Gut microbiota impacts bone via B.vulgatus-valeric acid-related pathways

Although gut microbiota influences osteoporosis risk, the individual species involved, and underlying mechanisms, are unknown. We performed integrative analyses in a Chinese cohort with metagenomics/targeted metabolomics/whole-genome sequencing. Bacteroides vulgatus was found negatively associated with bone mineral density (BMD), this association was validated in US Caucasians. Serum valeric acid was positively associated with BMD, and B.vulgatus causally downregulated it. Ovariectomized mice fed B.vulgatus had decreased bone formation and increased bone resorption, lower BMD and poorer bone micro-structure. Valeric acid suppressed NF-κB p65 protein production (pro-inflammatory), and enhanced IL-10 mRNA expression (anti-inflammatory), leading to suppressed maturation of osteoclast-like cells, and enhanced maturation of osteoblasts in vitro. B.vulgatus and valeric acid represent promising targets for osteoporosis prevention/treatment. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement HW Deng and H Shen were partially supported by grants from the National Institutes of Health [U19AG05537301, R01AR069055, P20GM109036, R01MH104680, R01AG061917], and the Edward G. Schlieder Endowment and the Drs. W. C. Tsai and P. T. Kung Professorship from Tulane University. J Shen was partially supported by grants from the Science and Technology Program of Guangzhou, China [201604020007], and the National Natural Science Foundation of China [81770878]. HM Xiao was partially supported by the National Key R&D Program of China (2016YFC1201805 and 2017YFC1001100). ### Author Declarations All relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript. Yes All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The data that support the findings of this study are available from the corresponding author upon request and approval of the team and respective institutions.