Epithelial autophagy as rheostat of intestinal inflammation

Genome wide association studies have unravelled an unexpected role for autophagy, a cellular degradation pathway, in Crohns disease. Specifically, genetic variation in ATG16L1 has been linked to the development of Crohns disease which renders cells susceptible to autophagy defects. In previous work, the applicant and his colleagues demonstrated that impaired ATG16L1-mediated autophagy in intestinal epithelial cells (IECs) evokes susceptibility to Crohns-like intestinal inflammation in mouse models, in part by defective removal of inflammatory signalling nodes. In a current concept of inflammatory bowel diseases, a reasonably well-defined genetic landscape (that only explains a minority of cases) provides the basis for environmental triggers that instigate chronic remittent inflammatory responses. Which and how dietary factors instigate disease processes remains largely enigmatic. The increasing incidence of inflammatory bowel diseases was paralleled by Westernisation of dietary habits which is partly characterised by enrichment of -6 polyunsaturated fatty acids contained in meat, eggs and oils_ENREF_3. In an expiring FWF project, the applicant and his team delineated the biological function of an anti-oxidative enzyme called Glutathione peroxidase 4 in CD, following a genetic risk association. He and his team demonstrated that Glutathione peroxidase 4 protects against Crohns-like intestinal inflammation in mice that were exposed to polyunsaturated fatty acids. In the proposed work, the applicant and his team will investigate how dietary polyunsaturated fatty acids trigger an inflammatory response in the intestine to develop novel therapeutic approaches. The applicant proposes that ATG16L1-mediated autophagy critically controls intestinal inflammation that is triggered by dietary lipids, which they will proof by pharmacologic and genetic experiments. The proposed project seeks to establish a mechanistic interplay between genetic and environmental factors that have been associated with the development of Crohns disease. This project will be performed by Dr. Timon Adolph, PhD and his team in the Gastroenterology Laboratory at the Medical University of Innsbruck and in collaboration with local and international research groups.

The FWF stand-alone project P33070 successfully established a mechanism by which intestinal epithelial autophagy controlled experimental gut inflammation elicited by dietary polyunsaturated fatty acids (PUFA). Dietary PUFAs in a Western diet elicit lipid peroxidation in gut epithelium, which instigates toll-like receptor 2 signalling and expression of inflammatory cytokines. This mechanism is suppressed by an anti-oxidative enzyme called Glutathione peroxidase 4 (GPX4) and drives PUFA-induced gut inflammation in mice, which can be targeted to treat experimental diet-induced Crohn-like disease. These findings are notable because GPX4 activity is impaired in patients with inflammatory bowel diseases and specifically Crohn's disease, which will lead to clinical trials that address how we can use dietary restriction of lipid intake to prevent gut inflammation in humans. These results were published in Gastroenterology in 2022 and discussed in several news outlets.