Figure 3. Microbial mechanisms contributing to oral tolerance and allergic sensitization in the colon.

Microbial diversity and abundance promote tolerance (A). Microbes ferment fiber to produce short chain fatty acids (SCFAs) that bind G-protein coupled receptors (GPRs) on: 1) intestinal epithelial cells (IECs) to activate inflammasome production of IL-18 that promotes epithelial barrier integrity; 2) dendritic cells (DCs) to drive naïve T cells to become Tregs; 3) Tregs to induce proliferation. Additionally, SCFAs promote acetylation of histone H3 to preserve or induce FoxP3⁺ Tregs. Microbe induced IL-22 production by RORγt⁺ innate lymphocytes and CD4⁺ T cells promotes barrier integrity and IEC synthesis of antimicrobial peptides and mucus. “Tolerogenic” colonic DCs and lymphocytes likely migrate to mesenteric lymph nodes. In allergic sensitization (B), changes in microbial abundance and diversity (eg, after antibiotic exposure) decrease SCFA, IL-18 and IL-22 levels, compromising epithelial integrity, thereby facilitating epithelial passage of microbial and food antigens. DC activation promotes inflammation, the development of Th2 cell-associated immune responses (including production of allergen-specific IgE antibodies), and allergic sensitization.