Causal Effects of Gut Microbiota and Associated Metabolites on Retinal Diseases and Visual Impairment: A Mendelian...

Previous observational study findings have indicated a vital association between gut microbiota features and retinal diseases based on the "gut-retina" axis. However, whether their relationships underlie causal effects remains to be established.

Instrumental variables of 211 gut microbiota taxa were obtained from a genome-wide association study (GWAS), and 28 gut-associated metabolites and pathways were included as exposures. A two-sample Mendelian randomization (MR) study was carried out to estimate gut microbiota effects on diabetic retinopathy (DR), early age-related macular degeneration (eAMD), retinal detachments and breaks (RDs/RBs), retinal vascular occlusion (RVO), disorders of the choroid and retina (D-C/R), and visual impairment. MR methods, including inverse variance weighted (IVW), MR‒Egger, weighted median, simple mode, and weighted mode methods, were used to investigate the causal relationship between gut microbiota features and various outcomes. Heterogeneity, pleiotropy, and stability tests of MR results were performed, and Bonferroni's correction was used to test the strength of the causal relationships between exposures and outcomes, as well as reverse and multivariable MR analyses.

Through MR analysis of 211 microbes and six clinical phenotypes, a total of 35 gut microbiome and 3 associated metabolites were found to be associated with various outcomes. Cochrane's Q test revealed that there was no significant heterogeneity between various single-nucleotide polymorphisms. In addition, no significant level of pleiotropy was found according to the MR‒Egger and MR-PRESSO global tests. After the Bonferroni-corrected test, Genus id.2041 (OR = 0.874, 95% CI: 0.816-0.936, p = 1.10e - 04, IVW) showed robust causality with D-C/R, which had a nominal association with multiple other retinal diseases as well. Seven exposure-outcome effects markedly remained valid when BMI or alcohol intake frequency was separately included in multivariable MR analyses. According to the results of reverse MR analysis, no significant causal effect of outcomes was found on gut microbiota. No significant heterogeneity of instrumental variables or horizontal pleiotropy was found.

We confirmed a potential causal relationship between some gut microbiota features and retinal diseases, thus providing new insights into the gut microbiota-mediated mechanism of retinopathy and indicating vital biomarkers for potential diagnostic, therapeutic, and prevention strategies.