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Transporters and receptors for short-chain fatty acids as themolecular link between colonic bacteria and the hostVadivel Ganapathy, Muthusamy Thangaraju, Puttur D Prasad,Pamela M Martin and Nagendra Singh
Available online at www.sciencedirect.com
The mutually beneficial relationship between colonic bacteria
and the host has been recognized but the molecular aspects of
the relationship remain poorly understood. Dietary fiber is
critical to this relationship. The short-chain fatty acids acetate,
propionate and butyrate, generated by bacterial fermentation
of dietary fiber, serve as messengers between colonic bacteria
and the host. The beneficial effects of these bacterial
metabolites in colon include, but are not limited to, suppression
of inflammation and prevention of cancer. Recent studies have
identified the plasma membrane transporter SLC5A8 and the
cell-surface receptors GPR109A and GPR43 as essential for
the biologic effects of short-chain fatty acids in colon. These
three proteins coded by the host genome provide the molecular
link between colonic bacteria and the host.
Addresses
Department of Biochemistry and Molecular Biology, Medical College of
Georgia, Georgia Regents University, Augusta, GA, USA
Corresponding author: Ganapathy, Vadivel ([email protected])
Current Opinion in Pharmacology 2013, 13:xx–yy
This review comes from a themed issue on Gastrointestinal
Edited by David T Thwaites
1471-4892/$ – see front matter, # 2013 Elsevier Ltd. All rights
reserved.
http://dx.doi.org/10.1016/j.coph.2013.08.006
IntroductionThe human body harbors trillions (�1014) of microorgan-
isms, most of them present in the large intestine, playing
an important role in the health of the host. Though called
‘commensal bacteria’, the relationship between gut-
associated bacteria and the host is not commensal. The
term ‘commensalism’ was based on the belief that only
bacteria benefit from this co-habitation while the host
neither benefits nor is harmed. From what we know now,
nothing can be farther from the truth. Normal bacteria in
colon have profound effects on the host, including pro-
tection against enteric infections, production of vitamins,
maturation of intestinal function, assistance in digestion
and absorption, modulation of the mucosal immune sys-
tem in the gut, and maintenance of energy homeostasis
[1–3]. Thus, the term ‘mutualism’ is more justifiable than
‘commensalism’ to describe the relationship between gut
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bacteria and the host. The well-deserved recognition of
the importance of gut bacteria to our health has been one
of the hallmarks of the last decade, highlighted by the
initiation of the Human Microbiome Project by the
National Institutes of Health in the United States. This
project has delineated the range of structural and func-
tional diversity of the microbial communities that reside
in different parts, including the large intestine, of a
healthy human body [4��]. The recent progress relating
to the microbial ecology of the mammalian gut in health
and disease has been hailed as one of the ten major
breakthroughs of the year 2011 [5].
The health benefits of colonic bacteria are principally
related to dietary fiber, which includes resistant starch
and non-starch polysaccharides such as cellulose, hemi-
cellulose, pectins, and gums. There are two classes of
dietary fiber: soluble and insoluble. Most of the soluble
fibers are fermentable by colonic bacteria and used as the
nutrient source to support the growth of these microor-
ganisms in the colon. It has been known for decades that
the short-chain fatty acids (SCFAs: acetate, propionate,
and butyrate), produced by bacterial fermentation of
dietary fiber, are the mediators of the beneficial effects
of colonic bacteria on the host [6–8], but the molecular
mechanisms underlying the process remained poorly
understood. This has changed dramatically in recent
years. In this review, we summarize the recent discoveries
on the role of three genes in the host genome, namely
SLC5A8, GPR109A, and GPR43, as the critical determi-
nants of the bacteria–host communication.
SCFAs as bacterial metabolites and theirfunction in the colonMost of the bacteria in the mammalian large intestine are
anaerobes, which ferment dietary carbohydrates, particu-
larly resistant starch and dietary fiber, into acetate, pro-
pionate, and butyrate. The relative proportions of these
three bacterial metabolites in the colonic lumen are 6:3:1,
and the total concentration is approximately 100 mM.
These metabolites are readily absorbed in the colon
and serve as the preferred energy substrates for colono-
cytes. Only small amounts of these SCFAs leave the colon
intact, and consequently their concentrations in the portal
blood are only at micromolar levels. Among the three
SCFAs, butyrate has been investigated most extensively.
It promotes cell differentiation, suppresses colonic
inflammation, and causes cell cycle arrest and apoptosis
acids as the molecular link between colonic bacteria and the host, Curr Opin Pharmacol (2013),
Current Opinion in Pharmacology 2013, 13:1–6
2 Gastrointestinal
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in colon cancer cells. The beneficial effects of butyrate in
colon are mediated at least partly by its ability to inhibit
histone deacetylases (HDACs) [9]. Propionate is also an
inhibitor of HDACs. Since dietary fiber is the primary
source for the generation of SCFAs in the colon by
bacteria, the beneficial effects of these bacterial metab-
olites on the colon explain the well-recognized health
benefits of dietary fiber. This also provides the basis for
the promotion of the use of prebiotics (complex carbo-
hydrates that can be fermented by colonic bacteria) and
probiotics (live bacteria that promote colonic health),
often a combination of both (synbiotics), in current
clinical practice [10–12].
SLC5A8, a plasma membrane transporter, andits relevance to intracellular actions of SCFAsin colonocytes and immune cellsSLC5A8 was originally identified as a tumor suppressor
that is silenced in colon cancer by DNA methylation [13].
When re-expressed in colon cancer cells, SLC5A8 causes
growth arrest and apoptosis. However, the identity of the
substrate that is transported by the protein was not
known. How the transport function could be linked to
tumor suppression also remained unclear. Studies from
our laboratory showed for the first time that SLC5A8 is a
Na+-coupled transporter for a variety of SCFAs, including
butyrate [14,15]. Other investigators have confirmed
independently the functional identity of SLC5A8 [16].
How can a plasma membrane transporter function as a
tumor suppressor? The ability of SLC5A8 to transport
butyrate addresses this question. Butyrate, a bacterial
fermentation product in colon, is an inhibitor of HDACs.
HDAC inhibitors are effective anticancer agents [17].
SLC5A8 is expressed on the apical membrane of colo-
nocytes, thus having access to butyrate in the lumen [18]
and critical for butyrate to function as an HDAC inhibitor
inside colonocytes. There is ample evidence for an
inverse relationship between butyrate levels in colon
and incidence of colon cancer [19]. These findings
suggest that butyrate-dependent alterations in gene
expression in colonocytes via modulation of the acety-
lation status of histones and non-histone proteins may
underlie the tumor-suppressive function of this fatty acid.
On the basis of these data, we hypothesized that cancer
cells silence SLC5A8 to escape butyrate-induced cell
death. Our recent studies have provided evidence in
support of this hypothesis [20]. Ectopic expression of
SLC5A8 in colon cancer cells facilitates the entry of
butyrate into cells with subsequent inhibition of HDACs,
leading to apoptosis. This SLC5A8/butyrate-induced
apoptosis in cancer cells is associated with upregulation
of various pro-apoptotic proteins, including components
of TRAIL pathway, and downregulation of various anti-
apoptotic proteins.
Until now the role of SLC5A8 as a tumor suppressor has
been evaluated only in terms of its ability to transport the
Please cite this article in press as: Ganapathy V, et al.: Transporters and receptors for short-chain fatty
http://dx.doi.org/10.1016/j.coph.2013.08.006
Current Opinion in Pharmacology 2013, 13:1–6
endogenous HDAC inhibitors butyrate and propionate.
However, a recent study has uncovered a novel, hitherto
unrecognized, mechanism for the tumor-suppressive role
of this transporter that is independent of its transport
function [21�]. SLC5A8 in the plasma membrane binds
the anti-apoptotic protein survivin resulting in depletion
of nuclear survivin and also decreases cellular levels of
survivin through inhibition of transcription. These
SLC5A8-induced changes in the location and levels of
survivin cause cell-cycle arrest, disruption of the chromo-
some passenger complex involved in mitosis, induction of
apoptosis and enhancement in chemosensitivity. These
effects are seen only in tumor cells, thus unraveling a
novel, transport-independent, role for SLC5A8 as a tumor
suppressor.
HDAC inhibitors hold promise in the treatment of
immune and inflammatory diseases [22], and SCFAs
generated by colonic bacteria exhibit immunomodulatory
effects [23]. On the basis of this evidence, we examined
the role of SLC5A8 in the delivery of the HDAC inhibi-
tors butyrate and propionate into immune cells and the
relevance of this process to immune cell function
[24��,25��]. These studies showed that butyrate and pro-
pionate block the generation of dendritic cells from bone
marrow stem cells. This effect is obligatorily dependent
on Slc5a8 [24��]. Butyrate also suppresses T cell function
[25��]. Butyrate induces apoptosis in wild type T cells but
not in Fas-deficient and FasL-deficient T cells. The
mechanism involves at least partly butyrate-induced
HDAC inhibition and consequent upregulation of Fas
signaling. The effect is partially blocked when Slc5a8 is
knocked down in T cells.
GPR109A, a cell-surface G-protein-coupledreceptor, and its relevance to the biologicactions of butyrate in colonGPR109A (hydroxycarboxylic acid receptor 2 or HCA2)
was first identified as a G-protein-coupled receptor that is
induced by IFN-g in macrophages [26] and thus named
PUMA-G (Protein Upregulated in MAcrophages by IFN-
Gamma). GPR109A in humans corresponds to PUMA-G
in rodents [27]. GPR109A is expressed not only in macro-
phages but also in adipocytes. Two independent groups
of investigators, while searching for the mechanism
underlying the lipid-lowering effects of niacin, discovered
that niacin elicits its anti-lipolytic effect in adipocytes by
activation of GPR109A (originally called HM74A) with
subsequent inhibition of adenylyl cyclase [28,29].
The physiologic levels of nicotinate in blood (<0.1 mM)
are not sufficient to activate the receptor, suggesting that,
even though the interaction of niacin with GPR109A
explains its therapeutic actions, niacin is not a physiologic
ligand. Recently, Taggart et al. [30] have identified b-D-
hydroxybutyrate (the major ketone body in circulation) as
the physiologic agonist for GPR109A. In the same study,
acids as the molecular link between colonic bacteria and the host, Curr Opin Pharmacol (2013),
www.sciencedirect.com
Molecular mediators in bacteria-host communication Ganapathy et al. 3
COPHAR-1211; NO. OF PAGES 6
butyrate displayed significant interaction with GPR109A
(EC50, 1.6 mM). After reading the paper by Taggart et al.[30] that showed butyrate as one of the agonists for
GPR109A, we wondered if this receptor is expressed in
the intestinal tract. Since butyrate is present in the colonic
lumen in millimolar concentrations sufficient to activate
GPR109A maximally, we predicted that if the receptor is
expressed in colonic epithelial cells, butyrate would serve
as an effective agonist in colon at these concentrations.
Our subsequent studies showed that GPR109A is indeed
expressed abundantly on the luminal membrane of
mouse and human colonic epithelial cells [31��]. These
findings suggest that butyrate may potentially influence
colonic function by acting extracellularly as an agonist for
GPR109A. Since SLC5A8 is silenced in colon cancer to
prevent the biologic actions of butyrate in tumor cells, we
asked if the effects of butyrate mediated via GPR109A
are also blocked in colon cancer. This indeed turned out
to be the case. GPR109A is silenced in colon cancer and
re-expression of GPR109A in colon cancer cells induces
cell death in the presence of butyrate or niacin [32]. The
silencing of GPR109A in colon cancer involves DNA
methylation as is the case with SLC5A8.
GPR43, a cell-surface G-protein-coupledreceptor, and its relevance to the biologicactions of SCFAsGPR43 (free fatty acid receptor 2; FFAR2), is also a cell-
surface G-protein-coupled receptor expressed in the colon,
which is activated by SCFAs, primarily acetate and pro-
pionate [33,34]. Activation of GPR43 signaling by SCFAs
plays a role in the regulation of appetite, electrolyte and
fluid secretion, and inflammation [35,36,37��,38,39].
Gpr43�/� mice show reduced inflammatory responses
against infection with the pathogenic bacterium C. roden-tium while activation of the receptor with SCFAs in wild
type mice promotes recruitment of leukocytes, activation
of effector T cells, and production of chemokines and
cytokines during immune responses, thus enhancing pro-
tective immunity and tissue inflammation [37��,38]. How-
ever, in normal healthy colon, Gpr43 suppresses
inflammation, thus facilitating the survival of normal
microflora in the host colon [39]. Activation of Gpr43
signaling with SCFAs is necessary for protection against
certain inflammatory responses and Gpr43�/� mice are
more susceptible to inflammation in experimental models
of colitis [37��,39]. It seems likely that the biological role of
Gpr43 in colon may vary under conditions of colonization
with beneficial bacteria versus pathogenic bacteria. In both
cases, Gpr43 signaling appears to benefit the host because
it suppresses the host immune response against the
beneficial bacteria but activates the host immune response
against pathogenic bacteria.
The expression of GPR43 is markedly reduced in colon
cancer, both at the primary site of the tumor and also at
metastatic sites [40��]. Ectopic expression of GPR43 in
Please cite this article in press as: Ganapathy V, et al.: Transporters and receptors for short-chain fatty
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colon cancer cell lines induces cell cycle arrest, activates
caspases, and causes cell death. These data show that,
similar to GPR109A, GPR43 also functions as a tumor
suppressor in colon.
Influence of gut bacteria on the intestinalexpression of Slc5a8 and Gpr109aSince butyrate, a bacterial fermentation product, is the
substrate for SLC5A8 and agonist for GPR109A, we
asked: Do gut bacteria influence the expression of
SLC5A8 and GPR109A in colon? We addressed this ques-
tion by comparing the expression of these two genes in
the intestinal tract between conventional mice with nor-
mal bacteria in colon and germ-free mice with no bacteria
in the intestine or anywhere else in the body [31��].Slc5a8 mRNA and Gpr109a mRNA levels in colon and
ileum were reduced significantly in germ-free mice com-
pared to conventional mice. We then studied the effect of
re-colonization of colon in germ-free mice on the expres-
sion of Slc5a8 and Gpr109a [31��]. The changes observed
in germ-free mice were completely reversed when these
mice were maintained under conventional conditions for
3–4 weeks to re-colonize the colon. The changes in
expression of Slc5a8 and Gpr109a were demonstrable
not only at the level of mRNA but also at the level of
protein. This is the first time that the regulation of gene
expression in colon by gut bacteria has been demon-
strated.
Dietary fiber content and its relationship to thefunctions of SLC5A8, GPR109A, and GPR43Our hypothesis is that SLC5A8, GPR109A, and GPR43
are obligatory for the beneficial effects of SCFAs in colon.
Knockout mouse models with deletion of Slc5a8,
Gpr109a, and Gpr43 would be useful to test this hypoth-
esis. Slc5a8�/� mice have been generated recently [41].
Surprisingly, treatment of Slc5a8�/� mice with carcino-
gens or crossing these mice with ApcMin/+ mice did not
show any difference in tumor formation. Even though
these findings seem to question the tumor-suppressive
role of Slc5a8, we have to recognize that Slc5a8 is not the
only mediator of the biologic actions of SCFAs in colon.
Gpr109a and Gpr43 in colonic epithelium in Slc5a8�/�
mice are likely to compensate for the lack of intracellular
actions of SCFAs. It is also possible that SLC5A8 plays
only a minor role as a tumor suppressor in colon compared
to GPR109A and GPR43 under optimal dietary con-
ditions. This speculation is based on the physiologic
concentrations of SCFAs in the colonic lumen and their
concentrations necessary for the activity of SLC5A8,
GPR109A, and GPR43. The Michaelis constant for buty-
rate and propionate for transport via SLC5A8 is �50 mM
[14]. Since the luminal concentrations of butyrate and
propionate are in millimolar range, significant amounts of
these HDAC inhibitors may still enter colonic cells even
in the absence of SLC5A8, most likely via diffusion or via
other monocarboxylate transporters such as SLC16A1,
acids as the molecular link between colonic bacteria and the host, Curr Opin Pharmacol (2013),
Current Opinion in Pharmacology 2013, 13:1–6
4 Gastrointestinal
COPHAR-1211; NO. OF PAGES 6
Figure 1
High-fiber diet
(a)
(b)
Butyrate & Propionate
↓ HDAC
↓ Inflammation↓ Carcinogenesis
Colonic Epithelium
↑ Inflammation↑ Carcinogenesis
Colonic Epithelium
(SLC5A8 IS dispensable)
(SLC5A8 IS NOT dispensable)
Optimal activation ofGPR109A & GPR43
GPR109A & GPR43 ARE NOTdispensable
Low-fiber diet
Low concentration ofbutyrate & propionate
Low-fiber diet
Suboptimal activation ofGPR109A & GPR43
GPR109A & GPR43 ARE NOTdispensable
? ?
High-fiber diet
High concentration ofbutyrate & propionate
Diffusion
Na+
Na+
↓cAMP, ↑Ca2+i
↑cAMP, ↓Ca2+i
SLC5A8 GPR109A GPR43
Butyrate & Propionate
↓ HDAC
? ?
Diffusion
Na+
Na+
SLC5A8 GPR109A GPR43
High concentration ofbutyrate, propionate, acetate
Low concentration ofbutyrate, propionate, acetate
Current Opinion in Pharmacology
Role of SLC5A8, GPR109A, and GPR43 as suppressors of inflammation
and carcinogenesis in colon and the relevance of dietary fiber content to
this process.
which exhibit relatively lower affinity for these SCFAs.
Therefore, deletion of Slc5a8 may not have noticeable
effects on tumor progression in colon when dietary fiber
intake is optimal. In contrast, activation of GPR109A and
Please cite this article in press as: Ganapathy V, et al.: Transporters and receptors for short-chain fatty
http://dx.doi.org/10.1016/j.coph.2013.08.006
Current Opinion in Pharmacology 2013, 13:1–6
GPR43 by SCFAs requires millimolar concentrations.
Therefore, the extracellular actions of SCFAs on colon
cells are obligatorily dependent on these receptors, thus
making GPR109A and GPR43 much more important than
SLC5A8 as a tumor suppressor in colon under conditions
of optimal dietary fiber intake. On the basis of these data,
we postulate that SLC5A8 is obligatory to mediate the
beneficial effects of SCFAs via their intracellular actions,
for example, HDAC inhibition and energy production, in
colon only under conditions of low dietary fiber intake
whereas GPR109A and GPR43 are obligatory for the
beneficial effects of SCFAs via their extracellular actions
even when the dietary fiber intake is optimal (Figure 1).
As such, SLC5A8 is dispensable when dietary fiber intake
is optimal but it becomes indispensable when dietary
fiber content is low. In contrast, GPR109A and GPR43 are
indispensable irrespective of whether or not dietary fiber
content is optimal. Gpr109a�/� mice and Gpr43�/� mice
have been generated [28,37��,38,39], but the role of these
receptors in colon carcinogenesis has not been reported
using these knockout mice. Our prediction is that
deletion of Gpr109a and Gpr43 in mice would lead to
increased susceptibility to colonic inflammation and colon
cancer even under conditions of optimal dietary fiber
intake. Studies with Gpr43�/� mice have provided evi-
dence in support of this prediction with regard to colonic
inflammation. Gpr43�/� mice show increased suscepti-
bility to inflammation in experimental models of colitis
[37��,39]. Whether or not the other aspects of our pre-
diction are true remains to be seen.
Nutritional and pharmacological implicationsOptimal concentrations of SCFAs in the colonic lumen
are essential for maintenance of colonic health. The
concentrations of SCFAs in the colon can be reduced
under various conditions such as intake of low dietary
fiber and chronic use of antibiotics. Generation of SCFAs
in colon can be optimized with nutritional interventions
such as intake of appropriate prebiotics and probiotics. A
recent study has shown that supplementation of the
probiotic Lactobacillus GG and the butyrate ester tribu-
tyrin reduces antibiotic-induced intestinal and colonic
injury at least partly via upregulation of SLC5A8 and
GPR109A [42�]. There is also potential for pharmaco-
logical approaches. High-affinity pharmacologic agonists
have been identified for these receptors [34,43,44]; pro-
phylactic use of such agonists may have potential in the
prevention of colitis and colon cancer.
ConclusionsOn the basis of our current knowledge, we conclude that
firstly the anti-inflammatory and tumor-suppressive func-
tions of the high-affinity butyrate/propionate transporter
SLC5A8 are dispensable under conditions of high-fiber
intake but not dispensable under conditions of low-fiber
intake, secondly the anti-inflammatory and tumor-sup-
pressive signaling via the low-affinity SCFA receptors
acids as the molecular link between colonic bacteria and the host, Curr Opin Pharmacol (2013),
www.sciencedirect.com
Molecular mediators in bacteria-host communication Ganapathy et al. 5
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GPR109A and GPR43 is optimal only when the dietary
fiber content is high but becomes suboptimal under
conditions of low fiber intake, thirdly the protective effects
of GPR109A and GPR43 against inflammation and car-
cinogenesis are not dispensable even when dietary fiber
intake is high, and finally decrease in fiber intake increases
the risk of inflammation and cancer in colon primarily
through suboptimal signaling via GPR109A and GPR43
(Figure 1). It makes sense that tumor cells silence the
expression of these proteins to protect themselves against
the tumor-suppressive actions of normal colonic bacteria.
However, our present knowledge of the molecular mech-
anisms underlying the anti-inflammatory and tumor-sup-
pressive effects of SCFAs is minimal (Figure 1). Butyrate
and propionate, following their entry into cells via
SLC5A8, inhibit HDACs, but how this phenomenon is
linked to suppression of inflammation and carcinogenesis is
poorly understood. Similarly, both GPR109A and GPR43
couple to either Gi resulting in decreased cellular levels of
cAMP or Gq resulting in increased calcium signaling, but
the details of downstream components linking these recep-
tors to suppression of inflammation and carcinogenesis are
still lacking. There is obviously a clear need for more
research in this area.
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� of special interest
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Current Opinion in Pharmacology 2013, 13:1–6
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27. Offermanns S: The nicotinic acid receptor GPR109A (HM74A orPUMA-G) as a new therapeutic target. Trends Pharmacol Sci2006, 27:384-390.
28. Tunaru S, Kero J, Schaub A, Wufka C, Blaukat A, Pfeffer K,Offermanns S: PUMA-G and HM74A are receptors for nicotinicacidandmediate its anti-lipolyticeffect.Nat Med2003,9:352-355.
29. Wise A, Foord SM, Fraser NJ, Barnes AA, Elshourbagy N, Eilert M,Ignar DM, Murdock PR, Steplewski K, Green A et al.: Molecularidentification of high and low affinity receptors for nicotinicacid. J Biol Chem 2003, 278:9869-9874.
30. Taggart AKP, Kero J, Gan X, Cai TQ, Cheng K, Ippolito M, Ren N,Kaplan R, Wu K, Wu TJ et al.: (D)-b-Hydroxybutyrate inhibitsadipocyte lipolysis via the nicotinic acid receptor PUMA-G.J Biol Chem 2005, 280:26649-26652.
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Cresci GA, Thangaraju M, Mellinger JD, Liu K, Ganapathy V:Colonic gene expression in conventional and germ-free micewith a focus on the butyrate receptor GPR109A and thebutyrate transporter SLC5A8. J Gastrointest Surg 2010,14:449-461.
This represents the first report on the regulation of the SCFA transporterSlc5a8 and the SCFA receptor Gpr109a by colonic bacteria. Absence ofbacteria in colon suppresses the expression of the transporter and thereceptor, and re-colonization of the colon with bacteria reverses thiseffect.
32. Thangaraju M, Cresci GA, Liu K, Ananth S, Gnanaprakasam JP,Browning DD, Mellinger JD, Smith SB, Digby GJ, Lambert NAet al.: GPR109A is a G-protein-coupled receptor for thebacterial fermentation product butyrate and functions as atumor suppressor in colon. Cancer Res 2009, 69:2826-2832.
33. Tazoe H, Otomo Y, Kaji I, Tanaka R, Karaki SI, Kuwahara A: Rolesof short-chain fatty acid receptors GPR41 and GPR43 oncolonic functions. J Physiol Pharmacol 2008, 59(Suppl 2):251-262.
34. Bindels LB, Dewulf EM, Delzenne NM: GPR43/FFA2:physiopathological relevance and therapeutic prospects.Trends Pharmacol Sci 2013, 34:226-232.
35. Sleeth ML, Thompson EL, Ford HE, Zac-Varghese SE, Frost G:Free fatty acid receptor 2 and nutrient sensing: a proposedrole for fibre, fermentable carbohydrates and short-chain fattyacids in appetite regulation. Nutr Res Rev 2010, 23:135-145.
Please cite this article in press as: Ganapathy V, et al.: Transporters and receptors for short-chain fatty
http://dx.doi.org/10.1016/j.coph.2013.08.006
Current Opinion in Pharmacology 2013, 13:1–6
36. Karaki S, Kuwahara A: Propionate-induced epithelial K+ andClS/HCO3
S secretion and free fatty acid receptor 2 (FFA2GPR43) expression in the guinea pig distal colon. Pflugers Arch2011, 461:141-152.
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Kim MH, Kang SG, Park JH, Yanagisawa M, Kim CH: Short-chainfatty acids activate GPR41 and GPR43 on intestinal epithelialcells to promote inflammatory responses in mice.Gastroenterology 2013, 145:396-406.
Using Gpr43-knockout mice, this study shows that the SCFA receptorGpr43 is critical for the modulation of host immune responses undervarious experimental conditions such as exposure of the colon to ethanol,trinitrobenzenesulfonic acid or C. rodentium.
38. Sina C, Gavrilova O, Forster M, Till A, Derer S, Hildebrand F,Raabe B, Chalaris A, Scheller J, Rehmann A et al.: G protein-coupled receptor 43 is essential for neutrophil recruitmentduring intestinal inflammation. J Immunol 2009, 183:7514-7522.
39. Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D,Schilter HC, Rolph MS, Mackay F, Artis D et al.: Regulation ofinflammatory responses by gut microbiota andchemoattractant receptor GPR43. Nature 2009,461:1282-1286.
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Tang Y, Chen Y, Jiang H, Robbins GT, Nie D: G-protein-coupledreceptor for short-chain fatty acids suppresses colon cancer.Int J Cancer 2011, 128:847-856.
This represents the first report on the loss of GPR43 expression in primarycolon cancer specimens. These studies also show, using colon cancercell lines, that GPR43 functions as a tumor suppressor through inhibitionof cell proliferation and induction of apoptotic cell death in cancer cells.
41. Frank H, Groger N, Diener M, Becker C, Braun T, Boettger T:Lactaturia and loss of sodium-dependent lactate uptake in thecolon of SLC5A8-deficient mice. J Biol Chem 2008,283:24729-24737.
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Cresci G, Nagy LE, Ganapathy V: Lactobacillus GG and tributyrinsupplementation reduces antibiotic-induced intestinal injury.J Parenter Enteral Nutr 2013. (in press).
This is the first report on the regulation of colonic expression of thebutyrate transporter Slc5a8 and the butyrate receptor Gpr109a in mice bya probiotic (Lactobacillus GG) and a butyrate prodrug (tributyrin).
43. Blad CC, Ahmed K, IJzerman AP, Offermanns S: Biological andpharmacological roles of HCA receptors. Adv Pharmacol 2011,62:219-250.
44. Kim S, Kim YM, Kwak YS: A novel therapeutic target, GPR43;where it stands in drug discovery. Arch Pharm Res 2012,35:1505-1509.
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