{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:18:58Z","timestamp":1787026738293,"version":"build-2736575974"},"reference-count":65,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,9,26]],"date-time":"2023-09-26T00:00:00Z","timestamp":1695686400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82273465"],"award-info":[{"award-number":["82273465"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008866","name":"Changhai Hospital of Shanghai","doi-asserted-by":"publisher","award":["2020YXK042"],"award-info":[{"award-number":["2020YXK042"]}],"id":[{"id":"10.13039\/501100008866","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>In recent decades, the decline of male sperm quality has become a worldwide phenomenon, with sperm quality of critical importance for the ability to conceive naturally. Recent studies suggest that male fertility function is closely linked to the gut microbiota, however, the cause-and-effect association between the gut microbiota and male infertility risk is currently unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed one two-sample Mendelian randomization (MR) study, which uses summary data on human gut microbiota from the MiBioGen consortium as factors of exposure. FinnGen Consortium R8 data was used to obtain GWAS data for male infertility. To evaluate cause-and-effect associations linking gut microbiota and male infertility risk with multiple Mendelian randomization methods, we included inverse variance weighted (IVW), MR-Egger, and Maximum Likelihood (ML) Ratio. The heterogeneity of instrumental variables was evaluated through Cochran's Q, Rucker's Q, and leave-one-out analysis methods.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We found a positive association between Allisonella, Anaerotruncus, Barnesiella, Intestinibacter, and Lactococcus with male infertility risk according to the MR analysis results. Bacteroides Romboutsia, Ruminococcaceae (NK4A2140group), and Ruminococcaceae (UCG011) play a protective function in male infertility pathogenesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>It was found that gut microbiota and infertility are causally related in this study. In subsequent studies, there is a need to build a larger and more comprehensive GWAS database on male infertility, which will reveal the underlying mechanisms for gut microbiota and male infertility. There is a need for randomized controlled trials for validating the protective effect of the associated gut microbiota against male infertility risk, and for exploring the associated mechanisms.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmicb.2023.1228693","type":"journal-article","created":{"date-parts":[[2023,9,27]],"date-time":"2023-09-27T01:20:16Z","timestamp":1695777616000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["Male infertility risk and gut microbiota: a Mendelian randomization study"],"prefix":"10.3389","volume":"14","author":[{"given":"Zhi-da","family":"Fu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-li","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,9,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e103809","DOI":"10.1371\/journal.pone.0103809","article-title":"The gut microbiota and developmental programming of the testis in mice","volume":"9","author":"Al-Asmakh","year":"2014","journal-title":"PLoS ONE"},{"key":"B2","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/0268-960X(89)90024-6","article-title":"Therapeutic options in chronic myeloid leukaemia","volume":"3","author":"Allan","year":"1989","journal-title":"Blood Rev"},{"key":"B3","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":"B4","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":"B5","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1002\/jrsm.1346","article-title":"Meta-analysis and Mendelian randomization: a review","volume":"10","author":"Bowden","year":"2019","journal-title":"Res. Synth. Methods"},{"key":"B6","doi-asserted-by":"publisher","first-page":"888","DOI":"10.1093\/biolre\/ioz229","article-title":"Chronic testicular chlamydia muridarum infection impairs mouse fertility and offspring developmentdagger","volume":"102","author":"Bryan","year":"2020","journal-title":"Biol. Reprod"},{"key":"B7","doi-asserted-by":"publisher","first-page":"306","DOI":"10.4103\/aja.aja_76_20","article-title":"A decrease of docosahexaenoic acid in testes of mice fed a high-fat diet is associated with impaired sperm acrosome reaction and fertility","volume":"23","author":"Bunay","year":"2021","journal-title":"Asian J. Androl"},{"key":"B8","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1002\/gepi.21758","article-title":"Mendelian randomization analysis with multiple genetic variants using summarized data","volume":"37","author":"Burgess","year":"2013","journal-title":"Genet. Epidemiol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"109915","DOI":"10.1016\/j.celrep.2021.109915","article-title":"Dissecting mammalian spermatogenesis using spatial transcriptomics","volume":"37","author":"Chen","year":"2021","journal-title":"Cell Rep"},{"key":"B10","doi-asserted-by":"publisher","first-page":"710","DOI":"10.1111\/1749-4877.12710","article-title":"Altitude-dependent metabolite biomarkers reveal the mechanism of plateau pika adaptation to high altitudes","volume":"2023","author":"Chen","year":"2023","journal-title":"Integr. Zool"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1608","DOI":"10.1136\/gutjnl-2019-319127","article-title":"Impairment of spermatogenesis and sperm motility by the high-fat diet-induced dysbiosis of gut microbes","volume":"69","author":"Ding","year":"2020","journal-title":"Gut"},{"key":"B12","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1038\/s41579-020-0433-9","article-title":"Gut microbiota in human metabolic health and disease","volume":"19","author":"Fan","year":"2021","journal-title":"Nat. Rev. Microbiol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1007\/s13311-017-0600-5","article-title":"Gut microbiota and the neuroendocrine system","volume":"15","author":"Farzi","year":"2018","journal-title":"Neurotherapeutics"},{"key":"B14","unstructured":"FinnGen R8 Release2022"},{"key":"B15","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1016\/j.tins.2013.01.005","article-title":"Gut-brain axis: how the microbiome influences anxiety and depression","volume":"36","author":"Foster","year":"2013","journal-title":"Trends Neurosci"},{"key":"B16","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1038\/s41564-018-0306-4","article-title":"Gut microbiome structure and metabolic activity in inflammatory bowel disease","volume":"4","author":"Franzosa","year":"2019","journal-title":"Nat. Microbiol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.psyneuen.2015.06.002","article-title":"Prenatal stress-induced alterations in major physiological systems correlate with gut microbiota composition in adulthood","volume":"60","author":"Golubeva","year":"2015","journal-title":"Psychoneuroendocrinology"},{"key":"B18","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1093\/nutrit\/nuv004","article-title":"Obesity and the gastrointestinal microbiota: a review of associations and mechanisms","volume":"73","author":"Graham","year":"2015","journal-title":"Nutr. Rev"},{"key":"B19","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1093\/ije\/29.4.722","article-title":"An introduction to instrumental variables for epidemiologists","volume":"29","author":"Greenland","year":"2000","journal-title":"Int. J. Epidemiol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1093\/aje\/kwv135","article-title":"Association between use of marijuana and male reproductive hormones and semen quality: a study among 1,215 healthy young men","volume":"182","author":"Gundersen","year":"2015","journal-title":"Am J Epidemiol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"e13124","DOI":"10.1111\/and.13124","article-title":"Smoking-induced genetic and epigenetic alterations in infertile men","volume":"50","author":"Gunes","year":"2018","journal-title":"Andrologia"},{"key":"B22","doi-asserted-by":"publisher","first-page":"14394","DOI":"10.1074\/jbc.RA119.009972","article-title":"Acyl-CoA synthetase 6 enriches seminiferous tubules with the omega-3 fatty acid docosahexaenoic acid and is required for male fertility in the mouse","volume":"294","author":"Hale","year":"2019","journal-title":"J. Biol. Chem"},{"key":"B23","doi-asserted-by":"publisher","first-page":"e0002822","DOI":"10.1128\/spectrum.00028-22","article-title":"Gut microbiota-testis axis: FMT mitigates high-fat diet-diminished male fertility via improving systemic and testicular metabolome","volume":"10","author":"Hao","year":"2022","journal-title":"Microbiol. Spectr"},{"key":"B24","doi-asserted-by":"publisher","first-page":"e1007081","DOI":"10.1371\/journal.pgen.1007081","article-title":"Orienting the causal relationship between imprecisely measured traits using GWAS summary data","volume":"13","author":"Hemani","year":"2017","journal-title":"PLoS Genet"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1716","DOI":"10.1053\/j.gastro.2009.08.042","article-title":"High-fat diet determines the composition of the murine gut microbiome independently of obesity","volume":"137","author":"Hildebrandt","year":"2009","journal-title":"Gastroenterology"},{"key":"B26","doi-asserted-by":"publisher","first-page":"956","DOI":"10.1172\/JCI41303","article-title":"The key role of vitamin A in spermatogenesis","volume":"120","author":"Hogarth","year":"2010","journal-title":"J. Clin. Invest"},{"key":"B27","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1093\/humupd\/dmv016","article-title":"Infertility around the globe: new thinking on gender, reproductive technologies and global movements in the 21st century","volume":"21","author":"Inhorn","year":"2015","journal-title":"Hum. Reprod. Update"},{"key":"B28","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1097\/MCO.0b013e3283476e74","article-title":"Nutrient-induced inflammation in the intestine","volume":"14","author":"Ji","year":"2011","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"B29","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":"B30","doi-asserted-by":"publisher","DOI":"10.1101\/2022.03.03.22271360","article-title":"FinnGen: unique genetic insights from combining isolated population and national health register data","author":"Kurki","year":"2022","journal-title":"medRxiv [Preprint]"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1042923","DOI":"10.3389\/fmicb.2022.1042923","article-title":"Chronic alcohol-induced dysbiosis of the gut microbiota and gut metabolites impairs sperm quality in mice","volume":"13","author":"Li","year":"2022","journal-title":"Front. Microbiol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"863315","DOI":"10.3389\/fmicb.2022.863315","article-title":"The improvement of semen quality by dietary fiber intake is positively related with gut microbiota and SCFA in a boar model","volume":"13","author":"Lin","year":"2022","journal-title":"Front. Microbiol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"5301942","DOI":"10.1155\/2021\/5301942","article-title":"Cornuside alleviates diabetes mellitus-induced testicular damage by modulating the gut microbiota","volume":"2021","author":"Liu","year":"2021","journal-title":"Evid. Compl. Alternat. Med"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1257","DOI":"10.1016\/j.joca.2019.05.009","article-title":"Gut microbiota and obesity-associated osteoarthritis","volume":"27","author":"Liu","year":"2019","journal-title":"Osteoarthritis Cartilage"},{"key":"B35","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1111\/andr.13342","article-title":"Effects of diabetes mellitus on sperm quality and fertility outcomes: clinical evidence","volume":"11","author":"Lotti","year":"2023","journal-title":"Andrology"},{"key":"B36","doi-asserted-by":"publisher","first-page":"361","DOI":"10.3748\/wjg.v22.i1.361","article-title":"Gut microbiota in autism and mood disorders","volume":"22","author":"Mangiola","year":"2016","journal-title":"World J. Gastroenterol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1017\/S0029665120006916","article-title":"mechanisms and functional importance in the gut","volume":"80","author":"Martin-Gallausiaux","year":"2021","journal-title":"Proc. Nutr. Soc"},{"key":"B38","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1016\/j.eururo.2021.08.014","article-title":"European association of urology guidelines on male sexual and reproductive health: 2021 update on male infertility","volume":"80","author":"Minhas","year":"2021","journal-title":"Eur. Urol"},{"key":"B39","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1017\/S0007114512001213","article-title":"Influence of a high-fat diet on gut microbiota, intestinal permeability and metabolic endotoxaemia","volume":"108","author":"Moreira","year":"2012","journal-title":"Br. J. Nutr"},{"key":"B40","doi-asserted-by":"publisher","first-page":"157","DOI":"10.3389\/fgene.2020.00157","article-title":"LDlinkR: an R package for rapidly calculating linkage disequilibrium statistics in diverse populations","volume":"11","author":"Myers","year":"2020","journal-title":"Front. Genet"},{"key":"B41","doi-asserted-by":"publisher","first-page":"3036","DOI":"10.1093\/humrep\/deab179","article-title":"Association between intake of soft drinks and testicular function in young men","volume":"36","author":"Nassan","year":"2021","journal-title":"Hum. Reprod"},{"key":"B42","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1016\/j.fertnstert.2015.09.016","article-title":"Psychological stress and testicular function: a cross-sectional study of 1,215 Danish men","volume":"105","author":"Nordkap","year":"2016","journal-title":"Fertil. Steril."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1905","DOI":"10.1017\/S0007114514000117","article-title":"Impact of dietary fatty acids on metabolic activity and host intestinal microbiota composition in C57BL\/6J mice","volume":"111","author":"Patterson","year":"2014","journal-title":"Br. J. Nutr"},{"key":"B44","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":"B45","doi-asserted-by":"publisher","first-page":"3209","DOI":"10.1021\/acs.jafc.0c08187","article-title":"RS5 produced more butyric acid through regulating the microbial community of human gut microbiota","volume":"69","author":"Qin","year":"2021","journal-title":"J. Agric. Food Chem"},{"key":"B46","doi-asserted-by":"publisher","first-page":"7128","DOI":"10.1038\/s41467-022-34502-3","article-title":"Gut microbiome-wide association study of depressive symptoms","volume":"13","author":"Radjabzadeh","year":"2022","journal-title":"Nat. Commun"},{"key":"B47","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1016\/j.mce.2005.12.044","article-title":"Actions of 5alpha-reductase inhibitors on the epididymis","volume":"250","author":"Robaire","year":"2006","journal-title":"Mol. Cell Endocrinol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"e13082","DOI":"10.1111\/obr.13082","article-title":"Male adiposity, sperm parameters and reproductive hormones: an updated systematic review and collaborative meta-analysis","volume":"22","author":"Salas-Huetos","year":"2021","journal-title":"Obes. Rev"},{"key":"B49","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1016\/j.eururo.2016.04.010","article-title":"Cigarette smoking and semen quality: a new meta-analysis examining the effect of the 2010 world health organization laboratory methods for the examination of human semen","volume":"70","author":"Sharma","year":"2016","journal-title":"Eur. Urol"},{"key":"B50","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1016\/j.cell.2016.10.027","article-title":"The central nervous system and the gut microbiome","volume":"167","author":"Sharon","year":"2016","journal-title":"Cell"},{"key":"B51","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1039\/D1FO03145G","article-title":"Chestnut polysaccharides restore impaired spermatogenesis by adjusting gut microbiota and the intestinal structure","volume":"13","author":"Sun","year":"2022","journal-title":"Food Funct"},{"key":"B52","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1038\/nature18847","article-title":"The microbiome and innate immunity","volume":"535","author":"Thaiss","year":"2016","journal-title":"Nature"},{"key":"B53","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":"B54","doi-asserted-by":"publisher","first-page":"601","DOI":"10.3920\/BM2021.0015","article-title":"blend of 3 mushrooms dose-dependently increases butyrate production by the gut microbiota","volume":"12","author":"Verhoeven","year":"2021","journal-title":"Benef. Microbes"},{"key":"B55","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1111\/andr.13143","article-title":"Exploring the role of gut microbiome in male reproduction","volume":"10","author":"Wang","year":"2022","journal-title":"Andrology"},{"key":"B56","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1126\/science.1208344","article-title":"Linking long-term dietary patterns with gut microbial enterotypes","volume":"334","author":"Wu","year":"2011","journal-title":"Science"},{"key":"B57","doi-asserted-by":"publisher","first-page":"667097","DOI":"10.3389\/fimmu.2021.667097","article-title":"Causal effects of gut microbiome on systemic lupus erythematosus: a two-sample mendelian randomization study","volume":"12","author":"Xiang","year":"2021","journal-title":"Front. Immunol"},{"key":"B58","doi-asserted-by":"publisher","first-page":"1251","DOI":"10.1016\/j.ajhg.2021.05.014","article-title":"Constrained maximum likelihood-based Mendelian randomization robust to both correlated and uncorrelated pleiotropic effects","volume":"108","author":"Xue","year":"2021","journal-title":"Am. J. Hum. Genet"},{"key":"B59","doi-asserted-by":"publisher","first-page":"e0142322","DOI":"10.1128\/spectrum.01423-22","article-title":"Gut-testis axis: microbiota prime metabolome to increase sperm quality in young type 2 diabetes","volume":"10","author":"Yan","year":"2022","journal-title":"Microbiol. Spectr"},{"key":"B60","doi-asserted-by":"publisher","first-page":"1025918","DOI":"10.3389\/fcvm.2022.1025918","article-title":"Large-scale correlation analysis of deep venous thrombosis and gut microbiota","volume":"9","author":"Yang","year":"2022","journal-title":"Front. Cardiovasc. Med"},{"key":"B61","doi-asserted-by":"publisher","first-page":"57","DOI":"10.3390\/nu15041057","article-title":"No evidence of a genetic causal relationship between ankylosing spondylitis and gut microbiota: a two-sample mendelian randomization study","volume":"15","author":"Yang","year":"2023","journal-title":"Nutrients"},{"key":"B62","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1136\/gutjnl-2020-323347","article-title":"Disrupted spermatogenesis in a metabolic syndrome model: the role of vitamin A metabolism in the gut-testis axis","volume":"71","author":"Zhang","year":"2022","journal-title":"Gut"},{"key":"B63","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1186\/s40168-021-01157-z","article-title":"Polyamine metabolism links gut microbiota and testicular dysfunction","volume":"9","author":"Zhao","year":"2021","journal-title":"Microbiome"},{"key":"B64","doi-asserted-by":"publisher","first-page":"35261","DOI":"10.1007\/s11356-020-09854-2","article-title":"The gut-microbiota-testis axis mediated by the activation of the Nrf2 antioxidant pathway is related to prepuberal steroidogenesis disorders induced by di-(2-ethylhexyl) phthalate","volume":"27","author":"Zhao","year":"","journal-title":"Environ. Sci. Pollut. Res. Int"},{"key":"B65","doi-asserted-by":"publisher","first-page":"3308","DOI":"10.7150\/thno.43189","article-title":"Alginate oligosaccharides improve germ cell development and testicular microenvironment to rescue busulfan disrupted spermatogenesis","volume":"10","author":"Zhao","year":"","journal-title":"Theranostics"}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2023.1228693\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,27]],"date-time":"2023-09-27T01:20:19Z","timestamp":1695777619000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2023.1228693\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,26]]},"references-count":65,"alternative-id":["10.3389\/fmicb.2023.1228693"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2023.1228693","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,26]]},"article-number":"1228693"}}