Sodium-Coupled Transport of the Short Chain Fatty Acid Butyrate by SLC5A8 and Its Relevance to Colon Cancer

Thangaraju, Muthusamy; Cresci, Gail; Itagaki, Shin-ichi; Mellinger, John D.; Browning, Darren D.; Berger, Franklin G.; Prasad, Puttur D.; Ganapathy, Vadivel

doi:10.1007/s11605-008-0573-0

Cited by 74 publications

(103 citation statements)

References 31 publications

(47 reference statements)

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“…Recently we have shown that propionate, another short-chain fatty acid produced in the colon by bacterial fermentation, is also an inhibitor of HDACs (16). SLC5A8 has been shown to function as a tumor suppressor in the colon (17) and other tissues (13,18,19); the ability of this transporter to mediate the Na ϩ -coupled entry of HDAC inhibitors (butyrate, propionate, and pyruvate) into cells underlies the tumor-suppressive function of this transporter (15,16). While SLC5A8 is necessary for the intracellular actions of butyrate, butyrate also elicits biologic effects on colon cells extracellularly by serving as an agonist for the cell surface G-protein-coupled receptor GPR109A, but without involving HDAC inhibition (20).…”

Section: Dendritic Cells (Dcs)mentioning

confidence: 99%

“…Relevance of Slc5a8 to Butyrate-induced Blockade of DC Development-Slc5a8, a Na ϩ -coupled high-affinity transporter, is essential for the entry of butyrate into cells, particularly at low concentrations, to inhibit HDACs (14,15). To establish the role of Slc5a8 in butyrate-induced blockade of DC development, we examined the effects of butyrate on DC development from Lin Ϫ bone marrow cells from wild-type and Slc5a8 Ϫ/Ϫ mice (Fig.…”

Section: Figure 5 Role Of Hdacs In DC Development a Linmentioning

confidence: 99%

“…The Na ϩ -coupled monocarboxylate transporter SLC5A8 (human ortholog is in uppercase letters, and rodent ortholog is in lowercase letters) is necessary for the entry of butyrate into colon cells for subsequent inhibition of HDACs (14,15). Recently we have shown that propionate, another short-chain fatty acid produced in the colon by bacterial fermentation, is also an inhibitor of HDACs (16).…”

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Blockade of Dendritic Cell Development by Bacterial Fermentation Products Butyrate and Propionate through a Transporter (Slc5a8)-dependent Inhibition of Histone Deacetylases

Singh

Thangaraju

Prasad

et al. 2010

Journal of Biological Chemistry

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246

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Mammalian colon harbors trillions of bacteria, yet there is no undue inflammatory response by the host against these bacteria under normal conditions. The bacterial fermentation products acetate, propionate, and butyrate are believed, at least in part, to be responsible for these immunosuppressive effects. Dendritic cells play an essential role in presentation of antigens to T lymphocytes and initiation of adaptive immune responses. Here we report that butyrate and propionate block the generation of dendritic cells from bone marrow stem cells, without affecting the generation of granulocytes. This effect is dependent on the Na ؉ -coupled monocarboxylate transporter Slc5a8, which transports butyrate and propionate into cells, and on the ability of these two bacterial metabolites to inhibit histone deacetylases. Acetate, which is also a substrate for Slc5a8 but not an inhibitor of histone deacetylases, does not affect dendritic cell development, indicating the essential role of histone deacetylase inhibition in the process. The blockade of dendritic cell development by butyrate and propionate is associated with decreased expression of the transcription factors PU.1 and RelB. Butyrate also elicits its biologic effects through its ability to activate the G-proteincoupled receptor Gpr109a, but this mechanism is not involved in butyrate-induced blockade of dendritic cell development. The participation of Slc5a8 and the non-involvement of Gpr109a in butyrate effects have been substantiated using bone marrow cells obtained from Slc5a8 ؊/؊ and Gpr109a ؊/؊ mice.These findings uncover an important mechanism underlying the anti-inflammatory functions of the bacterial fermentation products butyrate and propionate.Dendritic cells (DCs) 2 function as sentinels in peripheral tissues and lymphoid organs guarding against pathogens (1-3). Normally, microorganism-induced immunosuppression is associated with harmful effects in host. In certain cases however, the same process may have beneficial effects on host. Mammalian colon harbors trillions of bacteria without eliciting significant immune activation. There is a mutual beneficial relationship between the gut microbiota and the host (8, 9). The bacterial fermentation products acetate, propionate, and butyrate (collectively called short-chain fatty acids) are believed to be the mediators of the beneficial effects of gut bacteria on the host (10, 11). Among these short-chain fatty acids, butyrate has received the most attention for its biologic effects. The beneficial effects of butyrate on colon range from being a nutrient for colonocytes to being an anti-inflammatory and antitumor agent (12, 13). Although the anti-inflammatory function of butyrate is well known at the phenomenological level, the molecular mechanisms underlying the process are not fully understood.Butyrate is an inhibitor of histone deacetylases (HDACs) (12, 13). The Na ϩ -coupled monocarboxylate transporter SLC5A8 (human ortholog is in uppercase letters, and rodent ortholog is in lowercase letters) is necessary fo...

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Section: Dendritic Cells (Dcs)mentioning

confidence: 99%

Section: Figure 5 Role Of Hdacs In DC Development a Linmentioning

confidence: 99%

mentioning

confidence: 99%

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Blockade of Dendritic Cell Development by Bacterial Fermentation Products Butyrate and Propionate through a Transporter (Slc5a8)-dependent Inhibition of Histone Deacetylases

Singh

Thangaraju

Prasad

et al. 2010

Journal of Biological Chemistry

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“…Monocarboxylate transporter 1 (MCT1), a member of SLC16 gene family, mediates the H ϩ -coupled transport of butyrate into colonocytes (18,34). Another transporter belonging to SLC5 solute-linked carrier family has recently been characterized as a Na ϩ -coupled transporter of butyrate and, therefore, known as sodium-coupled MCT1 (SMCT1) (16,40). Our laboratory's previous studies demonstrated the role of MCT1 in butyrate transport (18), its membrane localization along the length of the human intestine (15), and its transcriptional or posttranslational modulation by the transcription factor upstream stimulatory factor (17), butyrate (9), PKC- (35), somatostatin (36), and in response to enteropathogenic E. coli infection (7).…”

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confidence: 99%

The probiotic Lactobacillus plantarum counteracts TNF-α-induced downregulation of SMCT1 expression and function

Borthakur

Anbazhagan

Kumar

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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The major short-chain fatty acid (SCFA) butyrate is produced in the colonic lumen by bacterial fermentation of dietary fiber. Butyrate serves as primary fuel for the colonocytes and also ameliorates mucosal inflammation. Disturbed energy homeostasis seen in inflamed mucosa of inflammatory bowel disease patients has been attributed to impaired absorption of butyrate. Since sodium-coupled monocarboxylate transporter 1 (SMCT1, SLC5A8) has recently been shown to play a role in Na+-coupled transport of monocarboxylates, including SCFA, such as luminal butyrate, we examined the effects of proinflammatory TNF-α on SMCT1 expression and function and potential anti-inflammatory role of probiotic Lactobacillus species in counteracting the TNF-α effects. Rat intestinal epithelial cell (IEC)-6 or human intestinal Caco-2 cells were treated with TNF-α in the presence or absence of Lactobacilli culture supernatants (CS). TNF-α treatments for 24 h dose-dependently inhibited SMCT1-mediated, Na+-dependent butyrate uptake and SMCT1 mRNA expression in IEC-6 cells and SMCT1 promoter activity in Caco-2 cells. CS of L. plantarum (LP) stimulated Na+-dependent butyrate uptake (2.5-fold, P < 0.05), SMCT1 mRNA expression, and promoter activity. Furthermore, preincubating the cells with LP-CS followed by coincubation with TNF-α significantly attenuated the inhibitory effects of TNF-α on SMCT1 function, expression, and promoter activity. In vivo, oral administration of live LP enhanced SMCT1 mRNA expression in the colonic and ileal tissues of C57BL/6 mice after 24 h. Efficacy of LP or their secreted soluble factors to stimulate SMCT1 expression and function and to counteract the inhibitory effects of TNF-α on butyrate absorption could have potential therapeutic value.

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“…24,25 For example the butyrate transporter SLC5A8 (SMCT1) gene is commonly silenced epigenetically by aberrant methylation early in human colonic neoplasia 25 , but facilitates butyrate-induced cellular apoptosis when re-expressed in the presence of butyrate. 26 Together these data suggest that the evasion of butyrate-induced apoptosis may be a key step in colorectal oncogenesis. Situations of extensive DNA damage and compromised repair may result in the accumulation of mutations or silencing of repair and apoptotic genes.…”

Section: Discussionmentioning

confidence: 90%

Butyrylated starch affects colorectal cancer markers beneficially and dose-dependently in genotoxin-treated rats

Toden

Lockett²,

Topping

et al. 2014

Cancer Biology & Therapy

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Abbreviations: AI, apoptotic index; AOM, azoxymethane; HAMS, high amylose maize starch; HAMSB butyrylated high amylose maize starch; HAMSB0, base diet containing 0% HAMSB; HAMSB5, base diet containing 5% HAMSB; HAMSB10, base diet containing 10% HAMSB; HAMSB20, base diet containing 20% HAMSB; HAMSB40, base diet containing 40% HAMSB; RS, resistant starch; SCFA, short chain fatty acid; SSB, single-stranded DNA breaksPopulation studies suggest that greater dietary fiber intake may lower colorectal cancer (CRC) risk, possibly through the colonic bacterial fermentative production of butyrate. Butyrylated starch delivers butyrate to the colon of humans with potential to reduce CRC risk but high doses may exacerbate risk through promoting epithelial proliferation. Here we report the effects of increasing dietary butyrylated high amylose maize starch (HAMSB) on azoxymethane (AOM) induced distal colonic DNA damage, cell proliferation, mucus layer thickness and apoptosis in rats. Five groups of 15 rats were fed AIN-93G based diets containing 0-40% HAMSB for 4 weeks then injected with (AOM) and killed 6 hours later. Large bowel total SCFA, acetate and butyrate pools and hepatic portal venous plasma total SCFA, acetate and butyrate concentrations were higher with greater HAMSB intake. Distal colonic epithelial apoptotic index and colonic mucus thickness increased, while DNA single strand breaks decreased dose-dependently with greater HAMSB intake. Colonocyte proliferation rates were unaffected by diet. These data suggest that increasing large bowel butyrate may reduce the risk of CRC in a dose dependent manner by enhancing apoptotic surveillance in the colonic epithelium for damaged cells without promoting the risk of tumorigenesis through increased cell proliferation.

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Sodium-Coupled Transport of the Short Chain Fatty Acid Butyrate by SLC5A8 and Its Relevance to Colon Cancer

Abstract: These studies show that SLC5A8 mediates the tumor-suppressive effects of the bacterial fermentation product butyrate in the colon.

Cited by 74 publications

References 31 publications

Blockade of Dendritic Cell Development by Bacterial Fermentation Products Butyrate and Propionate through a Transporter (Slc5a8)-dependent Inhibition of Histone Deacetylases

Blockade of Dendritic Cell Development by Bacterial Fermentation Products Butyrate and Propionate through a Transporter (Slc5a8)-dependent Inhibition of Histone Deacetylases

The probiotic Lactobacillus plantarum counteracts TNF-α-induced downregulation of SMCT1 expression and function

Butyrylated starch affects colorectal cancer markers beneficially and dose-dependently in genotoxin-treated rats

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