Bile acid（BA） is de novo synthesized exclusively in the liver and has direct or indirect antimicrobial effects. On the other hand, the composition and size of the BA pool can be altered by intestinal microbiota via ...Bile acid（BA） is de novo synthesized exclusively in the liver and has direct or indirect antimicrobial effects. On the other hand, the composition and size of the BA pool can be altered by intestinal microbiota via the biotransformation of primary BAs to secondary BAs, and subsequently regulate the nuclear farnesoid X receptor（FXR; NR1H4）. The BA-activated FXR plays important roles in BA synthesis and metabolism, glucose and lipid metabolism, and even hepatic autophagy. BAs can also play a role in the interplays among intestinal microbes. In this review, we mainly discuss the interactions between BAs and intestinal microbiota and their roles in regulating host metabolism, and probably the autophagic signaling pathway.展开更多
Background:Probiotic VSL#3 is used to treat ulcerative colitis.This study examines the effect of VSL#3 in non-alcoholic steatohepatitis(NASH)that has liver carcinogenic potential.Methods:Western diet(WD)-fed wild-type...Background:Probiotic VSL#3 is used to treat ulcerative colitis.This study examines the effect of VSL#3 in non-alcoholic steatohepatitis(NASH)that has liver carcinogenic potential.Methods:Western diet(WD)-fed wild-type(WT)mice that do not have hepatic inflammation with lymphocyte infiltration and carcinogenic potential were used for baseline comparison.Age-,sex-,and diet-matched bile acid(BA)receptor farnesoid X receptor(FXR)knockout(KO)mice,which developed severe NASH and had the potential for liver cancer development,were supplemented with and without VSL#3 for 7 months.All the mice were euthanized when they were 10 months old.Results:Supplementation with VSL#3 completely abolished hepatic lymphocyte infiltration,reduced hepatic fat content,and improved insulin sensitivity in WD-fed FXR KO mice.In addition,VSL#3 normalized dysregulated BA homoeostasis by inhibiting the classical BA synthesis pathway,inducing the alternative BA pathway,and activating ileal G-protein coupled BA receptor 1(GPBAR1)-regulated signaling.Moreover,VSL#3 reconstructed the gut microbiota by reducing Bacteroidaceae,Porphyromonadaceae,and Helicobacteraceae as well as increasing Lachnospiraceae.Further,VSL#3 enriched the abundance of Ruminococcus and Faecalibacterium,which generate butyrate,at the genus level.It also increased the copy number of the butyrate-producing genes bcoA and buk,suggesting their anti-inflammatory and metabolic effects.Conclusions:VSL#3 is useful in reversing NASH that occurred due to dysregulated BA synthesis and dysbiosis,suggesting its potential in liver cancer prevention.展开更多
An increasing number of studies have indicated that gut microbiota and its metabolites are crucial in the development of hyperlipidemia.Bifidobacterium longum(B.longum)CCFM1077 has been shown to have lipid-lowering ef...An increasing number of studies have indicated that gut microbiota and its metabolites are crucial in the development of hyperlipidemia.Bifidobacterium longum(B.longum)CCFM1077 has been shown to have lipid-lowering effects in animals.This study aimed to evaluate the potential of B.longum CCFM1077 in lowering the lipid levels in patients with hyperlipidemia and investigate the effect of this bacterium on serum lipid abnormalities,gut microbiota,and fecal metabolites in these patients.This study was a six-week,randomized,double-blind,and placebo-controlled pilot clinical trial.Subjects with hyperlipidemia(N=62)were randomly assigned to receive placebo(N=31)or B.longum CCFM1077(1×1010colony-forming units(CFUs)per day;N=31).Serum lipid levels including total cholesterol(TC),lowdensity lipoprotein cholesterol(LDL-C),total triglyceride(TG),and high-density lipoprotein cholesterol(HDL-C)were examined at the baseline and interventio nal endpoints.Changes in the gut microbiota composition and diversity were measured based on 16S ribosomal RNA(rRNA)sequencing of the V3-V4region at the end of the intervention period.Non-targeted metabolomics of the feces was performed using ultra-performance liquid chromatography(UPLC)-Q-Exactive Orbitrap/mass spectrometer.Oral administration of B.longum CCFM1077 for six weeks significantly decreased the serum levels of TC(p<0.01)and LDL-C(p<0.01)in patients with hyperlipidemia.B.longum CCFM1077 treatment markedly increased gut microbiota diversity and the relative abundance of anti-obesity-related genera,including Lactobacillus,Butyricicoccus,Bifidobacterium,and Blautia,whereas it decreased the relative abundance of obesity-related genera,including Alistipes,Megamonas,and Catenibacterium.Additionally,some key metabolites(bile acids(BAs),biotin,and caffeine)and their corresponding metabolic pathways(primary BA biosynthesis,and taurine and hypotaurine,biotin,purine,and caffeine metabolisms)were enriched by B.longum CCFM1077,and thus it may lower lipid levels.B.longum CCFM1077 is a probiotic展开更多
The rapid worldwide rise in obesity rates over the past few decades imposes an urgent need to develop effective strategies for treating obesity and associated metabolic complications.Bariatric surgical procedures,such...The rapid worldwide rise in obesity rates over the past few decades imposes an urgent need to develop effective strategies for treating obesity and associated metabolic complications.Bariatric surgical procedures,such as Roux-en-Y gastric bypass(RYGB)and vertical sleeve gastrectomy(VSG),currently provide the most effective treatment for obesity and type 2 diabetes(T2D),as well as for non-alcoholic steatohepatitis(NASH).However,the underlying mechanisms of the beneficial effects of bariatric surgery remain elusive.Recent studies have identified bile acids as potential signaling molecules involved in the beneficial effects of bariatric surgery.This review focuses on the most recent studies on the roles of bile acids and bile acid receptors Farnesoid X receptor(FXR)and G protein-coupled bile acid receptor 5(TGR5)in bariatric surgery.We also discuss the possibility of modulating bile acid signaling as a pharmacological therapeutic approach to treating obesity and its associated metabolic complications.展开更多
Background and aims:Alcoholic liver disease(ALD)is an important and growing cause for the development of chronic liver diseases in the world.Bile acid(BA)levels are increased in patients with ALD anddysregulation of B...Background and aims:Alcoholic liver disease(ALD)is an important and growing cause for the development of chronic liver diseases in the world.Bile acid(BA)levels are increased in patients with ALD anddysregulation of BA homeostasis worsens ALD.BA synthesis is critically regulated by fibroblast growthfactor(FGF)15 in mice and FGF19 in humans.FGF15/19 are mainly produced in the ileum and their mainfunction is to suppress BA synthesis in the liver through the activation of fibroblast growth factor receptor 4(FGFR4)on hepatocytes.The effects of intestine-specific Fgf15 deficiency on the development ofALD were determined in the current study.Methods:Enterocyte-specific Fgf15 knockout mice(Fgf15intint^(-/-))and the established mouse model bychronic and binge ethanol feeding(NIAAA model)were adapted in this study.Results:The Fgf15intint^(-/-)mice had increased BA pool size,consistent with negative effects of FGF15-FGFR4signaling on BA synthesis.There were not obviously physical and hepatic histological abnormalitiespresented in Fgf15intint^(-/-)mice compared to wild-type mice.Following alcohol treatment,the Fgf15intint^(-/-)mice exhibited a higher degree of liver injury,increased hepatic expression of Cd14,a receptor forlipopolysaccharide expressed in the liver,and increased hepatic lipid levels.We did not observe alterations in the levels of fibrosis in the liver or expression of genes involved in hepatic fibrosis,regardless ofgenotypes or following the alcohol treatment.Conclusions:FGF15 may prevent hepatic steatosis in the development of ALD in mice,and maintainingFGF19/FGFR4 signaling may be critical in the prevention and/or treatment of ALD in humans in thefuture.展开更多
Over 20%of mortality during acute liver failure is associated with the development of hepatic encephalopathy(HE).Thus,HE is a complication of acute liver failure with a broad spectrum of neuropsychiatric abnormalities...Over 20%of mortality during acute liver failure is associated with the development of hepatic encephalopathy(HE).Thus,HE is a complication of acute liver failure with a broad spectrum of neuropsychiatric abnormalities ranging from subclinical alterations to coma.HE is caused by the diversion of portal blood into systemic circulation through portosystemic collateral vessels.Thus,the brain is exposed to intestinal-derived toxic substances.Moreover,the strategies to prevent advancement and improve the prognosis of such a liver-brain disease rely on intestinal microbial modulation.This is supported by the findings that antibiotics such as rifaximin and laxative lactulose can alleviate hepatic cirrhosis and/or prevent HE.Together,the significance of the gut-liver-brain axis in human health warrants attention.This review paper focuses on the roles of bacteria metabolites,mainly ammonia and bile acids(BAs)as well as BA receptors in HE.The literature search conducted for this review included searches for phrases such as BA receptors,BAs,ammonia,farnesoid X receptor(FXR),G protein-coupled bile acid receptor 1(GPBAR1 or TGR5),sphingosine-1-phosphate receptor 2(S1PR2),and cirrhosis in conjunction with the phrase hepatic encephalopathy and portosystemic encephalopathy.PubMed,as well as Google Scholar,was the search engines used to find relevant publications.展开更多
High sensitive immunoassay platforms have gained intense attention due to their vital roles in early-stage disease diagnosis and therapeutic information feedback. Although random covalent-binding of antibody has been ...High sensitive immunoassay platforms have gained intense attention due to their vital roles in early-stage disease diagnosis and therapeutic information feedback. Although random covalent-binding of antibody has been widely adopted in immunoassays due to its simplicity and effectiveness, it readily loses its activity and fails to exhibit high antigen-binding capacity. In this work, copolymer of zwitterionic sulfobetaine methacrylate（SBMA） and glycidyl methacrylate（GMA） brushes were immobilized onto inert polypropylene（PP） via surface-initiated atom transfer radical polymerization（ATRP） based on biomimetic dopamine pretreatment. Subsequently, boronic acid（BA） groups were covalently bonded via active GMA units, followed by the introduction of oriented immobilization of antibody. Owing to the oriented immobilization of antibody facilitated by BA groups in polymer brush, the bioactivity of antibody is well preserved, which endows the surface with significantly enhanced antigen-binding capacity. Moreover, the existence of SBMA segments in polymer brushes renders the surface high resistance to nonspecific protein adsorption, significantly alleviating the signal interference of antigen recognition. This strategy could find potential applications in developing high sensitive immunoassay platforms based on the different substrates.展开更多
Thirteen novel NO-releasing derivatives of betulinic acid （BA） bearing two types of NO-donors （nitrates and furoxans） were synthesized and evaluated for their antitumor activity. The results showed that furoxan-ba...Thirteen novel NO-releasing derivatives of betulinic acid （BA） bearing two types of NO-donors （nitrates and furoxans） were synthesized and evaluated for their antitumor activity. The results showed that furoxan-based derivatives exhibited higher antitumor activity than nitrate-based derivatives, with compounds lla and llb displaying promising potency against B16 cell lines and HepG2 cell lines （IC50 〈 1 μmol/L）. We supposed that NO-releasing amount of these derivatives which can be detected by Griess method may contribute more to their antitumor activity. As a result, furoxan-based derivatives released larger amount of NO than that of nitrate-based derivatives, which partially explained the higher anti-tumor activity of the former.展开更多
基金Project supported by the National Natural Science Foundation of China(No.31322053)the Hubei Province Distinguished Young Scholar(No.2012FFA015)the Fundamental Research Funds for the Central Universities(Nos.2013PY056 and 2013JQ001),China
文摘Bile acid（BA） is de novo synthesized exclusively in the liver and has direct or indirect antimicrobial effects. On the other hand, the composition and size of the BA pool can be altered by intestinal microbiota via the biotransformation of primary BAs to secondary BAs, and subsequently regulate the nuclear farnesoid X receptor（FXR; NR1H4）. The BA-activated FXR plays important roles in BA synthesis and metabolism, glucose and lipid metabolism, and even hepatic autophagy. BAs can also play a role in the interplays among intestinal microbes. In this review, we mainly discuss the interactions between BAs and intestinal microbiota and their roles in regulating host metabolism, and probably the autophagic signaling pathway.
基金This study supported by grants funded by National Institutes of Health CA179582 and CA222490.
文摘Background:Probiotic VSL#3 is used to treat ulcerative colitis.This study examines the effect of VSL#3 in non-alcoholic steatohepatitis(NASH)that has liver carcinogenic potential.Methods:Western diet(WD)-fed wild-type(WT)mice that do not have hepatic inflammation with lymphocyte infiltration and carcinogenic potential were used for baseline comparison.Age-,sex-,and diet-matched bile acid(BA)receptor farnesoid X receptor(FXR)knockout(KO)mice,which developed severe NASH and had the potential for liver cancer development,were supplemented with and without VSL#3 for 7 months.All the mice were euthanized when they were 10 months old.Results:Supplementation with VSL#3 completely abolished hepatic lymphocyte infiltration,reduced hepatic fat content,and improved insulin sensitivity in WD-fed FXR KO mice.In addition,VSL#3 normalized dysregulated BA homoeostasis by inhibiting the classical BA synthesis pathway,inducing the alternative BA pathway,and activating ileal G-protein coupled BA receptor 1(GPBAR1)-regulated signaling.Moreover,VSL#3 reconstructed the gut microbiota by reducing Bacteroidaceae,Porphyromonadaceae,and Helicobacteraceae as well as increasing Lachnospiraceae.Further,VSL#3 enriched the abundance of Ruminococcus and Faecalibacterium,which generate butyrate,at the genus level.It also increased the copy number of the butyrate-producing genes bcoA and buk,suggesting their anti-inflammatory and metabolic effects.Conclusions:VSL#3 is useful in reversing NASH that occurred due to dysregulated BA synthesis and dysbiosis,suggesting its potential in liver cancer prevention.
基金supported by the Natural Science Foundation of Jiangsu Province(BK20220155 and BE2021623)the National Natural Science Foundation of China(32021005,U1903205,and 32001665)the Key Scientific and Technological Research Projects in the Key Areas of the Xinjiang Production and Construction Corps(2018AB010)。
文摘An increasing number of studies have indicated that gut microbiota and its metabolites are crucial in the development of hyperlipidemia.Bifidobacterium longum(B.longum)CCFM1077 has been shown to have lipid-lowering effects in animals.This study aimed to evaluate the potential of B.longum CCFM1077 in lowering the lipid levels in patients with hyperlipidemia and investigate the effect of this bacterium on serum lipid abnormalities,gut microbiota,and fecal metabolites in these patients.This study was a six-week,randomized,double-blind,and placebo-controlled pilot clinical trial.Subjects with hyperlipidemia(N=62)were randomly assigned to receive placebo(N=31)or B.longum CCFM1077(1×1010colony-forming units(CFUs)per day;N=31).Serum lipid levels including total cholesterol(TC),lowdensity lipoprotein cholesterol(LDL-C),total triglyceride(TG),and high-density lipoprotein cholesterol(HDL-C)were examined at the baseline and interventio nal endpoints.Changes in the gut microbiota composition and diversity were measured based on 16S ribosomal RNA(rRNA)sequencing of the V3-V4region at the end of the intervention period.Non-targeted metabolomics of the feces was performed using ultra-performance liquid chromatography(UPLC)-Q-Exactive Orbitrap/mass spectrometer.Oral administration of B.longum CCFM1077 for six weeks significantly decreased the serum levels of TC(p<0.01)and LDL-C(p<0.01)in patients with hyperlipidemia.B.longum CCFM1077 treatment markedly increased gut microbiota diversity and the relative abundance of anti-obesity-related genera,including Lactobacillus,Butyricicoccus,Bifidobacterium,and Blautia,whereas it decreased the relative abundance of obesity-related genera,including Alistipes,Megamonas,and Catenibacterium.Additionally,some key metabolites(bile acids(BAs),biotin,and caffeine)and their corresponding metabolic pathways(primary BA biosynthesis,and taurine and hypotaurine,biotin,purine,and caffeine metabolisms)were enriched by B.longum CCFM1077,and thus it may lower lipid levels.B.longum CCFM1077 is a probiotic
基金This workwas supported by the National Cancer Institute 2R01CA139158,John Hench Foundation,George Schaeffer Foundation,Chinese National Natural Science Foundation(81270935)Transform Medicine Innovation Foundation of Shanghai Jiao Tong University School of Medicine(15ZH2001)+1 种基金Research Project Funded by the Shanghai Municipal Health Bureau(20114301)the Fund of the Key Laboratory of Stem Cell Biology of Chinese Academy of Sciences(201601).
文摘The rapid worldwide rise in obesity rates over the past few decades imposes an urgent need to develop effective strategies for treating obesity and associated metabolic complications.Bariatric surgical procedures,such as Roux-en-Y gastric bypass(RYGB)and vertical sleeve gastrectomy(VSG),currently provide the most effective treatment for obesity and type 2 diabetes(T2D),as well as for non-alcoholic steatohepatitis(NASH).However,the underlying mechanisms of the beneficial effects of bariatric surgery remain elusive.Recent studies have identified bile acids as potential signaling molecules involved in the beneficial effects of bariatric surgery.This review focuses on the most recent studies on the roles of bile acids and bile acid receptors Farnesoid X receptor(FXR)and G protein-coupled bile acid receptor 5(TGR5)in bariatric surgery.We also discuss the possibility of modulating bile acid signaling as a pharmacological therapeutic approach to treating obesity and its associated metabolic complications.
基金the USA National Institutes of Health(NIH)(grant number:GM135258,ES029258)the Vet-erans Affair(grant number:BX002741).
文摘Background and aims:Alcoholic liver disease(ALD)is an important and growing cause for the development of chronic liver diseases in the world.Bile acid(BA)levels are increased in patients with ALD anddysregulation of BA homeostasis worsens ALD.BA synthesis is critically regulated by fibroblast growthfactor(FGF)15 in mice and FGF19 in humans.FGF15/19 are mainly produced in the ileum and their mainfunction is to suppress BA synthesis in the liver through the activation of fibroblast growth factor receptor 4(FGFR4)on hepatocytes.The effects of intestine-specific Fgf15 deficiency on the development ofALD were determined in the current study.Methods:Enterocyte-specific Fgf15 knockout mice(Fgf15intint^(-/-))and the established mouse model bychronic and binge ethanol feeding(NIAAA model)were adapted in this study.Results:The Fgf15intint^(-/-)mice had increased BA pool size,consistent with negative effects of FGF15-FGFR4signaling on BA synthesis.There were not obviously physical and hepatic histological abnormalitiespresented in Fgf15intint^(-/-)mice compared to wild-type mice.Following alcohol treatment,the Fgf15intint^(-/-)mice exhibited a higher degree of liver injury,increased hepatic expression of Cd14,a receptor forlipopolysaccharide expressed in the liver,and increased hepatic lipid levels.We did not observe alterations in the levels of fibrosis in the liver or expression of genes involved in hepatic fibrosis,regardless ofgenotypes or following the alcohol treatment.Conclusions:FGF15 may prevent hepatic steatosis in the development of ALD in mice,and maintainingFGF19/FGFR4 signaling may be critical in the prevention and/or treatment of ALD in humans in thefuture.
基金the USA National Institutes of Health(NIH)R01CA222490.
文摘Over 20%of mortality during acute liver failure is associated with the development of hepatic encephalopathy(HE).Thus,HE is a complication of acute liver failure with a broad spectrum of neuropsychiatric abnormalities ranging from subclinical alterations to coma.HE is caused by the diversion of portal blood into systemic circulation through portosystemic collateral vessels.Thus,the brain is exposed to intestinal-derived toxic substances.Moreover,the strategies to prevent advancement and improve the prognosis of such a liver-brain disease rely on intestinal microbial modulation.This is supported by the findings that antibiotics such as rifaximin and laxative lactulose can alleviate hepatic cirrhosis and/or prevent HE.Together,the significance of the gut-liver-brain axis in human health warrants attention.This review paper focuses on the roles of bacteria metabolites,mainly ammonia and bile acids(BAs)as well as BA receptors in HE.The literature search conducted for this review included searches for phrases such as BA receptors,BAs,ammonia,farnesoid X receptor(FXR),G protein-coupled bile acid receptor 1(GPBAR1 or TGR5),sphingosine-1-phosphate receptor 2(S1PR2),and cirrhosis in conjunction with the phrase hepatic encephalopathy and portosystemic encephalopathy.PubMed,as well as Google Scholar,was the search engines used to find relevant publications.
基金financially supported by the Research Program Funds of Jilin University(Nos.419080500665 and 451170301076)
文摘High sensitive immunoassay platforms have gained intense attention due to their vital roles in early-stage disease diagnosis and therapeutic information feedback. Although random covalent-binding of antibody has been widely adopted in immunoassays due to its simplicity and effectiveness, it readily loses its activity and fails to exhibit high antigen-binding capacity. In this work, copolymer of zwitterionic sulfobetaine methacrylate（SBMA） and glycidyl methacrylate（GMA） brushes were immobilized onto inert polypropylene（PP） via surface-initiated atom transfer radical polymerization（ATRP） based on biomimetic dopamine pretreatment. Subsequently, boronic acid（BA） groups were covalently bonded via active GMA units, followed by the introduction of oriented immobilization of antibody. Owing to the oriented immobilization of antibody facilitated by BA groups in polymer brush, the bioactivity of antibody is well preserved, which endows the surface with significantly enhanced antigen-binding capacity. Moreover, the existence of SBMA segments in polymer brushes renders the surface high resistance to nonspecific protein adsorption, significantly alleviating the signal interference of antigen recognition. This strategy could find potential applications in developing high sensitive immunoassay platforms based on the different substrates.
基金financially supported by the National Natural Science Foundation of China (No.20972190)the Academic Leadership of ‘Qing Lan’ Project of Jiangsu Department of Education
文摘Thirteen novel NO-releasing derivatives of betulinic acid （BA） bearing two types of NO-donors （nitrates and furoxans） were synthesized and evaluated for their antitumor activity. The results showed that furoxan-based derivatives exhibited higher antitumor activity than nitrate-based derivatives, with compounds lla and llb displaying promising potency against B16 cell lines and HepG2 cell lines （IC50 〈 1 μmol/L）. We supposed that NO-releasing amount of these derivatives which can be detected by Griess method may contribute more to their antitumor activity. As a result, furoxan-based derivatives released larger amount of NO than that of nitrate-based derivatives, which partially explained the higher anti-tumor activity of the former.
