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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
Graphical Abstract
KEYWORDS
Article info
Publication history
Accepted:
January 17,
2023
Received in revised form:
January 16,
2023
Received:
March 12,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
ARTICLE SYNOPSIS
In this article, we found antibiotic pre-treatment could protect against liver I/R injury through altered gut microbiota, glutamine level and glutamine downstream products αKG in circulation.
αKG as a checkpoint could promote macrophage metabolic reprogramming and change the proportion of M1 and M2 macrophage.
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Copyright
© 2023 The Authors. Published by Elsevier Inc. on behalf of the AGA Institute.
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