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Publications

Journal Article Ahead of print

PubMed: 42393407 DOI: 10.1007/s10753-026-02554-y

Pre-Treatment with Estradiol, But not Progesterone, Exacerbates DSS Colitis: Dysregulated Innate Immunity and Impaired Epithelial Damage Response.

Inflammation

Authors: Anja Hjelt, Lauri Polari, Heli Jokela, Pia Rantakari, Heidi Gerke, Diana M Toivola, Claes Ohlsson, Matti Poutanen, Jorma Määttä

Affiliations

  • Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, Turku, 20520, Finland.
  • Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, Turku, 20520, Finland.
  • Department of Natural and Health Sciences, Faculty of Science and Engineering, Biochemistry and Cell Biology, Åbo Akademi University, Turku, Finland.
  • InFLAMES Research Flagship Center, BioCity, Tykistökatu 6A, Turku, 20520, Finland.
  • Turku Bioscience Center, University of Turku and Åbo Akademi University, Tykistökatu 6, Turku, 20520, Finland.
  • Department of Internal Medicine and Clinical Nutrition, The Sahlgrenska Osteoporosis Centre, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
  • Turku Center for Disease Modeling, University of Turku, Turku, Finland.
  • Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, Turku, 20520, Finland.
  • Turku Center for Disease Modeling, University of Turku, Turku, Finland.

Abstract

Epidemiological data have indicated an increased risk of inflammatory bowel disease associated with the female sex and contraceptive hormones. However, in preclinical models of estradiol in colitis, results have been inconsistent, and both alleviating and aggravating effects have been reported. Previously, we suggested that the estrogen receptor α mediates inflammation in the colon. Here, we investigated the effects of estradiol and progesterone in dextran sulphate sodium-induced colitis, using sham-operated or ovariectomized female mice with or without hormonal supplementation initiated three weeks before inflammation. We found that sham-operated, or ovariectomized mice supplemented either with only estradiol or estradiol and progesterone exhibited more severe intestinal inflammation compared to ovariectomized mice at day 7 of colitis. Simultaneously, progesterone supplementation of ovariectomized mice did not affect the inflammatory status. Estrogen receptors were expressed in several different cell types of the colonic mucosa, although at low levels. The estrogen receptor α was observed in the epithelium as well as in mononuclear phagocytes and T and B cells. The estrogen receptor β was found in the epithelium, and the G protein-coupled estrogen receptor in the lamina propria and vessel structures. Further, hormone depletion increased homeostatic immune cells, while estradiol exposure altered the expression of 791 genes involved in pathways promoting the antimicrobial response, immune cell activation, and metabolism related to epithelial integrity. With our results, we are the first to present strong and detailed evidence of estradiol as an inflammatory agent in the colon of female mice when allowing the appearance of longer-term effects.

MeSH

Cells, Estrogens, Colitis, Estradiol, Receptors, Estrogen, Colon, Hormones, Immunity, Therapeutics, Immunity, Innate, Progesterone, Epithelium