Clinical, experimental and pathophysiological effects of Yaq-001: a non-absorbable, gut-restricted adsorbent in models and patients with cirrhosis.

OBJECTIVE: Targeting bacterial translocation in cirrhosis is limited to antibiotics with risk of antimicrobial resistance. This study explored the therapeutic potential of a non-absorbable, gut-restricted, engineered carbon bead adsorbent, Yaq-001 in models of cirrhosis and acute-on-chronic liver failure (ACLF) and, its safety and tolerability in a clinical trial in cirrhosis. DESIGN: Performance of Yaq-001 was evaluated in vitro. Two-rat models of cirrhosis and ACLF, (4 weeks, bile duct ligation with or without lipopolysaccharide), receiving Yaq-001 for 2 weeks; and two-mouse models of cirrhosis (6-week and 12-week carbon tetrachloride (CCl4)) receiving Yaq-001 for 6 weeks were studied. Organ and immune function, gut permeability, transcriptomics, microbiome composition and metabolomics were analysed. The effect of faecal water on gut permeability from animal models was evaluated on intestinal organoids. A multicentre, double-blind, randomised, placebo-controlled clinical trial in 28 patients with cirrhosis, administered 4 gr/day Yaq-001 for 3 months was performed. RESULTS: Yaq-001 exhibited rapid adsorption kinetics for endotoxin. In vivo, Yaq-001 reduced liver injury, progression of fibrosis, portal hypertension, renal dysfunction and mortality of ACLF animals significantly. Significant impact on severity of endotoxaemia, hyperammonaemia, liver cell death, systemic inflammation and organ transcriptomics with variable modulation of inflammation, cell death and senescence in the liver, kidneys, brain and colon was observed. Yaq-001 reduced gut permeability in the organoids and impacted positively on the microbiome composition and metabolism. Yaq-001 regulated as a device met its primary endpoint of safety and tolerability in the clinical trial. CONCLUSIONS: This study provides strong preclinical rationale and safety in patients with cirrhosis to allow clinical translation. TRIAL REGISTRATION NUMBER: NCT03202498.

Endoscopic procedures in hepatology: Current trends and new developments.

Gastrointestinal endoscopy has long been a reliable backbone in the diagnosis and management of hepatobilary disorders and their complications. However, with evolving non-invasive testing, personalised medicine has reframed the utility and necessity of endoscopic screening. Conversely, the growing interest and use of endoscopic ultrasound (EUS) and advanced endoscopy within gastrointestinal units has also opened novel diagnostic and therapeutic avenues for patients with various hepatobiliary diseases. The integration of "advanced endoscopy" within the practice of hepatology is nowadays referred to as "endo-hepatology". In essence, endo-hepatology consists of two pillars: one focusing primarily on disorders of the liver parenchyma, vascular disorders, and portal hypertension, which is mainly captured via EUS, while the other targets the hepatobiliary tract via endoscopic retrograde cholangiopancreatography and advanced imaging. Applications under the umbrella of endo-hepatology include, amongst others, EUS-guided liver biopsy, EUS-guided portal pressure gradient measurement, coil and glue embolisation of gastric varices as well as cholangioscopy. As such endo-hepatology could become an attractive concept wherein advanced endoscopy might reinforce the medical management of patients with hepatobiliary disorders and their complications after initial basic work-up. In this review, we discuss current trends and future developments within endo-hepatology and the remaining hurdles to overcome.

Antegrade balloon dilatation of the duodenal papilla during laparoscopic cholecystectomy versus endoscopic retrograde cholangiography in patients with acute choledocholithiasis: a case control matched study.

INTRODUCTION: In acute obstructive common bile duct (CBD) stones endoscopic retrograde cholangiography for CBD stone removal before cholecystectomy (ChE) ('ERC-first') is the gold standard of treatment. Intraoperative antegrade balloon dilatation of the duodenal papilla during ChE with flushing of CBD stones to the duodenum ('ABD-during-ChE') may be an alternative 'one-stop-shop' treatment option. However, a comparison of outcomes of the 'ABD-during-ChE' technique and the'ERC-first' approach has never been performed. METHODS: Retrospective case control matched study of patients suffering from obstructive CBD stones (< 8 mm) without severe pancreatitis or cholangitis that underwent the traditional 'ERC-first' approach versus the 'ABD-during-ChE' technique. Primary endpoint was the overall Comprehensive Complication Index (CCI®) from diagnosis to complete CBD stone removal and performed ChE. RESULTS: A total of 70 patients were included (35 patients each in the 'ERC first'- and 'ABD-during-ChE'-group). There were no statistical significant differences in terms of demographics and disease specific characteristics between the two study groups. However, there was a not significant difference towards an increased overall CCI® in the 'ERC-first' group versus the 'ABD-during-ChE' group (14.4 ± 15.4 versus 9.8 ± 11.1, p = 0.225). Of note, six major complications (Clavien-Dindo classification ≥ IIIa) occurred in the 'ERC-first' group versus two in the 'ABD-during-ChE' group (17% versus 6%, p = 0.136). In addition, significantly more interventions and a longer overall time from diagnosis to complete clearance of bile ducts and performed ChE was found, when comparing the 'ERC-first' group and the 'ABD-during-ChE' group (3.7 ± 0.8 versus 1.1 ± 0.4, p < 0.001; 160.5 ± 228.6 days versus 12.0 ± 18.0 days, p < 0.001). CONCLUSION: In patients suffering from acute obstructive CBD stones smaller than 8 mm, compared to the 'ERC-first' approach, the 'ABD-during-ChE' technique resulted in significantly less interventions and reduced overall treatment time from diagnosis to complete clearance of bile ducts and performed ChE. This comes together with a strong trend of less intervention related complications in the 'ABD-during-ChE' group.

Soluble CD137 is a novel serum marker of liver cirrhosis in patients with hepatitis C and alcohol-associated disease etiology.

Defective T-cell functions play a role in the persistence of HCV infection. Activated T cells express CD137, which costimulates antivirus T-cell responses, and this activity is antagonized by soluble CD137 (sCD137). Here, we show that in sera of 81 patients with chronic HCV, sCD137 levels did not correlate with measures of viral infection, and did not decline after virus eradication using direct-acting antivirals. Thus, serum sCD137 was similar in patients infected with HCV and in uninfected controls. Of note, in HCV patients with liver cirrhosis and patients with mostly alcohol-associated liver cirrhosis, sCD137 was increased. A negative association of sCD137 and albumin existed in both cohorts. sCD137 concentrations were similar in hepatic and portal vein blood excluding the liver as the origin of higher levels. Recombinant sCD137 reduced Th1 and Th2 but not Th17 cell polarization in vitro, and accordingly lowered IFN-γ, TNF, and IL-13 in cell media. Serum sCD137 is associated with inflammatory states, and positively correlated with serum TNF in cirrhotic HCV patients following virus eradication. Our study argues against a role of sCD137 in HCV infection and suggests a function of sCD137 in liver cirrhosis, which yet has to be defined.

Predictors and management of post-banding ulcer bleeding in cirrhosis: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Post-banding ulcer bleeding (PBUB) is an understudied complication of oesophageal varices endoscopic band ligation (EBL). This systematic review with meta-analysis aimed at: (a) evaluating the incidence of PBUB in patients with cirrhosis treated with EBL in primary or secondary prophylaxis or urgent treatment for acute variceal bleeding and (b) identifying predictors of PBUB. METHODS: We conducted a systematic review of articles in English published in 2006-2022 using the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Searches were made in eight databases including Embase, PubMed and Cochrane Library. Random-effects meta-analysis was used to determine the incidence, mean interval and predictors of PBUB. RESULTS: Eighteen studies (9034 patients) were included. The incidence of PBUB was 5.5% (95% CI 4.3-7.1). The mean time for it to occur was 11 days (95% CI 9.94-11.97). Model for End-stage Liver Disease (MELD) score (OR 1.162, 95% CI 1.047-1.291) and EBL done in emergency setting (OR 4.902, 95% CI 2.99-8.05) independently predicted post-ligation ulcer bleeding. Treatment included drugs, endoscopic procedures and transjugular intrahepatic portosystemic shunt. Refractory bleeding was treated with self-expandable metallic stents or balloon tamponade. Mortality was on average 22.3% (95% CI 14.1-33.6). CONCLUSIONS: Patients with high MELD score and receiving EBL in an emergency setting are more prone to develop PBUB. Prognosis is still poor and the best therapeutic strategy to address remains to be ascertained.

Hepatocyte expressed chemerin-156 does not protect from experimental non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is a rapidly growing liver disease. The chemoattractant chemerin is abundant in hepatocytes, and hepatocyte expressed prochemerin protected from NASH. Prochemerin is inactive and different active isoforms have been described. Here, the effect of hepatocyte expressed muChem-156, a highly active murine chemerin isoform, was studied in the methionine-choline deficient dietary model of NASH. Mice overexpressing muChem-156 had higher hepatic chemerin protein. Serum chemerin levels and the capability of serum to activate the chemerin receptors was unchanged showing that the liver did not release active chemerin. Notably, activation of the chemerin receptors by hepatic vein blood did not increase in parallel to total chemerin protein in patients with liver cirrhosis. In experimental NASH, muChem-156 had no effect on liver lipids. Accordingly, overexpression of active chemerin in hepatocytes or treatment of hepatocytes with recombinant chemerin did not affect cellular triglyceride and cholesterol levels. Importantly, overexpression of muChem-156 in the murine liver did not change the hepatic expression of inflammatory and profibrotic genes. The downstream targets of chemerin such as p38 kinase were neither activated in the liver of muChem-156 producing mice nor in HepG2, Huh7 and Hepa1-6 cells overexpressing this isoform. Recombinant chemerin had no effect on global gene expression of primary human hepatocytes and hepatic stellate cells within 24 h of incubation. Phosphorylation of p38 kinase was, however, increased upon short-time incubation of HepG2 cells with chemerin. These findings show that muChem-156 overexpression in hepatocytes does not protect from liver steatosis and inflammation.

Determination of bile acids from human gallbladder by 1 H-MRS-Protocol optimization and estimation of reproducibility.

Bile exerts multiple functions in the liver and gut and is involved in multiple disease processes. It is secreted continuously from the liver and stored in the gallbladder until needed, and closely reflects the available bile acid pool. The study objective was therefore to develop a reliable MRS protocol and to assess variability of bile acid determination in human gallbladder. MRS measurements were performed on a 3 T MR scanner with 20 subjects to optimize protocols (26 measurements) and conduct a prospective reproducibility study (18 measurements). Measurements were carried out with subjects lying in either supine (23 scans) or prone positions (21 scans) to compare results from the two positions. For reproducibility determination, six of the 20 volunteers (three males, three females, age = 34.9 ± 10.9 years, BMI = 23.4 ± 2.1 kg/m2 ) were measured three times: back to back to assess technical variability and once again after three weeks to assess total variability, including additional physiological variability. A single voxel was measured in the gallbladder with respiratory triggering. For quantification, apparent T2 times were determined and a non-water-suppressed spectrum was acquired. Total bile acids, glycine and taurine conjugated bile acids, and lipids including choline-containing phospholipids were determined. Higher quality and reliability of gallbladder spectra were obtained with subjects measured in prone compared with supine position. All measurements of the reproducibility sub-study were of sufficient quality to be included in the analysis. Average coefficients of variation within subjects for the main compounds were 37% for total variation (including physiological and technical variation) and 24% for technical variation alone. These values were much smaller than those between subjects, which were >54% for both back-to-back and three weeks separated measurements. These results suggest diagnostic applicability of the method, especially for longitudinal studies aiming at non-invasive characterization of bile composition in humans with various diseases and/or interventional maneuvers.

Evaluating key characteristics of ideal colorectal cancer screening modalities: the microsimulation approach.

BACKGROUND AND AIMS: Screening for colorectal cancer (CRC) can effectively reduce CRC incidence and mortality. Besides colonoscopy, tests for the detection of biomarkers in stool, blood, or serum, including the fecal immunochemical test (FIT), ColoGuard, Epi proColon, and PolypDx, have recently been advanced. We aimed to identify the characteristics of theoretic, highly efficient screening tests and calculated the effectiveness and cost effectiveness of available screening tests. METHODS: Using the microsimulation-based colon modeling open-source tool (CMOST), we simulated 142,501 theoretic screening tests with variable assumptions for adenoma and carcinoma sensitivity, specificity, test frequency, and adherence, and we identified highly efficient tests outperforming colonoscopy. For available screening tests, we simulated 10 replicates of a virtual population of 2 million individuals, using epidemiologic characteristics and costs assumptions of the United States. RESULTS: Highly efficient theoretic screening tests were characterized by high sensitivity for advanced adenoma and carcinoma and high patient adherence. All simulated available screening tests were effective at 100% adherence to screening and at expected real-world adherence rates. All tests were cost effective below the threshold of 100,000 U.S. dollars per life year gained. With perfect adherence, FIT was the most effective and cost-efficient intervention, whereas Epi proColon was the most effective at expected real-world adherence rates. In our sensitivity analysis, assumptions for patient adherence had the strongest impact on effectiveness of screening. CONCLUSIONS: Our microsimulation study identified characteristics of highly efficient theoretic screening tests and confirmed the effectiveness and cost-effectiveness of colonoscopy and available urine-, blood-, and stool-based tests. Better patient adherence results in superior effectiveness for CRC prevention in the whole population.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) levels are not associated with severity of liver disease and are inversely related to cholesterol in a cohort of thirty eight patients with liver cirrhosis.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is of particular importance in cholesterol metabolism with high levels contributing to hypercholesterolemia. Cholesterol and sphingolipids are low in patients with liver cirrhosis. Purpose of this study was to find associations of plasma PCSK9 with circulating cholesterol and sphingolipid species and measures of liver disease severity in patients with liver cirrhosis. METHODS: PCSK9 protein levels were determined by ELISA in systemic vein (SVP), hepatic vein (HVP) and portal vein plasma of patients with mostly alcoholic liver cirrhosis. PCSK9 and LDL-receptor protein expression were analysed in cirrhotic and non-cirrhotic liver tissues. RESULTS: Serum PCSK9 was reduced in patients with liver cirrhosis in comparison to non-cirrhotic patients. In liver cirrhosis, plasma PCSK9 was not correlated with Child-Pugh score, Model for End-Stage Liver Disease score, bilirubin or aminotransferases. A negative association of SVP PCSK9 with albumin existed. PCSK9 protein in the liver did not change with fibrosis stage and was even positively correlated with LDL-receptor protein levels. Ascites volume and variceal size were not related to PCSK9 levels. Along the same line, transjugular intrahepatic shunt to lower portal pressure did not affect PCSK9 concentrations in the three blood compartments. Serum cholesterol, sphingomyelin and ceramide levels did not correlate with PCSK9. Stratifying patients by high versus low PCSK9 levels using the median as cut-off, several cholesteryl ester species were even low in the subgroup with high PCSK9 levels. A few sphingomyelin species were also reduced in the patients with PCSK9 levels above the median. PCSK9 is highly expressed in the liver but systemic, portal and hepatic vein levels were similar. PCSK9 was not correlated with the inflammatory proteins C-reactive protein, IL-6, galectin-3, resistin or pentraxin 3. Of note, HVP PCSK9 was positively associated with HVP chemerin and negatively with HVP adiponectin levels. CONCLUSIONS: In the cohort of patients with liver cirrhosis mostly secondary to alcohol consumption high PCSK9 was associated with low levels of certain cholesteryl ester and sphingomyelin species. Positive correlations of PCSK9 and LDL-receptor protein in the liver of patients with chronic liver injury are consistent with these findings.

Paneth cells promote angiogenesis and regulate portal hypertension in response to microbial signals.

BACKGROUND & AIMS: Paneth cells (PCs) synthesize and secrete antimicrobial peptides that are key mediators of host-microbe interactions, establishing a balance between intestinal microflora and enteric pathogens. We observed that their number increases in experimental portal hypertension and aimed to investigate the mechanisms by which these cells can contribute to the regulation of portal pressure. METHODS: We first treated Math1Lox/LoxVilcreERT2 mice with tamoxifen to induce the complete depletion of intestinal PCs. Subsequently, we performed partial portal vein or bile duct ligation. We then studied the effects of these interventions on hemodynamic parameters, proliferation of blood vessels and the expression of genes regulating angiogenesis. Intestinal organoids were cultured and exposed to different microbial products to study the composition of their secreted products (by proteomics) and their effects on the proliferation and tube formation of endothelial cells (ECs). In vivo confocal laser endomicroscopy was used to confirm the findings on blood vessel proliferation. RESULTS: Portal hypertension was significantly attenuated in PC-depleted mice compared to control mice and was associated with a decrease in portosystemic shunts. Depletion of PCs also resulted in a significantly decreased density of blood vessels in the intestinal wall and mesentery. Furthermore, we observed reduced expression of intestinal genes regulating angiogenesis in Paneth cell depleted mice using arrays and next generation sequencing. Tube formation and wound healing responses were significantly decreased in ECs treated with conditioned media from PC-depleted intestinal organoids exposed to intestinal microbiota-derived products. Proteomic analysis of conditioned media in the presence of PCs revealed an increase in factors regulating angiogenesis and additional metabolic processes. In vivo endomicroscopy showed decreased vascular proliferation in the absence of PCs. CONCLUSIONS: These results suggest that in response to intestinal flora and microbiota-derived factors, PCs secrete not only antimicrobial peptides, but also pro-angiogenic signaling molecules, thereby promoting intestinal and mesenteric angiogenesis and regulating portal hypertension. LAY SUMMARY: Paneth cells are present in the lining of the small intestine. They prevent the passage of bacteria from the intestine into the blood circulation by secreting substances to fight bacteria. In this paper, we discovered that these substances not only act against bacteria, but also increase the quantity of blood vessels in the intestine and blood pressure in the portal vein. This is important, because high blood pressure in the portal vein may result in several complications which could be targeted with novel approaches.

Isoproterenol Disrupts Intestinal Barriers Activating Gut-Liver-Axis: Effects on Intestinal Mucus and Vascular Barrier as Entry Sites.

BACKGROUND: The gut-liver-axis presents the pathophysiological hallmark for multiple liver diseases and has been proposed to be modulated during stress and shock. Access to the gut-liver-axis needs crossing of the mucus and gut-vascular barrier. The role of ß-adrenoreceptor-activation for both barriers has not been defined and is characterized here. METHODS: Splanchnic ß-adrenergic stimulation was achieved by chronic intraperitoneal application of isoproterenol via alzet-pump in vivo. The intestinal permeability and gut-vascular barrier function was assessed in ileal loop experiments. The extravasation of predefined sizes of fluorescence isothiocyanate (FITC)-dextran molecules in ileal microcirculation was evaluated by intravital confocal laser endomicroscopy in vivo. Mucus parameters thickness, goblet cell count and mucin-expression were assessed by stereomicroscopy, immunostaining and RNA-sequencing respectively. Ileal lamina propria (LP) as well as mesenteric lymph node mononuclear cells was assessed by FACS. RESULTS: Healthy mice lack translocation of 4 kDa-FITC-dextran from the small intestine to the liver, whereas isoproterenol-treated mice demonstrate pathological translocation (PBT). Mucus layer is reduced in thickness with loss of goblet-cells and mucin-2-staining and -expression in isoproterenol-treated animals under standardized gnotobiotic conditions. Isoproterenol disrupts the gut vascular barrier displaying Ileal extravasation of large-sized 70- and 150 kDa-FITC-dextran. This pathological endothelial permeability and accessibility induced by isoproterenol associates with an augmented expression of plasmalemmal-vesicle-associated-protein-1 in intestinal vessel. Ileal LP after isoproterenol treatment contains more CD11c+-dendritic cells (DC) with increased appearance of CCR7+ DC in mesenteric lymph nodes. CONCLUSIONS: Isoproterenol impairs the intestinal muco-epithelial and endothelial-vascular barrier promoting PBT to the liver. This barrier dysfunction on multiple levels potentially can contribute to liver injury induced by catecholamines during states of increased ß-adrenergic drive.

Tailored access to the hepatobiliary system in post-bariatric patients: a tertiary care bariatric center experience.

BACKGROUND: In bariatric surgery patients, pancreaticobiliary access via endoscopic retrograde cholangiopancreatography (ERCP) is technically challenging and the optimal approach for the evaluation and treatment of biliary tree-related pathologies has been debated. Besides laparoscopy-assisted ERCP (LA-ERCP) as standard of care, EUS-directed transgastric ERCP (EDGE) and hepaticogastrostomy (HGS) with placement of a fully covered metal stent have emerged as novel techniques. The objective of this study was to evaluate safety and efficacy of three different endoscopic approaches (LA-ERCP, EDGE, and HGS) in bariatric patients. METHODS: In this retrospective review, consecutive patients with Roux-en-Y gastric bypass (RYGB) and Sleeve Gastrectomy (SG) who underwent from 2013 to 2019 a LA-ERCP, an EDGE, or a HGS at a tertiary care reference center for bariatric surgery were analyzed. Patient demographics, type of procedure and indication, data regarding cannulation and therapeutic intervention of the common bile duct (procedure success), and clinical outcomes were analyzed. RESULTS: A total of 19 patients were included. Indications for LA-ERCP, EDGE, or HGS were mostly choledocholithiasis (78.9%) and in a few cases papillitis stenosans. Eight patients (57.1%) with LA-ERCP underwent concomitant cholecystectomy. Procedure success was achieved in 100%. Adverse events (AEs) were identified in 15.7% of patients (all ERCP related). All AEs were rated as moderate and there were no serious AEs. CONCLUSION: This case series indicates that ERCP via a transgastric approach (LA-ERCP, EDGE, or HGS) is a minimally invasive, effective, and feasible method to access the biliary tree in bariatric patients. These techniques offer an appealing alternative treatment option compared to percutaneous transhepatic cholangiography and drainage- or deep enteroscopy-assisted ERCP. In bariatric patients who earlier had a cholecystectomy, EUS-guided techniques were the preferred treatment options for biliary pathologies.

[H. pylori-associated gastritis: diagnostic, treatment and surveillance]. / H. pylori-assoziierte Gastritis: Diagnostik, Therapie und Nachsorge.

H. pylori-associated gastritis: diagnostic, treatment and surveillance Abstract. Helicobacter pylori infections are limited to the stomach and represent globally the infectious disease with the highest prevalence. H. pylori infection causes in almost 100 % a chronic gastritis and is the main cause of relevant diseases such as atrophic gastritis, peptic ulcer disease and gastric cancer (class I carcinogen according to WHO). Accordingly, a H. pylori associated gastritis signifies a high-impact health economic disease, leading to significant morbidity and mortality. This review summarizes key points regarding diagnosis, treatment and follow-up.

Microbiota-driven gut vascular barrier disruption is a prerequisite for non-alcoholic steatohepatitis development.

BACKGROUND & AIMS: Fatty liver disease, including non-alcoholic fatty liver (NAFLD) and steatohepatitis (NASH), has been associated with increased intestinal barrier permeability and translocation of bacteria or bacterial products into the blood circulation. In this study, we aimed to unravel the role of both intestinal barrier integrity and microbiota in NAFLD/NASH development. METHODS: C57BL/6J mice were fed with high-fat diet (HFD) or methionine-choline-deficient diet for 1 week or longer to recapitulate aspects of NASH (steatosis, inflammation, insulin resistance). Genetic and pharmacological strategies were then used to modulate intestinal barrier integrity. RESULTS: We show that disruption of the intestinal epithelial barrier and gut vascular barrier (GVB) are early events in NASH pathogenesis. Mice fed HFD for only 1 week undergo a diet-induced dysbiosis that drives GVB damage and bacterial translocation into the liver. Fecal microbiota transplantation from HFD-fed mice into specific pathogen-free recipients induces GVB damage and epididymal adipose tissue enlargement. GVB disruption depends on interference with the WNT/ß-catenin signaling pathway, as shown by genetic intervention driving ß-catenin activation only in endothelial cells, preventing GVB disruption and NASH development. The bile acid analogue and farnesoid X receptor agonist obeticholic acid (OCA) drives ß-catenin activation in endothelial cells. Accordingly, pharmacologic intervention with OCA protects against GVB disruption, both as a preventive and therapeutic agent. Importantly, we found upregulation of the GVB leakage marker in the colon of patients with NASH. CONCLUSIONS: We have identified a new player in NASH development, the GVB, whose damage leads to bacteria or bacterial product translocation into the blood circulation. Treatment aimed at restoring ß-catenin activation in endothelial cells, such as administration of OCA, protects against GVB damage and NASH development. LAY SUMMARY: The incidence of fatty liver disease is reaching epidemic levels in the USA, with more than 30% of adults having NAFLD (non-alcoholic fatty liver disease), which can progress to more severe non-alcoholic steatohepatitis (NASH). Herein, we show that disruption of the intestinal epithelial barrier and gut vascular barrier are early events in the development of NASH. We show that the drug obeticholic acid protects against barrier disruption and thereby prevents the development of NASH, providing further evidence for its use in the prevention or treatment of NASH.

FXR modulates the gut-vascular barrier by regulating the entry sites for bacterial translocation in experimental cirrhosis.

BACKGROUND & AIMS: Pathological bacterial translocation (PBT) in cirrhosis is the hallmark of spontaneous bacterial infections, increasing mortality several-fold. Increased intestinal permeability is known to contribute to PBT in cirrhosis, although the role of the mucus layer has not been addressed in detail. A clear route of translocation for luminal intestinal bacteria is yet to be defined, but we hypothesize that the recently described gut-vascular barrier (GVB) is impaired in experimental portal hypertension, leading to increased accessibility of the vascular compartment for translocating bacteria. MATERIALS: Cirrhosis was induced in mouse models using bile-duct ligation (BDL) and CCl4. Pre-hepatic portal-hypertension was induced by partial portal vein ligation (PPVL). Intestinal permeability was compared in these mice after GFP-Escherichia coli or different sized FITC-dextrans were injected into the intestine. RESULTS: Healthy and pre-hepatic portal-hypertensive (PPVL) mice lack translocation of FITC-dextran and GFP-E. coli from the small intestine to the liver, whereas BDL and CCl4-induced cirrhotic mice demonstrate pathological translocation, which is not altered by prior thoracic-duct ligation. The mucus layer is reduced in thickness, with loss of goblet cells and Muc2-staining and expression in cirrhotic but not PPVL mice. These changes are associated with bacterial overgrowth in the inner mucus layer and pathological translocation of GFP-E. coli through the ileal epithelium. GVB is profoundly altered in BDL and CCl4-mice with Ileal extravasation of large-sized 150 kDa-FITC-dextran, but only slightly altered in PPVL mice. This pathological endothelial permeability and accessibility in cirrhotic mice is associated with augmented expression of PV1 in intestinal vessels. OCA but not fexaramine stabilizes the GVB, whereas both FXR-agonists ameliorate gut to liver translocation of GFP-E. coli. CONCLUSIONS: Cirrhosis, but not portal hypertension per se, grossly impairs the endothelial and muco-epithelial barriers, promoting PBT to the portal-venous circulation. Both barriers appear to be FXR-modulated, with FXR-agonists reducing PBT via the portal-venous route. LAY SUMMARY: For intestinal bacteria to enter the systemic circulation, they must cross the mucus and epithelial layer, as well as the gut-vascular barrier. Cirrhosis disrupts all 3 of these barriers, giving bacteria access to the portal-venous circulation and thus, the gut-liver axis. Diminished luminal bile acid availability, cirrhosis and the associated reduction in farnesoid x receptor (FXR) signaling seem, at least partly, to mediate these changes, as FXR-agonists reduce bacterial translocation via the portal-venous route to the liver in cirrhosis.

Multidrug-resistant bacterial infections in patients with decompensated cirrhosis and with acute-on-chronic liver failure in Europe.

BACKGROUND & AIMS: Antibiotic resistance has been increasingly reported in patients with decompensated cirrhosis in single-center studies. Prospective investigations reporting broad epidemiological data are scarce. We aimed to analyze epidemiological changes in bacterial infections in patients with decompensated cirrhosis. METHODS: This was a prospective evaluation of 2 series of patients hospitalized with decompensated cirrhosis. The Canonic series included 1,146 patients from Northern, Southern and Western Europe in 2011. Data on epidemiology, clinical characteristics of bacterial infections, microbiology and empirical antibiotic schedules were assessed. A second series of 883 patients from Eastern, Southern and Western Europe was investigated between 2017-2018. RESULTS: A total of 455 patients developed 520 infections (39.7%) in the first series, with spontaneous bacterial peritonitis, urinary tract infections and pneumonia the most frequent infections. Nosocomial episodes predominated in this series. Nearly half of the infections were culture-positive, of which 29.2% were caused by multidrug-resistant organisms (MDROs). MDR strains were more frequently isolated in Northern and Western Europe. Extended-spectrum beta-lactamase-producing Enterobacteriaceae were the most frequent MDROs isolated in this series, although prevalence and type differed markedly among countries and centers. Antibiotic resistance was associated with poor prognosis and failure of antibiotic strategies, based on third-generation cephalosporins or quinolones. Nosocomial infection (odds ratio [OR] 2.74; p < 0.001), intensive care unit admission (OR 2.09; p = 0.02), and recent hospitalization (OR 1.93; p = 0.04) were identified as independent predictors of MDR infection. The prevalence of MDROs in the second series (392 infections/284 patients) was 23%; 38% in culture-positive infections. A mild increase in the rate of carbapenem-resistant Enterobacteriaceae was observed in this series. CONCLUSIONS: MDR bacterial infections constitute a prevalent, growing and complex healthcare problem in patients with decompensated cirrhosis and acute-on-chronic liver failure across Europe, negatively impacting on prognosis. Strategies aimed at preventing the spread of antibiotic resistance in cirrhosis should be urgently evaluated. LAY SUMMARY: Infections caused by bacteria resistant to the main antibiotic families are prevalent in patients with cirrhosis. This study demonstrates that this healthcare problem is increasing and extends through all European regions. Infections caused by these difficult to treat bacteria resolve less frequently and often cause the death of the patient. The type of resistant bacteria varies markedly among different hospitals.

Over-the-Scope Clips Are More Effective Than Standard Endoscopic Therapy for Patients With Recurrent Bleeding of Peptic Ulcers.

BACKGROUND & AIMS: Endoscopic hemostasis is effective in treatment of bleeding peptic ulcers. However, rebleeding is difficult to treat and associated with substantial morbidity and mortality. We performed a prospective randomized trial to determine whether over-the-scope clips (OTSCs) are more effective than standard treatment of severe recurrent upper gastrointestinal bleeding. METHODS: We performed our study at 9 academic referral centers (in Germany, Switzerland, and Hong Kong) from March 2013 through September 2016. Adult patients with recurrent peptic ulcer bleeding following initially successful hemostasis (66 patients in the intent-to-treat analysis) were randomly assigned to groups (1:1) that underwent hemostasis with either OTSC or standard therapy. Standard therapy was defined as hemostasis with through-the-scope clips (TTSC, n = 31) or thermal therapy plus injection with diluted adrenaline (n = 2). The primary endpoint was further bleeding (a composite endpoint of a persistent bleeding despite endoscopic therapy according to the protocol or recurrent bleeding within 7 days after successful hemostasis). Patients with further bleeding were allowed to cross over to OTSC therapy. Main secondary endpoints were mortality, necessity of surgical or angiographic salvage therapy, duration of stay in the hospital or intensive care, number of blood units transfused, and complications associated with endoscopic therapy. RESULTS: Persistent bleeding after per-protocol hemostasis was observed in 14 patients (42.4%) in the standard therapy group and 2 patients (6.0%) in the OTSC group (P = .001). Recurrent bleeding within 7 days occurred in 5 patients (16.1%) in the standard therapy group vs 3 patients (9.1%) in the OTSC group (P = .468). Further bleeding occurred in 19 patients (57.6%) in the standard therapy group and in 5 patients (15.2%) in the OTSC group (absolute difference 42.4%; 95% confidence interval 21.6-63.2; P = .001) Within 30 days of follow-up, 1 patient in the standard therapy group (3.0%) and 1 patient in the OTSC group (3.0%) required surgical therapy (P = .999). Within 30 days of the procedure, 2 patients died in the standard therapy group (6.3%) and 4 patients died in the OTSC group (12.1%) (P = .672). There were no significant differences in the other secondary endpoints. CONCLUSIONS: In prospective randomized trial, we found endoscopic treatment with OTSCs to be superior to standard therapy with TTSCs for patients with recurrent peptic ulcer bleeding. STING Study, Clinicaltrials.gov no: NCT1836900.

[Updated S2k-Guideline "Complications of liver cirrhosis". German Society of Gastroenterology (DGVS)]. / Aktualisierte S2k-Leitlinie der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) "Komplikationen der Leberzirrhose".

This guideline provides evidence-based key recommendations for diagnosis and therapy of complications of liver cirrhosis and upgrades the 2011 version. An interdisciplinary team of medical experts and patient support groups developed the guideline following the AWMF recommendations for evidence based consensus guidelines. New chapters concerning diagnosis and therapy of hepatic encephalopathy were added.

Bacterial and fungal infections in acute-on-chronic liver failure: prevalence, characteristics and impact on prognosis.

Bacterial infection is a frequent trigger of acute-on-chronic liver failure (ACLF), syndrome that could also increase the risk of infection. This investigation evaluated prevalence and characteristics of bacterial and fungal infections causing and complicating ACLF, predictors of follow-up bacterial infections and impact of bacterial infections on survival. PATIENTS: 407 patients with ACLF and 235 patients with acute decompensation (AD). RESULTS: 152 patients (37%) presented bacterial infections at ACLF diagnosis; 46%(n=117) of the remaining 255 patients with ACLF developed bacterial infections during follow-up (4 weeks). The corresponding figures in patients with AD were 25% and 18% (p<0.001). Severe infections (spontaneous bacterial peritonitis, pneumonia, severe sepsis/shock, nosocomial infections and infections caused by multiresistant organisms) were more prevalent in patients with ACLF. Patients with ACLF and bacterial infections (either at diagnosis or during follow-up) showed higher grade of systemic inflammation at diagnosis of the syndrome, worse clinical course (ACLF 2-3 at final assessment: 47% vs 26%; p<0.001) and lower 90-day probability of survival (49% vs 72.5%;p<0.001) than patients with ACLF without infection. Bacterial infections were independently associated with mortality in patients with ACLF-1 and ACLF-2. Fungal infections developed in 9 patients with ACLF (2%) and in none with AD, occurred mainly after ACLF diagnosis (78%) and had high 90-day mortality (71%). CONCLUSION: Bacterial infections are extremely frequent in ACLF. They are severe and associated with intense systemic inflammation, poor clinical course and high mortality. Patients with ACLF are highly predisposed to develop bacterial infections within a short follow-up period and could benefit from prophylactic strategies.