Dissecting the causal effect between gut microbiota, DHA, and urate metabolism: A large-scale bidirectional Mendelian randomization

Tianzhichao Hou; Huajie Dai; Qi Wang; Yanan Hou; Xiaoyun Zhang; Hong Lin; Shuangyuan Wang; Mian Li; Zhiyun Zhao; Jieli Lu; Yu Xu; Yuhong Chen; Yanyun Gu; Jie Zheng; Tiange Wang; Weiqing Wang; Yufang Bi; Guang Ning; Min Xu

doi:10.3389/fimmu.2023.1148591

Dissecting the causal effect between gut microbiota, DHA, and urate metabolism: A large-scale bidirectional Mendelian randomization

Front Immunol. 2023 Mar 30:14:1148591. doi: 10.3389/fimmu.2023.1148591. eCollection 2023.

Authors

Tianzhichao Hou^{1

2}, Huajie Dai^{1

2}, Qi Wang^{1

2}, Yanan Hou^{1

2}, Xiaoyun Zhang^{1

2}, Hong Lin^{1

2}, Shuangyuan Wang^{1

2}, Mian Li^{1

2}, Zhiyun Zhao^{1

2}, Jieli Lu^{1

2}, Yu Xu^{1

2}, Yuhong Chen^{1

2}, Yanyun Gu^{1

2}, Jie Zheng^{1

2}, Tiange Wang^{1

2}, Weiqing Wang^{1

2}, Yufang Bi^{1

2}, Guang Ning^{1

2}, Min Xu^{1

2}

Affiliations

¹ Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Abstract

Objectives: Our aim was to investigate the interactive causal effects between gut microbiota and host urate metabolism and explore the underlying mechanism using genetic methods.

Methods: We extracted summary statistics from the abundance of 211 microbiota taxa from the MiBioGen (N =18,340), 205 microbiota metabolism pathways from the Dutch Microbiome Project (N =7738), gout from the Global Biobank Meta-analysis Initiative (N =1,448,128), urate from CKDGen (N =288,649), and replication datasets from the Global Urate Genetics Consortium (N gout =69,374; N urate =110,347). We used linkage disequilibrium score regression and bidirectional Mendelian randomization (MR) to detect genetic causality between microbiota and gout/urate. Mediation MR and colocalization were performed to investigate potential mediators in the association between microbiota and urate metabolism.

Results: Two taxa had a common causal effect on both gout and urate, whereas the Victivallaceae family was replicable. Six taxa were commonly affected by both gout and urate, whereas the Ruminococcus gnavus group genus was replicable. Genetic correlation supported significant results in MR. Two microbiota metabolic pathways were commonly affected by gout and urate. Mediation analysis indicated that the Bifidobacteriales order and Bifidobacteriaceae family had protective effects on urate mediated by increasing docosahexaenoic acid. These two bacteria shared a common causal variant rs182549 with both docosahexaenoic acid and urate, which was located within MCM6/LCT locus.

Conclusions: Gut microbiota and host urate metabolism had a bidirectional causal association, implicating the critical role of host-microbiota crosstalk in hyperuricemic patients. Changes in gut microbiota can not only ameliorate host urate metabolism but also become a foreboding indicator of urate metabolic diseases.

Keywords: docosahexaenoic acids; gout; gut microbiome; mediation; mendelian randomization; uric acid.

Publication types

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

MeSH terms

Docosahexaenoic Acids
Gastrointestinal Microbiome*
Gout* / genetics
Humans
Mendelian Randomization Analysis
Uric Acid

Substances

Docosahexaenoic Acids
Uric Acid

Grants and funding

This work was funded by the National Natural Science Foundation of China (81941017, 82270859, 81930021, 81970728, 91857205, and 82088102), the Shanghai Municipal Education Commission–Gaofeng Clinical Medicine Grant Support (20152508 Round 2), the Shanghai Shenkang Hospital Development Center (SHDC12019101, SHDC2020CR1001A, and SHDC2020CR3069B), the Shanghai Jiao Tong University School of Medicine (DLY201801), and the Ruijin Hospital (2018CR002). MX, ML, TW, YX, JL, YB, WW, and GN are members of innovative research teams of high-level local universities in Shanghai. The study sponsors were not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; and they did not impose any restrictions regarding the publication of the report.