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
Bile acids are a family of atypical steroids generated at the interface of liver-intestinal microbiota acting on a ubiquitously expressed family of membrane and nuclear receptors known as bile acid activated receptors...Bile acids are a family of atypical steroids generated at the interface of liver-intestinal microbiota acting on a ubiquitously expressed family of membrane and nuclear receptors known as bile acid activated receptors.The two best characterized receptors of this family are the nuclear receptor,farnesoid X re-ceptor(FXR)and the G protein-coupled receptor,G protein-coupled bile acid receptor 1(GPBAR1).FXR and GPBAR1 regulate major aspects of lipid and glucose metabolism,energy balance,autophagy and immunity and have emerged as potential pharmaceutical targets for the treatment of metabolic and inflammatory disorders.Clinical trials in non-alcoholic fatty liver disease(NAFLD),however,have shown that selective FXR agonists cause side effects while their efficacy is partial.Because FXR and GPBAR1 exert additive effects,dual FXR/GPBAR1 ligands have been developed for the treatment of metabolic disorders and are currently advanced to clinical trials.Here,we will review the role of FXR and GPBAR1 agonism in NAFLD and how the two receptors could be exploited to target multiple components of the disease.展开更多
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.
文摘Bile acids are a family of atypical steroids generated at the interface of liver-intestinal microbiota acting on a ubiquitously expressed family of membrane and nuclear receptors known as bile acid activated receptors.The two best characterized receptors of this family are the nuclear receptor,farnesoid X re-ceptor(FXR)and the G protein-coupled receptor,G protein-coupled bile acid receptor 1(GPBAR1).FXR and GPBAR1 regulate major aspects of lipid and glucose metabolism,energy balance,autophagy and immunity and have emerged as potential pharmaceutical targets for the treatment of metabolic and inflammatory disorders.Clinical trials in non-alcoholic fatty liver disease(NAFLD),however,have shown that selective FXR agonists cause side effects while their efficacy is partial.Because FXR and GPBAR1 exert additive effects,dual FXR/GPBAR1 ligands have been developed for the treatment of metabolic disorders and are currently advanced to clinical trials.Here,we will review the role of FXR and GPBAR1 agonism in NAFLD and how the two receptors could be exploited to target multiple components of the disease.
