Study On The Function Of Rheb In The Acute Colitis

mTOR signal pathway regulates cell growth, proliferation and survival by sensing the extracellular nutritional status and directing protein synthesis, which is important in the physiology and pathology. However, its role in the bowel acute injury repair is not clear. Rheb is a small GTPase, GTP-bound Rheb interacts directly with TORC1 to activate TORC1 kinase. Previous reports have determined the role of Rheb in embryonic development and myelination in postnatal brain. In this study, we generated Rheb knockout mouse strain to study the role of Rheb/mTORC1 signaling in colitis. Since Rheb null allele is embryonic lethal, we use Rheb heterozygous mice in this study. Through histology and immonostaining against specific markers, intestinal epithelial cell homeostasis is not affected in Rheb+/- mice. Rheb+/- and wild-type littermates were subjected to dextran sulfate sodium (DSS) induced experimental acute colitis model, and the symptoms were determined. Rheb+/- mice exhibited more severer symptoms than the wild-type controls in DSS induced acute colitis model, and all mutant mice were dead 10 days after DSS treatment due to impaired proliferation and induced cell apoptosis. Through bone marrow transplantation, we found that mTORC1 in nonhematopoietic cells played a major role in protecting mice from colitis. Reactivation of mTORC1 activity by amino acids had a positive therapeutic effect in mTORC1 deficient Rheb+/- mice. In summary, Rheb/mTORC1 has protective effect to enterocyte in acute colitis induced by dextran sulfate sodium. As mTORC1 is an important therapeutic target for multiple diseases, our findings will have important implications for the clinical usage of mTORC1 inhibitors in patients with acute inflammatory bowel disease.