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

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Abstract

Although the significance of human genetic polymorphisms in therapeutic outcomes is well established, the importance of our “second genome” (the microbiome) has been largely overlooked. In this Review, we highlight recent studies that shed light on the mechanisms linking 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 the development of a next 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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Responses of Gut Microbiota and Glucose and Lipid Metabolism to Prebiotics in Genetic Obese and Diet-Induced Leptin-Resistant Mice

Amandine Everard, Vladimir Lazarevic, Muriel Derrien … (2011)

OBJECTIVE To investigate deep and comprehensive analysis of gut microbial communities and biological parameters after prebiotic administration in obese and diabetic mice. RESEARCH DESIGN AND METHODS Genetic (ob/ob) or diet-induced obese and diabetic mice were chronically fed with prebiotic-enriched diet or with a control diet. Extensive gut microbiota analyses, including quantitative PCR, pyrosequencing of the 16S rRNA, and phylogenetic microarrays, were performed in ob/ob mice. The impact of gut microbiota modulation on leptin sensitivity was investigated in diet-induced leptin-resistant mice. Metabolic parameters, gene expression, glucose homeostasis, and enteroendocrine-related L-cell function were documented in both models. RESULTS In ob/ob mice, prebiotic feeding decreased Firmicutes and increased Bacteroidetes phyla, but also changed 102 distinct taxa, 16 of which displayed a >10-fold change in abundance. In addition, prebiotics improved glucose tolerance, increased L-cell number and associated parameters (intestinal proglucagon mRNA expression and plasma glucagon-like peptide-1 levels), and reduced fat-mass development, oxidative stress, and low-grade inflammation. In high fat–fed mice, prebiotic treatment improved leptin sensitivity as well as metabolic parameters. CONCLUSIONS We conclude that specific gut microbiota modulation improves glucose homeostasis, leptin sensitivity, and target enteroendocrine cell activity in obese and diabetic mice. By profiling the gut microbiota, we identified a catalog of putative bacterial targets that may affect host metabolism in obesity and diabetes.

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Xenobiotics shape the physiology and gene expression of the active human gut microbiome.

Corinne Ferrier Maurice, Henry Joseph Haiser, Peter James Turnbaugh (2013)

The human gut contains trillions of microorganisms that influence our health by metabolizing xenobiotics, including host-targeted drugs and antibiotics. Recent efforts have characterized the diversity of this host-associated community, but it remains unclear which microorganisms are active and what perturbations influence this activity. Here, we combine flow cytometry, 16S rRNA gene sequencing, and metatranscriptomics to demonstrate that the gut contains a distinctive set of active microorganisms, primarily Firmicutes. Short-term exposure to a panel of xenobiotics significantly affected the physiology, structure, and gene expression of this active gut microbiome. Xenobiotic-responsive genes were found across multiple bacterial phyla, encoding antibiotic resistance, drug metabolism, and stress response pathways. These results demonstrate the power of moving beyond surveys of microbial diversity to better understand metabolic activity, highlight the unintended consequences of xenobiotics, and suggest that attempts at personalized medicine should consider interindividual variations in the active human gut microbiome. Copyright © 2013 Elsevier Inc. All rights reserved.

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Dietary Polyphenols Promote Growth of the Gut Bacterium Akkermansia muciniphila and Attenuate High-Fat Diet–Induced Metabolic Syndrome

Diana Roopchand, Rachel Carmody, Peter Kühn … (2015)

Dietary polyphenols protect against metabolic syndrome, despite limited absorption and digestion, raising questions about their mechanism of action. We hypothesized that one mechanism may involve the gut microbiota. To test this hypothesis, C57BL/6J mice were fed a high-fat diet (HFD) containing 1% Concord grape polyphenols (GP). Relative to vehicle controls, GP attenuated several effects of HFD feeding, including weight gain, adiposity, serum inflammatory markers (tumor necrosis factor [TNF]α, interleukin [IL]-6, and lipopolysaccharide), and glucose intolerance. GP lowered intestinal expression of inflammatory markers (TNFα, IL-6, inducible nitric oxide synthase) and a gene for glucose absorption (Glut2). GP increased intestinal expression of genes involved in barrier function (occludin) and limiting triglyceride storage (fasting-induced adipocyte factor). GP also increased intestinal gene expression of proglucagon, a precursor of proteins that promote insulin production and gut barrier integrity. 16S rRNA gene sequencing and quantitative PCR of cecal and fecal samples demonstrated that GP dramatically increased the growth of Akkermansia muciniphila and decreased the proportion of Firmicutes to Bacteroidetes, consistent with prior reports that similar changes in microbial community structure can protect from diet-induced obesity and metabolic disease. These data suggest that GP act in the intestine to modify gut microbial community structure, resulting in lower intestinal and systemic inflammation and improved metabolic outcomes. The gut microbiota may thus provide the missing link in the mechanism of action of poorly absorbed dietary polyphenols.

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Author and article information

Journal

Journal ID (nlm-journal-id): 101190261

Journal ID (pubmed-jr-id): 31733

Journal ID (nlm-ta): Nat Rev Microbiol

Journal ID (iso-abbrev): Nat. Rev. Microbiol.

Title: Nature reviews. Microbiology

ISSN (Print): 1740-1526

ISSN (Electronic): 1740-1534

Publication date Nihms-submitted: 23 December 2016

Publication date (Electronic): 14 March 2016

Publication date (Print): April 2016

Publication date PMC-release: 01 April 2017

Volume: 14

Issue: 5

Pages: 273-287

Affiliations

[1 ]Department of Microbiology & Immunology, G.W. Hooper Foundation, University of California San Francisco, 513 Parnassus Ave, San Francisco, CA 94143, USA

Author notes

[* ]Correspondence to: Peter J. Turnbaugh, Assistant Professor, Department of Microbiology & Immunology, G.W. Hooper Research Foundation, 513 Parnassus Avenue HSE 1001F, San Francisco, CA 94143-0552, Peter.Turnbaugh@ 123456ucsf.edu , office: (415) 502-3237, fax: (415) 502-8424

Article

Accession ID: PMC5243131 Pmcid ID: PMC5243131 Pmc-uid ID: 5243131 Manuscript ID: nihpa838273

DOI: 10.1038/nrmicro.2016.17

PMC ID: 5243131

PubMed ID: 26972811

SO-VID: 53116eb6-e48c-4899-961d-2483473968c7

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