探索近视的潜在治疗靶点：肠道微生物群的因果分析和生物学注释

IF 3.1 4区生物学 Q2 BIOLOGY

Computational Biology and Chemistry Pub Date : 2025-08-19 DOI:10.1016/j.compbiolchem.2025.108634

Zixun Wang , Yimeng Sun , Xiaoling Zhang , Luqiang Wang , Desheng Song , Jingtao Yu , Xiaoxue Hu , Weiping Lin , Ruihua Wei

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引用次数: 0

摘要

目的通过遗传学手段探讨肠道微生物群（GM）组成与近视发展之间的因果关系，旨在发现具有治疗潜力的特定微生物类群，并阐明其潜在的生物学途径。方法对473个GM分类群（ = 5959）和26184例近视患者的GWAS进行双向双样本孟德尔随机化（MR）统计。逆方差加权（IVW）和四种互补方法评估因果关系（F-statistics>10），并通过敏感性分析验证稳健性。生物注释整合了蛋白质相互作用网络和途径富集来解码机制。结果我们的反方差加权孟德尔随机化分析确定了15个与近视有因果关系的微生物特征（FDR < 0.05）。保护类群包括dygonomonadaceae科（OR = 0.947, 95 % CI: 0.910-0.986）和大单胞菌funiformis (OR = 0.979, 0.964-0.995)，风险相关类群包括Omnitrophota纲（OR = 1.144, 1.022-1.280）和velezensis芽孢杆菌（OR = 1.072, 1.017-1.129）。敏感性分析通过非显著异质性（Q > 0.05）、无水平多效性（Egger截距P >； 0.1）和无影响异常值（MR-PRESSO P >； 0.3）证明了稳健性。宿主基因变异显著富集于PI3K-Akt （P = 9.4 ×10⁻5）和Ras信号通路（P = 3.7 ×10⁻3）。三个中心基因（PIK3R1、KITLG和IL2RB）可能通过TGF-β/ smad调控的细胞外基质降解和酪氨酸羟化酶下调的多巴胺能缺乏介导巩膜发病。微生物代谢相互作用分析显示，megamonas衍生的短链脂肪酸抑制PI3K-Akt/HDAC信号传导（β =−0.27 ± 0.08,P = 0.002）。相比之下，与风险相关的类群马氏Prevotella massilia通过吲哚-3-乙酸酯/AhR激活升高氧化应激标志物（β = 0.34 ± 0.12,P = 0.009）。这是第一个磁共振生物学注释研究，揭示了微生物群相关宿主基因与PI3K-Akt/ ras驱动的眼信号通路中巩膜免疫失调之间的一致性。巨单胞菌衍生的scfa作为治疗靶点的研究结果为通过微生物组干预治疗近视提供了一种可行的方法。

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

Purpose

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.

Methods

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.

Results

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).

Conclusion

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.

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来源期刊

Computational Biology and Chemistry 生物-计算机：跨学科应用

CiteScore

6.10

自引率

3.20%

发文量

142

审稿时长

24 days

期刊介绍： Computational Biology and Chemistry publishes original research papers and review articles in all areas of computational life sciences. High quality research contributions with a major computational component in the areas of nucleic acid and protein sequence research, molecular evolution, molecular genetics (functional genomics and proteomics), theory and practice of either biology-specific or chemical-biology-specific modeling, and structural biology of nucleic acids and proteins are particularly welcome. Exceptionally high quality research work in bioinformatics, systems biology, ecology, computational pharmacology, metabolism, biomedical engineering, epidemiology, and statistical genetics will also be considered. Given their inherent uncertainty, protein modeling and molecular docking studies should be thoroughly validated. In the absence of experimental results for validation, the use of molecular dynamics simulations along with detailed free energy calculations, for example, should be used as complementary techniques to support the major conclusions. Submissions of premature modeling exercises without additional biological insights will not be considered. Review articles will generally be commissioned by the editors and should not be submitted to the journal without explicit invitation. However prospective authors are welcome to send a brief (one to three pages) synopsis, which will be evaluated by the editors.