An-Luo-Hua-Xian Pill Improves the Regression of Liver Fibrosis in Chronic Hepatitis B Patients Treated with Entecavir

Background and Aims:Chronic hepatitis B(CHB)can cause liver fibrosis and lead to cirrhosis and cancer.As the effectiveness of antiviral therapy to reverse liver fibrosis is limited,We aimed to evaluate the effect of An-Luo-Hua-Xian pill(ALHX)on fibrosis regression in CHB patients treated with entecavir(ETV).Methods:Treatment-naïve patients with CHB were randomly treated with ETV alone or combined with ALHX(ETV+ALHX)between October 1,2013 and December 31,2020.Demographic,laboratory,and liver histology data before and after 78 weeks of treatment were collected.The Ishak fibrosis score(F)was used and fibrosis regression required a decrease in F of≥1 after treatment.Results:A total of 780 patients were enrolled,and 394 with a second liver biopsy after treatment were included in the per-protocol population,132 in ETV group and 262 in ETV+ALHX group.After 78 weeks of treatment,the fibrosis regression rate in the ETV+ALHX group was significantly higher than that of the ETV group at baseline F≥3 patients:124/211(58.8%)vs.45/98(45.9%),p=0.035.The percentage of patients with a decreased liver stiffness measurement(LSM)was higher in the ETV+ALHX group:156/211(73.9%)vs.62/98(63.%),p=0.056.Logistic regression analysis showed that ETV combined with ALHX was associated with fibrosis regression[odds ratio(OR)=1.94,p=0.018],and a family history of hepatocellular carcinoma was on the contrary.(OR=0.41,p=0.031).Conclusions:ETV combined with ALHX increased liver fibrosis regression in CHB patients.

Efficacy and Economic Evaluation of Nonbiological Artificial Liver Therapy in Acute-on-chronic Hepatitis B Liver Failure

Background and Aims:Nonbiological artificial liver(NBAL)is frequently used as a first-line treatment for hepatitis B virus-associated acute-on-chronic liver failure(HBV-ACLF).This study aimed to compare the therapeutic efficacy and cost-effectiveness ratio(CER)of comprehensive medical treatment,plasma exchange(PE),and double plasma molecular adsorption system(DPMAS)plus half-dose PE(DPMAS+PE)in patients with HBV-ACLF.Methods:A total of 186 patients with HBV-ACLF randomly received comprehensive medical treatment,PE,or DPMAS+PE and were prospectively evaluated.Patients were divided into four subgroups based on the pretreatment prothrombin activity(PTA):Group I(PTA>40%),group II(PTA 30–40%),group III(PTA 20–30%),and group IV(PTA<20%).The main outcome measures were 28 day effectiveness;90 day liver transplantation-free survival;change of biochemical parameters;and CER.Results:DPMAS+PE treatment was associated with significantly higher 28 day effectiveness and 90 day liver transplantation-free survival compared with PE treatment in patients with group I liver failure.Clearance of serum total bilirubin(TBIL),AST,and creatinine(Cr)were significantly higher in the DPMAS+PE group than in the PE group.For subjects with group I liver failure,DPMAS+PE treatment had advantages of lower CER values and better cost-effectiveness.Conclusions:Compared with comprehensive medical treatment and PE alone,DPMAS with halfdose sequential PE treatment more effectively improved TBIL,AST,and Cr in HBV-ACLF patients,improved 28 day effectiveness and 90 day survival rates in patients with group I liver failure,and was more cost effective.DPMAS+PE is a viable NBAL approach for treatment of HBV-ACLF.

Nonalcoholic Fatty Liver Disease in Lean/Nonobese and Obese Individuals:A Comprehensive Review on Prevalence,Pathogenesis,Clinical Outcomes,and Treatment

Nonalcoholic fatty liver disease(NAFLD)is the most common liver disease worldwide,with an estimated prevalence of 25% globally.NAFLD is closely associated with metabolic syndrome,which are both becoming increasingly more common with increasing rates of insulin resistance,dyslipidemia,and hypertension.Although NAFLD is strongly associated with obesity,lean or nonobese NAFLD is a relatively new phenotype and occurs in patients without increased waist circumference and with or without visceral fat.Currently,there is limited literature comparing and illustrating the differences between lean/nonobese and obese NAFLD patients with regard to risk factors,pathophysiology,and clinical outcomes.In this review,we aim to define and further delineate different phenotypes of NAFLD and present a comprehensive review on the prevalence,incidence,risk factors,genetic predisposition,and pathophysiology.Furthermore,we discuss and compare the clinical outcomes,such as insulin resistance,dyslipidemia,hypertension,coronary artery disease,mortality,and progression to nonalcoholic steatohepatitis,among lean/nonobese and obese NAFLD patients.Finally,we summarize the most up to date current management of NAFLD,including lifestyle interventions,pharmacologic therapies,and surgical options.

Reduction in Intrahepatic cccDNA and Integration of HBV in Chronic Hepatitis B Patients with a Functional Cure

Background and Aims:Functional cure(FC)is characterized by the clearance of the hepatitis B surface antigen from the serum of patients with chronic hepatitis B(CHB).However,the level of intrahepatic covalently closed circular DNA(cccDNA)and hepatitis B virus(HBV)integration remains unclear.We conducted this study to determine them and reveal their value in the treatment of CHB.Methods:There were two sessions to elucidate the changes in intrahepatic cccDNA and HBV integration after antiviral therapy.In the first session,116 patients were enrolled and divided into FC,non-functional cure(NFC),and CHB groups,including 48 patients with functionally cured CHB,27 with CHB without functional cure after antiviral treatment,and 41 with treatment-naïve CHB.Patients were tested for both intrahepatic cccDNA and other viral markers.All patients in the FC group were followed up for at least 24 weeks to observe relapse.In the second session,another ten patients were included for in-depth whole-genome sequencing to analyze HBV integration.Results:Thirteen patients in the FC group were negative for intrahepatic cccDNA.Intrahepatic cccDNA was much higher in the CHB group compared with the FC group.Seven patients had HBsAg seroreversion,including two with virological relapse.Integration of HBV was detected in one(33.3%)functionally cured patients and in seven(100%)with CHB.28.0%of the HBV breakpoints were assigned in the 1,500 nt to 1,900 nt range of the HBV genome.Conclusions:After achieving an FC,the rate of intrahepatic cccDNA and HBV integration was significantly reduced in patients with CHB.For those patients who cleared intrahepatic cccDNA,the chances of developing virological relapse were even lower.

Guidelines for the Prevention and Treatment of Chronic Hepatitis B(version 2022)

To facilitate the achieving of the goal of“eliminating viral hepatitis as a major public health threat by 2030”set by the World Health Organization,the Chinese Society of Hepatology together with the Chinese Society of Infectious Diseases(both are branches of the Chinese Medical Association)organized a panel of experts and updated the guidelines for prevention and treatment of chronic hepatitis B in China(version 2022).With the support of available evidence,this revision of the guidelines focuses on active prevention,large scale testing,and expansion of therapeutic indication of chronic hepatitis B with the aim of reducing the hepatitis B related disease burden.

96-Week Treatment of Tenofovir Amibufenamide and Tenofovir Disoproxil Fumarate in Chronic Hepatitis B Patients

Background and Aims:Tenofovir amibufenamide(TMF)is a novel phosphoramidated prodrug of tenofovir with nonin-ferior efficacy and better bone and renal safety to tenofovir disoproxil fumarate(TDF)in 48 weeks of treatment.Here,we update 96-week comparison results.Methods:Patients with chronic hepatitis B were assigned(2:1)to receive either 25 mg TMF or 300 mg TDF with matching placebo for 96 weeks.The virological suppression was defined as HBV DNA levels<20 IU/mL at week 96.Safety was evaluated thoroughly with focusing on bone,renal,and metabolic pa-rameters.Results:Virological suppression rates at week 96 were similar between TMF and TDF group in both HBeAg-positive and HBeAg-negative populations.Noninferior efficacy was maintained in the pooled population,while it was first achieved in patients with HBV DNA≥7 or 8 log10 IU/mL at baseline.Non-indexed estimated glomerular filtration rate for renal safety assessment was adopted,while a smaller decline of which was seen in the TMF group than in the TDF group(p=0.01).For bone mineral density,patients receiv-ing TMF displayed significantly lower reduction levels in the densities of spine,hip,and femur neck at week 96 than those receiving TDF.In addition,the lipid parameters were stable after week 48 in all groups while weight change still showed the opposite trend.Conclusions:TMF maintained similar efficacy at week 96 compared with TDF with continued superior bone and renal safety profiles(NCT03903796).

An Ideal Hallmark Closest to Complete Cure of Chronic Hepatitis B Patients:High-sensitivity Quantitative HBsAg Loss

In the era of antiviral therapy,the main goal of treatment has shifted from the persistent inhibition of hepatitis B virus(HBV)replication to the pursuit of serological clearance of HBs surface antigen(HBsAg).Based on the life cycle of HBV,HBsAg originates from covalently closed circular DNA(cccDNA)and integrated HBV DNA,thus reflecting their transcriptional activity.Complete HBsAg loss may mean elimination or persistent inactivity of the HBV genome including cccDNA and integrated HBV DNA.HBsAg loss improves the recovery of abnormal immune function,which in turn,may further promote the clearance of residual viruses.Combined with functional cure and the great improvement of clinical outcomes,the continuous seroclearance of high-sensitivity quantitative HBsAg may represent the complete cure of chronic hepatitis B(CHB).For many other risk factors besides HBV itself,patients with HBsAg loss still need regular monitoring.In this review,we summarized the evolution of CHB treatment,the origin of serum HBsAg,the pattern of HBsAg seroclearance,and the effect of HBsAg loss on immune function and disease outcomes.In addition,we discuss the significance of high-sensitivity HBsAg detection and its possibility as a surrogate of complete cure.

The Gut Microbiome and Ferroptosis in MAFLD

Metabolic-associated fatty liver disease(MAFLD)is a new disease definition,and is proposed to replace the previous name,nonalcoholic fatty liver disease(NAFLD).Globally,MAFLD/NAFLD is the most common liver disease,with an incidence rate ranging from 6%to 35%in adult populations.The pathogenesis of MAFLD/NAFLD is closely related to insulin resistance(IR),and the genetic susceptibility to acquired metabolic stress-associated liver injury.Similarly,the gut microbiota in MAFLD/NAFLD is being revaluated by scientists,as the gut and liver influence each other via the gut-liver axis.Ferroptosis is a novel form of programmed cell death caused by iron-dependent lipid peroxidation.Emerging evidence suggests that ferroptosis has a key role in the pathological progression of MAFLD/NAFLD,and inhibition of ferroptosis may become a novel therapeutic strategy for the treatment of NAFLD.This review focuses on the main mechanisms behind the promotion of MAFLD/NAFLD occurrence and development by the intestinal microbiota and ferroptosis.It outlines new strategies to target the intestinal microbiota and ferroptosis to facilitate future MAFLD/NAFLD therapies.

Role of Transarterial Chemoembolization in the Treatment of Hepatocellular Carcinoma

Hepatocellular carcinoma(HCC)is one of the most common cancers worldwide.According to the Barcelona Clinic Liver Cancer(BCLC)staging system,transarterial chemoembolization(TACE)is the first-line recommendation for intermediate-stage HCC.In real-world clinical practice,TACE also plays an important role in early-and advanced-stage HCC.This review article by the experts from Chinese Liver Cancer Clinical Study Alliance(CHANCE)summarizes the available clinical evidence pertaining to the current application of TACE in patients with early-,intermediate-,and advanced-stage HCC.In addition,combination of TACE with other treatment modalities,especially immunotherapy,is reviewed.

Naringenin is a Potential Immunomodulator for Inhibiting Liver Fibrosis by Inhibiting the cGAS-STING Pathway

Background and Aims:Naringenin is an anti-inflammatory flavonoid that has been studied in chronic liver disease.The mechanism specific to its antifibrosis activity needs further investigation This study was to focused on the cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)pathway in hepatic stellate cells and clarified the antifibrosis mechanism of naringenin.Methods:The relationship between the cGAS-stimulator of interferon genes(STING)pathway and liver fibrosis was analyzed using the Gene Expression Omnibus database.Histopathology,immunohistochemistry,fluorescence staining,Western blotting and polymerase chain reaction were performed to assess gene and protein expression levels associated with the cGAS pathway in clinical liver tissue samples and mouse livers.Molecular docking was performed to evaluate the relationship between naringenin and cGAS,and western blotting was performed to study the expression of inflammatory factors downstream of cGAS in vitro.Results:Clinical database analyses showed that the cGAS-STING pathway is involved in the occurrence of chronic liver disease.Naringenin ameliorated liver injury and liver fibrosis,decreased collagen deposition and cGAS expression,and inhibited inflammation in carbon tetrachloride(CCl4)-treated mice.Molecular docking found that cGAS may be a direct target of naringenin.Consistent with the in vivo results,we verified the inhibitory effect of naringenin on activated hepatic stellate cells(HSCs).By using the cGAS-specific agonist double-stranded(ds)DNA,we showed that naringenin attenuated the activation of cGAS and its inflammatory factors affected by dsDNA.We verified that naringenin inhibited the cGAS-STING pathway,thereby reducing the secretion of inflammatory factors by HSCs to ameliorate liver fibrosis.Conclusions:Interrupting the cGAS-STING pathway helped reverse the fibrosis process.Naringenin has potential as an antihepatic fibrosis drug.

Efficacy and Safety of Yanggan Jian in Hepatitis B Virusrelated Decompensated Cirrhosis:A Randomized,Doubleblind,Controlled Trial

Background and Aims:The aim was to evaluate the efficacy and safety of Yanggan Jian(YGJ)in HBV-infected patients with decompensated cirrhosis.Methods:This randomized,double-blind controlled trial enrolled 160 patients with HBV-related decompensated cirrhosis who were already receiving or about to start antiviral therapy.Patients were randomly assigned to receive YGJ or placebo for 24 weeks,and were followed-up to 36 weeks.The primary outcome was the proportion of patients with a≥2 point reduction in Child-Turcotte-Pugh(CTP)score from baseline at week 24.Secondary outcomes were CTP class and score,serum liver function indices,mortality,incidence of hepatocellular carcinoma and variceal bleeding.Results:The proportion of patients with a CTP score reduction≥2 was significantly greater in the YGJ than in the placebo group(p=0.009);the percentage of patients with CTP class C was significantly less than that in the placebo group(p<0.05),and the YGJ group had a significantly greater mean change from baseline in CTP score at week 24(p=0.034).The improvement in measured values and change from baseline of prothrombin time,serum albumin,platelets,cholinesterase,international normalized ratio,and activated partial thromboplastin time were significantly better with YGJ than with placebo.Between-group differences in cumulative rates of variceal bleeding,hepatocellular carcinoma,death,or the frequency of any adverse event(AE),AEs related to treatment,or discontinuation because of AEs were not significant.Conclusions:YGJ significantly improved CTP scores and hepatic synthetic and reserve function in patients with HBV-related decompensated cirrhosis,and was safe and well tolerated.

RP11-40C6.2 Inactivates Hippo Signaling by Attenuating YAP1 Ubiquitylation in Hepatitis B Virus-associated Hepatocellular Carcinoma

Background and Aims:Chronic hepatitis caused by hepatitis B virus(HBV)infection is a leading cause of hepatocellular carcinoma(HCC).We investigated the roles of oncogenic HBV infection-associated long noncoding RNAs in HCC.Methods:Bioinformatics analysis of data from the Cancer Genome Atlas(TCGA)was performed to screen potential oncogenic HBV-related lncRNAs.Next,we assessed their expression in clinical samples and investigated their correlation with clinical characteristics.The detailed oncogenic effects were analyzed by performing in vitro and in vivo studies.Results:RP11-40C6.2,an HBV infection-related lncRNA,was identified by analysis of the TCGA–Liver Hepatocellular Carcinoma database.Gene Set Enrichment Analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis of differentially expressed genes revealed a strong association of RP11-40C6.2 with the Hippo signaling pathway.RP11-40C6.2 was overexpressed in HCC patients with HBV infection compared to those without HBV infection.RP11-40C6.2 transcription showed a positive association with HBV-X protein(HBx),but not HBV core protein(HBc)expression,both of which are carcinogenic proteins.Luciferase gene reporter and ChIP assays revealed that YAP1/TAZ/TEADs complex enhanced RP11-40C6.2 transcription by binding to its promoter area.RP11-40C6.2 showed oncogenic characteristics in HCC cell lines and in animal models that were mediated via activation of YAP1.In vitro ubiquitylation assay revealed that RP11-40C6.2 can promote the stabilization of YAP1 by stopping phosphorylation at its s127 residue and further stopping its degradation through binding to 14-3-3.Conclusions:RP11-40C6.2 is an HBV infection-related lncRNA that exerts its oncogenic effects by targeting the Hippo signaling pathway.

Intestinal Barrier Function in the Pathogenesis of Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease(NAFLD)is the most common chronic liver disease worldwide.The mechanisms involved in NAFLD onset are complicated and multifactorial.Recent literature has indicated that altered intestinal barrier function is related to the occurrence and progression of liver disease.The intestinal barrier is important for absorbing nutrients and electrolytes and for defending against toxins and antigens in the enteric environment.Major mechanisms by which the intestinal barrier influences the development of NAFLD involve the altered epithelial layer,decreased intracellular junction integrity,and increased intestinal barrier permeability.Increased intestinal permeability leads to luminal dysbiosis and allows the translocation of pathogenic bacteria and metabolites into the liver,inducing inflammation,immune response,and hepatocyte injury in NAFLD.Although research has been directed to NAFLD in recent decades,the pathophysiological changes in NAFLD initiation and progression are still not completely understood,and the therapeutic targets remain limited.A deeper understanding on the correlation between NAFLD pathogenesis and intestinal barrier regulation must be attained.Therefore,in this review,the components of the intestinal barrier and their respective functions and disruptions during the progression of NAFLD are discussed.

MELD or MELD-Na as a Predictive Model for Mortality Following Transjugular Intrahepatic Portosystemic Shunt Placement

Background and Aim:The model for end-stage liver disease(MELD)was originally developed to predict survival after transjugular intrahepatic portosystemic shunt(TIPS).The MELD-sodium(MELD-Na)score has replaced MELD for organ allocation for liver transplantation.However,there are limited studies to compare the MELD with MELD-Na to predict mortality after TIPS.Methods:We performed a retrospective chart review of patients who underwent TIPS placement between 2006 and 2016 at our institution.The primary outcome was mortality,and the secondary outcomes sought to assess which variables could provide prognostic information for mortality after TIPS placement.We performed receiver operating characteristic(ROC)curve analysis to assess the performance of MELD and MELD-Na.Results:There were 186 eligible patients in the analysis.The mean pre-TIPS MELD and MELD-Na were 13 and 15,respectively.Overall,mortality after TIPS was 15%at 30 days and 16.7%at 90 days.In a comparison of the areas under the ROCs for MELD and MELD-Na,MELD was superior to MELD-Na for 30-day(0.762 vs.0.709)and 90-day(0.780 vs.0.730)mortality after TIPS.The optimal cutoff score for 30-day mortality was 15(0.676–0.848)for MELD and 17(0.610–0.808)for MELD-Na,whereas the optimal cutoff score for 90-day mortality was 16(95%CI:0.705–0.855)for MELD and 17(95%CI:0.643–0.817)for MELDNa.There were 24 patients with high MELD-Na≥17,but with low MELD<15,and 90-day mortality in this group was 8.3%.Conclusions:Although MELD-Na is a superior prognostic tool to MELD for predicting overall mortality in cirrhotic patients,MELD tended to outperform MELD-Na to predict mortality after TIPS.

Characteristics of Drug-induced Liver Injury in Chronic Liver Disease:Results from the Thai Association for the Study of the Liver(THASL)DILI Registry

Background and Aims:The impact of drug-induced liver injury(DILI)on patients with chronic liver disease(CLD)is unclear.There are few reports comparing DILI in CLD and non-CLD patients.In this study,we aimed to determine the incidence and outcomes of DILI in patients with and without CLD.Methods:We collected data on eligible individuals with suspected DILI between 2018 and 2020 who were evaluated systematically for other etiologies,causes,and the severity of DILI.We compared the causative agents,clinical features,and outcomes of DILI among subjects with and without CLD who were enrolled in the Thai Association for the Study of the Liver DILI registry.Subjects with definite,or highly likely DILI were included in the analysis.Results:A total of 200 subjects diagnosed with DILI were found in the registry.Of those,41 had CLD and 159 had no evidence of CLD in their background.Complementary and alternative medicine(CAM)products were identified as the most common class of DILI agents.Approximately 59%of DILI in the CLD and 40%in non-CLD group were associated with CAM use.Individuals with pre-existing CLD had similar severity including mortality.Twelve patients(6%)developed adverse outcomes related to DILI including seven(3.5%)deaths and five(2.5%)with liver failure.Mortality was 4.88%in CLD and 3.14%in non-CLD subjects over median periods of 58(8–106)days and 22(1–65)days,respectively.Conclusions:In this liver disease registry,the causes,clinical presentation,and outcomes of DILI in subjects with CLD and without CLD patients were not different.Further study is required to confirm our findings.

Assessing Donor Liver Quality and Restoring Graft Function in the Era of Extended Criteria Donors

Liver transplantation(LT)is the final treatment option for patients with end-stage liver disease.The increasing donor shortage results in the wide usage of grafts from extended criteria donors across the world.Using such grafts is associated with the elevated incidences of post-transplant complications including initial nonfunction and ischemic biliary tract diseases,which significantly reduce recipient survival.Although several clinical factors have been demonstrated to impact donor liver quality,accurate,comprehensive,and effective assessment systems to guide decision-making for organ usage,restoration or discard are lacking.In addition,the development of biochemical technologies and bioinformatic analysis in recent years helps us better understand graft injury during the perioperative period and find potential ways to restore graft function.Moreover,such advances reveal the molecular profiles of grafts or perfusate that are susceptible to poor graft function and provide insight into finding novel biomarkers for graft quality assessment.Focusing on donors and grafts,we updated potential biomarkers in donor blood,liver tissue,or perfusates that predict graft quality following LT,and summarized strategies for restoring graft function in the era of extended criteria donors.In this review,we also discuss the advantages and drawbacks of these potential biomarkers and offer suggestions for future research.

New Algorithm Rules Out Acute-on-chronic Liver Failure Development within 28 Days from Acute Decompensation of Cirrhosis

Background and Aims:Approximately 10%of patients with acute decompensated(AD)cirrhosis develop acute-on-chronic liver failure(ACLF)within 28 days.Such cases have high mortality and are difficult to predict.Therefore,we aimed to establish and validate an algorithm to identify these patients on hospitalization.Methods:Hospitalized patients with AD who developed ACLF within 28 days were considered pre-ACLF.Organ dysfunction was defined accord-ing to the chronic liver failure-sequential organ failure as-sessment(CLIF-SOFA)criteria,and proven bacterial infec-tion was taken to indicate immune system dysfunction.A retrospective multicenter cohort and prospective one were used to derive and to validate the potential algorithm,re-spectively.A miss rate of<5%was acceptable for the calcu-lating algorithm to rule out pre-ACLF.Results:In the deri-vation cohort(n=673),46 patients developed ACLF within 28 days.Serum total bilirubin,creatinine,international normalized ratio,and present proven bacterial infection at admission were associated with the development of ACLF.AD patients with≥2 organ dysfunctions had a higher risk for pre-ACLF patients[odds ratio=16.58195%confidence interval:(4.271-64.363),p<0.001].In the derivation co-hort,67.5%of patients(454/673)had≤1 organ dysfunction and two patients(0.4%)were pre-ACLF,with a miss rate of 4.3%(missed/total,2/46).In the validation cohort,65.9%of patients(914/1388)had≤1 organ dysfunction,and four(0.3%)of them were pre-ACLF,with a miss rate of 3.4%(missed/total,4/117).Conclusions:AD patients with≤1 organ dysfunction had a significantly lower risk of developing ACLF within 28 days of admission and could be safely ruled out with a pre-ACLF miss rate of<5%.

Akkermansia muciniphila and Bifidobacterium bifidum Prevent NAFLD by Regulating FXR Expression and Gut Microbiota

Background and aims:Non-alcoholic fatty liver disease(NAFLD)is closely associated with gut microbiota and has become the most common chronic liver disease worldwide,but the relationship between specific strains and NAFLD has not been fully elucidated.We aimed to investigate whether Akkermansia muciniphila and Bifidobacterium bifidum could prevent NAFLD,the effects of their action alone or in combination,possible mechanisms,and modulation of the gut microbiota.Methods:Mice were fed with high-fat diets(HFD)for 20 weeks,in which experimental groups were pretreated with quadruple antibiotics and then given the corresponding bacterial solution or PBS.The expression of the glycolipid metabolism indicators,liver,and intestinal farnesol X receptors(FXR),and intestinal mucosal tight junction proteins were detected.We also analyzed the alterations of inflammatory and immune status and the gut microbiota of mice.Results:Both strains were able to attenuate mass gain(p<0.001),insulin resistance(p<0.001),and liver lipid deposition(p<0.001).They also reduced the levels of the pro-inflammatory factors(p<0.05)and the proportion of Th17(p<0.001),while elevating the proportion of Treg(p<0.01).Both strains activated hepatic FXR while suppressing intestinal FXR(p<0.05),and elevating tight junction protein expression(p<0.05).We also perceived changes in the gut microbiota and found both strains were able to synergize beneficial microbiota to function.Conclusions:Administration of A.muciniphila or B.bifidum alone or in combination was protective against HFD-induced NAFLD formation and could be used as alternative treatment strategy for NAFLD after further exploration.

Impact of Helicobacter pylori Infection on the Pathogenesis and Management of Nonalcoholic Fatty Liver Disease

Helicobacter pylori(H.pylori)infection is widely prevalent worldwide.H.pylori infection has been reported to be a risk factor for the development of insulin resistance,nonalco-holic fatty liver disease(NAFLD),nonalcoholic steatohepatitis(NASH),liver fibrosis,and cirrhosis.Because treatment for NAFLD,other than weight loss is limited,the treatment for H.pylori infection is well established.It is important to determine whether screening and treatment for H.pylori infection should be considered in patients with no gastrointestinal symptoms.The aim of this mini-review is to evaluate the association be-tween H.pylori infection and NAFLD including epidemiology,pathogenesis,and the evidence for H.pylori infection as a modifiable risk factor for preventing or treating NAFLD.

Combination Therapies for Advanced Biliary Tract Cancer

Biliary tract cancers(BTCs)are a group of malignant neoplasms that have recently increased in incidence and have a poor prognosis.Surgery is the only curative therapy.However,most patients are only indicated for palliative therapy because of advanced-stage disease at diagnosis and rapid progression.The current first-line treatment for advanced BTC is gemcitabine and cisplatin chemotherapy.Nonetheless,many patients develop resistance to this regimen.Over the years,few chemotherapy regimens have managed to improve the overall survival of patients.Accordingly,novel therapies such as targeted therapy have been introduced to treat this patient population.Extensive research on tumorigenesis and the genetic profiling of BTC have revealed the heterogenicity and potential target pathways,such as EGFR,VEGF,MEK/ERK,PI3K and mTOR.Moreover,mutational analysis has documented the presence of IDH1,FGFR2,HER2,PRKACA,PRKACB,BRAF,and KRAS gene aberrations.The emergence of immunotherapy in recent years has expanded the treatment landscape for this group of malignancies.Cancer vaccines,adoptive cell transfer,and immune checkpoint inhibitors have been extensively investigated in trials of BTC.Therefore,patient stratification and a combination of various therapies have become a reasonable and important clinical strategy to improve patient outcomes.This review elaborates the literature on combined treatment strategies for advanced BTC from the past few years and ongoing clinical trials to provide new inspiration for the treatment of advanced BTC.