This study aims to elucidate how butyrate, a short-chain fatty acid, regulates the Treg/Th17 balance in ulcerative colitis (UC) via the cAMP-PKA/mTOR signaling pathway, offering novel treatment strategies. Dextran sulfate sodium (DSS) was used to induce ulcerative colitis in a mouse model. Various butyrate dosages were administered to the mice. The mice's body weight, colon length, spleen index (SI), and disease activity index (DAI) were all assessed.HE staining and Masson staining were used for histopathological evaluation. Immunohistochemistry and RT-qPCR were applied to detect fibrosis markers. Flow cytometry, RT-qPCR, and ELISA were employed to analyze immune cell subsets and cytokines. RT-qPCR and Western blotting were utilized to explore the cAMP-PKA/mTOR signaling pathway. Specific inhibitors were used to further confirm the mechanism of its action. Butyrate treatmentreduced DAI and SI, and reversed pathological changes (weight loss, colon shortening, splenomegaly) in DSS-induced UC model mice, with the high-dose group showing the best recovery. It inhibited colon fibrosis,and decreased fibrosis markers. By regulating the regulatory T cell (Treg)/T helper 17 cell (Th17) balance, butyrate restored immune homeostasis. Flow cytometry showed DSS-induced immune imbalance was reversed in a dose-dependent manner. Additionally, butyrate modulated the cAMP-PKA/mTOR signaling pathway, reversing DSS-induced gene and protein expression changes. Specific inhibitor experiments confirmed that butyrate exerted its therapeutic effects via this pathway. Butyrate can markedly alleviate acute UC intestinal inflammation and block chronic fibrosis progression. The bidirectional regulation of the cAMP-PKA/mTOR signaling pathway is the key mechanism for butyrate to restore immune homeostasis.
Li et al. (Sun,) studied this question.