PR001903 (Project)

Description:Colitis has a multifactorial pathogenesis with a strong cross-talk among microbiota, hypoxia and tissue metabolism. Here, we aimed to characterize the molecular signature of the disease in symptomatic and pre-symptomatic stages of the inflammatory process at the tissue and fecal level. The study is based on two different murine models for colitis. High-resolution Magic Angle Spinning NMR on cryopreserved “intact” colon tissues and LC-MS/MS on colon tissue extracts were used to derive untargeted metabolomics and proteomics information, respectively. Solution NMR was used to derive metabolomic profiles of fecal extracts. By combining metabolomic and proteomic analyses of the tissues, we found increased anaerobic glycolysis, accompanied by altered citric acid cycle and oxidative phosphorylation in inflamed colons; these changes associate with inflammation-induced hypoxia taking place in colon tissues. Pre-symptomatic states can be discriminated from healthy samples before macroscopic inflammation is observed. Different colitis states are characterized by significantly different metabolomic profiles of fecal extracts, attributable to both the dysbiosis characteristic of colitis, as well as the dysregulated tissue metabolism. Strong and distinctive fecal metabolomic signatures can be detected before onset of symptoms. Therefore, untargeted metabolomics of tissues and fecal extracts provides a comprehensive picture of the changes accompanying the disease onset already at pre-clinical stages, highlighting the diagnostic potential of global metabolomics for inflammatory diseases.