The gut microbiome is a neglected component of the first-pass metabolism of xenobiotics before reaching the general circulation.
Direct microbial metabolism of xenobiotics and their metabolites often involves reduction or hydrolysis, but most of the enzymes responsible for these reactions remain unknown.
Microbial metabolism influences both efficacy and toxicity, producing bioactive compounds, inactive metabolites and toxins.
Relevant host–microbial interactions include the expression of host genes that are involved in drug transport and metabolism, the interference with host enzymatic activity and the modulation of immune responses.
The translational implications of these studies include the development of novel co-therapies and the identification of new biomarkers and drugs.
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.
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The authors apologize to all of those colleagues whose work could not be included in this Review owing to space constraints. The authors also thank the reviewers for their comments and suggestions. This work was supported by the US National Institutes of Health (R01AT008618, R01HL122593 and F32DK101154), the Young Investigator Grant for Probiotics Research, the George Williams Hooper Research Foundation and the University of California San Francisco (UCSF) Department of Microbiology & Immunology. P.J.T. is a Nadia's Gift Foundation Innovator supported, in part, by the Damon Runyon Cancer Research Foundation (DRR-42-16).
P.J.T. is on the Scientific Advisory Board for Seres Therapeutics and Whole Biome, has consulted for Pfizer in the past year and has current research support from MedImmune.
The combined genetic material and metabolic activities of the microbiota.
The collection of all microorganisms (archaea, bacteria, microscopic fungi, parasites and viruses) found in a given body habitat.
Compounds that are foreign to a biological system. For humans, these include drugs, dietary bioactive compounds, food additives and environmental toxins.
- Azo bond
A chemical bond composed of N=N.
The study of how genetic factors influence therapeutic outcomes.
The use of sequencing-based genomic methods to analyse the links between genetics and therapeutic outcomes.
The proportion of an administered compound that reaches systemic circulation and thus has the potential to influence the intended target.
- First-pass metabolism
The metabolism of orally ingested compounds before reaching general circulation.
- Biliary excretion
The transfer of xenobiotics and other compounds from the plasma to bile through hepatocytes, which is followed by the release of the compounds into the gut lumen.
- Enterohepatic circulation
The circulation of xenobiotics and endogenous compounds that are absorbed from the intestines, transported to the liver, and then re-enter the intestine through the bile ducts, where they may be reabsorbed or metabolized by the gut microbiota.
A chemical reaction in which the oxidation state of a chemical bond is reduced. For example, a carbon–carbon bond modified to a carbon–hydrogen bond is a reductive transformation.
A chemical reaction in which a chemical bond is cleaved using a water molecule, which acts as the nucleophile.
- Cytochrome P450 enzymes
(CYPs) A family of enzymes that is responsible for the oxidative biotransformation of xenobiotics and other compounds.
Drugs that are administered in an inactive form and become active when metabolized.
A B vitamin that is essential for DNA synthesis, DNA repair and other biological reactions.
Animals devoid of microorganisms.
The colonization of germ-free animals with individual microorganisms or defined microbial communities.
The addition of glucuronic acid to a substrate. Glucuronidation is used as a mechanism of xenobiotic metabolism by the host.
- Bile acids
Steroid acids produced by the liver that emulsify fats during digestion.
The remaining compound after the removal of a glycosyl moiety.
- Serum metabolome
The collection of all metabolites found in serum.
The addition of a chemical unit (for example, glucuronic acid or glutathione) to xenobiotics, increasing the solubility and molecular weight of the parent compound and facilitating elimination from the body.
- Metabolic syndrome
A collection of physiological and biochemical conditions, defined as a combination of high blood pressure, increased blood sugar levels, excess fat and abnormal cholesterol levels. This syndrome increases the risk of heart disease, stroke and diabetes.
An oral medication used to treat type 2 diabetes.
A manual for the preparation and use of medicinal drugs. The name is derived from the Greek words pharmakon (drug) and -poios (making).
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Spanogiannopoulos, P., Bess, E., Carmody, R. et al. The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism. Nat Rev Microbiol 14, 273–287 (2016). https://doi.org/10.1038/nrmicro.2016.17
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