Gut bacteria convert cortisol into a distinct hostsignalling molecule

Abstract

Microorganisms extensively modify host steroids, but whether these reactions merely eliminate hormones or create signals with new biological identities is largely unknown. Gut bacteria have been known for more than four decades to reduce cortisol to 20-dihydrocortisol, yet the physiological consequence of this transformation remained unresolved. Here we show that microbial cortisol reduction creates a distinct host signalling molecule. A 2.0-[A] structure of the bacterial enzyme DesC, together with molecular dynamics, biochemical perturbation and hybrid quantum mechanics/molecular mechanics simulations, defines substrate recognition and an ordered hydride-transfer and proton-relay mechanism. In gnotobiotic mice, isogenic bacteria expressing active DesC--but not a catalytically inactive S47A variant produced 20-dihydrocortisol in the intestine and circulation and reprogrammed colonic transcription. In primary intestinal epithelial cells, 20-dihydrocortisol, but not cortisol, activated ERK-dependent inflammatory and growth-associated programmes. These responses required nuclear receptor subfamily 4 group A member 3 (NR4A3), whose purified ligand-binding domain bound 20-dihydrocortisol but showed no detectable binding to cortisol. A Chicago colonoscopy cohort linked chronic cortisol exposure, faecal desC, the microbial metabolite and colorectal phenotypes. Thus, bacterial metabolism can change receptor selectivity and biological activity rather than simply terminate host hormone action, expanding the endocrine chemistry of the host.