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Cited by 717Gut microbiota and healthPharmacogenetics and Drug MetabolismDrug Transport and Resistance Mechanisms

The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism

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Spanogiannopoulos, Peter, Bess, Elizabeth N., Carmody, Rachel N., Turnbaugh, Peter J.·2016·Nature Reviews Microbiology
DOI 10.1038/nrmicro.2016.17PMC PMC5243131
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Abstract

Although the importance of human genetic polymorphisms in therapeutic outcomes is well established, the role of our 'second genome' (the microbiome) has been largely overlooked. In this Review, we highlight recent studies that have shed light on the mechanisms that link the human gut microbiome to the efficacy and toxicity of xenobiotics, including drugs, dietary compounds and environmental toxins. Continued progress in this area could enable more precise tools for predicting patient responses and for the development of a new generation of therapeutics based on, or targeted at, the gut microbiome. Indeed, the admirable goal of precision medicine may require us to first understand the microbial pharmacists within.

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Crossref · 10.1038/nrmicro.2016.17

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  • Interpretationcitation

    The prevalence of reduction and hydrolysis may indicate core microbial species or gene families that act on many small molecules.

    “The commonality of these two reaction types (reduction and hydrolysis) may also imply that there are core microbial species or gene families that impact a wide range of small molecules37.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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  • Premisecitation

    A similar β-glucuronidase mechanism contributes to side effects of nonsteroidal anti-inflammatory drugs including diclofenac, indomethacin, and ketoprofen.

    “A similar mechanism contributes to the side effects of nonsteroidal anti-inflammatory drugs (NSAIDs), including diclofenac, indomethacin and ketoprofen53.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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  • Premisereasoning

    Known gut microbial drug metabolism repeatedly involves two broad chemical transformations: reduction and hydrolysis.

    “two broad chemical transformation patterns have been repeatedly found: reduction and hydrolysis”
    Quote in the paperSubstantial claim
  • Premisecitation

    Intact sulfasalazine is recovered from stool of antibiotic-treated or germ-free rats but not from conventionally raised animals.

    “Intact sulfasalazine can be recovered from the stool of antibiotic-treated or germ-free rats, but not in conventionally-raised animals42.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Peppercorn, M. A. & Goldman, P. The role of intestinal bacteria in the metabolism of salicylazosulfapyridine. J. Pharmacol. Exp. Ther. 181, 555–562 (1972). source

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  • Premisecitation

    In vitro and/or in vivo evidence supports gut microbial metabolism of 50 drugs.

    “In fact, there is already in vitro and/or in vivo evidence for the metabolism of 50 drugs by the gut microbiota28”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Haiser, H. J. & Turnbaugh, P. J. Developing a metagenomic view of xenobiotic metabolism. Pharmacol. Res. 69, 21–31 (2013). source

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  • May combine two claims. 41
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    Premisecitation

    Microbial β-glucuronidases liberate NSAID glucuronides, allowing aglycone reabsorption; gut epithelial cells then metabolize NSAIDs into reactive metabolites that cause mitochondrial and ER stress, compromise mucosa, and promote inflammation.

    “Microbial β-glucuronidases can then liberate the glucuronide, allowing reabsorption of the aglycone into enterocytes. NSAIDs can be further metabolized into reactive metabolites by these gut epithelial cells, which causes mitochondrial and ER stress, compromising mucosal integrity and promoting inflammation51, 54.”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    Premisecitation

    Prontosil is cleaved by the microbiota to triaminobenzene and sulfanilamide, a bacteriostatic antibiotic that inhibits folate metabolism.

    “prontosil is cleaved by the microbiota, which results in the production of triaminobenzene and sulfanilamide21, a bacteriostatic antibiotic that inhibits folate metabolism.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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  • May combine two claims. The quote only partly states this claim.

    Interpretationreasoning

    Reduction and hydrolysis may reflect the energetic demands of gut microorganisms, with reduction expanding electron acceptors for anaerobic respiration and hydrolysis providing growth substrates.

    “These two reactions may reflect the energetic demands of the gut microbiota.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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    Premisecitation

    Irinotecan is converted to SN-38, glucuronidated to SN-38G, biliary excreted, and then microbial β-glucuronidases liberate SN-38 in the gut; this SN-38 is toxic to intestinal epithelium and is thought to worsen diarrhea in up to 80% of colorectal cancer patients.

    “The resulting SN-38 in the gut lumen exhibits toxicity towards intestinal epithelial cells and is thought to exacerbate the diarrhea found in up to 80% of CRC patients50, 51.”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    Premisecitation

    Microbial arylamine N-acetyltransferases inactivate 5-aminosalicylic acid, and their activity can vary up to 10-fold between individuals.

    “the bioactive component of sulfasalazine, 5-aminosalicylic acid, is inactivated by microbial arylamine N-acetyltransferases. The activity of these enzymes can vary up to 10-fold between individuals46”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    Azoreductases are widespread across human gut bacterial phyla, have broad substrate compatibility, and metabolize azo compounds at rates that depend on the broader chemical structure.

    “Azoreductases are widespread across multiple bacterial phyla found in the human gut28 and possess broad substrate compatibility43, 44; however, they metabolize azo compounds at different rates depending on the broader chemical structure of the molecule45.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [28] Haiser, H. J. & Turnbaugh, P. J. Developing a metagenomic view of xenobiotic metabolism. Pharmacol. Res. 69, 21–31 (2013). source

      Not checked in the free run.

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  • May combine two claims.

    Premisecitation

    A simplified four-strain gut microbiota restores sulfasalazine metabolism in gnotobiotic rats, and bacterial isolates from these animals cleave sulfasalazine in vitro.

    “a simplified gut microbiota composed of 4 bacterial strains (Bacteroides sp., Streptococcus faecalis, and 2 Lactobacillus sp.) is sufficient to restore sulfasalazine metabolism in gnotobiotic rats and the in vitro incubation of sulfasalazine with bacterial isolates from these animals results in drug cleavage42.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Peppercorn, M. A. & Goldman, P. The role of intestinal bacteria in the metabolism of salicylazosulfapyridine. J. Pharmacol. Exp. Ther. 181, 555–562 (1972). source

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Interpretationcitation

    The number of drugs metabolized by the gut microbiota is likely greater than 50 because systematic analyses are lacking and the microbiome is genetically diverse.

    “This number is likely an underestimate given the lack of any systematic analyses of the gut microbial metabolism of drugs and the vast genetic diversity within the microbiome34.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    In E. lenta DSM2243, digoxin induces the cardiac glycoside reductase operon, and Cgr2 is predicted to accept electrons from Cgr1 and reduce the lactone ring of digoxin.

    “In E. lenta DSM2243, digoxin induces the expression of a 2-gene operon, referred to as the cardiac glycoside reductase (cgr) operon.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Haiser, H. J., Seim, K. L., Balskus, E. P. & Turnbaugh, P. J. Mechanistic insight into digoxin inactivation by Eggerthella lenta augments our understanding of its pharmacokinetics. Gut Microbes 5, 233–238 (2014). source

      Not checked in the free run.

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    Premisecitation

    Digoxin reduction is enhanced by a complex gut microbiome and suppressed by dietary protein.

    “digoxin reduction is enhanced in the presence of a complex gut microbiome and suppressed by dietary protein67”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] Haiser, H. J. et al. Predicting and manipulating cardiac drug inactivation by the human gut bacterium Eggerthella lenta. Science 341, 295–298 (2013). This study is the first to show that the bacterial inactivation of drugs can be predicted with a genetic marker and can be prevented using dietary intervention. source

      Not checked in the free run.

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    Premisereasoning

    Tempol increases intestinal concentrations of multiple taurine-conjugated bile acids, including T-β-MCA, which is an antagonist of FXR.

    “Consistent with these findings, tempol increases the intestinal concentration of multiple taurine-conjugated bile acids, including tauro-β-muricholic acid (T-β-MCA). T-β-MCA is an antagonist of the farnesoid X receptor (FXR), a master regulator of lipid, glucose, and bile acid metabolism85, 87, 88.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [85] Li, F. et al. Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nat. Commun. 4, 2384 (2013). source

      Not checked in the free run.

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    Premisecitation

    Many diet-derived bioactive compounds are metabolized by the gut microbiota, and some require this transformation for activation and/or absorption.

    “Many of these “diet-derived bioactive compounds” are metabolized by the gut microbiota (Fig. 4, Supplementary information S2 (table) and Supplementary information S3 (table)) and some are dependent on this transformation for activation and/or absorption47.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    In mouse liver, more than 100 genes are differentially expressed between germ-free and colonized mice, and CYPs are among the largest groups of differentially expressed genes.

    “In the liver, more than 100 genes are differentially expressed between germ-free and colonized mice69. One of the largest groups of differentially expressed genes is the CYPs39.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [69] Bjorkholm, B. et al. Intestinal microbiota regulate xenobiotic metabolism in the liver. PLoS ONE 4, e6958 (2009). source

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    Premisecitation

    Germ-free animals show elevated CYP expression and metabolize pentobarbital more efficiently than colonized animals.

    “Germ-free animals, which show elevated expression of CYPs compared to colonized animals, are more efficient at metabolizing pentobarbital compared to colonized animals69.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Bjorkholm, B. et al. Intestinal microbiota regulate xenobiotic metabolism in the liver. PLoS ONE 4, e6958 (2009). source

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    Premisecitation

    Tempol treatment in mice alters the relative abundance of distal gut bacterial phyla, increasing Bacteroidetes and decreasing Firmicutes, with the genus Lactobacillus significantly reduced.

    “Treatment of mice with tempol altered the relative abundance of the two dominant bacterial phyla in the distal gut, increasing the abundance of Bacteroidetes and decreasing the abundance of Firmicutes85. Within the Firmicutes phylum, the genus Lactobacillus was significantly reduced (Fig. 3).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] Li, F. et al. Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nat. Commun. 4, 2384 (2013). source

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    Interpretationcitation

    The cgr operon is absent from non-reducing E. lenta strains, suggesting that it is necessary for digoxin reduction.

    “The cgr operon is not found in the genomes of strains of E. lenta that lack the ability to reduce digoxin, suggesting that the cgr operon is necessary for the reduction of digoxin”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Haiser, H. J., Seim, K. L., Balskus, E. P. & Turnbaugh, P. J. Mechanistic insight into digoxin inactivation by Eggerthella lenta augments our understanding of its pharmacokinetics. Gut Microbes 5, 233–238 (2014). source

      Not checked in the free run.

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    Premisecitation

    The gut microbiota alters the serum metabolome: 10% of shared metabolites differ in abundance by at least 50%, and the microbiota contributes unique microbial compounds to systemic circulation.

    “Comparisons of germ-free and colonized mice revealed that the gut microbiota not only alters the abundance of endogenous metabolites, with 10% of shared metabolites differing in abundance by at least 50%, but also contributes uniquely microbial compounds to systemic circulation73, 74.”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    Premisecitation

    The gut microbiota affects expression of multiple host genes involved in drug metabolism and transport, both locally and in distant organs such as the liver.

    “Comparisons of germ-free and colonized mice have revealed that the microbiota impacts the expression of multiple host genes involved in drug metabolism and transport68, 69.”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    Interpretationcitation

    Neither the presence nor abundance of Eggerthella lenta predicts digoxin reduction; strain-level variation within E. lenta appears to explain this discrepancy.

    “neither the presence nor the abundance of this species predicts digoxin reductions64–66. This discrepancy appears to be driven by strain-level variations in the E. lenta population67.”
    Quote in the paperSubstantial claim0 of 4 sources checked
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      Not checked in the free run.

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    Interpretationcitation

    Tempol does not further reduce adiposity in intestinal FXR-null mice, which is consistent with changes in microbial bile acid metabolism and FXR signaling contributing to tempol's mechanism of action.

    “Tempol does not further reduce adiposity in intestinal specific FXR-null mice85, consistent with the hypothesis that changes in microbial bile acid metabolism and subsequent signaling via the FXR pathway contribute to the mechanism of action of tempol.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] Li, F. et al. Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nat. Commun. 4, 2384 (2013). source

      Not checked in the free run.

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    Interpretationreasoning

    p-cresol and acetaminophen are both substrates of human SULT1A1, and competition between them likely impairs acetaminophen detoxification and increases accumulation of the toxic metabolite NAPQI.

    “p-cresol and acetaminophen are both substrates of the human cytosolic sulfotransferase SULT1A181 (Fig. 3). This competition likely impedes the host’s ability to detoxify acetaminophen, increasing the likelihood of accumulating the toxic metabolite NAPQI.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    Mice fed high-fat diets supplemented with polyphenols showed reduced diet-induced weight gain and adiposity, improved insulin sensitivity, and diminished markers of intestinal inflammation and oxidative stress compared with controls.

    “Mice fed high-fat diets supplemented with polyphenols showed reduced diet-induced weight gain and adiposity, improved insulin sensitivity, and diminished markers of intestinal inflammation and oxidative stress compared to controls20, 96.”
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    Premisecitation

    An RNA-sequencing study confirmed differential expression of xenobiotic-metabolism genes in liver between germ-free and colonized mice and reported increased AhR, CAR, PPARα, and Nrf2 in germ-free mice.

    “A recent RNA-sequencing based study confirmed the differential expression of multiple genes involved in xenobiotic metabolism in the liver of germ-free and colonized mice72. Furthermore, this study reported a significant increase in the expression of the xenobiotic-sensing transcription factors aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), peroxisome proliferator-activ”
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    Premisecitation

    Emulsifier feeding shifts gut microbiome composition, decreasing Bacteroidales and increasing mucolytic bacteria such as Ruminococcus gnavus.

    “The composition of the gut microbiome was also impacted with decreased abundances of the Bacteroidales (phylum: Bacteroidetes) and increased levels of mucolytic bacteria, such as Ruminococcus gnavus135.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    Ellagic acid metabolism varies significantly among individuals and can be grouped into three categories, including a subset of individuals who produce no urolithins.

    “A recent survey found that ellagic acid metabolism varied significantly among individuals but could be generally grouped into three categories depending on the metabolites generated, including a subset of individuals that did not produce any urolithins106, 107.”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    Premisecitation

    Bacterial beta-glucuronidases appear druggable, as multiple inhibitors exist that have minimal impact on the mammalian homolog.

    “The answer appears to be yes for the bacterial β-glucuronidases, for which multiple inhibitors now exist that have minimal impact on the mammalian homolog143–146.”
    Quote in the paperSubstantial claim0 of 4 sources checked
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    Premisecitation

    In germ-free rats colonized with a bacterial consortium that converts secoisolariciresinol to enterodiol and enterolactone and fed a flaxseed-rich diet, breast tumor number was 2.5 times lower and tumor size and weight were about 2 times lower than in germ-free rats.

    “For the colonized group, the number of breast tumors was 2.5 times lower and the tumor size and weight were ~2 times lower than was observed for the germ-free group.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    In animal models, giving melamine together with broad-spectrum antibiotics reduced kidney damage, potentially by decreasing microbial conversion of melamine to cyanuric acid.

    “Administration of melamine in combination with broad-spectrum antibiotics resulted in decreased kidney damage in animal models138, potentially due to the decreased microbial conversion of melamine into cyanuric acid139, 140.”
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    Premisecitation

    In gnotobiotic rats monoassociated with Escherichia coli carrying or lacking uidA, microbial β-glucuronidase increased colonic genotoxicity of IQ threefold and led to multiple peaks in urinary and fecal excretion.

    “Microbial β-glucuronidase increased the colonic genotoxicity of 2-amino-3-methylimidazo[4,5-f]quinolone (IQ) threefold and led to multiple peaks in urinary and fecal excretion of the compound, consistent with enterohepatic circulation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    In vitro exposure of a complex human fecal microbial community to black tea or grape-derived polyphenols can directly increase Akkermansia muciniphila abundance, suggesting limited dependence on host factors.

    “a recent in vitro study reported that exposure of a complex human fecal microbial community to black tea or grape-derived polyphenols can directly increase the abundance of A. muciniphila, suggesting a limited dependence on host factors in this process103.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] Kemperman, R. A. et al. Impact of polyphenols from black tea and red wine/grape juice on a gut model microbiome. Food Res. Int. 53, 659–669 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TMAO is linked to cholesterol accumulation in macrophages and foam cell deposition and to higher risk of a major adverse cardiac event.

    “a metabolite linked to accumulation of cholesterol in macrophages and foam cell deposition127, and higher risk of a major adverse cardiac event128.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [127] Wang, Z. et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57–63 (2011). This study demonstrates that the metabolism of dietary lipids by gut bacteria contributes to heart disease. source

      Not checked in the free run.

    • cites [128] Tang, W. H. et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N. Engl. J. Med. 368, 1575–1584 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Crystallography and bioinformatics showed that beta-glucuronidase inhibitors interact with a bacterial loop that is highly conserved and well distributed across gut bacterial enzymes but absent from the mammalian enzyme.

    “This specificity towards the bacterial enzymes was revealed with the assistance of crystallography and bioinformatics, which demonstrated that these inhibitors interacted with a “bacterial loop” that is highly conserved and well distributed across the gut bacteria enzymes, but is absent from the mammalian enzyme146.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [146] Wallace, B. D. et al. Alleviating cancer drug toxicity by inhibiting a bacterial enzyme. Science 330, 831–835 (2010). This is the first study to show that the toxicity associated with the microbial metabolism of cancer drugs in the gut can be mitigated using bacterial enzyme-specific small-molecule inhibitors. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The gut microbiota influences pharmacology and nutrition.

    “The emerging appreciation that the gut microbiota influences pharmacology and nutrition has begun to reveal the immediate translational potential of this research28, 30, 142.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [28] Haiser, H. J. & Turnbaugh, P. J. Developing a metagenomic view of xenobiotic metabolism. Pharmacol. Res. 69, 21–31 (2013). source

      Not checked in the free run.

    • cites [30] Nicholson, J. K., Holmes, E. & Wilson, I. D. Gut microorganisms, mammalian metabolism and personalized health care. Nat. Rev. Microbiol. 3, 431–438 (2005). source

      Not checked in the free run.

    • cites [142] Sonnenburg, J. L. & Fischbach, M. A. Community health care: therapeutic opportunities in the human microbiome. Sci. Transl. Med. 3, 78ps12 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    This suggests that the composition of the gut microbiota is a key driver of metabolic syndrome and low-grade inflammation.

    “This suggests that the composition of the gut microbiota is a key driver of metabolic syndrome and low-grade inflammation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [135] Chassaing, B. et al. Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature 519, 92–96 (2015). This research shows that dietary supplements can disrupt mucus–bacterial interactions, promoting gut inflammation. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Emulsifier-induced shifts in microbial community structure are accompanied by low-grade inflammation, increased gut permeability, increased weight and adiposity, and development of metabolic syndrome.

    “These shifts in microbial community structure were accompanied by low-grade inflammation, increased gut permeability, increased weight and adiposity, and development of metabolic syndrome.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [135] Chassaing, B. et al. Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature 519, 92–96 (2015). This research shows that dietary supplements can disrupt mucus–bacterial interactions, promoting gut inflammation. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Klebsiella terrigena is sparsely distributed in the gut of healthy individuals, present in about 1% of the population.

    “Interestingly, K. terrigena is sparsely distributed in the gut of healthy individuals, being present in approximately 1% of the population141.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [141] Podschun, R. Isolation of Klebsiella terrigena from human feces: biochemical reactions, capsule types, and antibiotic sensitivity. Zentralbl. Bakteriol. 275, 73–78 (1991). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Feeding mice the emulsifiers carboxymethylcellulose and polysorbate-80 reduces intestinal mucus thickness and increases microbial encroachment toward epithelial cells.

    “Controlled feeding of two emulsifying agents, carboxymethylcellulose and polysorbate-80 (Tween 80), to mice resulted in a reduction of the thickness of intestinal mucus and, as a result, microbial cells showed increased encroachment towards epithelial cells135.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [135] Chassaing, B. et al. Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature 519, 92–96 (2015). This research shows that dietary supplements can disrupt mucus–bacterial interactions, promoting gut inflammation. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Choline-containing compounds are metabolized by microbial glycyl radical enzymes to trimethylamine, which is absorbed and oxidized by hepatic flavin monooxygenases to TMAO.

    “In the colon, choline-containing compounds undergo metabolism by microbial glycyl radical enzymes126 to form the intermediate gas trimethylamine (TMA; Fig. 4). In turn, TMA is absorbed and oxidized by hepatic flavin monooxygenases, forming TMA N-oxide (TMAO)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [126] Craciun, S. & Balskus, E. P. Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme. Proc. Natl Acad. Sci. USA 109, 21307–21312 (2012). source

      Not checked in the free run.

    • cites [127] Wang, Z. et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57–63 (2011). This study demonstrates that the metabolism of dietary lipids by gut bacteria contributes to heart disease. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Melamine and its microbial metabolite cyanuric acid form an insoluble complex that impairs kidney function and causes severe renal toxicity.

    “The industrial compound melamine and its microbial metabolite, cyanuric acid, form an insoluble complex that interferes with kidney function, leading to severe renal toxicity136.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [136] Hau, A. K., Kwan, T. H. & Li, P. K. Melamine toxicity and the kidney. J. Am. Soc. Nephrol. 20, 245–250 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic non-caloric artificial sweetener consumption in mice impacts gut microbial community structure, increasing Bacteroides and some Clostridiales.

    “Chronic NAS consumption in mice was shown to impact gut microbial community structure133, resulting in an increase in abundance of bacteria belonging to the Bacteroides genus and some members of the Clostridiales order.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [133] Suez, J. et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature 514, 181–186 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Gut microorganisms have evolved numerous enzymes that directly metabolize xenobiotics and their metabolites, and ill-defined mechanisms for controlling host xenobiotic metabolism and transport.

    “Gut microorganisms have evolved numerous enzymes that allow them to directly metabolize xenobiotics and their metabolites, as well as ill-defined mechanisms for controlling host xenobiotic metabolism and transport.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationreasoning

    The microbiome will be a key component of a 21st century pharmacopoeia, providing a modifier, target, and source for future drugs.

    “that the microbiome will be a key component of a 21st century pharmacopoeia, as it provides a modifier, target and source for the drugs of the future.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Findings from animal models about microbiome-drug interactions can be extrapolated to humans.
42 of 42

  • The paper relies on this without support.

    The importance of the human microbiome for therapeutic outcomes has been largely overlooked.

    “the importance of our “second genome” (the microbiome) has been largely overlooked”

  • The paper relies on this without support.

    The links between the microbiota and pharmacology remain critically underexplored.

    “the links between the microbiota and pharmacology remain critically underexplored”

  • The paper relies on this without support.

    Findings from animal models about microbiome-drug interactions can be extrapolated to humans.

    “Notably, β-glucuronidase inhibitors are capable of rescuing mice from drug toxicity.”

  • The paper relies on this without support.

    A fraction of patients receiving tacrolimus require an increase in dosing.

    “The immunosuppressant drug tacrolimus has a very narrow therapeutic range and a fraction of patients receiving this therapy require an increase in dosing.”
4 of 4

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 [104]

    The section “Microbial metabolism of drugs and their metabolites” (page unavailable) says gut microbes can affect the bioavailability of oral drugs and that reduction and hydrolysis are recurring gut-microbial reactions. It does not establish that the mouth is the first microbial compartment encountered by a swallowed supplement or that oral bacteria carry those activities; searches for mouth, saliva, and oral bacteria did not locate that evidence in our copy. (LLM, conf=0.87)

    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 [104]

    In “Microbial metabolism of drugs and their metabolites” (page not available), the review explains that gut bacteria metabolize drugs and that bacterial β-glucuronidases can reactivate biliary-excreted drugs and permit reabsorption. The passages do not identify berberine as altering those processes or establish gut-barrier modulation as a route by which berberine changes other drugs’ disposition; a search for berberine found no pertinent passage. (LLM, conf=0.85)

    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 [104]

  • No study has yet measured the disposition of a co-administered drug before and after berberine while characterizing the microbiota in the same subjects, which is what would move Axis 4 from candidate to demonstrated.

    “No study has yet measured the disposition of a co-administered drug before and after berberine while characterizing the microbiota in the same subjects, which is what would move Axis 4 from candidate to demonstrated.”

    From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [104]

    The Abstract says links between the microbiota and pharmacology remain underexplored, and the Outlook calls for broader metagenomic and metabolomic studies (page numbers unavailable). Searches for berberine and for a before-and-after study measuring a co-administered drug’s disposition while characterizing the same subjects’ microbiota found no passage addressing that specific research gap. (LLM, conf=0.75)

    Experimental — accuracy not yet measured

  • 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 [104]

    The Abstract and Outlook (page unavailable) discuss gut microbial xenobiotic metabolism, but do not address the oral compartment. Searches for berberine concentrations and oral microbiota found no passage supporting the claim that oral berberine exposure is highest, unexamined, or part of the proposed research program. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Reference note reverses the microbial reaction

    Minor

    The reference note attributes the carcinogenic effect to microbial glucuronidation, but the main text says microbial enzymes remove the glucuronide group to reactivate the compound. These describe opposite transformations.

1 of 1

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Authors
Spanogiannopoulos, P., Bess, E. N., Carmody, R. N., & Turnbaugh, P. J.
Affiliations
University of California, San Francisco (US)
Corresponding author
Turnbaugh, Peter J.
ORCID
Venue
Nature Reviews Microbiology
Publisher
Springer Science and Business Media LLC
Published
2016-03-14
Volume
14
Issue
5
Pages
273-287
ISSN
  • 1740-1526 (ISSN-L)
  • 1740-1534
DOI
10.1038/nrmicro.2016.17
PMC
PMC5243131
OpenAlex
W2294346158
Cited by
717
References
168
Citations by year
2026: 67 · 2025: 58 · 2024: 64 · 2023: 57 · 2022: 76 · 2021: 70 · 2020: 102 · 2019: 74 · 2018: 72 · 2017: 59 · 2016: 17 · 2015: 1
FWCI
6.64
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Reviews Microbiology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Damon Runyon Cancer Research Foundation (DRR4216)
  • Pfizer
  • Seres Therapeutics
  • National Institutes of Health
  • University of California, San Francisco
  • National Heart, Lung, and Blood Institute (R01HL122593)
  • National Institute of Diabetes and Digestive and Kidney Diseases (F32DK101154, P30DK098722)
  • National Center for Complementary and Integrative Health (R01AT008618)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords
gut microbiota, xenobiotic metabolism, drug metabolism, dietary compounds, environmental toxins, gut microbiota metabolites, drug toxicity, precision medicine, metagenomics, human genetic polymorphism
MeSH terms
Gastrointestinal Microbiome, Animals, Diet, Drug Therapy, Pharmaceutical Preparations, Humans, Immune System, Pharmacogenetics, Xenobiotics, Metagenome, Metabolome

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 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

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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