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<p>Ketogenic diet (KD) is widely recognized for its immunomodulatory and metabolic benefits, but the impact on inflammatory bowel disease remains controversial. Here, we demonstrate that KD maintains homeostasis under physiological conditions but exacerbates colitis by triggering a ketogenesis-microbe-immune cascade upon mucosal injury. Mechanistically, KD elevates luminal β-hydroxybutyrate (β-HB), promoting the expansion of <i>Thomasclavelia spiroformis</i> (<i>T. spiroformis</i>). In turn, <i>T. spiroformis</i> activates colonic γδ17 T cells via cell wall components, ultimately driving IL-17A-mediated iinflammation. Adoptive transfer of γδ17 T cells into <i>Tcrd</i><sup><i>-/-</i></sup> mice confirmed their pathogenicity. Ketogenesis or IL-17A blockades abolish KD-exacerbated colitis, whereas β-HB supplementation or ketogenesis activation recapitulated disease exacerbation. Clinically, <i>T. spiroformis</i> abundance correlates with fecal β-HB and serum IL-17A in ulcerative colitis (UC) patients, but not Crohn’s disease, supporting a UC-specific β-HB-<i>T. spiroformis</i>-γδ17 T cell axis. Thus, we identify a diet-induced immunometabolic circuit linking ketogenesis to colitis, highlighting ketone metabolism and IL-17A signaling as potential therapeutic targets.</p>

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Ketogenic diet exacerbates DSS-induced colitis through a β-hydroxybutyrate-Thomasclavelia spiroformis-γδ17 T cell axis in mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月23日

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  • Yameng Liu,
  • Xuan Wu,
  • Li Chen,
  • Shan Wang,
  • Jingyi Xu,
  • Weifeng Wang,
  • Xueting Yao,
  • Wei Xie,
  • Xianchun Zhong,
  • Shuai Li,
  • Yueying Li,
  • Lin Han,
  • Cen Xie,
  • Lei Chen,
  • Frank J. Gonzalez,
  • Weiwei Liu

摘要

Ketogenic diet (KD) is widely recognized for its immunomodulatory and metabolic benefits, but the impact on inflammatory bowel disease remains controversial. Here, we demonstrate that KD maintains homeostasis under physiological conditions but exacerbates colitis by triggering a ketogenesis-microbe-immune cascade upon mucosal injury. Mechanistically, KD elevates luminal β-hydroxybutyrate (β-HB), promoting the expansion of Thomasclavelia spiroformis (T. spiroformis). In turn, T. spiroformis activates colonic γδ17 T cells via cell wall components, ultimately driving IL-17A-mediated iinflammation. Adoptive transfer of γδ17 T cells into Tcrd-/- mice confirmed their pathogenicity. Ketogenesis or IL-17A blockades abolish KD-exacerbated colitis, whereas β-HB supplementation or ketogenesis activation recapitulated disease exacerbation. Clinically, T. spiroformis abundance correlates with fecal β-HB and serum IL-17A in ulcerative colitis (UC) patients, but not Crohn’s disease, supporting a UC-specific β-HB-T. spiroformis-γδ17 T cell axis. Thus, we identify a diet-induced immunometabolic circuit linking ketogenesis to colitis, highlighting ketone metabolism and IL-17A signaling as potential therapeutic targets.