Periodic Reporting for period 1 - MEGI CD (Metabolic Gut Inflammation in Crohn's disease)
Periodo di rendicontazione: 2022-04-01 al 2024-09-30
Westernization of diet is suspected to contribute to the global rise of inflammatory bowel diseases. How a Western diet affects chronic gut inflammation is poorly understood but may involve diet-induced gut microbial perturbation. In this ongoing project, we study how a Western diet enriched with polyunsaturated fatty acids is able to induce gut inflammation in a genetically susceptible host and whether this underlies aspects of inflammation in patients with inflammatory bowel diseases. We will study experimental model systems in vitro, transgenic mouse models after exposure to a model Western diet and a human cohort with Crohn’s disease tissue, to determine the effect of dietary fat on the course of disease. With the help of these studies, we will be able to design and test a specific diet for this inflammatory condition, and we will be able to identify inflammatory pathways (fueled by dietary lipids) that can be pharmacologically targeted to treat Crohn’s disease.
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.
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.
Our approach aims at understating how Westernization of diet impacts the development and course of human Crohn’s disease, which reflects an unmet clinical need across the globe. Our study will help to understand epidemiologic risk associations and results from ongoing nutritional trials to better define dietary culprits that trigger or worsen gut inflammation in Crohn’s disease. Indeed, our experimental evidence point into the direction that dietary lipids trigger metabolic inflammation, which emerges as a feature of Crohn’s disease. We propose that these insights will help to understand this condition and promote future translational research to bring novel therapies to clinical exploration. We suggest that human studies on diet and related lipid stress will help to define an anti-inflammatory diet in Crohn’s disease, a concept that consequently warrants controlled clinical trials. Our approach is novel, as dietary polyunsaturated fatty acids have not been demonstrated to be a driver of gut inflammation, and because observational evidence (from associations) indicate that dietary polyunsaturated fatty acids negatively affect the course of human Crohn’s disease. As such, we are convinced to develop dietary research in inflammatory bowel diseases in a novel direction with our approach. In the next years, the translation from insights gained by this model will help us to better understand the pathophysiology of human Crohn’s disease and to develop targeted nutritional therapies besides broad immunosuppression.