Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43

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 diseases1,2. 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 Bacteriodes3, and a concurrent reduction in SCFAs4. Moreover, increased intake of fermentable dietary fibre, or SCFAs, seems to be clinically beneficial in the treatment of colitis5,6,7,8,9. SCFAs bind the G-protein-coupled receptor 43 (GPR43, also known as FFAR2)10,11, 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.

Figure 1: Exacerbated colitis in germ-free mice is ameliorated by acetate.
Figure 2: GPR43 expression and role in inflammatory responses.
Figure 3: Inflammatory arthritis and allergic airway disease and GPR43 deficiency.
Figure 4: GPR43 signalling and immune cell functions.

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Acknowledgements

The authors thank P. Silvera and S. Tangye for supply of certain Genechip data sets, L. Tsai for help with heatmaps, and D. Kobuley, J. Nicoli and M. Abt for help in the germ-free animal facilities. K.M.M. and C.R.M. are supported by the Australian NHMRC, and the CRC for Asthma and Airways. A.N. is a recipient of a Fellowship award from the Crohn’s and Colitis Foundation of America. F.S. and D.Y. are Cancer Institute NSW Fellows.

Author Contributions C.R.M. conceived and supervised the project, and K.M.M. performed the vast majority of the in vitro and in vivo experiments (other than those detailed below) and provided intellectual input to scientific direction and interpretations. A.T.V., M.M.T. and D.A. contributed to experiments with germ-free mice. F.M., M.S.R. and F.S. identified GPR43 as a receptor with an interesting transcript expression, and A.N. and R.J.X. were responsible for all of the subsequent bioinformatic analyses. H.C.S., D.Y. and J.K. provided general support for many of the experiments.

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Correspondence to Charles R. Mackay.

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Maslowski, K., Vieira, A., Ng, A. et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43 . Nature 461, 1282–1286 (2009). https://doi.org/10.1038/nature08530

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