{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T02:13:35Z","timestamp":1791598415460,"version":"4.3.4"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,16]],"date-time":"2022-06-16T00:00:00Z","timestamp":1655337600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012041","name":"Versus Arthritis","doi-asserted-by":"publisher","award":["21593"],"award-info":[{"award-number":["21593"]}],"id":[{"id":"10.13039\/501100012041","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012041","name":"Versus Arthritis","doi-asserted-by":"publisher","award":["21786"],"award-info":[{"award-number":["21786"]}],"id":[{"id":"10.13039\/501100012041","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/T000910\/1"],"award-info":[{"award-number":["MR\/T000910\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>It is well appreciated that there is a female preponderance in the development of most autoimmune diseases. Thought to be due to a complex interplay between sex chromosome complement and sex-hormones, however, the exact mechanisms underlying this sex-bias remain unknown. In recent years, there has been a focus on understanding the central pathogenic role of the bacteria that live in the gut, or the gut-microbiota, in the development of autoimmunity. In this review, we discuss evidence from animal models demonstrating that the gut-microbiota is sexually dimorphic, that there is a bidirectional relationship between the production of sex-hormones and the gut-microbiota, and that this sexual dimorphism within the gut-microbiota may influence the sex-bias observed in autoimmune disease development. Collectively, these data underline the importance of considering sex as a variable when investigating biological pathways that contribute to autoimmune disease risk.<\/jats:p>","DOI":"10.3389\/fmed.2022.910561","type":"journal-article","created":{"date-parts":[[2022,6,16]],"date-time":"2022-06-16T07:19:00Z","timestamp":1655363940000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["Mini-Review: Gut-Microbiota and the Sex-Bias in Autoimmunity \u2013 Lessons Learnt From Animal Models"],"prefix":"10.3389","volume":"9","author":[{"given":"Elizabeth C.","family":"Rosser","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina M.","family":"de Gruijter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana E.","family":"Matei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1016\/j.tig.2020.06.016","article-title":"Genetics and epigenetics of sex bias: insights from human cancer and autoimmunity","volume":"36","author":"Credendino","year":"2020","journal-title":"Trends Genet."},{"key":"B2","doi-asserted-by":"publisher","first-page":"3167","DOI":"10.3389\/fimmu.2018.03167","article-title":"Sex and pubertal differences in the type 1 interferon pathway associate with both X chromosome number and serum sex hormone concentration","volume":"9","author":"Webb","year":"2018","journal-title":"Front Immunol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.cophys.2018.03.010","article-title":"The evolution of greater humoral immunity in females than males: implications for vaccine efficacy","volume":"6","author":"Fink","year":"2018","journal-title":"Curr Opin Physiol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/s13293-019-0278-y","article-title":"SeXY chromosomes and the immune system: reflections after a comparative study","volume":"11","author":"Meester","year":"2020","journal-title":"Biol Sex Differ."},{"key":"B5","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/B978-0-12-802388-4.00004-5","article-title":"Sex hormone receptor expression in the immune system","volume":"4","author":"Buskiewicz","year":"2016","journal-title":"Sex Differences in Physiology"},{"key":"B6","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1016\/j.immuni.2013.08.013","article-title":"Gender bias in autoimmunity is influenced by microbiota","volume":"39","author":"Yurkovetskiy","year":"2013","journal-title":"Immunity."},{"key":"B7","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1146\/annurev-immunol-020711-074937","article-title":"The microbiome in infectious disease and inflammation","volume":"30","author":"Honda","year":"2012","journal-title":"Annu Rev Immunol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"862","DOI":"10.1016\/j.molmed.2020.04.001","article-title":"The gut microbiota: emerging evidence in autoimmune diseases","volume":"26","author":"Zhang","year":"2020","journal-title":"Trends Mol Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1016\/j.immuni.2010.06.001","article-title":"Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells","volume":"32","author":"Wu","year":"2010","journal-title":"Immunity."},{"key":"B10","doi-asserted-by":"publisher","first-page":"2646","DOI":"10.1002\/art.39783","article-title":"Dysbiosis contributes to arthritis development via activation of autoreactive t cells in the intestine","volume":"68","author":"Maeda","year":"2016","journal-title":"Arthritis Rheumatol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1334","DOI":"10.1038\/nm.3680","article-title":"Regulatory B cells are induced by gut microbiota-driven interleukin-1beta and interleukin-6 production","volume":"20","author":"Rosser","year":"2014","journal-title":"Nat Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"6041","DOI":"10.4049\/jimmunol.0900747","article-title":"Role of gut commensal microflora in the development of experimental autoimmune encephalomyelitis","volume":"183","author":"Ochoa-Reparaz","year":"2009","journal-title":"J Immunol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1599","DOI":"10.1007\/s11011-018-0266-7","article-title":"Antibiotics protect against EAE by increasing regulatory and anti-inflammatory cells","volume":"33","author":"Seifert","year":"2018","journal-title":"Metab Brain Dis."},{"key":"B14","doi-asserted-by":"publisher","first-page":"3747","DOI":"10.1167\/iovs.16-19733","article-title":"Gut microbial alterations associated with protection from autoimmune uveitis","volume":"57","author":"Nakamura","year":"2016","journal-title":"Invest Ophthalmol Vis Sci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"5065703","DOI":"10.1155\/2016\/5065703","article-title":"The microbiota determines susceptibility to experimental autoimmune uveoretinitis","volume":"2016","author":"Heissigerova","year":"2016","journal-title":"J Immunol Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"15613","DOI":"10.1038\/s41598-017-15802-x","article-title":"Alteration of the intestinal microbiome characterizes preclinical inflammatory arthritis in mice and its modulation attenuates established arthritis","volume":"7","author":"Rogier","year":"2017","journal-title":"Sci Rep."},{"key":"B17","doi-asserted-by":"publisher","first-page":"7551","DOI":"10.1128\/AEM.02676-14","article-title":"Dynamics of gut microbiota in autoimmune lupus","volume":"80","author":"Zhang","year":"2014","journal-title":"Appl Environ Microbiol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"10776","DOI":"10.1038\/s41598-017-11069-4","article-title":"Gender-based differences in host behavior and gut microbiota composition in response to high fat diet and stress in a mouse model","volume":"7","author":"Bridgewater","year":"2017","journal-title":"Sci Rep."},{"key":"B19","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/j.yexmp.2017.11.014","article-title":"Age, sex, and TNF associated differences in the gut microbiota of mice and their impact on acute TNBS colitis","volume":"103","author":"Kozik","year":"2017","journal-title":"Exp Mol Pathol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/s13293-018-0186-6","article-title":"Sex and strain dependent differences in mucosal immunology and microbiota composition in mice","volume":"9","author":"Elderman","year":"2018","journal-title":"Biol Sex Differ."},{"key":"B21","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1080\/19490976.2016.1203502","article-title":"Sex differences and hormonal effects on gut microbiota composition in mice","volume":"7","author":"Org","year":"2016","journal-title":"Gut Microbes."},{"key":"B22","doi-asserted-by":"publisher","first-page":"4500","DOI":"10.1038\/ncomms5500","article-title":"Individual diet has sex-dependent effects on vertebrate gut microbiota","volume":"5","author":"Bolnick","year":"2014","journal-title":"Nat Commun."},{"key":"B23","doi-asserted-by":"publisher","first-page":"36137","DOI":"10.1038\/srep36137","article-title":"Sex differences in colonization of gut microbiota from a man with short-term vegetarian and inulin-supplemented diet in germ-free mice","volume":"6","author":"Wang","year":"2016","journal-title":"Sci Rep."},{"key":"B24","doi-asserted-by":"publisher","first-page":"754","DOI":"10.3389\/fimmu.2017.00754","article-title":"The impact of gut microbiota on gender-specific differences in immunity","volume":"8","author":"Fransen","year":"2017","journal-title":"Front Immunol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1084","DOI":"10.1126\/science.1233521","article-title":"Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity","volume":"339","author":"Markle","year":"2013","journal-title":"Science."},{"key":"B26","doi-asserted-by":"publisher","first-page":"e36095","DOI":"10.1371\/journal.pone.0036095","article-title":"Loss of sex and age driven differences in the gut microbiome characterize arthritis-susceptible 0401 mice but not arthritis-resistant 0402 mice","volume":"7","author":"Gomez","year":"2012","journal-title":"PLoS ONE."},{"key":"B27","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1007\/s00248-010-9787-2","article-title":"Genotype is a stronger determinant than sex of the mouse gut microbiota","volume":"61","author":"Kovacs","year":"2011","journal-title":"Microb Ecol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1002\/dev.21827","article-title":"Gonadal steroid hormone secretion during the juvenile period depends on host-specific microbiota and contributes to the development of odor preference","volume":"61","author":"Kamimura","year":"2019","journal-title":"Dev Psychobiol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1186\/s40168-020-00913-x","article-title":"Gut microbiota steroid sexual dimorphism and its impact on gonadal steroids: influences of obesity and menopausal status","volume":"8","author":"Mayneris-Perxachs","year":"2020","journal-title":"Microbiome."},{"key":"B30","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.jsbmb.2011.08.002","article-title":"Hydroxysteroid dehydrogenases (HSDs) in bacteria: a bioinformatic perspective","volume":"129","author":"Kisiela","year":"2012","journal-title":"J Steroid Biochem Mol Biol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1494","DOI":"10.1128\/AAC.01664-10","article-title":"Effect of antibiotic treatment on the intestinal metabolome","volume":"55","author":"Antunes","year":"2011","journal-title":"Antimicrob Agents Chemother."},{"key":"B32","doi-asserted-by":"publisher","first-page":"928290","DOI":"10.1155\/2013\/928290","article-title":"Role of sex steroid hormones in bacterial-host interactions","volume":"2013","author":"Garcia-Gomez","year":"2013","journal-title":"Biomed Res Int."},{"key":"B33","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1186\/s40168-017-0300-8","article-title":"Control of lupus nephritis by changes of gut microbiota","volume":"5","author":"Mu","year":"2017","journal-title":"Microbiome."},{"key":"B34","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.jneuroim.2017.06.007","article-title":"Estrogen protection against EAE modulates the microbiota and mucosal-associated regulatory cells","volume":"310","author":"Benedek","year":"2017","journal-title":"J Neuroimmunol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"e01202","DOI":"10.7554\/eLife.01202","article-title":"Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis","volume":"2","author":"Scher","year":"2013","journal-title":"Elife."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jaut.2009.12.007","article-title":"Mechanism by which HLA-DR4 regulates sex-bias of arthritis in humanized mice","volume":"35","author":"Behrens","year":"2010","journal-title":"J Autoimmun."},{"key":"B37","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1016\/j.cmet.2020.03.003","article-title":"Microbiota-derived metabolites suppress arthritis by amplifying aryl-hydrocarbon receptor activation in regulatory B cells","volume":"31","author":"Rosser","year":"2020","journal-title":"Cell Metab"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1748","DOI":"10.1038\/s41598-017-01576-9","article-title":"Gender differences in bile acids and microbiota in relationship with gender dissimilarity in steatosis induced by diet and FXR inactivation","volume":"7","author":"Sheng","year":"2017","journal-title":"Sci Rep."},{"key":"B39","doi-asserted-by":"publisher","first-page":"e00048","DOI":"10.1128\/mSystems.00048-19","article-title":"Antibiotic exposure has sex-dependent effects on the gut microbiota and metabolism of short-chain fatty acids and amino acids in mice","volume":"4","author":"Gao","year":"2019","journal-title":"mSystems"},{"key":"B40","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1016\/j.medj.2021.04.013","article-title":"Intestinal barrier dysfunction plays an integral role in arthritis pathology and can be targeted to ameliorate disease","volume":"2","author":"Matei","year":"2021","journal-title":"Med"},{"key":"B41","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1007\/s10620-015-3935-y","article-title":"Assessment of the intestinal barrier with five different permeability tests in healthy C57BL\/6J and BALB\/cJ mice","volume":"61","author":"Volynets","year":"2016","journal-title":"Dig Dis Sci."},{"key":"B42","doi-asserted-by":"publisher","first-page":"e0184274","DOI":"10.1371\/journal.pone.0184274","article-title":"The effect of age on the intestinal mucus thickness, microbiota composition and immunity in relation to sex in mice","volume":"12","author":"Elderman","year":"2017","journal-title":"PLoS ONE."},{"key":"B43","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1080\/19490976.2018.1528822","article-title":"Analysis of 1135 gut metagenomes identifies sex-specific resistome profiles","volume":"10","author":"Sinha","year":"2019","journal-title":"Gut Microbes."},{"key":"B44","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1186\/1479-5876-10-253","article-title":"Fecal microbial determinants of fecal and systemic estrogens and estrogen metabolites: a cross-sectional study","volume":"10","author":"Flores","year":"2012","journal-title":"J Transl Med."},{"key":"B45","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1191\/096120300680198926","article-title":"Profile of sex hormones in male patients with systemic lupus erythematosus","volume":"9","author":"Mok","year":"2000","journal-title":"Lupus."},{"key":"B46","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1002\/art.1780300301","article-title":"Low plasma androgens in women with systemic lupus erythematosus","volume":"30","author":"Lahita","year":"1987","journal-title":"Arthritis Rheum."},{"key":"B47","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1001\/archneur.64.5.683","article-title":"Testosterone treatment in multiple sclerosis: a pilot study","volume":"64","author":"Sicotte","year":"2007","journal-title":"Arch Neurol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.3389\/fimmu.2020.01271","article-title":"Androgen-mediated anti-inflammatory cellular processes as therapeutic targets in lupus","volume":"11","author":"Jones","year":"2020","journal-title":"Front Immunol."}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2022.910561\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,16]],"date-time":"2022-06-16T07:19:05Z","timestamp":1655363945000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2022.910561\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,16]]},"references-count":48,"alternative-id":["10.3389\/fmed.2022.910561"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2022.910561","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,16]]},"article-number":"910561"}}