Metabolic signatures underlying the liver-eye axis: a large cohort study

Objective To examine the association between liver function and retinal thickness, and whether metabolic signatures (MSs) of liver function mediate these associations. Methods We used data from 31019 participants in the UK Biobank (UKB). Liver function was measured using seven serum-based circulating biomarkers: alanine transaminase, aspartate transaminase, gamma-glutamyltransferase, alkaline phosphatase, total bilirubin, total protein, and albumin. Measurements of retinal thickness in the macular were obtained using optical coherence tomography, including the retinal nerve fiber layer, ganglion cell-inner plexiform layer, inner nuclear layer, inner nuclear layer-external limiting membrane, external limiting membrane-inner and outer photoreceptor segments, inner and outer photoreceptor segments-retinal pigment epithelium (ISOSRPE), and retinal pigment epithelium (RPE). The circulating metabolome was quantified using nuclear magnetic resonance spectroscopy. A linear regression model and formal mediation analyses were performed. Results After adjusting for all covariates, we found that abnormal liver function was significantly associated with thicker RPE thickness ( β [SE]: 0.094(0.034); P =  0.021) and thinner ISOSPRE thickness ( β [SE]: -0.172(0.048); P  < 0.001). Among the 249 metabolites, 23 were selected using elastic network regression to construct an MS for liver function. The mediation proportion of MS in the association between liver function and ISOSRPE thickness was 0.281 ( P  < 0.001). Among the 23 metabolites, six metabolites played a significant mediating role in the association between liver function and ISOSRPE thickness, with mediation proportions ranging from 0.032 to 0.164. Conclusion This study demonstrated significant associations of liver function with retinal thickness and revealed the potential underlying metabolomic mechanisms, providing insights into the liver-eye axis.