How to Determine the Role of the Microbiome in Drug Disposition

Bisanz, Jordan E.; Spanogiannopoulos, Peter; Pieper, Lindsey M.; Bustion, Annamarie E.; Turnbaugh, Peter J.

doi:10.1124/dmd.118.083402

Cited by 39 publications

(25 citation statements)

References 98 publications

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“…Several drugs were incubated in this system and shown to undergo various reduction reactions such as S-oxide reduction, nitro reduction, ring opening of benzisoxazole, and reductive cleavage of an azo bond, similar to transformations that had been previously reported to occur in vivo (van de Steeg et al, 2018). In addition, Bisanz et al (2018) reviewed the stateof-the-art of microbial metabolism of small molecules. The authors have guided the readers on screening new therapeutics in in vitro microbial assays, ex vivo incubations in/or preparations from human stool samples, and in vivo models derived by colonizing microbes in laboratory animals that are raised in "sterile" conditions.…”

Section: In Vitro Modelsmentioning

confidence: 93%

Emerging Models of Drug Metabolism, Transporters, and Toxicity

Sawant-Basak

Obach

2018

Drug Metab Dispos

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This commentary summarizes expert mini-reviews and original research articles that have been assembled in a special issue on novel models of drug metabolism and disposition. The special issue consists of research articles or reviews on novel static or microflow based models of the intestine, liver, eye, and kidney. This issue reviews static intestinal systems like mucosal scrapings and cryopreserved intestinal enterocytes, as well as novel bioengineered or chemically engineered intestinal models derived from primary human tissue, iPSCs, enteroids, and crypts. Experts have reviewed hepatic systems like cryopermeabilized Metmax hepatocytes and longer term, hepatocyte coculture system from HmREL, yielding in vivo-like primary and secondary drug metabolite profiles. Additional liver models, including micropattern hepatocyte coculture, 3D liver spheroids, and microflow systems, applicable to the study of drug disposition and toxicology have also been reviewed. In this commentary, we have outlined expert opinions and current efforts on hepaticand nephrotoxicity models. Ocular disposition models including corneal permeability models have been included within this special issue. This commentary provides a summary of in vivo mini-reviews of the issue, which have discussed the applications and drawbacks of pig and humanized mice models of P450, UGT, and rat organic anionic transporting polypeptide 1a4. While not extensively reviewed, novel positron emissions tomography imaging-based approaches to study the distribution of xenobiotics have been highlighted. This commentary also outlines in vitro and in vivo models of drug metabolism derived from breakthrough genetic, chromosomal, and tissue engineering techniques. The commentary concludes by providing a futuristic view of the novel models discussed in this issue.

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Section: In Vitro Modelsmentioning

confidence: 93%

Emerging Models of Drug Metabolism, Transporters, and Toxicity

Sawant-Basak

Obach

2018

Drug Metab Dispos

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“…2016; Ngara and Zhang, 2018), or from pharmacomicrobiomic discovery methodologies (Bisanz et al, 2018). A remarkable example is the recent high-throughput systematic pharmacomicrobiomic screens to detect specific drug-bacterial interactions and separate them from drug-host interaction (e.g., Zimmermann et al, 2019a;Zimmermann et al, 2019b).…”

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confidence: 99%

Toxicomicrobiomics: The Human Microbiome vs. Pharmaceutical, Dietary, and Environmental Xenobiotics

et al. 2020

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The harmful impact of xenobiotics on the environment and human health is being more widely recognized; yet, inter-and intraindividual genetic variations among humans modulate the extent of harm, mostly through modulating the outcome of xenobiotic metabolism and detoxification. As the Human Genome Project revealed that host genetic, epigenetic, and regulatory variations could not sufficiently explain the complexity of interindividual variability in xenobiotics metabolism, its sequel, the Human Microbiome Project, is investigating how this variability may be influenced by human-associated microbial communities. Xenobioticmicrobiome relationships are mutual and dynamic. Not only does the human microbiome have a direct metabolizing potential on xenobiotics, but it can also influence the expression of the host metabolizing genes and the activity of host enzymes. On the other hand, xenobiotics may alter the microbiome composition, leading to a state of dysbiosis, which is linked to multiple diseases and adverse health outcomes, including increased toxicity of some xenobiotics. Toxicomicrobiomics studies these mutual influences between the everchanging microbiome cloud and xenobiotics of various origins, with emphasis on their fate and toxicity, as well the various classes of microbial xenobiotic-modifying enzymes. This review article discusses classic and recent findings in toxicomicrobiomics, with examples of interactions between gut, skin, urogenital, and oral microbiomes with pharmaceutical, foodderived, and environmental xenobiotics. The current state and future prospects of toxicomicrobiomic research are discussed, and the tools and strategies for performing such studies are thoroughly and critically compared.

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“…Xenobiotics are introduced into the intestine through the oral route as dietary components or pharmaceuticals. IECs play essential roles in orally delivered pharmaceutical biology, functioning as primary sites of absorption, metabolism, and excretion (2)(3)(4). As the front line of the host-xenobiotic interface, the intestinal epithelium is also a primary site of action for xenobiotic toxicity.…”

mentioning

confidence: 99%

Epithelial delamination is protective during pharmaceutical-induced enteropathy

Espenschied

Cronan

Matty

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Intestinal epithelial cell (IEC) shedding is a fundamental response to intestinal damage, yet underlying mechanisms and functions have been difficult to define. Here we model chronic intestinal damage in zebrafish larvae using the nonsteroidal antiinflammatory drug (NSAID) Glafenine. Glafenine induced the unfolded protein response (UPR) and inflammatory pathways in IECs, leading to delamination. Glafenine-induced inflammation was augmented by microbial colonization and associated with changes in intestinal and environmental microbiotas. IEC shedding was a UPR-dependent protective response to Glafenine that restricts inflammation and promotes animal survival. Other NSAIDs did not induce IEC delamination; however, Glafenine also displays off-target inhibition of multidrug resistance (MDR) efflux pumps. We found a subset of MDR inhibitors also induced IEC delamination, implicating MDR efflux pumps as cellular targets underlying Glafenine-induced enteropathy. These results implicate IEC delamination as a protective UPR-mediated response to chemical injury, and uncover an essential role for MDR efflux pumps in intestinal homeostasis.

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How to Determine the Role of the Microbiome in Drug Disposition

Cited by 39 publications

References 98 publications

Emerging Models of Drug Metabolism, Transporters, and Toxicity

Emerging Models of Drug Metabolism, Transporters, and Toxicity

Toxicomicrobiomics: The Human Microbiome vs. Pharmaceutical, Dietary, and Environmental Xenobiotics

Epithelial delamination is protective during pharmaceutical-induced enteropathy

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