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. 2024 Dec 16:15:1447877.
doi: 10.3389/fmicb.2024.1447877. eCollection 2024.

Exploring the causal relationship of gut microbiota in nonunion: a Mendelian randomization analysis mediated by immune cell

Yun-Fei Yu  1 , Hai-Feng Gong  2 , Wei-Ju Li  3 , Mao Wu  1 , Gang Hu  1
Affiliations

Exploring the causal relationship of gut microbiota in nonunion: a Mendelian randomization analysis mediated by immune cell

Yun-Fei Yu et al. Front Microbiol. .

Abstract

Background: Emerging research indicates that gut microbiota (GM) are pivotal in the regulation of immune-mediated bone diseases. Nonunion, a bone metabolic disorder, has an unclear causal relationship with GM and immune cells. This study aims to elucidate the causal relationship between GM and nonunion using Mendelian Randomization (MR) and to explore the mediating role of immune cells.

Methods: Using a two-step, two-sample Mendelian randomization approach, this study explores the causal link between GM and nonunion, as well as the mediating role of immune cells in this relationship. Data were sourced from multiple cohorts and consortiums, including the MiBioGen consortium. GM data were derived from a recently published dataset of 473 gut microbiota, and nonunion data were obtained from genome-wide association studies (GWAS).

Results: MR analysis identified 12 bacterial genera with protective effects against nonunion and seven bacterial genera associated with a higher risk of nonunion, including Agathobacter sp000434275, Aureimonas, Clostridium M, Lachnospirales, Megamonas funiformis, and Peptoccia. Reverse MR analysis indicated that nonunion does not influence GM. Additionally, MR analysis identified 12 immune cell types positively associated with nonunion and 14 immune cell types negatively associated with nonunion. Building on these findings, we conducted mediation MR analysis to identify 24 crucial GM and immune cell-mediated relationships affecting nonunion. Notably, Campylobacter D, Megamonas funiformis, Agathobacter sp000434275, Lachnospirales, Clostridium E sporosphaeroides, and Clostridium M significantly regulated nonunion through multiple immune cell characteristics.

Conclusions: To our knowledge, our research results are the first to emphasize a causal relationship between the gut microbiome and nonunion, potentially mediated by immune cells. The correlations and mediation effects identified in our study provide valuable insights into potential therapeutic strategies targeting the gut microbiome, informing global action plans.

Keywords: Mendelian randomization; gut microbiota; immune cell; instrumental variable; nonunion.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Three significant assumptions of gut microbiota on nonunion via MR.
Figure 2
Figure 2
Flow chart. Outlines the methodology used to investigate the link between gut microbiota and nonuion via GWAS data. SNP selection criteria were applied before harmonization for MR analysis to determine the causal relationships and identify significant GM. Mediation analysis further quantified the potential influence of immune cell traits on the microbiota-nonunion association.
Figure 3
Figure 3
Volcano plot of correlations related to the influence of GM on nonunion. This plot includes both odds ratios (ORs) in log 2 scale and P-values in –log 10 estimated by the inverse variance weighted method for GWAS.
Figure 4
Figure 4
Forest plot of the causal effects of gut microbiota on the risk of nonunion derived from the IVW method. OR, odds ratio; CI, confidence interval.
Figure 5
Figure 5
Leave-one-out plot to visualize the causal effect of each GM associated with nonunion when leaving one SNP out. (A) Aureimonas. (B) Lachnospirales. (C) Rhodococcus. (D) UBA1611. (E) UBA1777 sp900319835. (F) Campylobacter D.
Figure 6
Figure 6
Volcano plot of correlations related to the influence of immune cell on nonunion. This plot includes both odds ratios (ORs) in log2 scale and P-values in –log10 estimated by the inverse variance weighted method for GWAS.
Figure 7
Figure 7
Forest plot of the causal effects of immune cell on the risk of nonunion derived from the IVW method. OR, odds ratio; CI, confidence interval.
Figure 8
Figure 8
Leave-one-out plot to visualize the causal effect of each immune cell associated with nonunion when leaving one SNP out. (A) CD86+ plasmacytoid DC AC. (B) CD28- CD8br %CD8br.
Figure 9
Figure 9
Mendelian randomization analysis between GM and Mediator.
Figure 10
Figure 10
Mediation analysis of immune cell trait between GM and nonunion.
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