A large cohort analysis of metabolic signatures underlying the liver-eye axis

The role of the liver, a vital metabolic organ, in ocular health and the corresponding mechanisms remains unclear. This study aimed to examine the association between liver function and retinal thickness, and whether metabolic signatures (MS) of liver function mediate these associations. We used data from 31019 participants in UK Biobank. Liver function was measured using seven serum-based circulating biomarkers: alanine transaminase, aspartate transaminase, gamma-glutamyltransferase, alkaline phosphatase, total bilirubin, total protein, and albumin levels. Retinal thickness was measured 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. We find that abnormal liver function is significantly associated with increased RPE thickness (β [SE]: 0.094(0.034); P = 0.021) and decreased ISOSRPE thickness (β [SE]: −0.172 (0.048); P < 0.001), after adjusting for demographic, lifestyle factors, best-corrected visual acuity, and intraocular pressures. Among the 249 metabolites, 23 are selected using lasso regression to construct MS for liver function. The mediation proportion of MS in association between liver function and ISOSRPE thickness is 28.6% (P = 0.004). Among the 23 metabolites, six play a significant mediating role in the association between liver function and ISOSRPE thickness, with mediation proportions ranging from 3.20% to 16.4%. This study demonstrates significant associations of liver function with retinal thickness and reveals potential underlying metabolomic mechanisms, providing insights into the liver-eye axis. Whether the liver, as a vital metabolic organ, may have direct impact on eye health - as well as the corresponding mechanisms - remains unclear. In this study, we focused on over 31,000 participants from the UK Biobank, using various methods to measure liver function, eye health, and compounds in the blood. We found that poorer liver function was associated with decreased health of the retina. Crucially, about 28.6% of this association was explained by a pattern in the blood, with six specific compounds playing key roles. This evidence reveals a “liver–eye axis” mediated through the bloodstream, suggesting that improving liver function may also benefit long-term eye health. Wu et al. examine the association between liver function and retinal thickness, along with the mediating role of metabolic signatures. They find that abnormal liver function is associated with retinal layer thinning, with about 28.6% of this association mediated by circulating metabolites, providing insights into the liver-eye axis.