Investigating causal associations among gut microbiota, metabolites, and liver diseases: a Mendelian randomization study

Lilong Zhang; Liuliu Zi; Tianrui Kuang; Kunpeng Wang; Zhendong Qiu; Zhongkai Wu; Li Liu; Rongqiang Liu; Peng Wang; Weixing Wang

doi:10.3389/fendo.2023.1159148

Investigating causal associations among gut microbiota, metabolites, and liver diseases: a Mendelian randomization study

Front Endocrinol (Lausanne). 2023 Jul 5:14:1159148. doi: 10.3389/fendo.2023.1159148. eCollection 2023.

Authors

Lilong Zhang^{1

2

3}, Liuliu Zi^{1

2

3}, Tianrui Kuang^{1

2

3}, Kunpeng Wang^{1

2

3}, Zhendong Qiu^{1

2

3}, Zhongkai Wu^{1

2

3}, Li Liu^{1

2

3}, Rongqiang Liu^{1

2

3}, Peng Wang^{1

2

3}, Weixing Wang^{1

2

3}

Affiliations

¹ Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
² Hubei Key Laboratory of Digestive System Disease, Wuhan, Hubei, China.
³ Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.

Abstract

Objective: There 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.

Methods: Instrumental 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).

Results: IVW 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.

Conclusion: In conclusion, our research supported causal links between the gut microbiome and its metabolites and NAFLD, ALD, and viral hepatitis.

Keywords: alcoholic liver disease; gut microbiota; gut microbiota-derived metabolites; mendelian randomization analysis; nonalcoholic fatty liver disease; viral hepatitis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alanine
Clostridiales
Gastrointestinal Microbiome*
Humans
Mendelian Randomization Analysis
Non-alcoholic Fatty Liver Disease* / etiology
Non-alcoholic Fatty Liver Disease* / genetics

Substances

threonic acid
Alanine

Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (No. 82172855, 81870442), and the Natural Science Foundation of Hubei Province, China (No. 2021CFB365).