7285 Inhibition of 11β-Hydroxysteroid Dehydrogenase 2 by a Gut Microbiome Derived Metabolite

Abstract Disclosure: S.O. Moser: None. M.D. McCurry: None. J. Walsh: None. D.V. Winter: None. M. Smieško: None. D.J. Morris: None. A.S. Devlin: None. A. Odermatt: None. In sodium-transporting epithelial cells, 11β-hydroxysteroid dehydrogenase 2 (11βHSD2) protects the mineralocorticoid receptor (MR) from activation by glucocorticoids. MR activation results in sodium and water retention and potassium excretion. Apparent mineralocorticoid excess (AME) results from HSD11B2 mutations, leading to cortisol-driven MR activation characterized by low renin and aldosterone levels. 11βHSD2 inhibition contributes to acquired AME, associated with essential hypertension. Licorice-derived glycyrrhetinic acid inhibits 11βHSD2, allowing cortisol accumulation and subsequent MR activation. A "cloud" of steroids and steroid-like factors is proposed to influence the activities of 11βHSD isoforms and modulate MR and GR activity in vivo. These endogenous steroidal compounds, termed glycyrrhetinic acid-like factors (GALFs), are produced by peripheral tissues and gut microbiota. GALFs exhibit potent inhibitory effects towards 11βHSD2. The significance of these GALFs in the microenvironment is emphasized when investigating essential hypertension. Experimental interventions, such as antibiotic treatment and fecal transplant, demonstrated the microbiota's influence on blood pressure regulation. 3α,11β-Dihydroxy-5β-tetrahydroprogesterone (3α,11β-diOH-5β-THP) and 3β,11β-dihydroxy-5α-tetrahydroprogesterone (3β,11β-diOH-5α-THP) are metabolites that may be formed from tetrahydrocorticosterone by the gut microbiota. In this study, we assessed the potential of 3α,11β-diOH-5β-THP and 3β,11β-diOH-5α-THP to inhibit 11βHSD2 activity as well as their capability to modulate MR transcriptional activity. Comparison of 3α,11β-diOH-5β-THP and 3β,11β-diOH-5α-THP showed that 3β,11β-diOH-5α-THP is a potent inhibitor of human 11βHSD2, with an IC50 of 47 nM whilst 3α,11β-diOH-5β-THP had an IC50 of approximately 10 µM. Both metabolites were less potent inhibitors against mouse 11βHSD2, with an IC50 of 1.3 µM for 3β,11β-diOH-5α-THP and about 25% inhibition at 20 µM 3α,11β-diOH-5β-THP. 3α,11β-diOH-5α-THP was previously shown to inhibit 11βHSD2 with an IC50 of 0.12 µM using sheep microsomes. This data suggests that a 5α-conformation of the steroid core is important for the inhibitory capacity towards 11βHSD2. 3β,11β-diOH-5α-THP was able to activate human MR, although with an EC50 two or three orders of magnitude higher than those for cortisol or aldosterone. Similarly, 3β,11β-diOH-5α-THP was able to activate mouse MR, with an one or two orders in magnitude higher EC50 than those for cortisol and aldosterone. 3α,11β-diOH-5β-THP did not activate human and mouse MR at 1 µM. In conclusion, these results highlight an endogenous metabolite that influences the functional interaction of 11βHSD2 and MR, with relevance for essential hypertension. Presentation: 6/2/2024