Introduction
Term disambiguation
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Microbiome and microbiomics: To the best of our knowledge, the term ‘microbiome’ was first suggested in 2000 by the Nobel Laureate, Joshua Lederberg, to describe the sum of microbial genomes associated with the human body, which he described as a part of “the human extended genome” (URL:http://www.project-syndicate.org/commentary/microbiology-s-world-wide-web). Soon after, it was used in the same meaning in literature[21, 22]. Currently, however, microbiome is being used to denote two different concepts: (i) the collective microbial genome of a community (i.e., microbial metagenome) or (ii) the sum of all microscopic life forms, viz. microbes, within an environment (i.e., micro.biome). Microbiome was initially confined to host-associated metagenomes, but is now being used interchangeably with microbial metagenome (e.g., the Earth Microbiome Projecthttp://www.earthmicrobiome.org/[23]). The less frequently used term, ‘microbiomics’, describes the study of functional aspects related to the microbiome, including the integration of high-throughput genome-wide data[24].
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Pharmacogenomics and pharmacomicrobiomics: Pharmacogenomics[25] is a well-established term that describes the effect of human genome variations on drug disposition and action. The term can certainly be applied not just to the human nuclear and mitochondrial genomes, but also to the human extended genome or the genome of the human supraorganism[18]; yet, to specify the impact of the human-associated microbiome on drugs, we have coined the term pharmacomicrobiomics[17, 18], which we consider as a natural expansion of pharmacogenomics, which is likely to spread when more HMP data accrue.
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Metabolomics and metabonomics: Those two verbally similar terms have been sometimes used interchangeably to describe the high-throughput study of all genome-encoded metabolites produced by a particular organism or a community; however, Nicholson and coworkers carefully denote the difference between the two terms as they use metabolomics to describe the study of genetically controlled metabolites and fluxes produced by one type of cells or tissues, whereas they define metabonomics as the measurement of metabolites produced by a collection of cells/genomes within a multicellular organism or an ecosystem[26] (the latter once described as the ‘meta-metabolome’[27]).
Role of gut microbiota in xenobiotic metabolism
Chemical (drug or herbal remedy) {CID} | Pharmacological effect | Role of gut microbiota in metabolism | Altered metabolism and subsequent outcome | References |
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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 | |
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. | |
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] |
Enzyme | Function | Effect of gut microbiome |
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Ethoxyresorufin-O-deethylase (EROD) | A CYP450-dependent enzyme responsible for the biotransformation of HAAs | The presence of normal gut microbiota in rats potentiates EROD activity upon ingestion of fried meat |
Glutathione S-transferase A 1/2 (GSTA1/2) | Being among the alpha class of GST enzyme family that is preferentially expressed in the colon rather than the liver, it plays a central role in phase II detoxification of xenobiotics. In addition, GSTA1/2 class displays a glutathione peroxidase activity, which underlies its antioxidant and cyto-protective effects. | Measuring GSTA1/2 levels in both germfree rats and microbiota–reassociated rats showed 4- and 5-fold increase in the enzyme level in germfree males and females, respectively. |
Glutathione S-transferase A4(GSTA4) | Among the alpha class of GST enzymes that possess high affinity to alk-2-enes | Germfree rats showed 1.5- and 1.9-fold increase in the levels of GSTA4 than microbiota–reassociated rats in males and females, respectively. |
Glutathione S-transferase M1 (GSTM1) | GSTM1 is one of the mu class of GSTs which detoxify carcinogens, toxins, drugs and oxidative stress products. | Germfree female rats showed a statistically significant but modest elevation in colonic GSTM1 levels compared to rats with gut microbiota. However, male rats didn't exhibit this elevation. This increase in germfree female rats may be coincidental in spite of the statistical significance. |
Epoxide hydroxylase 1 (EPHX1) enzyme | Responsible for the activation and detoxification of xenobiotics as polycyclic aromatic hydrocarbons | Germfree rats showed a substantial increase in the colonic levels of EPHX1 than rats associated with rat gut microbiota. |
Epoxide hydroxylase 2 (EPHX2) enzyme | Located in cell cytosol and perixosomes and detoxifies specific peroxides by catalyzing their conversion into dihydrodiols | Germfree rats showed a moderate increase in the colonic levels of EPHX2 than rats associated with rat gut microbiota. |
Sulfotransferase 1C2 (SULT1C2) enzyme | Among the SULT1 enzyme subfamily, which conjugates phenolic compounds with sulfo groups obtained from 3'-Phosphoadenosine-5'-phosphosulfate (PAPS) | Germfree female rats showed a statistically significant modest increase (1.6-fold) in colonic levels of SULT1C2. |
Sulfotransferase 1B1 (SULT1B1) enzyme | A member of the SULT1 enzyme subfamily | On the contrary to SULT1C2, germfree male and female rats showed a statistically significant decrease (0.4- and 0.6-fold, respectively) in the enzyme level than gut microbiota- associated rats. |
N-acetyltransferase 1 (NAT1) & N-acetyltransferase 2 (NAT2) enzyme | Detoxify hydrazine and arylamine drugs | NAT enzyme levels were modestly elevated in germfree rats in comparison with rats with conventional gut microbiota. |
Glutathione peroxidase 2 (GPX2) enzyme | A selenium-dependent member of the GPX family of glutathione peroxidase that is present in the epithelium of the gastrointestinal tract | Elevated GPX2 mRNA levels have been correlated with the reintroduction of microbiota in germfree rats. |
Impact of microbiome variations on drug response and toxicity
Drug {CID} | Pharmacological effect | Role of gut microbiota in metabolism | Effect of microbiota on clinical outcome | References |
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Acetaminophen {1983} | Analgesic and antipyretic | Competitive o-sulfonation between p-cresol, produced by some gut bacterial communities, and acetaminophen increases acetaminophen toxicity. Therefore, assessment of microbiome activity has been suggested as a guideline prior to the administration of acetamniophen. | Exaggerate clinical effect and toxicity | [43] |
Chloramphenicol {5959} | Antibiotic | Some patients display bone marrow aplasia following the oral administration of chloramphenicol owing to the presence of coliforms that mediate the metabolic conversion of chloramphenicol to a toxic form known as p-aminophenyl-2-amin-1,2-propanediol. | Increase toxicity | [45] |
Digoxin {2724385} | Cardiotonic | Altered concentration of Eggerthella lenta between populations affects the concentration of reduced digoxin metabolite. 36 % of North Americans vs. 13.7 % southern Indians were able to metabolize digoxin, a difference that was correlated with altered concentrations of E. lenta between the two populations. Concomitant administration of digoxin and erythromycin or tetracycline resulted in digoxin intoxication. Accordingly, it is recommended to avoid the concurrent use of both medications. | Potentiate both activity and toxicity | |
Flucytosine {3366} | Antifungal | Patients who have received antibiotics showed lowered metabolic transformation of flucytosine (commonly known as 5-fluorocytosine) to 5-fluorouracil (5-FU). | Potentiate effect | [44] |
Metronidazole {4173} | Antibiotic: antifungal and antimicrobial (against anaerobic microbes) | Bacteroides fragilis is among gut commensals, and its infection is commonly treated by metronidazole. A strain of B. fragilis that overexpresses recA was resistant to metronidazole in comparison to the wild-type strain. Inactivation of recA resulted in the increased sensitivity to metronidazole, and the B. fragilis recA mutants had more double strand breaks. | Provide resistance to the antimcrobial/antifungal effect | [46] |
Metronidazole {4173} | Antibiotic: antifungal and antimicrobial (against anaerobic microbes) | Comparison of metronidazole metabolites between germfree rats and conventional rats showed the exclusive excretion of the metabolites by conventional rats. Those metabolites were retrieved upon adding Clostridium perfringens to metronidazole. | Lower the effect by activating metabolism | [13] |
Sulfasalazine | Azodyes/Antibiotics | Salfasalazine is a prodrug that requires activation by azoreduction, mediated by intestinal bacteria, to result in sulfapyridine and 5-aminosalisylic acid. Patients who have undergone ileostomy had lower plasma levels of sulfapyridine than controls. Futhermore, antibiotic administration resulted in decrease of the azoreduction split. Intestinal microbiota mediate the clearance of both sulfapyridine and 5-aminosalisylic acid, where the decrease in acetylation rate is associated by increased side effects. | Activate the drug | [47] |
Sulfinpyrazone {5342} | Azodyes/Antibiotics | The gut microbiota plays a major role in the azoreduction of sulfinpyrazone. Ilesotomy patients had dramatically lower levels of the sulfide form than controls (the area under the curve, AUC, for sulfide metabolite was 25-fold lower in the plasma in case of ileostomy patients). | Activate the drug | [47] |
Sulindac {1548887} | Non steroidal anti-inflammatory drug (NSAID) | Sulindac is a prodrug that undergoes reductive metabolism by gut microbiota and liver enzymes into an active sulfone metabolite. Patients with ileostomy exhibited half the AUC following 12 hours of oral administration of 200 mg dose. | Activate the drug | |
Sorivudine {5282192} | Antiviral | A toxic interaction was reported in 18 Japanese people upon concomitant oral administration of sorivudine and 5-FU. Bacteroides sp. are responsible for this toxicity owing to their production to (E)-5-(2-bromovinyl) uracil (BVU) metabolite which in turn deactivates dihydropyrimidine dehydrogenase (DPD) responsible for the metabolism of 5-FU. Germfree rats had significantly lower BVU levels in both urine and blood. | Increase toxicity | |
Zonisamide {5734} | Anticonvulsant | Gut microbiota is central to the metabolism of zonisamide by reduction producing 2-sulfomoyacetylphenol. Germfree rats had lower levels of this metabolite, and its levels were increased after those rats were inoculated with gut microbiota. | Lower the effect | [51] |
A systems biology view of the host-microbiota metabolome and co-metabolome
Web resources for exploring gut pharmacomicrobiomics
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Human variome resources:
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HVP (Human Variome Project):http://www.humanvariomeproject.org[58]
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Human microbiome resources:
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MetaHIT (Metagenomics of the Human Intestinal Tract):http://www.metahit.eu[42]
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HMP:http://hmpdacc.org[41]
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Tools or databases for browsing the human microbiome:
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MG-RAST:http://metagenomics.anl.gov[60]
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The SEED Servers:http://www.theseed.org/servers[61]
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Pharmacogenomics/pharmacomicrobiomics databases:
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PharmGKB (Pharmacogenomics Knowledge Base):http://www.pharmgkb.org[62]
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PacDB (Pharmacogenetics and Cell Database):http://www.pacdb.org[63]
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CTDB (Comparative Toxigenomics Database):http://ctdbase.org[64]
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The PharmacoMicrobiomics Portal:http://www.pharmacomicrobiomics.org[65]
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Enzymes/pathways databases:
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KEGG (Kyoto Encyclopedia of Genes and Genomes):http://www.genome.jp/kegg/[66]
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BRENDA (BRaunschweig ENzyme Database):http://www.brenda-enzymes.org[68]
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