Acute Colitis Drives Tolerance By Persistently Altering The Epithelial Barrier And Innate And Adaptive Immunity

Background Inflammatory bowel disease (IBD) has a remitting and relapsing disease course; however, relatively little is understood regarding how inflammatory damage in acute colitis influences the microbiota, epithelial barrier, and immune function in subsequent colitis.Methods Mice were administered trinitrobenzene sulphonic acid (TNBS) via enema, and inflammation was assessed 2 days (d2) or 28 days (d28) later. Colitis was reactivated in some mice by re-treating at 28 days with TNBS and assessing 2 days later (d30). Epithelial responsiveness to secretagogues, microbiota composition, colonic infiltration, and immune activation was compared between all groups.Results At day 28, the distal colon had healed, mucosa was restored, and innate immune response had subsided, but colonic transepithelial transport (P = 0.048), regulatory T-cell (T-REG) infiltration (P = 0.014), adherent microbiota composition (P = 0.0081), and responsiveness of stimulated innate immune bone marrow cells (P < 0.0001 for IL-1 beta) differed relative to health. Two days after subsequent instillation of TNBS (d30 mice), the effects on inflammatory damage (P < 0.0001), paracellular permeability (P < 0.0001), and innate immune infiltration (P < 0.0001 for Ly6C+ Ly6G- macrophages) were reduced relative to d2 colitis. However, T-REG infiltration was increased (P < 0.0001), and the responsiveness of stimulated T cells in the mesenteric lymph nodes shifted from pro-inflammatory at d2 to immune-suppressive at d30 (P < 0.0001 for IL-10). These effects were observed despite similar colonic microbiota composition and degradation of the mucosal layer between d2 and d30.Conclusions Collectively, these results indicate that acute colitis chronically alters epithelial barrier function and both innate and adaptive immune responses. These effects reduce the consequences of a subsequent colitis event, warranting longitudinal studies in human IBD subjects.