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  • Clinical Research Article
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Causal relationship between gut microbiota, metabolites, and short stature: a Mendelian randomization study

Abstract

Background

Previous evidence suggests close relationships between the gut microbiota and short stature, but the causal relationship between them remains unclear. Our study performed Mendelian randomization (MR) analysis to investigate the causal relationships between gut microbiota, blood metabolites, and short stature, and to identify the potential role of blood metabolites as mediators.

Methods

We extracted summary-level data for 119 genera gut microbiota, 309 blood metabolites, and short stature from published genome-wide association studies (GWASs). We applied two-sample MR to infer the causal links, and a two-step MR was employed to quantify the proportion of the effect of gut microbiota on short stature mediated by blood metabolites.

Results

Increased Prevotella9, Alloprevotella, FamilyXIIIAD3011group, 3-(4-hydroxyphenyl) lactate, and cyclo (leu-pro) were potentially associated with higher short stature risk while Parasutterella, Clostridium sensu stricto 1, Roseburia, caffeine, laurate (12:0), and 4-hydroxyhippurate were related to lower short stature risk. Mediation analysis indicated that 4-hydroxyhippurate levels acted as a mediator between Clostridium sensu stricto 1 and short stature, with an indirect effect proportion of 43.03%.

Conclusion

Our study demonstrates the causal relationships among gut microbiota, blood metabolites, and short stature, and computes the proportion of the effect mediated by blood metabolites, provides new insights for studying the gut-bone axis theory in short stature.

Impact

  • Our study used Mendelian randomization to demonstrate a causal relationship between gut microbiota, blood metabolites and short stature and identified a mediating role for metabolites.

  • Current studies on the relationship between gut microbiota and short stature are observational and cannot infer causality, our research provides new evidence for this problem.

  • This is the first Mendelian randomization study of gut microbiota, blood metabolites and short stature, providing new insights into the gut-skeletal axis theory of short stature.

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Fig. 1: Study workflow.

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Data availability

Publicly available datasets were analyzed in this study. Gut microbiota: https://mibiogen.gcc.rug.nl/. Metabolites: http://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/. Short Stature: https://r9.finngen.fi/. Further inquiries can be directed to the corresponding author.

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Acknowledgements

We thank all the MiBioGen consortium, Finngen, and Dr Shin SY for making the summary statistics publicly available and are grateful to all the investigators and participants who contributed to those studies. This work was supported by the Science and Technology Program of Liaoning Province (2023-BS-216).

Author information

Authors and Affiliations

Authors

Contributions

Z.Z. and H.S. contributed to the study design and the writing of the manuscript. P.Z. and F.C. contributed to the data collection, analysis, and the visualization. X.X. and T.Z. supervised the study and revised the manuscript. All authors reviewed the manuscript and approved the submitted version.

Corresponding authors

Correspondence to Xuwu Xiao or Tingting Zhao.

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Competing interests

The authors declare no competing interests.

Ethics approval

Review or approval by an ethics committee was not needed for this study. Each GWAS summary data involved in this study obtained ethical approval from their respective institutions, and all data are publicly available.

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Zheng, Z., Sun, H., Zhang, P. et al. Causal relationship between gut microbiota, metabolites, and short stature: a Mendelian randomization study. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-03985-3

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