Research Paper Volume 15, Issue 16 pp 8345—8366

Investigating causal associations among gut microbiota, gut microbiota-derived metabolites, and gestational diabetes mellitus: a bidirectional Mendelian randomization study

Xinrui Wu1,2, , Dihui Lin1, , Qi Li3, , Jiawang Cai1, , Houxiang Huang1, , Tianyu Xiang2, , Hongzhuan Tan2, ,

  • 1 School of Medicine, Jishou University, Jishou, China
  • 2 Xiangya School of Public Health, Central South University, Changsha, China
  • 3 Xiangxi Center for Disease Control and Prevention, Jishou, China

Received: May 17, 2023       Accepted: July 20, 2023       Published: August 23, 2023
How to Cite

Copyright: © 2023 Wu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Background: Previous studies have shown that gut microbiota (GM) and gut microbiota-derived metabolites are associated with gestational diabetes mellitus (GDM). However, the causal associations need to be treated with caution due to confounding factors and reverse causation.

Methods: This study obtained genetic variants from genome-wide association study including GM (N = 18,340), GM-derived metabolites (N = 7,824), and GDM (5,687 cases and 117,89 controls). To examine the causal association, several methods were utilized, including inverse variance weighted, maximum likelihood, weighted median, MR-Egger, and MR.RAPS. Additionally, reverse Mendelian Randomization (MR) analysis and multivariable MR were conducted to confirm the causal direction and account for potential confounders, respectively. Furthermore, sensitivity analyses were performed to identify any potential heterogeneity and horizontal pleiotropy.

Results: Greater abundance of Collinsella was detected to increase the risk of GDM. Our study also found suggestive associations among Coprobacter, Olsenella, Lachnoclostridium, Prevotella9, Ruminococcus2, Oscillibacte, and Methanobrevibacter with GDM. Besides, eight GM-derived metabolites were found to be causally associated with GDM. For the phenylalanine metabolism pathway, phenylacetic acid was found to be related to the risk of GDM.

Conclusions: The study first used the MR approach to explore the causal associations among GM, GM-derived metabolites, and GDM. Our findings may contribute to the prevention and treatment strategies for GDM by targeting GM and metabolites, and offer novel insights into the underlying mechanism of the disease.


GDM: Gestational diabetes mellitus; GM: Gut microbiota; MR: Mendelian randomization; IV: instrumental variable; RCT: randomized controlled trial; GWAS: genome-wide association study; IVW: inverse-variance weighted; MaxLik: maximum likelihood; WM: weighted median; MR.RAPS: Mendelian randomization robust adjusted profile score; MR-PRESSO: Mendelian randomization Pleiotropy RESidual Sum and Outlier; MVMR: multivariable Mendelian randomization; BMI: body mass index; OR: odds ratio; CI: confidence interval; PA: phenylacetic acid; PAGln: phenylacetylglutamine; TMAO: trimethylamine-N-oxide.