The Association between Gut Microbiota and Osteoporosis was Mediated by Amino Acid Metabolism: Multi-omics Integration in a Large Adult Cohort

Several small studies suggested gut microbiome might influence osteoporosis, but rare metabolomics evidence from human study had explained the link. This study examined the association of gut microbiome dysbiosis with osteoporosis and explored the potential pathways by using fecal and serum metabolomics. We analyzed gut microbiota compositions by 16S rRNA profiling and bone density (BMD) using a dual-energy X-ray absorptiometry in 1776 community-based adults. Targeted metabolomics in feces (15 categories) and serum (12 categories) were further analyzed in 971 participants with ultra-performance liquid chromatography coupled to tandem mass spectrometry. This study showed osteoporosis was related to gut microbiota beta diversity, taxonomy and functional composition. The relative abundance of Actinobacillus, Blautia, Oscillospira, Bacteroides and Phascolarctobacterium was positively, while Veillonellaceae other, Collinsella and Ruminococcaceae other were inversely, associated with the presence of osteoporosis, which related to higher levels of peptidases and transcription machinery in microbial function. Fecal and serum metabolomics analyses suggested that the tyrosine metabolism and the tryptophan metabolism in feces and the valine, leucine and isoleucine degradation in serum were significantly linked to the identified microbiota biomarkers and osteoporosis. This large population-based study provided the robust evidence connecting gut dysbiosis, fecal and serum metabolomics with osteoporosis. Our results suggested that gut dysbiosis and amino acid metabolism could be potential targets for the intervention of osteoporosis. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research was funded by the National Natural Science Foundation of China (No. 81773416 and 81273049); The Yili Nutrition Research fund of the Chinese Nutrition Society (No. CNS2014017B) ; and the 5010 Program for Clinical Researches by the Sun Yat-Sen University (No. 2007032). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The research was approved after necessary changes were made. 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 raw data of 16 S rRNA gene sequences are available at CNSA (https://db.cngb.org/cnsa/) of CNGBdb at accession number CNP0000829.