肠道菌群与非结核分枝杆菌肺感染的因果效应:一项双向两样本孟德尔随机化分析

doi:10.19982/j.issn.1000-6621.20250292

摘要/Abstract

摘要：

目的: 评估肠道菌群与非结核分枝杆菌肺感染(non-tuberculous mycobacteria lung infection,NTM-LI)之间的因果方向。方法: 采用两样本双向孟德尔随机化(Mendelian randomization,MR)分析。肠道菌群与NTM-LI的全基因组关联研究汇总数据分别来自GWAS Catalog和芬兰数据库。工具变量筛选基于全基因组显著性、连锁不平衡分析和弱工具变量检验。主要使用逆方差加权法(IVW)评估因果效应,辅以MR-Egger、加权中位数、简单众数和加权众数法验证。通过Cochran Q、留一法、MR-Egger截距检验和MR-PRESSO评估异质性、敏感性和水平多效性。反向MR分析采用相同流程。结果: IVW分析显示,特定肠道菌群丰度变化与NTM-LI发病风险明显相关。其中,羊毛状臭气杆菌(OR=1.798,95%CI:1.017~3.180,P=0.044)、懒惰脱硫弧菌(OR=1.508,95%CI:1.069~2.128,P=0.019)及汉氏布劳特氏菌(OR=2.487,95%CI:1.222~5.062,P=0.012)被识别为风险因子。相反,苏黎世杆菌科(OR=0.570,95%CI:0.343~0.949,P=0.031)、RUG420 sp900317985(OR=0.153,95%CI:0.036~0.649,P=0.011)、厚壁菌门E(OR=0.084,95%CI:0.009~0.814,P=0.033)、人肠道杆菌属(OR=0.386,95%CI:0.197~0.756,P=0.006)和CAG-145 sp000435615(OR=0.575,95%CI:0.357~0.927,P=0.023)表现出保护效应。未发现明显异质性、水平多效性或离群值干扰。反向MR未支持NTM-LI对菌群的反向因果。结论: 本研究通过MR揭示特定肠道菌群与NTM-LI之间存在一定的因果关系,靶向调控这些菌群或为NTM-LI防治提供新策略。

关键词: 肠道菌群, 分枝杆菌感染, 肺疾病, 因果律, 孟德尔随机化

Abstract:

Objective: To assess the causal direction between gut microbiota and non-tuberculous mycobacteria lung infection (NTM-LI). Methods: This study used a bidirectional two-sample Mendelian randomization (MR). Genome-wide association studies (GWAS) data of gut microbiota and NTM-LI were obtained from the GWAS Catalog and the FinnGen databases, respectively. Instrumental variables (IV) were selected based on genome-wide significance thresholds, linkage disequilibrium analysis, and weak instrumental variable screening. The primary causal effect assessed using the inverse-variance weighted (IVW) method, supplemented by using MR-Egger, weighted median, simple mode, and weighted mode methods. Heterogeneity, sensitivity, and horizontal pleiotropy were evaluated using Cochran’s Q test, leave-one-out analysis, MR-Egger intercept test, and MR-PRESSO, respectively. Reverse MR analysis followed the same protocol. Results: IVW analysis revealed that changes in the abundance of specific gut microbiota taxa were significantly associated with the risk of NTM-LI. Odoribacter laneus (OR=1.798, 95%CI: 1.017-3.180, P=0.044), Desulfovibrio piger (OR=1.508, 95%CI: 1.069-2.128, P=0.019) and Blautia hansenii (OR=2.487, 95%CI: 1.222-5.062, P=0.012) could increase the risk of NTM-LI. Conversely, Turicibacteraceae (OR=0.570, 95%CI: 0.343-0.949, P=0.031), RUG420 sp900317985 (OR=0.153, 95%CI: 0.036-0.649, P=0.011), Firmicutes E (OR=0.084, 95%CI: 0.009-0.814, P=0.033), Enteroscipio (OR=0.386, 95%CI: 0.197-0.756, P=0.006), and CAG-145 sp000435615 (OR=0.575, 95%CI: 0.357-0.927, P=0.023) could reduce the risk of NTM-LI. No significant heterogeneity, horizontal pleiotropy, and outlier interference was detected. Furthermore, reverse MR analysis did not support effect of NTM-LI on gut microbiota composition. Conclusion: This MR analysis reveals a potential causal relationship between specific gut microbiota and NTM-LI. Targeted modulation of these specific gut microbial taxa holds promise as a novel intervention strategy for the prevention and treatment of NTM-LI.

Key words: Gut microbiota, Mycobacterium infections, Lung diseases, Causality, Mendelian randomization

中图分类号:

R563

谭霄, 李芳萍, 张谦, 张美家. 肠道菌群与非结核分枝杆菌肺感染的因果效应:一项双向两样本孟德尔随机化分析[J]. 中国防痨杂志, 2026, 48(1): 121-130. doi: 10.19982/j.issn.1000-6621.20250292

Tan Xiao, Li Fangping, Zhang Qian, Zhang Meijia. Causal effects of gut microbiota on non-tuberculous mycobacterial lung infection: a bidirectional two-sample mendelian randomization study[J]. Chinese Journal of Antituberculosis, 2026, 48(1): 121-130. doi: 10.19982/j.issn.1000-6621.20250292

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暴露/结局	数据来源	样本数(例)	样本来源	数据下载链接
肠道菌群	FINRISK 2002	5959	欧洲人种	https://www.ebi.ac.uk/gwas/
非结核分枝杆菌肺病	The FinnGen Biobank	483557	欧洲人种	https://www.finngen.fi/en

肠道菌群	方法	单核苷酸多态性(个)	P值	OR(95%CI)值
苏黎世杆菌科	IVW	18	0.031	0.570(0.343~0.949)
	MR-Egger	18	0.430	0.615(0.189~2.000)
	WME	18	0.164	0.626(0.323~1.211)
	SM	18	0.666	0.760(0.224~2.581)
	WM	18	0.725	0.818(0.272~2.457)
RUG420 sp900317985	IVW	17	0.011	0.153(0.036~0.649)
	MR-Egger	17	0.040	0.018 (0.000~0.599)
	WME	17	0.047	0.125(0.016~0.970)
	SM	17	0.173	0.056(0.001~2.927)
	WM	17	0.206	0.063(0.001~3.843)
厚壁菌门E	IVW	19	0.033	0.084(0.009~0.814)
	MR-Egger	19	0.998	0.995(0.006~163.499)
	WME	19	0.299	0.201(0.010~4.150)
	SM	19	0.486	0.138(0.001~32.230)
	WM	19	0.466	0.138(0.001~25.124)
人肠道杆菌属	IVW	24	0.006	0.386(0.197~0.756)
	MR-Egger	24	0.373	0.445(0.077~2.553)
	WME	24	0.052	0.431(0.185~1.006)
	SM	24	0.281	0.429(0.096~1.924)
	WM	24	0.225	0.408(0.100~1.670)
CAG-145 sp000435615	IVW	19	0.023	0.575(0.357~0.927)
	MR-Egger	19	0.413	0.642(0.227~1.810)
	WME	19	0.134	0.614(0.324~1.163)
	SM	19	0.534	0.668(0.192~2.324)
	WM	19	0.552	0.679(0.194~2.377)

肠道菌群	方法	单核苷酸多态性(个)	P值	OR(95%CI)值
羊毛状臭气杆菌	IVW	24	0.044	1.798(1.017~3.180)
	MR-Egger	24	0.806	1.161(0.358~3.766)
	WME	24	0.172	1.674(0.799~3.505)
	SM	24	0.519	1.690(0.351~8.126)
	WM	24	0.467	1.690(0.421~6.782)
懒惰脱硫弧菌	IVW	24	0.019	1.508(1.069~2.128)
	MR-Egger	24	0.119	1.849(0.879~3.887)
	WME	24	0.342	1.262(0.781~2.041)
	SM	24	0.595	1.260(0.544~2.917)
	WM	24	0.662	1.232(0.488~3.110)
汉氏布劳特氏菌	IVW	19	0.012	2.487(1.222~5.062)
	MR-Egger	19	0.017	6.986(1.666~29.299)
	WME	19	0.007	3.740(1.445~9.680)
	SM	19	0.072	5.006(0.959~26.129)
	WM	19	0.083	4.704(0.901~24.574)

暴露	MR-Egger截距	多效性检验P值	MR-PRESSO全局检验P值
苏黎世杆菌科	-0.009	0.891	0.981
RUG420 sp900317985	0.085	0.208	0.461
厚壁菌门E	-0.065	0.304	0.923
人肠道杆菌属	-0.011	0.866	0.139
CAG-145 sp000435615	-0.014	0.818	0.977
羊毛状臭气杆菌	0.047	0.413	0.355
懒惰脱硫弧菌	-0.033	0.551	0.982
汉氏布劳特氏菌	-0.098	0.126	0.392

暴露	Cochrane Q值	异质性检验P值	暴露	Cochrane Q值	异质性检验P值
苏黎世杆菌科	7.718	0.518	CAG-145 sp000435615	8.236	0.975
RUG420 sp900317985	16.041	0.370	羊毛状臭气杆菌	25.711	0.315
厚壁菌门E	10.111	0.928	懒惰脱硫弧菌	11.610	0.976
人肠道杆菌属	31.511	0.111	汉氏布劳特氏菌	19.367	0.370