Integrating the gut microbiome and pharmacology

Abstract

The gut microbiome harbors trillions of organisms that contribute to human health and disease. These bacteria can also affect the properties of medical drugs used to treat these diseases, and drugs, in turn, can reshape the microbiome. Research addressing interdependent microbiome-host-drug interactions thus has broad impact. In this Review, we discuss these interactions from the perspective of drug bioavailability, absorption, metabolism, excretion, toxicity, and drug-mediated microbiome modulation. We survey approaches that aim to uncover the mechanisms underlying these effects and opportunities to translate this knowledge into new strategies to improve the development, administration, and monitoring of medical drugs.

Fig. 1.. Direct and indirect impacts of the gut microbiome on drug pharmacokinetics.

Bacteria may affect drug absorption through bioaccumulation (uptake of the parent drug), bile salt metabolism (changes to emulsification/solubilization of lipophilic drugs), or altered drug uptake through passive (paracellular) diffusion or protein carrier–mediated transport (influx and efflux) (25). Bacteria can also metabolize drugs directly, produce metabolites that alter expression and activity of host DMEs, and modify bile acids that act on host nuclear receptors (e.g., PXR). Bacteria affect drug excretion by removing glucuronides or sulfates from phase 2 host drug metabolites, possibly promoting their entry into the enterohepatic circulation and further metabolism. Bacteria may also convert host drug metabolites back into their active and toxic forms (e.g., via deglucuronidation or sulfatase activity), transform drugs into metabolites with local or systemic toxicity (toxification), or negatively alter gut microbiome composition (dysbiosis).

Fig. 2.. Effects of blocking bacterial drug metabolizing enzymes.

Inhibition of the metabolism of the drug levodopa to dopamine by the bacterial enzyme TyrDC increases the bioavailability of levodopa. (Left) Bacteria in the small intestine can decarboxylate levodopa to dopamine through the action of TyrDC. Because levodopa, but not dopamine, can cross the blood-brain barrier into the central nervous system, bacterial metabolism of levodopa in the gut reduces its bioavailability such that less levodopa enters the central nervous system. (Right) Microbial decarboxylation of levodopa in the gut of gnotobiotic mice can be blocked using an inhibitor of TyrDC, (S)-α-fluoromethyltyrosine (S-AFMT) (16). This results in increased serum concentrations of levodopa enabling more levodopa to enter the central nervous system, thus improving drug efficacy in the mice (16).

Fig. 3.. Host-microbiome-drug interactions in humans and mice.

(A) Parallel studies in humans and in mice with a humanized gut microbiota can provide mechanistic insights into the role of the gut microbiome in drug PK/PD and toxicity. For example, complete or fractionated fecal microbiomes from patients (e.g., drug responders and nonresponders) can be transplanted into wild-type or transgenic Germ-free mice to determine how gut microbiome differences contribute to drug responses. (B) Shown are opportunities to leverage the human gut microbiome to improve development, administration, and monitoring of clinical drugs. Understanding the role of the gut microbiome in drug responses could enable prescreening of individuals and selection of those most likely to respond to a drug successfully and safely. This knowledge also could be used to optimize drug dosing and could inform microbiome interventions such as (1) prebiotics, (2) probiotics, (3) postbiotics, (4) targeted antibiotics or bacterial enzymatic inhibitors, (5) bacteriophages, and (6) fecal microbiota transplants.