Microbiota, dieta e sistema imune: um diálogo constante via ativação do receptor acoplado à proteína-G 43 (Gpr43)

Abstract

The commensal bacterial of the gastrointestinal tract shapes the development of the immune system. The gut microbiota produces factors that are beneficial to the host for the regulation of immune responses. One of these factors may be the shortchain fatty acids (SCFA), which are produced by fermentation of dietary fiber by healthy microbiota such as Bifidobacterium and Bacteroides. SCFAs bind to Gprotein coupled receptor 43 (GPR43, also known as FFAR2), and in this work we show that SCFAGPR43 interactions exerts modulator effects in inflammatory responses. Stimulation of GPR43 by SCFA was necessary for the resolution of inflammatory responses. GPR43-deficient (Gpr43-/-) mice showed exacerbated or unresolving inflammation in models of colitis, arthritis and asthma. Interestingly, the Gpr43-/- mice showed impair response to gout by the inability to activate inflammasoma complex. However, acetate treatment before and after gout induction in wt mice abolished tissue injury promoting resolution of the inflammation. Furthermore, mice fed with higher fiber diet or with Bifidobacterium longum reduced cells infiltrate in mice challenged with MSU. Germ-free mice (GF), which are devoid of bacteria and no or little SCFAs production, showed a similar response to Gpr43-/- mice. GF mice showed an exacerbated response in colitis, asthma and rheumatoid arthritis models. However, if we treated GF with acetate (the most abundant SCFA) before such diseases, a protective effect was observed. Furthermore, GF mice MSU challenged showed a similar hiporresponsive and inhibited recruitment of cells when compared to Gpr43-/- mice. Although, when we treated GF with acetate before challenged with MSU this phenotype was reversed. Thus, these data suggested an ability of acetate to prime the immune system and allow inflammatory cell recruitment during response to MSU challenge. In summary, this work suggests that endogenous microbiota shapes the hosts ability to respond to inflammatory stimuli and SCFA-GPR43 interactions could represent a central mechanism to account for affects of diet and gut microbiota on immune responses providing a molecular link between diet, gastrointestinal bacterial metabolism and inflammatory responses.