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Mapping the microbiome-derived metabolism of drugs
Javdan B, Lopez J, Chankhamion P, et al. Personalized mapping of drug metabolism by the human gut microbiome. Cell 2020;1817:1661–79.
The gut microbiome is encoded by an estimated 100 times more genes than the human genome. Microbiome-derived metabolism (MDM) is the processing of a drug into metabolites by microbiome-derived enzymes. Previously monocultures have been used to study drug metabolism. This paper characterises the diversity of the microbiome and provides a framework for mapping MDM. An ex vivo culture system from a pilot donor stool sample was optimised and incubated with various orally administered drugs. A drug was MDM+ if in culture the drug was no longer detected, it produced a new metabolite and it was metabolised in the same way in at least two experiments. Of 575 drugs tested, 76% were successfully analysed, and of these 13% were MDM+ (ie, the microbiota could alter the medication). Several MDM reactions had been previously described but 80% were novel reactions. Next, an additional 20 healthy donor stool samples were cultured and quantitative metabolomics was used to determine MDM for 23 drugs. Some drugs were MDM+ across donors; some MDM− across donors and others exhibited variability. Functional metagenomics was employed to identify metabolising enzymes. Finally, to test whether these interactions occur in vivo, two groups of mice were treated with antibiotics to abolish their native microbiome and one group colonised with pilot donor stool. One reaction, the deglycosylation of fluoropyrimidine capecitabine, which occurred in donor stool, was tested, and this occurred only in the colonised mice. In summary, new microbiome–drug interactions were identified and there was interindividual variability, of relevance in personalised drug development.
Single cell approaches unravel molecular circuits driving checkpoint inhibitor-associated colitis
Luoma A, Suo S, Williams H, et al. Molecular pathways of colon inflammation induced by cancer immunotherapy. Cell 2020;182(3):655–71.e22. doi: 10.1016/j.cell.2020.06.001.
The monoclonal antibodies ipilimumab and pembrolizumab, …
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; internally peer reviewed.