The Pathogenetic Role Of Intestinal Microbiota In Severe Liver Injury Based On "Gut-liver Axis"

Background and objectiveSevere liver injury is recognized as clinical syndrome characterized by massive hepatocyte damage and rapid development of hepatocellular dysfunction.Severe liver injury,one of the common sever illnesses,is appearance disease that has high mortality rate.There is common cause for severe liver injury,including drug induced liver injury,viral hepatitis induced liver dysfunction and liver injury caused by sepsis.Currently,specific therapeutic approaches for severe liver injury are not available.The liver transplantation is usually treated patients with severe liver injury.It is reported that gut microbiota plays key role in liver disease pathogenesis.However,detailed effect of gut microbiota on severe liver injury remains elusive.Based on the theory of" gut-liver axis",we aimed to explore the role of gut microbiota in regulating progression of acetaminophen hepatotoxicity and sepsis-related liver injury,thus to develop novel therapeutic strategy to treat severe liver injury.Contents and methods1.Investigation the crosstalk between gut microbiota and diurnal variation of hepatotoxicity induced by APAP.(1)We performed ABX and FMT experiment to prove the role of gut microbiota in APAP induced liver injury.(2)Multi-omics analysis was preformed to identify potential key gut microbiota derived metabolites in different periods.2.Elaboration the role of metabolites in regulating APAP hepatotoxicity(1)Verification metabolites regulation APAP induced hepatic injury and revelation underlying molecular mechanism.(2)Development therapeutic strategy to protect against severe liver injury by reduced level of metabolites.3.Investigation the connection between gut microbiota and susceptibility of sepsis-induced liver injury(1)We carried out FMT experiment to manifest the role of gut microbiota in susceptibility to sepsis-induced liver injury.(2)Multi-omics analysis was performed to identify potential key gut microbiota derived metabolites in sepsis induced liver injury.4.Investigation the role of metabolites in regulating progression of sepsis induced liver dysfunction.(1)Demonstration metabolites protection mice against CLP-induced sepsis and revelation underlying molecular mechanism.(2)Clinical transformational research.Result1.The gut microbial metabolite,1-phenyl-1,2-propanedione could delete hepatic GSH to enhance APAP hepatotoxicity.2.Saccharomyces cerevisiae administration could reduce hepatic PPD to decrease APAP hepatotoxicity.3.The gut microbial metabolite,granisetron could protect against sepsis induced liver injury by supression inflammation response of macrophage,thus mediation the susceptibility to sepsis in mice.4.The level of granisetron levels in feces showed a negative correlation with degree of liver damage of sepsis patients.ConclusionThe gut microbiota could regulate inflammation responses and oxidative stress by produce metabolites which directly enter into liver and participation in the pathogenesis of acute severe liver injury.In future,novel therapeutic approach for severe liver injury by targeting gut microbiota should be developed.