{"title":"Gut microbiota-mediated targeting of EHMT2 in individuals of European ancestry: A novel therapeutic approach for Alzheimer's disease.","authors":"Yan Yan, Yuyan Pan, Simin Lu, Jia Kou, Xiangnan Chen, Weian Zeng, Dexing Luo, Liuji Qiu, Hongying Zhang, Dongtai Chen","doi":"10.1177/13872877251372945","DOIUrl":null,"url":null,"abstract":"<p><p>BackgroundEuchromatic 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.ObjectiveTo address this, we conducted a Mendelian randomization (MR) analysis using genome-wide association data exclusively from individuals of European ancestry.MethodsWe 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.ResultsInverse-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, <i>p</i> = 0.0012], and AD (OR = 0.8585, 95% CI: 0.8056-0.9148, <i>p</i> < 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 <i>Lactobacillaceae id.1836,</i> genus <i>Dialister id.2183</i>, and unknown genus <i>id.959</i>) had positive mediating effects.ConclusionsEHMT2 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.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":" ","pages":"13872877251372945"},"PeriodicalIF":3.1000,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Alzheimer's Disease","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1177/13872877251372945","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
BackgroundEuchromatic 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.ObjectiveTo address this, we conducted a Mendelian randomization (MR) analysis using genome-wide association data exclusively from individuals of European ancestry.MethodsWe 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.ResultsInverse-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.ConclusionsEHMT2 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.
期刊介绍:
The Journal of Alzheimer''s Disease (JAD) is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment and psychology of Alzheimer''s disease. The journal publishes research reports, reviews, short communications, hypotheses, ethics reviews, book reviews, and letters-to-the-editor. The journal is dedicated to providing an open forum for original research that will expedite our fundamental understanding of Alzheimer''s disease.