Human gut microbial communities can metabolize chemicals and alter their toxicity. Understanding the toxicological relevance of the gut microbiome in chemical disposition and toxicity requires insight on the functional transformation capacities of the human gut microbiome, uptake potential of microbial metabolites, and the influence of microbial transformation on chemical toxicity. The heterocylic amine 2-amino-3,8-dimethylimidazo[4,5-<i>f</i>]quinoxaline (MeIQx) is a mutagen and probable human carcinogen that reaches the human colon and can be transformed to 9-hydroxyl-2,7-dimethyl-7,9,10,11-tetrahydropyrimido[2′,1′:2,3]imidazo[4,5-<i>f</i>]quinoxaline (MeIQx-M1) by the function of a microbial glycerol dehydratase enzyme. Our data suggests that this transformation is relevant also for the glucuronidated form of the compound, and that the transformation involves microbial production of acrolein. Results suggest that MeIQx and its microbial metabolite are similarly transported from the mucosal side to the serosal side of intestinal tissue. Physiologically based pharmacokinetic modeling, taking microbial biotransformation into account, suggests the requirement of high levels of intestinal acrolein to significantly alter the availability of MeIQx. Furthermore, in vitro evaluation of cytotoxicity and mutagenicity are consistent with the glycerol dehydratase-catalyzed transformation being a detoxification process. Moreover, metagenomics profiles from healthy individuals vs cancer patients suggest a protective role of the presence of this microbial gene. These findings delineate a chemical basis for how inter-individual differences in human gut microbial communities have the potential to influence toxicological impacts of dietary chemicals.

Chemical metabolism and toxicological relevance of microbial glycerol dehydratase from human gut microbiota

2019 Fall National Meeting

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