{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T17:32:29Z","timestamp":1787160749551,"version":"build-2736575974"},"posted":{"date-parts":[[2025,10,17]]},"group-title":"Immunology","reference-count":81,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T00:00:00Z","timestamp":1760659200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"funder":[{"name":"NICHD\/NIH","award":["R00 HD098330"],"award-info":[{"award-number":["R00 HD098330"]}]},{"name":"NIAMS\/NIH T32","award":["AR080622"],"award-info":[{"award-number":["AR080622"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Polycystic ovary syndrome (PCOS) is a reproductive disorder with heterogeneous symptoms and severity. Despite extensive research documenting chronic immune dysfunction as a hallmark of PCOS, the specific molecular mechanisms driving immune activation and its connection to the syndrome\u2019s diverse symptoms remain poorly understood. Emerging evidence suggests that gut-derived bacterial endotoxins, particularly lipopolysaccharide (LPS), may breach the intestinal barriers in PCOS patients and trigger systemic inflammation through Toll-like receptor 4 (TLR4), a pattern recognition receptor of the innate immune system. This study investigated whether TLR4 serves as a critical mechanistic driver of PCOS pathogenesis by examining the effect of genetic TLR4 knockout (TLR4\n                  <jats:sup>-\/-<\/jats:sup>\n                  ) in a letrozole (LET)-induced mouse model of PCOS. Our results demonstrate that TLR4 deficiency reduces many PCOS-like symptoms, including elevated luteinizing hormone, anovulation, and metabolic dysfunction. TLR4 knockout also preserved estrous cycling and fertility, improved glucose tolerance, maintained gut barrier integrity, and reduced inflammatory markers in LET-treated females. These findings establish TLR4 as a key mediator orchestrating PCOS\u2019s multi-system pathology, positioning TLR4 as a critical convergence point rather than affecting individual symptoms in isolation. This novel work reveals that TLR4-mediated inflammation drives multiple PCOS pathologies, opening avenues for targeted anti-inflammatory treatments in women with this disorder.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>Polycystic ovary syndrome (PCOS) affects up to 15% of reproductive-age women worldwide. This study reveals that TLR4, an innate immune receptor, is key to the pathophysiology of PCOS-like symptoms in female mice. When TLR4 was genetically deleted, mice treated with letrozole to induce PCOS-like symptoms maintained normal weight, glucose regulation, estrous cycling, and fertility. The improvements coincided with preserved gut barrier breakdown and reduced inflammation. These findings identify TLR4 as a key mediator between gut health, immune activation, and PCOS pathophysiology, suggesting that targeting TLR4 could offer new therapeutic approaches for this common but poorly understood syndrome affecting millions of women.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.10.16.682907","type":"posted-content","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T19:45:14Z","timestamp":1760730314000},"source":"Crossref","is-referenced-by-count":2,"title":["Toll-like Receptor 4 Contributes to PCOS-like Metabolic and Reproductive Pathogenesis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-2089-4277","authenticated-orcid":false,"given":"Kiara","family":"Wiggins","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4997-379X","authenticated-orcid":false,"given":"Zena","family":"Del Mundo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio Ayala","family":"Angulo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5610-4777","authenticated-orcid":false,"given":"Nandini","family":"Naidu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelina","family":"Saba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Garcia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3897-6207","authenticated-orcid":false,"given":"Christy","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1154-7063","authenticated-orcid":false,"given":"Naveena","family":"Ujagar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4829-7021","authenticated-orcid":false,"given":"Jamie-Jean","family":"De La Torre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"De Robles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angie","family":"Rivera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davina","family":"Trinh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5420-9692","authenticated-orcid":false,"given":"Roberto","family":"Tinoco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8631-6097","authenticated-orcid":false,"given":"Alexander S.","family":"Kauffman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6672-6117","authenticated-orcid":false,"given":"Varykina G.","family":"Thackray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anshu","family":"Agrawal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8026-4759","authenticated-orcid":false,"given":"Marcus","family":"Seldin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1605-9646","authenticated-orcid":false,"given":"Gabriela Pacheco","family":"Sanchez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4996-2190","authenticated-orcid":false,"given":"Dequina","family":"Nicholas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025102109300698000_2025.10.16.682907v1.1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dew218"},{"key":"2025102109300698000_2025.10.16.682907v1.2","doi-asserted-by":"publisher","DOI":"10.4103\/jhrs.JHRS_95_18"},{"key":"2025102109300698000_2025.10.16.682907v1.3","doi-asserted-by":"crossref","first-page":"103821","DOI":"10.1016\/j.drudis.2023.103821","article-title":"Polycystic ovary syndrome: Current scenario and future insights","volume":"28","year":"2023","journal-title":"Drug Discov. Today"},{"key":"2025102109300698000_2025.10.16.682907v1.4","doi-asserted-by":"crossref","first-page":"100159","DOI":"10.1016\/j.endmts.2024.100159","article-title":"When one size does not fit all: Reconsidering PCOS etiology, diagnosis, clinical subgroups, and subgroup-specific treatments","volume":"14","year":"2024","journal-title":"Endocr. Metab. Sci"},{"key":"2025102109300698000_2025.10.16.682907v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2018.24"},{"key":"2025102109300698000_2025.10.16.682907v1.6","doi-asserted-by":"publisher","DOI":"10.1111\/jne.12590"},{"key":"2025102109300698000_2025.10.16.682907v1.7","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.jsbmb.2015.10.002","article-title":"The neuroendocrine genesis of polycystic ovary syndrome: A role for arcuate nucleus GABA neurons","volume":"160","year":"2016","journal-title":"J. Steroid Biochem. Mol. Biol"},{"key":"2025102109300698000_2025.10.16.682907v1.8","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.115.130484"},{"key":"2025102109300698000_2025.10.16.682907v1.9","first-page":"173","article-title":"Impact of updated international diagnostic criteria for the diagnosis of polycystic ovary syndrome","volume":"4","year":"2023","journal-title":"FS Rep"},{"key":"2025102109300698000_2025.10.16.682907v1.10","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22052734"},{"key":"2025102109300698000_2025.10.16.682907v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2010.11.036"},{"key":"2025102109300698000_2025.10.16.682907v1.12","doi-asserted-by":"crossref","first-page":"3972","DOI":"10.1038\/s41598-024-53958-5","article-title":"Association of dietary inflammatory index with C-reactive protein and interleukin-6 in women with and without polycystic ovarian syndrome","volume":"14","year":"2024","journal-title":"Sci. Rep"},{"key":"2025102109300698000_2025.10.16.682907v1.13","doi-asserted-by":"crossref","unstructured":"G. Pacheco-Sanchez , R. Herrera , M. D. Pisarska , R. Azziz , D. A. Nicholas , J. L. Chan , Multiracial Cytokine Profiling Reveals Immune Dysregulation not Chronic Inflammation in Polycystic Ovary Syndrome. J. Clin. Endocrinol. Metab., dgaf524 (2025).","DOI":"10.1210\/clinem\/dgaf524"},{"key":"2025102109300698000_2025.10.16.682907v1.14","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.86454"},{"key":"2025102109300698000_2025.10.16.682907v1.15","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/5894768"},{"key":"2025102109300698000_2025.10.16.682907v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2011.11.023"},{"key":"2025102109300698000_2025.10.16.682907v1.17","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.594150"},{"key":"2025102109300698000_2025.10.16.682907v1.18","doi-asserted-by":"crossref","first-page":"e0145337","DOI":"10.1371\/journal.pone.0145337","article-title":"Serum LBP Is Associated with Insulin Resistance in Women with PCOS","volume":"11","year":"2016","journal-title":"PLOS ONE"},{"key":"2025102109300698000_2025.10.16.682907v1.19","doi-asserted-by":"crossref","first-page":"2303","DOI":"10.1093\/humrep\/deaa194","article-title":"Elevation of markers of endotoxemia in women with polycystic ovary syndrome","volume":"35","year":"2020","journal-title":"Hum. Reprod. Oxf. Engl"},{"key":"2025102109300698000_2025.10.16.682907v1.20","doi-asserted-by":"publisher","DOI":"10.1210\/jendso\/bvz039"},{"key":"2025102109300698000_2025.10.16.682907v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2024.03.004"},{"key":"2025102109300698000_2025.10.16.682907v1.22","doi-asserted-by":"crossref","unstructured":"Y. Wang , H. Xiao , Y. Liu , Q. Tong , Y. Yu , B. Qi , X. Bu , T. Pan , Y. Xing , Effects of Bu Shen Hua Zhuo formula on the LPS\/TLR4 pathway and gut microbiota in rats with letrozole-induced polycystic ovary syndrome. Front. Endocrinol. 13 (2022).","DOI":"10.3389\/fendo.2022.891297"},{"key":"2025102109300698000_2025.10.16.682907v1.23","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.670054"},{"key":"2025102109300698000_2025.10.16.682907v1.24","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1080\/19396368.2016.1187683","article-title":"Abnormal expression of TLRs may play a role in lower embryo quality of women with polycystic ovary syndrome","volume":"62","year":"2016","journal-title":"Syst. Biol. Reprod. Med"},{"key":"2025102109300698000_2025.10.16.682907v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/nri1391"},{"key":"2025102109300698000_2025.10.16.682907v1.26","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s12863-015-0165-4","article-title":"Association of TNF-alpha, IL-6 and IL-1beta gene polymorphisms with polycystic ovary syndrome: a meta-analysis","volume":"16","year":"2015","journal-title":"BMC Genet"},{"key":"2025102109300698000_2025.10.16.682907v1.27","doi-asserted-by":"publisher","DOI":"10.1210\/er.2014-1100"},{"key":"2025102109300698000_2025.10.16.682907v1.28","doi-asserted-by":"publisher","DOI":"10.2337\/db06-1491"},{"key":"2025102109300698000_2025.10.16.682907v1.29","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4878"},{"key":"2025102109300698000_2025.10.16.682907v1.30","doi-asserted-by":"crossref","first-page":"7441","DOI":"10.1038\/s41598-017-07858-6","article-title":"Knockdown of Tlr4 in the Arcuate Nucleus Improves Obesity Related Metabolic Disorders","volume":"7","year":"2017","journal-title":"Sci. Rep"},{"key":"2025102109300698000_2025.10.16.682907v1.31","doi-asserted-by":"crossref","first-page":"2988","DOI":"10.1210\/en.2016-1898","article-title":"Hyperandrogenemia Induced by Letrozole Treatment of Pubertal Female Mice Results in Hyperinsulinemia Prior to Weight Gain and Insulin Resistance","volume":"158","year":"2017","journal-title":"Endocrinology"},{"key":"2025102109300698000_2025.10.16.682907v1.32","doi-asserted-by":"crossref","first-page":"8659","DOI":"10.1038\/s41598-025-93215-x","article-title":"Adropin ameliorates reproductive dysfunctions in letrozole-induced PCOS mouse","volume":"15","year":"2025","journal-title":"Sci. Rep"},{"key":"2025102109300698000_2025.10.16.682907v1.33","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0223274"},{"key":"2025102109300698000_2025.10.16.682907v1.34","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/deae153"},{"key":"2025102109300698000_2025.10.16.682907v1.35","doi-asserted-by":"publisher","DOI":"10.1210\/endocr\/bqaa018"},{"key":"2025102109300698000_2025.10.16.682907v1.36","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1016\/j.cmet.2018.04.017","article-title":"Hold the Door: Role of the Gut Barrier in Diabetes","volume":"27","year":"2018","journal-title":"Cell Metab"},{"key":"2025102109300698000_2025.10.16.682907v1.37","doi-asserted-by":"publisher","DOI":"10.1126\/science.aar3318"},{"key":"2025102109300698000_2025.10.16.682907v1.38","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-018-0116-z"},{"key":"2025102109300698000_2025.10.16.682907v1.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.08.011"},{"key":"2025102109300698000_2025.10.16.682907v1.40","doi-asserted-by":"crossref","first-page":"766586","DOI":"10.3389\/fimmu.2021.766586","article-title":"IL-22 Binding Protein (IL-22BP) in the Regulation of IL-22 Biology","volume":"12","year":"2021","journal-title":"Front. Immunol"},{"key":"2025102109300698000_2025.10.16.682907v1.41","doi-asserted-by":"crossref","unstructured":"A. Fantou , E. Lagrue , T. Laurent , L. Delbos , S. Blandin , A. Jarry , G. Beriou , C. Braudeau , N. Salabert , E. Marin , A. Moreau , J. Podevin , A. Bourreille , R. Josien , J. C. Martin , IL-22BP production is heterogeneously distributed in Crohn\u2019s disease. Front. Immunol. 13 (2022).","DOI":"10.3389\/fimmu.2022.1034570"},{"key":"2025102109300698000_2025.10.16.682907v1.42","doi-asserted-by":"publisher","DOI":"10.1172\/JCI28898"},{"key":"2025102109300698000_2025.10.16.682907v1.43","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2851"},{"key":"2025102109300698000_2025.10.16.682907v1.44","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4878"},{"key":"2025102109300698000_2025.10.16.682907v1.45","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0047713"},{"key":"2025102109300698000_2025.10.16.682907v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2009.09.006"},{"key":"2025102109300698000_2025.10.16.682907v1.47","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2008.11.009"},{"key":"2025102109300698000_2025.10.16.682907v1.48","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1186\/s13098-025-01730-8","article-title":"Expanding therapeutic horizons: glucagon-like peptide-1 receptor agonists and sodium glucose transporter-2 inhibitors in poly cystic ovarian syndrome: a comprehensive review including systematic review and network meta-analysis of randomized clinical trials","volume":"17","year":"2025","journal-title":"Diabetol. Metab. Syndr"},{"key":"2025102109300698000_2025.10.16.682907v1.49","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1093\/ejendo\/lvaf154","article-title":"Fasting and postprandial oxytocin and incretin dynamics in women with polycystic ovary syndrome and healthy controls","volume":"193","year":"2025","journal-title":"Eur. J. Endocrinol"},{"key":"2025102109300698000_2025.10.16.682907v1.50","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.cca.2022.04.234","article-title":"Immune regulation in polycystic ovary syndrome","volume":"531","year":"2022","journal-title":"Clin. Chim. Acta"},{"key":"2025102109300698000_2025.10.16.682907v1.51","doi-asserted-by":"crossref","first-page":"2412558","DOI":"10.1002\/advs.202412558","article-title":"Gut Microbiota Modulation by Inulin Improves Metabolism and Ovarian Function in Polycystic Ovary Syndrome","volume":"12","year":"2025","journal-title":"Adv. Sci"},{"key":"2025102109300698000_2025.10.16.682907v1.52","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/del371"},{"key":"2025102109300698000_2025.10.16.682907v1.53","doi-asserted-by":"crossref","first-page":"103083","DOI":"10.1016\/j.jri.2020.103083","article-title":"IL-18 and IL-18 binding protein concentration in ovarian follicular fluid of women with unexplained infertility to PCOS during in vitro fertilization","volume":"138","year":"2020","journal-title":"J. Reprod. Immunol"},{"key":"2025102109300698000_2025.10.16.682907v1.54","doi-asserted-by":"crossref","first-page":"685724","DOI":"10.3389\/fimmu.2021.685724","article-title":"The Release of Peripheral Immune Inflammatory Cytokines Promote an Inflammatory Cascade in PCOS Patients via Altering the Follicular Microenvironment","volume":"12","year":"2021","journal-title":"Front. Immunol"},{"key":"2025102109300698000_2025.10.16.682907v1.55","first-page":"e2401772","article-title":"Androgens Modulate the Immune Profile in a Mouse Model of Polycystic Ovary Syndrome","volume":"11","year":"2024","journal-title":"Adv. Sci. Weinh. Baden-Wurtt. Ger"},{"key":"2025102109300698000_2025.10.16.682907v1.56","doi-asserted-by":"crossref","first-page":"629554","DOI":"10.3389\/fendo.2021.629554","article-title":"Toll-Like Receptor 4 Inhibits Estradiol Secretion via NF-\u03baB Signaling in Human Granulosa Cells","volume":"12","year":"2021","journal-title":"Front. Endocrinol"},{"key":"2025102109300698000_2025.10.16.682907v1.57","doi-asserted-by":"crossref","first-page":"29848","DOI":"10.1038\/s41598-024-81034-5","article-title":"Curcumin mitigates polycystic ovary syndrome in mice by suppressing TLR4\/MyD88\/NF-\u03baB signaling pathway activation and reducing intestinal mucosal permeability","volume":"14","year":"2024","journal-title":"Sci. Rep"},{"key":"2025102109300698000_2025.10.16.682907v1.58","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-14-0589"},{"key":"2025102109300698000_2025.10.16.682907v1.59","first-page":"674106","article-title":"Gut microbiota, microinflammation, metabolic profile, and zonulin concentration in obese and normal weight subjects","volume":"2013","year":"2013","journal-title":"Int. J. Endocrinol"},{"key":"2025102109300698000_2025.10.16.682907v1.60","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00235.2016"},{"key":"2025102109300698000_2025.10.16.682907v1.61","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0168390"},{"key":"2025102109300698000_2025.10.16.682907v1.62","doi-asserted-by":"publisher","DOI":"10.1016\/j.mehy.2012.04.016"},{"key":"2025102109300698000_2025.10.16.682907v1.63","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0509-0"},{"key":"2025102109300698000_2025.10.16.682907v1.64","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2020.06.033"},{"key":"2025102109300698000_2025.10.16.682907v1.65","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1097\/SHK.0000000000000900","article-title":"Interleukin-22 Prevents Microbial Dysbiosis and Promotes Intestinal Barrier Regeneration Following Acute Injury","volume":"48","year":"2017","journal-title":"Shock Augusta Ga"},{"key":"2025102109300698000_2025.10.16.682907v1.66","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2020.06.033"},{"key":"2025102109300698000_2025.10.16.682907v1.67","doi-asserted-by":"publisher","DOI":"10.1186\/s12866-019-1425-7"},{"key":"2025102109300698000_2025.10.16.682907v1.68","doi-asserted-by":"crossref","first-page":"e0146509","DOI":"10.1371\/journal.pone.0146509","article-title":"The Gut Microbiome Is Altered in a Letrozole-Induced Mouse Model of Polycystic Ovary Syndrome","volume":"11","year":"2016","journal-title":"PLOS ONE"},{"key":"2025102109300698000_2025.10.16.682907v1.69","doi-asserted-by":"crossref","first-page":"otad030","DOI":"10.1093\/crocol\/otad030","article-title":"IgA Determines Bacterial Composition in the Gut","volume":"5","year":"2023","journal-title":"Crohns Colitis 360"},{"key":"2025102109300698000_2025.10.16.682907v1.70","doi-asserted-by":"crossref","unstructured":"Y. Yang , J. Cheng , C. Liu , X. Zhang , N. Ma , Z. Zhou , W. Lu , C. Wu , Gut microbiota in women with polycystic ovary syndrome: an individual based analysis of publicly available data. eClinicalMedicine 77 (2024).","DOI":"10.1016\/j.eclinm.2024.102884"},{"key":"2025102109300698000_2025.10.16.682907v1.71","doi-asserted-by":"crossref","first-page":"110958","DOI":"10.1016\/j.biopha.2020.110958","article-title":"Alterations in the intestinal microbiome associated with PCOS affect the clinical phenotype","volume":"133","year":"2021","journal-title":"Biomed. Pharmacother. Biomedecine Pharmacother"},{"key":"2025102109300698000_2025.10.16.682907v1.72","doi-asserted-by":"crossref","unstructured":"Y. Li , Y. Zhu , D. Li , W. Liu , Y. Zhang , W. Liu , C. Zhang , T. Tao , Depletion of gut microbiota influents glucose metabolism and hyperandrogenism traits of mice with PCOS induced by letrozole. Front. Endocrinol. 14 (2023).","DOI":"10.3389\/fendo.2023.1265152"},{"key":"2025102109300698000_2025.10.16.682907v1.73","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-11370-y"},{"key":"2025102109300698000_2025.10.16.682907v1.74","doi-asserted-by":"crossref","first-page":"103289","DOI":"10.1016\/j.jri.2021.103289","article-title":"Beneficial effects of minocycline on the ovary of polycystic ovary syndrome mouse model: Molecular docking analysis and evaluation of TNF-\u03b1, TNFR2, TLR-4 gene expression","volume":"144","year":"2021","journal-title":"J. Reprod. Immunol"},{"key":"2025102109300698000_2025.10.16.682907v1.75","first-page":"323","article-title":"Emodin improves glucose metabolism and ovarian function in PCOS mice via the HMGB1\/TLR4\/NF-\u03baB molecular pathway","volume":"166","year":"2023","journal-title":"Reprod. Camb. Engl"},{"key":"2025102109300698000_2025.10.16.682907v1.76","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/S0169-7439(01)00155-1","article-title":"PLS-regression: a basic tool of chemometrics","volume":"58","year":"2001","journal-title":"Chemom. Intell. Lab. Syst"},{"key":"2025102109300698000_2025.10.16.682907v1.77","doi-asserted-by":"crossref","first-page":"2505","DOI":"10.1097\/01.aids.0000432455.06476.bc","article-title":"HIV-1 infection induces strong production of IP-10 through TLR7\/9-dependent pathways","volume":"27","year":"2013","journal-title":"AIDS Lond. Engl"},{"key":"2025102109300698000_2025.10.16.682907v1.78","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2019.07.004"},{"key":"2025102109300698000_2025.10.16.682907v1.79","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2018.10.009"},{"key":"2025102109300698000_2025.10.16.682907v1.80","doi-asserted-by":"publisher","DOI":"10.1038\/srep16622"},{"key":"2025102109300698000_2025.10.16.682907v1.81","doi-asserted-by":"publisher","DOI":"10.1007\/s40615-025-02642-z"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.10.16.682907","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T09:50:12Z","timestamp":1768470612000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.10.16.682907"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,17]]},"references-count":81,"URL":"https:\/\/doi.org\/10.1101\/2025.10.16.682907","relation":{},"subject":[],"published":{"date-parts":[[2025,10,17]]},"subtype":"preprint"}}