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

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

  • Cell Mol Gastroenterol Hepatol. 2023 Jan 24;S2352-345X(23)00004-8. doi: 10.1016/j.jcmgh.2023.01.004.
Tianfei Lu 1,  Qing Li 2,  Weiwei Lin 3,  Xianzhe Zhao 4,  Fu Li 5,  Jianmei Ji 6,  Yu Zhang 7,  Ning Xu 8
Affiliations

Affiliations

  • 1 Abdominal Transplant Surgery Center, Ruijing Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
  • 2 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.
  • 3 Department of Laboratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
  • 4 Shanghai Rat&Mouse Biotech Co., Ltd. Shanghai, China.
  • 5 Department of Cholangio-Pancreatic Surgery, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • 6 Digestive Endoscopy Center, Department of Gastroenterology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • 7 Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: Dr_zhangyu@zju.edu.cn.
  • 8 Department of Liver Surgery and Liver Transplantation Center, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China. Electronic address: xuning@renji.com.
PMID: 36706918 DOI: 10.1016/j.jcmgh.2023.01.004
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.

Keywords

Liver ischemia/reperfusion injury; a-ketoglutarate; glutamine; immunometabolism; macrophage reprogramming; microbiota.

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