Redox signaling regulates commensal-mediated mucosal homeostasis and restitution and requires formyl peptide receptor 1

Abstract

The mammalian gut microbiota is essential for normal intestinal development, renewal and repair. Injury to the intestinal mucosa can occur with infection, surgical trauma, and in idiopathic inflammatory bowel disease. Repair of mucosal injury, termed restitution, as well as restoration of intestinal homeostasis involves induced and coordinated proliferation and migration of intestinal epithelial cells. N-formyl peptide receptors (FPRs) are widely expressed pattern recognition receptors that can specifically bind and induce responses to host derived and bacterial peptides and small molecules. Here we report that specific members of the gut microbiota stimulate FPR1 on intestinal epithelial cells to generate reactive oxygen species via enterocyte NADPH oxidase NOX1, causing rapid phosphorylation of Focal Adhesion Kinase (FAK) and ERK MAPK. These events stimulate migration and proliferation of enterocytes adjacent to colonic wounds. Together, these findings identify a novel role of FPR1 as pattern recognition receptors for perceiving the enteric microbiota that promotes repair of mucosal wounds via generation of ROS from the enterocyte NOX1.

Annexin A1–containing extracellular vesicles and polymeric nanoparticles promote epithelial wound repair

“…Increased MMP activity has been identified in inflamed tissues and such MMP activity has been reported to dampen inflammation by promoting cleavage of chemokines (16,40). Given this scenario, one can envision that increased MMPs facilitate resolution of inflammation both by promoting cleavage of ANXA1 and release of the N-terminal peptide, Ac2-26 (7,(41)(42)(43)(44)(45)(46). Pharmacological inhibition of MMP9 markedly reduced ANXA1 detection in EVs (Supplemental Figure 1, A and B).…”

Sex steroid deficiency–associated bone loss is microbiota dependent and prevented by probiotics

“…The fact that LGGM maintained a degree of protection from bone loss suggests that direct contact with the mucus layer may not be the only mode by which LGG exerts probiotic effects and that other properties of LGG -such as the production of short chain fatty acids, which have been shown to modulate cytokine levels in the intestine -is also a mechanism to consider (79). LGG has been shown to facilitate stem cell turnover (5), to facilitate wound restitution in the gut (6), to mediate cytoprotective effects in the gut (4), and to facilitate cell proliferation and migration (80,81). It is also known that permeability along paracellular spaces in the epithelium is controlled by intercellular tight junctional proteins (82,83) and regulated, at least in part, by the MAPK and PI3 kinase signaling pathways (84).…”

“…Of these surfaces, the gastrointestinal tract harbors the largest and most diverse population of microorganisms, which have been shown to elicit positive influences on health. For example, the intestinal microbiota induces the generation of immunomodulatory factors that regulate intestinal inflammatory responses (3), cytoprotection (4), barrier integrity, and homeostasis (5), as well as wound restitution (6). It is now clear that the gut microbiota influences not only the local immune response, but also contributes to immune responses distant from mucosal surfaces, including the CNS, joints, and lungs (3,(7)(8)(9).…”

Redox signaling mediated by the gut microbiota

“…In addition, investigations utilizing germ-free mice have established a function for the gut microbiome and metabolic regulation [8]. The gut microbiome has also been shown to positively influence homeostasis of the intestinal mucosa by enhancing barrier function, as well as epithelial cell proliferation and survival [9][10][11][12][13][14][15]. For instance, villi of the small intestine of the germ-free mice have impaired angiogenesis [16] and have slower turnover rates of epithelial cells [17].…”