In a recent study published in the npj Biofilms Microbiomes, researchers investigated the association between gut microbiota (GM) composition and incident fractures in the Finnish Risk Monitoring Program (FINRISK) 2002 cohort.
Study: Associations between gut microbiota and incident fractures in the FINRISK cohort. Image Credit: Emily frost/Shutterstock.com
Background
Fragility fractures, often caused by osteoporosis (a disease causing fragile bones prone to fractures), affect one in two women and one in four men, with low bone mineral density (BMD) being the primary risk factor.
Beyond BMD, fracture risk is influenced by bone quality and non-skeletal factors like neuromuscular control. GM plays a role in regulating bone mass, but previous studies on GM and bone health have shown inconsistent results due to small sample sizes and cross-sectional designs.
Further research is needed to clarify previous studies' inconsistent results and explore the potential association between GM composition and fracture risk in a large, prospective cohort.
About the study
In the present study, researchers used data from the FINRISK 2002 cohort, targeting Finnish residents aged 25 to 74 who lived in one of six regions: North Karelia, Oulu, Lapland, Northern Savo, Turku and Loimaa, or Helsinki and Vantaa.
Participants were randomly selected based on gender and age group through the National Population Information System, and 13,498 individuals were invited, with 8,783 participating. Among them, 7,231 provided fecal samples, and 7,102 had sufficient phenotype data for analysis.
After excluding participants with low-read counts and those who were pregnant at baseline, 7,043 individuals were included in the final analysis.
Baseline visits occurred over three months in early 2002, and all participants provided written informed consent in accordance with ethical regulations approved by the Helsinki University Hospital District's Coordinating Ethics Committee.
Participants completed questionnaires on physical activity, smoking status, alcohol and dietary intake, and hormone replacement therapy use. Medication use was tracked, particularly those affecting the GM and high-sensitive C-reactive protein.
(CRP) was measured in serum samples. Fracture data were collected from Finnish health records, focusing on incident fractures, with adjustments made for previous fractures. Major diseases, including inflammatory bowel disease, cardiovascular disease, cancer, and diabetes, were identified using various national registers.
Fecal samples were collected, stored, and later sequenced for microbiome analysis, with taxonomic and functional profiling performed using advanced bioinformatics tools.
Statistical analyses, including Cox regression, assessed the associations between gut microbiota composition and fracture risk, adjusting for various covariates. Missing data were not imputed, and multiple models were used to account for different variables, with conservative corrections for multiple testing.
Study results
The study focused on alpha and beta diversity measures to evaluate overall GM composition. The main model, adjusted for age, medications, gender, antibiotics, and previous fractures, revealed that higher alpha diversity, measured by the Shannon index, was associated with a decreased risk of fractures (HR 0.92 per standard deviation increase, 95% CI 0.87–0.96, P = 0.006).
Similarly, beta diversity, assessed through the first principal component of the Aitchison distance, was linked to fracture risk (HR 0.90, 95% CI 0.85–0.96, P = 0.0007). These results suggest a significant association between overall GM composition and incident fracture risk.
Further analysis identified the Tenericutes phylum, particularly the Mollicutes class, as being associated with decreased fracture risk. Specific orders within Mollicutes, such as Mycoplasmatales, Acholeplasmatales, and Entomoplasmatales, were significant contributors to this association.
Exploratory analyses of the most abundant genera and species pointed to Parabacteroides, Lachnoclostridium, and species like Oscillibacter sp. ER4 and Parabacteroides distasonis as being related to fracture risk.
Sensitivity analyses, excluding individuals with conditions or treatments that could confound results, supported these findings, though caution was advised in interpreting the association with Oscillibacter sp. ER4 due to unmet proportional hazard assumptions.
Gender-stratified analyses indicated that the Shannon index was associated with fractures in women but not in men, though no statistically significant interaction between gender and the Shannon index was observed.
The associations between Proteobacteria, Tenericutes, and beta diversity with fracture risk were significant in women but showed similar trends in men despite the smaller male sub-cohort.
Sub-analyses focused on major osteoporotic fractures (MOF) and hip fractures revealed that Proteobacteria was associated with an increased risk. At the same time, Tenericutes was linked to a decreased risk, consistent with findings for fractures at any bone site.
Additionally, GM composition was associated with the inflammatory marker CRP, with Proteobacteria linked to increased CRP levels and Tenericutes and Shannon index to decreased levels. These associations between GM composition and fracture risk were not significantly altered when adjusted for CRP levels.
Functional profiling identified 785 functional groups associated with fracture risk, mostly linked to decreased risk and often related to amino acid metabolism.
Notably, functional groups associated with the relative abundance of Proteobacteria and Tenericutes were strongly correlated with fracture risk, suggesting their potential involvement in the observed associations between GM composition and fracture risk.
For instance, functional groups related to branched-chain amino acid synthesis were negatively correlated with Proteobacteria. At the same time, Tenericutes showed positive correlations with butyrate metabolism pathways, highlighting possible mechanisms underlying these associations.
Conclusions
To summarize, higher alpha diversity correlated with a lower fracture risk, while the relative abundance of Proteobacteria, particularly Gammaproteobacteria, was linked to an increased risk. Conversely, Tenericutes abundance was associated with reduced fracture risk. Functional analyses identified pathways related to bone health that may mediate these effects.
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