Ouyang Chen, Liu Pengpeng, Liu Yiwei, Lan Jianwei, Liu Quanyan
Department of Hepatobiliary Surgery, Tianjin Medical University General Hospital, Tianjin, 300052, P.R. China.
BMC Gastroenterol. 2024 Jul 31;24(1):244. doi: 10.1186/s12876-024-03277-w.
Although gut microbiota and serum metabolite composition have been observed to be altered in patients with non-alcoholic fatty liver disease (NAFLD), previous observational studies have demonstrated inconsistent results. As this may be influenced by factors such as confounders and reverse causality, we used Mendelian randomization to clarify the causal effect of gut microbiota and blood metabolites on NAFLD.
In this research, we performed a two-step Mendelian randomization analysis by utilizing genome-wide association study (GWAS) data obtained from MiBioGen and UK Biobank. To mitigate potential errors, we employed False Discovery Rate (FDR) correction and linkage unbalanced regression (LDSC) analysis. Sensitivity analyses including cML-MA and bidirectional Mendelian randomization were performed to ensure the robustness of the results.
In this study, a total of nine gut microbiota and seven metabolites were found to be significantly associated with NAFLD. MR analysis of the above findings revealed a causal relationship between Ruminococcus2 and cysteine-glutathione disulfide (OR = 1.17, 95%CI = 1.006-1.369, P = 0.041), as well as 3-indoleglyoxylic acid (OR = 1.18, 95%CI = 1.011-1.370, P = 0.036). For each incremental standard deviation in Ruminococcus2 abundance, there was a corresponding 26% reduction in NAFLD risk (OR = 0.74, 95%CI = 0.61-0.89, P = 0.0012), accompanied by a 17% increase in cysteine-glutathione disulfide levels (OR = 1.17, 95%CI = 1.01-1.37, P = 0.041) and an 18% increase in 3-indoleglyoxylic acid levels (OR = 1.18, 95%CI = 0.81-1.00, P = 0.036). The proportion mediated by cysteine-glutathione disulfide is 11.2%, while the proportion mediated by 3-indoleglyoxylic acid is 7.5%.
Our study suggests that increased abundance of specific gut microbiota may reduce the risk of developing NAFLD, and this relationship could potentially be mediated through blood metabolites.
尽管已观察到非酒精性脂肪性肝病（NAFLD）患者的肠道微生物群和血清代谢物组成发生改变，但先前的观察性研究结果并不一致。由于这可能受到混杂因素和反向因果关系等因素的影响，我们使用孟德尔随机化来阐明肠道微生物群和血液代谢物对NAFLD的因果效应。
在本研究中，我们利用从MiBioGen和英国生物银行获得的全基因组关联研究（GWAS）数据进行了两步孟德尔随机化分析。为了减轻潜在误差，我们采用了错误发现率（FDR）校正和连锁不平衡回归（LDSC）分析。进行了包括cML-MA和双向孟德尔随机化在内的敏感性分析，以确保结果的稳健性。
在本研究中，共发现9种肠道微生物群和7种代谢物与NAFLD显著相关。对上述结果的孟德尔随机化分析揭示了瘤胃球菌2与半胱氨酸-谷胱甘肽二硫化物之间的因果关系（OR = 1.17，95%CI = 1.006-1.369，P = 0.041），以及3-吲哚乙醛酸之间的因果关系（OR = 1.18，95%CI = 1.011-1.370，P = 0.036）。瘤胃球菌2丰度每增加一个标准差，NAFLD风险相应降低26%（OR = 0.74，95%CI = 0.61-0.89，P = 0.0012），同时半胱氨酸-谷胱甘肽二硫化物水平增加17%（OR = 1.17，95%CI = 1.01-1.37，P = 0.041），3-吲哚乙醛酸水平增加18%（OR = 1.18，95%CI = 0.81-1.00，P = 0.036）。半胱氨酸-谷胱甘肽二硫化物介导的比例为11.2%，而3-吲哚乙醛酸介导的比例为7.5%。
我们的研究表明，特定肠道微生物群丰度的增加可能会降低患NAFLD的风险，这种关系可能通过血液代谢物介导。
