The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism

Abstract

Although the importance of human genetic polymorphisms in therapeutic outcomes is well established, the role of our 'second genome' (the microbiome) has been largely overlooked. In this Review, we highlight recent studies that have shed light on the mechanisms that link the human gut microbiome to the efficacy and toxicity of xenobiotics, including drugs, dietary compounds and environmental toxins. Continued progress in this area could enable more precise tools for predicting patient responses and for the development of a new generation of therapeutics based on, or targeted at, the gut microbiome. Indeed, the admirable goal of precision medicine may require us to first understand the microbial pharmacists within.

Figure 1. Mechanisms linking the gut microbiota and xenobiotic metabolism

A. The gut microbiota can directly metabolize xenobiotics into active, inactive, or toxic metabolites. Xenobiotics may also shape the composition of the gut microbiota through antimicrobial activity or selective growth. The gut microbiota can indirectly influence xenobiotics through the modulation of host pathways for metabolism and transport. B. The gut microbiota can also influence xenobiotic metabolisms as a component of first-pass metabolism. Prior to entering systemic circulation and reaching the target tissue, orally ingested compounds are subject to metabolism in the intestine and liver, lowering the eventual systemic drug concentration. The gut microbiota may metabolize compounds prior to absorption, after efflux from the intestinal epithelium, or following biliary excretion from the liver.

Figure 2. Major reaction types catalyzed by the gut microbiome and their pharmacological consequences

A majority of known microbial biotransformations segregate into one of two reaction classes: reduction, in which compounds gain electrons from electron donors (part a), and hydrolysis, in which chemical bonds are cleaved through the addition of water (part b). The sites of modifications are highlight in yellow (reduction) and blue (hydrolysis). For a comprehensive list of drug biotransformations see Supplementary information S1 (Table). The microbial metabolism of pharmaceuticals can lead to their activation (part c), inactivation (part d) or result in the production of toxic compounds (part e); this is illustrated by the differential effects of the drugs in germ-free animals, compared to colonized animals. Activation refers to the conversion of a prodrug to its bioactive form, contributing to therapeutic concentrations. Examples include the prodrug sulfasalazine and prontosil. Inactivation refers to the conversion of an active metabolite to a downstream metabolite with reduced bioactivity. Examples include the cardiac drug digoxin and the anti-inflammatory drug methotrexate. Toxicity occurs due to the microbial production of metabolites that are toxic to the host. Examples include the hydrolysis of SN-38G to SN-38, the hydrolysis of glucuronidated NSAIDs to NSAIDs, and the metabolism of melamine to cyanuric acid.

Figure 3. Host-microbiota interactions shape therapeutic outcomes

A. Simvastatin drug levels in the host positively correlate with levels of secondary bile acids. The metabolism of bile acids by gut bacteria possibly contributes to the absorption of simvastatin through modulating the expression of host transporters or through directly competing with the transporter. B. The protective effects of tempol on diet-induced obesity are mediated through the gut microbiota. Tempol treatment reduces the abundance of Lactobacillus spp., which is involved in deconjugating taurine-conjugated bile acids into free bile acids via bile salt hydrolases (BSH). This results in elevated levels of taurine-conjugated bile acids, such as tauro-β-muricholic acid, a known antagonist of the metabolic regulator farnesoid X receptor (FXR). C. Microbial metabolites compete with drugs for host xenobiotic metabolism enzymes. The microbial product p-cresol, a product of tyrosine metabolism, and acetaminophen both serve as substrates for the same enzyme, the host sulfotransferase SULT. Therefore, elevated levels of p-cresol inhibit the conversion of acetaminophen-glucuronide (the active form) to acetaminophen-sulfate (the inactive form) by SULT.

Figure 4. Microbial metabolism of dietary compounds

A. The plant-derived dietary lignans pinoresinol and secoisolariciresinol are metabolized by several bacteria into the cancer-protective compounds enterodiol and enterolactone. B. The microbiota is responsible for the reactivation of the heterocyclic amine 2-amino-3-methylimidazo[4,5-f] quinoline after hepatic inactivation, which leads to delayed excretion of the carcinogenic compound. C. The microbial production of trimethylamine from choline-containing compounds represents a critical link between dietary phosphatidylcholine and the atherosclerotic metabolite trimethylamine N-oxide (TMAO). D. The metabolism of melamine by the gut microbiome leads to kidney stones. Klebsiella terragena converts melamine to cyanuric acid, which complexes with melamine into insoluble aggregates in the kidney.

Figure 5. Translational implications of microbiome research in pharmacology

A. Metagenomic and metabolomic approaches enable the dissection of microbial communities at multiple scales from complex communities to individual metabolites. This information can be used to find biomarkers, to develop co-therapies that target the microbiota or to identify novel drugs. B. Inhibiting microbial enzymes in the gut. Such examples include using small molecules to inhibit bacterial β-glucuronidase activity (left panel) and the dietary inhibition of cardiac drug inactivation by Eggerthella lenta (right panel). C. Microbiome-based diagnostics. Examples include measuring: the abundance of bacterial species that are associated with tacrolimus efficacy (left panel); the presence or absence of genes that are associated with the bioavailability of digoxin (middle panel); and the levels of the microbial metabolite p-cresol, which is associated with acetaminophen metabolism (right panel).