Exercise-induced -hydroxybutyrate promotes Treg cell differentiation to ameliorate colitis in mice

Increasing attention is being paid to the mechanistic investigation of exercise-associated chronic inflammatory disease improvement. Ulcerative colitis (UC) is one type of chronic inflammatory bowel disease with increasing incidence and prevalence worldwide. It is known that regular moderate aerobic exercise (RMAE) reduces the incidence or risk of UC, and attenuates disease progression in UC patients. However, the mechanisms of this RMAE's benefit are still under investigation. Here, we revealed that beta-hydroxybutyrate (beta-HB), a metabolite upon prolonged aerobic exercise, could contribute to RMAE preconditioning in retarding dextran sulfate sodium (DSS)-induced mouse colitis. When blocking beta-HB production, RMAE preconditioning-induced colitis amelioration was compromised, whereas supplementation of beta-HB significantly rescued impaired beta-HB production-associated defects. Meanwhile, we found that RMAE preconditioning significantly caused decreased colonic Th17/Treg ratio, which is considered to be important for colitis mitigation; and the downregulated Th17/Treg ratio was associated with beta-HB. We further demonstrated that beta-HB can directly promote the differentiation of Treg cell rather than inhibit Th17 cell generation. Furthermore, beta-HB increased forkhead box protein P3 (Foxp3) expression, the core transcriptional factor for Treg cell, by enhancing histone H3 acetylation in the promoter and conserved noncoding sequences of the Foxp3 locus. In addition, fatty acid oxidation, the key metabolic pathway required for Treg cell differentiation, was enhanced by beta-HB treatment. Lastly, administration of beta-HB without exercise significantly boosted colonic Treg cell and alleviated colitis in mice. Together, we unveiled a previously unappreciated role for exercise metabolite beta-HB in the promotion of Treg cell generation and RMAE preconditioning-associated colitis attenuation.