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Gut Reactions: Breaking Down Xenobiotic–Microbiome Interactions
Open accessAbstract
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.
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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.
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In the paper
“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).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > II. The Gut Microbiome
What the sources say
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In the paper
“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.”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > I. Introduction
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“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).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > II. The Gut Microbiome
What the sources say
- Not checked yetcites Lynch and Pedersen, 2016 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“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).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > II. The Gut Microbiome
What the sources say
- Not checked yetcites Qin et al., 2010 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, the metabolism of many clinically used drugs is likely to be influenced by either direct or indirect effects of the gut microbiome.”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > I. Introduction
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“However, these samples are not representative of the microbiome of more proximal regions of the large intestine, and the nonuniform localization and spatial organization of the gut microbiota along the gastrointestinal tract require further evaluation in terms of the functional implications for microbial xenobiotic metabolism (Tropini et al., 2017).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > II. The Gut Microbiome
What the sources say
- Not checked yetcites Tropini et al., 2017 source
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In the paper
“Data indicate a narrowing of diversity and distinctive microbiota configurations associated with ageing in long-stay care individuals compared with that of community dwellers (Claesson et al., 2012;Jeffery et al., 2016).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > II. The Gut Microbiome
What the sources say
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In the paper
“Once present in the intestinal lumen, an array of bacterial enzymes is capable of a diverse set of chemical reactions.”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > A. Direct Microbial Metabolism of Xenobiotics
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In the paper
“Despite these concerns over under-represented microbes and/or reduced microbial gene richness, the importance of the dictum that structure begets function for the role of gut microbiota composition in xenobiotic metabolism is difficult to gauge given that members of this bacterial ecosystem may exhibit both functional redundancy and pleiotropy (Clarke et al., 2014b;Moya and Ferrer, 2016).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > II. The Gut Microbiome
What the sources say
- Not checked yetcites Clarke et al., 2014b
- Not checked yetcites Moya and Ferrer, 2016
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In the paper
“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).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > I. Introduction
What the sources say
- Not checked yetcites Li et al., 2014
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In the paper
“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).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > A. Direct Microbial Metabolism of Xenobiotics
What the sources say
- Not checked yetcites Pellock and Redinbo, 2017
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In the paper
“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).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > II. The Gut Microbiome
What the sources say
- Not checked yetcites Clarke et al., 2014a
- Not checked yetcites Perez-Munoz et al., 2017 source
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In the paper
“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).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > II. The Gut Microbiome
What the sources say
- Not checked yetcites Clarke et al., 2014b
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In the paper
“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).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > II. The Gut Microbiome
What the sources say
- Not checked yetcites Michalopoulos, 2007 source
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > II. The Gut Microbiome
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear? Based: unclearIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > A. Direct Microbial Metabolism of Xenobiotics
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In the paper
“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).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > II. The Gut Microbiome
What the sources say
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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In the paper
“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”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > II. The Gut Microbiome
What the sources say
- Not checked yetcites Portune et al., 2017 source
- Not checked yetcites Campbell and Wisniewski, 2017
- Not checked yetcites Dikongue and Segurel, 2017
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > II. The Gut Microbiome
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In the paper
“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).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > A. Direct Microbial Metabolism of Xenobiotics
What the sources say
- Not checked yetcites Setchell et al., 2002 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > B. Microbial Regulation of Host Hepatic Drug Metabolism
What the sources say
- Not checked yetcites Jourova et al., 2017 source
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In the paper
“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).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > B. Microbial Regulation of Host Hepatic Drug Metabolism
What the sources say
- Not checked yetcites Selwyn et al., 2015a
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In the paper
“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.”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > B. Microbial Regulation of Host Hepatic Drug Metabolism
What the sources say
- Not checked yetcites Selwyn et al., 2015b
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In the paper
“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.”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > B. Microbial Regulation of Host Hepatic Drug Metabolism
What the sources say
- Not checked yetcites Jourova et al., 2017 source
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In the paper
“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).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > A. Direct Microbial Metabolism of Xenobiotics
What the sources say
- Not checked yetcites Pollet et al., 2017 source
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In the paper
“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.”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > B. Microbial Regulation of Host Hepatic Drug Metabolism
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“CYP3a11 is the mouse homolog of human CYP3A4, and this enzyme metabolizes more than 60% of all drugs.”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > B. Microbial Regulation of Host Hepatic Drug Metabolism
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > A. Direct Microbial Metabolism of Xenobiotics
What the sources say
- Not checked yetcites Thaiss et al., 2016a
- Not checked yetcites Chilloux and Dumas, 2017
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None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > A. Direct Microbial Metabolism of Xenobiotics
What the sources say
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In the paper
“It should be noted that ciprofloxacin is metabolized in the liver and can directly inhibit CYP1A2, CYP2D6, and CYP3A4 (Bolhuis et al., 2011).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > B. Microbial Regulation of Host Hepatic Drug Metabolism
What the sources say
- Not checked yetcites Bolhuis et al., 2011 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > B. Microbial Regulation of Host Hepatic Drug Metabolism
What the sources say
- Not checked yetcites Toda et al., 2009b
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None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > IV. Factors Influencing the Rate and Extent of Gut Microbiome Xenobiotic Metabolism
What the sources say
- Not checked yetcites Das et al., 2016
- Not checked yetcites Quigley, 2017 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Also stated in: § IV. Factors Influencing the Rate and Extent of Gut Microbiome Xenobiotic Metabolism · plain
In the paper
“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).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > IV. Factors Influencing the Rate and Extent of Gut Microbiome Xenobiotic Metabolism
What the sources say
- Not checked yetcites Hall et al., 1999 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > IV. Factors Influencing the Rate and Extent of Gut Microbiome Xenobiotic Metabolism
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“gut microbiota community structure and metabolic activity also feature biologic rhythms”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > IV. Factors Influencing the Rate and Extent of Gut Microbiome Xenobiotic Metabolism
What the sources say
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > IV. Factors Influencing the Rate and Extent of Gut Microbiome Xenobiotic Metabolism
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In the paper
“Oral delivery of advanced drug formulations designed for extended release (e.g., sustained release tablets) is on the increase”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > IV. Factors Influencing the Rate and Extent of Gut Microbiome Xenobiotic Metabolism
What the sources say
- Not checked yetcites Sousa et al., 2008 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > VII. The Gut Microbiome and Xenobiotics in Health and Disease: a Reciprocal Relationship
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“digoxin use is on the decline amid the emergence of alternative therapies with preferable safety profiles (Haynes et al., 2008;Eade et al., 2013).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > A. The Microbiome and Therapeutic Mechanism of Action, Efficacy, and Adverse Effects
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > V. The Evolution of Microbial Enzymes for Xenobiotic Metabolism
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In the paper
“Host-microbe interactions are frequently viewed from an evolutionary perspective (Davenport et al., 2017).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > V. The Evolution of Microbial Enzymes for Xenobiotic Metabolism
What the sources say
- Not checked yetcites Davenport et al., 2017 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > V. The Evolution of Microbial Enzymes for Xenobiotic Metabolism
What the sources say
- Not checked yetcites Haiser et al., 2013 source
- Not checked yetcites Peppercorn and Goldman, 1972b
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“which is also associated with gut microbiome alterations (Dinan and Cryan, 2017)”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > IV. Factors Influencing the Rate and Extent of Gut Microbiome Xenobiotic Metabolism
What the sources say
- Not checked yetcites Dinan and Cryan, 2017
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > V. The Evolution of Microbial Enzymes for Xenobiotic Metabolism
What the sources say
- Not checked yetcites Bordenstein and Theis, 2015
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Circadian rhythm disruption and appetite fluctuations, including carbohydrate craving, are prominent in stress-related psychiatric disorders such as major depression (Otte et al., 2016)”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > IV. Factors Influencing the Rate and Extent of Gut Microbiome Xenobiotic Metabolism
What the sources say
- Not checked yetcites Otte et al., 2016 source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“The metabolism of azo dyes to aromatic amines is also carried out by azoreductases”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > A. The Microbiome and Therapeutic Mechanism of Action, Efficacy, and Adverse Effects
What the sources say
- Not checked yetcites Chung et al., 1992 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > A. The Microbiome and Therapeutic Mechanism of Action, Efficacy, and Adverse Effects
What the sources say
- Not checked yetcites Lehouritis et al., 2015 source
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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.”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > B. Impact of Current and Putative Therapeutic Interventions on Microbial Community Structure and Function
What the sources say
- Not checked yetcites Maier et al., 2018 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > A. The Microbiome and Therapeutic Mechanism of Action, Efficacy, and Adverse Effects
What the sources say
- Not checked yetcites van Hogezand et al., 1992 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > B. Impact of Current and Putative Therapeutic Interventions on Microbial Community Structure and Function
What the sources say
- Not checked yetcites Maurice et al., 2013 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting possible differential processing of TMA in men and women.”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > A. The Microbiome and Therapeutic Mechanism of Action, Efficacy, and Adverse Effects
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“circulating TMAO may play a role in the protection from hyperammonemia (Kloiber et al., 1988) and from glutamate neurotoxicity (Minana et al., 1996).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > A. The Microbiome and Therapeutic Mechanism of Action, Efficacy, and Adverse Effects
What the sources say
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“Chronic exposure of mice to TMAO attenuates diet-associated glucose tolerance, reducing endoplasmic stress and adipogenesis in adipocytes (Dumas et al., 2017).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > A. The Microbiome and Therapeutic Mechanism of Action, Efficacy, and Adverse Effects
What the sources say
- Not checked yetcites Dumas et al., 2017 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > B. Impact of Current and Putative Therapeutic Interventions on Microbial Community Structure and Function
What the sources say
- Not checked yetcites Watson et al., 2017
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > B. Impact of Current and Putative Therapeutic Interventions on Microbial Community Structure and Function
What the sources say
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > C. Environmental and Industrial Chemicals
What the sources say
- Not checked yetcites Cuhra et al., 2016 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > B. Impact of Current and Putative Therapeutic Interventions on Microbial Community Structure and Function
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“Traffic-related air pollution can result in a decreased relative abundance of Bacteroidaceae and an increased relative abundance of Coriobacteriaceae (Alderete et al., 2018).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > C. Environmental and Industrial Chemicals
What the sources say
- Not checked yetcites Alderete et al., 2018 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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.”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > B. Impact of Current and Putative Therapeutic Interventions on Microbial Community Structure and Function
What the sources say
- Not checked yetcites Ryan et al., 2017 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > X. Summary, Conclusions, and Perspectives
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Stress exposure is also an important consideration, particularly during the extremes of life when the gut microbiota is more chaotic and vulnerable.”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > X. Summary, Conclusions, and Perspectives
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“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).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > VIII. Experimental Approaches in Pharmacomicrobiomics
What the sources say
- Not checked yetcites Hill and Spence, 2016
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“as are other lifestyle factors such as exercise, which is also known to improve gut microbiota profiles (O'Sullivan et al., 2015).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > X. Summary, Conclusions, and Perspectives
What the sources say
- Not checked yetcites O'Sullivan et al., 2015
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > X. Summary, Conclusions, and Perspectives
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > X. Summary, Conclusions, and Perspectives
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > X. Summary, Conclusions, and Perspectives
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Oxygen partial pressures along the gastrointestinal tract also contribute to these metabolic niches.”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > X. Summary, Conclusions, and Perspectives
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“The pharmacomicrobiomic web portal currently lists over 90 examples of such chemicals (http://pharmacomicrobiomics. com/view/chemical/).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > X. Summary, Conclusions, and Perspectives
What the sources say
- Not checked yetcites http://pharmacomicrobiomics. com/view/chemical/
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > X. Summary, Conclusions, and Perspectives
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > A. Psychobiotics
What the sources say
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The expression of host hepatic CYP genes involved in xenobiotic metabolism is also influenced by the gut microbiome.”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > X. Summary, Conclusions, and Perspectives
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no reason why it holds.
In the paper
“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”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > VIII. Experimental Approaches in Pharmacomicrobiomics
What the sources say
- Not checked yetcites Clark and Walker, 2018
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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).”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > VIII. Experimental Approaches in Pharmacomicrobiomics
What the sources say
- Not checked yetcites Wallace et al., 2010 source
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Monoassociation with E. coli Nissle 1917 but not”
§ Gut reactions: breaking down xenobiotic-microbiome interactions > X. Summary, Conclusions, and Perspectives
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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.”
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 source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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 check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“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]
Experimental — accuracy not yet measured
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“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 [105]
Experimental — accuracy not yet measured
Citations
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“The results are also consistent with report-ed interactions between these drugs (antipsychotics, PPIs, and anticancer drugs) and the gut microbiome documented in previous preclinical and clinical studies (Davey et al., 2012, 2013; Imhann et al., 2016; Gopalakrishnan et al., 2018).”
BackgroundResultRichness of human gut microbiome correlates with metabolic markers
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Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis
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A clinician's guide to microbiome analysis
Claesson, M. J., Clooney, A. G., & O'Toole, P. W. (2017) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2017.97 · Cited by 153
MicroRNAs as biomarkers for major depression: a role for let-7b and let-7c
Gururajan, A., Naughton, M., Scott, K. A., O’Connor, R. M., Moloney, G. M., Clarke, G. A., Dowling, J. L., Walsh, A. E. L., Ismail, M. F., Shorten, G., et al. (2016) · Translational Psychiatry · doi:10.1038/tp.2016.131 · Cited by 150
Self-citationCano‐Garrido, O., Seras‐Franzoso, J., & García‐Fruitós, E. (2015) · Microbial Cell Factories · doi:10.1186/s12934-015-0313-6 · Cited by 148
Bahr, S. M., Weidemann, B. J., Castro, A. N., Walsh, J. W., deLeon, O., Burnett, C. M. L., Pearson, N. A., Murry, D. J., Grobe, J. L., & Kirby, J. R. (2015) · EBioMedicine · doi:10.1016/j.ebiom.2015.10.018 · Cited by 143
MicroRNA-based therapeutics in cardiovascular disease: screening and delivery to the target
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Molecular Insights into Microbial β-Glucuronidase Inhibition to Abrogate CPT-11 Toxicity
Roberts, A. B., Wallace, B. D., Venkatesh, M. K., Mani, S., & Redinbo, M. R. (2013) · Molecular Pharmacology · doi:10.1124/mol.113.085852 · Cited by 140
Joyce, S. A., Shanahan, F., Hill, C., & Gahan, C. G. (2014) · Gut Microbes · doi:10.4161/19490976.2014.969986 · Cited by 139
Characterization of Choline Trimethylamine-Lyase Expands the Chemistry of Glycyl Radical Enzymes
Craciun, S., Marks, J. A., & Balskus, E. P. (2014) · ACS Chemical Biology · doi:10.1021/cb500113p · Cited by 139
Flagged first, then by citations
3 of the 323 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Cryan, J. F., O'Riordan, K. J., Cowan, C. S. M., Sandhu, K. V., Bastiaanssen, T. F. S., Boehme, M., Codagnone, M. G., Cussotto, S., Fulling, C., Golubeva, A. V., et al. (2019) · Physiological Reviews · doi:10.1152/physrev.00018.2018 · Cited by 5,286
Self-citationMicrobiota in health and diseases
Hou, K., Wu, Z.-X., Chen, X.-Y., Wang, J.-Q., Zhang, D., Xiao, C., Zhu, D., Koya, J. B., Wei, L., Li, J., et al. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-00974-4 · Cited by 3,171
Probiotics and prebiotics in intestinal health and disease: from biology to the clinic
Sanders, M. E., Merenstein, D. J., Reid, G., Gibson, G. R., & Rastall, R. A. (2019) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0173-3 · Cited by 2,059
The gut microbiome in neurological disorders
Cryan, J. F., O'Riordan, K. J., Sandhu, K., Peterson, V., & Dinan, T. G. (2020) · The Lancet Neurology · doi:10.1016/s1474-4422(19)30356-4 · Cited by 1,336
Self-citationInteraction of the microbiota with the human body in health and diseases
Altveş, S., Yıldız, H. K., & Vural, H. C. (2019) · Bioscience of Microbiota Food and Health · doi:10.12938/bmfh.19-023 · Cited by 398
Metadata
- Authors
- Clarke, G., Sandhu, K. V., Griffin, B. T., Dinan, T. G., Cryan, J. F., & Hyland, N. P.
- Affiliations
- University College Cork (IE)
- Venue
- Pharmacological Reviews
- Publisher
- Elsevier BV
- Published
- 2019-04
- Volume
- 71
- Issue
- 2
- Pages
- 198-224
- ISSN
- 0031-6997 (ISSN-L)
- 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
- hybrid
- doi.org
- 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.
A language model drew the claims from the paper on 2026-10-08, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-08 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
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.
What counts as a claim ›How we measure confidence ›How we check this ›
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