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Gut microbiota-derived glutamine attenuates liver ischemia/reperfusion injury via macrophage metabolic reprogramming

  • Author Footnotes
    # These authors contributed equally to this work.
    Tianfei Lu
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    # These authors contributed equally to this work.
    Affiliations
    Abdominal Transplant Surgery Center, Ruijing Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
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    # These authors contributed equally to this work.
    Qing Li
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    # These authors contributed equally to this work.
    Affiliations
    Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Gastroenterology Department, F-75012 Paris, France; Paris Centre for Microbiome Medicine FHU, Paris, France
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    # These authors contributed equally to this work.
    Weiwei Lin
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    # These authors contributed equally to this work.
    Affiliations
    Department of Laboratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
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  • Xianzhe Zhao
    Affiliations
    Shanghai Rat&Mouse Biotech Co., Ltd. Shanghai, China
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  • Fu Li
    Affiliations
    Department of Cholangio-Pancreatic Surgery, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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  • Jianmei Ji
    Affiliations
    Digestive Endoscopy Center, Department of Gastroenterology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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  • Yu Zhang
    Correspondence
    Correspondence:
    Affiliations
    Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
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  • Author Footnotes
    9 Lead Contact
    Ning Xu
    Correspondence
    Correspondence:
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    9 Lead Contact
    Affiliations
    Department of Liver Surgery and Liver Transplantation Center, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
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  • Author Footnotes
    9 Lead Contact
    # These authors contributed equally to this work.
Open AccessPublished:January 24, 2023DOI:https://doi.org/10.1016/j.jcmgh.2023.01.004
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      ABSTRACT

      Objective & Aims

      Many studies have revealed crucial roles of the gut microbiota and its metabolites in liver disease progression. However, the mechanism underlying their effects on liver ischemia/reperfusion (I/R) injury remain largely unknown. Here, we investigate the function of gut microbiota and its metabolites in liver I/R injury.

      Methods

      C57BL/6 mice was pretreated with an antibiotic cocktail. Then, we used multi-omics detection methods including 16s rRNA sequencing, ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC–MS/MS) to explore the changes of gut microbiota and metabolites both in feces and portal blood in order to reveal the mechanism of their protective effect in liver I/R injury.

      Results

      We found that antibiotic pretreatment (ABX) could significantly reduce the severity of I/R-induced hepatic injury, and this effect could be transferred to germ-free (GF) mice by fecal microbiota transplantation (FMT), suggesting a protective role of the gut microbiota depletion. During I/R, the rates of serum α-ketoglutarate (aKG) production and glutamate reduction, downstream products of gut microbiota-derived glutamine were more significant in the ABX mice. Then, we showed that aKG could promote alternative (M2) macrophage activation through oxidative phosphorylation (OXPHOS) and Oligomycin A could inhibit M2 macrophage polarization and reversed this protective effect.

      Conclusions

      These findings show that the gut microbiota and its metabolites play critical roles in hepatic I/R injury by modulating macrophage metabolic reprogramming. Potential therapies that target macrophage metabolism, including antibiotic therapies and novel immunometabolism modulators can be exploited for the treatment of liver I/R injury.

      Graphical abstract

      KEYWORDS