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Gut microbiota mediates diurnal variation of acetaminophen induced acute liver injury in mice

  • Author Footnotes
    † These authors contribute equally to this work.
    Shenhai Gong
    Footnotes
    † These authors contribute equally to this work.
    Affiliations
    State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China

    Guangdong Provincial Key Laboratory of Proteomics, Southern Medical University, Guangzhou, China

    Department of Pathophysiology, Southern Medical University, Guangzhou, China
    Search for articles by this author
  • Author Footnotes
    † These authors contribute equally to this work.
    Tian Lan
    Footnotes
    † These authors contribute equally to this work.
    Affiliations
    Guangdong Pharmaceutical University, Guangzhou, China
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  • Liyan Zeng
    Affiliations
    School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
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  • Haihua Luo
    Affiliations
    State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China

    Guangdong Provincial Key Laboratory of Proteomics, Southern Medical University, Guangzhou, China

    Department of Pathophysiology, Southern Medical University, Guangzhou, China
    Search for articles by this author
  • Xiaoyu Yang
    Affiliations
    State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China

    Guangdong Provincial Key Laboratory of Proteomics, Southern Medical University, Guangzhou, China

    Department of Pathophysiology, Southern Medical University, Guangzhou, China
    Search for articles by this author
  • Na Li
    Affiliations
    State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China

    Guangdong Provincial Key Laboratory of Proteomics, Southern Medical University, Guangzhou, China

    Department of Pathophysiology, Southern Medical University, Guangzhou, China
    Search for articles by this author
  • Xiaojiao Chen
    Affiliations
    State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
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  • Zhanguo Liu
    Affiliations
    Department of Intensive Care Unit, Zhujiang Hospital, Southern Medical University, Guangzhou, China
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  • Rui Li
    Affiliations
    Guangdong Pharmaceutical University, Guangzhou, China
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  • Sanda Win
    Affiliations
    University of Southern California Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, USA
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  • Shuwen Liu
    Affiliations
    State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China

    School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
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  • Hongwei Zhou
    Affiliations
    State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
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  • Bernd Schnabl
    Affiliations
    Department of Medicine, University of California San Diego, La Jolla, USA
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  • Author Footnotes
    ‡ These authors share co-senior author.
    Yong Jiang
    Correspondence
    Corresponding authors. Addresses: Department of Pathophysiology, Southern Medical University, Guangzhou, China. Tel.: +86 (20)61648231 (Y. Jiang), or Department of Pathophysiology, Southern Medical University, Guangzhou, China. Tel.: +86 (20)61648172 839 (P. Chen).
    Footnotes
    ‡ These authors share co-senior author.
    Affiliations
    State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China

    Guangdong Provincial Key Laboratory of Proteomics, Southern Medical University, Guangzhou, China

    Department of Pathophysiology, Southern Medical University, Guangzhou, China
    Search for articles by this author
  • Author Footnotes
    ‡ These authors share co-senior author.
    Neil Kaplowitz
    Footnotes
    ‡ These authors share co-senior author.
    Affiliations
    University of Southern California Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, USA
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  • Author Footnotes
    ‡ These authors share co-senior author.
    Peng Chen
    Correspondence
    Corresponding authors. Addresses: Department of Pathophysiology, Southern Medical University, Guangzhou, China. Tel.: +86 (20)61648231 (Y. Jiang), or Department of Pathophysiology, Southern Medical University, Guangzhou, China. Tel.: +86 (20)61648172 839 (P. Chen).
    Footnotes
    ‡ These authors share co-senior author.
    Affiliations
    State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China

    Guangdong Provincial Key Laboratory of Proteomics, Southern Medical University, Guangzhou, China

    Department of Pathophysiology, Southern Medical University, Guangzhou, China

    Department of Intensive Care Unit, Zhujiang Hospital, Southern Medical University, Guangzhou, China
    Search for articles by this author
  • Author Footnotes
    † These authors contribute equally to this work.
    ‡ These authors share co-senior author.
Published:March 07, 2018DOI:https://doi.org/10.1016/j.jhep.2018.02.024

      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

      Keywords

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