Identification of specific gut microbial strains that play a role in skeletal homeostasis

The mammalian gastrointestinal mucosa is a unique environment colonized by a highly complex mixture of microorganisms that coexist in symbiosis with the host. Researchers have linked disruptions in gut microbiota (GM) homeostasis to several pathological conditions. Using microcomputed tomographic, we found significant changes in the trabecular and cortical bone compartments related to the gut microbiome only. Here, we aimed to identify specific GM strains that effect bone mass and elucidate their mechanism of action. We compared the skeletal response of mice treated with antibiotics (AB) that target different strains of bacteria. In the femurs and vertebrae of mice receiving Vancomycin, an AB that targets Gram-positive bacteria, we found a significantly increased trabecular BV/TV. Skeletal responses induced by vancomycin and other types of AB suggested that specific strains of anaerobic Gram-positive bacteria stimulate bone resorption and induce bone loss. Further experiments investigated the contribution of inflammatory mechanisms (dendritic and T cells in the bone marrow, cytokine levels), endocrine changes (serotonin, primarily secreted by intestinal enterochromaffin cells) and bacteria-secreted metabolites in the gut-to-bone axis. Looking for specific strains that regulate bone density, we sequenced the bacteria from the feces of vancomycin-treated mice and identified a short list of 19 strains that may be associated with the skeletal response. Notably, we found that the metabolites secreted by a specific strain had a direct effect on osteoblasts leading to a significant decrease in the RANKL:OPG ratio. Further experiments are ongoing to validate the determinant role of specific strains in the regulation of bone homeostasis.