Low Gut Microbial Diversity Augments Estrogen-Driven Pulmonary Fibrosis in Female-Predominant Interstitial Lung Disease
Although profibrotic cytokines, such as IL-17A and TGF-β1, 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, hav...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-02-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/12/5/766 |
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| author | Ozioma S. Chioma Elizabeth Mallott Binal Shah-Gandhi ZaDarreyal Wiggins Madison Langford Andrew William Lancaster Alexander Gelbard Hongmei Wu Joyce E. Johnson Lisa Lancaster Erin M. Wilfong Leslie J. Crofford Courtney G. Montgomery Luc Van Kaer Seth Bordenstein Dawn C. Newcomb Wonder Puryear Drake |
| author_facet | Ozioma S. Chioma Elizabeth Mallott Binal Shah-Gandhi ZaDarreyal Wiggins Madison Langford Andrew William Lancaster Alexander Gelbard Hongmei Wu Joyce E. Johnson Lisa Lancaster Erin M. Wilfong Leslie J. Crofford Courtney G. Montgomery Luc Van Kaer Seth Bordenstein Dawn C. Newcomb Wonder Puryear Drake |
| author_sort | Ozioma S. Chioma |
| collection | DOAJ |
| description | Although profibrotic cytokines, such as IL-17A and TGF-β1, 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-β1 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. |
| first_indexed | 2024-03-11T07:28:26Z |
| format | Article |
| id | doaj.art-2b5fde885bc54e49986452f6ae18e637 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-11T07:28:26Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-2b5fde885bc54e49986452f6ae18e6372023-11-17T07:27:52ZengMDPI AGCells2073-44092023-02-0112576610.3390/cells12050766Low Gut Microbial Diversity Augments Estrogen-Driven Pulmonary Fibrosis in Female-Predominant Interstitial Lung DiseaseOzioma S. Chioma0Elizabeth Mallott1Binal Shah-Gandhi2ZaDarreyal Wiggins3Madison Langford4Andrew William Lancaster5Alexander Gelbard6Hongmei Wu7Joyce E. Johnson8Lisa Lancaster9Erin M. Wilfong10Leslie J. Crofford11Courtney G. Montgomery12Luc Van Kaer13Seth Bordenstein14Dawn C. Newcomb15Wonder Puryear Drake16Departments of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USADepartment of Biology, Washington University in St. Louis, St. Louis, MO 63130, USADepartments of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USADepartments of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USADepartments of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USADepartments of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USAOtolaryngology-Head and Neck Surgery, Vanderbilt University School of Medicine, Nashville, TN 37232, USAOtolaryngology-Head and Neck Surgery, Vanderbilt University School of Medicine, Nashville, TN 37232, USAPathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USADepartments of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USADepartments of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USADepartments of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USAGenes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USAPathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USADepartment of Biology and Entomology, Pennsylvania State University, College Station, PA 16801, USADepartments of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USADepartments of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USAAlthough profibrotic cytokines, such as IL-17A and TGF-β1, 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-β1 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.https://www.mdpi.com/2073-4409/12/5/766estrogengut microbiomelung fibrosissarcoidosisTh17 cells |
| spellingShingle | Ozioma S. Chioma Elizabeth Mallott Binal Shah-Gandhi ZaDarreyal Wiggins Madison Langford Andrew William Lancaster Alexander Gelbard Hongmei Wu Joyce E. Johnson Lisa Lancaster Erin M. Wilfong Leslie J. Crofford Courtney G. Montgomery Luc Van Kaer Seth Bordenstein Dawn C. Newcomb Wonder Puryear Drake Low Gut Microbial Diversity Augments Estrogen-Driven Pulmonary Fibrosis in Female-Predominant Interstitial Lung Disease Cells estrogen gut microbiome lung fibrosis sarcoidosis Th17 cells |
| title | Low Gut Microbial Diversity Augments Estrogen-Driven Pulmonary Fibrosis in Female-Predominant Interstitial Lung Disease |
| title_full | Low Gut Microbial Diversity Augments Estrogen-Driven Pulmonary Fibrosis in Female-Predominant Interstitial Lung Disease |
| title_fullStr | Low Gut Microbial Diversity Augments Estrogen-Driven Pulmonary Fibrosis in Female-Predominant Interstitial Lung Disease |
| title_full_unstemmed | Low Gut Microbial Diversity Augments Estrogen-Driven Pulmonary Fibrosis in Female-Predominant Interstitial Lung Disease |
| title_short | Low Gut Microbial Diversity Augments Estrogen-Driven Pulmonary Fibrosis in Female-Predominant Interstitial Lung Disease |
| title_sort | low gut microbial diversity augments estrogen driven pulmonary fibrosis in female predominant interstitial lung disease |
| topic | estrogen gut microbiome lung fibrosis sarcoidosis Th17 cells |
| url | https://www.mdpi.com/2073-4409/12/5/766 |
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