The role of the gut microbiota and frailty on bone metabolism, and the risk of injurious falls and fractures

Abstract

Aging is intrinsically linked to musculoskeletal decline, culminating in increased risk of frailty, falls, fractures, and associated morbidity and mortality. This thesis investigates the association between gut microbiota composition, physical function, and skeletal integrity in older adults, with the aim of identifying novel predictors and preventive strategies for fracture risk. Utilizing both observational and interventional approaches, this work combines four distinct studies to examine: the predictive value of functional mobility assessments for fracture risk; the efficacy of the probiotic Limosilactobacillus reuteri ATCC PTA 6475 (L. reuteri 6475) in mitigating bone loss in early postmenopausal women and in healthy adults undergoing glucocorticoid therapy; and the associations between gut microbiota composition and frailty outcomes in elderly women. In Paper I, a prospective analysis from the SUPERB cohort demonstrated that one-leg standing (OLS) and walking speed are independent and robust predictors of fracture risk in older women, outperforming traditional metrics such as bone mineral density (BMD). Paper II, a two-year randomized clinical trial, evaluated L. reuteri 6475 supplementation in early postmenopausal women found no significant effect on bone loss prevention, although subgroup analyses suggested BMI-dependent responses. Paper III assessed the potential of L. reuteri 6475 to mitigate glucocorticoid-induced bone turnover suppression in healthy adults but found no protective effect on bone or glucose metabolism. Manuscript IV employed metagenomic sequencing in the SUPERB cohort and identified distinct gut microbial signatures associated with frailty, reduced physical performance, increased risk of injurious falls, and mortality. Importantly, a newly developed Frailty-Mortality Index (FMI) showed strong associations with microbial diversity, suggesting its utility as a composite predictor of musculoskeletal aging. Collectively, this thesis underscores the multifaceted contributions of gut microbiota and frailty to skeletal decline and fracture risk in aging populations. While L. reuteri 6475 did not significantly prevent bone loss in two interventional settings, microbial profiling revealed novel taxa linked to frailty and falls, highlighting opportunities for future development of targeted, next-generation probiotics. These findings advocate for a personalized, preventive approach to bone health, integrating physical function assessments and microbiota-based diagnostics to refine fracture risk prediction and inform novel therapeutic strategies for healthy aging.