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. doi: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}
}
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https://doi.org/10.1038/s41598-020-60982-8
https://doi.org/10.1038/s41598-020-60982-8
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Cited by: 11 works
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Figures / Tables:
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 »
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Works referenced in this record:
The role of intestinal microbiota in murine models of acetaminophen-induced hepatotoxicity
journal, October 2014
- Possamai, Lucia A.; McPhail, Mark JW; Khamri, Wafa
- Liver International, Vol. 35, Issue 3
The Microbial Detection Array for Detection of Emerging Viruses in Clinical Samples - A Useful Panmicrobial Diagnostic Tool
journal, June 2014
- Rosenstierne, Maiken W.; McLoughlin, Kevin S.; Olesen, Majken Lindholm
- PLoS ONE, Vol. 9, Issue 6
Antibiotics-induced gut microbiota dysbiosis promotes tumor initiation via affecting APC-Th1 development in mice
journal, June 2017
- Xu, Chengming; Ruan, Banjun; Jiang, Yinghao
- Biochemical and Biophysical Research Communications, Vol. 488, Issue 2
Large scale multiplex PCR improves pathogen detection by DNA microarrays
journal, January 2009
- Palka-Santini, Maria; Cleven, Berit E.; Eichinger, Ludwig
- BMC Microbiology, Vol. 9, Issue 1
The Madness of Microbiome: Attempting To Find Consensus “Best Practice” for 16S Microbiome Studies
journal, February 2018
- Pollock, Jolinda; Glendinning, Laura; Wisedchanwet, Trong
- Applied and Environmental Microbiology, Vol. 84, Issue 7
Acetaminophen (Paracetamol) Oral Absorption and Clinical Influences
journal, October 2013
- Raffa, Robert B.; Pergolizzi, Joseph V.; Taylor, Robert
- Pain Practice, Vol. 14, Issue 7
Gut microbiome-host interactions in health and disease
journal, January 2011
- Kinross, James M.; Darzi, Ara W.; Nicholson, Jeremy K.
- Genome Medicine, Vol. 3, Issue 3
Simultaneous delivery of antibiotics neomycin and ampicillin in drinking water inhibits fermentation of resistant starch in rats
journal, December 2016
- Carvajal-Aldaz, Diana G.; Guice, Justin L.; Page, Ryan C.
- Molecular Nutrition & Food Research, Vol. 61, Issue 3
Drug Metabolism by the Host and Gut Microbiota: A Partnership or Rivalry?
journal, August 2015
- Swanson, Hollie I.
- Drug Metabolism and Disposition, Vol. 43, Issue 10
Gut microbiome interactions with drug metabolism, efficacy, and toxicity
journal, January 2017
- Wilson, Ian D.; Nicholson, Jeremy K.
- Translational Research, Vol. 179
The role of intestinal flora in metabolism of phenolic sulfate esters
journal, October 1986
- Kim, Dong-Hyun; Kobashi, Kyoichi
- Biochemical Pharmacology, Vol. 35, Issue 20
Administration of a Probiotic Can Change Drug Pharmacokinetics: Effect of E. coli Nissle 1917 on Amidarone Absorption in Rats
journal, February 2014
- Matuskova, Zuzana; Anzenbacherova, Eva; Vecera, Rostislav
- PLoS ONE, Vol. 9, Issue 2
Urinary excretion of reduced metabolites of digoxin
journal, July 1981
- Lindenbaum, John; Tse-Eng, Doris; Butler, Vincent P.
- The American Journal of Medicine, Vol. 71, Issue 1
Effect of Probiotics on Pharmacokinetics of Orally Administered Acetaminophen in Mice
journal, December 2017
- Kim, Jeon-Kyung; Choi, Min Sun; Jeong, Jin-Ju
- Drug Metabolism and Disposition, Vol. 46, Issue 2
A microbial detection array (MDA) for viral and bacterial detection
journal, January 2010
- Gardner, Shea N.; Jaing, Crystal J.; McLoughlin, Kevin S.
- BMC Genomics, Vol. 11, Issue 1
The Footprints of Gut Microbial–Mammalian Co-Metabolism
journal, December 2011
- Zheng, Xiaojiao; Xie, Guoxiang; Zhao, Aihua
- Journal of Proteome Research, Vol. 10, Issue 12
The role of intestinal microflora in the formation of the methylthio adduct metabolites of paracetamol
journal, April 1988
- Mikov, M.; Caldwell, J.; Dolphin, C. T.
- Biochemical Pharmacology, Vol. 37, Issue 8
Optimization and clinical validation of a pathogen detection microarray
journal, January 2007
- Wong, Christopher W.; Heng, Charlie; Wan Yee, Leong
- Genome Biology, Vol. 8, Issue 5
Ancient pathogen DNA in archaeological samples detected with a Microbial Detection Array
journal, March 2014
- Devault, Alison M.; McLoughlin, Kevin; Jaing, Crystal
- Scientific Reports, Vol. 4, Issue 1
Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism
journal, August 2009
- Clayton, T. A.; Baker, D.; Lindon, J. C.
- Proceedings of the National Academy of Sciences, Vol. 106, Issue 34
Short-Term Effect of Antibiotics on Human Gut Microbiota
journal, April 2014
- Panda, Suchita; El khader, Ismail; Casellas, Francesc
- PLoS ONE, Vol. 9, Issue 4
Microarray-based detection and genotyping of viral pathogens
journal, November 2002
- Wang, D.; Coscoy, L.; Zylberberg, M.
- Proceedings of the National Academy of Sciences, Vol. 99, Issue 24, p. 15687-15692
Discovery of Swine as a Host for the Reston ebolavirus
journal, July 2009
- Barrette, R. W.; Metwally, S. A.; Rowland, J. M.
- Science, Vol. 325, Issue 5937
Microarrays for Pathogen Detection and Analysis
journal, September 2011
- McLoughlin, K. S.
- Briefings in Functional Genomics, Vol. 10, Issue 6
Use of Microdosing and Accelerator Mass Spectrometry To Evaluate the Pharmacokinetic Linearity of a Novel Tricyclic GyrB/ParE Inhibitor in Rats
journal, August 2014
- Malfatti, Michael A.; Lao, Victoria; Ramos, Courtney L.
- Antimicrobial Agents and Chemotherapy, Vol. 58, Issue 11
The identification of [2-14C]2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine metabolites in humans
journal, April 1999
- Malfatti, Michael A.; Kulp, Kristen S.; Knize, Mark G.
- Carcinogenesis, Vol. 20, Issue 4
The Microbial Detection Array Combined with Random Phi29-Amplification Used as a Diagnostic Tool for Virus Detection in Clinical Samples
journal, August 2011
- Erlandsson, Lena; Rosenstierne, Maiken W.; McLoughlin, Kevin
- PLoS ONE, Vol. 6, Issue 8
Evaluation of pharmacokinetic differences of acetaminophen in pseudo germ-free rats: PHARMACOKINETICS OF ACETAMINOPHEN IN PSEUDO GERM-FREE RATS
journal, July 2012
- Lee, Soo Hyun; An, Ji Hye; Lee, Hwa Jeong
- Biopharmaceutics & Drug Disposition, Vol. 33, Issue 6
Xenobiotics Shape the Physiology and Gene Expression of the Active Human Gut Microbiome
journal, January 2013
- Maurice, Corinne Ferrier; Haiser, Henry Joseph; Turnbaugh, Peter James
- Cell, Vol. 152, Issue 1-2
The Pervasive Effects of an Antibiotic on the Human Gut Microbiota, as Revealed by Deep 16S rRNA Sequencing
journal, November 2008
- Dethlefsen, Les; Huse, Sue; Sogin, Mitchell L.
- PLoS Biology, Vol. 6, Issue 11
Host-microbial interactions in the metabolism of therapeutic and diet-derived xenobiotics
journal, August 2014
- Carmody, Rachel N.; Turnbaugh, Peter J.
- Journal of Clinical Investigation, Vol. 124, Issue 10
Analysis of sensitivity and rapid hybridization of a multiplexed Microbial Detection Microarray
journal, June 2014
- Thissen, James B.; McLoughlin, Kevin; Gardner, Shea
- Journal of Virological Methods, Vol. 201
Genomic approaches to studying the human microbiota
journal, September 2012
- Weinstock, George M.
- Nature, Vol. 489, Issue 7415
Reduced stem cell mobilization in mice receiving antibiotic modulation of the intestinal flora: involvement of endotoxins as cofactors in mobilization
journal, January 2004
- Velders, Gerjo A.; van Os, Ronald; Hagoort, Henny
- Blood, Vol. 103, Issue 1
Cytochrome P450 enzymes involved in acetaminophen activation by rat and human liver microsomes and their kinetics
journal, July 1993
- Patten, Chris J.; Thomas, Paul E.; Guy, Robert L.
- Chemical Research in Toxicology, Vol. 6, Issue 4
Geographic differences in digoxin inactivation, a metabolic activity of the human anaerobic gut flora.
journal, July 1989
- Mathan, V. I.; Wiederman, J.; Dobkin, J. F.
- Gut, Vol. 30, Issue 7
Quinolone Activity Against Anaerobes
journal, January 1999
- Appelbaum, Peter C.
- Drugs, Vol. 58, Issue Supplement 2
Panmicrobial Oligonucleotide Array for Diagnosis of Infectious Diseases
journal, January 2007
- Palacios, Gustavo; Quan, Phenix-Lan; Jabado, Omar J.
- Emerging Infectious Diseases, Vol. 13, Issue 1
The influence of gut microbiota on drug metabolism and toxicity
journal, November 2015
- Li, Houkai; He, Jiaojiao; Jia, Wei
- Expert Opinion on Drug Metabolism & Toxicology, Vol. 12, Issue 1
Application of a pathogen microarray for the analysis of viruses and bacteria in clinical diagnostic samples from pigs
journal, April 2015
- Jaing, Crystal J.; Thissen, James B.; Gardner, Shea N.
- Journal of Veterinary Diagnostic Investigation, Vol. 27, Issue 3
Detection of Adventitious Viruses from Biologicals Using a Broad-Spectrum Microbial Detection Array
journal, November 2011
- Jaing, C.; Gardner, S.; McLoughlin, K.
- PDA Journal of Pharmaceutical Science and Technology, Vol. 65, Issue 6
Figures / Tables found in this record:
Figures/Tables have been extracted from DOE-funded journal article accepted manuscripts.