Activation of Gpr109a, Receptor for Niacin and the Commensal Metabolite Butyrate, Suppresses Colonic Inflammation and Carcinogenesis

Singh, Nagendra; Gurav, Ashish; Sivaprakasam, Sathish; Brady, Evan K.; Padia, Ravi N.; Shi, Huidong; Thangaraju, Muthusamy; Prasad, Puttur D.; Manicassamy, Santhakumar; Munn, David H.; Lee, Jeffrey R.; Offermanns, Stefan; Ganapathy, Vadivel

doi:10.1016/j.immuni.2013.12.007

Cited by 1,826 publications

(1,604 citation statements)

References 48 publications

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“…The priming by bacterial components probably involves a combination of TLR Clinical score activation, and inflammasome activation by SCFAs occurs through their binding to the metabolite-sensing GPCRs GPR43 and GPR109A. GPR109A has previously been shown to be involved in IL-18 production 30 , and our studies here identify the inflammasome pathway for this increase. Similar to SCFAs, K þ efflux activates the inflammasome pathway in primed epithelial cells.…”

Section: Discussionsupporting

confidence: 50%

Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome

et al. 2015

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Diet and the gut microbiota may underpin numerous human diseases. A major metabolic product of commensal bacteria are short-chain fatty acids (SCFAs) that derive from fermentation of dietary fibre. Here we show that diets deficient or low in fibre exacerbate colitis development, while very high intake of dietary fibre or the SCFA acetate protects against colitis. SCFAs binding to the 'metabolite-sensing' receptors GPR43 and GPR109A in non-haematopoietic cells mediate these protective effects. The inflammasome pathway has hitherto been reported as a principal pathway promoting gut epithelial integrity. SCFAs binding to GPR43 on colonic epithelial cells stimulates K þ efflux and hyperpolarization, which lead to NLRP3 inflammasome activation. Dietary fibre also shapes gut bacterial ecology, resulting in bacterial species that are more effective for inflammasome activation. SCFAs and metabolite receptors thus explain health benefits of dietary fibre, and how metabolite signals feed through to a major pathway for gut homeostasis.

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Section: Discussionsupporting

confidence: 50%

Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome

et al. 2015

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“…It is of great clinical relevance that lower abundance of GPR109A ligands, niacin and butyrate in gut is associated with colonic inflammation. Recently, Singh et al [170] have demonstrated an…”

Section: Scfas Induction Of Tregs By Gpr43 and Gpr109a Expressionmentioning

confidence: 99%

Induction of regulatory T cells: A role for probiotics and prebiotics to suppress autoimmunity

Dwivedi

Kumar

Laddha³

et al. 2016

Autoimmunity Reviews

122

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“…Butyrate-dependent HDAC inhibition in DCs may lead to indirect promotion of Treg cell differentiation in the colon by inducing Raldh1 expression 54) . Exposure to butyrate also confers anti-inflammatory properties to macrophages and DCs, most likely through activation of Gpr109a-dependent signaling 55) . Notably, the frequency of butyrate-producing bacteria is reduced in patients with IBD 56) .…”

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confidence: 99%

Commensal microbiota-derived signals regulate host immune system through epigenetic modifications

Takahashi

Hase

2015

Inflammation and Regeneration

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Commensal microbiota colonizing the digestive tract is a symbiotic partner of its host, as it plays a critical role in nutrient metabolism as well as the development and maturation of the host immune system. Although it is clear that regulation of the host-commensal relationship is crucial to mammalian health, the underlying mechanisms regulating gut homeostasis are yet to be elucidated. Epigenetic modifications, including DNA methylation and histone methylation/acetylation, alter the structure of chromatin to regulate the transcriptional program of eukaryotic cells. At the whole genome level, these modifications possibly play a key role in regulating the mutually beneficial relationship between the host and the gut microbiota. In this review, we describe how the commensal microbiota and its metabolic by-products modify the epigenome of host cells, and in turn, change their development and functional behavior.Rec.2/24/2015, Acc.3/1/2015, pp129-136

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Activation of Gpr109a, Receptor for Niacin and the Commensal Metabolite Butyrate, Suppresses Colonic Inflammation and Carcinogenesis

Cited by 1,826 publications

References 48 publications

Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome

Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome

Induction of regulatory T cells: A role for probiotics and prebiotics to suppress autoimmunity

Commensal microbiota-derived signals regulate host immune system through epigenetic modifications

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