{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T16:25:40Z","timestamp":1788020740806,"version":"build-2784847793"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T00:00:00Z","timestamp":1692230400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Recent observational studies and clinical trials demonstrated an association between gut microbiota and musculoskeletal (MSK) diseases. Nonetheless, whether the gut microbiota composition has a causal effect on the risk of MSK diseases remains unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Based on large-scale genome-wide association studies (GWAS), we performed a two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between gut microbiota and six MSK diseases, namely osteoporosis (OP), fracture, sarcopenia, low back pain (LBP), rheumatoid arthritis (RA), and ankylosing spondylitis (AS). Instrumental variables for 211 gut microbiota taxa were obtained from the largest available GWAS meta-analysis (<jats:italic>n<\/jats:italic>\u2009=\u200918,340) conducted by the MiBioGen consortium. And the summary-level data for six MSK diseases were derived from published GWAS. The inverse-variance weighted (IVW) method was conducted as a primary analysis to estimate the causal effect, and the robustness of the results was tested via sensitivity analyses using multiple methods. The Bonferroni-corrected test was used to determine the strength of the causal relationship between gut microbiota and various MSK diseases. Finally, a reverse MR analysis was applied to evaluate reverse causality.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>According to the IVW method, we found 57 suggestive causal relationships and 3 significant causal relationships between gut microbiota and MSK diseases. Among them, <jats:italic>Genus Bifidobacterium<\/jats:italic> (\u03b2: 0.035, 95% CI: 0.013\u20130.058, <jats:italic>p<\/jats:italic>\u2009=\u20090.0002) was associated with increased left handgrip strength, <jats:italic>Genus Oxalobacter<\/jats:italic> (OR: 1.151, 95% CI: 1.065\u20131.245, <jats:italic>p<\/jats:italic>\u2009=\u20090.0003) was correlated with an increased risk of LBP, and <jats:italic>Family Oxalobacteraceae<\/jats:italic> (OR: 0.792, 95% CI: 0.698\u20130.899, <jats:italic>p<\/jats:italic>\u2009=\u20090.0003) was linked with a decreased risk of RA. Subsequently, sensitivity analyses revealed no heterogeneity, directional pleiotropy, or outliers for the causal effect of specific gut microbiota on MSK diseases (<jats:italic>p<\/jats:italic>\u2009&amp;gt;\u20090.05). Reverse MR analysis showed fracture may result in a higher abundance of <jats:italic>Family Bacteroidales<\/jats:italic> (<jats:italic>p<\/jats:italic>\u2009=\u20090.030) and sarcopenia may lead to a higher abundance of <jats:italic>Genus Sellimonas<\/jats:italic> (<jats:italic>p<\/jats:italic>\u2009=\u20090.032).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Genetic evidence suggested a causal relationship between specific bacteria taxa and six MSK diseases, which highlights the association of the \u201cgut-bone\/muscle\u201d axis. Further exploration of the potential microbiota-related mechanisms of bone and muscle metabolism might provide novel insights into the prevention and treatment of MSK diseases.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmicb.2023.1238800","type":"journal-article","created":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T23:27:09Z","timestamp":1692314829000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":21,"title":["Causal effects of specific gut microbiota on musculoskeletal diseases: a bidirectional two-sample Mendelian randomization study"],"prefix":"10.3389","volume":"14","author":[{"given":"Shuai","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huawei","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohe","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guowei","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiwei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,8,17]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1642","DOI":"10.1002\/art.40917","article-title":"HLA alleles associated with risk of ankylosing spondylitis and rheumatoid arthritis influence the Gut microbiome","volume":"71","author":"Asquith","year":"2019","journal-title":"Arthritis Rheumatol."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1016\/j.berh.2015.08.002","article-title":"Economic impact of musculoskeletal disorders (MSDs) on work in Europe","volume":"29","author":"Bevan","year":"2015","journal-title":"Best Pract. Res. Clin. Rheumatol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"100946","DOI":"10.1016\/j.arr.2019.100946","article-title":"Gut microbiota and osteoarthritis management: an expert consensus of the European society for clinical and economic aspects of osteoporosis, osteoarthritis and musculoskeletal diseases (ESCEO)","volume":"55","author":"Biver","year":"2019","journal-title":"Ageing Res. Rev."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1093\/ije\/dyv080","article-title":"Mendelian randomization with invalid instruments: effect estimation and bias detection through egger regression","volume":"44","author":"Bowden","year":"2015","journal-title":"Int. J. Epidemiol."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1002\/gepi.21965","article-title":"Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator","volume":"40","author":"Bowden","year":"2016","journal-title":"Genet. Epidemiol."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"17","DOI":"10.3390\/ijms17060932","article-title":"Effect of a prebiotic formulation on frailty syndrome: a randomized, double-blind clinical trial","volume":"17","author":"Buigues","year":"2016","journal-title":"Int. J. Mol. Sci."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"e13105","DOI":"10.1111\/acel.13105","article-title":"Physical fitness in community-dwelling older adults is linked to dietary intake, gut microbiota, and metabolomic signatures","volume":"19","author":"Castro-Mejia","year":"2020","journal-title":"Aging Cell"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1038\/ng.2667","article-title":"Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci","volume":"45","author":"Cortes","year":"2013","journal-title":"Nat. Genet."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"e54421","DOI":"10.1128\/AEM.00544-21","article-title":"Forty years of Oxalobacter formigenes, a gutsy oxalate-degrading specialist","volume":"87","author":"Daniel","year":"2021","journal-title":"Appl. Environ. Microbiol."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"R89","DOI":"10.1093\/hmg\/ddu328","article-title":"Mendelian randomization: genetic anchors for causal inference in epidemiological studies","volume":"23","author":"Davey","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"2078","DOI":"10.1136\/gutjnl-2018-316639","article-title":"Beyond Oxalobacter: the gut microbiota and kidney stone formation","volume":"67","author":"Falony","year":"2018","journal-title":"Gut"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"1189","DOI":"10.1002\/art.41644","article-title":"Inflammasome activation in ankylosing spondylitis is associated with Gut Dysbiosis","volume":"73","author":"Guggino","year":"2021","journal-title":"Arthritis Rheumatol."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"12","DOI":"10.3390\/nu12041145","article-title":"Exercise training combined with Bifidobacterium longum OLP-01 supplementation improves exercise physiological adaption and performance","volume":"12","author":"Huang","year":"2020","journal-title":"Nutrients"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"1747","DOI":"10.2337\/db19-0153","article-title":"Assessment of causal direction between Gut Microbiota-dependent metabolites and Cardiometabolic health: a bidirectional Mendelian randomization analysis","volume":"68","author":"Jia","year":"2019","journal-title":"Diabetes"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1038\/s41588-020-00763-1","article-title":"Large-scale association analyses identify host factors influencing human gut microbiome composition","volume":"53","author":"Kurilshikov","year":"2021","journal-title":"Nat. Genet."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"1059281","DOI":"10.3389\/fmicb.2022.1059281","article-title":"Causal associations between gut microbiota and adverse pregnancy outcomes: a two-sample Mendelian randomization study","volume":"13","author":"Li","year":"2022","journal-title":"Front. Microbiol."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"6665563","DOI":"10.1155\/2021\/6665563","article-title":"The Gut Microbiota and its relevance to peripheral lymphocyte subpopulations and cytokines in patients with rheumatoid arthritis","volume":"2021","author":"Li","year":"2021","journal-title":"J Immunol Res"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1186\/s40168-017-0316-0","article-title":"Oxalobacter formigenes-associated host features and microbial community structures examined using the American Gut project","volume":"5","author":"Liu","year":"2017","journal-title":"Microbiome"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"e927","DOI":"10.1002\/mbo3.927","article-title":"Anti-TNF-alpha therapy alters the gut microbiota in proteoglycan-induced ankylosing spondylitis in mice","volume":"8","author":"Liu","year":"2019","journal-title":"Microbiology"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"3686748","DOI":"10.1155\/2020\/3686749","article-title":"The interplay between immune system and Microbiota in osteoporosis","volume":"2020","author":"Locantore","year":"2020","journal-title":"Mediat. Inflamm."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1016\/j.berh.2014.08.002","article-title":"Burden of disability due to musculoskeletal (MSK) disorders","volume":"28","author":"March","year":"2014","journal-title":"Best Pract. Res. Clin. Rheumatol."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"1145","DOI":"10.1007\/s12602-018-9443-6","article-title":"Supportive role of probiotic strains in protecting rats from Ovariectomy-induced cortical bone loss","volume":"11","author":"Montazeri-Najafabady","year":"2019","journal-title":"Probiotics Antimicrob. Proteins"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1038\/s41588-018-0302-x","article-title":"An atlas of genetic influences on osteoporosis in humans and mice","volume":"51","author":"Morris","year":"2019","journal-title":"Nat. Genet."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1099\/mgen.0.000476","article-title":"Comprehensive genome analyses of Sellimonas intestinalis, a potential biomarker of homeostasis gut recovery","volume":"6","author":"Munoz","year":"2020","journal-title":"Microb. Genom."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"2197","DOI":"10.1016\/S0140-6736(12)61689-4","article-title":"Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the global burden of disease study 2010","volume":"380","author":"Murray","year":"2012","journal-title":"Lancet"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1038\/nature12873","article-title":"Genetics of rheumatoid arthritis contributes to biology and drug discovery","volume":"506","author":"Okada","year":"2014","journal-title":"Nature"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1007\/s00198-020-05728-y","article-title":"Association between gut microbiota, bone metabolism, and fracture risk in postmenopausal Japanese women","volume":"32","author":"Ozaki","year":"2021","journal-title":"Osteoporos. Int."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1038\/s42003-020-01334-0","article-title":"The genetic architecture of appendicular lean mass characterized by association analysis in the UK biobank study","volume":"3","author":"Pei","year":"2020","journal-title":"Commun. Biol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"1177","DOI":"10.1093\/aje\/kwt084","article-title":"Efficient design for Mendelian randomization studies: subsample and 2-sample instrumental variable estimators","volume":"178","author":"Pierce","year":"2013","journal-title":"Am. J. Epidemiol."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1007\/s40520-019-01131-8","article-title":"Nutritional influence on bone: role of gut microbiota","volume":"31","author":"Rizzoli","year":"2019","journal-title":"Aging Clin. Exp. Res."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"T279","DOI":"10.1016\/j.recot.2023.03.002","article-title":"[translated article] pilot study to determine the association between gut microbiota and fragility hip fracture","volume":"67","author":"Rosello-Anon","year":"2023","journal-title":"Rev. Esp. Cir. Ortop. Traumatol."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"e230","DOI":"10.1097\/BPO.0000000000001131","article-title":"The economic burden of musculoskeletal disease in children and adolescents in the United States","volume":"38","author":"Rosenfeld","year":"2018","journal-title":"J. Pediatr. Orthop."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1093\/ije\/dyy262","article-title":"An examination of multivariable Mendelian randomization in the single-sample and two-sample summary data settings","volume":"48","author":"Sanderson","year":"2019","journal-title":"Int. J. Epidemiol."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"844","DOI":"10.1136\/annrheumdis-2019-215142","article-title":"The world-wide burden of musculoskeletal diseases: a systematic analysis of the World Health Organization burden of diseases database","volume":"78","author":"Sebbag","year":"2019","journal-title":"Ann. Rheum. Dis."},{"key":"ref35","first-page":"S334","article-title":"Direct correlation between hyperoxaluria\/oxalate stone disease and the absence of the gastrointestinal tract-dwelling bacterium Oxalobacter formigenes: possible prevention by gut recolonization or enzyme replacement therapy","volume":"10","author":"Sidhu","year":"1999","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/ije\/dyg070","article-title":"'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease?","volume":"32","author":"Smith","year":"2003","journal-title":"Int. J. Epidemiol."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"1462","DOI":"10.1136\/annrheumdis-2013-204680","article-title":"The global burden of other musculoskeletal disorders: estimates from the global burden of disease 2010 study","volume":"73","author":"Smith","year":"2014","journal-title":"Ann. Rheum. Dis."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"1395","DOI":"10.1093\/rheumatology\/41.12.1395","article-title":"Comparison of the faecal microflora of patients with ankylosing spondylitis and controls using molecular methods of analysis","volume":"41","author":"Stebbings","year":"2002","journal-title":"Rheumatology (Oxford)"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"e1001779","DOI":"10.1371\/journal.pmed.1001779","article-title":"UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age","volume":"12","author":"Sudlow","year":"2015","journal-title":"PLoS Med."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"11","DOI":"10.3390\/nu11071633","article-title":"Muscle mass and function in aging: a focus on physical frailty and sarcopenia","volume":"11","author":"Ticinesi","year":"2019","journal-title":"Nutrients"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"1124945","DOI":"10.3389\/fmicb.2023.1124945","article-title":"The associations of gut microbiota, endocrine system and bone metabolism","volume":"14","author":"Tu","year":"2023","journal-title":"Front. Microbiol."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1002\/JLB.3MR0321-755R","article-title":"The microbiota-gut-bone axis and bone health","volume":"110","author":"Tu","year":"2021","journal-title":"J. Leukoc. Biol."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1016\/j.mehy.2015.01.010","article-title":"The relationship between colonization of Oxalobacter formigenes serum oxalic acid and endothelial dysfunction in hemodialysis patients: from impaired colon to impaired endothelium","volume":"84","author":"Turkmen","year":"2015","journal-title":"Med. Hypotheses"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1038\/s41588-018-0099-7","article-title":"Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases","volume":"50","author":"Verbanck","year":"2018","journal-title":"Nat. Genet."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.ajhg.2011.11.029","article-title":"Five years of GWAS discovery","volume":"90","author":"Visscher","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"2163","DOI":"10.1016\/S0140-6736(12)61729-2","article-title":"Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the global burden of disease study 2010","volume":"380","author":"Vos","year":"2012","journal-title":"Lancet"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"423","DOI":"10.3920\/BM2014.0088","article-title":"The effect of probiotics on serum levels of cytokine and endotoxin in peritoneal dialysis patients: a randomised, double-blind, placebo-controlled trial","volume":"6","author":"Wang","year":"2015","journal-title":"Benef. Microbes"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"15","DOI":"10.3390\/nu15051266","article-title":"Bifidobacterium as a potential biomarker of sarcopenia in elderly women","volume":"15","author":"Wang","year":"2023","journal-title":"Nutrients"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"535310","DOI":"10.3389\/fcimb.2020.535310","article-title":"Fecal and serum Metabolomic signatures and microbial community profiling of postmenopausal osteoporosis mice model","volume":"10","author":"Wen","year":"2020","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"160","DOI":"10.3389\/fcimb.2020.00160","article-title":"Gut microbiome reveals specific Dysbiosis in primary osteoporosis","volume":"10","author":"Xu","year":"2020","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref51","doi-asserted-by":"publisher","first-page":"5703","DOI":"10.1039\/d0fo03468a","article-title":"The modulatory effect and implication of gut microbiota on osteoporosis: from the perspective of \"brain-gut-bone\" axis","volume":"12","author":"Zhang","year":"2021","journal-title":"Food Funct."},{"key":"ref52","doi-asserted-by":"publisher","first-page":"1007165","DOI":"10.3389\/fimmu.2022.1007165","article-title":"Gut microbiota and rheumatoid arthritis: from pathogenesis to novel therapeutic opportunities","volume":"13","author":"Zhao","year":"2022","journal-title":"Front. 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