Devendran, S. | bioRxiv Science

bioRxiv2023

Emergence of community behaviors in the gut microbiota upon drug treatment

Pharmaceuticals can directly inhibit the growth of gut bacteria, but the degree such interactions manifest in complex community settings is an open question. Here we compared the effects of 30 drugs on a 32-species synthetic community with their effects on each community member in isolation. While most individual drug-species interactions remained the same in the community context, communal behaviors emerged in 26% of all tested cases. Cross-protection, during which drug-sensitive species became protected in community, was 6-times more frequent than cross-sensitization, the converse phenomenon. Cross-protection decreased and cross-sensitization increased at higher drug concentrations, suggesting that the resilience of microbial communities can collapse when perturbations get stronger. By metabolically profiling drug-treated communities, we showed that both drug biotransformation and bioaccumulation contribute mechanistically to communal protection. As a proof-of-principle, we molecularly dissected a prominent case: species expressing specific nitroreductases degraded niclosamide, thereby protecting both themselves and sensitive community members.

microbiology↗

bioRxiv2020

Bacteria on steroids: the enzymatic mechanism of an NADH-dependent dehydrogenase that regulates the conversion of cortisol to androgen in the gut microbiome

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.

microbiology↗