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.

Proteomic Characterization of the Cellular Effects of AhR Activation by Microbial Tryptophan Catabolites in Endotoxin-Activated Human Macrophages

“…Homeostasis of a healthy gut microbiome requires a balance between proinflammatory processes to fight pathogens and anti-inflammatory processes to protect commensals [ 73 , 74 ]. For this balance, the activation tuning of AhR by microbial tryptophan metabolites is essential [ 15 , 74 ].…”

“…Homeostasis of a healthy gut microbiome requires a balance between proinflammatory processes to fight pathogens and anti-inflammatory processes to protect commensals [ 73 , 74 ]. For this balance, the activation tuning of AhR by microbial tryptophan metabolites is essential [ 15 , 74 ]. In turn, a restricted capability to produce indoles from tryptophan is associated with metabolic syndrome [ 14 ], and a complete lack is linked to inflammatory bowels disease [ 19 ].…”

The Short-Chain Fatty Acids Propionate and Butyrate Augment Adherent-Invasive Escherichia coli Virulence but Repress Inflammation in a Human Intestinal Enteroid Model of Infection

“…Because an anti-inflammatory role for propionate and butyrate has previously been reported in vivo , we were surprised to observe a proinflammatory effect for these SCFAs in Caco-2 monolayers ( 3 , 10 ). We considered that the Caco-2 cell line, which is derived from an adenocarcinoma, might not accurately model the response of the healthy mammalian intestine to SCFAs.…”

“…Therefore, there is a clinical need for new therapies. Because of their anti-inflammatory effects, SCFAs have been proposed as treatments for pathological conditions of the bowel that involve inflammation, including infection, malignancy, and idiopathic inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis ( 10 ).…”

Biological Treatments in Inflammatory Bowel Disease: A Complex Mix of Mechanisms and Actions

“…This is associated with dysbiosis (altered gut microbiome composition), whose role as a causative factor or a consequence of mucosal inflammation is not yet clear [12,13]. Furthermore, the mucosal immune system constitutes the third most recognized component contributing to the complex underlying etiopathogenic mechanisms [14]. Indeed, pronounced infiltration of the lamina propria with a mix of neutrophils, macrophages, dendritic cells, and natural killer (NK) T cells is found in active IBD [15].…”