PDLIM2 loss in the epithelium impairs antioxidant responses and adhesion signals preceding the development of ulcerative colitis

Inflammatory bowel disease (IBD), particularly ulcerative colitis, involves impaired wound healing processes contributing to sustained immune and microbial interactions that aggravate intestinal injury. Chronic inflammation and its associated morbidities pose a significant burden for patients. Here we investigated the functions of PDLIM2, a known transcriptional regulator in terminating inflammatory signals and maintaining epithelial integrity, in colitis progression. In a murine model, PDLIM2 expression was gradually lost over the course of colitis progression. PDLIM2 min was associated with a shift in gut microbial diversity, composition and predicted functionality, and with exacerbated and unresolved epithelial damage and inflammation. Mechanistic studies in colon epithelial cells demonstrated PDLIM2 suppression impairs adhesion signals, mitochondrial function, and antioxidant buffering necessary for cell polarisation and wound healing. Importantly, in human tissues while PDLIM2 is highly expressed in normal epithelial enterocyte populations, we observed its suppression in colon samples of both ulcerative colitis and Crohns disease preceding the development of inflammation. We conclude that PDLIM2 is required for maintaining intestinal integrity and is potentially a novel therapeutic target for restoring epithelial integrity in IBD-associated conditions.