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. 2025 Jul 26:18:4233-4241.
doi: 10.2147/JMDH.S524720. eCollection 2025.

The Gut Microbiota and the Nerve-Bone Axis: Insights from a Mendelian Randomization and Mediation Analysis

Xiuqi Qiao  1   2 , Yuan Lou  1   2 , Huan Chen  1   2 , Heng Zhang  2   3 , Jiaming Cao  1   2 , Xu Feng  2   4 , Lixin Guo  1   2 , Qi Pan  1   2
Affiliations

The Gut Microbiota and the Nerve-Bone Axis: Insights from a Mendelian Randomization and Mediation Analysis

Xiuqi Qiao et al. J Multidiscip Healthc. .

Abstract

Background: This study aims to explore the interconnections among gut microbiota, autonomic nervous system (ANS), and bone through the proposed gut-nerve-bone axis using Mendelian randomization (MR) mediation analysis.

Methods: Genetic variants associated with gut microbiota were extracted from the MiBioGen consortium. Summary statistics for bone mineral density (BMD) were derived from a UK Biobank genome-wide association study dataset. We used heart rate variability (HRV) to represent the activity of ANS in the MR analysis. Initially, we employed a two-sample MR approach to evaluate the causal impact of gut microbiota on BMD. Subsequently, we used an additional mediation analysis to assess the effect of HRV on these associations, and sensitivity analysis was used to ensure the reliability of our results.

Results: Coprococcus 2 (β=0.03, 95% confidence interval, CI: 0.00 to 0.05, P=0.02), Lachnospiraceae NC2004 (β=0.01, 95% CI: 0.00 to 0.03, P<0.05), and another 11 genetically predicted taxa exhibited correlations with BMD. Among three types of HRV, pvRSA/HF and RMSSD were both associated with gut microbiota and BMD. The effect of Lachnospiraceae NC2004 on BMD occurs through RMSSD with a mediated proportion of 40.0% (95% CI: 21.1 to 58.9%, P=0.03) of the total effect. Sensitivity analyses reinforced the validity of our interpretations.

Conclusion: In summary, the present research supports a genetic correlation among gut microbiota, ANS, and BMD, which reinforces the concept of a gut-nerve-bone axis. Notably, the interplay between gut microbiota and BMD may be mediated by ANS. Additional mechanistic and clinical investigations are required to corroborate our findings.

Keywords: Mendelian randomization; autonomic nervous system; bone mineral density; gut microbiota; heart rate variability.

Plain language summary

Autonomic nervous system (ANS) disorders are closely related to osteoporosis. But there is no evidence to approve its association. This manuscript is the first to assess the association between ANS and bone mineral density (BMD). Furthermore, it may be the first to explore causal links among gut-nerve-bone axis.

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Conflict of interest statement

The authors declare that they have no conflicts of interest for this work.

Figures

Figure 1
Figure 1
Overview of the study design. (A) The two-step MR framework. (B) The flowchart for implementing the two-step MR approach.
Figure 2
Figure 2
The effects of gut microbiota on BMD by two-sample Mendelian randomization.
Figure 3
Figure 3
Mediation effect of gut microbiota on BMD via HRV.
See this image and copyright information in PMC

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