摘 要：饮食和肠道微生物组成与慢性呼吸系统疾病的发生发展密切相关，但由于混杂因素和反向因果的影响，这些因果关联仍未知。“肠-肺轴”提供了理解二者相互作用的合理框架，但其直接的遗传学证据仍然有限。本研究采用一种两阶段双样本孟德尔随机化框架，辅以多变量孟德尔随机化（MVMR）以校正多效性影响，并结合Benjamini-Hochberg法对多重检验进行错误发现率（FDR）校正，系统评估了饮食习惯和肠道微生物类群对主要慢性呼吸系统疾病的因果贡献。研究共鉴定出22项对疾病风险具有因果效应的饮食因素，以及225个作为独立风险或保护因素的肠道微生物分类单元。中介分析进一步显示，12项饮食习惯对疾病风险的影响可通过32个特定肠道微生物传递。值得注意的是，遗传预测的猪肉摄入量与慢性阻塞性肺疾病（COPD）风险增加相关（OR=10.53，95% CI ［8.54, 13.00］），其中部分效应由 CAG-485 sp002404675 丰度升高所介导。相反，面包摄入对哮喘具有保护作用（OR=0.68，95% CI［0.64, 0.72］），但这一益处因相关的韦荣球菌（Veillonella）丰度下降而减少约45%。综上所述，这些发现为“肠-肺轴”提供了遗传学证据，表明肠道微生物组在饮食与慢性呼吸系统疾病风险之间发挥着因果中介作用。然而，鉴于本研究仅基于欧洲血统人群，在将这些因果效应估计值推广至非欧洲人群（如东亚群体）时应持谨慎态度。本研究也为靶向肠道菌群的疾病预防和治疗策略提供了新的可能性。
关键词： 孟德尔随机化；肠道微生物组；呼吸系统疾病；饮食；欧洲血统人群 
中图分类号：R56              文献标志码：A             DOI：10.3969/j.issn.1007-7146.2026.01.005
（Acta Laser Biology Sinica, 2026, 35(1): 035-052）

Abstract: Although diet and gut microbial composition have been linked to chronic respiratory diseases, these associations remain difficult to interpret because of confounding and reverse causation. The gut-lung axis provides a plausible framework for this interaction, yet direct genetic evidence is limited. Using a two-step, two-sample Mendelian randomization (MR) framework, supplemented by multivariable MR (MVMR) to adjust for pleiotropic effects and Benjamini-Hochberg false discovery rate (FDR) correction for multiple testing, we assessed the causal contributions of dietary habits and gut microbial taxa to major chronic respiratory diseases. We identified 22 dietary factors with causal effects on disease risk and 225 microbial taxa that acted as independent risk or protective contributors. Mediation analyses further showed that the effects of 12 dietary habits were transmitted through 32 specific microbial taxa. Notably, genetically predicted pork intake increased the risk of chronic obstructive pulmonary disease (COPD) (OR=10.53, 95% CI [8.54, 13.00]), an effect partly mediated by elevated abundance of CAG-485 sp002404675. In contrast, bread consumption conferred protection against asthma (OR=0.68, 95% CI [0.64, 0.72]), whereas this benefit was offset by approximately 45% through a pathway involving reduced Veillonella abundance. Collectively, these findings provide genetic support for the gut-lung axis and demonstrate that the gut microbiome functions as a causal mediator linking diet to chronic respiratory disease risk. However, since this study was based on individuals of European ancestry, caution is warranted when generalizing these causal estimates to non-European populations, such as East Asian groups. This work suggests new opportunities for microbiota-targeted prevention and therapeutic strategies.
Key words: Mendelian randomization; gut microbiome; respiratory disease; dietary; European descent populations
CLC number: R56                 Document code: A        DOI: 10.3969/j. issn.1007-7146.2026.01.005