Though several studies have reported the involvement of pro-fibrotic substances in the pathogenesis of interstitial lung disease, none have characterized the interplay of intestinal dysbiosis, gonadal hormones, and the molecular regulators of profibrotic chemokine and cytokines. Now, a recent study published in Cell has established the synergistic link between estrogen level and intestinal dysbiosis and the pathophysiology of idiopathic pulmonary fibrosis (IPF).
The study conducted by Chioma and co-researchers involved female patients with sarcoidosis (n=31), IPF (n=45), and scleroderma (n=11). Patients with IPF and systemic sclerosis were identified using the American Thoracic Society and American College of Rheumatology criteria. Assessment of lung fibrosis among reproductive-age females in different rearing environments showed that gut dysbiosis facilitates fibrosis. In addition, hormone reduction following ovariectomy also increased the incidence of lung fibrosis, thereby suggesting the pathologic influence of gonadal hormones and gut microbiota on lung fibrosis severity. A significant reduction in pSTAT3 and IL-17A levels was observed in female sarcoidosis patients and a subsequent increase in TGF-β1 levels in CD4+ T cells compared to male counterparts.
The study demonstrated that female gonadotrophic hormones are profibrotic, but they reduce inflammation induced by IL-17A expression in CD4+ T cells by binding to the signal transducer and activator of the transcription 3 locus. Gut dysbiosis has been identified as a key contributor to lung fibrosis severity. The findings highlighted the pro-fibrotic nature of estrogen and the augmentation of severe pulmonary fibrosis by intestinal dysbiosis in menstruating females.
The present study suggesting the interplay of gonadal hormones and intestinal microflora in the pathogenesis of pulmonary fibrosis underscores the need for sex-based and personalized immunological therapeutics for the management of chronic pulmonary inflammation.
- Chioma OS, Mallott E, Shah-Gandhi B, Wiggins Z, Langford M, Lancaster AW, Gelbard A, Wu H, Johnson JE, Lancaster L, Wilfong EM. Low Gut Microbial Diversity Augments Estrogen-driven Pulmonary Fibrosis in Female-Predominant Interstitial Lung Disease. Cells. 2023 Feb 28;12(5):766.