HeMAFA · Healthy Microbiota Avoiding Fractures during Ageing

The basic research problem: Gradual loss of bone and muscle mass with ageing leads to increased risk of fractures in the elderly population. There is a large medical need for new fracture preventive therapies with minimal side effects and novel biomarkers that improve the prediction of fracture risk. The aim of the proposed research is to test our hypothesis that the increased fracture risk in elderly people is caused by an age-dependent unhealthy change of the gut microbiota (GM) composition, resulting in reduced bone and muscle mass, and thereby increased fracture risk. Methodology: We will identify age-dependent GM signatures that are causally associated with reduced bone and muscle mass and thereby increased fracture risk in elderly subjects. A major emphasis will be to determine causality of the GM using a variety of recently developed GM-related genetic instruments (for GM composition and function as well as for circulating metabolites) as exposures in 2-sample Mendelian randomization (MR). In addition, we will use faecal microbiota transplantation (FMT) to directly determine causality of age-dependent GM alterations for reductions in bone and muscle mass. Based on this information, we will design candidate probiotic treatments and test their efficacy in mouse osteoporosis models. Finally, we will determine the clinical usefulness of the identified GM signatures for fracture prediction in elderly subjects.Research progress beyond the state of the art: We will employ three complementary methods, 2-sample MR, FMT, and treatment studies, to determine causality for GM on musculoskeletal parameters. For this research, we have established large well-characterized Nordic cohorts with metagenome sequence data and information on incident fractures available in 2023. Identification of a GM-signature with a robust effect on age-related bone and muscle loss will open-up completely new avenues to avoid fractures in elderly.