Cross-talk between gut bacteria and intestinalepithelial cells in IBD

Commensal bacteria in the healthy gut contribute to mucosal homeostasis by regulating innate and adaptive immune responses and promoting epithelial restitution. Inflammatory bowel disease (IBD) is thought to result from a dysregulated mucosal immune response to the gut microbiota in genetically susceptible individuals. Secretory IgA (SIgA) antibodies play a critical role in shaping the composition of the gut microbiota and in maintenance of intestinal homeostasis. The polymeric immunoglobulin receptor (pIgR) transports polymeric IgA antibodies from the basolateral to the apical surface of intestinal epithelial cells (IEC), and also contributes to innate defense mechanisms. We recently found that expression of pIgR was significantly decreased in the colonic mucosa in patients with Crohn's disease (CD). Using in vitro tissue culture models of human intestinal epithelial cells, we have demonstrated that pIgR expression is regulated by host-derived cytokines, bacterial products, and by the probiotic E. coli strain Nissle 1917. Importantly, E. coli Nissle 1917, Bifidobacterium-fermented milk and VSL#3 (a mixture of 8 Gram-positive Lactobacillus, Bifidobacterium and Streptococcus spp.) have shown promise in treating symptoms of IBD. Our recent data demonstrate that E. coli Nissle directly enhances pIgR expression in intestinal epithelial cells via Toll-like receptor (TLR) signaling utilizing the intracellular adaptor MyD88. We hypothesize that pIgR expression is regulated via homeostatic interactions between gut bacteria and host cells, and that this process is dysregulated in IBD. The goal of our proposed experiments is to determine the mechanisms through which gut bacteria regulate pIgR expression, and to gain insight into how these homeostatic pathways are dysregulated in IBD. In Aim 1, we will test the hypothesis that expression of pIgR is regulated by bacterial cross-talk with intestinal epithelial cells (IEC) and lamina propria mononuclear cells (LPMC), and that this process is dysregulated in IBD. In Aim 2, we will test the hypothesis that pIgR contributes directly to regulation of intestinal inflammation in T cell-dependent and T cell independent mouse models of experimental colitis. In Aim 3, we will test the hypothesis that regulation of pIgR expression by gut bacteria in vivo requires coordinated TLR/MyD88 signaling by IEC and LPMC.