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

Area of Science:

• Immunology
• Metabolomics
• Gastroenterology

Background:

• Autoimmune uveitis (AU) currently lacks targeted therapies, relying primarily on broad immunosuppression.
• The role of immunometabolism in AU pathogenesis remains incompletely understood.

Purpose of the Study:

• To identify novel therapeutic targets for autoimmune uveitis.
• To investigate the role of gut-derived metabolites in regulating ocular inflammation.

Main Methods:

• Metabolomic analysis of AU patients and experimental autoimmune uveitis (EAU) mouse models.
• Administration of hyodeoxycholate (HDCA) in EAU models.
• Analysis of cytokine profiles and macrophage polarization.
• Investigation of molecular mechanisms involving Farnesoid X Receptor (FXR) and SREBP1c.

Main Results:

• Systemic depletion of HDCA and oleic acid correlated with AU disease severity.
• HDCA administration attenuated EAU, reducing pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and increasing IL-10.
• HDCA inhibited FXR in splenic macrophages, promoting oleic acid production via SREBP1c activation.
• Oleic acid suppressed Th17 responses and promoted M2 macrophage polarization in the eye.

Conclusions:

• HDCA acts as a key immunometabolic regulator in autoimmune uveitis.
• A novel spleen-to-eye immunometabolic axis driven by HDCA-mediated macrophage reprogramming was identified.
• HDCA represents a promising therapeutic candidate for autoimmune uveitis.