Commensal bacteria-induced MyD88 signaling regulates intestinal permeability to food allergen via anti-microbial peptide and mucin production (MUC9P.741)

Intestinal epithelial cells (IEC) play a critical role in maintaining the integrity of the mucosal barrier. We have recently shown that germ free mice exhibit increased intestinal permeability to food allergens, suggesting a role for microbiota-derived signals in protecting the barrier. Decreased permeability to the peanut allergen Ara h 6 in mice selectively colonized with a consortium of Firmicutes in the Clostridia class is associated with upregulation of antimicrobial peptide expression (RegIIIβ/γ) and the production of mucins (MUC2/13). RegIIIβ/γ are well known targets of MyD88 signaling. We hypothesized that Clostridia signals through MyD88 in IECs to enhance barrier protection and generated mice lacking MyD88 in IECs (Myd88ΔIEC). Myd88-/- and Myd88ΔIEC mice exhibit increased permeability to Ara h 6, downregulated expression of RegIIIβ/γ in IECs, and reduced production of MUC2/13 in goblet cells. Antibiotic mediated depletion of commensal bacteria exacerbated the permeability defect in Myd88ΔIEC mice and also led to a barrier defect in MyD88-sufficient littermate controls. Colonization with Clostridia rescues this defect in control mice but not in the Myd88ΔIEC mice indicating that signaling through MyD88 in the intestinal epithelium is necessary for bacteria-induced barrier protection. This restricted permeability of the gut limits the access of dietary antigens to the systemic circulation and contributes to protection against allergic sensitization in these mice.