Exploring potential therapeutic targets for myopia: Causal analysis and biological annotation with gut microbiota

This study investigates the causal relationship between gut microbiota (GM) composition and myopia development through genetic instruments, aiming to identify specific microbial taxa with therapeutic potential and elucidate their underlying biological pathways.

We performed bidirectional two-sample Mendelian randomization (MR) using summary statistics from GWAS of 473 GM taxa (n = 5959) and myopia (26,184 cases). Inverse variance weighted (IVW) and four complementary methods assessed causality (F-statistics>10), with sensitivity analyses to validate robustness. Biological annotation integrates protein-protein interaction networks and pathway enrichment to decode mechanisms.

Our inverse-variance weighted Mendelian randomization analysis identified 15 microbial features exhibiting causal associations with myopia (FDR < 0.05). Protective taxa included Family Dysgonomonadaceae (OR = 0.947, 95 % CI: 0.910-0.986) and species Megamonas funiformis (OR = 0.979, 0.964-0.995), while risk-associated taxa comprised Class Omnitrophota (OR = 1.144, 1.022-1.280) and species Bacillus velezensis (OR = 1.072, 1.017-1.129). Sensitivity analyses demonstrated robustness through nonsignificant heterogeneity (Q > 0.05), absence of horizontal pleiotropy (Egger intercept P > 0.1), and no influential outliers (MR-PRESSO P > 0.3). Host genetic variants were significantly enriched in PI3K-Akt (P = 9.4 ×10⁻⁵) and Ras signaling pathways (P = 3.7 ×10⁻³). Three hub genes (PIK3R1, KITLG, and IL2RB) may mediate scleral pathogenesis through TGF-β/Smad-regulated extracellular matrix degradation and dopaminergic deficiency via downregulation of tyrosine hydroxylase. Microbial metabolic interaction analyses revealed that Megamonas-derived short-chain fatty acids suppressed PI3K-Akt/HDAC signaling (β = -0.27 ± 0.08, P = 0.002). In contrast, the risk-associated taxon Prevotella massilia elevated oxidative stress markers via indole-3-acetate/AhR activation (β = 0.34 ± 0.12, P = 0.009).

This first MR-biological annotation study revealed a degree of congruence between microbiota-associated host genes and the PI3K-Akt/Ras-driven scleral-immune dysregulation in ocular signaling pathways. The findings of Megamonas-derived SCFAs as therapeutic targets provide a viable approach for addressing myopia through microbiome intervention.