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<p>Autoimmune uveitis (AU) lacks targeted therapies beyond immunosuppression. We identified hyodeoxycholate (HDCA), a gut-derived secondary bile acid, as a key immunometabolic regulator in AU. Metabolomics revealed systemic depletion of HDCA and oleic acid (C18:1n9) in AU patients and experimental AU (EAU) mice, correlating with disease severity. HDCA administration effectively attenuated EAU by reducing pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and elevating IL-10. Mechanistically, HDCA inhibits Farnesoid X Receptor in splenic red pulp macrophages, activating SREBP1c-dependent fatty acid synthase, which enhances oleic acid production. Systemic oleic acid suppresses ocular Th17 responses and promotes M2 macrophage polarization, enhancing anti-inflammatory immunity. These findings define a spleen-to-eye immunometabolic axis driven by HDCA-mediated macrophage reprogramming, positioning HDCA as a promising therapeutic for AU.</p><p></p>

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Gut-derived hyodeoxycholate reprograms the spleen–eye immunometabolic axis to suppress autoimmune uveitis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月11日

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  • Yitao Li,
  • Weijia Zheng,
  • Jiao Ma,
  • Lu Liu,
  • Xintong Yang,
  • Junliang Kuang,
  • Nickie Chan,
  • Chengqiang Wang,
  • Yang Li,
  • Aihua Zhao,
  • Ruonan Wang,
  • Xiaojiao Zheng,
  • Gerry Melino,
  • Aiping Lu,
  • Xiaolu Yang,
  • Wei Jia

摘要

Autoimmune uveitis (AU) lacks targeted therapies beyond immunosuppression. We identified hyodeoxycholate (HDCA), a gut-derived secondary bile acid, as a key immunometabolic regulator in AU. Metabolomics revealed systemic depletion of HDCA and oleic acid (C18:1n9) in AU patients and experimental AU (EAU) mice, correlating with disease severity. HDCA administration effectively attenuated EAU by reducing pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and elevating IL-10. Mechanistically, HDCA inhibits Farnesoid X Receptor in splenic red pulp macrophages, activating SREBP1c-dependent fatty acid synthase, which enhances oleic acid production. Systemic oleic acid suppresses ocular Th17 responses and promotes M2 macrophage polarization, enhancing anti-inflammatory immunity. These findings define a spleen-to-eye immunometabolic axis driven by HDCA-mediated macrophage reprogramming, positioning HDCA as a promising therapeutic for AU.