Metabolomic signatures suggest altered bile acid and energy metabolism in CRB1- retinopathies

INTRODUCTION: ) results in barrier dysfunction permitting translocation of bacteria to the retina. OBJECTIVE: Whole metabolomic analysis in patients can provide further insights into disease pathophysiology and aid the identification of potential systemic biomarkers. METHODS: Blood plasma from 25 molecularly confirmed CRB1-retinopathy patients from Moorfields Eye Hospital with 25 age- and gender-matched healthy controls underwent ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). MetaboLync pathway analysis identified affected metabolic pathways. RESULTS: Of 872 compounds, 244 were significantly altered in CRB1 patients. Key findings included disrupted bile acid metabolism, with elevated primary and secondary bile acids alongside increased gut microbial phenylalanine pathway metabolites, indicative of altered gut microbiome-related metabolic activity and altered enterohepatic circulation. However, sucrose and butyrate levels remained unchanged amongst groups, suggesting absence of metabolomic evidence for severe intestinal barrier dysfunction. Reductions in antioxidants and neuroprotective agents were found alongside energy metabolism dysregulation. CONCLUSION: These findings reveal metabolic dysregulation in CRB1-retinopathy, including altered gut microbiome-related metabolic activity, and no strong metabolomic evidence of severe intestinal barrier disruption. The reductions in antioxidants, energy pathways and neuroprotective agents highlight potential therapeutic targets to delay disease progression. Further investigation into gut microbiome composition and intestinal permeability in humans with CRB1 retinopathies is warranted.