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Table 1 Role of gut microbiota in the metabolism of dietary compounds and phytochemicals

From: Gut Pharmacomicrobiomics: the tip of an iceberg of complex interactions between drugs and gut-associated microbes

Chemical (drug or herbal remedy) {CID} Pharmacological effect Role of gut microbiota in metabolism Altered metabolism and subsequent outcome References
Heterocyclic aromatic amines (HAAs) Carcinogenic agents HAAs, originally derived from cooking proteins, are pro-mutagenic compounds known to be carcinogenic to rats and mice reviewed in[30]. Normally upon ingestion of a cooked protein, gut microbiota metabolize these compounds to yield unconjugated mutagen metabolites detectable in urine and stool, and human liver enzymes CYP450 IA1 and IA2 activate these compounds to the active mutagenic forms. Enhancement of CYP450 activity, deconjugation of HAAs and consequent increased mutagenic activity [29]
   The effect of elevated active mutagens metabolites was reported to be significantly higher in conventional rats than germfree rats. Conventional rats have shown elevated activity of ethoxyresorufin-O-deethylase (EROD), which is a CYP450-dependent enzyme responsible for the biotransformation of HAAs and is increased in the small intestine upon ingestion of fried meat. Thus, the intestinal microbiota is thought to play a central role in HAA metabolism and thereby, in the response to mutagens through enhancing the activity of CYP450 enzymes responsible for the activation of mutagens.   
Cycasin {5459896} Toxic glycoside Members of the gut microbiota hydrolyze cycasin into the carcinogenic derivative, methylazoxymethanol. Microbiome-induced hydrolysis leading to direct toxic effect [7]
Rutin {5280805} A quercetin glucoside with angio-protective effects Several gut anaerobes, e.g., Bacteriodes uniformans, Bacteroides ovatus, and Butrivibrio sp. hydrolyze dietary rutin into its corresponding quercetin aglycone and polyphenols. The release of both the free quercetin aglycone and the phenolic metabolites underlies rutin’s mutagenic effect and the further inhibition of platelet aggregation, respectively. The free quercetin aglycone is a mutagen. Furthermore, the administration of rutin has been correlated with the increase of mutagenic activity of other glycosides with mutagenic aglycone component. The increase in glycosidic activity was expected to further increase the release of quercetin; however, the activation of quercetin was decreased in rats fed with rutin in contrast to the free aglycones of other mutagens such as 2-amino-3-methylimidazo [4,5-f] quinoline (IQ), 2-amino-3,4-dimethylimidazo [4,5-f] quinoline (MeIQ), and 2-amino-3,8-dimethylimidazo-[4,5-f] quinoxaline (MeIQx). Microbiome-induced hydrolysis leading to indirect mutagenic effect [31]
Aflatoxin B1 {186907} Carcinogenic mycotoxins Rats with conventional gut microbiota have shown two-fold increase in aflatoxin concentration in S9 liver fraction. Additionally, an in vivo-modified Ames test showed that rats with conventional gut microbiota have higher number of mutants of the indicator organism, Salmonella Typhimurium TA98, than germfree rats. Potentiated toxic effects [31]
(+)- catechin and (−)-epichatechins {9064, 72276} Anti-oxidants The effects of (+)-catechins and (−)-epicatechins on liver and intestinal enzymes have been reported to be different between germfree rats and rats with human gut microbiota. In germfree rats, (+)-catechins and (−)-epicatechins resulted in increase in the levels of liver CYP450 2C11 and (+)- catechins caused elevation in the specific activity of liver Uridine 5'-diphospho-glucuronosyltransferase UGT-chloramphenicol. On the other hand, cytosolic glutathion-S-transferase (GST) levels were higher in rats harboring human gut microbiota upon the administration of (+)-catechins. However, in both germfree and human microbiota inoculated rats, (+)-catechins and (−)-epicatechins increased the specific activity of UGT-4-methyl umbelliferone in the intestine. Furthermore, the specific activity of intestinal UGT-chloramphenicol was higher in rats inoculated with human microbiota. Indirect potentiating/lowering effect on drug metabolism depending on the type of co-administered drug, the metabolic pathway adapted, and the effect of the resulting metabolite [32]
2-methoxy esterone Anti-angiogenic Members of the gut microbiota are believed to convert 2-methoxy esterone to the active steroid form. This was demonstrated upon incubation of 2-methoxy esterone with isolated rat cecum, where two different reactions were found to take place: oxidoreduction at C17 and demethylation at C2 resulting into the active form. Oxidoreduction and demethylation resulting in activation of prodrug [33]
Chlorogenic acid {1794427} Antioxidant Gut microbiota metabolize chlorogenic acid to 3-hydroxycinnamic acid and 3-(3-hydroxyphenyl)propionic acid, which are subjects to phase II conjugation followed by excretion in urine. In absence of gut microbiota, chlorogenic acid is metabolized to benzoic acid, which in turn is conjugated with glycine yielding hippuric acid. Gonthier et al. found that the bioavailability of chlorogenic acid relies on its metabolism by gut microbiota[34]. Microbial metabolism resulting in potentiated clinical effect [34, 35]
Soy-derived phytoestrogens Xeno-estrogens Some microbial communities in the gut produce active metabolites from soy-derived phytoestrogens resulting in enhanced efficacy. In addition, the phytoestrogens metabolites produced by gut microbiota are suggested to affect cytochrome P enzymes, which are responsible for estrogen hydroxylation, and therefore result in lower toxic events. According to the type of microbiota present, toxicity or lower action may result. [36, 37]
Baicalin {64982} Potential antioxidant, anti-inflammatory and liver tonic Gut microbiota normally hydrolyze baicalin into its corresponding aglycone baicalein, which is readily absorbable and subject to re-conjugation following absorption. Absence of gut microbiota in germfree rats reportedly resulted in lower levels of baicalin in plasma following oral administration. Potentiated clinical effect [38]
Anthocyanins {145858} Potential anticancer, anti-oxidant and anti-inflammatory Gut microbes are responsible for the hydrolysis of the glycosidic linkage between the sugar and the aglycone by means of β-glucosidases resulting in the release of the free aglycone active form. Microbial hydrolysis leading to activation of prodrug [39]
Genistin {5281377} Anti-cancer, estrogenic and antiatherosclerotic Gut microbes hydrolyze the glycosidic linkage between the sugar and the aglycone by means of β-glucosidases resulting in the release of the free aglycone active form genistein. Microbial hydrolysis leading to activation of prodrug [39]
Naringin {442428 Anti-oxidant, anti-cancer and blood cholesterol lowering effect Same as with anthocyanins and genistin, microbial β-glucosidases lead to the release of the free aglycone active form naringenin. Microbial hydrolysis leading to activation of prodrug [39]
  1. CID = Chemical ID from the PubChem database (URL:http://pubchem.ncbi.nlm.nih.gov)[40] is provided in curly braces for all drugs or botanicals.