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 Pan1,2 

1Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 2Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 3Department of Health Service, Guard Bureau of the General Office of the Central Committee of the Communist Party of China, Beijing, People’s Republic of China; 4Department of General Practitioner, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China

Correspondence: Lixin Guo, Email glx1218@163.com Qi Pan, Email panqi621@126.com

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.
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.

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