Gut Reactions: Breaking Down Xenobiotic–Microbiome Interactions

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).”

What the sources say

• Not checked yetcites Li et al., 2014

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).”

What the sources say

• Not checked yetcites Pellock and Redinbo, 2017

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).”

What the sources say

• Not checked yetcites Clarke et al., 2014a
• Not checked yetcites Perez-Munoz et al., 2017 source

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).”

What the sources say

• Not checked yetcites Clarke et al., 2014b

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).”

What the sources say

• Not checked yetcites Michalopoulos, 2007 source

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.”

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.”

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).”

What the sources say

• Not checked yetcites Bokulich et al., 2016 source
• Not checked yetcites Clarke et al., 2014a
• Not checked yetcites Hill et al., 2017 source

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”

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

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.”

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).”

What the sources say

• Not checked yetcites Setchell et al., 2002 source

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).”

What the sources say

• Not checked yetcites Jourova et al., 2017 source

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).”

What the sources say

• Not checked yetcites Selwyn et al., 2015a

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.”

What the sources say

• Not checked yetcites Selwyn et al., 2015b

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.”

What the sources say

• Not checked yetcites Jourova et al., 2017 source

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).”

What the sources say

• Not checked yetcites Pollet et al., 2017 source

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.”

In the paper

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

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).”

What the sources say

• Not checked yetcites Thaiss et al., 2016a
• Not checked yetcites Chilloux and Dumas, 2017

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).”

What the sources say

• Not checked yetcites Peppercorn and Goldman, 1972b
• Not checked yetcites Wallace et al., 2010 source
• Not checked yetcites Haiser et al., 2013 source

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).”

What the sources say

• Not checked yetcites Bolhuis et al., 2011 source

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).”

What the sources say

• Not checked yetcites Toda et al., 2009b

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.”

What the sources say

• Not checked yetcites Das et al., 2016
• Not checked yetcites Quigley, 2017 source

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).”

What the sources say

• Not checked yetcites Hall et al., 1999 source

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.”

In the paper

“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

“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.”

In the paper

“Oral delivery of advanced drug formulations designed for extended release (e.g., sustained release tablets) is on the increase”

What the sources say

• Not checked yetcites Sousa et al., 2008 source

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.”

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).”

What the sources say

• Not checked yetcites Haynes et al., 2008 source
• Not checked yetcites Eade et al., 2013 source

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.”

In the paper

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

What the sources say

• Not checked yetcites Davenport et al., 2017 source

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.”

What the sources say

• Not checked yetcites Haiser et al., 2013 source
• Not checked yetcites Peppercorn and Goldman, 1972b

In the paper

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

What the sources say

• Not checked yetcites Dinan and Cryan, 2017

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).”

What the sources say

• Not checked yetcites Bordenstein and Theis, 2015

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)”

What the sources say

• Not checked yetcites Otte et al., 2016 source

In the paper

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

What the sources say

• Not checked yetcites Chung et al., 1992 source

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).”

What the sources say

• Not checked yetcites Lehouritis et al., 2015 source

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.”

What the sources say

• Not checked yetcites Maier et al., 2018 source

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).”

What the sources say

• Not checked yetcites van Hogezand et al., 1992 source

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).”

What the sources say

• Not checked yetcites Maurice et al., 2013 source

In the paper

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

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).”

What the sources say

• Not checked yetcites Kloiber et al., 1988 source
• Not checked yetcites Minana et al., 1996 source

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).”

What the sources say

• Not checked yetcites Dumas et al., 2017 source

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).”

What the sources say

• Not checked yetcites Watson et al., 2017

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).”

What the sources say

• Not checked yetcites Chen et al., 2016 source
• Not checked yetcites Bird et al., 2017 source
• Not checked yetcites Sung et al., 2017 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 Cuhra et al., 2016 source

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).”

What the sources say

• Not checked yetcites Bahra et al., 2015 source
• Not checked yetcites Bahr et al., 2015 source

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).”

What the sources say

• Not checked yetcites Alderete et al., 2018 source

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.”

What the sources say

• Not checked yetcites Ryan et al., 2017 source

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).”

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.”

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).”

What the sources say

• Not checked yetcites Hill and Spence, 2016

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).”

What the sources say

• Not checked yetcites O'Sullivan et al., 2015

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.”

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.”

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.”

In the paper

“Oxygen partial pressures along the gastrointestinal tract also contribute to these metabolic niches.”

In the paper

“The pharmacomicrobiomic web portal currently lists over 90 examples of such chemicals (http://pharmacomicrobiomics. com/view/chemical/).”

What the sources say

• Not checked yetcites http://pharmacomicrobiomics. com/view/chemical/

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.”

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).”

What the sources say

• Not checked yetcites Allen et al., 2016 source
• Not checked yetcites Papalini et al., 2018
• Not checked yetcites Kelly et al., 2017 source

In the paper

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

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”

What the sources say

• Not checked yetcites Clark and Walker, 2018

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).”

What the sources say

• Not checked yetcites Wallace et al., 2010 source

In the paper

“Monoassociation with E. coli Nissle 1917 but not”