Department of Gastroenterology, First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China.
The First Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou, China.
Front Endocrinol (Lausanne). 2024 Oct 21;15:1442603. doi: 10.3389/fendo.2024.1442603. eCollection 2024.
Previous studies have suggested a potential association between gut microbiota and the development of alcohol-related liver disease (ALD). However, the causal relationship between gut microbiota and ALD, as well as the role of inflammatory cytokines as mediators, remains unclear. This study aims to explore the causal relationship between gut microbiota and ALD using Mendelian randomization (MR) methods, and to analyze the mediating role of inflammatory cytokines.
Gut microbiota, 91 inflammatory cytokines, and ALD were identified from summary data of large-scale genome-wide association studies (GWAS). MR was employed to investigate the causal relationship between gut microbiota, cytokines, and ALD, with the inverse variance-weighted method (IVW) as the primary statistical approach. Additionally, we examined whether inflammatory cytokines act as mediating factors in the pathway from gut microbiota to ALD.
The IVW results confirmed two positive and one negative causal effect between genetic liability in the gut microbiota and ALD. (= 0.003) was identified as a protective factor for ALD, while (=0.023) and (=0.038) were identified as risk factors for ALD. Furthermore, there were five positive and two negative causal effects between inflammatory cytokines and ALD, with CUB domain-containing protein 1 (P= 0.035), Macrophage colony-stimulating factor 1 (P=0.047), Cystatin D (P = 0.035), Fractalkine (P=0.000000038), Monocyte chemoattractant protein-1 (P=0.004) positively associated with ALD onset. CD40L receptor (P= 0.044) and Leukemia inhibitory factor (P = 0.024) exhibited protective effects against ALD. Mediation MR analysis indicated that CUB domain-containing protein 1 (mediation proportion=1.6%, P=0.035), Cystatin D (mediation proportion=1.5%, P=0.012), and Monocyte chemoattractant protein-1 (mediation proportion=3.3%, P=0.005) mediated the causal effect of on ALD.
In conclusion, our study supports a causal relationship among gut microbiota, inflammatory cytokines and ALD, with inflammatory cytokines potentially acting as mediating factors in the pathway from gut microbiota to ALD.
先前的研究表明，肠道微生物群与酒精性肝病（ALD）的发展之间可能存在关联。然而，肠道微生物群与 ALD 之间的因果关系，以及炎症细胞因子作为中介的作用仍不清楚。本研究旨在使用孟德尔随机化（MR）方法探讨肠道微生物群与 ALD 之间的因果关系，并分析炎症细胞因子的介导作用。
从大规模全基因组关联研究（GWAS）的汇总数据中鉴定出肠道微生物群、91 种炎症细胞因子和 ALD。采用逆方差加权法（IVW）作为主要统计方法，进行肠道微生物群、细胞因子与 ALD 之间因果关系的 MR 分析。此外，我们还研究了炎症细胞因子是否在肠道微生物群到 ALD 的途径中充当中介因素。
IVW 结果证实了肠道微生物群遗传易感性与 ALD 之间存在两种正相关和一种负相关的因果关系。（=0.003）被鉴定为 ALD 的保护因素，而（=0.023）和（=0.038）被鉴定为 ALD 的风险因素。此外，炎症细胞因子与 ALD 之间存在五种正相关和两种负相关的因果关系，其中 CUB 结构域蛋白 1（P=0.035）、巨噬细胞集落刺激因子 1（P=0.047）、胱抑素 D（P=0.035）、趋化因子 Fractalkine（P=0.000000038）和单核细胞趋化蛋白-1（P=0.004）与 ALD 发病呈正相关。CD40L 受体（P=0.044）和白血病抑制因子（P=0.024）对 ALD 具有保护作用。中介 MR 分析表明，CUB 结构域蛋白 1（中介比例=1.6%，P=0.035）、胱抑素 D（中介比例=1.5%，P=0.012）和单核细胞趋化蛋白-1（中介比例=3.3%，P=0.005）介导了对 ALD 的因果效应。
综上所述，本研究支持肠道微生物群、炎症细胞因子与 ALD 之间存在因果关系，炎症细胞因子可能在肠道微生物群到 ALD 的途径中充当中介因素。
