Effect of the gut microbiome, plasma metabolome, peripheral cells, and inflammatory cytokines on obesity: a bidirectional two-sample Mendelian randomization study and mediation analysis

Front Immunol. 2024 Mar 15:15:1348347. doi: 10.3389/fimmu.2024.1348347. eCollection 2024.


Background: Obesity is a metabolic and chronic inflammatory disease involving genetic and environmental factors. This study aimed to investigate the causal relationship among gut microbiota abundance, plasma metabolomics, peripheral cell (blood and immune cell) counts, inflammatory cytokines, and obesity.

Methods: Summary statistics of 191 gut microbiota traits (N = 18,340), 1,400 plasma metabolite traits (N = 8,299), 128 peripheral cell counts (blood cells, N = 408,112; immune cells, N = 3,757), 41 inflammatory cytokine traits (N = 8,293), and 6 obesity traits were obtained from publicly available genome-wide association studies. Two-sample Mendelian randomization (MR) analysis was applied to infer the causal links using inverse variance-weighted, maximum likelihood, MR-Egger, weighted median, weighted mode, and Wald ratio methods. Several sensitivity analyses were also utilized to ensure reliable MR results. Finally, we used mediation analysis to identify the pathway from gut microbiota to obesity mediated by plasma metabolites, peripheral cells, and inflammatory cytokines.

Results: MR revealed a causal effect of 44 gut microbiota taxa, 281 plasma metabolites, 27 peripheral cells, and 8 inflammatory cytokines on obesity. Among them, five shared causal gut microbiota taxa belonged to the phylum Actinobacteria, order Bifidobacteriales, family Bifidobacteriaceae, genus Lachnospiraceae UCG008, and species Eubacterium nodatum group. Furthermore, we screened 42 shared causal metabolites, 7 shared causal peripheral cells, and 1 shared causal inflammatory cytokine. Based on known causal metabolites, we observed that the metabolic pathways of D-arginine, D-ornithine, linoleic acid, and glycerophospholipid metabolism were closely related to obesity. Finally, mediation analysis revealed 20 mediation relationships, including the causal pathway from gut microbiota to obesity, mediated by 17 metabolites, 2 peripheral cells, and 1 inflammatory cytokine. Sensitivity analysis represented no heterogeneity or pleiotropy in this study.

Conclusion: Our findings support a causal relationship among gut microbiota, plasma metabolites, peripheral cells, inflammatory cytokines, and obesity. These biomarkers provide new insights into the mechanisms underlying obesity and contribute to its prevention, diagnosis, and treatment.

Keywords: Mendelian randomization; gut microbiota; inflammatory cytokines; mediation analysis; obesity; peripheral cells; plasma metabolites.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actinobacteria*
  • Cytokines
  • Gastrointestinal Microbiome*
  • Genome-Wide Association Study
  • Mediation Analysis
  • Mendelian Randomization Analysis
  • Metabolome


  • Cytokines

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This study was funded by the National Key R&D Program of China (2020YFA0804000) and the Tou-Yan Innovation Team Program of Heilongjiang Province (2019–15).