Causal relationship between gut microbiota, metabolites, and short stature: a Mendelian randomization study.

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.