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

IF 3.1 3区 医学 Q2 NEUROSCIENCES
Yan Yan, Yuyan Pan, Simin Lu, Jia Kou, Xiangnan Chen, Weian Zeng, Dexing Luo, Liuji Qiu, Hongying Zhang, Dongtai Chen
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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.

欧洲血统个体中肠道微生物介导的EHMT2靶向:阿尔茨海默病的一种新治疗方法。
去色组蛋白赖氨酸n -甲基转移酶2 (EHMT2)是一种神经炎性组蛋白甲基转移酶,已被提出作为阿尔茨海默病(AD)的治疗靶点,可能通过调节肠道微生物群来实现。然而,由于观察性研究的混淆和缺乏人类遗传证据,因果关系尚不清楚。为了解决这一问题,我们使用来自欧洲血统个体的全基因组关联数据进行了孟德尔随机化(MR)分析。方法从IEU OpenGWAS和FinnGen数据库中获取EHMT2表达、AD (n = 39,106)、211个肠道微生物群和结直肠癌(n = 6847)的全基因组关联研究(GWAS)汇总统计数据。MR用于评估因果效应,CRC作为阳性对照。采用5个回归模型评估因果关系,两步磁共振评估肠道菌群的中介作用。敏感性分析检验了结果的稳健性。结果反方差加权(IVW)分析显示,EHMT2抑制与降低结直肠癌(OR = 0.7850, 95% CI: 0.6782-0.9086, p = 0.0012)和AD (OR = 0.8585, 95% CI: 0.8056-0.9148, p乳杆菌科)的风险相关。1836, Dialister属。2183,未知属id。959)有正向的中介作用。结论sehmt2抑制可能通过调节特定的肠道菌群,特别是3个关键菌群,在AD中发挥保护作用。这些发现强调了潜在的微生物介导的表观遗传机制在AD发病机制中,需要进一步的机制和转化研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Alzheimer's Disease
Journal of Alzheimer's Disease 医学-神经科学
CiteScore
6.40
自引率
7.50%
发文量
1327
审稿时长
2 months
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.
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