Table_9_Investigating causal associations among gut microbiota, metabolites, and liver diseases: a Mendelian randomization study.docx

ObjectiveThere is some evidence for an association between gut microbiota and nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), and viral hepatitis, but no studies have explored their causal relationship.MethodsInstrumental variables of the gut microbiota (N = 13266) and gut microbiota-derived metabolites (N = 7824) were acquired, and a Mendelian randomization study was performed to explore their influence on NAFLD (1483 European cases and 17,781 European controls), ALD (2513 European cases and 332,951 European controls), and viral hepatitis risk (1971 European cases and 340,528 European controls). The main method for examining causality is inverse variance weighting (IVW).ResultsIVW results confirmed that Anaerotruncus (p = 0.0249), Intestinimonas (p = 0.0237), Lachnoclostridium (p = 0.0245), Lachnospiraceae NC2004 group (p = 0.0083), Olsenella (p = 0.0163), and Peptococcus (p = 0.0472) were protective factors for NAFLD, and Ruminococcus 1 (p = 0.0120) was detrimental for NAFLD. The higher abundance of three genera, Lachnospira (p = 0.0388), Desulfovibrio (p = 0.0252), and Ruminococcus torques group (p = 0.0364), was correlated with a lower risk of ALD, while Ruminococcaceae UCG 002 level was associated with a higher risk of ALD (p = 0.0371). The Alistipes (p = 0.0069) and Ruminococcaceae NK4A214 group (p = 0.0195) were related to a higher risk of viral hepatitis. Besides, alanine (p = 0.0076) and phenyllactate (p = 0.0100) were found to be negatively correlated with NAFLD, while stachydrine (Op = 0.0244) was found to be positively associated with NAFLD. The phenylacetate (p = 0.0353) and ursodeoxycholate (p = 0.0144) had a protective effect on ALD, while the threonate (p = 0.0370) exerted a detrimental influence on ALD. The IVW estimates of alanine (p = 0.0408) and cholate (p = 0.0293) showed their suggestive harmful effects against viral hepatitis, while threonate (p = 0.0401) displayed its suggestive protective effect against viral hepatitis.ConclusionIn conclusion, our research supported causal links between the gut microbiome and its metabolites and NAFLD, ALD, and viral hepatitis.

研究目的：目前存在一些证据表明肠道菌群与非酒精性脂肪性肝病（NAFLD）、酒精性肝病（ALD）以及病毒性肝炎之间存在关联，然而尚未有研究探讨其因果关系。研究方法：收集了肠道菌群（N = 13266）及其衍生代谢物（N = 7824）的仪器变量，并通过孟德尔随机化研究探讨其对NAFLD（1483例欧洲病例和17,781例欧洲对照）、ALD（2513例欧洲病例和332,951例欧洲对照）以及病毒性肝炎风险（1971例欧洲病例和340,528例欧洲对照）的影响。考察因果关系的最主要方法是逆方差加权法（IVW）。研究结果：逆方差加权法的结果证实，Anaerotruncus（p = 0.0249）、Intestinimonas（p = 0.0237）、Lachnoclostridium（p = 0.0245）、Lachnospiraceae NC2004菌群（p = 0.0083）、Olsenella（p = 0.0163）和Peptococcus（p = 0.0472）是NAFLD的保护因素，而Ruminococcus 1（p = 0.0120）对NAFLD有害。Lachnospira（p = 0.0388）、Desulfovibrio（p = 0.0252）和Ruminococcus torques菌群（p = 0.0364）的丰度较高与ALD风险降低相关，而Ruminococcaceae UCG 002水平与ALD风险增加相关（p = 0.0371）。Alistipes（p = 0.0069）和Ruminococcaceae NK4A214菌群（p = 0.0195）与病毒性肝炎风险增加相关。此外，丙氨酸（p = 0.0076）和苯乳酸（p = 0.0100）与NAFLD呈负相关性，而Stachydrine（Op = 0.0244）与NAFLD呈正相关性。苯乙酸（p = 0.0353）和熊去氧胆酸（p = 0.0144）对ALD具有保护作用，而苏氨酸（p = 0.0370）对ALD有不利影响。丙氨酸（p = 0.0408）和胆酸（p = 0.0293）的IVW估计显示出其对病毒肝炎的潜在有害作用，而苏氨酸（p = 0.0401）表现出其对病毒肝炎的潜在保护作用。研究结论：综上所述，本研究证实了肠道菌群及其代谢物与NAFLD、ALD和病毒性肝炎之间的因果关系。