A new genetic study reveals that some gut bacteria and blood chemicals aren’t just linked to short stature—they may be causing it, opening doors to microbiota-based interventions for childhood growth issues.
Study: Causal relationship between gut microbiota, metabolites, and short stature: a Mendelian randomization study. Image Credit: Tomsickova Tatyana / Shutterstock
In a recent study published in the journal Pediatric Research, researchers investigated the causal relationship between blood metabolites, gut microbiota, and the risk of short stature (SS).
SS is a common endocrine and metabolic disease in children, defined as a height below the third percentile or two standard deviations below the mean height of children of the same age, sex, and race under comparable growth conditions. In 2019, there were around 144 million children with stunted height globally. Various epigenetic, environmental, and genetic factors regulate SS. Around 60% of children with SS have unknown pathogenesis and unidentifiable etiology, viz., idiopathic SS (ISS).
One study suggested that the gut microbiota and metabolites contribute to human bone health. Further, another study reported shorter femur lengths in germ-free mice, and colonization by normal gut flora increased bone formation rate and femur length. This suggests that gut microbiota play a vital role in longitudinal bone growth. While studies have assessed associations between SS and gut microbiota, they are observational; thus, causal relationships cannot be inferred.
This is the first study to use Mendelian randomization to investigate causality between gut microbiota, blood metabolites, and SS.
About the Study
In the present study, researchers investigated the causal relationship between SS, blood metabolites, and gut microbiota, as well as how blood metabolites influence this relationship. They performed a two-step Mendelian randomization (MR) analysis using genome-wide association study (GWAS) summary data. GWAS summary data on SS, gut microbiota, and metabolomics were acquired from separate studies.
The GWAS data for short stature were obtained from the FinnGen R9 dataset, comprising 611 cases and 361,988 controls, with a mean age of approximately 8 years. Notably, the GWAS data were derived primarily from European populations, which may limit generalizability to other ethnic groups.
Instrumental variables were selected if the single-nucleotide polymorphism loci showed significant associations with the exposure. Inverse-variance weighting (IVW) was the primary MR method, while simple mode, weighted mode, weighted median, and MR Egger regression were complementary methods. MR-Egger intercept was used to assess horizontal pleiotropy. Heterogeneity was assessed using Cochran’s Q statistic. The causal relationship was deemed stable if the effect directions of the complementary methods were consistent with the findings of the IVW analysis.
Additionally, a two-step mediation analysis was conducted to investigate the mediation of blood metabolites in the association between SS and the gut microbiota.
Findings
The IVW analysis suggested seven causal relationships between gut microbiota and SS. After validation with complementary methods, six effect directions were in line with IVW results. Three genera (Alloprevotella, Prevotella9, and FamilyXIIIAD3011) were positively associated with the risk of SS, and three others (Parasutterella, Roseburia, and Clostridium sensu stricto 1) were negatively associated. The protective role of Parasutterella may relate to its involvement in testosterone and bile acid metabolism, as suggested in prior research.
In addition, the team performed a reverse MR analysis to examine whether SS has a causal effect on identified genera. This revealed no reverse causality between SS and these gut microbes. Furthermore, IVW results revealed six causal relationships between blood metabolites and SS, and after validation with complementary methods, five of the effect directions were concordant with the IVW results.
Three metabolites (caffeine, 4-hydroxyhippurate, and laurate) were negatively associated with SS risk, and two (cyclo (leu-pro) and 3-(4-hydroxyphenyl) lactate) were positively associated. The odds ratios (ORs) ranged from 0.08 to 16.12, demonstrating substantial variation in effect size.
While caffeine showed a protective effect here, the authors caution that animal studies have reported caffeine may inhibit bone growth, suggesting this finding warrants further investigation. There was no heterogeneity or pleiotropy. Furthermore, the mediation analysis revealed an indirect effect of Clostridium sensu stricto 1 on SS through 4-hydroxyhippurate, with a mediation effect proportion of 43.03%. This metabolite is linked to flavonoid metabolism, which depends on gut microbiota for processing.
The five metabolites identified span four major metabolic pathways: lipid, amino acid, peptide, and xenobiotic (compounds not naturally produced by the body, such as dietary or environmental chemicals).
Conclusions
The study examined causal relationships between blood metabolites, gut microbiota, and SS risk. The team identified Alloprevotella, FamilyXIIIAD3011, and Prevotella9 as risk factors for SS. Indeed, a previous study reported a higher abundance of Prevotella in children with ISS compared to healthy children, and this level returned to normal upon treatment with recombinant human growth hormone.
In contrast, Roseburia, Parasutterella, and Clostridium sensu stricto 1 were protective factors for SS. Five blood metabolites were causally related to SS. Specifically, 3-(4-hydroxyphenyl) lactate and cyclo(Leu-Pro) were associated with a higher risk of SS. In contrast, caffeine, laurate, and 4-hydroxyhippurate were associated with a lower SS risk. The mediation analysis revealed a novel mediating role of 4-hydroxyhippurate in the relationship between SS and Clostridium sensu stricto 1.
Taken together, the findings illustrate causal relationships between blood metabolites, gut microbiota, and SS and that 4-hydroxyhippurate mediates the effect of Clostridium sensu stricto 1 on SS. The effect directions of different methods were consistent, and there was no heterogeneity or reverse causality. However, the study’s reliance on genus-level microbiota data limits resolution, and species- or strain-specific effects remain unexplored. The lack of demographic subgroup analysis also limits insight into how these associations may differ across age, sex, or ancestry groups. Overall, future clinical diagnosis and treatment of SS should consider the regulation of gut microbiota.