A New Risk Gene Is Associated with Very Early Onset Inflammatory Bowel Disease and Autoimmune Hepatobiliary Disease: A Mechanistic Study Using Patient Organoids and Transgenic Models

Abstract Text: Very early onset inflammatory bowel disease (VEO-IBD) and autoimmune hepatobiliary disease including primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) are debilitating conditions with unclear etiologies. In a patient with VEO-IBD, PSC, celiac disease, hypothyroidism, and a strong family history of autoimmune disease, whole exome sequencing (WES) identified two rare, novel, pathogenic variants in CGNL1, which encodes an epithelial junctional protein. Both pathogenic variants were also present in the patient’s younger sister with early onset and severe IBD and PSC-AIH. Furthermore, multiple relatives of the patient suffer from IBD, celiac disease, eosinophilic esophagitis, type-1 diabetes, and hypothyroidism. The RNA and protein levels of CGNL1 were diminished in the patient’s intestinal epithelium compared to healthy individuals and other IBD patients. Intestinal epithelial organoids (IEOs) from the affected patient formed smaller 3D spheroids with altered cell composition and significantly impaired barrier function compared to those from healthy controls and other IBD patients. Electron microscopy demonstrated disrupted tight junctions and adherens junctions in the patient’s IEOs. Similarly, impaired junctional complexes in intestinal epithelial cells and elevated intestinal permeability were present in Cgnl1-/- mice, which also showed increased susceptibility to colitis and C. rodentium infection. Single-cell analysis revealed diminished expression of CGNL1 in the intestinal and hepatic epithelial cells from patients with IBD or PSC/AIH, respectively. To summarize, we identified CGNL1 as a new risk gene that may contribute to VEO-IBD and autoimmune hepatobiliary disease by disrupting gut barrier integrity. This study expands our understanding of epithelial barrier impairment in the pathogenesis of VEO-IBD.