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      Discovery and characterization of a prevalent human gut bacterial enzyme sufficient for the inactivation of a family of plant toxins

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          Abstract

          Although the human gut microbiome plays a prominent role in xenobiotic transformation, most of the genes and enzymes responsible for this metabolism are unknown. Recently, we linked the two-gene ‘cardiac glycoside reductase’ ( cgr) operon encoded by the gut Actinobacterium Eggerthella lenta to inactivation of the cardiac medication and plant natural product digoxin. Here, we compared the genomes of 25 E. lenta strains and close relatives, revealing an expanded 8-gene cgr-associated gene cluster present in all digoxin metabolizers and absent in non-metabolizers. Using heterologous expression and in vitro biochemical characterization, we discovered that a single flavin- and [4Fe-4S] cluster-dependent reductase, Cgr2, is sufficient for digoxin inactivation. Unexpectedly, Cgr2 displayed strict specificity for digoxin and other cardenolides. Quantification of cgr2 in gut microbiomes revealed that this gene is widespread and conserved in the human population. Together, these results demonstrate that human-associated gut bacteria maintain specialized enzymes that protect against ingested plant toxins.

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          Trillions of microbes live within the human gut and influence our health. In particular, these microbes can modify food and drugs into compounds (metabolites) that humans cannot produce on their own. These compounds are often beneficial to the human host, but in some cases – for example, if the modification alters how a drug works – can be detrimental.

          Digoxin is a toxic chemical produced by plants that, in low doses, can be used to treat heart conditions. It has been known for decades that the human gut bacterium Eggerthella lenta transforms digoxin into a metabolite that is an ineffective drug. Microbes use biological catalysts called enzymes to produce metabolites, but it was not known which enzymes enable E. lenta to modify digoxin.

          Using biochemical and genomic techniques, Koppel et al. now show that an enzyme called Cgr2 inactivates digoxin and other related plant toxins. Data about the gut microbes in nearly 1,900 people from three continents revealed that bacteria that can produce Cgr2 were present in the guts of more than 40% of the individuals, although often in low abundance. Further experiments did not reveal any obvious benefits that E. lenta gains from modifying digoxin. Instead, Koppel et al. propose that the bacteria carry out this modification to protect their human host from plant toxins.

          The results presented by Koppel et al. emphasise that the activities of gut microbes should be considered when designing new drugs or assessing how they work in the human body. The strategies used to identify Cgr2 could now be applied to discover other important gut microbe-drug interactions. Ultimately, this knowledge will help us to predict and control the activities of gut microbes in ways that could improve human health.

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          Most cited references76

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          Extensive personal human gut microbiota culture collections characterized and manipulated in gnotobiotic mice.

          The proportion of the human gut bacterial community that is recalcitrant to culture remains poorly defined. In this report, we combine high-throughput anaerobic culturing techniques with gnotobiotic animal husbandry and metagenomics to show that the human fecal microbiota consists largely of taxa and predicted functions that are represented in its readily cultured members. When transplanted into gnotobiotic mice, complete and cultured communities exhibit similar colonization dynamics, biogeographical distribution, and responses to dietary perturbations. Moreover, gnotobiotic mice can be used to shape these personalized culture collections to enrich for taxa suited to specific diets. We also demonstrate that thousands of isolates from a single donor can be clonally archived and taxonomically mapped in multiwell format to create personalized microbiota collections. Retrieving components of a microbiota that have coexisted in single donors who have physiologic or disease phenotypes of interest and reuniting them in various combinations in gnotobiotic mice should facilitate preclinical studies designed to determine the degree to which tractable bacterial taxa are able to transmit donor traits or influence host biology.
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            The MPI bioinformatics Toolkit as an integrative platform for advanced protein sequence and structure analysis

            The MPI Bioinformatics Toolkit (http://toolkit.tuebingen.mpg.de) is an open, interactive web service for comprehensive and collaborative protein bioinformatic analysis. It offers a wide array of interconnected, state-of-the-art bioinformatics tools to experts and non-experts alike, developed both externally (e.g. BLAST+, HMMER3, MUSCLE) and internally (e.g. HHpred, HHblits, PCOILS). While a beta version of the Toolkit was released 10 years ago, the current production-level release has been available since 2008 and has serviced more than 1.6 million external user queries. The usage of the Toolkit has continued to increase linearly over the years, reaching more than 400 000 queries in 2015. In fact, through the breadth of its tools and their tight interconnection, the Toolkit has become an excellent platform for experimental scientists as well as a useful resource for teaching bioinformatic inquiry to students in the life sciences. In this article, we report on the evolution of the Toolkit over the last ten years, focusing on the expansion of the tool repertoire (e.g. CS-BLAST, HHblits) and on infrastructural work needed to remain operative in a changing web environment.
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              Toxic cardenolides: chemical ecology and coevolution of specialized plant-herbivore interactions.

              Cardenolides are remarkable steroidal toxins that have become model systems, critical in the development of theories for chemical ecology and coevolution. Because cardenolides inhibit the ubiquitous and essential animal enzyme Na⁺/K⁺-ATPase, most insects that feed on cardenolide-containing plants are highly specialized. With a huge diversity of chemical forms, these secondary metabolites are sporadically distributed across 12 botanical families, but dominate the Apocynaceae where they are found in > 30 genera. Studies over the past decade have demonstrated patterns in the distribution of cardenolides among plant organs, including all tissue types, and across broad geographic gradients within and across species. Cardenolide production has a genetic basis and is subject to natural selection by herbivores. In addition, there is strong evidence for phenotypic plasticity, with the biotic and abiotic environment predictably impacting cardenolide production. Mounting evidence indicates a high degree of specificity in herbivore-induced cardenolides in Asclepias. While herbivores of cardenolide-containing plants often sequester the toxins, are aposematic, and possess several physiological adaptations (including target site insensitivity), there is strong evidence that these specialists are nonetheless negatively impacted by cardenolides. While reviewing both the mechanisms and evolutionary ecology of cardenolide-mediated interactions, we advance novel hypotheses and suggest directions for future work. © 2012 The Authors. New Phytologist © 2012 New Phytologist Trust.
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                Author and article information

                Contributors
                Role: Reviewing Editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                15 May 2018
                2018
                : 7
                Affiliations
                [1 ]deptDepartment of Chemistry and Chemical Biology Harvard University CambridgeUnited States
                [2 ]deptDepartment of Microbiology & Immunology University of California San FranciscoUnited States
                [3 ]deptDepartment of Biochemistry Brandeis University WalthamUnited States
                [4 ]Chan Zuckerberg Biohub San FranciscoUnited States
                [5 ]Broad Institute CambridgeUnited States
                [6]Max Planck Institute for Developmental Biology Germany
                [7]Max Planck Institute for Developmental Biology Germany
                Article
                33953
                10.7554/eLife.33953
                5953540
                29761785
                24d26c6a-28b3-4c99-9693-8b6da34d5a2e
                © 2018, Koppel et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                Product
                Funding
                Funded by: Smith family;
                Award ID: Graduate Science and Engineering Fellowship
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000001, National Science Foundation;
                Award ID: Graduate student fellowship, DGE1144152
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: Training grant, GM095450-01
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100000038, Natural Sciences and Engineering Research Council of Canada;
                Award ID: Postdoctoral fellowship
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: GM111978
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: R01HL122593
                Award Recipient :
                Funded by: Searle Scholars Program;
                Award ID: SSP-2016-1352; EB:12-SSP-243
                Award Recipient :
                Funded by: UCSF Department of Microbiology and Immunology;
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100001021, Damon Runyon Cancer Research Foundation;
                Award ID: DRR-42-16
                Award Recipient :
                Funded by: Chan Zuckerberg Biohub;
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100008069, University of California, San Francisco;
                Award ID: Program for Breakthrough Biomedical Research
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000008, David and Lucile Packard Foundation;
                Award ID: 2013-39267
                Award Recipient :
                Funded by: George W. Merck Fellowship;
                Award ID: 27-14
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000865, Bill and Melinda Gates Foundation;
                Award ID: OPP1158186
                Award Recipient :
                Funded by: Searle Scholars Program;
                Award ID: 12-SSP-243
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Microbiology and Infectious Disease
                Custom metadata
                A unique, widely distributed gut bacterial enzyme selectively metabolizes plant-derived cardiac glycoside drugs.

                Life sciences
                gut microbiome,digoxin,enzyme,xenobiotic,eggerthella lenta,other
                Life sciences
                gut microbiome, digoxin, enzyme, xenobiotic, eggerthella lenta, other

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