摘要
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
This study supported by grants funded by National Institutes of Health CA179582 and CA222490.
作者简介
Prasant Kumar Jena,These authors contributed equally to this work;Lili Sheng,These authors contributed equally to this work;corresponding author:Yui-Jui Yvonne Wan,PhD.Department of Pathology and Laboratory Medicine,University of California,Davis Health Systems,Room 3400B,Research Building III,46452nd Ave,Sacramento,CA 95817,USA.Email:yjywan@ucdavis.edu.
