Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Department of Population Health and Pathobiology, North Carolina State University, Raleigh, NC, 27607, USA.
Arch Toxicol. 2019 Jan;93(1):25-35. doi: 10.1007/s00204-018-2332-7. Epub 2018 Oct 24.
The mammalian gut microbiome (GM) plays a critical role in xenobiotic biotransformation and can profoundly affect the toxic effects of xenobiotics. Previous in vitro studies have demonstrated that gut bacteria have the capability to metabolize arsenic (As); however, the specific roles of the gut microbiota in As metabolism in vivo and the toxic effects of As are largely unknown. Here, we administered sodium arsenite to conventionally raised mice (with normal microbiomes) and GM-disrupted mice with antibiotics to investigate the role of the gut microbiota in As biotransformation and its toxicity. We found that the urinary total As levels of GM-disrupted mice were much higher, but the fecal total As levels were lower, than the levels in the conventionally raised mice. In vitro experiments, in which the GM was incubated with As, also demonstrated that the gut bacteria could adsorb or take up As and thus reduce the free As levels in the culture medium. With the disruption of the gut microbiota, arsenic biotransformation was significantly perturbed. Of note, the urinary monomethylarsonic acid/dimethylarsinic acid ratio, a biomarker of arsenic metabolism and toxicity, was markedly increased. Meanwhile, the expression of genes of one-carbon metabolism, including folr2, bhmt, and mthfr, was downregulated, and the liver S-adenosylmethionine (SAM) levels were significantly decreased in the As-treated GM-disrupted mice only. Moreover, As exposure altered the expression of genes of the p53 signaling pathway, and the expression of multiple genes associated with hepatocellular carcinoma (HCC) was also changed in the As-treated GM-disrupted mice only. Collectively, disruption of the GM enhances the effect of As on one-carbon metabolism, which could in turn affect As biotransformation. GM disruption also increases the toxic effects of As and may increase the risk of As-induced HCC in mice.
哺乳动物肠道微生物群（GM）在异源生物转化中起着关键作用，并能深刻影响异源生物的毒性效应。先前的体外研究表明，肠道细菌具有代谢砷（As）的能力；然而，肠道微生物群在体内 As 代谢及其毒性中的具体作用在很大程度上仍是未知的。在这里，我们给常规饲养的小鼠（具有正常微生物群）和用抗生素处理的 GM 破坏的小鼠施用亚砷酸钠，以研究肠道微生物群在 As 生物转化及其毒性中的作用。我们发现 GM 破坏的小鼠的尿总 As 水平要高得多，但粪便总 As 水平则低于常规饲养的小鼠。体外实验中，将 GM 与 As 孵育，也表明肠道细菌可以吸附或摄取 As，从而降低培养基中的游离 As 水平。由于肠道微生物群的破坏，砷的生物转化受到显著干扰。值得注意的是，砷代谢和毒性的生物标志物——尿单甲基砷酸/二甲基砷酸比值显著增加。同时，砷处理的 GM 破坏小鼠的一碳代谢基因，包括 folr2、bhmt 和 mthfr 的表达显著下调，并且肝脏 S-腺苷甲硫氨酸（SAM）水平也显著降低。此外，砷暴露改变了 p53 信号通路基因的表达，并且只有在砷处理的 GM 破坏小鼠中，与肝细胞癌（HCC）相关的多个基因的表达也发生了改变。总的来说，GM 的破坏增强了 As 对一碳代谢的影响，这反过来又可能影响 As 的生物转化。GM 破坏还增加了 As 的毒性作用，并可能增加小鼠中 As 诱导的 HCC 的风险。
