Commensal‐epithlial signaling mediated via Formyl Peptide Receptor

Abstract

Commensal bacteria and/or their products engender beneficial effects to the mammalian gut, including stimulating homeostatic cellular turnover and enhancing wound healing, without activating innate immune pathways. In the present study we observed commensal bacterial mediated activation of the pro‐proliferative ERK MAPK signaling pathway in gut epithelial cells and describe a mechanism for commensal‐host crosstalk. A range of commensal bacteria tested induced ERK phosphorylation without JNK or NF‐κB signaling. ERK‐specific phosphorylation was recapitulated using a purified small peptide, N‐formyl‐Met‐Leu‐Phe (fMLF), a bacterial product known to stimulate signaling in mammalian phagocytes. The fMLF tripeptide is recognized via the recently characterized epithelial formyl peptide receptors (FPR) located on the apical surface. Both commensal bacteria and fMLF application to apical surfaces of polarized gut epithleilal cells resulted in FPR activation. Also, pretreatment of model epithelia and the murine gastrointestinal tract with Boc2 (specific fMLF peptide antagonist) or pertussis toxin (Gi‐protein inhibitor) abolished commensal‐mediated ERK phosphorylation. Together, these data show commensal bacteria specifically activate the pro‐proliferative ERK pathway in an FPR‐dependent manner, and suggest a mechanism by which commensal bacteria contribute to gut epithelia homeostasis.