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      Arsenic Exposure Perturbs the Gut Microbiome and Its Metabolic Profile in Mice: An Integrated Metagenomics and Metabolomics Analysis

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          Abstract

          Background: The human intestine is host to an enormously complex, diverse, and vast microbial community—the gut microbiota. The gut microbiome plays a profound role in metabolic processing, energy production, immune and cognitive development, epithelial homeostasis, and so forth. However, the composition and diversity of the gut microbiome can be readily affected by external factors, which raises the possibility that exposure to toxic environmental chemicals leads to gut microbiome alteration, or dysbiosis. Arsenic exposure affects large human populations worldwide and has been linked to a number of diseases, including cancer, diabetes, and cardiovascular disorders.

          Objectives: We investigated the impact of arsenic exposure on the gut microbiome composition and its metabolic profiles.

          Methods: We used an integrated approach combining 16S rRNA gene sequencing and mass spectrometry–based metabolomics profiling to examine the functional impact of arsenic exposure on the gut microbiome.

          Results: 16S rRNA gene sequencing revealed that arsenic significantly perturbed the gut microbiome composition in C57BL/6 mice after exposure to 10 ppm arsenic for 4 weeks in drinking water. Moreover, metabolomics profiling revealed a concurrent effect, with a number of gut microflora–related metabolites being perturbed in multiple biological matrices.

          Conclusions: Arsenic exposure not only alters the gut microbiome community at the abundance level but also substantially disturbs its metabolic profiles at the function level. These findings may provide novel insights regarding perturbations of the gut microbiome and its functions as a potential new mechanism by which arsenic exposure leads to or exacerbates human diseases.

          Citation: Lu K, Abo RP, Schlieper KA, Graffam ME, Levine S, Wishnok JS, Swenberg JA, Tannenbaum SR, Fox JG. 2014. Arsenic exposure perturbs the gut microbiome and its metabolic profile in mice: an integrated metagenomics and metabolomics analysis. Environ Health Perspect 122:284–291;  http://dx.doi.org/10.1289/ehp.1307429

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

          Dallas R Donohoe, Nikhil Garge, Xinxin Zhang … (2011)
          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.
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            Adipocytes as regulators of energy balance and glucose homeostasis.

            Evan Rosen, Bruce M Spiegelman (2006)
            Adipocytes have been studied with increasing intensity as a result of the emergence of obesity as a serious public health problem and the realization that adipose tissue serves as an integrator of various physiological pathways. In particular, their role in calorie storage makes adipocytes well suited to the regulation of energy balance. Adipose tissue also serves as a crucial integrator of glucose homeostasis. Knowledge of adipocyte biology is therefore crucial for understanding the pathophysiological basis of obesity and metabolic diseases such as type 2 diabetes. Furthermore, the rational manipulation of adipose physiology is a promising avenue for therapy of these conditions.
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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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                Author and article information

                Journal
                Journal ID (nlm-ta): Environ Health Perspect
                Journal ID (iso-abbrev): Environ. Health Perspect
                Journal ID (publisher-id): EHP
                Title: Environmental Health Perspectives
                Publisher: National Institute of Environmental Health Sciences
                ISSN (Print): 0091-6765
                ISSN (Electronic): 1552-9924
                Publication date (Electronic): 10 January 2014
                Publication date (Print): March 2014
                Volume: 122
                Issue: 3
                Pages: 284-291
                Affiliations
                [1 ]Department of Biological Engineering,
                [2 ]Department of Biology, and
                [3 ]Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
                [4 ]Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
                [5 ]Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
                Author notes
                Address correspondence to K. Lu, 140 Environmental Health Science Building, University of Georgia, Athens, GA 30602 USA. Telephone: (706) 542-1001. E-mail: kunlu@ 123456uga.edu
                Article
                Publisher ID: ehp.1307429
                DOI: 10.1289/ehp.1307429
                PMC ID: 3948040
                PubMed ID: 24413286
                SO-VID: 00b71ec6-c9f2-4cdb-af25-656bd4b9b0e2
                License:

                Publication of EHP lies in the public domain and is therefore without copyright. All text from EHP may be reprinted freely. Use of materials published in EHP should be acknowledged (for example, “Reproduced with permission from Environmental Health Perspectives”); pertinent reference information should be provided for the article from which the material was reproduced. Articles from EHP, especially the News section, may contain photographs or illustrations copyrighted by other commercial organizations or individuals that may not be used without obtaining prior approval from the holder of the copyright.

                History
                Date received : 26 July 2013
                Date accepted : 09 January 2014
                Date: 10 January 2014
                Date: 01 March 2014
                Categories
                Subject: Research

                ScienceOpen disciplines: Public health
                Data availability:
                ScienceOpen disciplines: Public health

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