Impact of Bacterial Metabolites on Gut Barrier Function and Host Immunity: A Focus on Bacterial Metabolism and Its Relevance for Intestinal Inflammation

Abstract

The diverse and dynamic microbial community of the human gastrointestinal tract plays a vital role in health, with gut microbiota supporting the development and function of the gut immune barrier. Crosstalk between microbiota-gut epithelium and the gut immune system determine the individual health status, and any crosstalk disturbance may lead to chronic intestinal conditions, such as inflammatory bowel diseases (IBD) and celiac disease. Microbiota-derived metabolites are crucial mediators of host-microbial interactions. Some beneficially affect host physiology such as short-chain fatty acids (SCFAs) and secondary bile acids. Also, tryptophan catabolites determine immune responses, such as through binding to the aryl hydrocarbon receptor (AhR). AhR is abundantly present at mucosal surfaces and when activated enhances intestinal epithelial barrier function as well as regulatory immune responses. Exogenous diet-derived indoles (tryptophan) are a major source of endogenous AhR ligand precursors and together with SCFAs and secondary bile acids regulate inflammation by lowering stress in epithelium and gut immunity, and in IBD, AhR expression is downregulated together with tryptophan metabolites. Here, we present an overview of host microbiota-epithelium- gut immunity crosstalk and review how microbial-derived metabolites contribute to host immune homeostasis. Also, we discuss the therapeutic potential of bacterial catabolites for IBD and celiac disease and how essential dietary components such as dietary fibers and bacterial tryptophan catabolites may contribute to intestinal and systemic homeostasis.

Keywords: SCFAs; bacterial metabolites; dietary fiber; gut immune barrier; gut microbiota; inflammation; secondary bile acids; tryptophan.

Figure 1

Endogenous or dietary compounds and dietary-derived bacterial metabolites effects on the gut immune barrier. (1) Direct effect of dietary fiber. Some dietary fibers have been shown to have direct effects on immune cells. E.g., low degree of methyl esterification (Low-DM) pectin binds to TLR2, inhibiting TLR2-1 heterodimer activation, thus reducing NF-κB activation. (2) Bacterial fermentation of dietary fiber by SCFAs-producing bacteria. SCFAs inhibit histone deacetylases (HDACs) and thus NF-kB-induced pro-inflammatory mediators: (2A) induce neutrophil chemotaxis by binding to GPR43, (2B) promote IgA secretion (2C), stimulate Tregs proliferation and differentiation by activating GPR43 and inhibiting HDACs (2D), influence NLRP3 by activating GPR43 or GPR109A facilitating IL-18 expression, thus promoting repair and maintaining barrier function (2E, 2F). (3) Bacterial tryptophan metabolism: Indole promotes epithelial barrier function through the pregnane X receptor (PXR). Bacterial tryptophan metabolites are AhR ligands in ILCs, RORγt interacts with AhR stimulating IL-22 expression (3A, 3B), IL-22 promotes antimicrobial peptide expression and enhances goblet cell proliferation for mucin secretion (2E). (4) Bacterial bile acid metabolites: Gut metabolites-derived from microbiota, endogenous or dietary compounds participate in microbiota-host interactions, exerting diverse effects on epithelial or immune cells through different signaling pathways. Secondary bile acids regulate epithelial integrity by binding to the farnesoid X receptor (FXR) in epithelial cells (4A), regulate macrophages differentiation into M2 profile via TGR5 and FXR activation, reversing inflammatory pathways producing IL-10 (4B), with further IL-10 production by Treg (2D). Additionally, TGR5 signaling involves NF-κB inhibition, and FXR signaling repressing NF-κB-responsive elements (NRE) in macrophages and dendritic cells (4B, 4C).