Gene-environment interactions in Inflammatory Bowel Disease: Emphasis on smoking and autophagy

Crohn’s disease (CD) and ulcerative colitis (UC) are autoimmune chronic inflammatory disorders of the intestine that are collectively known as inflammatory bowel diseases (IBDs). It finds its origin in an exaggerated inflammatory response to gut luminal contents, caused by an inaccurate response to environmental factors due to the specific genetic makeup of the individual. A typical environmental factor from the Western life style is cigarette smoking, which is beneficial for UC, but detrimental for CD. In this thesis, we aimed to identify smoke-induced mechanisms that could explain the dichotomy in UC and CD. We found that cigarette smoking protects intestinal epithelial cells and T-cells against inflammation-induced apoptosis. This generalized effect of cigarette smoke may lead to mucosal healing in UC, but at the same time further impair proper T-cell termination in CD. To extend our search for genes/proteins responsible for the smoke-induced anti-apoptotic signaling, we found that smoke dose-dependently enhanced the expression of heat shock protein HSPA6 and that HSPA6 physically interacts with and stabilizes the anti-apoptotic protein, Bcl-XL. Further, we found that HSPA6 resides in an UC susceptibility locus. These results reveal a potential mechanism in the smoke-dependent effect on UC. It remains to be determined which smoke-contained component(s) are responsible for the induction of HSPA6 and contribute to the anti-apoptotic effect of cigarette smoking and potential protection against colitis.
The T300A variant in ATG16L1 is one of the most well known CD-associated variants and a potential interaction with cigarette smoking was not yet identified.
ATG16L1 is essential for non-selective autophagy, a process important for cell survival, but it also plays a crucial role in confering resistance to infection by elimination intracellular pathogens, thereby defining mucosal tolerance. Here, we show that uptake of E. coli and of the pathogenic variant (AIEC) was increased in monocytes carrying the T300A variant and cigarette smoke only impaired the uptake of AIEC. Further, monocytes carrying the T300A variant showed impaired killing of AIEC, especially in combination with inflammatory triggers or cigarette smoke, resulting in modulation of intestinal flora, thereby further aggravating CD pathology.