{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T04:46:04Z","timestamp":1785818764793,"version":"3.56.0"},"reference-count":52,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,2,28]],"date-time":"2023-02-28T00:00:00Z","timestamp":1677542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Foundation for Sarcoidosis Research (FSR) Fellowship","award":["T32 AR059039-10"],"award-info":[{"award-number":["T32 AR059039-10"]}]},{"name":"Foundation for Sarcoidosis Research (FSR) Fellowship","award":["FSR 19-505-SGP"],"award-info":[{"award-number":["FSR 19-505-SGP"]}]},{"name":"Foundation for Sarcoidosis Research (FSR) Fellowship","award":["HL117074"],"award-info":[{"award-number":["HL117074"]}]},{"name":"Foundation for Sarcoidosis Research (FSR) Fellowship","award":["K24 HL127301"],"award-info":[{"award-number":["K24 HL127301"]}]},{"name":"Foundation for Sarcoidosis Research (FSR) Fellowship","award":["K24 HL127301-1S"],"award-info":[{"award-number":["K24 HL127301-1S"]}]},{"name":"Foundation for Sarcoidosis Research (FSR) Fellowship","award":["5 T32 HL094296"],"award-info":[{"award-number":["5 T32 HL094296"]}]},{"name":"Foundation for Sarcoidosis Research (FSR) Fellowship","award":["NHLBI R01HL113326-06"],"award-info":[{"award-number":["NHLBI R01HL113326-06"]}]},{"name":"Foundation for Sarcoidosis Research (FSR) Fellowship","award":["NIGMS P30 GM110766-01"],"award-info":[{"award-number":["NIGMS P30 GM110766-01"]}]},{"name":"Foundation for Sarcoidosis Research (FSR) Fellowship","award":["R01 HL122554"],"award-info":[{"award-number":["R01 HL122554"]}]},{"name":"Foundation for Sarcoidosis Research (FSR) Fellowship","award":["R01 AI139046"],"award-info":[{"award-number":["R01 AI139046"]}]},{"name":"Foundation for Sarcoidosis Research (FSR) Fellowship","award":["T32HL087738"],"award-info":[{"award-number":["T32HL087738"]}]},{"name":"Foundation for Sarcoidosis Research (FSR) Fellowship","award":["T32GM007347"],"award-info":[{"award-number":["T32GM007347"]}]},{"name":"Ellen Dreiling Research Fund Endowment and the Vanderbilt Microbiome Initiative","award":["T32 AR059039-10"],"award-info":[{"award-number":["T32 AR059039-10"]}]},{"name":"Ellen Dreiling Research Fund Endowment and the Vanderbilt Microbiome Initiative","award":["FSR 19-505-SGP"],"award-info":[{"award-number":["FSR 19-505-SGP"]}]},{"name":"Ellen Dreiling Research Fund Endowment and the Vanderbilt Microbiome Initiative","award":["HL117074"],"award-info":[{"award-number":["HL117074"]}]},{"name":"Ellen Dreiling Research Fund Endowment and the Vanderbilt Microbiome Initiative","award":["K24 HL127301"],"award-info":[{"award-number":["K24 HL127301"]}]},{"name":"Ellen Dreiling Research Fund Endowment and the Vanderbilt Microbiome Initiative","award":["K24 HL127301-1S"],"award-info":[{"award-number":["K24 HL127301-1S"]}]},{"name":"Ellen Dreiling Research Fund Endowment and the Vanderbilt Microbiome Initiative","award":["5 T32 HL094296"],"award-info":[{"award-number":["5 T32 HL094296"]}]},{"name":"Ellen Dreiling Research Fund Endowment and the Vanderbilt Microbiome Initiative","award":["NHLBI R01HL113326-06"],"award-info":[{"award-number":["NHLBI R01HL113326-06"]}]},{"name":"Ellen Dreiling Research Fund Endowment and the Vanderbilt Microbiome Initiative","award":["NIGMS P30 GM110766-01"],"award-info":[{"award-number":["NIGMS P30 GM110766-01"]}]},{"name":"Ellen Dreiling Research Fund Endowment and the Vanderbilt Microbiome Initiative","award":["R01 HL122554"],"award-info":[{"award-number":["R01 HL122554"]}]},{"name":"Ellen Dreiling Research Fund Endowment and the Vanderbilt Microbiome Initiative","award":["R01 AI139046"],"award-info":[{"award-number":["R01 AI139046"]}]},{"name":"Ellen Dreiling Research Fund Endowment and the Vanderbilt Microbiome Initiative","award":["T32HL087738"],"award-info":[{"award-number":["T32HL087738"]}]},{"name":"Ellen Dreiling Research Fund Endowment and the Vanderbilt Microbiome Initiative","award":["T32GM007347"],"award-info":[{"award-number":["T32GM007347"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Although profibrotic cytokines, such as IL-17A and TGF-\u03b21, have been implicated in the pathogenesis of interstitial lung disease (ILD), the interactions between gut dysbiosis, gonadotrophic hormones and molecular mediators of profibrotic cytokine expression, such as the phosphorylation of STAT3, have not been defined. Here, through chromatin immunoprecipitation sequencing (ChIP-seq) analysis of primary human CD4+ T cells, we show that regions within the STAT3 locus are significantly enriched for binding by the transcription factor estrogen receptor alpha (ERa). Using the murine model of bleomycin-induced pulmonary fibrosis, we found significantly increased regulatory T cells compared to Th17 cells in the female lung. The genetic absence of ESR1 or ovariectomy in mice significantly increased pSTAT3 and IL-17A expression in pulmonary CD4+ T cells, which was reduced after the repletion of female hormones. Remarkably, there was no significant reduction in lung fibrosis under either condition, suggesting that factors outside of ovarian hormones also contribute. An assessment of lung fibrosis among menstruating females in different rearing environments revealed that environments favoring gut dysbiosis augment fibrosis. Furthermore, hormone repletion following ovariectomy further augmented lung fibrosis, suggesting pathologic interactions between gonadal hormones and gut microbiota in relation to lung fibrosis severity. An analysis of female sarcoidosis patients revealed a significant reduction in pSTAT3 and IL-17A levels and a concomitant increase in TGF-\u03b21 levels in CD4+ T cells compared to male sarcoidosis patients. These studies reveal that estrogen is profibrotic in females and that gut dysbiosis in menstruating females augments lung fibrosis severity, supporting a critical interaction between gonadal hormones and gut flora in lung fibrosis pathogenesis.<\/jats:p>","DOI":"10.3390\/cells12050766","type":"journal-article","created":{"date-parts":[[2023,2,28]],"date-time":"2023-02-28T03:29:46Z","timestamp":1677554986000},"page":"766","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Low Gut Microbial Diversity Augments Estrogen-Driven Pulmonary Fibrosis in Female-Predominant Interstitial Lung Disease"],"prefix":"10.3390","volume":"12","author":[{"given":"Ozioma S.","family":"Chioma","sequence":"first","affiliation":[{"name":"Departments of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Mallott","sequence":"additional","affiliation":[{"name":"Department of Biology, Washington University in St. Louis, St. Louis, MO 63130, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binal","family":"Shah-Gandhi","sequence":"additional","affiliation":[{"name":"Departments of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"ZaDarreyal","family":"Wiggins","sequence":"additional","affiliation":[{"name":"Departments of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madison","family":"Langford","sequence":"additional","affiliation":[{"name":"Departments of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew William","family":"Lancaster","sequence":"additional","affiliation":[{"name":"Departments of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Gelbard","sequence":"additional","affiliation":[{"name":"Otolaryngology-Head and Neck Surgery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongmei","family":"Wu","sequence":"additional","affiliation":[{"name":"Otolaryngology-Head and Neck Surgery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joyce E.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Lancaster","sequence":"additional","affiliation":[{"name":"Departments of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6584-1578","authenticated-orcid":false,"given":"Erin M.","family":"Wilfong","sequence":"additional","affiliation":[{"name":"Departments of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie J.","family":"Crofford","sequence":"additional","affiliation":[{"name":"Departments of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA"},{"name":"Department of Biology, Washington University in St. Louis, St. Louis, MO 63130, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney G.","family":"Montgomery","sequence":"additional","affiliation":[{"name":"Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5275-2309","authenticated-orcid":false,"given":"Luc","family":"Van Kaer","sequence":"additional","affiliation":[{"name":"Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth","family":"Bordenstein","sequence":"additional","affiliation":[{"name":"Department of Biology and Entomology, Pennsylvania State University, College Station, PA 16801, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawn C.","family":"Newcomb","sequence":"additional","affiliation":[{"name":"Departments of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, 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