Highlights
- •The diurnal variation of acetaminophen induced acute liver injury is dependent on gut microbiota.
- •Gut microbiota derived PPD played the key role in the diurnal variation of acetaminophen induced hepatotoxicity.
- •PPD participated in liver damage development by directly depleting hepatic glutathione levels.
Background & Aims
Acetaminophen (APAP) induced hepatotoxicity is a leading cause of acute liver failure
worldwide. It is well established that the liver damage induced by acetaminophen exhibits
diurnal variation. However, the detailed mechanism for the hepatotoxic variation is
not clear. Herein, we aimed to determine the relative contributions of gut microbiota
in modulating the diurnal variation of hepatotoxicity induced by APAP.
Methods
Male Balb/C mice were treated with or without antibiotics and a single dose of orally
administered APAP (300 mg/kg) at ZT0 (when the light is on-start of resting period)
and ZT12 (when the light is off-start of active period).
Results
In agreement with previous findings, hepatic injury was markedly enhanced at ZT12
compared with ZT0. Interestingly, upon antibiotic treatment, ZT12 displayed a protective
effect against APAP hepatotoxicity similar to ZT0. Moreover, mice that received the
cecal content from ZT12 showed more severe liver damage than mice that received the
cecal content from ZT0. 16S sequencing data revealed significant differences in the
cecal content between ZT0 and ZT12 in the compositional level. Furthermore, metabolomic
analysis showed that the gut microbial metabolites were also different between ZT0
and ZT12. Specifically, the level of 1-phenyl-1,2-propanedione (PPD) was significantly
higher at ZT12 than ZT0. Treatment with PPD alone did not cause obvious liver damage.
However, PPD synergistically enhanced APAP-induced hepatic injury in vivo and in vitro. Finally, we found Saccharomyces cerevisiae, which could reduce intestinal PPD levels, was able to markedly alleviate APAP-induced
liver damage at ZT12.
Conclusions
The gut microbial metabolite PPD was responsible, at least in part, for the diurnal
variation of hepatotoxicity induced by APAP by decreasing glutathione levels.
Lay summary
Acetaminophen (APAP) induced acute liver failure because of over dose is a leading
public health problem. APAP-induced liver injury exhibits diurnal variation, specifically
APAP causes more severe liver damage when taken at night compared with in the morning.
Herein, we showed that gut microbial metabolite, 1-phenyl-1,2-propanedione is involved
in the rhythmic hepatotoxicity induced by APAP, by depleting hepatic glutathione (an
important antioxidant) levels. Our data suggest gut microbiota may be a potential
target for reducing APAP-induced acute liver injury.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: March 07, 2018
Accepted:
February 20,
2018
Received in revised form:
February 1,
2018
Received:
November 27,
2017
Identification
Copyright
© 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
