Abstract:
BACKGROUND: Osteoporotic fracture is the most serious complication of osteoporosis. Previous studies have demonstrated that gut microbiota has a regulatory effect on skeletal tissue and that gut microbiota has an important relationship with osteoporotic fracture, but the causal relationship between the two is unclear.
OBJECTIVE: To explore the causal relationship between gut microbiota and osteoporotic fractures using Mendelian randomization method. 
METHODS: The genome-wide association study (GWAS) datasets of gut microbiota and osteoporotic fracture were obtained from the IEU Open GWAS database and the Finnish database R9, respectively. Using gut microbiota as the exposure factor and osteoporotic fracture as the outcome variable, Mendelian randomization analyses with random-effects inverse variance weighted, MR-Egger regression, weighted median, simple model, and weighted model methods were performed to assess whether there is a causal relationship between gut microbiota and osteoporotic fracture. Sensitivity analyses were performed to test the reliability and robustness of the results. Reverse Mendelian randomization analyses were performed to further validate the causal relationship identified in the forward Mendelian randomization analyses.
RESULTS AND CONCLUSION: The results of this Mendelian randomization analysis indicated a causal relationship between gut microbiota and osteoporotic fracture. Elevated abundance of Actinomycetales [odds ratio (OR)=1.562, 95% confidence interval (CI): 1.027-2.375, P=0.037), Actinomycetaceae (OR=1.561, 95% CI: 1.027-2.374, P=0.037), Actinomyces (OR =1.544, 95% CI: 1.130-2.110, P=0.006), Butyricicoccus (OR=1.781, 95% CI: 1.194-2.657, P=0.005), Coprococcus 2 (OR=1.550, 95% CI: 1.068-2.251, P=0.021), Family XIII UCG-001 (OR=1.473, 95% CI: 1.001-2.168, P=0.049), Methanobrevibacter (OR=1.274, 95% CI: 1.001-1.621, P=0.049), and Roseburia (OR=1.429, 95% CI: 1.015-2.013, P=0.041) would increase the risk of osteoporotic fractures in patients. Elevated abundance of Bacteroidia (OR=0.660, 95% CI: 0.455-0.959, P=0.029), Bacteroidales (OR=0.660, 95% CI: 0.455-0.959, P=0.029), Christensenellacea (OR=0.725, 95% CI: 0.529-0.995, P=0.047), Ruminococcaceae (OR=0.643, 95% CI: 0.443-0.933, P=0.020), Enterorhabdus (OR=0.558, 95% CI: 0.395-0.788, P=0.001), Eubacterium rectale group (OR=0.631, 95% CI: 0.435-0.916, P=0.016), Lachnospiraceae UCG008 (OR=0.738, 95% CI: 0.546-0.998, P=0.048), and Ruminiclostridium 9 (OR=0.492, 95% CI: 0.324-0.746, P=0.001) would reduce the risk of osteoporotic fractures in patients. We identified 16 gut microbiota associated with osteoporotic fracture by the Mendelian randomization method. That is, using gut microbiota as the exposure factor and osteoporotic fracture as the outcome variable, eight gut microbiota showed positive causal associations with osteoporotic fracture and another eight gut microbiota showed negative causal associations with osteoporotic fracture. The results of this study not only identify new biomarkers for the early prediction of osteoporotic fracture and potential therapeutic targets in clinical practice, but also provide an experimental basis and theoretical basis for the study of improving the occurrence and prognosis of osteoporotic fracture through gut microbiota in bone tissue engineering.

Key words: Mendelian randomization, gut microbiota, osteoporotic fractures, causality, genetics, genome-wide association study, single nucleotide polymorphism, instrumental variable, risk factor