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The role of intestinal microbiota in murine models of acetaminophen-induced hepatotoxicity

BACKGROUND & AIM: Variations in intestinal microbiota may influence acetaminophen metabolism. This study aimed to determine whether intestinal microbiota are a source of differential susceptibility to acetaminophen-induced hepatotoxicity. METHODS: Conventionally housed C3H/HeH (CH) and C3H/HeH g...

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Autores principales: Possamai, Lucia A, McPhail, Mark JW, Khamri, Wafa, Wu, Bishan, Concas, Danilo, Harrison, Mark, Williams, Roger, Cox, Roger D, Cox, I Jane, Anstee, Quentin M, Thursz, Mark R
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5873516/
https://www.ncbi.nlm.nih.gov/pubmed/25244648
http://dx.doi.org/10.1111/liv.12689
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author Possamai, Lucia A
McPhail, Mark JW
Khamri, Wafa
Wu, Bishan
Concas, Danilo
Harrison, Mark
Williams, Roger
Cox, Roger D
Cox, I Jane
Anstee, Quentin M
Thursz, Mark R
author_facet Possamai, Lucia A
McPhail, Mark JW
Khamri, Wafa
Wu, Bishan
Concas, Danilo
Harrison, Mark
Williams, Roger
Cox, Roger D
Cox, I Jane
Anstee, Quentin M
Thursz, Mark R
author_sort Possamai, Lucia A
collection PubMed
description BACKGROUND & AIM: Variations in intestinal microbiota may influence acetaminophen metabolism. This study aimed to determine whether intestinal microbiota are a source of differential susceptibility to acetaminophen-induced hepatotoxicity. METHODS: Conventionally housed C3H/HeH (CH) and C3H/HeH germ free (GF) mice were administered a 200mg/kg IP dose of acetaminophen. The severity of hepatotoxicity at 8 hours was assessed by histology and biochemical indices. A urinary metabolic profile was obtained using (1)H-NMR. Baseline hepatic glutathione content and CYP2E1 expression were quantified. An additional group of C3H/HeJ (LPS-r) mice were assessed to determine the contribution of LPS/TLR4 signalling. RESULTS: Baseline glutathione levels were significantly reduced (p=0.03) in GF mice. CYP2E1 mRNA expression and protein levels were not altered. Inter-individual variability did not differ between GF and CH groups. No significant differences in the extent of hepatocellular injury (ALT or percentage necrosis) were demonstrated. However, a milder acute liver failure (ALF) phenotype was shown in GF compared with CH mice, with reduced plasma bilirubin and creatinine and increased blood glucose. Differential acetaminophen metabolism was demonstrated. GF mice displayed a higher urinary acetaminophen-sulphate:glucuronide ratio compared with CH (p=0.01). Urinary analysis showed metabolic differentiation of GF and CH groups at baseline and 8 hours(cross-validated ANOVA p=1x10(-22)). Interruption of TLR4 signalling in LPS-r mice had additional protective effects. CONCLUSION: Variations in intestinal microbiota do not fully explain differential susceptibility to acetaminophen-induced hepatotoxicity. GF mice experienced some protection from secondary complications following acetaminophen overdose and this may be mediated through reduced TLR4/LPS signalling.
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spelling pubmed-58735162018-03-28 The role of intestinal microbiota in murine models of acetaminophen-induced hepatotoxicity Possamai, Lucia A McPhail, Mark JW Khamri, Wafa Wu, Bishan Concas, Danilo Harrison, Mark Williams, Roger Cox, Roger D Cox, I Jane Anstee, Quentin M Thursz, Mark R Liver Int Article BACKGROUND & AIM: Variations in intestinal microbiota may influence acetaminophen metabolism. This study aimed to determine whether intestinal microbiota are a source of differential susceptibility to acetaminophen-induced hepatotoxicity. METHODS: Conventionally housed C3H/HeH (CH) and C3H/HeH germ free (GF) mice were administered a 200mg/kg IP dose of acetaminophen. The severity of hepatotoxicity at 8 hours was assessed by histology and biochemical indices. A urinary metabolic profile was obtained using (1)H-NMR. Baseline hepatic glutathione content and CYP2E1 expression were quantified. An additional group of C3H/HeJ (LPS-r) mice were assessed to determine the contribution of LPS/TLR4 signalling. RESULTS: Baseline glutathione levels were significantly reduced (p=0.03) in GF mice. CYP2E1 mRNA expression and protein levels were not altered. Inter-individual variability did not differ between GF and CH groups. No significant differences in the extent of hepatocellular injury (ALT or percentage necrosis) were demonstrated. However, a milder acute liver failure (ALF) phenotype was shown in GF compared with CH mice, with reduced plasma bilirubin and creatinine and increased blood glucose. Differential acetaminophen metabolism was demonstrated. GF mice displayed a higher urinary acetaminophen-sulphate:glucuronide ratio compared with CH (p=0.01). Urinary analysis showed metabolic differentiation of GF and CH groups at baseline and 8 hours(cross-validated ANOVA p=1x10(-22)). Interruption of TLR4 signalling in LPS-r mice had additional protective effects. CONCLUSION: Variations in intestinal microbiota do not fully explain differential susceptibility to acetaminophen-induced hepatotoxicity. GF mice experienced some protection from secondary complications following acetaminophen overdose and this may be mediated through reduced TLR4/LPS signalling. 2014-10-08 2015-03 /pmc/articles/PMC5873516/ /pubmed/25244648 http://dx.doi.org/10.1111/liv.12689 Text en http://creativecommons.org/licenses/by/4.0/ Open Access, Creative Commons licence http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Possamai, Lucia A
McPhail, Mark JW
Khamri, Wafa
Wu, Bishan
Concas, Danilo
Harrison, Mark
Williams, Roger
Cox, Roger D
Cox, I Jane
Anstee, Quentin M
Thursz, Mark R
The role of intestinal microbiota in murine models of acetaminophen-induced hepatotoxicity
title The role of intestinal microbiota in murine models of acetaminophen-induced hepatotoxicity
title_full The role of intestinal microbiota in murine models of acetaminophen-induced hepatotoxicity
title_fullStr The role of intestinal microbiota in murine models of acetaminophen-induced hepatotoxicity
title_full_unstemmed The role of intestinal microbiota in murine models of acetaminophen-induced hepatotoxicity
title_short The role of intestinal microbiota in murine models of acetaminophen-induced hepatotoxicity
title_sort role of intestinal microbiota in murine models of acetaminophen-induced hepatotoxicity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5873516/
https://www.ncbi.nlm.nih.gov/pubmed/25244648
http://dx.doi.org/10.1111/liv.12689
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