S. O. Moser, J. T. Walsh, P. M. Spane, T. Harkonen, M. Lalli, I. Zalosnik, D. V. Winter, J. Park, M. Magicheva-Gupta, M. D. McCurry, D. J. Morris, Y.-J. Bang, J. R. Huh, P. A. Labelle, A. T. Chan, D. A. Drew, M. Song, J. D. Lewis, G. D. Wu, J. E. Bisanz, T. Vatanen, R. E. van Diest, M. Knip, A. Odermatt, A. S. Devlin
11{beta}-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.