Separating host and microbiome contributions to drug pharmacokinetics and drug toxicity

These GEITP pages have discussed, on several occasions, the importance of the “brain-gut-microbiome” (i.e. interaction of each patient’s gut bacteria/virus/fungus with intestine AND brain of the same patient). Of all the many ways the ecosystem of microbes (comprising 92% of YOUR total DNA) in a person’s gut and other tissues might affect health — its potential influences on brain may be the most far-reaching. Now, a study of two larger groups of Europeans [see attached article] has identified several species of gut bacteria that are largely missing in people who exhibit major depressive disorder (MDD). Researchers cannot say whether the absence (of these specific bacterial species) is the cause, or an effect, of the illness — but they have shown that many gut bacteria could produce, or degrade, substances that affect nerve cell function, and perhaps also mood.

Several studies in mice had indicated that gut microbes can affect behavior, and studies of small cohorts of humans had suggested this microbial repertoire is altered during depression. To test such an association in a larger group, authors [see attached] examined 1,054 Belgians they had recruited to assess a “normal” microbiome. Some in the group (N of 173) had been diagnosed with MDD — or had performed poorly on a quality-of-life survey — and the team compared their microbiomes with those of “non-depressed” participants. Two kinds of bacteria, Coprococcus and Dialister, were missing from microbiomes of the depressed subjects, but were not absent from those describing on the questionnaire “a high quality of life”. The finding (reported last week in Nat Microbiol) continued to be significant, when researchers had allowed for factors such as age, sex, or antidepressant use (all of which influence the microbiome). When the team looked at a 2nd group (1,054 Dutch people whose microbiomes had also been sampled) — they found the same two bacterial species were missing in depressed people; they were also missing in seven subjects suffering from MDD (the data “do not prove causality”, but they are “an independent observation backed by two groups of people”).

Searching for something that could correlate microbes to mood — authors compiled a list of 56 substances important for proper nervous system function that gut microbes either produce or break down; they found that Coprococcus produces a metabolite of dopamine (a brain signal involved in depression), although it’s not clear whether the bacteria degrade the neurotransmitter or whether the metabolite has its own function. The same microbe produces an anti-inflammatory substance called butyrate; it is known that increased inflammation may play a role in depression. Subjects with MDD also had an increase in bacteria implicated in Crohn disease, an inflammatory disorder. How do these bacterial metabolites get into the central nervous system? Authors suggest that one possible channel is the vagus nerve, which links brain to the gut.

Authors of the 1-MB article [attached] describes attempts to study interpersonal variation in drug efficacy and drug toxicity; however, quantifying microbial contributions to drug metabolism is challenging — particularly in cases where host and microbiome perform the same metabolic transformation. Authors combined gut commensal (living in a relationship in which one organism derives food or other benefits from another organism, without hurting or helping it) genetics with gnotobiotics [denoting an environment for rearing organisms in which all microorganisms are either known or excluded (e.g. ‘germ-free mouse colony’)] to measure brivudine drug metabolism (analog of thymidine, which gets incorporated into viral DNA — blocking the action of DNA polymerases, thus inhibiting viral replication) across tissues in mice that vary in a single microbiome-encoded enzyme. Informed by information from these measurements, authors built a pharmacokinetic model that quantitatively predicts microbiome contributions to systemic drug and metabolite exposure — (as a function of bioavailability, host and microbial drug-metabolizing activity, drug and metabolite absorption, and intestinal transit kinetics). Studies of clonazepam (used to treat seizures and panic attacks) illustrated how this approach dissociates microbiome contributions to metabolism of drugs, subject to multiple metabolic routes and transformations.

Together, these two studies provide experimental and computational strategies to untangle host and microbial contributions to drug metabolism and effects on brain. Quantitative understanding of the interplay between host and microbiome-encoded metabolic activities will clarify how nutritional, environmental, genetic, and galenic (principles of preparing and compounding medicines in order to optimize their absorption) factors affect drug metabolism and could enable tailored intervention strategies to improve drug responses. This approach could also be adapted to other foreign chemicals, food components, and endogenous metabolites. 🙂

DwN

Science 8 Feb 2o19; 363: 600 + 6 pp & p. 569 [editorial]­­

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