Year: 2026
Type: preprint
Abstract: SUMMARY 11β-hydroxysteroid dehydrogenase 2 (HSD11B2) protects the mineralocorticoid receptor from glucocorticoid overstimulation by inactivating cortisol. HSD11B2 inhibition can drive receptor overactivation and contribute to hypertension; however, endogenous inhibitors remain poorly defined. Glycyrrhetinic acid-like factors (GALFs) are steroid-like metabolites that inhibit HSD11B2. Given the capacity of gut bacteria to metabolize host steroids, we hypothesized that the gut microbiome could generate GALF-like inhibitors. Here, we identify two 11-oxygenated steroid metabolites that potently inhibit human HSD11B2 in colonic cells and organoids, enabling cortisol-dependent mineralocorticoid receptor activation. We identify gut bacteria and enzymes that produce these compounds and show that their levels are markedly reduced in antibiotic-treated humans. One metabolite is elevated during pregnancy, and both are higher in individuals with stage 2 hypertension-range blood pressure. These findings reveal a bacterial route to altered host cortisol signaling and suggest a potential link between microbiome-derived GALFs and blood pressure regulation.
Authors: Seraina O. Moser, Jasmine T. Walsh, Philipp M. Späne, Taina Härkönen, Marianne Lalli, Ines Zalosnik, Denise V. Winter, Junehee Park, Marina Magicheva-Gupta, Megan D. McCurry, David J. Morris, Ye-Ji Bang, Jun R. Huh, Perry A. Labelle, Andrew T. Chan, David A. Drew, Mingyang Song, James D. Lewis, Gary D. Wu, Jordan E. Bisanz, Tommi Vatanen, Rianne Elaine van Diest, Mikael Knip, Alex Odermatt, A. Sloan Devlin
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7204042757
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