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

  • Cell Death Differ. 2026 Mar 11. doi: 10.1038/s41418-026-01696-8.
Yitao Li  #  1 ,  Weijia Zheng  #  2 ,  Jiao Ma  1 ,  Lu Liu  2 ,  Xintong Yang  1 ,  Junliang Kuang  3 ,  Nickie Chan  1 ,  Chengqiang Wang  1 ,  Yang Li  3 ,  Aihua Zhao  3 ,  Ruonan Wang  4  5 ,  Xiaojiao Zheng  3 ,  Gerry Melino  6 ,  Aiping Lu  7 ,  Xiaolu Yang  8  9 ,  Wei Jia  10  11  12
Affiliations
  • 1. School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
  • 2. Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China.
  • 3. Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4. Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 5. National Clinical Research Center for Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 6. Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy. [email protected].
  • 7. School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China. [email protected].
  • 8. Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 9. National Clinical Research Center for Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 10. School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China. [email protected].
  • 11. Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China. [email protected].
  • 12. Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 41813862 DOI: 10.1038/s41418-026-01696-8
Abstract

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.

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