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. 2018 Dec 5;3(6):e00521-18.
doi: 10.1128/mSphere.00521-18.

Marginal Zinc Deficiency and Environmentally Relevant Concentrations of Arsenic Elicit Combined Effects on the Gut Microbiome

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Free PMC article

Marginal Zinc Deficiency and Environmentally Relevant Concentrations of Arsenic Elicit Combined Effects on the Gut Microbiome

Christopher A Gaulke et al. mSphere. .
Free PMC article

Abstract

Extensive research shows that dietary variation and toxicant exposure impact the gut microbiome, yielding effects on host physiology. However, prior work has mostly considered such exposure-microbiome interactions through the lens of single-factor exposures. In practice, humans exposed to toxicants vary in their dietary nutritional status, and this variation may impact subsequent exposure of the gut microbiome. For example, chronic arsenic exposure affects 200 million people globally and is often comorbid with zinc deficiency. Zinc deficiency can enhance arsenic toxicity, but it remains unknown how zinc status impacts the gut microbiome's response to arsenic exposure and whether this response links to host toxicity. Using 16S amplicon sequencing, we examined the combinatorial effects of exposure to environmentally relevant concentrations of arsenic on the composition of the microbiome in C57BL/6 mice fed diets varying in zinc concentration. Arsenic exposure and marginal zinc deficiency independently altered microbiome diversity. When combined, their effects on microbiome community structure were amplified. Generalized linear models identified microbial taxa whose relative abundance in the gut was perturbed by zinc deficiency, arsenic, or their interaction. Further, we correlated taxonomic abundances with host DNA damage, adiponectin expression, and plasma zinc concentration to identify taxa that may mediate host physiological responses to arsenic exposure or zinc deficiency. Arsenic exposure and zinc restriction also result in increased DNA damage and decreased plasma zinc. These physiological changes are associated with the relative abundance of several gut taxa. These data indicate that marginal zinc deficiency sensitizes the microbiome to arsenic exposure and that the microbiome associates with some toxicological effects of arsenic.IMPORTANCE Xenobiotic compounds, such as arsenic, have the potential to alter the composition and functioning of the gut microbiome. The gut microbiome may also interact with these compounds to mediate their impact on the host. However, little is known about how dietary variation may reshape how the microbiome responds to xenobiotic exposures or how these modified responses may in turn impact host physiology. Here, we investigated the combinatorial effects of marginal zinc deficiency and physiologically relevant concentrations of arsenic on the microbiome. Both zinc deficiency and arsenic exposure were individually associated with altered microbial diversity and when combined elicited synergistic effects. Microbial abundance also covaried with host physiological changes, indicating that the microbiome may contribute to or be influenced by these pathologies. Collectively, this work demonstrates that dietary zinc intake influences the sensitivity of the microbiome to subsequent arsenic exposure.

Keywords: arsenic; gut; microbiome; zinc.

Figures

FIG 1
FIG 1
Zinc restriction and arsenic exposure reduce plasma zinc concentrations but not growth of mice. (A) Plasma zinc concentration in animals fed zinc-adequate (ZA) (gray boxes) and marginally zinc-deficient (MZD) diets (blue boxes) and exposed to environmentally relevant concentrations of arsenic. Boxes represent the interquartile range (IQR); the line inside each box represents the median. Upper whiskers on boxes represent the smaller of the maximum value or quartile 3 + (1.5 × IQR). Lower whiskers on boxes represent the larger of the minimum value or quartile 1 − (1.5 × IQR). (B) Weight of mice (g) across the length of the study. Points on each lines indicate the mean weight of animals within a group at a given time point, and whiskers represent the mean ± the standard error of the mean.
FIG 2
FIG 2
Zinc restriction and arsenic exposure disrupt host physiology. (A) Plasma adiponectin concentrations and (B) comet assay tail moment in zinc-adequate (ZA) and marginally zinc-deficient (MZD) diet-fed animals exposed to arsenic. Boxes represent the interquartile range (IQR), and the line inside each box represents the median. Upper whiskers on boxes represent the smaller of the maximum value or quartile 3 + (1.5 × IQR). Lower whiskers on boxes represent the larger of the minimum value or quartile 1 − (1.5 × IQR).
FIG 3
FIG 3
Marginal zinc deficiency alters microbiome diversity. (A) Intragroup Bray-Curtis β-diversity and (B) Shannon entropy of animals fed zinc-adequate (ZA) and marginally zinc-deficient (MZD) diets. Boxes represent the interquartile range (IQR), and the line inside each box represents the median. Upper whiskers on boxes represent the smaller of the maximum value or quartile 3 + (1.5 × IQR). Lower whiskers on boxes represent the larger of the minimum value or quartile 1 − (1.5 × IQR). (C) Scatter plot displaying association between Shannon entropy and plasma zinc concentration. ***, P < 0.001.
FIG 4
FIG 4
Zinc deficiency sensitizes the gut microbiome to arsenic exposure. (A) Intragroup Bray-Curtis β-diversity, (B) Shannon entropy, and (C) nonmetric multidimensional scaling ordination of β-diversity with adonis R2 and P values for animals fed zinc-adequate (ZA) diets. (D) Intragroup Bray-Curtis β-diversity, (E) Shannon entropy, and (F) nonmetric multidimensional scaling ordination of β-diversity with adonis R2 and P values for animals fed marginally zinc-deficient (MZD) diets. Colored ellipses indicate the 95% confidence interval for each group. For box plots, the boxes represent the interquartile range (IQR), and the line inside each box represents the median. Upper whiskers on boxes represent the smaller of the maximum value or quartile 3 + (1.5 × IQR). Lower whiskers on boxes represent the larger of the minimum value or quartile 1 − (1.5 × IQR). *, P < 0.05; **, P < 0.01; ***, P < 0.001.
FIG 5
FIG 5
Arsenic exposure and zinc deficiency associate with altered abundance of gut taxa. Shown is a heat map of negative binomial generalized linear model coefficients for the following parameters: arsenic concentration, [As]; zinc status, Diet(ZA); the interaction between zinc status and arsenic concentration, Diet(ZA):[As]; and starting abundance, Start. Red- and blue-colored cells indicate negative and positive slopes, respectively. An asterisk in a cell indicates a q value of <0.20.

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