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Review
. 2017 Jun 23;356(6344):eaag2770.
doi: 10.1126/science.aag2770.

Chemical transformation of xenobiotics by the human gut microbiota

Nitzan Koppel  1 , Vayu Maini Rekdal  1 , Emily P Balskus  2   3
Affiliations
Review

Chemical transformation of xenobiotics by the human gut microbiota

Nitzan Koppel et al. Science. .

Abstract

The human gut microbiota makes key contributions to the metabolism of ingested compounds (xenobiotics), transforming hundreds of dietary components, industrial chemicals, and pharmaceuticals into metabolites with altered activities, toxicities, and lifetimes within the body. The chemistry of gut microbial xenobiotic metabolism is often distinct from that of host enzymes. Despite their important consequences for human biology, the gut microbes, genes, and enzymes involved in xenobiotic metabolism are poorly understood. Linking these microbial transformations to enzymes and elucidating their biological effects is undoubtedly challenging. However, recent studies demonstrate that integrating traditional and emerging technologies can enable progress toward this goal. Ultimately, a molecular understanding of gut microbial xenobiotic metabolism will guide personalized medicine and nutrition, inform toxicology risk assessment, and improve drug discovery and development.

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Figures

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Human gut microbes metabolize xenobiotics. Themicroorganisms that inhabit the human gut alter the chemical structures of ingested compounds, including dietarycomponents, industrial chemicals, and drugs.These changes affect xenobiotic toxicity, biological activity, and bioavailability.The gutmicrobialenzymesresponsibleformanyofthesetransformationsarepoorlyunderstood.Me,methyl.
Fig. 1
Fig. 1
Identifying gut microbial genes that predict cardiac drug metabolism. (A) E. lenta reductive metabolism leads to cardiac drug inactivation. (B) A combination of culture-based studies, sequencing, and bioinformatics helped to identify microbial genes associated with digoxin metabolism in humans.
Fig. 2
Fig. 2
Uncovering gut microbial enzymes that convert dietary choline to disease-associated metabolites. (A) Choline is metabolized by a gut microbial-human co-metabolic pathway into the disease-associated metabolites trimethylamine (TMA) and trimethylamine N-oxide (TMAO). (B) A chemically guided, rational genome-mining effort enabled the identification and characterization of enzymes involved in gut microbial anaerobic choline metabolism.
Fig. 3
Fig. 3
Preventing drug reactivation and toxicity by inhibiting gut microbial enzymes. (A) Microbial cleavage of the glucuronidated drug conjugate of the cancer chemotherapeutic SN-38 leads to drug reactivation and toxicity within the gut. UDP, uridine diphosphate. (B) High-throughput screening identified specific inhibitors of bacterial β-glucuronidases. These compounds alleviated the GI toxicity associated with irinotecan metabolism. Et, ethyl.
Fig. 4
Fig. 4
Potential implications of understanding gut microbial xenobiotic metabolism. (A) Interfacing clinical studies and hypothesis-driven research in model systems is essential for elucidating the biological consequences of gut microbial xenobiotic metabolism. Incorporating a mechanistic understanding of microbial transformations, along with knowledge of host genetics and metabolism, could (B) inform personalized nutrition, (C) improve toxicological risk assessment, and (D) enable personalized medicine.
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