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Title: Manipulation of the Gut Microbiome Alters Acetaminophen Biodisposition in Mice

Abstract

The gut microbiota is a vast and diverse microbial community that has co-evolved with its host to perform a variety of essential functions involved in the utilization of nutrients and the processing of xenobiotics. Shifts in the composition of gut microbiota can disturb the balance of organisms which can infuence the biodisposition of orally administered drugs. To determine how changes in the gut microbiome can alter drug disposition, the pharmacokinetics (PK), and biodistribution of acetaminophen were assessed in C57Bl/6 mice after treatment with the antibiotics ciprofoxacin, amoxicillin, or a cocktail of ampicillin/neomycin. Altered PK, and excretion profles of acetaminophen were observed in antibiotic exposed animals. Plasma Cmax was signifcantly decreased in antibiotic treated animals suggesting decreased bioavailability. Urinary metabolite profles revealed decreases in acetaminophen-sulfate metabolite levels in both the amoxicillin and ampicillin/neomycin treated animals. The ratio between urinary and fecal excretion was also altered in antibiotic treated animals. Analysis of gut microbe composition revealed that changes in microbe content in antibiotic treated animals was associated with changes in acetaminophen biodisposition. These results suggest that exposure to amoxicillin or ampicillin/neomycin can alter the biodisposition of acetaminophen and that these alterations could be due to changes in gut microbiome composition.

Authors:
; ; ; ; ; ; ;
Publication Date:
Research Org.:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC); USDOE Laboratory Directed Research and Development (LDRD) Program; National Institutes of Health (NIH); National Institute of General Medical Sciences (NIGMS); USDOE National Nuclear Security Administration (NNSA)
OSTI Identifier:
1619817
Alternate Identifier(s):
OSTI ID: 1624526; OSTI ID: 1661045
Report Number(s):
LLNL-JRNL-770539
Journal ID: ISSN 2045-2322; 4571; PII: 60982
Grant/Contract Number:  
AC52-07NA27344
Resource Type:
Published Article
Journal Name:
Scientific Reports
Additional Journal Information:
Journal Name: Scientific Reports Journal Volume: 10 Journal Issue: 1; Journal ID: ISSN 2045-2322
Publisher:
Nature Publishing Group
Country of Publication:
United Kingdom
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Science & technology - other topics; drug effectiveness; antibiotics; microbiome; pharmacokinetics

Citation Formats

Malfatti, Michael A., Kuhn, Edward A., Murugesh, Deepa K., Mendez, Melanie E., Hum, Nicholas, Thissen, James B., Jaing, Crystal J., and Loots, Gabriela G.. Manipulation of the Gut Microbiome Alters Acetaminophen Biodisposition in Mice. United Kingdom: N. p., 2020. Web. https://doi.org/10.1038/s41598-020-60982-8.
Malfatti, Michael A., Kuhn, Edward A., Murugesh, Deepa K., Mendez, Melanie E., Hum, Nicholas, Thissen, James B., Jaing, Crystal J., & Loots, Gabriela G.. Manipulation of the Gut Microbiome Alters Acetaminophen Biodisposition in Mice. United Kingdom. https://doi.org/10.1038/s41598-020-60982-8
Malfatti, Michael A., Kuhn, Edward A., Murugesh, Deepa K., Mendez, Melanie E., Hum, Nicholas, Thissen, James B., Jaing, Crystal J., and Loots, Gabriela G.. Thu . "Manipulation of the Gut Microbiome Alters Acetaminophen Biodisposition in Mice". United Kingdom. https://doi.org/10.1038/s41598-020-60982-8.
@article{osti_1619817,
title = {Manipulation of the Gut Microbiome Alters Acetaminophen Biodisposition in Mice},
author = {Malfatti, Michael A. and Kuhn, Edward A. and Murugesh, Deepa K. and Mendez, Melanie E. and Hum, Nicholas and Thissen, James B. and Jaing, Crystal J. and Loots, Gabriela G.},
abstractNote = {The gut microbiota is a vast and diverse microbial community that has co-evolved with its host to perform a variety of essential functions involved in the utilization of nutrients and the processing of xenobiotics. Shifts in the composition of gut microbiota can disturb the balance of organisms which can infuence the biodisposition of orally administered drugs. To determine how changes in the gut microbiome can alter drug disposition, the pharmacokinetics (PK), and biodistribution of acetaminophen were assessed in C57Bl/6 mice after treatment with the antibiotics ciprofoxacin, amoxicillin, or a cocktail of ampicillin/neomycin. Altered PK, and excretion profles of acetaminophen were observed in antibiotic exposed animals. Plasma Cmax was signifcantly decreased in antibiotic treated animals suggesting decreased bioavailability. Urinary metabolite profles revealed decreases in acetaminophen-sulfate metabolite levels in both the amoxicillin and ampicillin/neomycin treated animals. The ratio between urinary and fecal excretion was also altered in antibiotic treated animals. Analysis of gut microbe composition revealed that changes in microbe content in antibiotic treated animals was associated with changes in acetaminophen biodisposition. These results suggest that exposure to amoxicillin or ampicillin/neomycin can alter the biodisposition of acetaminophen and that these alterations could be due to changes in gut microbiome composition.},
doi = {10.1038/s41598-020-60982-8},
journal = {Scientific Reports},
number = 1,
volume = 10,
place = {United Kingdom},
year = {2020},
month = {3}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1038/s41598-020-60982-8

Figures / Tables:

Figure 1 Figure 1: Plasma concentration time profiles of acetaminophen. Plasma concentration time profiles of a single oral dose acetaminophen (100 mg/kg) following a 10-day oral exposure to antibiotics in male C57Bl/6 mice. Control (•), ciprofloxacin (♦), amoxicillin (▲), ampicillin/neomycin (■). Data is expressed as the mean (n = 4) ± SE.more » *p < 0.05.« less

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