Gut bacteria and blood metabolites directly affect children's height, study the study

Gut bacteria and blood metabolites directly affect children's height, study the study

A new genetic study shows that some gut bacteria and blood chemicals aren't just associated with short stature—they may cause it, opening the door to microbiota-based interventions for childhood growth problems.

In a study recently published in the journalChildren's researchResearchers examined the causal relationship between blood metabolites, gut microbiota and the risk of short stature (SS).

SS is a common endocrine and metabolic disorder in children, defined as 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 stunted children worldwide. Various epigenetic, environmental and genetic factors regulate SS. Around 60% of children with SS have an unknown pathogenesis and unidentifiable etiology, namely idiopathic SS (ISS).

A study suggested that the gut microbiota and metabolites contribute to human bone health. Furthermore, another study reported shorter femur lengths in germ-free mice and colonization by normal intestinal flora increased bone formation rate and femur length. This suggests that gut microbiota plays an important role in longitudinal bone growth. While studies have assessed associations between SS and gut microbiota, they are observational; Therefore, 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

Children with higher Prevotella9 levels showed reduced insulin-like growth factor-1 (IGF-1) activity, a key hormone for bone development, suggesting a direct microbiome growth axis.

In the present study, researchers examined the causal relationship between SS, blood metabolites, and gut microbiota, as well as how blood metabolites influence this relationship. They performed a two-stage MENDELIAN randomization (MR) analysis using the Genome-Wide Association Study (GWAS) summary rates. GWAS summary data on SS, gut microbiota and metabolomics were collected from separate studies.

The short stature GWAS data were obtained from the Finngen R9 dataset containing 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 individual nucleotide polymorphism loci showed significant associations with exposure. Inverse variance weighting (IVW) was the primary MR method, while simple mode, weighted mode, weighted median, and MR Egger regression were complementary methods. The MR Egger intercept was used to assess horizontal pleiotropy. Heterogeneity was assessed using Cochran's Q statistic. The causal relationship was considered stable if the effect directions of the complementary methods agreed with the results of the IVW analysis.

Additionally, a two-stage mediation analysis was performed to examine the mediation of blood metabolites in the association between SS and gut microbiota.

Results

The intestinal genus Roseburia produces butyrate, a fatty acid previously linked to bone density in mice, but its role in human height remained unexplored until this study.

The IVW analysis proposed seven causal relationships between gut microbiota and SS. After validation with complementary methods, six effect directions were consistent with the IVW results. Three genera (Alloprevotella, Prevotella9 and familyxiiiad3011) were positively associated with the risk of SS and three others (Parautterella, Roseburia andClostridium sensu stricto 1) were negatively associated. The protective role of Parautterella may relate to its involvement in testosterone and bile acid metabolism, as suggested in previous research.

In addition, the team conducted a reverse MR analysis to examine whether SS has a causal influence on the identified genera. This did not reveal reverse causality between SS and these gut microbes. In addition, IVW results showed six causal relationships between blood metabolites and SS, and after validation with complementary methods, five of the effect directions were consistent 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, showing substantial variation in effect size.

While caffeine showed a protective effect here, the authors caution that animal studies have reported that caffeine may inhibit bone growth, suggesting that this finding requires further study. There was no heterogeneity or pleiotropy. In addition, the mediation analysis revealed an indirect effect ofClostridium sensu stricto 1on SS by 4-HydroxyhipPurate with a placement ratio of 43.03%. This metabolite is associated with flavonoid metabolism, which depends on the gut microbiota for processing.

The five metabolites identified four major metabolic pathways: lipid, amino acid, peptide, and xenobiotic (compounds not naturally produced by the body, such as dietary or environmental chemicals).

Conclusions

No association was found between vitamin D metabolites and short stature, contradicting hypotheses that micronutrient deficiencies dominate risks.

The study examined the causal relationships between blood metabolites, gut microbiota and SS risk. The team identified Alloprevotella, familyxiiiad3011 and prevotella9 as risk factors for SS. In a previous study, a previous study reported a higher frequency of prevotella in children with ISS compared to healthy children, and this level returned to normal with treatment with recombinant human growth hormone.

In contrast, Roseburiae, Parautterella andClostridium sensu stricto 1were protective factors for SS. Five blood metabolites were causally related to SS. In particular, 3-(4-hydroxyphenyl)-lactate and cyclo(Leu-pro) were associated with a higher risk of SS. In contrast, caffeine, laurates, and 4-HydroxyhipPurate were associated with a lower risk of SS. Mediation analysis revealed a novel mediating role of 4-hydroxyhippurate in the relationship between SS andClostridium sensu stricto 1.

Taken together, the results illustrate the causal relationships between blood metabolites, gut microbiota and SS and that 4-HydroxyhipPurate mediates the effects ofClostridium sensu stricto 1on 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 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 vary by age, gender, or ancestry. Overall, future clinical diagnosis and treatment of SS should consider the regulation of gut microbiota.

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