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Arsenic’s Toxicity: Microbiome Alterations in the Mouse Gut


Exposure to arsenic affects large human populations worldwide and has been linked to several health hazards, such as but not limited to cancer (skin, bladder, lung and liver), diabetes and cardiovascular disorders. In addition, there are large differences in susceptibility to arsenic-induced diseases among individuals which is frequently associated with different spectra of arsenic metabolism. As underlying causes, several mechanisms, such as genetic poly- morphisms, epigenetics, and nutrition homeostasis, have been proposed.

Accumulating evidence indicates that perturbations of the gut microbiome and functions may play an important role in the development of human diseases. The gut microbiota has important functions in metabolic processing, energy production, immune cell development, food digestion, epithelial homeostasis, etc. The gut microbiome also metabolizes arsenic, generating several intermediate compounds that are either more or less toxic than the ingested arsenic itself. Earlier research had already revelead that bacterial infection significantly perturbed the gut microbiome composition in C57BL/6 mice, which in turn resulted in altered spectra of arsenic metabolites in urine, with inorganic arsenic species and methylated and thiolated arsenic being perturbed.

Does arsenic exposure have an important impact on the gut microbiome composition and activity ? This is the question that a group of US based researchers tried to answer.

The new study:
The researchers from MIT and University of North Carolina at Chapel Hill investigated the impact of arsenic exposure on the gut microbiome composition and its metabolic profiles. C57BL/6 mice were exposed to 10 ppm arsenic in drinking water for 4 weeks. After this period of arsenic exposure, 16S rRNA gene sequencing was used to compare the gut microbiome profiles of arsenic-exposed mice with those of untreated mice. Additionally, study leader Kun Lu amnd his colleagues analyzed several hundred metabolites in blood, urine, and feces with liquid chromatography/mass spectroscopy to obtain an overview of how changes in the microbiome affected metabolic function.

Schemata showing that arsenic exposure not only perturbs the microbiome of the mouse gut but also alters its metabolic profile

The gene sequencing revealed that arsenic exposure significantly perturbed the gut microbiome composition in C57BL/6 mice. In control mice drinking arsenic-free water, the gut was populated predominantly with Bacteroidetes and Firmicutes families. While the population of Bacteroidetes remained similar in arsenic-treated mice, several Firmicutes families significantly decreased. Firmicutes make up the largest portion of the mouse and human gut microbiome and have been shown to be involved in energy resorption and obesity.

Analysis of the metabolites revealed a concurrent effect, with a number of gut microflora–related metabolites being perturbed in multiple biological matrices (with 146 increased and 224 decreased molecular features). Some of the most influenced metabolites were identified by MS/MS. The structures of these metabolites were diverse, including amino acid derivatives, bile acids, lipids, fatty acids, isoflavones, indole derivatives, and glucuronide and carnitine conjugates, with many of the metabolites being either directly generated or modulated by the gut bacteria. Some of these metabolites are linked to obesity, insulin resistance, and cardiovascular disease. For example, “bile acids may be potentially involved in arsenic-induced insulin resistance, but this needs to be confirmed,” says Lu.

The authors conclude that their findings indicate that arsenic exposure not only perturbs the gut microbiome at the abundance level but that it also alters metabolic profiles of the gut microbiome, supporting the hypothesis that perturbations of the gut microbiome may serve as a new mechanism by which arsenic exposure leads to or exacerbates human

Many questions remain to be answered:
  • Can these results obtained from a mouse model be transfered to humans with a different microbiome ?
  • Will the human gut microbiome be influenced from a typical exposure situation that is characterized by lower arsenic concentrations for a longer time?
  • How does arsenic impact the microbiome during its development shortly after birth ?
  • What is the influence of sex-specific influences and toxicity phenotypes ?
These and many other questions need to be addressed in future studies.

Michael Sperling

The cited study:

Kun Lu, Ryan Phillip Abo, Katherine Ann Schlieper, Michelle E. Graffam, Stuart Levine, John S. Wishnok, James A. Swenberg, Steven R. Tannenbaum, James G. Fox, Arsenic Exposure Perturbs the Gut Microbiome and Its Metabolic Profile in Mice: An Integrated Metagenomics and Metabolomics Analysis, Environ. Health. Perspect., 122 (2014) 284–291. doi: 10.1289/ehp.1307429

Related studies (newest first):

Kun Lu, Peter Hans Cable, Ryan Phillip Abo, Hongyu Ru, Michelle E. Graffam, Katherine Ann Schlieper, Nicola M.A. Parry, Stuart Levine, Wanda M. Bodnar, John S. Wishnok, Miroslav Styblo, James A. Swenberg, James G. Fox, Steven R. Tannenbaum, Gut Microbiome Perturbations Induced by Bacterial Infection Affect Arsenic Biotransformation, Chem. Res. Toxicol., 26/12 (2013) 1893–1903. DOI: 10.1021/tx4002868

Pradeep Alava, Filip Tack, Gijs Du Laing, Tom Van de Wiele, Arsenic undergoes significant speciation changes upon incubation of contaminated rice with human colon micro biota, J. Hazard. Mater., 262 (2013) 1237–1244. doi: 10.1016/j.jhazmat.2012.05.042

T.S. Pinyayev, M.J. Kohan, K. Herbin-Davis, J.T. Creed, D.J. Thomas, Preabsorptive metabolism of sodium arsenate by anaerobic microbiota of mouse cecum forms a variety of methylated and thiolated arsenicals, Chem. Res. Toxicol., 24 (2011) 475–477. doi: 10.1021/tx200040w

X. Ren, C.M. McHale, C.F. Skibola, A.H. Smith, M.T. Smith, L. Zhang, An emerging role for epigenetic dysregulation in arsenic toxicity and carcinogenesis, Environ. Health Perspect., 119 (2011) 11–19.  doi: 10.1289/ehp.1002114

L. Smeester, J.E. Rager, K.A. Bailey, X. Guan, N. Smith, G. Garcia-Vargas, L.-M. Del Razo, Z. Drobna, H. Kelkar, M. Styblo, R.C. Fryet, Epigenetic changes in individuals with arsenicosis, Chem. Res. Toxicol.,  24 (2011) 165–167. doi: 10.1021/tx1004419

T. Van de Wiele, C.M. Gallawa, K.M. Kubachka, J.T. Creed, N. Basta, E.A. Dayton, S. Whitacre, G. Du Laing, K. Bradham, Arsenic metabolism by human gut microbiota upon in vitro digestion of contaminated soils, Environ. Health Perspect., 118 (2010) 1004–1009. doi: 10.1289/ehp.0901794.

 Related EVISA Resources

Link database: Toxicity of arsenic species
Brief summary: Speciation and Toxicity
Brief summary: ICP-MS: A versatile detection system for speciation analysis
Brief summary: LC-ICP-MS: The most often used hyphenated system for speciation analysis

 Related EVISA News

August 2, 2010: Gut bacteria transform inorganic arsenate leading to more toxic arsenic species
February 23, 2010: Accumulation or production of arsenobetaine in humans?
September 5, 2008: Exposure to inorganic arsenic may increase diabetes risk
January 17, 2007: Human metabolism of arsenic is altered by fasting
June 27, 2005: Susceptibility to arsenic toxicity influenced by genes

last time modified: August 22, 2016


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