Exposure to Arsenite in CD-1 Mice during Juvenile and Adult Stages: Effects on Intestinal Microbiota and Gut-Associated Immune Status

Abstract

Intestinal microbiota composition and gut-associated immune response can contribute to the toxicity of arsenic. We investigated the potential toxicity of short-term arsenic exposure on gut microbiome composition, intestinal immune status, microbial arsenic resistance gene, and arsenic metabolic profiles in adult and developmental stages of CD-1 mice. The potential toxicity of arsenite [As(III)] was determined for two life stages: (i) adult animals at 24 or 48 h after single gavage (0.05 mg/kg body weight [b.w.] [low dose], 0.1 mg/kg b.w. [medium dose], and 0.2 mg/kg b.w. [high dose]) and repeated exposure at 1 mg/liter for 8 days and (ii) postnatal day 10 (PND10) and PND21 after single gavage (0.05 mg/kg b.w.). Dose- and time-dependent responses in bacterial recovery/microbial composition were observed in adults after a single gavage. Repeated exposure caused a transient decrease in the recovery of intestinal bacteria, a shift in the bacterial population with abundance of arsenic resistance genes, and evidence for host metabolism of arsenite into less-reactive trivalent methylated species. Arsenic exposure in adult animals induced high levels of CC chemokines and of proinflammatory and anti-inflammatory cytokine secretion in intestine. Arsenic exposure at PND21 resulted in the development of distinct bacterial populations. Results of this study highlight significant changes in the intestinal microbiome and gut-associated immune status during a single or repeated exposure to arsenic in juvenile and adult animals. The data warrant investigation of the long-term effects of oral arsenic exposure on the microbiome and of immune system development and responses. Transformation of organic arsenic to toxic inorganic arsenic (iAs) is likely carried out by intestinal bacteria, and iAs may alter the viability of certain microbial populations. This study addressed the impact of arsenic exposure on intestinal microbiota diversity and host gut-associated immune mediators during early development or adulthood using scenarios of acute or repeated doses. During acute arsenic exposure, animals developed defense functions characterized by higher abundances of bacteria that are involved in arsenic resistance or detoxification mechanisms. Arsenite had a negative effect on the abundance of bacterial species that are involved in the conversion of protein to butyrate, which is an alternative energy source in the intestine. The intestinal mucosal immune cytokine profile reflected a mechanism of protection from arsenic toxicity.

The Human Gut Microbiome’s Influence on Arsenic Toxicity

“…Notably, effects were stratified by sex and feeding status, with male and formula fed infants more susceptible to arsenic-related effects on the microbiome [128]. This is in contrast with findings in CD-1 mice that female mice were more sensitive to arsenic-induced microbiome perturbation [127]. In Bangladeshi children (4-6 years of age), high levels of arsenic in home drinking water were associated with a greater abundance of Gammaproteobacteria in the microbiome, more specifically, members of the Enterobacteriaceae family [129].…”

“…Even though microbiome change can be quantified following arsenic exposure, it can be difficult to determine whether these changes have deleterious effects. For example, lab animal studies have made efforts to identify plausible links between arsenicinduced changes in the microbiome and host physiology, including altered host nitrogen homeostasis [64], energy metabolism [126], gut immune signaling [127], and epithelial histology [123]. In all of these cases, however, it remains unclear whether the observed changes in the host were caused directly by changes in the microbiota, arsenic toxicity, or interactions between them.…”

Arsenic and the gastrointestinal tract microbiome

“…Other mouse gut microbiome‐related changes included downregulation of host genes encoding one‐carbon and glutathione metabolisms, significantly decreased liver S‐adenosylmethionine levels, and numerous genes encoding various functions associated with hepatocellular carcinoma were significantly altered (Chi et al ., ). Arsenic exposed adult mice display higher levels of CC chemokines, and pro‐inflammatory and anti‐inflammatory cytokine secretion in the intestine accompanied by significant changes in the gut microbiome (Gokulan et al ., ). It is also reasonable to assume microbiome change/differences relate to host genotype as shown in significant microbiome compositional differences between wild‐type and interleukin‐10 knockout mice that in turn was tied to altered arsenic metabolism (Lu et al ., ), supporting the link between microbiome composition and pre‐systemic arsenical metabolism.…”

Molecular Aspects of Colorectal Adenomas: The Interplay among Microenvironment, Oxidative Stress, and Predisposition

“…Heavy metal contact consequent to food uptake or occupational exposure is considered responsible for gut microbiota dysbiosis. Metabolites of arsenic alter gut bacterial species, the production of butyrate, and the gut-associated immune system [34]. Cadmium exposure determines an inflammatory response and tight junction alterations in the intestinal barrier that increase gut permeability and favour the Bacteroidetes in the microbiome [35].…”