Stress increases plasma concentrations of corticosteroids, however, their tissue levels are unclear. Using a repeated social defeat paradigm, we examined the impact of chronic stress on tissue levels of corticosterone (CORT), progesterone (PROG), 11-deoxycorticosterone (11DOC) and 11-dehydrocorticosterone (11DHC) and on gut microbiota, which may reshape the stress response. Male BALB/c mice, liquid chromatography-tandem mass spectrometry and 16S RNA gene sequencing were used to screen steroid levels and fecal microbiome, respectively. Stress induced greater increase of CORT in the brain, liver, and kidney than in the colon and lymphoid organs, whereas 11DHC was the highest in the colon, liver and kidney and much lower in the brain and lymphoid organs. The CORT/11DHC ratio in plasma was similar to the brain but much lower in other organs. Stress also altered tissue levels of PROG and 11DOC and the PROG/11DOC ratio was much higher in lymphoid organs that in plasma and other organs. Stress impacted the β- but not the α-diversity of the gut microbiota and LEfSe analysis revealed several biomarkers associated with stress treatment. Our data indicate that social defeat stress modulates gut microbiota diversity and induces tissue-dependent changes in local levels of corticosteroids, which often do not reflect their systemic levels.

• MeSH
• chromatografie kapalinová MeSH
• deoxykortikosteron MeSH
• kortikosteron * MeSH
• mozek MeSH
• myši MeSH
• progesteron * MeSH
• steroidy MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• deoxykortikosteron MeSH
• kortikosteron * MeSH
• progesteron * MeSH
• steroidy MeSH

Glucocorticoids (GCs) are hormones that are released in response to stressors and exhibit many activities, including immunomodulatory and anti-inflammatory activities. They are primarily synthesized in the adrenal gland but are also produced in peripheral tissues via regeneration of adrenal 11-oxo metabolites or by de novo synthesis from cholesterol. The present study investigated the influence of the microbiota on de novo steroidogenesis and regeneration of corticosterone in the intestine of germ-free (GF) and specific pathogen-free mice challenged with a physical stressor (anti-CD3 antibody i.p. injection). In the small intestine, acute immune stress resulted in increased mRNA levels of the proinflammatory cytokines IL1β, IL6 and Tnfα and genes involved in de novo steroidogenesis (Stard3 and Cyp11a1), as well as in regeneration of active GCs from their 11-oxo metabolites (Hsd11b1). GF mice showed a generally reduced transcriptional response to immune stress, which was accompanied by decreased intestinal corticosterone production and reduced expression of the GC-sensitive marker Fkbp5. In contrast, the interaction between stress and the microbiota was not detected at the level of plasma corticosterone or the transcriptional response of adrenal steroidogenic enzymes. The results indicate a differential immune stress-induced intestinal response to proinflammatory stimuli and local corticosterone production driven by the gut microbiota.

• Klíčová slova
• 11β-hydroxysteroid dehydrogenase, anti-CD3 antibody, extra-adrenal steroidogenesis, glucocorticoids, intestine, microbiome,
• MeSH
• 11-beta-hydroxysteroiddehydrogenasy genetika   metabolismus   MeSH
• kortikosteron metabolismus   MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• myši MeSH
• steroidy metabolismus   MeSH
• střevní mikroflóra fyziologie   MeSH
• tandemová hmotnostní spektrometrie MeSH
• tenké střevo metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 11-beta-hydroxysteroiddehydrogenasy MeSH
• kortikosteron MeSH
• steroidy MeSH

Stress is an important risk factors for human diseases. It activates the hypothalamic-pituitary-adrenal (HPA) axis and increases plasma glucocorticoids, which are powerful regulators of immune system. The response of the target cells to glucocorticoids depends not only on the plasma concentrations of cortisol and corticosterone but also on their local metabolism. This metabolism is catalyzed by 11β-hydroxysteroid dehydrogenases type 1 and 2, which interconvert glucocorticoid hormones cortisol and corticosterone and their 11-oxo metabolites cortisone and 11-dehydrocorticosterone. The goal of this study was to determine whether stress modulates glucocorticoid metabolism within lymphoid organs - the structures where immune cells undergo development and activation. Using the resident-intruder paradigm, we studied the effect of social stress on glucocorticoid metabolism in primary and secondary lymphoid organs of Fisher 344 (F344) and Lewis (LEW) rats, which exhibit marked differences in their HPA axis response to social stressors and inflammation. We show that repeated social defeat increased the regeneration of corticosterone from 11-dehydrocorticosterone in the thymus, spleen and mesenteric lymphatic nodes (MLN). Compared with the F344 strain, LEW rats showed higher corticosterone regeneration in splenocytes of unstressed rats and in thymic and MLN mobile cells after stress but corticosterone regeneration in the stroma of all lymphoid organs was similar in both strains. Inactivation of corticosterone to 11-dehydrocorticosterone was found only in the stroma of lymphoid organs but not in mobile lymphoid cells and was not upregulated by stress. Together, our findings demonstrate the tissue- and strain-dependent regeneration of glucocorticoids following social stress.

• Klíčová slova
• Fisher 344 rats, Lewis rats, glucocorticoid metabolism, lymphoid organs, resident-intruder paradigm, social stress,
• Publikační typ
• časopisecké články MeSH

Recent in vitro studies have shown the involvement of pro-inflammatory cytokines in the regulation of the local metabolism of glucocorticoids via 11beta-hydroxysteroid dehydrogenase type 1 and type 2 (11HSD1 and 11HSD2). However, direct in vivo evidence for a relationship among the local metabolism of glucocorticoids, inflammation and steroid enzymes is still lacking. We have therefore examined the changes in the local metabolism of glucocorticoids during colonic inflammation induced by TNBS and the consequences of corticosterone metabolism inhibition by carbenoxolone on 11HSD1, 11HSD2, cyclooxygenase 2 (COX-2), mucin 2 (MUC-2), tumor necrosis factor alpha (TNF-alpha), and interleukin 1beta (IL-1beta). The metabolism of glucocorticoids was measured in tissue slices in vitro and their 11HSD1, 11HSD2, COX-2, MUC-2, TNF-alpha, and IL-1beta mRNA abundances by quantitative reverse transcription-polymerase chain reaction. Colitis produced an up-regulation of colonic 11HSD1 and down-regulation of 11HSD2 in a dose-dependent manner, and these changes resulted in a decreased capacity of the inflamed tissue to inactivate tissue corticosterone. Similarly, 11HSD1 transcript was increased in colonic intraepithelial lymphocytes of TNBS-treated rats. Topical intracolonic application of carbenoxolone stimulated 11HSD1 mRNA and partially inhibited 11HSD2 mRNA and tissue corticosterone inactivation and these changes were blocked by RU-486. The administration of budesonide mimicked the effect of carbenoxolone. In contrast to the local metabolism of glucocorticoids, carbenoxolone neither potentiates nor diminishes gene expression for COX-2, TNF-alpha, and IL-1beta, despite the fact that budesonide down-regulated all of them. These data indicate that inflammation is associated with the down-regulation of tissue glucocorticoid catabolism. However, these changes in the local metabolism of glucocorticoids do not modulate the expression of COX-2, TNF-alpha, and IL-1beta in inflamed tissue.

• MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 1 genetika   metabolismus   MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 2 genetika   metabolismus   MeSH
• antagonisté hormonů farmakologie   MeSH
• budesonid farmakologie   MeSH
• cyklooxygenasa 2 genetika   metabolismus   MeSH
• glukokortikoidy antagonisté a inhibitory   metabolismus   farmakologie   MeSH
• interleukin-1beta genetika   metabolismus   MeSH
• karbenoxolon farmakologie   MeSH
• kolitida chemicky indukované   metabolismus   MeSH
• kolon účinky léků   enzymologie   metabolismus   MeSH
• kortikosteron metabolismus   MeSH
• krysa rodu Rattus MeSH
• kyselina trinitrobenzensulfonová MeSH
• messenger RNA metabolismus   MeSH
• mifepriston farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• mucin 2 MeSH
• muciny genetika   metabolismus   MeSH
• peroxidasa metabolismus   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• potkani Wistar MeSH
• TNF-alfa genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 11-beta-hydroxysteroiddehydrogenasa typ 1 MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 2 MeSH
• antagonisté hormonů MeSH
• budesonid MeSH
• cyklooxygenasa 2 MeSH
• glukokortikoidy MeSH
• interleukin-1beta MeSH
• karbenoxolon MeSH
• kortikosteron MeSH
• kyselina trinitrobenzensulfonová MeSH
• messenger RNA MeSH
• mifepriston MeSH
• Muc2 protein, rat MeSH Prohlížeč
• mucin 2 MeSH
• muciny MeSH
• peroxidasa MeSH
• Ptgs2 protein, rat MeSH Prohlížeč
• TNF-alfa MeSH