title: Arsenic induces structural and compositional colonic microbiome change and promotes host nitrogen and amino acid metabolism.
abstract: Chronic exposure to arsenic in drinking water causes cancer and non-cancer diseases. However, mechanisms for chronic arsenic-induced pathogenesis, especially in response to lower exposure levels, are unclear. In addition, the importance of health impacts from xeniobiotic-promoted microbiome changes is just being realized and effects of arsenic on the microbiome with relation to disease promotion are unknown. To investigate impact of arsenic exposure on both microbiome and host metabolism, the stucture and composition of colonic microbiota, their metabolic phenotype, and host tissue and plasma metabolite levels were compared in mice exposed for 2, 5, or 10weeks to 0, 10 (low) or 250 (high) ppb arsenite (As(III)). Genotyping of colonic bacteria revealed time and arsenic concentration dependent shifts in community composition, particularly the Bacteroidetes and Firmicutes, relative to those seen in the time-matched controls. Arsenic-induced erosion of bacterial biofilms adjacent to the mucosal lining and changes in the diversity and abundance of morphologically distinct species indicated changes in microbial community structure. Bacterical spores increased in abundance and intracellular inclusions decreased with high dose arsenic. Interestingly, expression of arsenate reductase (arsA) and the As(III) exporter arsB, remained unchanged, while the dissimilatory nitrite reductase (nrfA) gene expression increased. In keeping with the change in nitrogen metabolism, colonic and liver nitrite and nitrate levels and ratios changed with time. In addition, there was a concomitant increase in pathogenic arginine metabolites in the mouse circulation. These data suggest that arsenic exposure impacts the microbiome and microbiome/host nitrogen metabolism to support disease enhancing pathogenic phenotypes.
authors.affiliation: Department of Biological Sciences, Duquesne University, Pittsburgh, PA 15282, United States.
authors.forename: Rishu
authors.initials: R
authors.lastname: Dheer
authors.affiliation: Department of Biological Sciences, Duquesne University, Pittsburgh, PA 15282, United States.
authors.forename: Jena
authors.initials: J
authors.lastname: Patterson
authors.affiliation: Department of Biological Sciences, Duquesne University, Pittsburgh, PA 15282, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Dudash
authors.affiliation: Department of Civil and Environmental Engineering, University of Pittsburgh Swanson School of Engineering, Pittsburgh, PA 15261, United States.
authors.forename: Elyse N
authors.initials: EN
authors.lastname: Stachler
authors.affiliation: Department of Civil and Environmental Engineering, University of Pittsburgh Swanson School of Engineering, Pittsburgh, PA 15261, United States.
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Bibby
authors.affiliation: Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, United States.
authors.forename: Donna B
authors.initials: DB
authors.lastname: Stolz
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh 15261, United States; Vascular Medicine Institute, University of Pittsburgh, Pittsburgh 15261, United States.
authors.forename: Sruti
authors.initials: S
authors.lastname: Shiva
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, United States.
authors.forename: Zeneng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, United States.
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh 15261, United States; Vascular Medicine Institute, University of Pittsburgh, Pittsburgh 15261, United States; Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15219, United States. Electronic address: aab20@pitt.edu.
authors.forename: Aaron
authors.initials: A
authors.lastname: Barchowsky
authors.affiliation: Department of Biological Sciences, Duquesne University, Pittsburgh, PA 15282, United States.
authors.forename: John F
authors.initials: JF
authors.lastname: Stolz
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000378:metabolism; D001151:Arsenic / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects / Q000235:genetics; D018441:Biofilms / Q000187:drug effects; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology*; D005838:Genotype; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D064307:Microbiota / Q000187:drug effects* / Q000235:genetics; D009566:Nitrates / Q000378:metabolism; D009572:Nitrite Reductases / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D009584:Nitrogen / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D009566:Nitrates; D009573:Nitrites; D001120:Arginine; D009572:Nitrite Reductases; D001151:Arsenic; D009584:Nitrogen
keywords: Arginine; Arsenic; Bacteroidetes; Colon microbiome; Firmicutes; Nitrite/nitrate