Gut microbiota-mediated targeting of EHMT2 in individuals of European ancestry: A novel therapeutic approach for Alzheimer's disease

Background Euchromatic histone-lysine N-methyltransferase 2 (EHMT2), a neuroinflammatory histone methyltransferase, has been proposed as a therapeutic target for Alzheimer's disease (AD), potentially via modulation of gut microbiota. However, causality remains unclear due to confounding in observational studies and lack of human genetic evidence. Objective To address this, we conducted a Mendelian randomization (MR) analysis using genome-wide association data exclusively from individuals of European ancestry. Methods We obtained genome-wide association study (GWAS) summary statistics for EHMT2 expression, AD (n = 39,106), 211 gut microbiota taxa, and colorectal cancer (CRC; n = 6847) from the IEU OpenGWAS and FinnGen databases. MR was used to evaluate the causal effects, with CRC as a positive control. Five regression models were utilized to evaluate the causal effects, and two-step MR assessed the mediating role of gut microbiota. Sensitivity analyses tested result robustness. Results Inverse-variance weighted (IVW) analyses showed that EHMT2 inhibition was associated with reduced risks of CRC [odds ratio (OR) = 0.7850, 95% CI: 0.6782–0.9086, p = 0.0012], and AD (OR = 0.8585, 95% CI: 0.8056–0.9148, p < 0.0001). EHMT2 inhibition also influenced the abundance of 67 gut microbiota taxa. Among them, 17 taxa were linked to AD risk, with four showing shared causal associations. Notably, three of them (family Lactobacillaceae id.1836, genus Dialister id.2183 , and unknown genus id.959 ) had positive mediating effects. Conclusions EHMT2 inhibition may play protective roles in AD via modulating specific gut microbiota, particularly three key taxa. These findings highlight a potential microbiota-mediated epigenetic mechanism in AD pathogenesis, warranting further mechanistic and translational studies.