Ketogenic diet exacerbates DSS-induced colitis through a ß-hydroxybutyrate -T. spiroformis-?d17 T cell axis in mice

Ketogenic diets (KD) benefit metabolic and neurological health by modulating gut microbiota, but their impact on inflammatory bowel disease, particularly ulcerative colitis (UC), remains controversial. Here, we show that KD aggravated colitis by triggering a ketogenesis-microbe-immune cascade. KD elevated luminal ß-hydroxybutyrate (ß-HB), which fueled the expansion of Thomasclavelia spiroformis (T. spiroformis), a pathobiont that activated mucosal ?d17 T cells potentially via peptidoglycans. These cells drived IL-17A production and inflammation; reconstitution of ?d17 T cells in Tcrd-/- mice confirmed their pathogenic role. Blocking ketogenesis or neutralizing IL-17A abolished KD-exacerbated colitis, whereas ß-HB supplementation and ketogenesis activation phenocopied disease worsening. In UC patients, T. spiroformis abundance correlated with fecal ß-HB and serum IL-17A levels, but not in Crohn's disease, supporting a UC-specific ß-HB-T. spiroformis-?d17 T cell axis. These findings uncover a metabolic-microbial-immune loop linking dietary ketosis to UC, and suggest that targeting ketone metabolism or IL-17A signaling may offer new therapeutic opportunities. Overall design: To elucidate the mechanisms of KD-driven immune dysregulation in colitis, we performed single-cell RNA sequencing (scRNA-seq) on colon tissues from DSS-treated mice fed either CD or KD.