Effect of Exercise on the Intestinal and Metabolic Homeostasis in Experimental Colitis

• Applicant: Dr. Viktor von Ehrlich-Treuenstätt
• Subject Area: General and Visceral Surgery ; Endocrinology, Diabetology, Metabolism ; Gastroenterology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 534731168

Exercise has been linked to improved conditions in various chronic diseases such as diabetes, metabolic syndrome, cardiovascular disease, and also Inflammatory Bowel Disease (IBD). However, the existing data is mostly observational and non-specific regarding the mechanism and degree to which exercise is beneficial. Recent literature suggests chronic intestinal inflammation, hyperpermeability of the gut barrier, and endotoxemia as potential key components of chronic disease progression and that exercise can improve IBD through a viable anti-inflammatory effect. However, the molecular and cellular mechanisms that mediate the metabolic benefits of physical activity remain unclear. The significance of the gut microbiome and gut metabolome to this anti-inflammatory effect is not yet elucidated. To address this gap, we plan to investigate the alterations in the gut microbiome and metabolome through exercise in a murine model of chronic colitis. Our preliminary feasibility studies in a colitis-induced mouse model demonstrated that exercise effectively alleviates colitis symptoms, reducing weight loss and histological scores of intestinal inflammation. Exercise led to increased aerobic bacterial colonies in stool, lower proinflammatory cytokine concentrations in blood serum, enhanced activity of intestinal alkaline phosphatase (IAP), and improved gut barrier permeability following dextran sodium sulfate (DSS) colitis induction. The Gastrointestinal Epithelial Biology laboratories, led by Dr. Richard Hodin and Dr. Nima Saeidi at Harvard Medical School, have made significant contributions to the understanding of colitis, metabolomics, and the role of IAP. Published studies have shown the positive impact of IAP on gut barrier integrity, colitis, and metabolic disease using loss-of-function and supplementation models. We hypothesize that exercise alternates the gut metabolome and microbiome. As exercise increases IAP activity, we also hypothesize that upregulation of IAP and improved gut barrier function might be the mechanism through which exercise is positively altering the gut metabolome and microbiome. We will perform extensive metabolic, lipidomic, and inflammatory profiling as well as IAP- and gut barrier permeability measurements in stool, blood serum, and tissue samples as well as next-generation sequencing of microbiota to characterize changes in exercised and non-exercised mice using different mouse models (exercise-, IAP-, chronic colitis model). The interplay between chronic gut inflammation, hyperpermeability, and various chronic diseases underscores the need for targeted treatment regimens addressing gut barrier function and dysbiosis. Exercise, probiotic treatment or IAP hold promise as potential therapeutic and preventive solutions in the future.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Hosts: Professor Dr. Richard Hodin; Professor Nima Saeidi, Ph.D.