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Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D et al.. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461: 1282-1286

Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia.
Nature (Impact Factor: 42.35). 10/2009; 461(7268):1282-6. DOI: 10.1038/nature08530
Source: PubMed

ABSTRACT The immune system responds to pathogens by a variety of pattern recognition molecules such as the Toll-like receptors (TLRs), which promote recognition of dangerous foreign pathogens. However, recent evidence indicates that normal intestinal microbiota might also positively influence immune responses, and protect against the development of inflammatory diseases. One of these elements may be short-chain fatty acids (SCFAs), which are produced by fermentation of dietary fibre by intestinal microbiota. A feature of human ulcerative colitis and other colitic diseases is a change in 'healthy' microbiota such as Bifidobacterium and Bacteriodes, and a concurrent reduction in SCFAs. Moreover, increased intake of fermentable dietary fibre, or SCFAs, seems to be clinically beneficial in the treatment of colitis. SCFAs bind the G-protein-coupled receptor 43 (GPR43, also known as FFAR2), and here we show that SCFA-GPR43 interactions profoundly affect inflammatory responses. Stimulation of GPR43 by SCFAs was necessary for the normal resolution of certain inflammatory responses, because GPR43-deficient (Gpr43(-/-)) mice showed exacerbated or unresolving inflammation in models of colitis, arthritis and asthma. This seemed to relate to increased production of inflammatory mediators by Gpr43(-/-) immune cells, and increased immune cell recruitment. Germ-free mice, which are devoid of bacteria and express little or no SCFAs, showed a similar dysregulation of certain inflammatory responses. GPR43 binding of SCFAs potentially provides a molecular link between diet, gastrointestinal bacterial metabolism, and immune and inflammatory responses.

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Available from: Frederic Sierro, Aug 26, 2015
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    • "SCFAs, which are also an important energy source of gastrointestinal colonocytes, specifically bind the G protein-coupled receptor 43 (GPR43; also known as free fatty acid receptor 2 [FFAR2]), which also mediates their effect on colonic Tregs (Smith et al., 2013). Indeed, Gpr À/À mice exhibit lower IL-10 expression compared to wild-type controls (Smith et al., 2013) and develop more severe inflammation when their airways are challenged with OVA (Maslowski et al., 2009). Microbial-derived SCFAs are produced through the fermentation of complex carbohydrates. "
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    • "It further controls the induction of response genes by immune and epithelial cells, to finally act on apoptosis/proliferation ratio and production of cytokines to regulate immune cell homeostasis (Hill and Artis, 2010). Secondary metabolites and short chain fatty acids also activate specific receptors to regulate inflammation (Maslowski et al., 2009; Kim et al., 2013). In addition, food microbes contribute to the production of bioactive peptides derived from their food matrices (Beermann and Hartung, 2013; Korhonen, 2009). "
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    • "Gpr43 knockout mice phenotype: Maslowski et al. 2009 1 "
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