Human Gut Bacteria Convert Endogenous Steroids into Host Cortisol Shuttle Inhibitors

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

doi:10.64898/2026.08.21.746344

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bioRxiv · 10.64898/2026.08.21.746344

Human Gut Bacteria Convert Endogenous Steroids into Host Cortisol Shuttle Inhibitors

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Abstract

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.

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Moser, S. O., Walsh, J. T., Spane, P. M., Harkonen, T., Lalli, M., Zalosnik, I., Winter, D. V., Park, J., Magicheva-Gupta, M., McCurry, M. D., Morris, D. J., Bang, Y.-J., Huh, J. R., Labelle, P. A., Chan, A. T., Drew, D. A., Song, M., Lewis, J. D., Wu, G. D., Bisanz, J. E., Vatanen, T., van Diest, R. E., Knip, M., Odermatt, A., Devlin, A. S.. 2026-08-22. Human Gut Bacteria Convert Endogenous Steroids into Host Cortisol Shuttle Inhibitors. https://doi.org/10.64898/2026.08.21.746344

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