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      Chemical transformation of xenobiotics by the human gut microbiota

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          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.

          BACKGROUND

          Humans ingest a multitude of smallmolecules that are foreign to the body (xenobiotics), including dietary components, environmental chemicals, and pharmaceuticals. The trillions of microorganisms that inhabit our gastrointestinal tract (the human gut microbiota) can directly alter the chemical structures of such compounds, thus modifying their lifetimes, bioavailabilities, and biological effects. Our knowledge of how gut microbial transformations of xenobiotics affect human health is in its infancy, which is surprising given the importance of the gut microbiota. We currently lack an understanding of the extent to which this metabolism varies between individuals, the mechanisms by which these microbial activities influence human biology, and how we might rationally manipulate these reactions. This deficiency stems largely from the difficulty of connecting this microbial chemistry to specific organisms, genes, and enzymes.

          ADVANCES

          Over the past several decades, studies of gut microbiota–mediated modification of xenobiotics have revealed that these organisms collectively have a larger metabolic repertoire than human cells. The chemical differences between human andmicrobial transformations of ingested compounds arise not only from the increased diversity of enzymes present in this complex and variable community but also from the distinct selection pressures that have shaped these activities. For example, whereas host metabolism evolved to facilitate excretion of many xenobiotics from the body, microbial modifications of these compounds and their human metabolites often support microbial growth through provision of nutrients or production of energy. Notably, the chemistry of microbial transformations often opposes or reverses that of host metabolism, altering the pharmacokinetic and pharmacodynamic properties of xenobiotics and associated metabolites.

          The range of xenobiotics subject to gutmicrobial metabolism is impressive and expanding. Gut microbes modify many classes of dietary compounds, including complex polysaccharides, lipids, proteins, and phytochemicals. These metabolic reactions are linked to a variety of health benefits, aswell as disease susceptibilities. Gut microbes are also able to transform industrial chemicals and pollutants, altering their toxicities and lifetimes in the body. Similarly, microbial transformations of drugs can change their pharmacokinetic properties, be critical for prodrug activation, and lead to undesirable side effects or loss of efficacy. In the vast majority of cases, the individual microbes and enzymes that mediate these reactions are unknown.

          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.

          Fueled by findings underscoring the relevance of microbial xenobiotic metabolism to human health, scientists are increasingly seeking to discover and manipulate the enzymatic chemistry involved in these transformations. Recent work exploring how gut microbes metabolize the drugs digoxin and irinotecan, as well as the dietary nutrient choline, provides guidance for such investigations. These studies, which combine traditional methods with modern approaches, illustrate how a molecular understanding of gut microbial xenobiotic metabolism can guide hypothesis-driven research into the roles these reactions play in both microbiota and host biology.

          OUTLOOK

          We still face a myriad of challenges in understanding the gut microbiota’s contribution to xenobiotic metabolism. It is imperative that we connect the many known microbial transformations with the genes and enzymes responsible for these activities, and knowledge of enzyme mechanism and biochemical logic will facilitate this objective. There also remains a great need to uncover currently unappreciated activities associated with this community. Revealing the full scope of microbially mediated transformations in the gut may give us newinsights into themany variable and contradictory studies regarding the effects of diet, pollutants, and drugs on human health. Microbial genes and enzymes will provide both specific targets for manipulation and diagnostic markers that can be incorporated into clinical studies and practice. Ultimately, a molecular understanding of gut microbial xenobiotic metabolism will inform personalized nutrition, toxicology risk assessment, precision medicine, and drug development.

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          Most cited references88

          • Record: found
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          • Article: not found

          Diversity of the human intestinal microbial flora.

          The human endogenous intestinal microflora is an essential "organ" in providing nourishment, regulating epithelial development, and instructing innate immunity; yet, surprisingly, basic features remain poorly described. We examined 13,355 prokaryotic ribosomal RNA gene sequences from multiple colonic mucosal sites and feces of healthy subjects to improve our understanding of gut microbial diversity. A majority of the bacterial sequences corresponded to uncultivated species and novel microorganisms. We discovered significant intersubject variability and differences between stool and mucosa community composition. Characterization of this immensely diverse ecosystem is the first step in elucidating its role in health and disease.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon.

            The microbiome is being characterized by large-scale sequencing efforts, yet it is not known whether it regulates host metabolism in a general versus tissue-specific manner or which bacterial metabolites are important. Here, we demonstrate that microbiota have a strong effect on energy homeostasis in the colon compared to other tissues. This tissue specificity is due to colonocytes utilizing bacterially produced butyrate as their primary energy source. Colonocytes from germfree mice are in an energy-deprived state and exhibit decreased expression of enzymes that catalyze key steps in intermediary metabolism including the TCA cycle. Consequently, there is a marked decrease in NADH/NAD(+), oxidative phosphorylation, and ATP levels, which results in AMPK activation, p27(kip1) phosphorylation, and autophagy. When butyrate is added to germfree colonocytes, it rescues their deficit in mitochondrial respiration and prevents them from undergoing autophagy. The mechanism is due to butyrate acting as an energy source rather than as an HDAC inhibitor. Copyright © 2011 Elsevier Inc. All rights reserved.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              How glycan metabolism shapes the human gut microbiota.

              Symbiotic microorganisms that reside in the human intestine are adept at foraging glycans and polysaccharides, including those in dietary plants (starch, hemicellulose and pectin), animal-derived cartilage and tissue (glycosaminoglycans and N-linked glycans), and host mucus (O-linked glycans). Fluctuations in the abundance of dietary and endogenous glycans, combined with the immense chemical variation among these molecules, create a dynamic and heterogeneous environment in which gut microorganisms proliferate. In this Review, we describe how glycans shape the composition of the gut microbiota over various periods of time, the mechanisms by which individual microorganisms degrade these glycans, and potential opportunities to intentionally influence this ecosystem for better health and nutrition.
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                Author and article information

                Journal
                Science
                Science
                Science
                Science (New York, N.y.)
                American Association for the Advancement of Science
                0036-8075
                1095-9203
                24 August 2018
                2018
                : 356
                : 6344
                : eaag2770
                Affiliations
                [1 ]Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA
                [2 ]Broad Institute, Cambridge, MA 02139, USA
                Author notes
                [* ]Corresponding author. Email: balskus@ 123456chemistry.harvard.edu
                Article
                Science-356-eaag2770
                10.1126/science.aag2770
                5534341
                28642381
                a474f28c-45cc-4412-89ef-5fad95bac94a
                2018 © The Authors, some rights reserved

                This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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                Microbiota

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