Abstract
Commensal gut microflora and dietary fiber protect against colonic inflammation and colon cancer through unknown targets. Butyrate, a bacterial product from fermentation of dietary fiber in the colon, has been implicated in this process. GPR109A (encoded by Niacr1) is a receptor for butyrate in the colon. GPR109A is also a receptor for niacin, which is also produced by gut microbiota and suppresses intestinal inflammation. Here we showed that Gpr109a signaling promoted anti-inflammatory properties in colonic macrophages and dendritic cells and enabled them to induce differentiation of Treg cells and IL-10-producing T cells. Moreover, Gpr109a was essential for butyrate-mediated induction of IL-18 in colonic epithelium. Consequently, Niacr1(-/-) mice were susceptible to development of colonic inflammation and colon cancer. Niacin, a pharmacological Gpr109a agonist, suppressed colitis and colon cancer in a Gpr109a-dependent manner. Thus, Gpr10a has an essential role in mediating the beneficial effects of gut microbiota and dietary fiber in colon.
Copyright © 2014 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Butyrates / immunology
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Carcinogenesis / immunology*
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Cell Differentiation / drug effects
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Cells, Cultured
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Colitis / complications
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Colitis / drug therapy
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Colitis / immunology*
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Colon / immunology*
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Colon / microbiology
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Colon / pathology
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Colonic Neoplasms / etiology
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Colonic Neoplasms / prevention & control*
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Dendritic Cells / immunology
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Disease Susceptibility
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Epithelial Cells / drug effects
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Epithelial Cells / immunology*
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Interleukin-10 / metabolism
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Interleukin-18 / genetics
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Interleukin-18 / metabolism
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Lymphocyte Activation / drug effects
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Macrophages / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Microbiota
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Niacin / administration & dosage
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Receptors, G-Protein-Coupled / genetics
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Receptors, G-Protein-Coupled / immunology
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Receptors, G-Protein-Coupled / metabolism*
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Receptors, Nicotinic / genetics
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Receptors, Nicotinic / immunology
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Receptors, Nicotinic / metabolism*
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Signal Transduction / drug effects
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T-Lymphocyte Subsets / immunology
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T-Lymphocytes, Regulatory / immunology
Substances
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Butyrates
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Hcar2 protein, mouse
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Interleukin-18
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Receptors, G-Protein-Coupled
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Receptors, Nicotinic
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Interleukin-10
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Niacin