Metabolomics Analysis of the Aqueous Humour Uncovers Potential Metabolite Biomarkers for Early Differential Detection of Macular Edema

Background: Macular edema (ME) is a major complication of several retinal diseases, and multiple mechanisms are involved in its development. This study aims to investigate the metabolite profiles of the aqueous humour in patients with ME of different aetiologies and identify potential metabolite biomarkers allowing ME diagnosis in the very early stages of the disease. Results: : The metabolic profiles of aqueous humour differed significantly between ME patients and healthy controls, and 105 differentially expressed metabolites were identified. Pathway analysis showed that the differentially expressed metabolites are mainly involved in lipid metabolism and amino acid metabolism. Further comparison analysis also revealed significant differences in the metabolic composition of aqueous humour of ME patients derived from age-related macular degeneration (AMD), diabetic retinopathy (DR) and branch retinal vein occlusion (BRVO). In total, 39 and 79 aetiology-specific altered metabolites were identified for AMD-ME and DME, respectively. Finally, a novel aqueous humour-derived machine learning-based metabolic model was developed, which successfully validated in the test cohort with an area under the receiver operating characteristic curve of 0.79 for AMD-ME, 0.94 for DME and 0.77 for BRVO-ME. Conclusions: : Our study illustrates the underlying metabolic basis of aqueous humour for different aetiologies across ME populations and identifies aqueous humour-derived metabolite biomarkers that will improve differential diagnosis and treatment stratification for ME of different aetiologies.