Gut Reactions: Breaking Down Xenobiotic–Microbiome Interactions

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).”

What the sources say

• Not checked yetcites Fraher et al., 2012 source
• Not checked yetcites Claesson et al., 2017 source

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.”

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.”

In 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).”

What the sources say

• Not checked yetcites Lynch and Pedersen, 2016 source

In 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).”

What the sources say

• Not checked yetcites Qin et al., 2010 source

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.”

In 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).”

What the sources say

• Not checked yetcites Tropini et al., 2017 source

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).”

What the sources say

• Not checked yetcites Claesson et al., 2012 source
• Not checked yetcites Jeffery et al., 2016 source

In the paper

“Once present in the intestinal lumen, an array of bacterial enzymes is capable of a diverse set of chemical reactions.”

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).”

What the sources say

• Not checked yetcites Clarke et al., 2014b
• Not checked yetcites Moya and Ferrer, 2016

In the paper

“Microbial colonization of germ-free animals normalized the expression of Cyp3a and Cyp4a gene clusters to those observed in conventional animals (Selwyn et al., 2016).”

What the sources say

• Not checked yetcites Selwyn et al., 2016 source

In the paper

“Although the extent of this variation is somewhat bewildering, an earlier study neatly demonstrated the important implications arising from these observations in that the propensity for enzyme inhibition varied according to the bacterial provenance of the orthologous enzymes (Wallace et al., 2015).”

What the sources say

• Not checked yetcites Wallace et al., 2015 source

In the paper

“The range of metabolic activity of the gut microbiome outlined above is supplemented via microbial regulation of host enzyme expression and activity in both the liver and large intestine, effectively regulating aspects of host drug absorption and metabolism (see Table 2).”

In the paper

“This transcriptional regulation of such a range of important host drug-processing genes by the gut microbiome may have important implications in terms of microbiome-drug interactions that are not currently routinely considered.”

In the paper

“Both mRNA and protein expression of CYP3a11 is markedly reduced in the livers of adult germ-free mice (Selwyn et al., 2015b).”

What the sources say

• Not checked yetcites Selwyn et al., 2015b

In the paper

“On the contrary, in the case in intestinal CYP enzymes, which are present in the intestine, but expressed in vastly lower amounts than the liver, intestinally mediated CYP metabolism can still be the major site of drug metabolism (Hall et al., 1999).”

What the sources say

• Not checked yetcites Hall et al., 1999 source

In the paper

“Microbial enzymes, such as b-glucuronidases, can differ in substrate selectivity and activity depending on the bacteria from which they arise (Pollet et al., 2017).”

What the sources say

• Not checked yetcites Pollet et al., 2017 source

In the paper

“It has been shown, for example, that ciprofloxacin (a broadspectrum fluoroquinolone antibiotic) reduces hepatic Cyp3a expression and metabolism of the benzodiazepine triazolam (Toda et al., 2009a).”

What the sources say

• Not checked yetcites Toda et al., 2009a

In the paper

“was inducible by the drug it metabolizes (Haiser et al., 2013).”

What the sources say

• Not checked yetcites Haiser et al., 2013 source

In the paper

“Host xenobiotic metabolism is influenced by circadian rhythms (Ozturk et al., 2017)”

What the sources say

• Not checked yetcites Ozturk et al., 2017 source

In the paper

“this operon was specific to drug-metabolizing strains of E. lenta”

What the sources say

• Not checked yetcites Haiser et al., 2013 source

In the paper

“actual metabolic activity of the gut microbiome may diverge from its functional potential (Tanca et al., 2017).”

What the sources say

• Not checked yetcites Tanca et al., 2017 source

In the paper

“Diurnal microbial behavior in turn is thought to influence the programming of the colonic and hepatic circadian transcriptome via fluctuating microbial metabolites”

What the sources say

• Not checked yetcites Thaiss et al., 2016b

In the paper

“these modified release formulations also increase the scope for drug-microbiome interactions (Enright et al., 2016)”

What the sources say

• Not checked yetcites Enright et al., 2016

In the paper

“interindividual differences in the abundance of a cytochrome-encoding operon, responsible for the deactivation of the cardiac drug digoxin, have recently been reported”

What the sources say

• Not checked yetcites Haiser et al., 2013 source

In the paper

“this may also be true of microbial enzymatic activity because gut microbiota community structure and metabolic activity also feature biologic rhythms”

What the sources say

• Not checked yetcites Voigt et al., 2016 source
• Not checked yetcites Johnson et al., 2017 source

In the paper

“biochemical modification of exogenous compounds by our gut microbes is not always geared toward elimination of these foreign compounds.”

In the paper

“studies suggest that we share a stable set of core functions despite these variable gut microbiota profiles (Human Microbiome Project Consortium, 2012)”

What the sources say

• Not checked yetcites Human Microbiome Project Consortium, 2012

In the paper

“regulated by diet and time of feeding rather than environmental 24-hour light-dark cycles (Voigt et al., 2016;Johnson et al., 2017).”

What the sources say

• Not checked yetcites Voigt et al., 2016 source
• Not checked yetcites Johnson et al., 2017 source

In the paper

“due to our reliance of fecal microbiota assessments, comparatively little is known about the microbiota of the less accessible small intestine (El Aidy et al., 2015).”

What the sources say

• Not checked yetcites El Aidy et al., 2015 source

In the paper

“Finally, it should also be recognized that although microbial abundance is lower in the small intestine, this should not lead to the implicit assumption that it will have a limited impact on the drugs that are predominantly absorbed in this region.”

In the paper

“For example, in the case of cyclosporine, it is estimated that up to half of the drug is metabolized by intestinal CYP enzymes (Benet and Cummins, 2001), illustrating that relatively low amounts of enzymes in the small intestine could still potentially have a significant impact for orally”

• Also stated in: § IV. Factors Influencing the Rate and Extent of Gut Microbiome Xenobiotic Metabolism · hedged

  “illustrating that relatively low amounts of enzymes in the small intestine could still potentially have a significant impact for orally administered drugs.”

What the sources say

• Not checked yetcites Benet and Cummins, 2001

In the paper

“the activity of the gut microbiota may exhibit resilience despite fluctuating community membership and structure (Song et al., 2015)”

What the sources say

• Not checked yetcites Song et al., 2015 source

In the paper

“host-genetic influences on gut microbiome composition (Goodrich et al., 2016;Rothschild et al., 2018) are also likely to play a role in influencing the rate and extent of microbial xenobiotic metabolism.”

What the sources say

• Not checked yetcites Goodrich et al., 2016 source
• Not checked yetcites Rothschild et al., 2018 source

In the paper

“Jet lag can disrupt this diurnal microbiota biology, a feature driven by alterations in feeding patterns (Thaiss et al., 2014).”

What the sources say

• Not checked yetcites Thaiss et al., 2014 source

In the paper

“For example, in the case of cyclosporine, it is estimated that up to half of the drug is metabolized by intestinal CYP enzymes (Benet and Cummins, 2001), illustrating that relatively low amounts of enzymes in the small intestine could still potentially have a significant impact for orally”

What the sources say

• Not checked yetcites Benet and Cummins, 2001

In the paper

“The microbiome-associated metabolite phenylacetic acid has also been shown to influence disease phenotype in nonalcoholic fatty liver disease, contributing to hepatic lipid accumulation (Hoyles et al., 2018a).”

What the sources say

• Not checked yetcites Hoyles et al., 2018a

In the paper

“there are examples of disease-associated gut microbiomes, such as depression, that do result in altered behavioral phenotypes and host physiologic characteristics when transferred into animal models (Kelly et al., 2016a).”

What the sources say

• Not checked yetcites Kelly et al., 2016a

In the paper

“it was only present in 26% of individuals”

What the sources say

• Not checked yetcites Rath et al., 2017 source

In the paper

“The reactions carried out by the gut microbiome frequently result in the release of small molecules or carbon sources that can be used for microbial growth (Koppel et al., 2017).”

What the sources say

• Not checked yetcites Koppel et al., 2017 source

In the paper

“excess conversion to TMA can lead to artherosclerosis as a consequence of further metabolism by host hepatic processing to TMAO (Zeisel and da Costa, 2009;Wang et al., 2011;Koeth et al., 2013;Craciun et al., 2014).”

What the sources say

• Not checked yetcites Zeisel and da Costa, 2009 source
• Not checked yetcites Wang et al., 2011 source
• Not checked yetcites Koeth et al., 2013 source

In the paper

“digoxin inactivation was significantly influenced by the presence or absence of metabolizing E. lenta strains in the gut microbiota of patients”

What the sources say

• Not checked yetcites Haiser et al., 2013 source

In the paper

“host responsible for processing of the intermediate TMA to the cardiotoxic TMA-N-oxide (TMAO”

In the paper

“TMA is also produced by carnitine oxygenase, a Rieske-type protein, using carnitine found in red meat as a substrate (Zhu et al., 2014).”

What the sources say

• Not checked yetcites Zhu et al., 2014 source

In the paper

“with a broad substrate specificity being a common feature of reactions catalyzed by both host and microbial enzyme (Patterson and Turnbaugh, 2014).”

What the sources say

• Not checked yetcites Patterson and Turnbaugh, 2014

In the paper

“variation in the number of mucosa-associated bacteria in the mouse gut across the circadian period, which was 10 times higher during the dark phase than during the light phase.”

What the sources say

• Not checked yetcites Thaiss et al., 2016b

In the paper

“these enzymes have an important role in the enterohepatic cycling of endogenous substances such as bile acids (Long et al., 2017).”

What the sources say

• Not checked yetcites Long et al., 2017 source

In the paper

“hydroxylation of lovastatin, albeit less well-characterized in terms of specific enzyme involvement, in an animal model following coadministration of an antibiotic that resulted in a more extreme depletion of the microbiota”

What the sources say

• Not checked yetcites Yoo et al., 2014 source

In the paper

“the production of trimethylamine (TMA) from dietary carnitine and choline (Wang et al., 2011;Koeth et al., 2013).”

What the sources say

• Not checked yetcites Wang et al., 2011 source
• Not checked yetcites Koeth et al., 2013 source

In the paper

“hepatic detoxification of acetaminophen that was dependent on the timing of administration (Thaiss et al., 2016b).”

What the sources say

• Not checked yetcites Thaiss et al., 2016b

In the paper

“TMAO can be produced from dietary TMA via metabolic retroconversion (Hoyles et al., 2018b)”

What the sources say

• Not checked yetcites Hoyles et al., 2018b

In the paper

“Toxic or adverse consequences can also ensue, as is the case for irinotecan (Wallace et al., 2010)”

What the sources say

• Not checked yetcites Wallace et al., 2010 source

In the paper

“the most common biotransformations carried out by the gut microbiome (hydrolysis and reduction) often serve to undo the oxidative and conjugative chemistry and indeed the intended eliminative purpose of host hepatic drug metabolism (Koppel et al., 2017).”

What the sources say

• Not checked yetcites Koppel et al., 2017 source

In the paper

“Gut microbiome alterations are frequently reported in stressrelated disorders such as depression, anxiety, and irritable bowel syndrome (Rajilic-Stojanovic et al., 2015;Foster et al., 2017).”

What the sources say

• Not checked yetcites Rajilic-Stojanovic et al., 2015 source
• Not checked yetcites Foster et al., 2017 source

In the paper

“Stress is known to impact on host xenobiotic metabolism, particularly via induction of hepatic drug-metabolizing enzymes possibly mediated by glucocorticoids or noradrenaline (Konstandi, 2013;Pantelidou et al., 2017).”

What the sources say

• Not checked yetcites Konstandi, 2013 source
• Not checked yetcites Pantelidou et al., 2017 source

In the paper

“Many of the therapeutic interventions for such disorders are subject to biotransformation by our gut microbiome (see Table 3)”

In the paper

“fibers, antibiotics, or supplementation with live cultures of lactobacilli were able to affect azoreductase enzyme activity (Chung et al., 1992)”

What the sources say

• Not checked yetcites Chung et al., 1992 source

In the paper

“Irinotecan can also alter the composition of the intestinal microbiome in rats”

What the sources say

• Not checked yetcites Lin et al., 2012
• Not checked yetcites Alexander et al., 2017 source

In the paper

“The hydrolysis of the antiviral drug sorivudine to bromovinyluracil, which is then subsequently metabolized by the host to an inhibitor of host dihydropyrimidine dehydrogenase, may lead to toxicity due to inhibited degradation and increased concentrations of coadministered 5-fluorouracil (5-FU) (Nakayama et al., 1997).”

What the sources say

• Not checked yetcites Nakayama et al., 1997 source

In the paper

“Metformin, used for the treatment of type 2 diabetes, has recently been shown to alter the gut microbiota composition of treatment-naive individuals in a way that improves glucose tolerance.”

What the sources say

• Not checked yetcites Wu et al., 2017

In the paper

“even in the absence of dietary sources of methylamines, baseline levels of TMA and TMAO are found in the circulation (De La Huerga et al., 1953;Hoyles et al., 2018b).”

What the sources say

• Not checked yetcites De La Huerga et al., 1953 source
• Not checked yetcites Hoyles et al., 2018b

In the paper

“fish and other seafood presumed to be beneficial to health also contain significant amounts of TMA precursors as well as free TMAO (Landfald et al., 2017).”

What the sources say

• Not checked yetcites Landfald et al., 2017

In the paper

“24% of the drugs with human targets across therapeutic classes inhibited the growth of at least one bacterial strain in vitro.”

What the sources say

• Not checked yetcites Maier et al., 2018 source

In the paper

“Many xenobiotics also impact on the composition of the gut microbiome, often in a clinically meaningful way.”

In the paper

“is downregulated by testosterone (Bennett et al., 2013)”

What the sources say

• Not checked yetcites Bennett et al., 2013 source

In the paper

“recent studies confirm the potential importance of patient stratification on the basis of gut microbiome composition to identify responders and nonresponders to immunotherapy for the treatment of epithelial tumors and melanomas (Gopalakrishnan et al., 2018;Jobin, 2018;Routy et al., 2018)”

What the sources say

• Not checked yetcites Gopalakrishnan et al., 2018 source
• Not checked yetcites Jobin, 2018 source
• Not checked yetcites Routy et al., 2018 source

In the paper

“the widely present bacterial uracil phosphoribosyltransferase (Martinussen and Hammer, 1994) can convert 5-FU to the RNA-damaging 5-fluorouridine monophosphate using the nematode Caenorhabditis elegans as a model system (Garcia-Gonzalez et al., 2017;Scott et al., 2017).”

What the sources say

• Not checked yetcites Garcia-Gonzalez et al., 2017 source
• Not checked yetcites Scott et al., 2017 source

In the paper

“Metformin appears to have a dose-dependent antimicrobial effect with inhibition of specific bacterial strains only apparent once tested at physiologic intestinal concentrations (Maier et al., 2018).”

What the sources say

• Not checked yetcites Maier et al., 2018 source

In the paper

“the microbiota is responsible for the conversion of the prodrug sulfasalazine into 5-aminosalicylate (5-ASA)”

What the sources say

• Not checked yetcites Peppercorn and Goldman, 1972b

In the paper

“substance use disorders are associated with reduced microbiota diversity (Xu et al., 2017).”

What the sources say

• Not checked yetcites Xu et al., 2017

In the paper

“Dietary phytochemicals can induce gut microbiota alterations, exerting prebiotic-like effects to stimulate the growth of beneficial bacteria (Laparra and Sanz, 2010).”

What the sources say

• Not checked yetcites Laparra and Sanz, 2010

In the paper

“Chronic alcohol abuse also alters gut microbiome composition (Leclercq et al., 2017)”

What the sources say

• Not checked yetcites Leclercq et al., 2017 source

In the paper

“There are also physiologic and morphologic differences between germ-free animals and conventional controls relevant for xenobiotic metabolism (Sousa et al., 2008).”

What the sources say

• Not checked yetcites Sousa et al., 2008 source

In the paper

“This includes both germ-free models or those generated via depletion of the gut microbiota with a cocktail of antibiotics, and can provide valuable pharmacokinetic and pharmacodynamic insights.”

In the paper

“fluctuations in microbial composition of the gut microbiome are associated with alterations in fecal miRNAs (Moloney et al., 2018).”

What the sources say

• Not checked yetcites Moloney et al., 2018 source

In the paper

“Flavonoids also shape gut microbiota membership and function (Oteiza et al., 2018).”

What the sources say

• Not checked yetcites Oteiza et al., 2018 source

In the paper

“Other dietary compounds known to alter the composition of the gut microbiome include noncaloric artificial sweeteners such as saccharin, sucralose, and aspartame (Suez et al., 2015), a feature with functional implications associated with the induction of glucose intolerance in mice (Suez et al., 2014).”

What the sources say

• Not checked yetcites Suez et al., 2015 source

In the paper

“Dietary omega-3 PUFA status impacts on the cecal microbiome and metabolome in mice (Robertson et al., 2017b)”

What the sources say

• Not checked yetcites Robertson et al., 2017b

In the paper

“These approaches are not without their limitations, not least because of the intrinsic gastrointestinal and microbial differences between humans and rodents (Nguyen et al., 2015).”

What the sources say

• Not checked yetcites Nguyen et al., 2015 source

In the paper

“The capacity of the gut microbiome to metabolize environmental chemicals is mediated by enzymes with a wide distribution such as b-glucoronidases, azoreductases, and nitroreductases, which are able to chemically transform a range of agents such as nitrotoluenes, pesticides, polychlorobiphenyls, azo dyes, and metals (Claus et al., 2016).”

What the sources say

• Not checked yetcites Claus et al., 2016 source

In the paper

“Other dietary compounds known to alter the composition of the gut microbiome include noncaloric artificial sweeteners such as saccharin, sucralose, and aspartame (Suez et al., 2015), a feature with functional implications associated with the induction of glucose intolerance in mice (Suez et al., 2014).”

What the sources say

• Not checked yetcites Suez et al., 2014 source

In the paper

“Methotrexate results in reduced microbiota diversity and compositional shifts in the abundance of Bacteroides associated with the induction of diarrhea in rats (Fijlstra et al., 2015).”

What the sources say

• Not checked yetcites Fijlstra et al., 2015 source

In the paper

“The capacity of the gut microbiome to metabolize environmental chemicals is mediated by enzymes with a wide distribution such as b-glucoronidases, azoreductases, and nitroreductases, which are able to chemically transform a range of agents such as nitrotoluenes, pesticides, polychlorobiphenyls, azo dyes, and metals (Claus et al., 2016).”

What the sources say

• Not checked yetcites Claus et al., 2016 source

In the paper

“Although probiotics are not thought to substantially change the global compositional characteristics of the gut microbiome (Kristensen et al., 2016), they do impact on functional metabolic outputs such as the production of short chain fatty acids and other pharmabiotics, which may be important in their propensity to influence host health (Patterson et al., 2014).”

What the sources say

• Not checked yetcites Patterson et al., 2014

In the paper

“olanzapine, which induces alterations in gut microbiome composition in rodents linked to the weight gain and other metabolic side effects that are associated with its use”

What the sources say

• Not checked yetcites Davey et al., 2012 source
• Not checked yetcites Morgan et al., 2014 source

In the paper

“Exposure to endocrine-disrupting chemicals such as bisphenol A and ethinyl estradiol, by incorporation into the diet from periconception through weaning, induced generational and sex-dependent gut microbiome changes in mice, including increased relative abundances of Bacteroides, Prevotellaceae, and Akkermansia (Javurek et al., 2016).”

What the sources say

• Not checked yetcites Javurek et al., 2016 source

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).”

What the sources say

• Not checked yetcites Tarazona et al., 2017 source

In the paper

“Heavy metals such as mercury, lead, cadmium, and arsenic may also have an important impact on the gut microbiota (Lu et al., 2015).”

What the sources say

• Not checked yetcites Lu et al., 2015

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).”

What the sources say

• Not checked yetcites Tarazona et al., 2017 source

In the paper

“host miRNA production by intestinal epithelial cells has a role in shaping the gut microbiome by affecting bacterial growth (Liu et al., 2016)”

What the sources say

• Not checked yetcites Liu et al., 2016 source

In the paper

“evidence emerge from studies in germ-free rodents of microbial regulation of miRNA expression in brain regions of importance for neuropsychiatry such as the amygdala, prefrontal cortex, and hippocampus (Chen et al., 2017;Hoban et al., 2017;Moloney et al., 2017).”

What the sources say

• Not checked yetcites Chen et al., 2017 source
• Not checked yetcites Hoban et al., 2017 source
• Not checked yetcites Moloney et al., 2017 source

In the paper

“Although probiotics are not thought to substantially change the global compositional characteristics of the gut microbiome (Kristensen et al., 2016), they do impact on functional metabolic outputs such as the production of short chain fatty acids and other pharmabiotics, which may be important in their propensity to influence host health (Patterson et al., 2014).”

What the sources say

• Not checked yetcites Kristensen et al., 2016 source

In the paper

“Prebiotic administration concurrently with olanzapine can reduce the antipsychoticinduced weight gain in rodents (Kao et al., 2018).”

What the sources say

• Not checked yetcites Kao et al., 2018 source

In the paper

“For example, host hepatic enzyme expression and activity are altered in animals reared in a germ-free environment (Selwyn et al., 2016).”

What the sources say

• Not checked yetcites Selwyn et al., 2016 source

In the paper

“Many of these same chemical agents can also alter the composition and/or function of the gut microbiota.”

In the paper

“other prescription medications are also associated with alterations in gut microbiome diversity, including PPIs, opioids, and NSAIDs (Le Bastard et al., 2018).”

What the sources say

• Not checked yetcites Le Bastard et al., 2018 source

In the paper

“Chronic exposure to low doses of the insecticide, Chlorpyrifos, changed the composition of the gut microbiota in both a simulated human intestinal microbiota preparation and rats, reducing the abundance of Lactobacillus spp.and Bifidobacterium spp, bacteria presumed to be beneficial (Joly et al., 2013).”

What the sources say

• Not checked yetcites Joly et al., 2013 source

In the paper

“Direct mechanisms include activation (conversion of prodrugs into active drugs) and deactivation (detoxification).”

In the paper

“Preclinical studies indicate that stress exposure across the life span can impact on gut microbiome composition.”

In the paper

“Fecalase or cecalase, stable and translationally relevant cell-free extracts of feces or cecal matter with bacterial enzymatic activity, are frequently used incubations (Tamura et al., 1980).”

What the sources say

• Not checked yetcites Tamura et al., 1980 source

In the paper

“Many of the in vitro approaches discussed are perhaps overly simplistic and do not best capitalize on the unique features of the gut ecosystem, such as microniches, pH gradients, and dynamic microbe-tissue interactions (Tralau and Luch, 2013).”

What the sources say

• Not checked yetcites Tralau and Luch, 2013

In the paper

“| Cyp1a2 (mice) | Increased mRNA | Largest effects seen at 90 days | Selwyn et al., 2015a |”

What the sources say

• Not checked yetcites Selwyn et al., 2015a
• Not checked yetcites Jourova et al., 2017 source

In the paper

“Indirect mechanisms include enterohepatic cycling, as microbial biotransformation of compounds conjugated in the liver releases the conjugated group, reactivating the compound.”

In the paper

“The localization and spatial organization of the gut microbiota are not uniform along the gastrointestinal tract.”

In the paper

“Also neglected to date is the gut mycobiome, and there are indications that our intestinal fungi are an important component of host-microbe interactions of relevance to immune homeostasis and inflammatory disorders (Leonardi et al., 2018) and stress-related disorders such as irritable bowel syndrome (Botschuijver et al., 2017).”

What the sources say

• Not checked yetcites Botschuijver et al., 2017 source

In the paper

“Hypothalamic-pituitary-adrenal axis programming and responses show a dependency on an intact gut microbiome(Clarke et al., 2014b).”

What the sources say

• Not checked yetcites Clarke et al., 2014b

In the paper

“Also neglected to date is the gut mycobiome, and there are indications that our intestinal fungi are an important component of host-microbe interactions of relevance to immune homeostasis and inflammatory disorders (Leonardi et al., 2018) and stress-related disorders such as irritable bowel syndrome (Botschuijver et al., 2017).”

What the sources say

• Not checked yetcites Leonardi et al., 2018 source

In the paper

“Although there are many examples of remediation opportunities, we should not neglect the prophylactic power of diet to help sculpt the diversity that is necessary in a healthy gut microbiome (Shanahan et al., 2017).”

What the sources say

• Not checked yetcites Shanahan et al., 2017 source

In the paper

“We can take encouragement in these efforts from recent observations regarding the importance of gut microbiome composition and the response to cancer therapeutic drugs (Jobin, 2018).”

What the sources say

• Not checked yetcites Jobin, 2018 source

In the paper

“Gut-derived microbial metabolites such as propionate, whose production could be stimulated by prebiotics, can also exert protective effects on blood-brain barrier integrity (Hoyles et al., 2018c).”

What the sources say

• Not checked yetcites Hoyles et al., 2018c

In the paper

“Currently, preclinical behavioral screening platforms are most frequently used to identify candidate psychobiotics for further evaluation in clinical platforms (Bravo et al., 2011;Savignac et al., 2014Savignac et al., , 2015;;Burokas et al., 2017).”

What the sources say

• Not checked yetcites Bravo et al., 2011 source
• Not checked yetcites Savignac et al., 2014 source
• Not checked yetcites Burokas et al., 2017 source

In the paper

“There are both direct and indirect mechanisms through which the gut microbiome can influence xenobiotic metabolism to modulate efficacy, absorption, and bioavailability.”

In the paper

“VSL3 moderately decreased mRNAs of Cyp3a44 and”

What the sources say

• Not checked yetcites Selwyn et al., 2016 source

In the paper

“Largest effects seen at 90 days in male animals only”

What the sources say

• Not checked yetcites Selwyn et al., 2015a

In the paper

“For example, a genetically engineered Lactococcus lactis-secreting interleukin-10 has been used to deliver a localized therapeutic dose of IL-10 for the amelioration of murine colitis in an animal model of IBD (Steidler et al., 2000).”

What the sources say

• Not checked yetcites Steidler et al., 2000 source

In the paper

“Largest effects seen at 90 days”

What the sources say

• Not checked yetcites Selwyn et al., 2015a

In the paper

“Bacterial metabolism of tryptophan to indole compounds may be equally important because either in their own right or following host processing, these microbial tryptophan metabolites can impact on host physiology and behavior (Lee et al., 2015).”

What the sources say

• Not checked yetcites Lee et al., 2015 source

In the paper

“the gut microbiome appears to be equally vulnerable and plastic in its response to homeostatic threats directed at either terminus of the gut-brain axis(Dinan and Cryan, 2017).”

What the sources say

• Not checked yetcites Dinan and Cryan, 2017

In the paper

“The gut microbiome recruits the gut-brain axis to signal to the central nervous system.”

In the paper

“Upregulated following colonization, but VSL3 probiotic”

What the sources say

• Not checked yetcites Selwyn et al., 2016 source

In the paper

“Concerns about the variability of the assay have seen the development of a fecal microbial enzyme mix (Yeo et al., 2012).”

What the sources say

• Not checked yetcites Yeo et al., 2012 source

In the paper

“cocktail was not able to normalize their expression;”

What the sources say

• Not checked yetcites Selwyn et al., 2016 source

In the paper

“Indeed, this is already partially functional in this regard because the detection of hydrogen signals can be used as a proxy for regional fermentation patterns (Fig. 7).”

What the sources say

• Not checked yetcites Kalantar-Zadeh et al., 2018 source

In the paper

“| Cyp2c (mice) | Increased mRNA | Largest effects seen at 90 days in male animals only | Selwyn et al., 2015a |”

What the sources say

• Not checked yetcites Selwyn et al., 2015a

In the paper

“Meanwhile, nextgeneration probiotics may be based on the use of microbes found to be deficient in certain disorders, as is the case of A. muciniphila in obesity, diabetes, and cardiometabolic diseases (Cani and de Vos, 2017)”

What the sources say

• Not checked yetcites Cani and de Vos, 2017

In the paper

“Communication along this axis is bidirectional.”

In the paper

“| Cyp3a (mice) | Decreased mRNA and protein | Upregulated following colonization, but VSL3 probiotic | Selwyn et al., 2016 |”

What the sources say

• Not checked yetcites Selwyn et al., 2016 source
• Not checked yetcites Selwyn et al., 2015a

In the paper

“An increased focus on this important area comes at a time when sequencing studies have identified gut microbiome alterations in many of the disorders treated by these same drugs.”

In the paper

“The reciprocal nature of these microbe-drug interactions has also been demonstrated with many of these therapeutic agents also modifying the composition and function of the gut microbiome (see Table 3)”

What the sources say

• Not checked yetcites Table 3

In the paper

“We have noted above a number of instances in which diet-microbe-host interactions can lead to adverse consequences.”

In the paper

“The gut microbiome can have a wide variety of direct and indirect effects on the metabolism of pharmaceuticals, dietary compounds, and environmental chemicals.”

In the paper

“Candidate psychobiotics that beneficially impact on host tryptophan metabolites include Bifidobacterium longum subsp.longum 35624 (previously B. infantis 35624) (Desbonnet et al., 2008) and L. reuteri (Marin et al., 2017).”

What the sources say

• Not checked yetcites Desbonnet et al., 2008 source
• Not checked yetcites Marin et al., 2017 source

In the paper

“similar to the human CYP4A cluster”

What the sources say

• Not checked yetcites Selwyn et al., 2016 source

In the paper

“Largest effects seen at 90 days”

What the sources say

• Not checked yetcites Selwyn et al., 2015a

In the paper

“| Cyp4a (mice) | Increased mRNA and protein | Downregulated following colonization, but VSL3 | Selwyn et al., 2016 |”

What the sources say

• Not checked yetcites Selwyn et al., 2016 source

In the paper

“Downregulated following colonization, but VSL3”

What the sources say

• Not checked yetcites Selwyn et al., 2016 source

In the paper

“probiotic cocktail was not able to normalize their”

What the sources say

• Not checked yetcites Selwyn et al., 2016 source

In the paper

“| Cyp2e1(mice) | Increased mRNA | Largest effects seen at 90 days | Selwyn et al., 2015a |”

• Also stated in: § X. Summary, Conclusions, and Perspectives · plain

  “| | Increased mRNA | Monoassociation with E. coli Nissle 1917 but not | |”

What the sources say

• Not checked yetcites Selwyn et al., 2015a