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.

• Keywords
• 11β-hydroxysteroid dehydrogenase, anti-CD3 antibody, extra-adrenal steroidogenesis, glucocorticoids, intestine, microbiome,
• MeSH
• 11-beta-Hydroxysteroid Dehydrogenases genetics   metabolism   MeSH
• Corticosterone metabolism   MeSH
• Real-Time Polymerase Chain Reaction MeSH
• Mice MeSH
• Steroids metabolism   MeSH
• Gastrointestinal Microbiome physiology   MeSH
• Tandem Mass Spectrometry MeSH
• Intestine, Small metabolism   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 11-beta-Hydroxysteroid Dehydrogenases MeSH
• Corticosterone MeSH
• Steroids 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-Hydroxysteroid Dehydrogenase Type 1 genetics   metabolism   MeSH
• 11-beta-Hydroxysteroid Dehydrogenase Type 2 genetics   metabolism   MeSH
• Hormone Antagonists pharmacology   MeSH
• Budesonide pharmacology   MeSH
• Cyclooxygenase 2 genetics   metabolism   MeSH
• Glucocorticoids antagonists & inhibitors   metabolism   pharmacology   MeSH
• Interleukin-1beta genetics   metabolism   MeSH
• Carbenoxolone pharmacology   MeSH
• Colitis chemically induced   metabolism   MeSH
• Colon drug effects   enzymology   metabolism   MeSH
• Corticosterone metabolism   MeSH
• Rats MeSH
• Trinitrobenzenesulfonic Acid MeSH
• RNA, Messenger metabolism   MeSH
• Mifepristone pharmacology   MeSH
• Disease Models, Animal MeSH
• Mucin-2 MeSH
• Mucins genetics   metabolism   MeSH
• Peroxidase metabolism   MeSH
• Reverse Transcriptase Polymerase Chain Reaction MeSH
• Rats, Wistar MeSH
• Tumor Necrosis Factor-alpha genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 11-beta-Hydroxysteroid Dehydrogenase Type 1 MeSH
• 11-beta-Hydroxysteroid Dehydrogenase Type 2 MeSH
• Hormone Antagonists MeSH
• Budesonide MeSH
• Cyclooxygenase 2 MeSH
• Glucocorticoids MeSH
• Interleukin-1beta MeSH
• Carbenoxolone MeSH
• Corticosterone MeSH
• Trinitrobenzenesulfonic Acid MeSH
• RNA, Messenger MeSH
• Mifepristone MeSH
• Muc2 protein, rat MeSH Browser
• Mucin-2 MeSH
• Mucins MeSH
• Peroxidase MeSH
• Ptgs2 protein, rat MeSH Browser
• Tumor Necrosis Factor-alpha MeSH