肠道菌群与耐药肺结核患者发生药物性肝损伤的关联性研究

doi:10.19982/j.issn.1000-6621.20260282

中国防痨杂志 ›› 2026, Vol. 48 ›› Issue (9): 1277-1289.doi: 10.19982/j.issn.1000-6621.20260282

肠道菌群与耐药肺结核患者发生药物性肝损伤的关联性研究

李程¹^,², 吴春丽¹^,², 夏凡¹^,², 于汶朵¹^,², 刘振国³, 易恒仲⁴, 文新民⁴, 唐志冈⁴, 黄晟⁴, 李瑶⁴, 陈梦施¹^,²(), 容鹏飞⁵()

¹ 中南大学湘雅公共卫生学院, 长沙 410013
² 临床流行病学湖南省重点实验室, 长沙 410013
³ 中南大学湘雅三医院感染科, 长沙 410013
⁴ 湖南省胸科医院内六科, 长沙 410013
⁵ 中南大学湘雅三医院放射科, 长沙 410013

收稿日期:2026-05-20 出版日期:2026-09-10 发布日期:2026-09-08
通信作者: 陈梦施,容鹏飞 E-mail:121444639@qq.com;rongpengfei66@163.com
基金资助:
湖南省自然科学基金面上项目(2023JJ30335);长沙市自然科学基金(kq2208097);长沙市自然科学基金(kq2208096);长沙市自然科学基金(kq2502213);湖南省自然科学基金医卫联合项目(2024JJ9476);湖南省自然科学基金医卫联合项目(2025JJ80686)

Study on the association between gut microbiota and drug-induced liver injury in patients with drug-resistant pulmonary tuberculosis

Li Cheng¹^,², Wu Chunli¹^,², Xia Fan¹^,², Yu Wenduo¹^,², Liu Zhenguo³, Yi Hengzhong⁴, Wen Xinmin⁴, Tang Zhigang⁴, Huang Sheng⁴, Li Yao⁴, Chen Mengshi¹^,²(), Rong Pengfei⁵()

¹ Xiangya School of Public Health, Central South University, Changsha 410013, China
² Hunan Provincial Key Laboratory of Clinical Epidemiology, Changsha 410013, China
³ Department of Infectious Diseases, the Third Xiangya Hospital of Central South University, Changsha 410013, China
⁴ Internal Medicine Department Six, Hunan Chest Hospital, Changsha 410013, China
⁵ Department of Radiology, the Third Xiangya Hospital of Central South University, Changsha 410013, China

Received:2026-05-20 Online:2026-09-10 Published:2026-09-08
Contact: Chen Mengshi,Rong Pengfei E-mail:121444639@qq.com;rongpengfei66@163.com
Supported by:
General Program of Hunan Provincial Natural Science Foundation(2023JJ30335);Changsha Natural Science Foundation(kq2208097);Changsha Natural Science Foundation(kq2208096);Changsha Natural Science Foundation(kq2502213);Medical and Health Joint Program of Hunan Provincial Natural Science Foundation(2024JJ9476);Medical and Health Joint Program of Hunan Provincial Natural Science Foundation(2025JJ80686)

摘要/Abstract

摘要：

目的: 比较发生与未发生药物性肝损伤(drug-induced liver injury,DILI)的耐药肺结核患者肠道微生物群及其功能通路的差异,以期发现与DILI发生相关的肠道微生物群和功能通路。 方法: 采用巢式病例对照设计,以湖南省胸科医院为研究现场,从2021年9月8日开始前瞻性纳入在医院就诊的新入院的耐药肺结核患者作为研究对象,构建耐药肺结核患者的随访队列。对纳入队列的研究对象进行随访,通过肝功能检查结果对研究对象进行评估,追踪其在治疗过程中有无出现DILI。截止到2022年11月4日,选择队列中被诊断为DILI的所有患者为 DILI组(68例),以性别、年龄(±3岁)、耐药治疗时长(±1个月)、样本采集时间(±1个月)为标准,采用1∶1匹配选取肝功能正常的耐药肺结核患者作为对照组(68例)。利用宏基因组测序技术提取研究对象粪样DNA信息并使用R等软件对两组间的肠道微生物多样性、组间差异物种、组间差异功能,以及差异物种与差异功能的关联性进行分析。 结果: DILI组和对照组的肠道微生物Alpha多样性和Beta多样性差异均无统计学意义(P>0.05)。经调整年龄等混杂因素后,发现有8个菌种的差异有统计学意义,分别是在DILI组富集的Dorea longicatena(P=0.007)、Prevotella sp.CAG:386(P=0.012)、Prevotella stercorea(P=0.013)和Prevotellamassilia timonensis(P=0.043),以及在对照组富集的Clostridium sp.CAG:7(P=0.020)、Eubacterium sp.CAG:38(P=0.002)、Faecalibacterium sp.CAG:82(P=0.047)和Klebsiella michiganensis(P<0.001)。在KEGG level 3水平上发现,丙酮酸代谢(P=0.010)、丁酸盐代谢(P=0.034)、缬氨酸、亮氨酸和异亮氨酸的降解(P=0.009)、乙氧基化物和二甲酸酯的代谢(P=0.041)、阳离子抗菌肽(CAMP)抗性(P=0.031)在对照组富集,而淀粉和蔗糖代谢(P=0.027)、果糖和甘露糖的代谢(P=0.005)在DILI组富集。7种差异功能通路与Klebsiella michiganensis的丰度呈正相关(P<0.05);缬氨酸、亮氨酸和异亮氨酸的降解功能与Eubacterium sp.CAG:38、Faecalibacterium sp.CAG:82等其余7种差异菌种的丰度呈负相关(P<0.05);乙氧基化物和二甲酸酯的代谢功能与Prevotella stercorea、Prevotellamassilia timonensis、Clostridium sp.CAG:7的丰度呈负相关(P<0.001);丙酮酸代谢功能与Prevotella stercorea、Prevotellamassilia timonensis的丰度呈负相关(P<0.001);丁酸盐代谢功能与Prevotella stercorea的丰度呈负相关(P<0.001)。 结论: 并发DILI的耐药肺结核患者在发生DILI之前与未并发者的肠道微生物组成已存在差异。淀粉、蔗糖、果糖、甘露糖和丙酮酸、丁酸盐代谢相关功能异常,以及缬氨酸、亮氨酸、异亮氨酸的降解相关功能异常,均可能与耐药肺结核患者发生DILI有关。

关键词: 结核, 抗多种药物性, 药物性肝损伤, 肠道微生物群, 病例对照研究, 因素分析, 统计学

Abstract:

Objective: To compare the differences in gut microbiota and their functional pathways between drug-resistant pulmonary tuberculosis (DR-PTB) patients with and without drug-induced liver injury (DILI), so as to identify gut microbiota and functional pathways associated with the development of DILI. Methods: A nested case-control design was adopted with Hunan Chest Hospital as the research site. Newly admitted inpatients diagnosed with DR-PTB were prospectively enrolled starting from September 8, 2021, to establish a follow-up cohort of DR-PTB patients. All cohort participants were followed up, and liver function tests were performed to monitor the occurrence of DILI during anti-tuberculosis treatment. By November 4, 2022, all patients diagnosed with DILI in the cohort were assigned to the DILI group (68 cases). Using a 1∶1 matching strategy, DR-PTB patients with normal liver function were selected as the control group (68 cases), matched by gender, age (±3 years), duration of anti-drug-resistant TB treatment (±1 month), and sample collection time (±1 month). Metagenomic sequencing was applied to extract DNA information from fecal samples. Software including R was used to analyze gut microbial alpha diversity, beta diversity, differential species, differential functional pathways, and correlations between differential species and differential functions across the two groups. Results: No statistically significant differences were observed in gut microbial alpha diversity and beta diversity between the DILI group and the control group (P>0.05). After adjusting for confounders such as age, eight bacterial species showed significant intergroup differences. Four species were enriched in the DILI group: Dorea longicatena (P=0.007), Prevotella sp. CAG:386 (P=0.012), Prevotella stercorea (P=0.013), and Prevotellamassilia timonensis (P=0.043). The other four species were enriched in the control group: Clostridium sp. CAG:7 (P=0.020), Eubacterium sp. CAG:38 (P=0.002), Faecalibacterium sp. CAG:82 (P=0.047), and Klebsiella michiganensis (P<0.001). At KEGG level 3, pyruvate metabolism (P=0.010), butanoate metabolism (P=0.034), valine, leucine and isoleucine degradation (P=0.009), ethoxylate and dicarboxylate metabolism (P=0.041), and cationic antimicrobial peptide (CAMP) resistance (P=0.031) were enriched in the control group. Starch and sucrose metabolism (P=0.027) and fructose and mannose metabolism (P=0.005) were enriched in the DILI group. The abundances of seven differential functional pathways were positively correlated with the abundance of Klebsiella michiganensis (P<0.05). The pathway of valine, leucine and isoleucine degradation was negatively correlated with the abundances of the other seven differential species including Eubacterium sp. CAG:38 and Faecalibacterium sp. CAG:82 (P<0.05). Ethoxylate and dicarboxylate metabolism was negatively correlated with the abundances of Prevotella stercorea, Prevotellamassilia timonensis and Clostridium sp. CAG:7 (P<0.001). Pyruvate metabolism was negatively correlated with the abundances of Prevotella stercorea and Prevotellamassilia timonensis (P<0.001). Butanoate metabolism was negatively correlated with the abundance of Prevotella stercorea (P<0.001). Conclusion: Differences in gut microbial composition already exist prior to DILI onset between DR-PTB patients who subsequently develop DILI and those who do not. Abnormal functions related to starch, sucrose, fructose, mannose, pyruvate and butanoate metabolism, as well as impaired valine, leucine and isoleucine degradation, may be associated with DILI occurrence in patients with drug-resistant pulmonary tuberculosis.

Key words: Tuberculosis, multidrug-resistant, Drug-induced liver injury, Gut microbiota, Case-control studies, Factor analysis, statistical

中图分类号:

李程, 吴春丽, 夏凡, 于汶朵, 刘振国, 易恒仲, 文新民, 唐志冈, 黄晟, 李瑶, 陈梦施, 容鹏飞. 肠道菌群与耐药肺结核患者发生药物性肝损伤的关联性研究[J]. 中国防痨杂志, 2026, 48(9): 1277-1289. doi: 10.19982/j.issn.1000-6621.20260282

Li Cheng, Wu Chunli, Xia Fan, Yu Wenduo, Liu Zhenguo, Yi Hengzhong, Wen Xinmin, Tang Zhigang, Huang Sheng, Li Yao, Chen Mengshi, Rong Pengfei. Study on the association between gut microbiota and drug-induced liver injury in patients with drug-resistant pulmonary tuberculosis[J]. Chinese Journal of Antituberculosis, 2026, 48(9): 1277-1289. doi: 10.19982/j.issn.1000-6621.20260282

图/表 11

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表6

表7

两组差异物种与差异功能的相关性分析

物种	丙酮酸代谢						丁酸盐代谢					缬氨酸、亮氨酸和异亮氨酸降解					乙氧基化物和二甲酸酯代谢
物种	r值		P值		Fdr校正P值		r值	P值		Fdr校正P值		r值		P值	Fdr校正P值		r值		P值		Fdr校正P值
s__Dorea longicatena	-0.125		0.147		0.178		-0.206	0.016		0.023		-0.467		0.000	0.000		-0.294		0.001		0.001
s__Prevotella sp.CAG:386	-0.213		0.013		0.019		-0.069	0.426		0.466		-0.503		0.000	0.000		-0.295		0.000		0.001
s__Prevotella stercorea	-0.432		0.000		0.000		-0.334	0.000		0.000		-0.422		0.000	0.000		-0.312		0.000		0.000
s__Prevotellamassilia timonensis	-0.439		0.000		0.000		-0.250	0.003		0.005		-0.409		0.000	0.000		-0.326		0.000		0.000
s__Clostridium sp.CAG:7	-0.206		0.016		0.022		-0.202	0.019		0.025		-0.565		0.000	0.000		-0.463		0.000		0.000
s__Eubacterium sp.CAG:38	-0.065		0.450		0.487		-0.126	0.143		0.177		-0.378		0.000	0.000		-0.170		0.048		0.063
s__Faecalibacterium sp.CAG:82	-0.039		0.650		0.675		-0.052	0.544		0.577		-0.360		0.000	0.000		-0.236		0.006		0.009
s__Klebsiella michiganensis	0.507		0.000		0.000		0.595	0.000		0.000		0.419		0.000	0.000		0.465		0.000		0.000
物种		阳离子抗菌肽抗性							淀粉和蔗糖代谢							果糖和甘露糖代谢
物种		r值		P值		Fdr校正P值			r值		P值		Fdr校正P值			r值		P值		Fdr校正P值
s__Dorea longicatena		-0.551		0.000		0.000			0.124		0.149		0.178			-0.113		0.191		0.223
s__Prevotella sp.CAG:386		-0.338		0.000		0.000			0.031		0.722		0.736			-0.003		0.976		0.976
s__Prevotella stercorea		-0.403		0.000		0.000			-0.105		0.222		0.256			-0.198		0.021		0.028
s__Prevotellamassilia timonensis		-0.332		0.000		0.000			-0.208		0.015		0.021			-0.158		0.067		0.084
s__Clostridium sp.CAG:7		-0.632		0.000		0.000			0.076		0.381		0.422			-0.125		0.146		0.178
s__Eubacterium sp.CAG:38		-0.455		0.000		0.000			0.048		0.579		0.608			-0.085		0.325		0.366
s__Faecalibacterium sp.CAG:82		-0.294		0.001		0.001			0.102		0.238		0.272			-0.029		0.736		0.743
s__Klebsiella michiganensis		0.687		0.000		0.000			0.188		0.029		0.038			0.321		0.000		0.000

表7

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变量	分类及赋值
民族	0=汉族,1=其他
婚姻状况	0=未婚,1=已婚,2=其他
职业	0=农民,1=专业技术人员,2=公司职员,3=无业人员,5=其他
受教育程度	0=小学及以下,1=初中,2=高中/中专/职高,3=大专及以上
医疗付费方式	0=城镇职工基本医疗保险,1=城镇居民基本医疗保险,2=自费,3=其他
胸部CT	0=无空洞,1=有空洞
抗酸杆菌涂片镜检	0=阴性,1=阳性
吸烟史	0=无,1=有
饮酒史	0=无,1=有
喝茶史	0=无,1=有
饮食习惯	0=素食为主,1=肉食为主,2=均衡饮食
淀粉类	0=基本不吃,1=每月1~4次,2=每周≥2次
蔬菜类	0=基本不吃,1=每月1~4次,2=每周≥2次
水果类	0=基本不吃,1=每月1~4次,2=每周≥2次
畜禽肉类	0=基本不吃,1=每月1~4次,2=每周≥2次
水产品类	0=基本不吃,1=每月1~4次,2=每周≥2次
蛋类	0=基本不吃,1=每月1~4次,2=每周≥2次
奶类	0=基本不吃,1=每月1~4次,2=每周≥2次
大豆类	0=基本不吃,1=每月1~4次,2=每周≥2次
坚果类	0=基本不吃,1=每月1~4次,2=每周≥2次
油炸烧烤类	0=基本不吃,1=每月1~4次,2=每周≥2次
腌制类	0=基本不吃,1=每月1~4次,2=每周≥2次
酸奶类	0=基本不吃,1=每月1~4次,2=每周≥2次
贝达喹啉	0=无,1=有
利奈唑胺	0=无,1=有
莫西沙星	0=无,1=有
左氧氟沙星	0=无,1=有
氯法齐明	0=无,1=有
环丝氨酸	0=无,1=有
对氨基水杨酸	0=无,1=有
丙硫异烟胺	0=无,1=有
阿米卡星	0=无,1=有

特征	对照组(68例)	DILI组(68例)	统计检验值	P值
民族[例(构成比,%)]			χ²=0.000	1.000
汉族	65(95.6)	65(95.6)
少数民族	3(4.4)	3(4.4)
婚姻状况[例(构成比,%)]			χ²=0.728	0.695
未婚	10(14.7)	9(13.2)
已婚	56(82.4)	55(80.9)
其他	2(2.9)	4(5.9)
职业[例(构成比,%)]			χ²=17.322	0.002
农民	36(52.9)	29(42.6)
专业技术人员	8(11.8)	5(7.4)
公司职员	7(10.3)	22(32.4)
无业人员	16(23.5)	6(8.8)
其他	1(1.5)	6(8.8)
体质量指数(kg/m²,$\overline{\mathit{x}}$±s)	21.30±2.74	21.00±2.83	t=0.262	0.609
胸部CT[例(构成比,%)]			χ²=0.118	0.731
有空洞	36(52.9)	34(50.0)
无空洞	32(47.1)	34(50.0)
抗酸杆菌涂片[例(构成比,%)]			χ²=0.765	0.382
阴性	60(88.2)	63(92.6)
阳性	8(11.8)	5(7.4)
吸烟史[例(构成比,%)]			χ²=1.106	0.293
无	24(35.3)	30(44.1)
有	44(64.7)	38(55.9)
饮酒史[例(构成比,%)]			χ²=3.741	0.053
无	21(30.9)	32(47.1)
有	47(69.1)	36(52.9)
喝茶史[例(构成比,%)]			χ²=0.654	0.419
无	54(79.4)	50(73.5)
有	14(20.6)	18(26.5)
服用氯法齐明[例(构成比,%)]			χ²=3.934	0.047
否	50(73.5)	39(57.4)
是	18(26.5)	29(42.6)
服用对氨基水杨酸[例(构成比,%)]			χ²=5.747	0.017
否	40(58.8)	53(77.9)
是	28(41.2)	15(22.1)

物种	相对丰度(%)		P值	Fdr校正P值
物种	药物性肝损伤组	对照组	P值	Fdr校正P值
p__Fusobacteria	0.775	0.441	0.011	0.041
p__Actinobacteria	0.642	0.236	0.000	0.002
p__Ascomycota	0.197	0.047	0.012	0.041
c__Betaproteobacteria	0.521	0.842	0.028	0.092
c__Fusobacteriia	0.775	0.441	0.011	0.055
c__Actinobacteria	0.409	0.183	0.011	0.055
o__Burkholderiales	0.513	0.826	0.035	0.176
o__Fusobacteriales	0.774	0.440	0.011	0.109
f__Prevotellaceae	7.512	2.277	0.021	0.210
g__Prevotella	7.131	2.135	0.019	0.190
s__Prevotella copri	2.821	0.611	0.029	0.072
s__Klebsiella pneumoniae	0.525	0.968	0.000	0.004
s__Bacteroides plebeius	0.468	0.781	0.005	0.025
s__Subdoligranulum variabile	0.487	0.748	0.013	0.044

各水平肠道微生物	log10平均相对丰度	LDA值	P值
药物性肝损伤组
c__Chlamydiia	3.05	2.57	0.045
f__Morganellaceae	3.39	2.78	0.045
g__Anaerostipes	3.14	2.53	0.024
g__Chlamydia	3.05	2.57	0.044
g__Prevotellamassilia	2.74	2.37	0.003
g__Ruminococcus	3.87	3.38	0.033
o__Chlamydiales	3.05	2.57	0.044
o__Lactobacillales	3.64	2.88	0.041
p__Actinobacteria	3.83	3.40	0.043
p__Chlamydiae	3.05	2.57	0.044
s__Chlamydia trachomatis	3.05	2.57	0.043
s__Dorea longicatena	2.89	2.37	0.037
s__Faecalibacterium prausnitzii	3.96	3.27	0.049
s__Prevotella sp.CAG:386	2.95	2.46	0.002
s__Prevotella sp.CAG:732	2.99	2.59	0.018
s__Prevotella stercorea	3.39	2.94	0.021
s__Prevotellamassilia timonensis	2.74	2.37	0.003
对照组
g__Klebsiella	4.29	3.62	0.017
g__Romboutsia	2.64	2.33	0.045
p__Proteobacteria	5.34	4.26	0.047
s__Clostridium sp.CAG:7	3.15	2.70	0.005
s__Eubacterium sp.CAG:38	3.13	2.79	0.019
s__Faecalibacterium sp.CAG:82	2.70	2.35	0.021
s__Klebsiella michiganensis	4.01	3.37	0.014
s__Prevotella sp.885	3.39	3.14	0.032

差异菌种	未调整F值	未调整P值	调整后F值^a	调整后P值^a
s__Chlamydia trachomatis	4.268	0.041	1.511	0.160
s__Dorea longicatena	4.506	0.036	2.810	0.007
s__Faecalibacterium prausnitzii	4.082	0.045	1.740	0.095
s__Prevotella sp.CAG:386	10.356	0.002	2.595	0.012
s__Prevotella sp.CAG:732	5.811	0.017	1.472	0.174
s__Prevotella stercorea	5.486	0.021	2.564	0.013
s__Prevotellamassilia timonensis	9.464	0.003	2.077	0.043
s__Clostridium sp.CAG:7	8.473	0.004	2.374	0.020
s__Eubacterium sp.CAG:38	5.697	0.018	3.323	0.002
s__Faecalibacterium sp.CAG:82	5.475	0.021	2.039	0.047
s__Klebsiella michiganensis	6.354	0.013	5.797	0.000
s__Prevotella sp.885	4.770	0.031	1.349	0.226

肠道菌群与耐药肺结核患者发生药物性肝损伤的关联性研究

Study on the association between gut microbiota and drug-induced liver injury in patients with drug-resistant pulmonary tuberculosis

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通路名称	log10平均相对丰度	LDA值	P值
对照组
丙酮酸代谢(KEGG等级3)	4.37	2.77	0.010
人类疾病(KEGG等级1)	4.79	2.77	0.012
耐药性抗菌剂(KEGG等级1)	4.40	2.53	0.041
丁酸盐代谢(KEGG等级3)	4.12	2.48	0.034
缬氨酸、亮氨酸和异亮氨酸降解(KEGG等级3)	3.69	2.40	0.009
乙氧基化物和二甲酸酯代谢(KEGG等级3)	4.23	2.46	0.041
阳离子抗菌肽抗性(KEGG等级3)	3.99	2.62	0.031
药物性肝损伤组
淀粉和蔗糖代谢(KEGG等级3)	4.46	2.95	0.027
果糖和甘露糖的代谢(KEGG等级3)	4.34	2.92	0.005
神经退行性疾病(KEGG等级3)	3.38	2.44	0.001

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