Pharma[e]cology: How the Gut Microbiome Contributes to Variations in Drug Response

Abstract

Drugs represent our first, and sometimes last, line of defense for many diseases, yet despite decades of research we still do not fully understand why a given drug works in one patient and fails in the next. The human gut microbiome is one of the missing puzzle pieces, due to its ability to parallel and extend host pathways for drug metabolism, along with more complex host-microbiome interactions. Herein, we focus on the well-established links between the gut microbiome and drugs for heart disease and cancer, plus emerging data on neurological disease. We highlight the interdisciplinary methods that are available and how they can be used to address major remaining knowledge gaps, including the consequences of microbial drug metabolism for treatment outcomes. Continued progress in this area promises fundamental biological insights into humans and their associated microbial communities and strategies for leveraging the microbiome to improve the practice of medicine.

Keywords: absorption; human microbiome; metabolism; pharmacodynamics; pharmacokinetics; pharmacomicrobiomics.

Figure 1

The gut microbiome affects drugs used to target multiple diseases. (a) It is now clear that our current understanding is just at the beginning stages, opening up many questions about the mechanisms through which the gut microbiome affects drug metabolism and disposition and their physiological/clinical relevance. (b–d) Representative examples of the impact of the gut microbiome on drugs used to treat (b) heart conditions, (c) cancer, and (d) the brain. (b) Digoxin, a treatment for heart failure and arrhythmia, is metabolized by Eggerthella lenta Cgr2 to dihydrodigoxin. Simvastatin, used to lower hypercholesterolemia, exhibits reduced efficacy in mouse models treated with antibiotics. Bacterial hydrolases deacetylate diltiazem, an antihypertensive drug. (c) Bacterial β-glucuronidase converts the inactive irinotecan metabolite SN-38G into active SN-38, causing increased toxicity. Capecitabine is more effective against tumor xenografts in mice colonized with Escherichia coli ΔpreTA than in mice colonized with E. coli overexpressing preTA (E. coli preTA⁺⁺). Gemcitabine, a chemotherapeutic agent, decreased tumor sizes for mice colonized with E. coli Δcdd but not for mice colonized with wild-type E. coli. (d) Both host and gut bacterial enzymes decarboxylate the Parkinson’s disease treatment l-dopa to dopamine, which cannot cross the blood-brain barrier to exert therapeutic benefit. Fluoxetine, a selective serotonin reuptake inhibitor used to treat depression, is sequestered by the gut bacterium Turicibacter sanguinis. Gut bacterial colonization also activates TLR2 and TLR4, increasing morphine tolerance. Abbreviations: ADME, absorption, distribution, metabolism, and elimination; Cgr2, cardiac glycoside reductase 2; FDA, US Food and Drug Administration; GF, germ-free; l-dopa, levodopa; TLR2/4, Toll-like receptor 2/4. Figure adapted from images created with BioRender.com.

Figure 2

Hallmarks of pharmacomicrobiomics. Members of the gut microbiota influence the absorption, distribution, metabolism, and elimination of drugs through at least three key mechanisms: direct metabolism, transport and accumulation, and immune interactions. Gut microbes can directly metabolize drugs, prematurely activating prodrugs such as l-dopa or inactivating drugs such as 5-FU. Gut bacteria can modulate how the immune system interacts with immunomodulatory drugs, including the alteration of ICI efficacy through bacterial metabolites and small molecules. Finally, gut bacteria can alter drug transport, either through altering expression and activity of host drug transporters such as P-gp or by sequestering the drug through bacterial homologs of host drug transporters such as SERT. Abbreviations: 5-FU, 5-fluorouracil; DHFU, dihydrofluorouracil; ICI, immune checkpoint inhibitor; l-dopa, levodopa; P-gp, P-glycoprotein; SERT, serotonin transporter. Figure adapted from images created with BioRender.com.