Mac-2-Binding Protein Glycosylation Isomer to Albumin Ratio Predicts Bacterial Infections in Cirrhotic Patients.

INTRODUCTION: Mac-2-binding protein glycosylation isomer (M2BPGi) is a novel biomarker for liver fibrosis, but little is known about its role in cirrhosis-associated clinical outcomes. This study aimed to investigate the predictive role of M2BPGi in cirrhosis-associated complications. METHODS: One hundred and forty-nine cirrhotic patients were retrospectively enrolled. Patients were followed up for 1 year, and cirrhosis-associated clinical events were recorded. Receiver operating characteristic curve (ROC) analysis was used to establish the values of the predictive models for cirrhotic outcomes, and Cox proportional hazards regression models were used to identify predictors of clinical outcomes. RESULTS: Sixty (40.3%) patients experienced cirrhosis-associated clinical events and had higher M2BPGi levels compared to those without events (8.7 vs. 5.1 cutoff index, p < 0.001). The most common cirrhosis-associated complications were bacterial infections (24.2%). On ROC analysis, M2BPGi to albumin ratio (M2BPGi/albumin) had comparable discriminant abilities for all cirrhosis-associated events (area under the ROC curve [AUC] = 0.74) compared with M2BPGi, Child-Pugh, model for end-stage liver disease, albumin-bilirubin scores, and neutrophil-to-lymphocyte ratio and was superior to M2BPGi alone for all bacterial infectious events (AUC = 0.80). Cox regression analysis revealed that the M2BPGi/albumin, but not M2BPGi alone, independently predicted all cirrhosis-associated events (hazard ratio [HR] = 1.34, p = 0.038) and all bacterial infectious events (HR = 1.51, p = 0.011) within 1 year. However, M2BPGi/albumin did not predict other cirrhotic complications and transplant-free survival. DISCUSSION/CONCLUSION: M2BPGi/albumin might serve as a potential prognostic indicator for patients with cirrhosis, particularly for predicting bacterial infections.

(Pro)renin receptor inhibition attenuated liver steatosis, inflammation, and fibrosis in mice with steatohepatitis.

The (Pro)renin receptor (PRR) is reportedly involved in hepatic lipid metabolism and hepatocyte PRR knockdown protects mice against hepatosteatosis. However, the impact of PRR inhibition on liver inflammation and fibrosis in nonalcoholic steatohepatitis (NASH) remains unclear. Herein, C57BL/6 mice were fed a normal chow diet or fast food diet (FFD) for 24 weeks. Lentivirus-mediated PRR short hairpin RNA (shRNA) or handle region peptide (HRP), a PRR blocker, was administered for PRR inhibition. Mouse primary hepatocytes were cultured with palmitic acid, prorenin, siRNA-targeted PRR, and HRP. In FFD-fed mice, PRR inhibition via lentivirus-mediated PRR knockdown or HRP significantly attenuated liver steatosis, inflammation, and fibrosis. Mechanistically, PRR knockdown or HRP decreased hepatic acetyl-CoA carboxylase (ACC) abundance and upregulated peroxisome proliferator-activated receptor-alpha (PPARα). HRP treatment also decreased hepatic PRR expression. In addition, intrahepatic oxidative stress, apoptosis and inflammatory cell recruitment were ameliorated by PRR knockdown or HRP treatment, along with suppression of proinflammatory cytokine expression. PRR inhibition downregulated the hepatic expression of profibrotic factors, as well as TGF-ß1/SMAD3 pathway. In primary mouse hepatocytes, PRR knockdown with siRNA or HRP downregulated cellular ACC and increased PPARα expression. In conclusion, our findings revealed that PRR inhibition attenuated hepatic steatosis, inflammation, and fibrosis in mice with NASH. Accordingly, targeting PRR signaling may serve as a potential treatment for NASH.

High carriage rate of extended-spectrum ß-lactamase Enterobacterales and diarrheagenic Escherichia coli in healthy donor screening for fecal microbiota transplantation.

The safety of fecal microbiota transplantation (FMT) has been highlighted by extended-spectrum ß-lactamase (ESBL)-producing Escherichia coli bacteremia transmitted from donors and acquisition of diarrheagenic E. coli (Shiga toxin-producing E. coli (STEC) and enteropathogenic E. coli (EPEC)) via FMT. The use of donor screening criteria to lower the risk of pathogen transmission via FMT is essential. This study aimed to demonstrate the outcomes of our strict donor screening program. This study was conducted at our FMT center between January 2019 and June 2022. Our donor screening program included an initial questionnaire and subsequent blood and stool testing. We further used selective culture for third-generation cephalosporin-resistant (3GCR) Enterobacterales and multiplex PCR to detect diarrheagenic E. coli in stools. The resistance mechanisms and sequence type of 3GCR Enterobacterales were determined. A total of 742 individuals were assessed, and 583 participants (78.6%) were excluded after questionnaire. Of the remaining 159 participants undergoing stool and blood tests, 37 participants were finally qualified (5.0%, 37/742). A high fecal carriage rate of ESBL-producing Enterobacterales (35.2%, 56/159), including E. coli (n=53) and Klebsiella pneumoniae (n=5), and diarrheagenic E. coli (31.4%, 50/159), including EPEC (n=41), enteroaggregative E. coli (n=11), enterotoxigenic E. coli (n=4), and STEC (n=1), was noted. CTX-M-79 and CTX-M-15 were dominant in E. coli and K. pneumoniae, respectively. The sequence types of the ESBL-producing strains were diverse. The screening for 3GCR Enterobacterales and diarrheagenic E. coli in stool is necessary. Our findings also support the effectiveness of multiplex PCR panels in FMT donor screening programs.

Alteration of gut microbial composition associated with the therapeutic efficacy of fecal microbiota transplantation in Clostridium difficile infection.

BACKGROUND/PURPOSE: Clostridium difficile infection (CDI) leads to a significant cause of hospital-acquired morbidity and mortality. Fecal microbiota transplantation (FMT) is effective to treat recurrent or refractory CDI (rCDI). However, the change of microbial composition contributed by FMT and its association with treatment outcomes is not well determined in Taiwan. We aimed to investigate the efficacy of FMT and the association with microbial alteration endemically. METHODS: Twelve patients who received FMT for rCDI in Taipei Veterans General Hospital were prospectively enrolled from April 2019 to July 2020. The clinical assessments and fecal microbial analyses in comparison with fecal materials of unrelated donors were conducted before and after FMT. RESULTS: The overall success rate of FMT for rCDI was 91.7%. A prominence of Proteobacteria, Gammaproteobacteria and Enterobacteriales were observed in the feces of patients with rCDI. Increased fecal phylogenetic diversities and a significant microbial dissimilarity were provided by successful FMT compared to patients before treatment. However, the distinctness was not obvious between patients' feces at baseline and after unsuccessful FMT. Moreover, dynamic change of fecal microbial composition after FMT was observed during follow-up but did not interrupt the treatment effects of FMT. CONCLUSION: Gut dysbiosis commonly co-exists in patients with rCDI. Restoration of gut microbial communities by FMT provides a promising strategy to treat antibiotic-failed CDI, and the extent of microbial change would be related to the treatment outcomes of FMT. Besides, the effectiveness of FMT for CDI could be maintained even the gut microbiota has diverged over time.

Virological and immunological predictors of long term outcomes of peginterferon alfa-2a therapy for HBeAg-negative chronic hepatitis B.

BACKGROUND/PURPOSE: Predictors of long-term outcomes of peginterferon (PegIFN) therapy for patients with chronic hepatitis B (CHB) remain to be explored. This study aimed to evaluate the predictive value of virological and immunological biomarkers and outcomes of PegIFN for CHB. METHODS: 57 HBeAg-negative CHB patients receiving 48 weeks of PegIFN therapy were prospectively followed for a median period of 5.3 years after the end of treatment (EOT). Serum CXCL9 and IP-10 levels were measured. Flow cytometry analysis for T cell subsets was performed in 23 patients. Factors associated with long-term outcomes were analyzed. RESULTS: The cumulative incidences of virological relapse, clinical relapse and HBsAg loss at year 7 were 18.1%, 0%, 31.6%, respectively, in patients with sustained off-treatment virological response (SVR), and 100%, 67.4%, 6.7%, respectively, in patients without SVR. By multivariate analysis, baseline CXCL9 > 80 pg/mL (hazard ratio (HR) = 0.418, p = 0.018) and on-treatment HBsAg declines were associated with a lower risk of virological relapse. Non-SVR was the only predictor of clinical relapse. CXCL9 >200 pg/mL (HR = 8.154, p = 0.038) and HBsAg <750 IU/mL (HR = 10.507, p = 0.036) were baseline predictors of HBsAg loss, while HBsAg decline >1 log at EOT (HR = 23.296, p = 0.005) was the on-treatment predictor of HBsAg loss. In subgroup patients with available PBMC, populations of T cell subsets correlated with virological and clinical relapses in univariate analysis. CONCLUSION: Baseline serum CXCL9 and HBsAg levels could predict HBsAg loss after PegIFN therapy for HBeAg-negative CHB. Combining virological and immunological biomarkers could predict long-term outcomes of PegIFN therapy for HBeAg-negative CHB.

Obeticholic acid ameliorates hepatorenal syndrome in ascitic cirrhotic rats by down-regulating the renal 8-iso-PGF2α-activated COX-TXA2 pathway.

BACKGROUNDS/AIMS: The present study explores the potential of chronic treatment with the Foresaid X receptor (FXR) agonist obeticholic acid (OCA), which inhibits oxidative stress-related pathogenesis, in ascitic cirrhotic rats with hepatorenal syndrome (HRS) developed 6 weeks after bile duct ligation (BDL). METHODS: Systemic, splanchnic, and renal hemodynamics and pathogenic cascades were measured in ascitic BDL and sham rats receiving 2-weeks of either vehicle or OCA treatments (sham-OCA and BDL-OCA groups), and NRK-52E cells, rat kidney tubular epithelial cells. RESULTS: Chronic OCA treatment significantly normalized portal hypertension, glomerular filtration rate, urine output, renal blood flow; decreased ascites, renal vascular resistance, serum creatinine, and the release of renal tubular damage markers, including urinary neutrophil gelatinase-associated lipocalin (uNGAL) and kidney injury moleculae-1 (uKim-1) in BDL-OCA rats. In the BDL group, inhibition of the renal oxidative stress (8-iso-PGF2α)-activated cyclooxygenase-thromboxane A2 [COX-TXA2] pathway, apoptosis, and tubular injury accompanied by a decrease in hyper-responsiveness to the vasoconstrictor 8-iso-PGF2α in perfused kidneys. In vitro experiments revealed that 8-iso-PGF2α induced oxidative stress, release of reactive oxygen species, and cell apoptosis, which were reversed by concomitant incubation with the FXR agonist. CONCLUSIONS: Through the inhibition of renal 8-iso-PGF2α production and the down-regulation of the COX-TXA2 pathway, our study suggests that chronic OCA treatment can ameliorate the HRS in ascitic cirrhotic rats. Thus, OCA is an agent with antioxidative stress, antivasoconstrictive, antiapoptotic properties which benefit ascitic, cirrhotic rats with systemic, hepatic, and renal abnormalities.

Outcomes of enteral metallic stent in patients with pancreatic carcinoma and gastric outlet obstruction: A single center experience.

BACKGROUND: Duodenal obstruction is uncommon in patients with pancreatic cancer. However, the obstruction rate is increasing as a result of advancements in chemotherapy and target therapy. This study aimed to investigate the effect of self-expandable metal stent placement on outcomes of patients with duodenal obstruction secondary to pancreatic carcinoma. METHODS: Twenty-nine consecutive inoperable patients with pancreatic cancer and gastric outlet obstruction who received metallic stent placement in our hospital between September 2009 and October 2017 were enrolled for analysis. RESULTS: Fifteen male patients and 14 female patients receiving stent placement with a median age of 68 years (range, 50-85 years) were included. The technical and clinical success rates of the procedure were 100% and 89.7%, respectively. The Gastric Outlet Obstruction Scoring System scores were significantly improved at day 1 (1.14 ± 0.51) and days 7 (2.21 ± 0.9) after the implantation compared to those prior to the procedure (0.38 ± 0.49) (p < 0.001). Aspiration pneumonia and bleeding developed in 1 patient (3.4%) after the procedure. Stent dysfunction developed in 6 of 29 patients (20.6%). The median stent patency time was 109 days (range, 10-314 days). The median survival time was 114 days (range, 15-323 days). Post-stent chemotherapy predicted better survival (hazard ratio: 0.2, 95% confidence interval: 0.08-0.51, p = 0.001). CONCLUSION: Metallic stent placement is an effective treatment for patients with inoperable pancreatic cancer leading to gastric outlet obstruction. Chemotherapy may be considered following stent placement.

Taiwanese consensus recommendations for acute pancreatitis.

The incidence of acute pancreatitis and related health care utilization are increasing. Acute pancreatitis may result in organ failure and various local complications with risks of morbidity and even mortality. Recent advances in research have provided novel insights into the assessment and management for acute pancreatitis. This consensus is developed by Taiwan Pancreas Society to provide an updated, evidence-based framework for managing acute pancreatitis.

Human relaxin-2 attenuates hepatic steatosis and fibrosis in mice with non-alcoholic fatty liver disease.

Human relaxin-2 reduces hepatic fibrosis in mice. However, the effects of relaxin-2 on hepatic steatosis and fibrosis in animals with non-alcoholic fatty liver disease (NAFLD) remain to be elucidated. C57BL/6 mice fed a high-fat diet (HFD) or methionine-choline-deficient (MCD) diet were randomly assigned to receive recombinant human relaxin-2 (25 or 75 µg/kg/day) or vehicle for 4 weeks. In HFD-fed mice, relaxin-2 decreased systemic insulin resistance and reduced body weight, epididymal fat mass and serum leptin and insulin concentrations. In livers of HFD-fed mice, relaxin-2 attenuated steatosis and increased phosphorylation of insulin receptor substrate-1, Akt and endothelial nitric oxide synthase (eNOS), and activated genes that regulate fatty acid oxidation and suppressed acetyl-CoA carboxylase. Relaxin-2 had no direct anti-steatotic effect on primary mouse hepatocytes, but S-nitroso-N-acetylpenicillamine attenuated palmitic acid-induced steatosis and activated genes regulating fatty acid oxidation in hepatocytes. In mice fed an MCD diet, relaxin-2 attenuated steatosis, inflammation and fibrosis. Relaxin-2 increased eNOS and Akt phosphorylation and transcript levels of cytochrome P450-4a10 and decreased acetyl-CoA carboxylase in MCD-fed mouse livers. Moreover, expression levels of Kupffer cell activation, hepatic stellate cell activation and hepatocyte apoptosis were decreased in MCD diet-fed mice receiving relaxin-2. In conclusion, relaxin-2 reduces hepatic steatosis by activating intrahepatic eNOS in HFD-fed mice and further attenuates liver fibrosis in MCD diet-fed mice. Therefore, human relaxin-2 is a potential therapeutic treatment for NAFLD.

Intestinal iNKT cells migrate to liver and contribute to hepatocyte apoptosis during alcoholic liver disease.

We investigated the migration of intestinal immune cells to the liver and their contribution to alcoholic liver disease. In mice fed ethanol, we found that an increased number of invariant natural killer T (iNKT) cells, which respond to the antigen presented by CD1d, migrated from mesenteric lymph nodes to the liver. iNKT cells react to lipid antigens, so we studied their activities in mice with intestinal epithelial cell-specific deletion of Pparg (PpargΔIEC) as a model for altering intestinal lipidomic profiles. Levels of CD1d increased in intestines of ethanol-fed PpargΔIEC mice, and in cell-tracking experiments, more iNKT cells migrated to the liver, compared with mice without disruption of Pparg. Livers of PpargΔIEC mice had increased markers of apoptosis and liver injury after ethanol feeding. iNKT cells isolated from livers of ethanol-fed PpargΔIEC mice induced apoptosis of cultured hepatocytes. An inhibitor of iNKT cells reduced ethanol-induced liver injury in PpargΔIEC mice. Duodenal tissues from patients with alcohol-use disorder have been found to have increased levels of CD1d compared with tissues from patients without alcohol overuse. Ethanol use, therefore, activates iNKT cells in the intestine to migrate to liver, where they-along with the resident hepatic iNKT cells-contribute to hepatocyte death and injury. NEW & NOTEWORTHY In this article, we studied migration of intestinal immune cells into the liver in response to ethanol-induced liver disease. We found that chronic ethanol feeding induces expression of CD1d by enterocytes, which activate invariant natural killer T (iNKT) cells in mesenteric lymph nodes; activation is further increased with loss of peroxisome proliferator-activated receptor gamma gene and altered lipid profiles. The activated iNKT cells migrate into the liver, where they promote hepatocyte apoptosis. Patients with alcohol use disorder have increased expression of CD1d in the small intestine. Strategies to block these processes might be developed to treat alcoholic liver disease.

Beneficial Effects of the Peroxisome Proliferator-Activated Receptor α/γ Agonist Aleglitazar on Progressive Hepatic and Splanchnic Abnormalities in Cirrhotic Rats with Portal Hypertension.

Recent studies have reported that peroxisome proliferator-activated receptor α (PPARα) agonist decreases intrahepatic resistance, whereas PPARγ agonist reduces portosystemic shunts (PSSs) and splanchnic angiogenesis in cirrhotic rats. The present study investigated the effects of a 21-day treatment with the dual PPARα/γ agonist aleglitazar (Ale) on progressive abnormalities in bile-duct-ligated and thioacetamide-induced cirrhotic rats with portal hypertension (PH). In vivo and in vitro effects were evaluated. Chronic Ale treatment significantly up-regulated PPARα/PPARγ receptors and down-regulated tumor necrosis factor-α (TNF-α) and NF-κB expression in the liver, splanchnic tissues, collateral vessels, and intestines of cirrhotic rats with PH. Notably, Ale improved PH by the suppression of systemic/tissue inflammation, hepatic fibrosis, hepatic Rho-kinase-mediated endothelin-1 hyperresponsiveness, intrahepatic/mesenteric angiogenesis, vascular endothelial growth factor expression, PSS, intestinal mucosal injury, and hyperpermeability in cirrhotic rats. Acute Ale treatment inhibited TNF-α-enhanced endothelin-1-induced contraction of primary hepatic stellate cells, vascular endothelial growth factor-induced migration/angiogenesis of liver sinusoidal endothelial cells, and TNF-α-induced disruption of Caco-2 cell monolayer-epithelial barrier. The present study suggested that Ale can potentially treat relevant abnormalities through the inhibition of inflammatory, vasoconstrictive, angiogenic, and mucosal-disrupted pathogenic markers in cirrhosis. Overall, chronic Ale treatment ameliorated PH syndrome by the suppression of hepatic fibrogenesis, neoangiogenesis, vasoconstrictor hyperresponsiveness, splanchnic vasodilatation, and PSS; and decreased intestinal mucosal injury and hyperpermeability in cirrhotic rats.

Dabigatran Reduces Liver Fibrosis in Thioacetamide-Injured Rats.

BACKGROUND: Liver fibrosis can progress to cirrhosis, hepatocellular carcinoma, or liver failure. Unfortunately, the antifibrotic agents are limited. Thrombin activates hepatic stellate cells (HSCs). Therefore, we investigated the effects of a direct thrombin inhibitor, dabigatran, on liver fibrosis. METHODS: Adult male Sprague-Dawley rats were injected intraperitoneally with thioacetamide (TAA, 200 mg/kg twice per week) for 8 or 12 weeks to induce liver fibrosis. The injured rats were assigned an oral gavage of dabigatran etexilate (30 mg/kg/day) or vehicle in the last 4 weeks of TAA administration. Rats receiving an injection of normal saline and subsequent oral gavage of dabigatran etexilate or vehicle served as controls. RESULTS: In the 8-week TAA-injured rats, dabigatran ameliorated fibrosis, fibrin deposition, and phosphorylated ERK1/2 in liver, without altering the transcript expression of thrombin receptor protease-activated receptor-1. In vitro, dabigatran inhibited thrombin-induced HSC activation. Furthermore, dabigatran reduced intrahepatic angiogenesis and portal hypertension in TAA-injured rats. Similarly, in the 12-week TAA-injured rats, a 4-week treatment with dabigatran reduced liver fibrosis and portal hypertension. CONCLUSIONS: By inhibiting thrombin action, dabigatran reduced liver fibrosis and intrahepatic angiogenesis. Dabigatran may be a promising therapeutic agent for treatment of liver fibrosis.

Effects and mechanisms of caffeine to improve immunological and metabolic abnormalities in diet-induced obese rats.

In obesity, there are no effective therapies for parallel immune and metabolic abnormalities, including systemic/tissue insulin-resistance/inflammation, adiposity and hepatic steatosis. Caffeine has anti-inflammation, antihepatic steatosis, and anti-insulin resistance effects. In this study, we evaluated the effects and molecular mechanisms of 6 wk of caffeine treatment (HFD-caf) on immunological and metabolic abnormalities of high-fat diet (HFD)-induced obese rats. Compared with HFD vehicle (HFD-V) rats, in HFD-caf rats the suppressed circulating immune cell inflammatory [TNFα, MCP-1, IL-6, intercellular adhesion molecule 1 (ICAM-1), and nitrite] profiles were accompanied by decreased liver, white adipose tissue (WAT), and muscle macrophages and their intracellular cytokine levels. Metabolically, the increase in metabolic rates reduced lipid accumulation in various tissues, resulting in reduced adiposity, lower fat mass, decreased body weight, amelioration of hepatic steatosis, and improved systemic/muscle insulin resistance. Further mechanistic approaches revealed an upregulation of tissue lipogenic [(SREBP1c, fatty acid synthase, acetyl-CoA carboxylase)/insulin-sensitizing (GLUT4 and p-IRS1)] markers in HFD-caf rats. Significantly, ex vivo experiments revealed that the cytokine release by the cocultured peripheral blood mononuclear cell (monocyte) and WAT (adipocyte), which are known to stimulate macrophage migration and hepatocyte lipogenesis, were lower in HFD-V groups than HFD-caf groups. Caffeine treatment simultaneously ameliorates immune and metabolic pathogenic signals present in tissue to normalize immunolgical and metabolic abnormalities found in HFD-induced obese rats.

Serum adrenomedullin and urinary thromboxane B2 help early categorizing of acute kidney injury in decompensated cirrhotic patients: A prospective cohort study.

AIMS: Increases in the systemic vasodilator adrenomedullin and the renal vasoconstrictors thromboxane A2 in cirrhotic patients are pathogenic factors for the development of functional acute kidney injury (AKI), including pre-renal azotemia (PRA) and hepatorenal syndrome (HRS), which is associated with high mortality. This study aims to find biomarkers that can diagnose HRS at an early stage, to enable treatment as soon as possible. METHODS: Acute decompensated cirrhotic patients who had been admitted to hospital were enrolled in this prospective cohort study. Blood and urinary samples were collected immediately after admission. In addition to initially categorizing AKI cases into PRA, acute tubular necrosis (ATN), and HRS groups, their final diagnosis was adjudicated by a nephrologist and a hepatologist who checked the corrected and misclassification rates for significant biomarkers. RESULTS: The cut-off values for serum adrenomedullin and urinary thromboxane B2 (TXB2 ), when used as predictors for functional AKI (adrenomedullin >283 pg/mL, urinary TXB2 >978 [pg/mg urinary creatinine]), for HRS (adrenomedullin >428, urinary TXB2 >1604), and for good terlipressin plus albumin treatment responders (adrenomedullin >490, urinary TXB2 >1863), were observed. Patients with HRS who could be treated, due to high mortality, had significantly higher serum adrenomedullin and urinary TXB2 levels compared to HRS patients receiving standard treatment. In addition to predicting 60-day mortality, a combination of these two markers further increased diagnostic accuracy for HRS among functional AKI. CONCLUSIONS: Prompt diagnosis of HRS by differentiating it from PRA and ATN can be achieved by using serum adrenomedullin and urinary TXB2 in acute decompensated cirrhotic patients. In combination with severe clinical courses, these two markers are useful to select HRS patients who cannot be treated.

Mechanisms of the prevention and inhibition of the progression and development of non-alcoholic steatohepatitis by genetic and pharmacological decoy receptor 3 supplementation.

AIMS: Treatment of non-alcoholic steatohepatitis (NASH) is difficult due to the absence of a proven treatment and its comprehensive mechanisms. In the NASH animal model, upregulated hepatic inflammation and oxidative stress, with the resultant M1 polarization of macrophages as well as imbalanced adipocytokines, all accelerate NASH progression. As a member of the tumor necrosis factor receptor superfamily, decoy receptor 3 (DcR3) not only neutralizes the death ligands, but also performs immune modulations. In this study, we aimed to investigate the possible non-decoy effects of DcR3 on diet-induced NASH mice. METHODS: Methionine- and choline-deficient (MCD) diet feeding for 9 weeks was applied to induce NASH in BALB/c mice. Decoy receptor 3 heterozygous transgenesis or pharmacological pretreatment with DcR3a for 1 month were designed as interventions. Intrahepatic inflammatory status as well as macrophage polarization, oxidative stress, and steatosis as well as lipogenic gene expression and fibrotic status were analyzed. Additionally, acute effects of DcR3a on HepG2 cells, Hep3B cells, and primary mouse hepatocytes in various MCD medium-stimulated changes were also evaluated. RESULTS: Both DcR3 genetic and pharmacologic supplement significantly reduced MCD diet-induced hepatic M1 polarization. In addition, DcR3 supplement attenuated MCD diet-increased hepatic inflammation, oxidative stress, adipocytokine imbalance, steatosis, and fibrogenesis. Moreover, acute DcR3a incubation in HepG2 cells, Hep3B cells, and mouse hepatocytes could normalize the expression of genes related to lipid oxidation along with inflammation and oxidative stress. CONCLUSION: The ability of DcR3 to attenuate hepatic steatosis and inflammation through its non-decoy effects of immune modulation and oxidative stress attenuation makes it a potential treatment for NASH.

Acute kidney injury predicts mortality in cirrhotic patients with gastric variceal bleeding.

BACKGROUND AND AIM: The International Club of Ascites (ICA) recently proposed a new definition of acute kidney injury (AKI) in cirrhotic patients. The study evaluated the ICA-AKI criteria and their association with the prognosis of cirrhotic patients with gastric variceal bleeding (GVB). METHODS: A retrospective cohort study using prospective database of cirrhotic patients hospitalized with the first presentation of acute GVB at Taipei Veterans General Hospital from April 2007 to December 2010 was performed to evaluate the development of AKI. The study used Cox proportional hazards model to examine the association of ICA-AKI criteria and mortality. RESULTS: Of 113 patients, 46 (41%) fulfilled the ICA-AKI criteria and most (70%) initially had stage 1 AKI. Child-Pugh score, systemic blood pressure at admission, and number of blood units transfused before endoscopy were independent predictors of AKI. Among patients with AKI, 30% progressed to higher stages with more advanced liver disease, lower serum sodium, more units of blood transfusion, higher frequency of infection, and higher serum creatinine levels at diagnosis of AKI. The 6-week mortality rate was significantly higher in patients with AKI than in patients without AKI (37% vs 3%, P < 0.001), and AKI stages were independent predictors of 3-month survival (93% in patients without AKI, 73% in stage 1, and 30% in stages 2 and 3, P = 0.005). CONCLUSIONS: The occurrence of AKI as defined by the ICA criteria is common in cirrhotic patients with acute GVB. The presence of AKI was associated with much higher 6-week mortality, and the stages of AKI further predicted 3-month survival.

Metallic Stent Expansion Rate at Day One Predicts Stent Patency in Patients with Gastric Outlet Obstruction.

BACKGROUND AND AIMS: Self-expandable metallic stent insertion has been a mainstream treatment for relieving the obstructive symptoms of malignant gastric outlet obstruction (MGOO), a late-stage complication of gastrointestinal malignancies. This study aims to investigate the predictive value of stent expansion rates in clinical outcomes in patients with MGOO. METHODS: Eighty-seven patients with inoperable MGOO receiving metallic stents were reviewed retrospectively from April 2010 to December 2014. Clinical outcomes, predictors of stent patency, and survival were analyzed. RESULTS: The technical and clinical success rates were 100 and 94.3%, respectively. The median stent patency time was 114 days (range 13-570 days). The median survival time was 133 days (range 13-1145 days). Stent dysfunctions occurred in 28 patients (32.2%), with restenosis accounting for the majority (82%). The stent expansion rate ≥75% at Day 1 predicted the stent patency [hazard ratio (HR) 0.12, P = 0.04]. However, it did not correlate with survival. Non-gastric cancer origins (HR 2.41, P = 0.002) and peritoneal carcinomatosis (HR 2.54, P = 0.001) correlated with poor survival. However, post-stent chemotherapy (HR 0.55, P = 0.03) was related to better outcome. The comparison of clinical outcomes of first and second stent insertions showed no significant difference in the stent expansion rate either at Day 0 and Day 1 (P = 0.97 and P = 0.57). CONCLUSIONS: Self-expandable metallic stent insertion is a safe and effective treatment for relieving the obstructive symptoms. The stent expansion rate ≥75% at Day 1 is a novel stent-related predictor of stent patency.

Genetic Loss of Immunoglobulin A Does Not Influence Development of Alcoholic Steatohepatitis in Mice.

BACKGROUND: Chronic alcohol abuse is associated with intestinal dysbiosis and bacterial translocation. Translocated commensal bacteria contribute to alcoholic liver disease. Secretory immunoglobulin A (IgA) in the intestine binds bacteria and prevents bacterial translocation. METHODS: To investigate the functional role of IgA in ethanol (EtOH)-induced liver disease in mice, we subjected wild type (WT) and IgA-deficient littermate mice to Lieber-DeCarli models of chronic EtOH administration and the model of chronic and binge EtOH feeding (the NIAAA model). RESULTS: Chronic EtOH feeding increased systemic levels of IgA, while fecal IgA was reduced in C57BL/6 WT mice. WT and Iga-/- littermate mice showed similar liver injury, steatosis, and inflammation following 4 weeks of EtOH feeding or chronic and binge EtOH feeding. IgA deficiency did not affect intestinal absorption or hepatic metabolism of EtOH. Pretreatment with ampicillin elevated intestinal IgA in WT littermate mice. Despite increased intestinal IgA, WT littermate mice exhibited a similar degree of liver disease compared with Iga-/- mice after 7 weeks of EtOH feeding. Interestingly, bacterial translocation to mesenteric lymph nodes was increased in Iga-/- mice fed an isocaloric diet, but was the same after EtOH feeding relative to WT littermate mice. The absence of intestinal IgA was associated with increased intestinal and plasma IgM in Iga-/- mice after EtOH feeding. CONCLUSIONS: Our findings indicate that absence of IgA does not affect the development of alcoholic liver disease in mice. Loss of intestinal IgA is compensated by increased levels of intestinal IgM, which likely limits bacterial translocation after chronic EtOH administration.

Allo-transplantation of mesenchymal stem cells attenuates hepatic injury through IL1Ra dependent macrophage switch in a mouse model of liver disease.

BACKGROUND & AIMS: Autologous transplantation of mesenchymal stem cells (MSCs) reduces concanavalin A (Con A)-induced hepatic injury in mice. However, the mechanism is unclear and the therapeutic effect of allo-transplantation remains unknown. Our aim was to investigate the effects and mechanisms related to allo-transplantation of MSCs when used to treat Con A hepatic injury. METHODS: After Con A-induced liver injury was created in C57BL/6J mice, MSCs derived from BALB/c mice or a vehicle control was administered. RESULTS: Allo-transplantation of MSCs derived from BALB/c mice attenuated hepatic apoptosis in C57BL/6J mice that had undergone Con A-induced liver injury. MSCs increased the level of serum interleukin (IL)-10 and the phosphorylation of hepatic STAT3, but decreased the level of hepatic IFN-γ and phospho-STAT1. Notably, the administered MSCs were trapped mostly in the lungs and promoted the macrophage M2 switch, which contributed to the increased IL10 levels in the lungs and serum. Loss of the therapeutic effect was observed after knock-down of the expression of interleukin 1 receptor antagonist (IL1Ra) in the MSCs. In vitro investigation supported the hypothesis that MSCs are able to switch Con A-stimulated macrophages to the M2 phenotype, which results in an increase in IL10 production. CONCLUSIONS: Allo-transplantation of MSCs reduces Con A liver injury by increasing IL10 production through an IL1Ra dependent macrophage switch.

Microbiota Protects Mice Against Acute Alcohol-Induced Liver Injury.

BACKGROUND: Our aim is to investigate the physiological relevance of the intestinal microbiota in alcohol-induced liver injury. Chronic alcohol abuse is associated with intestinal bacterial overgrowth, increased intestinal permeability, and translocation of microbial products from the intestine to the portal circulation and liver. Translocated microbial products contribute to experimental alcoholic liver disease. METHODS: We subjected germ-free and conventional C57BL/6 mice to a model of acute alcohol exposure that mimics binge drinking. RESULTS: Germ-free mice showed significantly greater liver injury and inflammation after oral gavage of ethanol (EtOH) compared with conventional mice. In parallel, germ-free mice exhibited increased hepatic steatosis and up-regulated expression of genes involved in fatty acid and triglyceride synthesis compared with conventional mice after acute EtOH administration. The absence of microbiota was also associated with increased hepatic expression of EtOH-metabolizing enzymes, which led to faster EtOH elimination from the blood and lower plasma EtOH concentrations. Intestinal levels of EtOH-metabolizing genes showed regional expression differences and were overall higher in germ-free mice relative to conventional mice. CONCLUSIONS: Our findings indicate that absence of the intestinal microbiota increases hepatic EtOH metabolism and the susceptibility to binge-like alcohol drinking.