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Cited by 319Pharmacogenetics and Drug MetabolismGut microbiota and healthDrug Transport and Resistance Mechanisms

Gut reactions: Breaking down xenobiotic–microbiome interactions

Open access
Clarke, Gerard, Sandhu, Kiran V., Griffin, Brendan T., Dinan, Timothy G., Cryan, John F., Hyland, Niall P.·2019·Pharmacological Reviews
DOI 10.1124/pr.118.015768
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Abstract

The microbiome plays a key role in health and disease, and there has been considerable interest in therapeutic targeting of the microbiome as well as mining this rich resource in drug discovery efforts. However, a growing body of evidence suggests that the gut microbiota can itself influence the actions of a range of xenobiotics, in both beneficial and potentially harmful ways. Traditionally, clinical studies evaluating the pharmacokinetics of new drugs have mostly ignored the important direct and indirect effects of the gut microbiome on drug metabolism and efficacy. Despite some important observations from xenobiotic metabolism in general, there is only an incomplete understanding of the scope of influence of the microbiome specifically on drug metabolism and absorption, and how this might influence systemic concentrations of parent compounds and toxic metabolites. The significance of both microbial metabolism of xenobiotics and the impact of the gut microbiome on host hepatic enzyme systems is nonetheless gaining traction and presents a further challenge in drug discovery efforts, with implications for improving treatment outcomes or counteracting adverse drug reactions. Microbial factors must now be considered when determining drug pharmacokinetics and the impact that an evolving and dynamic microbiome could have in this regard. In this review, we aim to integrate the contribution of the gut microbiome in health and disease to xenobiotic metabolism focusing on therapeutic interventions, pharmacological drug action, and chemical biotransformations that collectively will have implications for the future practice of precision medicine.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review argues that the gut microbiome exerts both direct (microbial biotransformation) and indirect (regulation of host hepatic enzymes) effects on xenobiotic metabolism, with consequences for drug activation, inactivation, toxicity, and therapeutic response. It calls for incorporating microbial factors into pharmacokinetic/pharmacodynamic profiling and precision medicine.

Key findings

  • Direct microbial biotransformation can activate prodrugs (e.g., sulfasalazine to 5-ASA by azoreductases), reactivate drugs (irinotecan to cytotoxic SN-38 via β-glucuronidases, causing GI side effects), or inactivate drugs (digoxin reduction contingent on specific *Eggerthella lenta* strains and inhibited by dietary arginine).
  • The gut microbiome indirectly regulates host hepatic drug-processing genes: germ-free mice show markedly reduced hepatic Cyp3a11 mRNA/protein (the mouse homolog of human CYP3A4, which metabolizes >60% of drugs), while Cyp1a2 and Cyp4a14 are substantially increased; effects are enzyme-specific and depend on age and sex, with the largest effects in male mice at 90 days.
  • A screen of >1000 marketed drugs against individual gut bacteria found that 24% of drugs with human targets inhibited growth of at least one bacterial strain in vitro; metformin, methotrexate, olanzapine, risperidone, PPIs, opioids, and NSAIDs are cited as altering microbiome composition/diversity.
  • Microbial metabolism of dietary choline and carnitine produces TMA, which host hepatic processing converts to TMAO, associated with atherosclerosis; choline TMA-lyase was present in only 26% of individuals in one cited study.

Methods

  • Narrative review integrating existing literature on gut microbiome–xenobiotic interactions; no primary data are generated.
  • Covers microbiome composition in health/disease, biochemistry of microbial xenobiotic metabolism, factors influencing its rate/extent, evolutionary perspectives, stress-related disorders, reciprocal drug–microbiome effects, experimental approaches (germ-free and antibiotic-depleted animals, monoassociation, *C. elegans*, in vitro batch/fermentation systems, fecalase/cecalase assays, functional metagenomics, in silico/PBPK modeling, organ-on-a-chip, organoids), and microbiome-based therapeutics.
  • Synthesizes findings into tables of microbial enzymes/biotransformations (Table 1), microbial regulation of host hepatic CYPs (Table 2), clinical specialties and pharmacomicrobiomics (Table 3), and outstanding questions (Table 4).

Limitations

  • Stated in the paper: overreliance on fecal samples means the microbiota of more proximal regions (especially the small intestine) is poorly understood; the small intestine has higher xenobiotic exposure but lower microbial density, and its contribution is understudied.
  • Stated in the paper: germ-free and antibiotic-depleted rodent models have intrinsic gastrointestinal and microbial differences from humans, and germ-free animals show physiologic/morphologic differences relevant to xenobiotic metabolism; the extent to which inducibility of microbial enzymes generalizes is unclear.
  • Evident from the text: because members of the bacterial ecosystem may exhibit functional redundancy and pleiotropy, the link between microbiota composition ("structure begets function") and xenobiotic metabolism is difficult to gauge; the paper also notes that actual metabolic activity may diverge from functional potential, and that many enzyme–species assignments remain unknown.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1124/pr.118.015768

Cites

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Statistics

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Claims the paper makes

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  • Premisecitation

    The large intestine is an important host site for microbial metabolism.

    “The large intestine is thus an important host site for microbial metabolism, a convenient truth that fortunately aligns with our reliance on the analysis of stool samples to gain insights into our microbial inhabitants (Fraher et al., 2012;Claesson et al., 2017).”
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    Metabolites produced by the gut microbiome can tune the expression and function of key liver enzymes such as those in the cytochrome P450 superfamily.

    “Indirectly, metabolites produced by the gut microbiome can also tune the expression and function of key liver enzymes such as those in the pivotal cytochrome P450 (CYP) superfamily.”
    Quote in the paperSubstantial claim
  • Interpretationnone given
    § Gut reactions: breaking down xenobiotic-microbiome interactions

    The gut microbiota can influence the actions of a range of xenobiotics, in both beneficial and potentially harmful ways.

    “However, a growing body of evidence suggests that the gut microbiota can itself influence the actions of a range of xenobiotics, in both beneficial and potentially harmful ways.”
    Quote in the paperSubstantial claim
  • Premisecitation

    The encoded metabolic activities of gut microbiome genes equate to a large metabolic capacity far in excess of the host genome.

    “With an aggregate gene catalog exceeding the human genome by more than a factor of 100 (Qin et al., 2010), the gut microbiome exhibits a diverse functional repertoire, and the encoded metabolic activities of these microbial genes equate to a large metabolic capacity far in excess of its counterpart host genome (Lynch and Pedersen, 2016).”
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    • cites Lynch and Pedersen, 2016 source

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    The gut microbiome's aggregate gene catalog exceeds the human genome by more than a factor of 100.

    “With an aggregate gene catalog exceeding the human genome by more than a factor of 100 (Qin et al., 2010), the gut microbiome exhibits a diverse functional repertoire, and the encoded metabolic activities of these microbial genes equate to a large metabolic capacity far in excess of its counterpart host genome (Lynch and Pedersen, 2016).”
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    Premisecitation

    Before orally delivered compounds reach the liver, an increasing number are first exposed to the gut microbiota and their associated metabolic enzymes, whose repertoire exceeds that of the liver.

    “This viewpoint overlooks the fact that before orally delivered compounds reach the liver, an increasing number are first exposed to the gut microbiota and their associated collection of metabolic enzymes (which exceeds the repertoire of the liver) (Li et al., 2014).”
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    Premisecitation

    Glucuronides are abundant in the gut and are subject to processing by microbial beta-glucuronidase enzymes, which liberate glucuronic acid sugars from conjugated compounds.

    “Glucuronides are abundant in the gut and are subject to processing by microbial b-glucuronidase enzymes, which act to liberate glucuronic acid sugars from conjugated compounds (Pellock and Redinbo, 2017).”
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    Premisecitation

    The infant gut is largely thought to be sterile in utero and colonized during birth and postnatally, with a trajectory toward adult-like complexity taking approximately 3 years.

    “Conversely, but equally important, the infant gut is largely thought to be sterile in utero and colonized during birth and postnatally with a trajectory toward an adult-like complexity taking approximately 3 years (Clarke et al., 2014a;Perez-Munoz et al., 2017).”
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    Premisecitation

    A typical healthy adult gut microbiota is characterized by both high compositional diversity and stability.

    “In contrast to this interindividual variation, a typical healthy adult gut microbiota is characterized by both high compositional diversity and stability (Clarke et al., 2014b).”
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    Interpretationcitation

    The ability of the gut microbiome to remodel and persist in the face of insults such as antibiotic use is probably only matched in the host by the regenerative capacity of the liver.

    “The ability of the gut microbiome to remodel and persist in the face of insults such as antibiotic use is probably only matched in the host by the regenerative capacity of the liver (Michalopoulos, 2007) (Fig. 1, A and B).”
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    Interpretationreasoning

    Colonization of bacteria increases to highest levels in the large intestine, such that sites with a higher exposure to xenobiotics may have a lower potential for microbial metabolism, such as the small intestine.

    “As indicated above, colonization of bacteria increases to highest levels in the large intestine such that sites with a higher exposure to xenobiotics in fact may have a lower potential for microbial metabolism, such as the small intestine.”
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    Premisenone given

    Direct microbial biotransformation of xenobiotics occurs following their ingestion, and the nature of these interactions depends on whether the compounds encountered by the gut microbiome are poorly absorbed or are first conjugated by the liver and subsequently reach the intestine via biliary excretion.

    “Direct microbial biotransformation of xenobiotics occurs following their ingestion, and the nature of these interactions depends on whether the compounds encountered by the gut microbiome are poorly absorbed or are first conjugated by the liver and subsequently reach the intestine via biliary excretion.”
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    Premisecitation

    There is divergence in intestinal microbiome assembly between different birth modes, between breast- and formula-fed infants, and between preterm and full-term infants, with implications for the associated microbial metabolite profile.

    “There is also a divergence in intestinal microbiome assembly between different birth modes (Bokulich et al., 2016), between breast-and formula-fed infants (Clarke et al., 2014a), and between preterm and full-term infants, with implications for the associated microbial metabolite profile (Hill et al., 2017).”
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    Premisecitation

    During adulthood, factors such as diet, exercise, geographical location, host genetics, and stress shape or distort the gut microbiome in the colonic metabolic niche.

    “Of course, during adulthood there are also a number of factors that shape or distort the gut microbiome in the colonic metabolic niche, reviewed in detail elsewhere, such as diet (Portune et al., 2017;Sandhu et al., 2017;Shanahan et al., 2017), exercise (Campbell and Wisniewski, 2017;Barton et al., 2018), geographical location (Dikongue and Segurel, 2017; Quigley, 2017), host genetics (Kurilshikov”
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    Premisenone given

    The gut microbiome is readily modifiable, for example by diet or antibiotic usage, and this can have important implications for expansion or contraction of its metabolic functions.

    “Unlike the host genome, the gut microbiome is readily modifiable (e.g., by diet or antibiotic usage), and this can have important implications for expansion or contraction of its metabolic functions.”
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    Premisecitation

    Daidzin and genistin, glycoside isoflavones, are converted to daidzein and genistein by bacterial beta-glucosidases, with the important estrogen equol being the end product following further biotransformation of daidzein.

    “Daidzin and genistin, glycoside isoflavones, are converted to daidzein and genistein by bacterial b-glucosidases, with the important estrogen equol being the end product following further biotransformation of daidzein (Setchell et al., 2002).”
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    Premisecitation

    Differential effects for these strains were noted with increased expression of hepatic Cyp2e1 following monoassociation with L. plantarum Nizo2877 but decreased expression following colonization of E. coli Nissle 1917.

    “Differential effects for these strains were also noted with increased expression of hepatic Cyp2e1 following monoassociation with L. plantarum Nizo2877 but decreased expression following colonization of E. coli Nissle 1917(Jourova et al., 2017).”
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    Premisecitation

    The impact of the gut microbiota on hepatic drug-processing genes is enzyme-specific and depends on both age and sex, with expression patterns varying across the life span according to developmental periods, and the most marked effects observed in male mice at 90 days of age.

    “Studies also indicate that the impact of the gut microbiota on hepatic drug-processing genes is enzyme-specific and depends on both age and sex, with expression patterns varying across the life span according to developmental periods, and the most marked effects observed in male mice at 90 days of age (Selwyn et al., 2015a).”
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    Premisecitation

    Gene expression levels of Cyp1a2 and Cyp4a14 were both substantially increased in germ-free mice.

    “Conversely, the same study showed that gene expression levels of Cyp1a2 (metabolic activation of procarcinogens and deactivation of certain anticancer drugs) and Cyp4a14 (metabolism of fatty acids and eicosanoids) were both substantially increased in germ-free mice.”
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    Premisecitation

    Colonization effects are likely strain specific because monoassociation of germ-free mice with both Lactobacillus plantarum Nizo2877 and Escherichia coli Nissle 1917 decreased the expression of Cyp1a2 mRNA to conventional levels but did not act to restore the decreased expression of Cyp3a11 mRNA.

    “Colonization effects are likely strain specific because monoassociation of germ-free mice with both Lactobacillus plantarum Nizo2877 and Escherichia coli Nissle 1917 decreased the expression of Cyp1a2 mRNA to conventional levels but did not act to restore the decreased expression of Cyp3a11 mRNA.”
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    Premisecitation

    A recent analysis of the Human Microbiome Project gastrointestinal database revealed a total of 3013 microbiome-encoded beta-glucuronidases, which clustered into structural categories with differing functional capacities for various glucuronide substrates.

    “A recent analysis of the Human Microbiome Project gastrointestinal database is instructive on the complexity of this metabolic function, revealing a total of 3013 microbiome-encoded b-glucuronidases, which clustered into structural categories with differing functional capacities for various glucuronide substrates (Pollet et al., 2017).”
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    Premisereasoning

    Administration of VSL3 did not impact the expression of Cyp3a and Cyp4a genes in germ-free animals but did modulate their expression in conventional animals, suggesting that the composition of the host microbiota can influence the effects of other microbes on expression of host drug-metabolizing enzymes.

    “Administration of VSL3, a probiotic formulation containing eight live strains of bacteria, did not impact on the expression of these genes in germ-free animals but did modulate their expression in conventional animals, suggesting that the composition of the host microbiota can influence the effects of other microbes on expression of host drug-metabolizing enzymes.”
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    Premisenone given

    CYP3a11 is the mouse homolog of human CYP3A4, and this enzyme metabolizes more than 60% of all drugs.

    “CYP3a11 is the mouse homolog of human CYP3A4, and this enzyme metabolizes more than 60% of all drugs.”
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    Premisecitation

    Western-style high-fat diets are associated with a diminished microbial capacity to metabolize flavonoids through bacterial chalcone synthase, and microbiome-derived flavonoids can ameliorate the rate of postdieting weight gain.

    “Experimentally, Western-style high-fat diets have been associated with a diminished microbial capacity to metabolize flavonoids through bacterial chalcone synthase, and microbiome-derived flavonoids can ameliorate the rate of postdieting weight gain (Thaiss et al., 2016a;Chilloux and Dumas, 2017).”
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    Interpretationcitation

    The functional metabolic repertoire of the gut microbiome includes the capacity for clinically relevant activation (e.g., sulfasalazine), reactivation (e.g., irinotecan/SN-38), and detoxification (e.g., digoxin) of xenobiotics, with broad implications for drug action and toxicity.

    “Taken together, this functional metabolic repertoire includes the capacity for clinically relevant activation (e.g., sulfasalazine) (Peppercorn and Goldman, 1972b), reactivation (e.g., irinotecan/SN-38) (Wallace et al., 2010), and detoxification (e.g., digoxin) (Haiser et al., 2013) of xenobiotics with broad implications for drug action and toxicity (see Table 1).”
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    Premisecitation

    Ciprofloxacin is metabolized in the liver and can directly inhibit CYP1A2, CYP2D6, and CYP3A4.

    “It should be noted that ciprofloxacin is metabolized in the liver and can directly inhibit CYP1A2, CYP2D6, and CYP3A4 (Bolhuis et al., 2011).”
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    Premisecitation

    The reduction in hepatic Cyp3a expression and triazolam metabolism by ciprofloxacin was associated with a reduction in lithocholic acid-producing bacteria, consistent with the suggestion that lithocholic acid influences hepatic CYP expression.

    “This was associated with a reduction in lithocholic acid-producing bacteria, consistent with the suggestion that lithocholic acid influences hepatic CYP expression (Toda et al., 2009b).”
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    Premisecitation

    Factors known to influence gut microbiome composition, such as age, geography, hormone status, and sex, overlap with variable drug pharmacokinetics and impact the relative abundances of genes coding for xenobiotic-metabolizing enzymes.

    “Factors that are known to influence the composition of the gut microbiome, such as age and geography, also overlap with variable drug pharmacokinetics and impact on the relative abundances of genes coding for xenobiotic-metabolizing enzymes (Das et al., 2016;Quigley, 2017).”
    • Also stated in: § IV. Factors Influencing the Rate and Extent of Gut Microbiome Xenobiotic Metabolism · plain
      “Other factors known to influence the composition of the gut microbiome, such as age, hormone status, and sex, also overlap with variable drug pharmacokinetics and impact on the relative abundances of genes coding for xenobioticmetabolizing enzymes.”
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    Premisecitation

    Drugs with low permeability through the intestinal membrane, or drugs subject to efflux by apically bound efflux proteins, can prolong drug residence within the intestine, with greater amounts reaching distal regions of the intestine.

    “Drugs with low permeability through the intestinal membrane, or drugs that are subject to efflux by apically bound efflux proteins (e.g., P glycoprotein), can prolong drug residence within the intestine, with greater amounts of those drugs reaching distal regions of the intestine (Hall et al., 1999).”
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    Premisenone given

    Many drugs display poor solubility, which can lead to slow and incomplete absorption with the drug being absorbed from distal regions of the small intestine and/or the colon.

    “However, many drugs display poor solubility, which can lead to slow and incomplete absorption with the drug being absorbed from distal regions of the small intestine and/or the colon.”
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    Premisecitation

    Gut microbiota community structure and metabolic activity feature biologic rhythms.

    “gut microbiota community structure and metabolic activity also feature biologic rhythms”
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    Premisenone given

    Xenobiotics can become a candidate substrate for direct processing if they are poorly absorbed, appropriately formulated, or indirectly reach the colonic lumen following biliary excretion, which is also a route through which i.v. administered drugs can become subject to chemical transformation by gut microbes.

    “Xenobiotics can become a candidate substrate for direct processing if they are poorly absorbed, appropriately formulated, or indirectly reach the colonic lumen following biliary excretion, which is also a route through which i.v.administered drugs can become subject to chemical transformation by gut microbes.”
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    Premisecitation

    Oral delivery of advanced drug formulations designed for extended release is on the increase.

    “Oral delivery of advanced drug formulations designed for extended release (e.g., sustained release tablets) is on the increase”
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    One of the most frequently reported findings across an array of disorders is a narrowing of gut microbiome diversity often accompanied by more specific but less consistent compositional alterations at various taxonomic levels.

    “one of the most frequently reported findings across an array of disorders is a narrowing of gut microbiome diversity often accompanied by more specific but less consistent compositional alterations at various taxonomic levels.”
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    Premisecitation

    Digoxin use is on the decline amid the emergence of alternative therapies with preferable safety profiles.

    “digoxin use is on the decline amid the emergence of alternative therapies with preferable safety profiles (Haynes et al., 2008;Eade et al., 2013).”
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    Interpretationnone given

    Both the host and the microbiome have evolved an extensive metabolic capacity to deal with exogenous molecules.

    “Both the host and the microbiome have evolved an extensive metabolic capacity to deal with exogenous molecules with the combined scope impressive in its breadth.”
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    Premisecitation

    Host-microbe interactions are frequently viewed from an evolutionary perspective.

    “Host-microbe interactions are frequently viewed from an evolutionary perspective (Davenport et al., 2017).”
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    Premisecitation

    Microbial biotransformations can deactivate digoxin and activate sulfasalazine.

    “this can have consequences in terms of deactivating or activating drugs in the case of digoxin (Haiser et al., 2013) and sulfasalazine (Peppercorn and Goldman, 1972b), respectively.”
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    Premisecitation

    Major depression is associated with gut microbiome alterations.

    “which is also associated with gut microbiome alterations (Dinan and Cryan, 2017)”
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    Premisecitation

    The hologenome theory of evolution has the holobiont encompassing a network of biomolecules derived from both the host plus its associated microbes.

    “This informs the hologenome theory of evolution with the holobiont encompassing a network of biomolecules derived from both the host plus its associated microbes (Bordenstein and Theis, 2015).”
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    Premisecitation

    Circadian rhythm disruption and appetite fluctuations, including carbohydrate craving, are prominent in stress-related psychiatric disorders such as major depression.

    “Circadian rhythm disruption and appetite fluctuations, including carbohydrate craving, are prominent in stress-related psychiatric disorders such as major depression (Otte et al., 2016)”
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    Premisecitation

    The metabolism of azo dyes to aromatic amines is carried out by azoreductases.

    “The metabolism of azo dyes to aromatic amines is also carried out by azoreductases”
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    Premisecitation

    Of a panel of 30 chemotherapeutic drugs examined in vitro against various bacteria, 10 were inhibited and six exhibited improved efficacy linked to modification of the chemical structure of the drug for gemcitabine, fludarabine, cladribine, and CB1954.

    “of a panel of 30 chemotherapeutic drugs examined in vitro against various bacteria, 10 were found to be inhibited and six exhibited improved efficacy in a way that could be linked to modification of the chemical structure of the drug in the case of gemcitabine, fludarabine, cladribine, and CB1954 (Lehouritis et al., 2015).”
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    Study design and conductcitation

    The Maier et al. screen largely focused on in vitro antibacterial activity of each drug against one representative bacterial strain per species, so implications for more complex bacterial communities need to be considered.

    “Although the study largely focused on the in vitro antibacterial activity of each drug screened against one representative bacterial strain per species, the implications for more complex bacterial communities need to be considered.”
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    Premisecitation

    5-ASA can be converted to N-acetyl 5-ASA by intestinal bacteria, a reaction that shows variability in human fecal samples.

    “5-ASA can be converted to N-acetyl 5-ASA by intestinal bacteria, a reaction that does show variability in human fecal samples (van Hogezand et al., 1992).”
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    Premisecitation

    Exposure to a panel of host-targeted drugs including digoxin and sulfasalazine induces subtle changes in community structure but more marked changes in the genes expressed by the gut microbiome, including genes involved in xenobiotic metabolism.

    “Exposure in incubation experiments to a panel of hosttargeted drugs, including digoxin and sulfasalazine, induces subtle changes in community structure, but more marked changes in the genes expressed by the gut microbiome, including those genes involved in xenobiotic metabolism (Maurice et al., 2013).”
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    Interpretationcitation

    Flavin monooxygenase 3 downregulation by testosterone suggests possible differential processing of TMA in men and women.

    “suggesting possible differential processing of TMA in men and women.”
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    Premisecitation

    Circulating TMAO may play a role in protection from hyperammonemia and from glutamate neurotoxicity.

    “circulating TMAO may play a role in the protection from hyperammonemia (Kloiber et al., 1988) and from glutamate neurotoxicity (Minana et al., 1996).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Kloiber et al., 1988 source

      Not checked in the free run.

    • cites Minana et al., 1996 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic exposure of mice to TMAO attenuates diet-associated glucose tolerance, reducing endoplasmic stress and adipogenesis in adipocytes.

    “Chronic exposure of mice to TMAO attenuates diet-associated glucose tolerance, reducing endoplasmic stress and adipogenesis in adipocytes (Dumas et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Dumas et al., 2017 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In clinical populations, omega-3 PUFA supplementation did not change gut microbiome diversity or composition at the phyla level but increased several short-chain fatty acid-producing bacteria such as Bifidobacterium, Roseburia, and Lactobacillus.

    “although omega-3 PUFA supplementation did not change gut microbiome diversity or composition at the phyla level, an increase in several short chain fatty acidproducing bacteria such as Bifidobacterium, Roseburia, and Lactobacillus was noted (Watson et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Watson et al., 2017

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Resveratrol may remodel the gut microbiome to yield cardiovascular benefits, antiobesity effects, and improvements in glucose homeostasis.

    “Recent evidence suggests that resveratrol, for example, may act to remodel the gut microbiome to yield cardiovascular benefits, antiobesity effects, and improvements in glucose homeostasis (Chen et al., 2016;Bird et al., 2017;Sung et al., 2017).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Chen et al., 2016 source

      Not checked in the free run.

    • cites Bird et al., 2017 source

      Not checked in the free run.

    • cites Sung et al., 2017 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Glyphosate is the most commonly used herbicide.

    “Glyphosate, the most commonly used herbicide (Cuhra et al., 2016), inhibits microbial enzymes (5enolpyruvylshikimate-3-phosphate synthase), and some glyphosate formulations do have antibacterial properties (Tarazona et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Cuhra et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Risperidone causes shifts in gut microbiome composition in mice and in children and adolescents.

    “Another antipsychotic, risperidone, also causes shifts in gut microbiome composition in mice (Bahra et al., 2015), and in children and adolescents (Bahr et al., 2015).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Bahra et al., 2015 source

      Not checked in the free run.

    • cites Bahr et al., 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Traffic-related air pollution can result in decreased relative abundance of Bacteroidaceae and increased relative abundance of Coriobacteriaceae.

    “Traffic-related air pollution can result in a decreased relative abundance of Bacteroidaceae and an increased relative abundance of Coriobacteriaceae (Alderete et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Alderete et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mice, plant sterol ester produced the strongest compositional effect on the gut microbiome, with more modest alterations following oat b-glucan and bile salt hydrolase-active L. reuteri APC 2587, and few effects for atorvastatin.

    “Plant sterol ester produced the strongest compositional effect with more modest alterations noted following oat b-glucan and bile salt hydrolase-active L. reuteri APC 2587, with few effects noted for atorvastatin.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Ryan et al., 2017 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Microbial biotransformation or other indirect actions of gut bacteria result in activation or inactivation of drugs and often generate byproducts that are toxic to the host.

    “For drug metabolism alone, the implications of microbial biotransformation or other indirect actions of gut bacteria are hugely significant because it results in the activation or inactivation of drugs and often generates byproducts that are toxic to the host (Fig. 8).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Stress exposure is an important consideration, particularly during the extremes of life when the gut microbiota is more chaotic and vulnerable.

    “Stress exposure is also an important consideration, particularly during the extremes of life when the gut microbiota is more chaotic and vulnerable.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Gastrointestinal organoids can more accurately model aspects of epithelial barrier dynamics, including cellular differentiation and proliferation, in specific intestinal segments, and bring advantages over cell culture models in unraveling the molecular basis of host-microbe interactions.

    “Gastrointestinal organoids can be used to more accurately model aspects of epithelial barrier dynamics, including cellular differentiation and proliferation, in specific intestinal segments bring advantages over cell culture models in unraveling the molecular basis of the host-microbe interactions (Hill and Spence, 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hill and Spence, 2016

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Exercise is known to improve gut microbiota profiles.

    “as are other lifestyle factors such as exercise, which is also known to improve gut microbiota profiles (O'Sullivan et al., 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites O'Sullivan et al., 2015

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These large-intestine bacteria are likely most important for pharmacomicrobiomics and reside in a reaction chamber with a mean pH of 6.4-7 and a lower redox potential than other gastrointestinal niches.

    “These bacteria are likely most important for pharmacomicrobiomics and reside in a reaction chamber with a mean pH of 6.4-7 and a lower redox potential than other gastrointestinal niches.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    The highest density of bacteria is present in the large intestine, with recent estimates of 10^13 bacterial cells in the large intestine associated with microbial genes encoding a broad range of enzymes necessary for xenobiotic biotransformation.

    “The highest density of bacteria is present in the large intestine, with recent estimates of 10 13 bacterial cells in the large intestine associated with microbial genes encoding a broad range of enzymes necessary for xenobiotic biotransformation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    There are many reports of elevated or decreased circulating levels of microbiome-associated metabolites in pathologic states, but there remains an incomplete understanding of their functional importance in the absence of disease.

    “Although there are many reports of elevated or decreased circulating levels of microbiomeassociated metabolites in pathologic states, there remains an incomplete understanding of their functional important in the absence of disease.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Oxygen partial pressures along the gastrointestinal tract contribute to metabolic niches.

    “Oxygen partial pressures along the gastrointestinal tract also contribute to these metabolic niches.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The pharmacomicrobiomic web portal currently lists over 90 examples of chemicals affected by the gut microbiome.

    “The pharmacomicrobiomic web portal currently lists over 90 examples of such chemicals (http://pharmacomicrobiomics. com/view/chemical/).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites http://pharmacomicrobiomics. com/view/chemical/

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Microbial metabolites and/or production of pathway intermediates are important from a pharmacokinetic perspective, as is the impact of bacterial translocation on immune responses in the context of therapeutic efficacy.

    “Microbial metabolites and/or production of pathway intermediates are also important from a pharmacokinetic perspective, as is the impact of bacterial translocation on immune responses in the context of therapeutic efficacy.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Psychobiotic treatment has met with mixed results in healthy human subjects, with strain-specific positive results and a failure to translate.

    “has met with somewhat mixed results in healthy human subjects with strain-specific positive results (Allen et al., 2016;Papalini et al., 2018) and a failure to translate (Kelly et al., 2017).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Allen et al., 2016 source

      Not checked in the free run.

    • cites Papalini et al., 2018

      Not checked in the free run.

    • cites Kelly et al., 2017 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    The expression of host hepatic CYP genes involved in xenobiotic metabolism is influenced by the gut microbiome.

    “The expression of host hepatic CYP genes involved in xenobiotic metabolism is also influenced by the gut microbiome.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Insights from invertebrate models such as the nematode C. elegans are increasingly used to inform understanding of host-microbe interactions.

    “Insights from invertebrate models, such as the nematode C. elegans, are Microbial Xenobiotic Metabolism increasingly used to inform our understanding of host-microbe interactions (Clark and Walker, 2018), and in the current context, a number of examples”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Clark and Walker, 2018

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Selective inhibition of bacterial beta-glucuronidases can alleviate drug-induced gastrointestinal toxicity arising from irinotecan.

    “The value of such an approach once it leads to well-defined enzyme biochemistry can be seen in an earlier study that demonstrated that it was possible to selectively inhibit bacterial b-glucuronidases to alleviate drug-induced gastrointestinal toxicity arising from irinotecan (Wallace et al., 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wallace et al., 2010 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Monoassociation with E. coli Nissle 1917 but not L. plantarum Nizo2877 decreases Cyp2e1 mRNA expression.

    “Monoassociation with E. coli Nissle 1917 but not”
    Quote in the paperSubstantial claim
65 of 65

  • The paper relies on this without support.

    Clinical studies evaluating the pharmacokinetics of new drugs have mostly ignored the important direct and indirect effects of the gut microbiome on drug metabolism and efficacy.

    “Traditionally, clinical studies evaluating the pharmacokinetics of new drugs have mostly ignored the important direct and indirect effects of the gut microbiome on drug metabolism and efficacy.”

  • The paper relies on this without support.

    There is only an incomplete understanding of the scope of influence of the microbiome specifically on drug metabolism and absorption, and how this might influence systemic concentrations of parent compounds and toxic metabolites.

    “Despite some important observations from xenobiotic metabolism in general, there is only an incomplete understanding of the scope of influence of the microbiome specifically on drug metabolism and absorption, and how this might influence systemic concentrations of parent compounds and toxic metabolites.”

  • The authors state this as an assumption.

    The majority of orally administered drugs are normally absorbed in the upper small intestine, assuming that the drug is highly soluble and highly permeable in this region.

    “The majority of orally administered drugs are normally absorbed in the upper small intestine, the prime absorptive region of the intestine, assuming that the drug is highly soluble and highly permeable in this region.”

  • The paper relies on this without support.

    The small-intestinal microbiota is less well studied due in part to the difficulty in obtaining relevant samples.

    “However, this needs to be considered in context of the less well studied smallintestinal microbiota, due in part to the difficulty in obtaining relevant samples.”

  • The paper relies on this without support.

    There remains no consensus on the actual membership of the core taxa present in the gut microbiome, and different sequencing and analysis approaches will give different results.

    “It should be noted that there remains to be a consensus on actual membership of the core taxa present in the gut microbiome, and different sequencing and analysis approaches will give different results.”

  • The paper relies on this without support.

    The contribution of modified release formulations to bioavailability is rarely appraised.

    “this is a feature rarely appraised for its contribution to bioavailability.”

  • The paper relies on this without support.

    Knowledge of interindividual variation of the gut microbiome during health and disease at the taxonomic level is more advanced than the grasp of the functional implications of these compositional differences.

    “our knowledge of interindividual variation of the gut microbiome during health and disease at the taxonomic level is more advanced than our grasp of the functional implications, if any, of these compositional differences.”

  • The paper relies on this without support.

    The functional implications of disease-associated gut microbiome alterations are not currently clear for microbial xenobiotic metabolism.

    “the functional implications of these gut microbiome alterations are not currently clear for microbial xenobiotic metabolism.”

  • The paper relies on this without support.

    Bacterial genes encoding porphyranases, agarases, and associated proteins transferred from marine red algae to bacteria residing in the gastrointestinal tract of Japanese individuals as a consequence of their seaweed consumption.

    “transfer of bacterial genes encoding porphyranases, agarases, and associated proteins from marine red algae to bacteria residing in the gastrointestinal tract of Japanese individuals as a consequence of their seaweed consumption.”

  • The paper relies on this without support.

    The majority of orally administered drugs are normally absorbed in the upper small intestine.

    “The majority of orally administered drugs are normally absorbed in the upper small intestine assuming that the drug is highly soluble and highly permeable in this region.”

  • The authors state this as an assumption.

    Orally administered drugs are highly soluble and highly permeable in the upper small intestine.

    “The majority of orally administered drugs are normally absorbed in the upper small intestine assuming that the drug is highly soluble and highly permeable in this region.”
11 of 11

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The mouth is the first microbial compartment that a swallowed supplement meets, and oral bacteria carry reductive and hydrolytic activities of the same type that make the intestinal microbiota a determinant of drug disposition.

    “The mouth is the first microbial compartment that a swallowed supplement meets, and oral bacteria carry reductive and hydrolytic activities of the same type that make the intestinal microbiota a determinant of drug disposition [103,104,105].”

    From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [105]

    The Introduction and “Direct Microbial Metabolism of Xenobiotics” (pages unavailable) support the claim that gut microbes can affect drug disposition through metabolic enzymes, including hydrolytic and reductive activities. The passages concern intestinal microbes; they do not establish that the mouth is the first microbial compartment a swallowed supplement encounters or that oral bacteria have those activities. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Berberine can indirectly influence the disposition of other drugs by at least three routes: altering bacterial drug metabolism, modifying the enterohepatic circuit through regulation of bacterial β-glucuronidases, and modulating gut-barrier integrity.

    “Therefore, berberine can indirectly influence the disposition of other drugs by at least three routes: altering bacterial drug metabolism, modifying the enterohepatic circuit through regulation of bacterial β-glucuronidases, and modulating gut-barrier integrity [95,104,105].”

    From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [105]

    Table 1 (page unavailable) describes bacterial β-glucuronidase acting on drugs during enterohepatic cycling, and the section on therapeutic effects describes drug–drug interactions arising from microbial biotransformation. The paper also discusses intestinal barrier function, but the passages do not establish that berberine alters any of these routes or thereby changes the disposition of other drugs. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • A growing body of evidence suggests that non-antibiotic drugs can also affect the composition of the gut microbiota, with potential implications for behavior and involvement of the microbiota in drug pharmacokinetics.

    “a growing body of evidence suggests that non-antibiotic drugs can also affect the composition of the gut microbiota, with potential implications for behavior, as well as the involvement of the microbiota in drug pharmacokinetics in general (Clarke et al., 2019).”

    From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Clarke et al., 2019

    Section B (page not available) reports that non-antibiotic drugs, including antipsychotics and proton-pump inhibitors, can alter gut microbiome composition. The Abstract (page not available) says the microbiome can affect drug metabolism and pharmacokinetics. Section IV discusses behavioral changes after transfer of depression-associated microbiomes into animals, but does not establish behavioral effects from drug-induced microbiome changes. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • The microbiome is a general mediator of xenobiotic metabolism, capable of activating, inactivating or recycling numerous drugs.

    “the microbiome is a general mediator of xenobiotic metabolism, capable of activating, inactivating or recycling numerous drugs [103,104,105].”

    From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [105]

  • The oral compartment, where berberine reaches its highest concentrations of all, is unexamined and belongs in the same research program.

    “The oral compartment, where berberine reaches its highest concentrations of all, is unexamined and belongs in the same program [103,104,105,106,107,108].”

    From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [105]

    Section IV discusses drug exposure and microbial metabolism in the intestine, while Section II identifies gaps in studying the small-intestinal microbiota. Searches for berberine, the oral cavity, and salivary microbiota found no passage addressing oral berberine concentrations or whether that compartment has been examined. The paper therefore does not verify the claim attributed to it. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

Cites

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3 of the 323 references couldn’t be matched to a known paper.

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Related

Authors
Clarke, G., Sandhu, K. V., Griffin, B. T., Dinan, T. G., Cryan, J. F., & Hyland, N. P.
Affiliations
University College Cork (IE)
ORCID
Venue
Pharmacological Reviews
Publisher
Elsevier BV
Published
2019-04
Volume
71
Issue
2
Pages
198-224
ISSN
0031-6997 (ISSN-L)
DOI
10.1124/pr.118.015768
OpenAlex
W2925298688
Semantic Scholar
f47afa752c20787d780ef6b45f4821dd8a2cb5d0
Cited by
319
References
323
Citations by year
2026: 34 · 2025: 26 · 2024: 42 · 2023: 43 · 2022: 42 · 2021: 56 · 2020: 60 · 2019: 16
FWCI
6.91
Type
journal article
Language
en
Open access
Licence
Locations
  • Pharmacological Reviews (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Cork Open Research Archive (University College Cork, Ireland) (publishedVersion, cc-by)
  • Arrow@dit (Dublin Institute of Technology) (submittedVersion, cc-by)
  • Cork Open Research Archive (University College Cork, Ireland) (submittedVersion, cc-by)
Funders
Science Foundation Ireland (SFI/12/RC/, 12/RC/2273, 12/RC/, SFI/12/RC/2273.)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords
gut microbiota, xenobiotic metabolism, drug metabolism, pharmacokinetics, microbiome-targeted therapy, drug discovery, drug absorption, microbial metabolites, adverse drug reactions, precision medicine
MeSH terms
Gastrointestinal Microbiome, Animals, Humans, Xenobiotics, Drug Discovery, Precision Medicine, Microbiota, Drug-Related Side Effects and Adverse Reactions

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-08.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-08.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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