Genetic support of the causal association between gut microbiome and COVID-19: a bidirectional Mendelian randomization study

Zengbin Li; Guixian Zhu; Xiangye Lei; Liqiong Tang; Guangyao Kong; Mingwang Shen; Lei Zhang; Lingqin Song

doi:10.3389/fimmu.2023.1217615

Genetic support of the causal association between gut microbiome and COVID-19: a bidirectional Mendelian randomization study

Front Immunol. 2023 Jul 7:14:1217615. doi: 10.3389/fimmu.2023.1217615. eCollection 2023.

Authors

Zengbin Li^{1

2}, Guixian Zhu¹, Xiangye Lei^{1

2}, Liqiong Tang¹, Guangyao Kong³, Mingwang Shen², Lei Zhang^{2

4

5}, Lingqin Song¹

Affiliations

¹ Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
² China-Australia Joint Research Center for Infectious Diseases, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, China.
³ National and Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
⁴ Melbourne Sexual Health Centre, Alfred Health, Melbourne, VIC, Australia.
⁵ Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia.

Abstract

Background: The association between gut microbiome and coronavirus disease 2019 (COVID-19) has attracted much attention, but its causality remains unclear and requires more direct evidence.

Methods: In this study, we conducted the bidirectional Mendelian randomization (MR) analysis to assess the causal association between gut microbiome and COVID-19 based on the summary statistics data of genome-wide association studies (GWASs). Over 1.8 million individuals with three COVID-19 phenotypes (severity, hospitalization and infection) were included. And 196 bacterial taxa from phylum to genus were analyzed. The inverse-variance weighted (IVW) analysis was chosen as the primary method. Besides, false discovery rate (FDR) correction of p-value was used. To test the robustness of the causal relationships with p-FDR < 0.05, sensitivity analyses including the secondary MR analyses, horizontal pleiotropy test, outliers test, and "leave-one-out" analysis were conducted.

Results: In the forward MR, we found that 3, 8, and 10 bacterial taxa had suggestive effects on COVID-19 severity, hospitalization and infection, respectively. The genus Alloprevotella [odds ratio (OR) = 1.67; 95% confidence interval (95% CI), 1.32-2.11; p = 1.69×10^-5, p-FDR = 2.01×10^-3] was causally associated with a higher COVID-19 severity risk. In the reverse MR, COVID-19 severity, hospitalization and infection had suggestive effects on the abundance of 4, 8 and 10 bacterial taxa, respectively. COVID-19 hospitalization causally increased the abundance of the phylum Bacteroidetes (OR = 1.13; 95% CI, 1.04-1.22; p = 3.02×10^-3; p-FDR = 2.72×10^-2). However, secondary MR analyses indicated that the result of COVID-19 hospitalization on the phylum Bacteroidetes required careful consideration.

Conclusion: Our study revealed the causal association between gut microbiome and COVID-19 and highlighted the role of "gut-lung axis" in the progression of COVID-19.

Keywords: COVID-19; Mendelian randomization; SARS-CoV-2; causality; gut microbiota; randomized controlled trial; rct.

Publication types

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

MeSH terms

Bacteroidetes
COVID-19*
Gastrointestinal Microbiome*
Genome-Wide Association Study
Humans
Mendelian Randomization Analysis

Grants and funding

LS was supported by the Free Exploration Research Project of the Second Affiliated Hospital of Xi’an Jiaotong University (Grant number: 2020YJ(ZYTS)282), Hospital Research Fund of the Second Affiliated Hospital of Xi’an Jiaotong University (Grant number: YJ(ZD)201706), and Wu Jieping Medical Foundation (320.6750.2021-16-32). LZ was supported by the Bill and Melinda Gates Foundation (INV-006104). The study design, data collection, analysis, interpretation, and decision to submit the article for publication were performed independently of the sponsors.