Pan Tongtong, Su Lihuang, Zhang Yiying, Yi Fangfang, Chen Yongping
Hepatology Diagnosis and Treatment Center, The First Affiliated Hospital of Wenzhou Medical University and Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, Wenzhou, China.
The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Front Microbiol. 2024 Jan 8;14:1320279. doi: 10.3389/fmicb.2023.1320279. eCollection 2023.
Enteric dysbacteriosis is strongly associated with nonalcoholic fatty liver disease (NAFLD). However, the underlying causal relationship remains unknown. Thus, the present study aimed to investigate the relationship between gut microbiota and NAFLD using Mendelian randomization (MR) and analyze the target genes potentially regulated by specific microbiota.
Bidirectional two-sample MR analysis was performed using inverse variance weighted (IVW) supplemented by MR-Egger, weighted median, simple mode, and weighted mode methods. Data were pooled from gut microbiota and NAFLD association studies. The least absolute shrinkage, selection operator regression, and the Support Vector Machine algorithm were used to identify genes regulated by these intestinal flora in NAFLD. The liver expression of these genes was verified in methionine choline-deficient (MCD) diet-fed mice.
IVW results confirmed a causal relationship between eight specific gut microbes and NAFLD. Notably, the order Actinomycetales, NB1n, the family Actinomycetaceae, Oxalobacteraceae and the genus were positively correlated, whereas Lactobacillaceae, the , and were negatively correlated with NAFLD onset. In NAFLD, these eight bacteria regulated four genes: colony-stimulating factor 2 receptor β, fucosyltransferase 2, 17-beta-hydroxysteroid dehydrogenase 14, and microtubule affinity regulatory kinase 3 (). All genes, except , were differentially expressed in the liver tissues of MCD diet-fed mice.
The abundance of eight gut microbiota species and NAFLD progression displayed a causal relationship based on the expression of the four target genes. Our findings contributed to the advancement of intestinal microecology-based diagnostic technologies and targeted therapies for NAFLD.
肠道菌群失调与非酒精性脂肪性肝病（NAFLD）密切相关。然而，潜在的因果关系仍不清楚。因此，本研究旨在利用孟德尔随机化（MR）研究肠道微生物群与NAFLD之间的关系，并分析特定微生物群可能调控的靶基因。
采用逆方差加权（IVW）法进行双向双样本MR分析，并辅以MR-Egger、加权中位数、简单模式和加权模式法。数据来自肠道微生物群与NAFLD关联研究的汇总。采用最小绝对收缩、选择算子回归和支持向量机算法来识别这些肠道菌群在NAFLD中调控的基因。在蛋氨酸胆碱缺乏（MCD）饮食喂养的小鼠中验证这些基因的肝脏表达。
IVW结果证实了8种特定肠道微生物与NAFLD之间存在因果关系。值得注意的是，放线菌目、NB1n、放线菌科、草酸杆菌科和某属呈正相关，而乳杆菌科、某属和某属与NAFLD发病呈负相关。在NAFLD中，这8种细菌调控了4个基因：集落刺激因子2受体β、岩藻糖基转移酶2、17-β-羟基类固醇脱氢酶14和微管亲和力调节激酶3（）。除了某基因外，所有基因在MCD饮食喂养小鼠的肝脏组织中均有差异表达。
基于4个靶基因的表达，8种肠道微生物群的丰度与NAFLD进展之间存在因果关系。我们的研究结果有助于推进基于肠道微生态的诊断技术和NAFLD的靶向治疗。
