The Microbiome and Bone Strength

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7. PROJECT SUMMARY The microbiome has been associated with disease processes throughout the body and is therefore an intriguing target for therapeutics and diagnostics. Multiple preclinical studies have shown that the microbiome can influence bone. Our prior work has indicated that modifications to the microbiome during bone acquisition can influence bone strength by modifying bone tissue quality. “Bone quality” describes aspects of bone that are not well represented by measures of bone mineral density (BMD). Our findings raise the intriguing possibility that microbiome-based therapies may be able to improve bone tissue quality – a contributor to bone strength that is not directly targeted by existing therapies. In the proposed work we ask: What microbial taxa within the gut microbiota are responsible for changes in bone strength and tissue quality? What is the pathway linking the gut microbiota to bone strength and tissue quality? and; How does the influence of the microbiome on bone strength vary based on age and the stage of skeletal maturity (growing v. skeletally mature)? The proposed work is based on our PRELIMINARY STUDIES in which we associated microbiome-induced impairment of bone strength with large changes in the microbial taxonomic and genetic composition as well as impaired production of vitamin K by the gut microbiota and reduced abundance of matrix bound osteocalcin (a vitamin K dependent protein). The proposed work has three aims: 1) Determine the components of the gut microbiota that lead to impaired bone strength and quality; 2) Determine the dependence of microbiome-induced reductions in bone tissue quality on microbiome-derived vitamin K.; and 3) Determine the modifications in bone matrix caused by changes in the microbiome in an adult skeleton as compared to the growing skeleton. The proposed work includes manipulation of the gut microbiota through transfer of gut flora among animals using gnotobiotic chambers and depletion of microbes (“knock out”) from the gut microbiota using narrow spectrum antibiotics. Taxonomic and functional characterization of the gut microbiota and examination of the resulting bone biomechanical, chemical and geometrical phenotypes is performed at the whole organ, micro- and nanoscale. By establishing a mechanistic relationship between the microbiome and bone strength in both the growing and adult skeleton, the proposed work will perform the necessary first steps toward the identification of microbiome therapeutics that modulate bone tissue quality to reduce bone fragility.