Abstract Introduction The human CRB1 gene encodes the CRB1 protein, primarily expressed in retinal Muller cells and photoreceptors, where it regulates apical-basal polarity and cellular signalling through its role in adherence junctions and maintaining the outer limiting membrane barrier. Dysfunction of CRB1 results in a range of retinal phenotypes with few systemic implications reported. It has been suggested that disrupted Crb1 expression in the gastrointestinal epithelium of rd8 mouse models ( Crb1 −/− ) 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.
Rodriguez-Martinez et al. (Fri,) studied this question.