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It is known that the gut commensal bacteria support intestinal epithelial barrier integrity. However, how specific microbes regulate barrier integrity is not fully understood. We and others find that barrier repair in models of colitis requires the microbiota and asked whether individual microbes are sufficient to replace functions of the total microbiota. We identified a mouse commensal E. coli that protects mice from enhanced damage in the absence of the microbiota in a mouse model of infectious colitis. Surprisingly, the protective E. coli induced IL-1β production by intestinal macrophages in vivo. Such IL-1β secretion activated type 3 innate lymphoid cells (ILC3) and induced IL-22 production that triggered epithelial barrier repair. In addition to mouse commensal E. coli, we also identified a subset of human E. coli isolates that offered protection utilizing the same cellular and molecular pathways. Together, we reveal a novel mechanism that select intestinal commensal bacteria activate inflammatory pathways to support gut barrier repair and maintain barrier integrity.

The intestinal epithelial barrier critically separates exogenous microbes from our internal tissues. Signals from commensal microbes are known to support intestinal barrier integrity and repair. However, the role of specific microbes in maintaining the intestinal barrier is not well-defined. We hypothesize that signals from distinct commensal microbes play different roles in regulating the barrier. We find that mice develop severe colitis with decreased ability to repair the intestinal barrier after antibiotic depletion of intestinal microbes. We further isolated a mouse commensal E. coli that protects from increased colitis after antibiotic treatment. This protection depends on the presence of intestinal antigen presenting cells (APCs) that express the chemokine receptor CX3CR1. We screened a panel of human mucosal-associated E. coli and identified a subset that also protect from colitis in a CX3CR1+ APC dependent manner. All protective E. coli induce IL-1β secretion by activation of the non-canonical inflammasome pathway in CX3CR1+ APCs. In vivo protection is lost if IL-1β signaling is blocked with anti-IL-1β antibody. This E. coli induced IL-1β production activates type 3 innate lymphoid cells (ILC3) to produce IL-22 which drives epithelial proliferation and barrier repair. Collectively, we identified a novel mechanism by which a subset of mucosal-associated intestinal E. coli activate IL-1β production by APCs to protect the intestinal barrier from damage.

Efficient functioning of the intestine and intestinal immune system depends on interactions between the host and microbiota. Breakdown in these interactions leads to reduced ability to respond to intestinal pathogens along with increased intestinal inflammation which together can lead to pathologic inflammatory conditions such as inflammatory bowel disease. While a number of intestinal immune cells are likely regulated by the microbiota, we have found critical regulation of intestinal antigen presenting cells (APCs) expressing the chemokine receptor, CX3CR1. CX3CR1+ APCs are able to secrete both pro- and anti-inflammatory cytokines and are capable of mediating intestinal protection or pathology. Using in vivo models, we identified a regulatory loop whereby intestinal CX3CR1+ APCs reduced induction of Th1 cells against intestinal pathogens and promoted generation of regulatory T cells against soluble food antigens and the microbiota itself. This regulatory response depends on anti-inflammatory cytokine IL-10 production by CX3CR1+ APCs. Disruption of the intestinal microbiota switched the functional capacity of CX3CR1+ APCs so they now drove inflammatory Th1 responses and mediated pathology in a model of colitis. Mechanistically, we determined that epithelial attachment by intestinal microbes was required to turn on anti-inflammatory functions by CX3CR1+ APCs. Our results identify a cellular mechanism by which the microbiota limits intestinal inflammation and promotes homeostasis. Our study demonstrates the potential therapeutic benefits of microbiota and host immune cell manipulation with the goal of amplifying or inhibiting intestinal T cell responses.