Innate Recognition of the Microbiota by TLR1 Promotes Epithelial Homeostasis and Prevents Chronic Inflammation

Abstract

There is cross-talk between the intestinal epithelium and the microbiota that functions to maintain a tightly regulated microenvironment and prevent chronic inflammation. This communication is partly mediated through the recognition of bacterial proteins by host-encoded innate receptors, such as TLRs. However, studies examining the role of TLR signaling on colonic homeostasis have given variable and conflicting results. Despite its critical role in mediating immunity during enteric infection of the small intestine, TLR1-mediated recognition of microbiota-derived ligands and their influence on colonic homeostasis has not been well studied. In this study, we demonstrate that defective TLR1 recognition of the microbiome by epithelial cells results in disruption of crypt homeostasis specifically within the secretory cell compartment, including a defect in the mucus layer, ectopic Paneth cells in the colon, and an increase in the number of rapidly dividing cells at the base of the crypt. As a consequence of the perturbed epithelial barrier, we found an increase in mucosal-associated and translocated commensal bacteria and chronic low-grade inflammation characterized by an increase in lineage-negative Sca1Thy1 innate lymphoid-like cells that exacerbate inflammation and worsen outcomes in a model of colonic injury and repair. Our findings demonstrate that sensing of the microbiota by TLR1 may provide key signals that regulate the colonic epithelium, thereby limiting inflammation through the prevention of bacterial attachment to the mucosa and exposure to the underlying immune system.

Downregulation of IL-18 Expression in the Gut by Metformin-induced Gut Microbiota Modulation

“…TLR1 recognizes bacterial lipoproteins and peptidoglycans and is known to mediate cytokine production along with TLR2. Recently, TLR1 has been reported to play an important role in the regulation of chronic inflammation by sensing the gut microbiota (26). In another study, TLR1 signaling was shown to regulate inflammation during intestinal infection, and TLR1 deficiency led to vulnerability to intestinal inflammation and tissue injury by dysbiosis (27).…”

Mucins in Intestinal Mucosal Defense and Inflammation: Learning From Clinical and Experimental Studies

“…Further evidence gleaned from genetic knockout models have helped highlight the differential effects of TLRs on mucin regulation. For instance, naïve Tlr1 −/− mice have defective production and/or secretion of MUC2 in the colon leading to a patchy and significantly depleted mucus layer ( 67 ). Tlr5 −/ − mice display a mosaic phenotype; a subset of these mice develop spontaneous colitis while the majority do not.…”

Contribution of Non-immune Cells to Activation and Modulation of the Intestinal Inflammation

“…IBD patients have increased levels of TLR4 expression, and lower level of TLR2 and TLR5 in epithelial cells, while TLR4 was shown to be expressed in the apical surface of epithelial cells (28). Current studies have demonstrated the importance of TLR1 in the prevention of gut inflammation (29). In addition to NOD-2 mutations, abnormal mucosal NLRP3 activity has been reported in IBD and in experimental colitis; GWAS studies revealed polymorphisms in these receptors (30–33).…”