Microbiota metabolite short chain fatty acids, GPCR, and inflammatory bowel diseases

Abstract

Gut microbiota has been well recognized in regulation of intestinal homeostasis and pathogenesis of inflammatory bowel diseases. However, the mechanisms involved are still not completely understood. Further, the components of the microbiota which are critically responsible for such effects are also largely unknown. Accumulating evidence suggests that, in addition to pathogen-associated molecular patterns, nutrition and bacterial metabolites might greatly impact the immune response in the gut and beyond. Short chain fatty acids (SCFA), which are metabolized by gut bacteria from otherwise indigestible fiber-rich diets, have been shown to ameliorate diseases in animal models of inflammatory bowel diseases (IBD) and allergic asthma. Although the exact mechanisms for the action of SCFA are still not completely clear, most notable among the SCFA targets is the mammalian G protein-coupled receptor pair of GPR41 and GPR43. In addition to the well-documented inhibition of histone deacetylases activity mainly by butyrate and propionate, which causes anti-inflammatory activities on IEC, macrophages, and dendritic cells, SCFA has recently been implicated in promoting development of Treg cells and possibly other T cells. In addition to animal models, the beneficial effects have also been reported from the clinical studies that used SCFA therapeutically in controlled trial settings in inflammatory disease, in that application of SCFA improved indices of IBD and therapeutic efficacy was demonstrated in acute radiation proctitis. In this review article, we will summarize recent progresses of SCFA in regulation of intestinal homeostasis as well as in pathogenesis of IBD.

Keywords: GPCR; IBD; Microbiota; Short chain fatty acids.

Figure 1. Formation, absorption and transportation of SCFA

Indigestible dietary fibers can be fermented in the cecum and colon by gut microbes to form SCFA, which usually are utilized in the enterocytes through different ways: passive diffusion; carrier-mediated transportation by Slc5a8 and Slc16a1; and binding GPR41, GPR43 and GPR109a. After being absorbed, SCFAs are transported into portal vein via superior mesenteric vein and inferior mesenteric vein depending on the absorption sites, and dispersed to peripheral tissues as skeletal muscle, liver and adipose tissue to take effects.

Figure 2. SCFA regulation of intestinal immunity

SCFA regulate the intestinal mucosal immunity through exerting their effects on various immune cells. SCFA regulate intestinal barrier integrity by inducing intestinal epithelial cell secretion of IL-18, antimicrobial peptides, mucin, and upregulating the expression of tight junction. SCFA induce neutrophils migration to inflammatory site and enhance their ability of phagocytosis. SCFA regulate the T cell function not only through GPCR pathway but also inhibition of HDAC. The differentiation of T cell is mediated both by SCFA regulation of DC and the direct act of SCFA on T cells. SCFA regulate the generation of Th1, Th17 and Treg in different cytokine milieu. SCFA also inhibit intestinal macrophage production of proinflamamtory cytokines through inhibition of HDAC, and possibly induce intestinal IgA production of B cells. Moreover, SCFAs inhibit the carcinogenesis through promoting apoptosis and suppressing proliferation of tumor cells.