Arsenic’s Toxicity: Microbiome Alterations in the Mouse Gut

Background:
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.



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
diseases.