Alcoholic liver disease progresses through several stages of tissue damage, from simple steatosis to alcoholic hepatitis, fibrosis, or cirrhosis. Alcohol also affects the intestine, increases intestinal permeability a...Alcoholic liver disease progresses through several stages of tissue damage, from simple steatosis to alcoholic hepatitis, fibrosis, or cirrhosis. Alcohol also affects the intestine, increases intestinal permeability and changes the bacterial microflora. Liver disease severity correlates with levels of systemic bacterial products in patients, and experimental alcoholic liver disease is dependent on gut derived bacterial products in mice. Supporting evidence for the importance of bacterial translocation comes from animal studies demonstrating that intestinal decontamination is associated with decreased liver fibrogenesis. In addition, mice with a gene mutation or deletion encoding receptors for either bacterial products or signaling molecules downstream from these receptors, are resistant to alcohol-induced liver disease. Despite this strong association, the exact molecular mechanism of bacterial translocation and of how changes in the intestinal microbiome contribute to liver disease progression remains largely unknown. In this review we will summarize evidence for bacterial translocation and enteric microbial changes in response to alcoholic liver injury and chronic alcoholic liver disease. We will further describe consequences of intestinal dysbiosis on host biology. We finally discuss how therapeutic interventions may modify the gastrointestinal microflora and prevent or reduce alcoholic liver disease progression.展开更多
Background:Cirrhosis with acute decompensation(AD)and acute-on-chronic liver failure(ACLF)are characterized by high morbidity and mortality.Cytolysin,a toxin from Enterococcus faecalis(E.faecalis),is associated with m...Background:Cirrhosis with acute decompensation(AD)and acute-on-chronic liver failure(ACLF)are characterized by high morbidity and mortality.Cytolysin,a toxin from Enterococcus faecalis(E.faecalis),is associated with mortality in alcohol-associated hepatitis(AH).It is unclear whether cytolysin also contributes to disease severity in AD and ACLF.Methods:We studied the role of fecal cytolysin in 78 cirrhotic patients with AD/ACLF.Bacterial DNA from fecal samples was extracted and real-time quantitative polymerase chain reaction(PCR)was performed.The association between fecal cytolysin and liver disease severity in cirrhosis with AD or ACLF was analyzed.Results:Fecal cytolysin and E.faecalis abundance did not predict chronic liver failure(CLIF-C)AD and ACLF scores.Presence of fecal cytolysin was not associated with other liver disease markers,including Fibrosis-4(FIB-4)index,‘Age,serum Bilirubin,INR,and serum Creatinine(ABIC)’score,Child-Pugh score,model for end-stage liver disease(MELD)nor MELD-Na scores in AD or ACLF patients.Conclusions:Fecal cytolysin does not predict disease severity in AD and ACLF patients.The predictive value of fecal cytolysin positivity for mortality appears to be restricted to AH.展开更多
BACKGROUND End-stage liver disease caused by non-alcoholic steatohepatitis(NASH)is the second leading indication for liver transplantation.To date,only moderately effective pharmacotherapies exist to treat NASH.Unders...BACKGROUND End-stage liver disease caused by non-alcoholic steatohepatitis(NASH)is the second leading indication for liver transplantation.To date,only moderately effective pharmacotherapies exist to treat NASH.Understanding the pathogenesis of NASH is therefore crucial for the development of new therapies.The inflammatory cytokine tumor necrosis factor alpha(TNF-α)is important for the progression of liver disease.TNF signaling via TNF receptor 1(TNFR1)has been hypothesized to be important for the development of NASH and hepatocellular carcinoma in whole-body knockout animal models.AIM To investigate the role of TNFR1 signaling in hepatocytes for steatohepatitis development in a mouse model of diet-induced NASH.METHODS NASH was induced by a western-style fast-food diet in mice deficient for TNFR1 in hepatocytes(TNFR1ΔHEP)and their wild-type littermates(TNFR1fl/fl).Glucose tolerance was assessed after 18 wk and insulin resistance after 19 wk of feeding.After 20 wk mice were assessed for features of NASH and the metabolic syndrome such as liver weight,liver steatosis,liver fibrosis and markers of liver inflammation.RESULTS Obesity,liver injury,inflammation,steatosis and fibrosis was not different between TNFR1ΔHEP and TNFR1fl/fl mice.However,Tnfr1 deficiency in hepatocytes protected against glucose intolerance and insulin resistance.CONCLUSION Our results indicate that deficiency of TNFR1 signaling in hepatocytes does not protect from diet-induced NASH.However,improved insulin resistance in this model strengthens the role of the liver in glucose homeostasis.展开更多
Metabolic dysfunction and alcohol-associated liver disease(MetALD)is a recently implemented nomenclature and disease terminology for patients with metabolic dysfunction-associated steatotic liver disease,who consume g...Metabolic dysfunction and alcohol-associated liver disease(MetALD)is a recently implemented nomenclature and disease terminology for patients with metabolic dysfunction-associated steatotic liver disease,who consume greater amounts of alcohol.MetALD is diagnosed in individuals who have at least one metabolic risk factor(such as obesity,type 2 diabetes mellitus,hypertension,etc)and consume 140–350 g/week of alcohol for women or 210–420 g/week for men.Conversely,alcohol-associated liver disease is diagnosed in individuals who consume>350 g/week of alcohol for women and>420 g/week for men.MetALD represents a heterogeneous spectrum of liver disease,with variations in clinical presentation and severity driven by differences in metabolic profiles,drinking patterns and individual susceptibility.Alcohol and metabolic risk factors are thought to act synergistically to accelerate steatohepatitis,fibrosis and hepatocellular carcinoma.However,the precise mechanisms underlying liver injury in MetALD still remain poorly understood.In this comprehensive review,we summarise the current definition,diagnostic criteria and clinical management of MetALD.We also discuss emerging insights into understanding its pathogenesis,examine relevant experimental models and highlight future challenges and research priorities in this evolving field.展开更多
Liver transplantation is oftentimes the last therapeutic resource for patients with late-stage chronic liver diseases,including cirrhosis and hepatocellular carcinoma.The liver's regenerative capacity is particula...Liver transplantation is oftentimes the last therapeutic resource for patients with late-stage chronic liver diseases,including cirrhosis and hepatocellular carcinoma.The liver's regenerative capacity is particularly critical following partial hepatectomy and transplantation.展开更多
The gut microbiota is a complex and plastic consortium of microorganisms that are intricately connected with human physiology.The liver is a central immunological organ that is particularly enriched in innate immune c...The gut microbiota is a complex and plastic consortium of microorganisms that are intricately connected with human physiology.The liver is a central immunological organ that is particularly enriched in innate immune cells and constantly exposed to circulating nutrients and endotoxins derived from the gut microbiota.The delicate interaction between the gut and liver prevents accidental immune activation against otherwise harmless antigens.Work on the interplay between the gut microbiota and liver has assisted in understanding the pathophysiology of various liver diseases.Of immense importance is the step from high-throughput sequencing(correlation)to mechanistic studies(causality)and therapeutic intervention.Here,we review the gut microbiota,liver immunology,and the interaction between the gut and liver.In addition,the impairment in the gut-liver axis found in various liver diseases is reviewed here,with an emphasis on alcohol-associated liver disease(ALD),nonalcoholic fatty liver disease(NAFLD),and autoimmune liver disease(AILD).On the basis of growing evidence from these preclinical studies,we propose that the gut-liver axis paves the way for targeted therapeutic modalities for liver diseases.展开更多
The gut microbiome is recognized as a key modulator of sepsis development.However,the contribution of the gut mycobiome to sepsis development is still not fully understood.Here,we demonstrated that the level of Candid...The gut microbiome is recognized as a key modulator of sepsis development.However,the contribution of the gut mycobiome to sepsis development is still not fully understood.Here,we demonstrated that the level of Candida albicans was markedly decreased in patients with bacterial sepsis,and the supernatant of Candida albicans culture significantly decreased the bacterial load and improved sepsis symptoms in both cecum ligation and puncture(CLP)-challenged mice and Escherichia coli-challenged pigs.Integrative metabolomics and the genetic engineering of fungi revealed that Candida albicans-derived phenylpyruvate(PPA)enhanced the bactericidal activity of macrophages and reduced organ damage during sepsis.Mechanistically,PPA directly binds to sirtuin 2(SIRT2)and increases reactive oxygen species(ROS)production for eventual bacterial clearance.Importantly,PPA enhanced the bacterial clearance capacity of macrophages in sepsis patients and was inversely correlated with the severity of sepsis in patients.Our findings highlight the crucial contribution of commensal fungi to bacterial disease modulation and expand our understanding of the host-mycobiome interaction during sepsis development.展开更多
Intestinal bacteria contribute to the pathogenesis of non-alcoholic fatty liver disease(NAFLD).Recently developed microbial profiling techniques are beginning to shed light on the nature of the changes in the gut micr...Intestinal bacteria contribute to the pathogenesis of non-alcoholic fatty liver disease(NAFLD).Recently developed microbial profiling techniques are beginning to shed light on the nature of the changes in the gut microbiota that accompany NAFLD and non-alcoholic steatohepatitis(NASH).In this review,we summarize the role of gut microbiota in the development of NAFLD,NASH,and hepatocellular carcinoma(HCC).We highlight the mechanisms by which gut microbiota contribute to NAFLD/NASH,including through alterations in gut epithelial permeability,choline metabolism,endogenous alcohol production,release of inflammatory cytokines,regulation of hepatic Toll-like receptor(TLR),and bile acid metabolism.In addition,we analyze possible mechanisms for enhanced hepatic carcinogenesis,including alterations in bile acid metabolism,release of inflammatory cytokines,and expression of TLR-4.Finally,we describe therapeutic approaches for NAFLD/NASH and preventive strategies for HCC involving modulation of the intestinal microbiota or affected host pathways.Although recent studies have provided useful information,large-scale prospective studies are required to better characterize the intestinal microbiota and metabolome,in order to demonstrate a causative role for changes in the gut microbiota in the etiology of NAFLD/NASH,to identify new therapeutic strategies for NAFLD/NASH,and to develop more effective methods of preventing HCC.展开更多
基金Supported by NIH grants No. K08 DK081830 and No. R01 AA020703the Pilot Project Program of the Southern California Research Center for ALPD and Cirrhosis No. P50AA11999 funded by the National Institute on Alcohol Abuse and AlcoholismABMRF/The Foundation for Alcohol Research to Schnabl B
文摘Alcoholic liver disease progresses through several stages of tissue damage, from simple steatosis to alcoholic hepatitis, fibrosis, or cirrhosis. Alcohol also affects the intestine, increases intestinal permeability and changes the bacterial microflora. Liver disease severity correlates with levels of systemic bacterial products in patients, and experimental alcoholic liver disease is dependent on gut derived bacterial products in mice. Supporting evidence for the importance of bacterial translocation comes from animal studies demonstrating that intestinal decontamination is associated with decreased liver fibrogenesis. In addition, mice with a gene mutation or deletion encoding receptors for either bacterial products or signaling molecules downstream from these receptors, are resistant to alcohol-induced liver disease. Despite this strong association, the exact molecular mechanism of bacterial translocation and of how changes in the intestinal microbiome contribute to liver disease progression remains largely unknown. In this review we will summarize evidence for bacterial translocation and enteric microbial changes in response to alcoholic liver injury and chronic alcoholic liver disease. We will further describe consequences of intestinal dysbiosis on host biology. We finally discuss how therapeutic interventions may modify the gastrointestinal microflora and prevent or reduce alcoholic liver disease progression.
基金This study was supported in part by National Institutes of Health(NIH)grant(K12 HD85036)University of California San Diego Altman Clinical and Translational Research Institute(ACTRI)/NIH grant(KL2TR001444)+14 种基金Pinnacle Research Award in Liver Diseases Grant(PNC22-159963)from the American Association for the Study of Liver Diseases Foundation(to Hartmann P)Deutsche Forschungsgemeinschaft(DFG,German Research Foundation)fellowship(LA 4286/1-1)the“Clinical and Translational Research Fellowship in Liver Disease”by the American Association for the Study of Liver Diseases(AASLD)Foundation(to Lang S)National Institutes of Health grants(R01 AA24726,R01 AA020703,U01 AA026939)Award Number BX004594 from the Biomedical Laboratory Research&Development Service of the VA Office of Research and DevelopmentBiocodex Microbiota Foundation Grant(to Schnabl B)services provided by NIH centers(P30 DK120515 and P50 AA011999)This study was also supported by the German Research Foundation(DFG)project(403224013-SFB 1382)(to Trebicka J)the German Federal Ministry of Education and Research(BMBF)for the DEEP-HCC project(to Trebicka J)the Hessian Ministry of Higher Education,Research and the Arts(HMWK)for the ENABLE and ACLF-I cluster projects(to Trebicka J)The MICROB-PREDICT(825694)DECISION(847949)GALAXY(668031)LIVERHOPE(731875)IHMCSA(964590)projects(all to Trebicka J)have received funding from the European Union’s Horizon 2020 research and innovation program.
文摘Background:Cirrhosis with acute decompensation(AD)and acute-on-chronic liver failure(ACLF)are characterized by high morbidity and mortality.Cytolysin,a toxin from Enterococcus faecalis(E.faecalis),is associated with mortality in alcohol-associated hepatitis(AH).It is unclear whether cytolysin also contributes to disease severity in AD and ACLF.Methods:We studied the role of fecal cytolysin in 78 cirrhotic patients with AD/ACLF.Bacterial DNA from fecal samples was extracted and real-time quantitative polymerase chain reaction(PCR)was performed.The association between fecal cytolysin and liver disease severity in cirrhosis with AD or ACLF was analyzed.Results:Fecal cytolysin and E.faecalis abundance did not predict chronic liver failure(CLIF-C)AD and ACLF scores.Presence of fecal cytolysin was not associated with other liver disease markers,including Fibrosis-4(FIB-4)index,‘Age,serum Bilirubin,INR,and serum Creatinine(ABIC)’score,Child-Pugh score,model for end-stage liver disease(MELD)nor MELD-Na scores in AD or ACLF patients.Conclusions:Fecal cytolysin does not predict disease severity in AD and ACLF patients.The predictive value of fecal cytolysin positivity for mortality appears to be restricted to AH.
基金Supported by the Swiss National Science Foundation,No.P2SKP3_158649,No.P3400PB_171581,and No.P3P3PB_171582(to Bluemel S)NIH grants(in part),No.R01 AA24726,No.U01 AA026939,and services provided by P30 DK120515(to Schnabl B).
文摘BACKGROUND End-stage liver disease caused by non-alcoholic steatohepatitis(NASH)is the second leading indication for liver transplantation.To date,only moderately effective pharmacotherapies exist to treat NASH.Understanding the pathogenesis of NASH is therefore crucial for the development of new therapies.The inflammatory cytokine tumor necrosis factor alpha(TNF-α)is important for the progression of liver disease.TNF signaling via TNF receptor 1(TNFR1)has been hypothesized to be important for the development of NASH and hepatocellular carcinoma in whole-body knockout animal models.AIM To investigate the role of TNFR1 signaling in hepatocytes for steatohepatitis development in a mouse model of diet-induced NASH.METHODS NASH was induced by a western-style fast-food diet in mice deficient for TNFR1 in hepatocytes(TNFR1ΔHEP)and their wild-type littermates(TNFR1fl/fl).Glucose tolerance was assessed after 18 wk and insulin resistance after 19 wk of feeding.After 20 wk mice were assessed for features of NASH and the metabolic syndrome such as liver weight,liver steatosis,liver fibrosis and markers of liver inflammation.RESULTS Obesity,liver injury,inflammation,steatosis and fibrosis was not different between TNFR1ΔHEP and TNFR1fl/fl mice.However,Tnfr1 deficiency in hepatocytes protected against glucose intolerance and insulin resistance.CONCLUSION Our results indicate that deficiency of TNFR1 signaling in hepatocytes does not protect from diet-induced NASH.However,improved insulin resistance in this model strengthens the role of the liver in glucose homeostasis.
基金supported in part by the intramural programme of the NIAAA(BG)and the NIAAA/NIDA(LL)SL is supported in part by U01 AA026917,UH2/UH3 AA026903,R01 AA030312 and the Department of Veterans Affairs Merit Award 1I01 CX000361 and I01 BX006202,and by the Dean’s Scholar Award from Indiana University School of Medicine+6 种基金W-XD is supported by R37 AA020518,R21 AA030617 and R01 AA031230GS is supported by R01 AA032418 and R56 AA017729BS is supported by NIH grants P30 DK120515 and P50 AA011999CL is supported by R01 AA029106 and R21 AA030654RL receives funding support from UL1 TR001442,U01 DK061734,U01 DK130190,R01 DK121378,P30 DK120515,P01 HL147835 and the John C Martin Foundation(RP124)FT is supported by the German Research Foundation(DFG CRC/TR 412,Project-ID 535081457 and SFB1382,Project-ID 403224013)under Germany's Excellence Strategy-EXC 3118/1-project number 533770413.
文摘Metabolic dysfunction and alcohol-associated liver disease(MetALD)is a recently implemented nomenclature and disease terminology for patients with metabolic dysfunction-associated steatotic liver disease,who consume greater amounts of alcohol.MetALD is diagnosed in individuals who have at least one metabolic risk factor(such as obesity,type 2 diabetes mellitus,hypertension,etc)and consume 140–350 g/week of alcohol for women or 210–420 g/week for men.Conversely,alcohol-associated liver disease is diagnosed in individuals who consume>350 g/week of alcohol for women and>420 g/week for men.MetALD represents a heterogeneous spectrum of liver disease,with variations in clinical presentation and severity driven by differences in metabolic profiles,drinking patterns and individual susceptibility.Alcohol and metabolic risk factors are thought to act synergistically to accelerate steatohepatitis,fibrosis and hepatocellular carcinoma.However,the precise mechanisms underlying liver injury in MetALD still remain poorly understood.In this comprehensive review,we summarise the current definition,diagnostic criteria and clinical management of MetALD.We also discuss emerging insights into understanding its pathogenesis,examine relevant experimental models and highlight future challenges and research priorities in this evolving field.
基金supported by services from the NIH center P30 DK120515(USA).
文摘Liver transplantation is oftentimes the last therapeutic resource for patients with late-stage chronic liver diseases,including cirrhosis and hepatocellular carcinoma.The liver's regenerative capacity is particularly critical following partial hepatectomy and transplantation.
基金supported in part by the National Natural Science Foundation of China(grants#81830016,81771732,and 81620108002 to X.M.,#81922010 and 81873561 to R.T.)supported in part by services provided by the NIH centers P30 DK120515 and P50 AA011999+1 种基金supported by the excellence initiative VASCage(Centre for Promoting Vascular Health in the Ageing Community)R8fD K-Centre(COMET program-Competence Centers for Excellent Technologies)funded by the Austrian Ministry for Transport,Innovation and Technology,the Austrian Ministry for Digital and Economic Affairs and the federal states Tyrol,Salzburg and Vienna.
文摘The gut microbiota is a complex and plastic consortium of microorganisms that are intricately connected with human physiology.The liver is a central immunological organ that is particularly enriched in innate immune cells and constantly exposed to circulating nutrients and endotoxins derived from the gut microbiota.The delicate interaction between the gut and liver prevents accidental immune activation against otherwise harmless antigens.Work on the interplay between the gut microbiota and liver has assisted in understanding the pathophysiology of various liver diseases.Of immense importance is the step from high-throughput sequencing(correlation)to mechanistic studies(causality)and therapeutic intervention.Here,we review the gut microbiota,liver immunology,and the interaction between the gut and liver.In addition,the impairment in the gut-liver axis found in various liver diseases is reviewed here,with an emphasis on alcohol-associated liver disease(ALD),nonalcoholic fatty liver disease(NAFLD),and autoimmune liver disease(AILD).On the basis of growing evidence from these preclinical studies,we propose that the gut-liver axis paves the way for targeted therapeutic modalities for liver diseases.
基金supported by the National Natural Science Foundation of China(32271230 and 32071124)to PCthe NIH Grant(P30DK120515)to BS+4 种基金the National Natural Science Foundation of China(82270581)to YCthe National Key R&D Project of China(2018YFC0115301)the National Natural Science Foundation of China(81974070)the Shenzhen Science and Technology Program(JCYJ20210324131010027)the Research Foundation of Shenzhen Hospital of Southern Medical University(PT2018GZR10)to WG.
文摘The gut microbiome is recognized as a key modulator of sepsis development.However,the contribution of the gut mycobiome to sepsis development is still not fully understood.Here,we demonstrated that the level of Candida albicans was markedly decreased in patients with bacterial sepsis,and the supernatant of Candida albicans culture significantly decreased the bacterial load and improved sepsis symptoms in both cecum ligation and puncture(CLP)-challenged mice and Escherichia coli-challenged pigs.Integrative metabolomics and the genetic engineering of fungi revealed that Candida albicans-derived phenylpyruvate(PPA)enhanced the bactericidal activity of macrophages and reduced organ damage during sepsis.Mechanistically,PPA directly binds to sirtuin 2(SIRT2)and increases reactive oxygen species(ROS)production for eventual bacterial clearance.Importantly,PPA enhanced the bacterial clearance capacity of macrophages in sepsis patients and was inversely correlated with the severity of sepsis in patients.Our findings highlight the crucial contribution of commensal fungi to bacterial disease modulation and expand our understanding of the host-mycobiome interaction during sepsis development.
基金This study was supported by the USA National Institutes of Health(NIH)grant R01 AA020703,and by Award Number I01BX002213 from the Biomedical Laboratory Research&Development Service of the VA Office of Research and Development to B.Schnab.
文摘Intestinal bacteria contribute to the pathogenesis of non-alcoholic fatty liver disease(NAFLD).Recently developed microbial profiling techniques are beginning to shed light on the nature of the changes in the gut microbiota that accompany NAFLD and non-alcoholic steatohepatitis(NASH).In this review,we summarize the role of gut microbiota in the development of NAFLD,NASH,and hepatocellular carcinoma(HCC).We highlight the mechanisms by which gut microbiota contribute to NAFLD/NASH,including through alterations in gut epithelial permeability,choline metabolism,endogenous alcohol production,release of inflammatory cytokines,regulation of hepatic Toll-like receptor(TLR),and bile acid metabolism.In addition,we analyze possible mechanisms for enhanced hepatic carcinogenesis,including alterations in bile acid metabolism,release of inflammatory cytokines,and expression of TLR-4.Finally,we describe therapeutic approaches for NAFLD/NASH and preventive strategies for HCC involving modulation of the intestinal microbiota or affected host pathways.Although recent studies have provided useful information,large-scale prospective studies are required to better characterize the intestinal microbiota and metabolome,in order to demonstrate a causative role for changes in the gut microbiota in the etiology of NAFLD/NASH,to identify new therapeutic strategies for NAFLD/NASH,and to develop more effective methods of preventing HCC.
