Gut Lactate Boosts Ruminococcus via Histone Lactylation to Mediate Time‐Restricted Feeding Protection in Crohn's Disease

ABSTRACT Background : Crohn's disease (CD) is characterized by impaired epithelial barrier function and dysregulated gut microbiota, particularly characterized by a reduced abundance of short‐chain fatty acid (SCFA)‐producing bacteria such as Ruminococcus . Time‐restricted feeding (TRF), which limits daily food intake to specific feeding windows, has been demonstrated to restore microbial balance, enrich SCFA‐producing bacteria, and enhance gut homeostasis. Nevertheless, the extent to which TRF confers protection against CD, as well as the mechanisms underlying this effect, remains largely unexplored. Methods : Fecal samples were obtained from patients with active CD and from healthy control subjects to quantify the abundance of Ruminococcus . Using 16S rRNA sequencing, we examined the impact of TRF regimens with varying fasting/feeding cycles (12/12, 16/8, and 20/4) on Ruminococcus . In preclinical CD models, we systematically evaluated the protective effect of TRF by analyzing colonic inflammation and fibrosis using histopathological techniques. RNA‐seq and epigenetic analyses were performed to elucidate the underlying mechanisms. Results : Fecal Ruminococcus abundance was significantly reduced in patients with CD and inversely correlated with disease activity indices. Among the tested regimens, only the 12/12 fasting/feeding regimen (TRF_12h), but not regimens with shorter feeding windows, robustly increased the Ruminococcus abundance and potently stimulated mitochondrial β‐oxidation and lactate generation. Preemptive administration of TRF_12h markedly protected against colitis severity and fibrosis in CD models, as evidenced by marked reductions in F4/80 + /MPO + inflammatory cell infiltration and decreased extracellular matrix deposition. RNA‐seq analysis revealed that TRF‐mediated epithelial protection was predominantly driven by SCFA‐dependent activation of hypoxia‐inducible factor‐1α (HIF‐1α) signaling. IEC‐specific knockout of HIF‐1α largely abrogated the protective effects of TRF, confirming its essential role. Mechanistically, TRF‐induced gut‐derived lactate promoted histone H4K12 lactylation (H4K12la), leading to upregulation of SLC9A3 expression, which reinforced a localized acidic microenvironment conducive to Ruminococcus enrichment. Conclusions : Collectively, TRF enriches SCFA‐producing Ruminococcus through a gut lactate‐driven histone lactylation‐SLC9A3 signaling axis, thereby alleviating inflammation and fibrosis in Crohn's disease under preventive conditions. Rum inococcus‐derived SCFA further enhances epithelial mitochondrial β‐oxidation and activates HIF‐1α‐dependent signaling pathways to strengthen the barrier integrity. This study provides a compelling mechanistic foundation for the clinical exploration of TRF as a therapeutic dietary strategy for patients with CD.