Claudin-3, Gut Dysbiosis and Inflammatory Bowel Disease

Omaha Va Medical Center, Omaha NE

Investigators

Linked publications & trials

Abstract

Inflammatory bowel disease (IBD), consisting primarily of the ulcerative colitis (UC) and Crohn’s disease (CD), is a group of debilitating auto-immune disorders, which significantly affect one’s life-style and carry a high risk of colon cancer. While significant advances have been made in the clinical management of these diseases, the overall incidence rate and disease severity in active duty army personnel and veterans is constantly increasing possibly due to the high level of stress involved. Moreover, IBD significantly increases the risk of colon cancer, and therefore physical and economical burden of these diseases upon our veteran population is significantly high. However, the etiology of IBD remains unclear. Taken together, there is an urgent and unmet need for improved understanding of the molecular mechanisms that promote IBD susceptibility and/or disease severity, as it can help identify novel therapeutic targets. In this regard, disruption of epithelial polarity and compartmentalization, assisted by the tight junction (TJ) deregulation, plays key role in inducing and promoting mucosal inflammation. Notably, an association between the leaky gut and IBD has long been suggested. However, despite this knowledge, progress in this area for therapeutic gains has been limited due primarily to the generic perspective that proteins constituting the TJ are static and redundant in their function. This proposal disagrees with this generic view and proposes key role of claudin-3, a TJ-integral protein, in dynamic regulation of the gut epithelial and inflammatory homeostasis. Our working hypothesis is that the loss of claudin-3, which characterizes IBD patients, deregulates mucosal barrier integrity to induce gut dysbiosis and pro-inflammatory environment. Accompanying deregulations of gp130/IL6/Stat3 and Hippo/Yap signaling cascades, due to the polarity defects ensued by deregulated Par-3 expression, render chronicity to the initial inflammatory insult by deregulating mucosal injury/repair leading ultimately to neoplastic growth. This proposal is built upon a strong scientific premise as a series of studies, including ours, have now identified claudin-3 (hereon Cldn3) as a key TJ-protein in maintaining gut epithelial barrier maturity and integrity. In this regard, we found Cldn3 to be the highest expressed cell-cell adhesion protein localized primarily amongst differentiated colonocyte at the crypt top in normal colon. Furthermore, Cldn3KO mice, used to model decreased Cldn3 levels in IBD patients, exhibited hyper-permeable gut and immune cell infiltration into the lamina propria. In addition, gut dysbiosis along with specific and robust increase in gp130/IL6/Stat3 expression characterized Cldn3KO mice. Cldn3 loss also compromised colonic epithelial cell (CEC) differentiation and polarity, and promoted Hippo/Yap-signaling. Importantly, Stat-3 and Yap-signaling pathways promote hyper-proliferation, chronic inflammation and malignant growth when deregulated. Accordingly, DSS colitis-challenged Cldn3KO mice exhibited severe colitis and dysplasia (versus WT-mice). Taken together, our data support the role of Cldn3 as a rheostat in regulating the colonic epithelial and immune signaling and thereby leading to the hypothesis that Cldn3 loss is promiscuous in promoting colitis. To test our hypothesis, we propose following studies: Aim-1. To determine the expression dynamics and context for the loss of Cldn3 expression in promoting IBD; Aim-2. To determine the role and potential collaboration between IL6/Stat3 and Hippo/Yap signaling in promoting colitis under conditions of the loss of Cldn3 expression; and Aim-3. To determine the causal integration between Cldn3 loss and gut dysbiosis in promoting IBD. Overall, this proposal presents a unique platform for dissecting circuity between mucosal barrier deregulation and polarity in regulating colitis and associated cancer for therapeutic gains. Outcome will be significant in improving survival and quality of life of our Veterans.