Exploring Gene-environment Interactions in Inflammatory Bowel Disease

Abstract

Inflammatory bowel disease (IBD) is family of complex conditions of the gastrointestinal tract. Pathogenesis of IBD remains unknown and is postulated to be multifactorial, including contributions from host genetics, environmental factors, the gut microbiome, and the immune response. This work explored environmental influences and gene-environment interactions in IBD. Vitamin D deficiency is an environmental factor involved in IBD pathogenesis. Although the mechanism remains unclear, previous studies suggest that a lack of vitamin D signaling causes a reduction in intestinal autophagy. A potential link between vitamin D deficiency and dysregulated autophagy is microRNA (miR)-142-3p, which suppresses autophagy. We found that vitamin D deficient mice had enhanced miR-142-3p expression in ileal tissues compared to control mice. Paneth cells of vitamin D deficient mice were morphologically abnormal and displayed evidence of an autophagy defect. These findings suggest that Paneth cells exhibit early markers of autophagy dysregulation within the intestinal epithelium in response to vitamin D deficiency and enhanced miR-142-3p expression. We demonstrated that treatment-naïve IBD patients with low vitamin D have increased miR-142-3p expression in colonic tissues procured from ‘involved’ areas of disease. Taken together, our findings demonstrate that insufficient vitamin D levels alter expression of autophagy-regulating miR-142-3p in intestinal tissues of mice and IBD patients, providing insight into the mechanisms by which vitamin D deficiency modulates IBD pathogenesis. We explored gene-environment interactions by evaluating the effects of vitamin D deficiency in mice that have an important IBD genetic risk variant, Nod2fs, which also disrupts autophagy. Interestingly, the combination of vitamin D deficiency and Nod2fs did not impact autophagy at baseline. However, upon microbial disturbances in the microbiome, the vitamin D deficient Nod2fs mice had pervasive autophagy defects. This is in line with the multi-hit model of IBD, which proposes that many insults converge to cause defects in the intestinal epithelium. In our gene-environment analyses, we also observed that the Nod2fs mutation led to reduced serum vitamin D, a novel interaction between an IBD genetic risk factor and environmental factor of interest. Through this work we were able to identify therapeutic targets of interest and contribute to the understanding of IBD pathogenesis.