Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43

By K. Maslowski, A. T. Vieira, Aylwin Ng, J. Kranich, F. Sierro, Di Yu, H. Schilter, M. Rolph, F. Mackay, D. Artis and 3 more. Nature, 2009

3,054 citations recorded by the source corpus.

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.

Subfields: Immunology, Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/a9560dc461ea6d592c42ec18a065d86cd42da53c

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Citations in the corpus

Homeostatic immunity and the microbiota (2017, positive): “For example, recognition of the commensal derived metabolites SCFA by innate immune cells is critical for the regulation of inflammation (Maslowski et al., 2009).”
Dietary Gut Microbial Metabolites, Short-chain Fatty Acids, and Host Metabolic Regulation (2015, background): “Gut microbiota and FFAR2 regulate inflammatory responses in colitis [41].”
Intestinal permeability – a new target for disease prevention and therapy (2014, background): “Saadat I, Higashi H, Obuse C, Umeda M, Murata-Kamiya N, Saito Y, Lu H, Ohnishi N, Azuma T, Suzuki A, Ohno S, Hatakeyama M: Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity.”
Intestinal microbiota in patients with nonalcoholic fatty liver disease (2013, neutral): “Insulin (pmol/L) 21 (15-61) 33 (15-465) 97 (29-437)”
The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition (2014, background): “have shown that the SCFA acetate ameliorates DSS colitis (14).”
Short Chain Fatty Acids (SCFAs)-Mediated Gut Epithelial and Immune Regulation and Its Relevance for Inflammatory Bowel Diseases (2019, background): “, IL-10 deficient mice show less severe chronic bowel inflammation in germfree (GF) conditions (13, 14), while acute chemically-induced colitis is exacerbated in GF mice compared to mice with a normal microbiome (15).”