Transporters and receptors for short-chain fatty acids as the molecular link between colonic...

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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 (vganapat@gru.edu)

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

Please cite this article in press as: Ganapathy V, et al.: Transporters and receptors for short-chain fatty

www.sciencedirect.com

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

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

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,

Molecular mediators in bacteria-host communication Ganapathy et al. 3

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

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,

4 Gastrointestinal

Figure 1

High-fiber diet

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

↓cAMP, ↑Ca2+i

↑cAMP, ↓Ca2+i

SLC5A8 GPR109A GPR43

Butyrate & Propionate

↓ HDAC

Diffusion

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

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

Molecular mediators in bacteria-host communication Ganapathy et al. 5

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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6 Gastrointestinal

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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.

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.

37.��

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.

40.��

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.

42.�

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.

Transporters and receptors for short-chain fatty acids as the molecular link between colonic...

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