The role of intestinal microbiota in murine models of acetaminophen-induced hepatotoxicity
- Resource Type
- Authors
- 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
- Source
- Liver international : official journal of the International Association for the Study of the Liver
- Subject
- Male
Proton Magnetic Resonance Spectroscopy
METABOLISM
KERATIN-18
MICROFLORA
Article
STERILE INFLAMMATION
microbiota
Animals
PARACETAMOL
metabonomics
acetaminophen
Mice, Inbred C3H
RECEPTOR 4
Science & Technology
Gastroenterology & Hepatology
NECROSIS
Alanine Transaminase
Cytochrome P-450 CYP2E1
acute liver failure
Glutathione
Intestines
Disease Models, Animal
MICE
Liver
germ-free
Cytokines
MOUSE-LIVER
ACUTE LIVER-FAILURE
Chemical and Drug Induced Liver Injury
Life Sciences & Biomedicine
- Language
- English
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 1H-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.