The role of sex steroid hormones in Crohn\'s disease

• Ano de defesa: 2023
• Autor(a) principal: Silva, Murillo Duarte
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: eng
• Instituição de defesa: Biblioteca Digitais de Teses e Dissertações da USP
• Palavras-chave em Português: Crohn's disease; Doença de Crohn
• Link de acesso: https://www.teses.usp.br/teses/disponiveis/17/17147/tde-30062023-093802/

Background: Crohn\'s disease (CD) is a chronic inflammatory disorder in the gastrointestinal tract of multifactorial etiology, being influenced by genetic predispositions, microbiota imbalance, and environmental factors. Considering that hormones are central regulators of human functions, the interaction between the endocrine and immune systems is of particular importance for homeostasis, with the capacity to modify several diseases course. Recently, several studies of sex steroid hormones immunomodulatory potential, such as dehydroepiandrosterone (DHEA), testosterone and estradiol, have been highlighted for a better understanding of immunoendocrine relationships and for clarifying the different outcomes of infectious or immune-mediated diseases, between male and female. Aim: To investigate the role of sex steroid hormones, androgens and estrogens, in Crohn\'s disease. Results: It was evaluated public transcriptome datasets (GSE100833 and GSE16879) of colonic biopsies from patients with CD, responders (RP) and non-responders (N-RP) to anti-TNF therapy, in addition to healthy controls (HC). Biopsies were collected before and after therapy. The analyzes were focused on endocrine pathways such as biosynthesis and metabolism of androgen and estrogen hormones, besides androgen (AR), estrogen alpha (ERα) and estrogen beta (ERβ) receptors signaling. The genes expression involved in the AR and ERα signaling pathways was predictive to the responsiveness to treatment, before the therapy, while other genes were able to differentiate only CD patients from HC. In the HC group, genes related to hormones inactivation and metabolism and also to the MAPK and ERBB pathways were more expressed, while others related to the hormones activation and formation were repressed. In patients, especially N-RP, pathways related to inflammation, such as IL-6, several chemokines and cell migration were induced. For ex vivo investigations, 39 CD and 20 HC individuals from HCFMRP/USP were recruited. Steroid hormones were measured by mass spectrometry in plasma samples. Cortisol, testosterone and DHEA were reduced in patients. With the aim of studying the mechanisms by which DHEA acts, peripheral blood mononuclear cells (PBMC) from eight HC were stimulated in vitro with anti-CD3 and anti-CD28 for three days, in the presence of DHEA and/or several antagonists to AR, ERα and ERβ. DHEA reduced the production of IL-6, IFN-γ and IL-10, but the specific blockade of ERβ restored the ability of PBMC to produce the cytokines. Finally, the potential of DHEA (40 mg/kg/day) to regulate intestinal inflammation in vivo was tested. For this purpose, experimental colitis was induced in male C57BL/6 mice with DSS 2.5% in drinking water by 10 days. Corroborating the other results, treatment with DHEA significantly attenuated the clinical score of the disease and other inflammatory markers, such as intestinal permeability, the total white blood cells count and the accumulation of neutrophils in the intestinal mucosa. Conclusion: The non-responsiveness to anti-TNF in CD is related to sex steroid hormones and DHEA supplementation, probably via ERβ, has the potential to reduce the production of inflammatory cytokines, restoring the mucosal barrier and regulating intestinal inflammation.