to delay the development of
diabetes (Li,Hatch,etal.,2010) suggesting that butyrate might play a role. In
this study, only one dose of butyrate was investigated, thus alternative dosing
strategies and perhaps in combination with other SCFAs such as acetate
would be necessary to draw firmer conclusions about the effects of SCFAs
on diabetes development. Moreover, analysis of fecal microbiota revealed
that Myd88
/
NOD mice, which are protected from diabetes development
under SPF conditions, had an increase in Bacteroidetes species when housed
under SPF conditions (Wen et al., 2008). Bacteroidetes produce large
amounts of SCFAs, thus protection from T1D in these Myd88
/
NOD
mice under SPF conditions could be via the anti-inflammatory effects pro-
vided by SCFAs. Similarly, fecal microbiota of patients suffering from rheu-
matoid arthritis (RA), another autoimmune disease, revealed that RA
patients had significantly less Bifidobacteria and Bacteroides species com-
pared to patients suffering from fibromyalgia, a noninflammatory musculo-
skeletal disease (Vaahtovuo, Munukka, Korkeamaki, Luukkainen, &
Toivanen, 2008). Thus, low levels of SCFAs might contribute or result from
the development of RA; however, prospective studies that assess the produc-
tion of SCFAs in RA patients as well as other inflammatory diseases would
be of great interest to determine if a defect in SCFA levels contributes to
disease onset.
111The Role of Short-Chain Fatty Acids in Health and Disease
Finally, Bo
¨ttcher et al. (2000) compared the production of SCFAs in aller-
gic and nonallergic children and found that allergic infants had lower levels of
propionate, acetate, and butyrate in their feces compared to nonallergic indi-
viduals. This may account for the observation that Gpr43
/
mice exhibit
exacerbated development of allergic airway inflammation (Maslowski et al.,
2009). These results suggest that SCFAs might play a protective role in allergic
disease. This would support a diet/fiber deficiency model (Maslowski et al.,
2009) for the increase in inflammatory diseases in Western countries.
5. PERSPECTIVE
The incidence of autoimmunity, IBD, and allergy has increased dramat-
ically inWestern and Westernized countries. This increase parallels a decrease in
the consumption of fiber and indigestible starches. Carefully designed studies
are now required to evaluate the effect of diet, independent of other possible
contributing factors (i.e., hygiene, infection, sunlight, etc.). These studies will
be critical for determining the role of diet, particularly fiber and SCFAs, in the
development of Western diseases. If indeed diet and the resulting changes to the
gut microbiota underlie certain Western lifestyle diseases, then there is enor-
mous potential for prevention or correction through diet, probiotics, or new
drugs targeting metabolite sensing mechanisms such as HDACs or GPCRs.
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119The Role of Short-Chain Fatty Acids in Health and Disease
... The reduction in fiber intake may account for the reduction in fecal short-chain fatty acids (SCFA) observed after bariatric surgery, which could be more pronounced in males, especially if they had more energy restriction [72][73][74][75]. The reduction in SCFA may facilitate cancer progression in males and ultimately counter any beneficial effect of weight loss [76][77][78][79][80]. Finally, a persistently higher risk of CRC in males with bariatric surgery compared to females with VSG or RYGB could be due to a reduction in estrogen levels with weight loss in males, a protective hormone against CRC [7,[81][82][83][84][85]. ...
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Purpose Sex differences exist in the associations between obesity and the risk of colorectal cancer (CRC). However, limited data exist on how sex affects CRC risk after bariatric surgery. Materials and Methods This retrospective cohort study used the 2012–2020 MarketScan database. We employed a propensity-score-matched analysis and precise coding to define CRC in this nationwide US study. Adjusted hazards ratio (HR) assessed CRC risk ≥ 6 months. In a restricted analysis, logistic regression with adjusted odds ratios (OR) examined CRC risk ≥ 3 years. Results Our sample included 327,734 controls with severe obesity and 88,630 patients with Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (VSG). The odds of cessation of diabetes mellitus medications, a surrogate for diabetes remission, were higher post-surgery vs. controls, especially in RYGB and males. In females, CRC risk decreased post-RYGB compared to controls (HR = 0.40, 95%CI: 0.18–0.87, p = 0.02). However, VSG was not associated with lower CRC risk in females. Paradoxically, in males compared to controls, CRC risk trended toward an almost significant increase, especially after 3 years or more from surgery (OR = 2.18, 95%CI: 0.97–4.89, p = 0.06). Males had a higher risk of CRC, particularly rectosigmoid cancer, than females after bariatric surgery (HR = 2.69, 95% CI: 1.35–5.38, p < 0.001). Furthermore, diabetes remission was not associated with a lower CRC risk post-surgery. Conclusion Our data suggest an increased risk of CRC in males compared to females after bariatric surgery. Compared to controls, there was a decrease in CRC risk in females’ post-RYGB but not VSG. Mechanistic studies are needed to explain these differences. Graphical abstract
... Nevertheless, no information was available concerning the effects of lentinan on IHNV infection in vivo. Some studies on crude polysaccharides have proven their encouraging effects on immune enhancement (35)(36)(37)(38). ...
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The effects of crude lentinan (CLNT) on the intestinal microbiota and the immune barrier were evaluated in rainbow trout (Oncorhynchus mykiss) infected by infectious hematopoietic necrosis virus (IHNV). The results showed that supplementary CLNT declined the rainbow trout mortality caused by IHNV, which suggested that CLNT has preventive effects on IHNV infection. IHNV destroyed intestinal integrity, as well as caused the intestinal oxidative and damage in rainbow trout. Supplementary CLNT significantly strengthened the intestinal immune barrier by declining intestinal permeability, as well as enhancing intestinal antioxidant and anti-inflammatory abilities in IHNV-infected rainbow trout (P<0.05). In addition, CLNT modified the aberrant changes of intestinal microbiota induced by IHNV, mainly represented by promoting the growths of Carnobacterium and Deefgea and inhibiting Mycobacterium and Nannocystis. Especially, supplementing with CLNT significantly promoted the growth of short-chain fatty acid–producing bacteria (P<0.05) and consequently increased the production of acetic acid, butanoic acid, and hexanoic acid in the intestine of IHNV-infected rainbow trout. Furthermore, it was speculated that CLNT could regulate the self-serving metabolic pathways of intestinal microbiota induced by IHNV, such as fatty acid metabolism and amino acid metabolism. Together, CLNT played the antiviral effects on IHNV infection through strengthening the intestinal immune barrier, as well as regulating intestinal microbiota and SCFA metabolism in rainbow trout. The present data revealed that CLNT exerted a promising prebiotic role in preventing the rainbow trout from IHNV infection.
... But perhaps most importantly, they may influence signalling in the host. Two major SCFA signalling mechanisms have been identified, inhibition of histone deacetylases (HDACs) and activation of G-protein-coupled receptors (GPCRs) (Tan et al., 2014). ...
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Together with proteins and fats, carbohydrates are one of the macronutrients in the human diet. Digestible carbohydrates, such as starch, starch-based products, sucrose, lactose, glucose and some sugar alcohols and unusual (and fairly rare) α-linked glucans, directly provide us with energy while other carbohydrates including high molecular weight polysaccharides, mainly from plant cell walls, provide us with dietary fibre. Carbohydrates which are efficiently digested in the small intestine are not available in appreciable quantities to act as substrates for gut bacteria. Some oligo- and polysaccharides, many of which are also dietary fibres, are resistant to digestion in the small intestines and enter the colon where they provide substrates for the complex bacterial ecosystem that resides there. This review will focus on these non-digestible carbohydrates (NDC) and examine their impact on the gut microbiota and their physiological impact. Of particular focus will be the potential of non-digestible carbohydrates to act as prebiotics, but the review will also evaluate direct effects of NDC on human cells and systems.
... It is worth noting that ketone bodies might contribute to histone modifications through increased acyl-CoA generation or through directly inhibiting HDAC activity. β-hydroxybutyrate, as well as other short chain fatty acids (e.g., butyrate) which is predominantly produced by intestinal microbiota, are known as HDAC inhibitors 592,593 . ...
Thesis
Chromatin-based events, prominently gene transcription are the basis of cellular characteristics in normal tissues and in cancer context. Histone posttranslational modifications are parts of specific regulatory circuits controlling chromatin-based biological processes. A myriad of specific types of histone modifications, including site-specific histone acetylation and methylation, etc. have been characterized with respect to their roles in gene transcriptional regulation. A critical family of chromatin regulators bridges histone modifications and gene transcriptional output is the readers. The specificity of readers recognizing histone modifications depends not only on the modifications, but also on their combinations. Additionally, it should be noted that histone modifications are dynamic and this process is impacted by a variety of factors, including cellular metabolites.Previously the team identified a gene FASTKD1 whose expression is associated with poor prognosis in acute lymphoblastic leukemia (ALL). During my research, we uncovered that this gene is a negative regulator of general mitochondrial activity, and more specifically controls the mitochondrial respiration. Using gene knockout cell models, we further characterized the link between mitochondrial activity with histone modifications, and highlighted the importance of fatty acid metabolism, especially β-oxidation, in mediating histone modifications. The association of mitochondrial activity-β-oxidation and histone acylations was also confirmed in patients’ primary blasts.BET family proteins are specific readers of histone acetylation and mediate transcription regulation. Previous studies uncovered that the first bromodomain of a BET protein, Brdt, recognizes diacetylated histone marks (H4K5acK8ac) but not K5 butyrylated histones. We noticed that FASTKD1-mediated mitochondrial activity prominently impacts non-acetyl acylations but not acetylations. Using our gene knockout cell model, we could demonstrate that the relative level of the acetyl and acyl marks tunes the bound state of BRD4 with chromatin. We showed that an increased ratio of acyl/acetyl disfavors BRD4-chromatin interaction, resulting in a loose and dynamic bound state, while a decreased ratio favors the binding and leads to a tight interaction. The functional output of this dynamic interaction is to re-distribute the BRD4 across the genome. More specifically, dynamic BRD4-chromatin interaction caused by high acyl/acetyl ratio makes BRD4 more available to be recruited on gene transcriptional start sites (TSS) and mediate the stimulated expression of a subset of genes mediated by BRD4. Gene functional analysis revealed that high acyl patients or high acyl/acetyl cells displayed increased expression of genes associated with ribosome synthesis, cell cycle and decreased expression of genes associated with stemness.Based on this work, we propose that cell metabolism, through modulating the histone acetyl/acyl ratio, controls a cellular reservoir of BRD4 (and probably many bromodomain-containing proteins). Our work not only added a new piece of evidence regarding the concept of metabolism-driven epigenetic modifications, but also emphasized on a collective and combinatorial actions of the relatively low abundant individual acylations.
... With the participation of intestinal microflora, the relative homeostasis of nutrients in the host is maintained. Intestinal microorganisms further decompose nutrients into smaller units, such as bile acids(BAs) (29), short-chain fatty acids(SCFAs) (30,31), free fatty acid (FFA), which contribute to the transport and absorption of nutrients. In some cases, intestinal microorganisms generate new substances (Figure 1). ...
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Non-alcoholic fatty liver disease (NAFLD) has recently become the most common liver disease with a global prevalence of over 25% and is expected to increase. Recently, experts have reached a consensus that “fatty liver disease associated with metabolic dysfunction or MAFLD” may be a more appropriate and inclusive definition than NAFLD. Like the former name NAFLD, MAFLD, as a manifestation of multiple system metabolic disorders involving the liver, has certain heterogeneity in its pathogenesis, clinical manifestations, pathological changes and natural outcomes. We found that there is a delicate dynamic balance among intestinal microflora, metabolites and host immune system to maintain a healthy intestinal environment and host health. On the contrary, this imbalance is related to diseases such as MAFLD. However, there are no clear studies on how dietary nutrients affect the intestinal environment and participate in the pathogenesis of MAFLD. This review summarizes the interactions among dietary nutrients, intestinal microbiota and MAFLD in an attempt to provide evidence for the use of dietary supplements to regulate liver function in patients with MAFLD. These dietary nutrients influence the development and progression of MAFLD mainly through the hepatic-intestinal axis by altering dietary energy absorption, regulating bile acid metabolism, changing intestinal permeability and producing ethanol. Meanwhile, the nutrients have the ability to combat MAFLD in terms of enriching abundance of intestinal microbiota, reducing Firmicutes/Bacteroidetes ratio and promoting abundance of beneficial gut microbes. Therefore, family therapy with MAFLD using a reasonable diet could be considered.
... The increased abundance of saccharolytic microbes is in turn associated with enhanced production of microbially derived secondary metabolites that improve overall gut and metabolic health (23). The beneficial effects of SCFA on gut barrier integrity, gut immune function, and overall metabolism have been extensively documented (23)(24)(25)(26)(27)(28)(29)(30). Other microbially produced metabolites with potential beneficial or deleterious effects on human health have been identified utilizing targeted and untargeted metabolomic approaches. ...
Article
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Dietary fiber, a nutrient derived mainly from whole grains, vegetables, fruits, and legumes, is known to confer a number of health benefits, yet most Americans consume less than half of the daily recommended amount. Convenience and affordability are key factors determining the ability of individuals to incorporate fiber-rich foods into their diet, and many Americans struggle to access, afford, and prepare foods rich in fiber. The objective of this clinical study was to test the changes in microbial community composition, human metabolomics, and general health markers of a convenient, easy to use prebiotic supplement in generally healthy young participants consuming a diet low in fiber. Twenty healthy adults participated in this randomized, placebo-controlled, double-blind, crossover study which was registered at clinicaltrials.gov as NCT03785860. During the study participants consumed 12 g of a prebiotic fiber supplement and 12 g of placebo daily as a powder mixed with water as part of their habitual diet in randomized order for 4 weeks, with a 4-week washout between treatment arms. Fecal microbial DNA was extracted and sequenced by shallow shotgun sequencing on an Illumina NovaSeq. Plasma metabolites were detected using liquid chromatography–mass spectrometry with untargeted analysis. The phylum Actinobacteria, genus Bifidobacterium , and several Bifidobacterium species ( B. bifidum, B. adolescentis, B. breve, B. catenulatum , and B. longum) significantly increased after prebiotic supplementation when compared to the placebo. The abundance of genes associated with the utilization of the prebiotic fiber ingredients ( sacA, xfp, xpk ) and the production of acetate ( poxB, ackA ) significantly changed with prebiotic supplementation. Additionally, the abundance of genes associated with the prebiotic utilization ( xfp, xpk ), acetate production ( ackA ), and choline to betaine oxidation ( gbsB ) were significantly correlated with changes in the abundance of the genus Bifidobacterium in the prebiotic group. Plasma concentrations of the bacterially produced metabolite indolepropionate significantly increased. The results of this study demonstrate that an easy to consume, low dose (12 g) of a prebiotic powder taken daily increases the abundance of beneficial bifidobacteria and the production of health-promoting bacteria-derived metabolites in healthy individuals with a habitual low-fiber diet. Clinical Trial Registration www.clinicaltrials.gov/ , identifier: NCT03785860
... We found that bacterial Chao1 richness, Shannon diversity, and the relative abundance of particular phyla (i.e., Proteobacteria, Tenericutes, and Actinobacteria) increased in NOD mice during aging (from 3 until 8 weeks of age), specifically in NOD mice not further progressing to overt hyperglycaemia. A greater intestinal microbiota diversity is conducive to enrichment of bacterial taxa that can produce bile acids and short chain fatty acids (SCFA) like acetate, butyrate, and propionate, which are beneficial for not only gut barrier function, and intestinal immunomodulation, but also help maintain homeostasis and health during the whole lifespan (66)(67)(68). The Bacteroidetes phylum is associated with the production of acetate and propionate, while the Firmicutes phylum mainly produces butyrate. ...
Article
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The hormonally-active form of vitamin D, 1,25-dihydroxyvitamin D3, can modulate both innate and adaptive immunity, through binding to the nuclear vitamin D receptor expressed in most immune cells. A high dose of regular vitamin D protected non-obese diabetic (NOD) mice against type 1 diabetes (T1D), when initiated at birth and given lifelong. However, considerable controversy exists on the level of circulating vitamin D (25-hydroxyvitamin D3, 25(OH)D3) needed to modulate the immune system in autoimmune-prone subjects and protect against T1D onset. Here, we evaluated the impact of two doses of dietary vitamin D supplementation (400 and 800 IU/day), given to female NOD mice from 3 until 25 weeks of age, on disease development, peripheral and gut immune system, gut epithelial barrier function, and gut bacterial taxonomy. Whereas serum 25(OH)D3 concentrations were 2.6- (400 IU/day) and 3.9-fold (800 IU/day) higher with dietary vitamin D supplementation compared to normal chow (NC), only the 800 IU/day vitamin D-supplemented diet delayed and reduced T1D incidence compared to NC. Flow cytometry analyses revealed an increased frequency of FoxP3+ Treg cells in the spleen of mice receiving the 800 IU/day vitamin D-supplemented diet. This vitamin D-induced increase in FoxP3+ Treg cells, also expressing the ecto-5’-nucleotidase CD73, only persisted in the spleen of mice at 25 weeks of age. At this time point, the frequency of IL-10-secreting CD4+ T cells was also increased in all studied immune organs. High-dose vitamin D supplementation was unable to correct gut leakiness nor did it significantly modify the increased gut microbial diversity and richness over time observed in NOD mice receiving NC. Intriguingly, the rise in alpha-diversity during maturation occurred especially in mice not progressing to hyperglycaemia. Principal coordinates analysis identified that both diet and disease status significantly influenced the inter-individual microbiota variation at the genus level. The abundance of the genera Ruminoclostridium_9 and Marvinbryantia gradually increased or decreased, respectively in faecal samples of mice on the 800 IU/day vitamin D-supplemented diet compared to mice on the 400 IU/day vitamin D-supplemented diet or NC, irrespective of disease outcome. In summary, dietary vitamin D reduced T1D incidence in female NOD mice at a dose of 800, but not of 400, IU/day, and was accompanied by an expansion of Treg cells in various lymphoid organs and an altered intestinal microbiota signature.
... In contrast, the genus Roseburia was found to be positively correlated in our study with the proportion of carbohydrate and fiber consumed. Roseburia produce short-chain fatty acids (SCFAs) from non-digestible carbohydrates, and SCFAs activate G-protein-coupled receptors (GPCRs), through which SCFAs exert various biological functions that are beneficial for the development of DM such as increasing the levels of glucagon like peptide-1 (GLP-1) and peptide tyrosine-tyrosine (PYY) [44,45]. Therefore, this correlation indicates that dietary intervention to increase the carbohydrate or fiber consumed may improve glucose metabolism at least, in part, by increasing the proportion of the genus Roseburia in gut microbiota and, thus, increasing the amounts of SCFAs. ...
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Upon food digestion, the gut microbiota plays a pivotal role in energy metabolism, thus affecting the development of type 2 diabetes (DM). We aimed to examine the influence of the composition of selected nutrients consumed on the association between the gut microbiota and DM. This cross-sectional study of a general population was conducted on 1019 Japanese volunteers. Compared with non-diabetic subjects, diabetic subjects had larger proportions of the genera Bifidobacterium and Streptococcus but smaller proportions of the genera Roseburia and Blautia in their gut microbiotas. The genera Streptococcus and Roseburia were positively correlated with the amounts of energy (p = 0.027) and carbohydrate and fiber (p = 0.007 and p = 0.010, respectively) consumed, respectively. In contrast, the genera Bifidobacterium and Blautia were not correlated with any of the selected nutrients consumed. Cluster analyses of these four genera revealed that the Blautia-dominant cluster was most negatively associated with DM, whereas the Bifidobacterium-dominant cluster was positively associated with DM (vs. the Blautia-dominant cluster; odds ratio 3.97, 95% confidence interval 1.68–9.35). These results indicate the possible involvement of nutrient factors in the association between the gut microbiota and DM. Furthermore, independent of nutrient factors, having a Bifidobacterium-dominant gut microbiota may be a risk factor for DM compared to having a Blautia-dominant gut microbiota in a general Japanese population.
Article
The objective of this study was to evaluate the effects of different SDF to IDF ratios on growth performance, serum indexes and fecal microbial community in pigs. Weaned and growing-finishing pigs were fed a diet containing five different ratios of SDF to IDF from 1:5 to 1:9 and from 1:3 to 1:7, respectively. Results showed a linear tendency that average daily gain (ADG) of weaned pigs decreased but the feed intake to weight gain ratio (F/G) increased as the ratio of SDF to IDF increased from 1:5 to 1:9 (p = 0.06). The ADG of growing-finishing pigs showed quadratic changes (p < 0.05) as ratios of SDF to IDF increased from 1:3 to 1:7. The Shannon index of fecal microbial diversity increased first and then decreased as the SDF to IDF ratio increased from 1:5 to 1:9 (p < 0.05). The Shannon and Chao indexes of fecal microbial diversity in growing-finishing pigs showed significant incremental linearly as the SDF to IDF ratio increased from 1:3 to 1:7 (p < 0.05). In conclusion, the recommended inclusion ratios of SDF to IDF in weaned and growing-finishing pigs diets are 1:7 and 1:5.
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Intestinal microbiota dysbiosis is related to many metabolic diseases in human health. Meanwhile, as an irregular environmental light-dark (LD) cycle, short day (SD) may induce host circadian rhythm disturbances and worsen the risks of gut dysbiosis. Herein, we investigated how LD cycles regulate intestinal metabolism upon the destruction of gut microbes with antibiotic treatments. The growth indices, serum parameters, concentrations of short-chain fatty acids (SCFAs), and relative abundance of intestinal microbes were measured after euthanasia; intestinal contents, epithelial metabolomics, and hepatic transcriptome sequencing were also assessed. Compared with a normal LD cycle (NLD), SD increased the body weight, spleen weight, and serum concentration of aspartate aminotransferase, while it decreased high-density lipoprotein. Meanwhile, SD increased the relative abundance of the Bacteroidetes phylum while it decreased the Firmicutes phylum in the gut of ABX mice, thus leading to a disorder of SCFA metabolism. Metabolomics data revealed that SD exposure altered gut microbial metabolism in ABX mice, which also displayed more serious alterations in the gut epithelium. In addition, most differentially expressed metabolites were decreased, especially the purine metabolism pathway in epithelial tissue. This response was mainly due to the down-regulation of adenine, inosine, deoxyguanosine, adenylsuccinic acid, hypoxanthine, GDP, IMP, GMP, and AMP. Finally, the transcriptome data also indicated that SD has some negative effects on hepatic metabolism and endocrine, digestive, and disease processes. Overall, SD induced an epithelial and hepatic purine metabolism pathway imbalance in ABX mice, as well as the gut microbes and their metabolites, all of which could contribute to host metabolism and digestion, endocrine system disorders, and may even cause diseases in the host.
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To investigate the association between intake of dietary fibre and whole grains and risk of colorectal cancer.
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B lymphopoiesis is the result of several cell-commitment, lineage-choice, and differentiation processes. Every differentiation step is characterized by the activation of a new, lineage-specific, genetic program and the extinction of the previous one. To date, the central role of specific transcription factors in positively regulating these distinct differentiation processes to acquire a B cell-specific genetic program is well established. However, the existence of specific transcriptional repressors responsible for the silencing of lineage inappropriate genes remains elusive. Here we addressed the molecular mechanism behind repression of non-lymphoid genes in B cells. We report that the histone deacetylase HDAC7 was highly expressed in pre-B cells but dramatically down-regulated during cellular lineage conversion to macrophages. Microarray analysis demonstrated that HDAC7 re-expression interfered with the acquisition of the gene transcriptional program characteristic of macrophages during cell transdifferentiation; the presence of HDAC7 blocked the induction of key genes for macrophage function, such as immune, inflammatory, and defense response, cellular response to infections, positive regulation of cytokines production, and phagocytosis. Moreover, re-introduction of HDAC7 suppressed crucial functions of macrophages, such as the ability to phagocytose bacteria and to respond to endotoxin by expressing major pro-inflammatory cytokines. To gain insight into the molecular mechanisms mediating HDAC7 repression in pre-B cells, we undertook co-immunoprecipitation and chromatin immunoprecipitation experimental approaches. We found that HDAC7 specifically interacted with the transcription factor MEF2C in pre-B cells and was recruited to MEF2 binding sites located at the promoters of genes critical for macrophage function. Thus, in B cells HDAC7 is a transcriptional repressor of undesirable genes. Our findings uncover a novel role for HDAC7 in maintaining the identity of a particular cell type by silencing lineage-inappropriate genes.
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Background GPR43 is a G-protein-coupled receptor that participates in adipocyte differentiation in mice and is over-expressed in adipose tissue of obese mice. The aim of this study was to investigate the implication of GPR43 in adipogenesis in humans and to determine the influence of obesity on its expression in human adipose tissue. Findings Preadipocytes were isolated from human omental adipose tissue and cultured during 13 days. One PPARγ agonist (troglitazone) and three GPR43 agonists (two physiological and one synthetic) were tested for their ability to induce differentiation. After 13 days, the three GPR43 agonists had no impact on aP2 expression, a marker of adipocyte differentiation, whereas troglitazone led to a huge over-expression of aP2 in these cells but tended to decrease GPR43 expression (p=0.06). GPR43 and inflammatory markers expression was also quantified in omental adipose tissue from lean and obese individuals. GPR43 expression in total adipose tissue was similar between obese patients and lean subjects and did not correlate with aP2 expression. In contrast, GPR43 expression positively correlated with TNFα mRNA. Conclusions Our results suggest the absence of relationship between GPR43 and adipocyte differentiation in humans, unlike what was observed in mice. Furthermore, GPR43 expression is not increased in adipose tissue from obese subjects but could be related to TNFα-related inflammatory processes.
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Routine use of antibiotics at subtherapeutic levels in animal feed drives the emergence of antimicrobial resistance. Development of antibiotic-alternative approaches to disease control and prevention for food animals is imperatively needed. Previously, we showed that butyrate, a major species of short-chain fatty acids (SCFAs) fermented from undigested fiber by intestinal microflora, is a potent inducer of endogenous antimicrobial host defense peptide (HDP) genes in the chicken (PLoS One 2011, 6: e27225). In the present study, we further revealed that, in chicken HD11 macrophages and primary monocytes, induction of HDPs is largely in an inverse correlation with the aliphatic hydrocarbon chain length of free fatty acids, with SCFAs being the most potent, medium-chain fatty acids moderate and long-chain fatty acids marginal. Additionally, three SCFAs, namely acetate, propionate, and butyrate, exerted a strong synergy in augmenting HDP gene expression in chicken cells. Consistently, supplementation of chickens with a combination of three SCFAs in water resulted in a further reduction of Salmonella enteritidis in the cecum as compared to feeding of individual SCFAs. More importantly, free fatty acids enhanced HDP gene expression without triggering proinflammatory interleukin-1β production. Taken together, oral supplementation of SCFAs is capable of boosting host immunity and disease resistance, with potential for infectious disease control and prevention in animal agriculture without relying on antibiotics.
Article
Short-chain fatty acids (SCFAs), including acetate, propionate and butyrate, are the most commonly found anions found in the monogastric mammalian large intestine, and are known to have a variety of physiological and pathophysiological effects on the gastrointestinal tract. We investigated the protein and mRNA expression levels of GPR41, a possible G protein coupled receptor for SCFA, using Western blot analysis and reverse transcriptase-polymerase chain reaction. We found that GPR41 protein and mRNA are expressed in human colonic mucosa. Immunohistochemistry for GPR41 showed that mucosal GPR41 protein is localized in cytoplasm of enterocytes and enteroendocrine cells. Moreover, GPR41-immunoreactive endocrine cells contained peptide YY but not serotonin or GPR43. The cellular population of GPR41 (0.01 ± 0.01 cells/crypt) was much smaller than that of GPR43 (0.33 ± 0.01 cells/crypt) in the human colon. However, the potency order of SCFA-induced phasic contraction of colonic smooth muscle that we previously reported is consistent with GPR41 (propionate >= butyrate > acetate) but not GPR43 (propionate = butyrate = acetate). Therefore, the present study suggests that GPR41 expressed in human colonic mucosa may function as a sensor for luminal SCFAs.
Article
Background Increased intestinal permeability has been reported in one study of adult asthmatics. Aim To determine whether children with asthma have altered intestinal permeability. Methods Thirty two asthmatic children, and 32 sex and age matched controls were recruited. The dual sugar (lactulose and mannitol) test was used to evaluate intestinal permeability, and the percentage of ingested lactulose (L) and mannitol (M) in the urine, and the L:M ratio were determined. All patients were skin prick tested for common aeroallergens, and specific IgE to some food items was determined. Results The median value of L in asthmatic children (2.29, IQR 0.91–4.07) was significantly higher than that in controls (0.69, IQR 0.45–1.08), and that of M was almost similar. The ratio L:M was significantly higher in asthmatic children (0.20, IQR 0.11–0.40) than in controls (0.06, IQR 0.04–0.09). Intestinal permeability did not correlate with eczema, inhaled steroids, positive skin prick test to aeroallergens, or severity of asthma. Conclusions Intestinal permeability is increased in children with asthma, suggesting that the whole mucosal system may be affected.
Article
An increasing focus on environmental sustainability has led to an ongoing global effort to better understand and engineer platform organisms that economically convert CO2 and other waste gases into useful biofuels and chemicals. Using stoichiometric and energetic analyses, we assess the efficiencies of four nonphotosynthetic CO2 fixation pathways of practical importance, with a focus on engineered strains. The analysis compares the pathways based on their ATP and H2/electron requirements, the number of enzymes required, and the production of three model chemicals: ethanol, acetate, and butanol. Our analysis shows that the Wood-Ljungdahl (WL) pathway is the most efficient, based on the most expensive substrate (i.e. H2 or electrons), for the production of acetate and ethanol. Chemoautotrophically, butanol formation is an ATP-limited process, making anaerobic production from the WL pathway inefficient; however, higher potential butanol titers are predicted for the aerobic pathways. Mixotrophic growth, in which organic substrates are fed alongside H2/CO2, alleviates the ATP limitations and thus improves the yields for both aerobic and anaerobic butanol production. We also calculate maximal yields, both chemoautotrophic and mixotrophic, based on the WL pathway for two other important molecules: 2,3-butanediol and butyrate.