In the last 24 months, we have experimentally addressed two aims of the study:
1. Determine the mechanism how dietary PUFAs instigate gut inflammation
First, we identified an inflammatory mechanism of polyunsaturated fatty acids in a Western diet in the context of impaired activity of the anti-oxidative enzyme GPX4 in gut epithelium (which is a feature of human Crohns disease). More specifically, GPX4 restricts oxidation of polyunsaturated fatty acids in gut epithelial cell membranes which is fueled by feeding these lipids. So called lipid peroxidation then induces a danger response of gut epithelium by toll-like receptor mediated sensing of oxidized phospholipids and related by-products. Toll-like receptor signaling in turn activates inflammatory pathways that instigate Crohn-like gut inflammation in a mouse model and this is druggable with anti-inflammatory compounds. As such, our work identifies a specific mechanism how dietary polyunsaturated fatty acids trigger Crohn-like gut inflammation and that this can be pharmacologically targeted in model systems. Next, we evaluated whether dietary polyunsaturated fatty acids elicit an inflammatory response from gut epithelium of patients with Crohn’s disease. Indeed, in patients with reduced activity of the anti-oxidative enzyme GPX4, dietary polyunsaturated fatty acids induced expression of, for example IL-8 (i.e. inflammatory mediator triggering enteritis in mice). Thus, we demonstrate that dietary polyunsaturated fatty acids trigger an inflammatory response from Crohn’s disease epithelium.
2. Establish the concept of PUFA-induced metabolic gut inflammation
The established mechanism explored in aim 1 described above indicated that the same mechanism that promotes metabolic inflammation in obesity also drives gut inflammation recapitulating aspects of human Crohn’s disease. We indeed corroborated this notion by experimental studies, demonstrating that the same pathway that has been previously implicated in the control of metabolic inflammation (so called endoplasmic reticulum stress), also contributes to dietary lipid-induced gut inflammation. We exemplify this in model epithelium in vitro and in a mouse model of Xbp1-restricted endoplasmic reticulum stress. Indeed, endoplasmic reticulum stress is induced by polyunsaturated fatty acids and contributes to inflammatory signaling via the endoplasmic reticulum sensor IRE1a. Therefore, we provide a molecular framework how dietary polyunsaturated fatty acids in a Western diet trigger Crohn’s like gut inflammation in mice, and specifically highlight that the same pathway that is implicated in metabolic inflammation of obesity also drives gut inflammation in mice in the context of lipid excess.
These two major findings have been published in Gastroenterology and Nature Reviews Gastroenterology & Hepatology recently, indicating the great interest for the field. We will use this novel model to further delineate cellular and molecular frameworks by unbiased approaches to improve our understanding of how a Western diet contributes to inflammatory diseases in the gut. These insights may be translated to foster our understanding of Crohn’s disease, which will help to develop targeted therapeutic strategies by modulation of diet or inhibition of related inflammatory pathways.
