Evidence for metabolic disturbances in the pathogenesis of immune-mediated disease in SAMP1/YitFcs Mice

Abstract

Abstract Background Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), affect ~1% of the people in the United States. SAMP1/YitFcs mice are a model of CD with terminal ileitis which is rare in other animal models of IBD. Switch of cell energy metabolism towards aerobic glycolysis is a hallmark of inflammation and has been implicated in immune-mediated diseases. Thus, we sought to determine how energy metabolism is altered in the SAMP mice. Methods Glucose metabolism in vivo was determined by 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET). Tissue taking up the 18F-FDG were collected for histology. Metabolic phenotype of activated B and CD4+ T lymphocytes isolated from mesenteric lymph nodes of control and SAMP mice was evaluated by extracellular flux analysis (SeaHorse). To relate the SAMP model to human disease, normal and inflamed ileum from mice and humans were assayed by RNAseq focusing on metabolism-related genes. Results PET scans showed a varying tissue distribution of 18F-FDG uptake in SAMP mice, including ileum, salivary glands and kidneys which all had histological evidence of inflammation. Compared to control, both SAMP B and T cells displayed an increase in glycolysis and oxidative phosphorylation (OXPHOS) rates which is supported by an overall increase in genes related to glucose metabolism, TCA cycle, OXPHOS and fatty acid oxidation in the ileum. Conclusion SAMP mice have a multi-organ immune-mediated disease relying on an increase in cell energy metabolism. Therefore, targeting aerobic glucose metabolism to limit inflammation emerges as a new strategy for CD treatment.