Lactobacillus lactis and Pediococcus pentosaceus-driven reprogramming of gut microbiome and metabolome ameliorates the progression of non-alcoholic fatty liver disease.

BACKGROUND: Although microbioa-based therapies have shown putative effects on the treatment of non-alcoholic fatty liver disease (NAFLD), it is not clear how microbiota-derived metabolites contribute to the prevention of NAFLD. We explored the metabolomic signature of Lactobacillus lactis and Pediococcus pentosaceus in NAFLD mice and its association in NAFLD patients. METHODS: We used Western diet-induced NAFLD mice, and L. lactis and P. pentosaceus were administered to animals in the drinking water at a concentration of 109 CFU/g for 8 weeks. NAFLD severity was determined based on liver/body weight, pathology and biochemistry markers. Caecal samples were collected for the metagenomics by 16S rRNA sequencing. Metabolite profiles were obtained from caecum, liver and serum. Human stool samples (healthy control [n = 22] and NAFLD patients [n = 23]) were collected to investigate clinical reproducibility for microbiota-derived metabolites signature and metabolomics biomarker. RESULTS: L. lactis and P. pentosaceus supplementation effectively normalized weight ratio, NAFLD activity score, biochemical markers, cytokines and gut-tight junction. While faecal microbiota varied according to the different treatments, key metabolic features including short chain fatty acids (SCFAs), bile acids (BAs) and tryptophan metabolites were analogously restored by both probiotic supplementations. The protective effects of indole compounds were validated with in vitro and in vivo models, including anti-inflammatory effects. The metabolomic signatures were replicated in NAFLD patients, accompanied by the comparable levels of Firmicutes/Bacteroidetes ratio, which was significantly higher (4.3) compared with control (0.6). Besides, the consequent biomarker panel with six stool metabolites (indole, BAs, and SCFAs) showed 0.922 (area under the curve) in the diagnosis of NAFLD. CONCLUSIONS: NAFLD progression was robustly associated with metabolic dys-regulations in the SCFAs, bile acid and indole compounds, and NAFLD can be accurately diagnosed using the metabolites. L. lactis and P. pentosaceus ameliorate NAFLD progression by modulating gut metagenomic and metabolic environment, particularly tryptophan pathway, of the gut-liver axis.

Effect of Korean Red Ginseng on metabolic syndrome.

Metabolic syndrome (MS) refers to a clustering of at least three of the following medical conditions: high blood pressure, abdominal obesity, hyperglycemia, low high-density lipoprotein level, and high serum triglycerides. MS is related to a wide range of diseases which includes obesity, diabetes, insulin resistance, cardiovascular disease, dyslipidemia, or non-alcoholic fatty liver disease. There remains an ongoing need for improved treatment strategies for MS. The most important risk factors are dietary pattern, genetics, old age, lack of exercise, disrupted biology, medication usage, and excessive alcohol consumption, but pathophysiology of MS has not been completely identified. Korean Red Ginseng (KRG) refers to steamed/dried ginseng, traditionally associated with beneficial effects such as anti-inflammation, anti-fatigue, anti-obesity, anti-oxidant, and anti-cancer effects. KRG has been often used in traditional medicine to treat multiple metabolic conditions. This paper summarizes the effects of KRG in MS and related diseases such as obesity, cardiovascular disease, insulin resistance, diabetes, dyslipidemia, or non-alcoholic fatty liver disease based on experimental research and clinical studies.

Lactobacillus attenuates progression of nonalcoholic fatty liver disease by lowering cholesterol and steatosis.

BACKGROUND/AIMS: Nonalcoholic fatty liver disease (NAFLD) is closely related to gut-microbiome. There is a paucity of research on which strains of gut microbiota affect the progression of NAFLD. This study explored the NAFLD-associated microbiome in humans and the role of Lactobacillus in the progression of NAFLD in mice. METHODS: The gut microbiome was analyzed via next-generation sequencing in healthy people (n=37) and NAFLD patients with elevated liver enzymes (n=57). Six-week-old male C57BL/6J mice were separated into six groups (n=10 per group; normal, Western, and four Western diet + strains [109 colony-forming units/g for 8 weeks; L. acidophilus, L. fermentum, L. paracasei, and L. plantarum]). Liver/body weight ratio, liver pathology, serum analysis, and metagenomics in the mice were examined. RESULTS: Compared to healthy subjects (1.6±4.3), NAFLD patients showed an elevated Firmicutes/Bacteroidetes ratio (25.0±29.0) and a reduced composition of Akkermansia and L. murinus (P<0.05). In the animal experiment, L. acidophilus group was associated with a significant reduction in liver/body weight ratio (5.5±0.4) compared to the Western group (6.2±0.6) (P<0.05). L. acidophilus (41.0±8.6), L. fermentum (44.3±12.6), and L. plantarum (39.0±7.6) groups showed decreased cholesterol levels compared to the Western group (85.7±8.6) (P<0.05). In comparison of steatosis, L. acidophilus (1.9±0.6), L. plantarum (2.4±0.7), and L. paracasei (2.0±0.9) groups showed significant improvement of steatosis compared to the Western group (2.6±0.5) (P<0.05). CONCLUSION: Ingestion of Lactobacillus, such as L. acidophilus, L. fermentum, and L. plantarum, ameliorates the progression of nonalcoholic steatosis by lowering cholesterol. The use of Lactobacillus can be considered as a useful strategy for the treatment of NAFLD.

Effect of Korean Red Ginseng in chronic liver disease.

Chronic liver disease, one of the most common diseases, typically arises from nonalcoholic fatty liver disease, alcoholic liver disease, chronic viral hepatitis, or hepatocellular carcinoma. Therefore, there is a pressing need for improved treatment strategies. Korean Red Ginseng has been known to have positive effects on liver disease and liver function. In this paper, we summarize the current knowledge on the beneficial effects of Korean Red Ginseng on chronic liver disease, a condition encompassing nonalcoholic fatty liver disease, alcoholic liver disease, chronic viral hepatitis, and hepatocellular carcinoma, as supported by experimental evaluation and clinical investigation.

Prognostic Significance of Hemodynamic and Clinical Stages in the Prediction of Hepatocellular Carcinoma.

BACKGROUND & GOALS: Early identification of hepatocellular carcinoma (HCC) is associated with improved survival for patients with chronic liver disease (CLD). We evaluated the prognostic significance of hemodynamic stage (HS) and clinical stage (CS) in predicting HCC in CLD patients. METHODS: Between January 2006 and May 2014, 801 patients with CLD who underwent hepatic venous pressure gradient (HVPG) measurement were prospectively enrolled. HS was classified by HVPG (mm Hg) as follows: HS-1 (HVPG≤6), HS-2 (612 mm Hg (P=0.033, OR=2.17), CS>2 (P=0.039, OR=2.36), and alpha-fetoprotein (AFP; P=0.017, OR=1.01) were significant predictors of HCC development in all patients. For patients with cirrhosis, ascites aggravation (OR=2.51), HVPG >12 mm Hg (OR=2.46), and CS >2 (OR=2.62) were correlated with HCC development. Areas under receiver operating characteristic curves of the prediction-model, CS, HVPG score, and AFP were 0.797, 0.707, 0.701, and 0.653, respectively. CONCLUSIONS: HCC development correlates with advancing liver fibrosis or disease as measured by HS and CS. In addition, ascites aggravation and elevated AFP appears to be associated with increased incidence of HCC.

Microbiota-based treatments in alcoholic liver disease.

Gut microbiota plays a key role in the pathogenesis of alcoholic liver disease (ALD). Consumption of alcohol leads to increased gut permeability, small intestinal bacterial overgrowth, and enteric dysbiosis. These factors contribute to the increased translocation of microbial products to the liver via the portal tract. Subsequently, bacterial endotoxins such as lipopolysaccharide, in association with the Toll-like receptor 4 signaling pathway, induce a gamut of damaging immune responses in the hepatic milieu. Because of the close association between deleterious inflammation and ALD-induced microbiota imbalance, therapeutic approaches that seek to reestablish gut homeostasis should be considered in the treatment of alcoholic patients. To this end, a number of preliminary studies on probiotics have confirmed their effectiveness in suppressing proinflammatory cytokines and improving liver function in the context of ALD. In addition, there have been few studies linking the administration of prebiotics and antibiotics with reduction of alcohol-induced liver damage. Because these preliminary results are promising, large-scale randomized studies are warranted to elucidate the impact of these microbiota-based treatments on the gut flora and associated immune responses, in addition to exploring questions about optimal delivery. Finally, fecal microbiota transplant has been shown to be an effective method of modulating gut microbiota and deserve further investigation as a potential therapeutic option for ALD.

Effects of Korean Red Ginseng (Panax ginseng), urushiol (Rhus vernicifera Stokes), and probiotics (Lactobacillus rhamnosus R0011 and Lactobacillus acidophilus R0052) on the gut-liver axis of alcoholic liver disease.

BACKGROUND: Roles of immune reaction and toll-like receptor-4 (TLR-4) have widely been established in the pathogenesis of alcoholic liver disease (ALD). METHODS: We evaluated the biologic efficacy of Korean Red Ginseng (KRG), urushiol, and probiotics (Lactobacillus rhamnosus R0011 and Lactobacillus acidophilus R0052) in mouse models of ALD. Sixty C57BL/6 mice were equally divided into six feeding groups for 10 weeks: normal diet, alcohol, control, alcohol + KRG, alcohol + urushiol, and alcohol + probiotics. Alcohol was administered via a Lieber-DeCarli liquid diet containing 10% alcohol. TLR-4 expression, proinflammatory cytokines, and histology, as well as the results of liver function tests were evaluated and compared. RESULTS: No between-group differences were observed with regard to liver function. TLR-4 levels were significantly lower in the KRG, urushiol, and probiotics groups than in the alcohol group (0.37 ± 0.06 ng/mL, 0.39 ± 0.12 ng/mL, and 0.33 ± 0.07 ng/mL, respectively, vs. 0.88 ± 0.31 ng/mL; p < 0.05). Interleukin-1ß levels in liver tissues were decreased among the probiotics and KRG groups. The tumor necrosis factor-α level of liver tissue was decreased in the KRG group. CONCLUSION: The pathological findings showed that alcohol-induced steatosis was significantly reduced by KRG and urushiol. As these agents improve immunologic capacity, they may be considered in potential anti-ALD treatments.

Transarterial chemoembolization in Barcelona Clinic Liver Cancer Stage 0/A hepatocellular carcinoma.

AIM: To evaluate the clinical characteristics of patients with Barcelona Clinic Liver Cancer (BCLC) stage 0 and A hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE). METHODS: Between January 2001 and September 2011, 129 patients with BCLC stage 0 and stage A HCC who underwent TACE were retrospectively enrolled. Patient characteristics, routine computed tomography and TACE findings, survival time and 1-, 5-, and 10-year survival rates, risk factors for mortality, and survival rates according to the number of risk factors were assessed. RESULTS: The mean size of HCC tumors was 2.4 ± 1.1 cm, and the mean number of TACE procedures performed was 2.5 ± 2.1. The mean overall survival time and 1-, 5-, and 10-year survival rates were 80.6 ± 4.9 mo and 91%, 63% and 49%, respectively. In the Cox regression analysis, a Child-Pugh score > 5 (P = 0.005, OR = 3.86), presence of arterio-venous shunt (P = 0.032, OR = 4.41), amount of lipiodol used (> 7 mL; P = 0.013, OR = 3.51), and female gender (P = 0.008, OR = 3.47) were risk factors for mortality. The 1-, 5-, and 10-year survival rates according to the number of risk factors present were 96%, 87% and 87% (no risk factors), 89%, 65%, and 35% (1 risk factor), 96%, 48% and unavailable (2 risk factors), and 63%, 17%, and 0% (3 risk factors), respectively (P < 0.001). CONCLUSION: TACE may be used as curative-intent therapy in patients with BCLC stage 0 and stage A HCC. The Child-Pugh score, arterio-venous shunt, amount of lipiodol used, and gender were related to mortality after TACE.

Catheter-free method is sufficient for preparation for transnasal endoscopy: randomized controlled trial.

BACKGROUND AND AIM: Although transnasal endoscopy (TNE) is generally a comfortable and safe procedure, it has some disadvantages, such as complicated preprocessing and occasional repulsion reaction during catheterization. In an attempt to simplify the preprocessing method, the efficacy of a catheter-free method in which a catheter is not inserted into the nasal cavity was assessed. METHODS: The present study was a prospective, open-label, single-center, randomized controlled study with parallel assignment allocation 1:1. Between March 2009 and August 2009, a total of 93 TNE-naïve patients were enrolled and randomized. Patients were prospectively randomized into two groups (catheter-free vs catheter-insertion method). Patients who prepared according to the catheter-free method and who were unsuccessful underwent the catheter-insertion method. Clinical characteristics, success rate, complications, vital signs, acceptability, and tolerability were assessed and compared. RESULTS: Success rates of the catheter-free and catheter-insertion methods were 88% (n=44) and 88% (n=38) (P>0.05), respectively. Causes of failure in the catheter-free method included severe rhinalgia (n=1, 2%) and narrowing of the nasal cavity (n=5, 10%). Causes of failure in the catheter-insertion method included narrowing of the nasal cavity (n=5, 11%). Six patients whose TNE failed with the catheter-free method also experienced failed TNE with the catheter-insertion method. There were no statistical differences in vital signs, acceptability, and tolerability. CONCLUSION: The catheter-free method is sufficient for preparation for TNE. The success rate of TNE depends more on the structure of the nasal cavity than the preprocessing method.

Characteristics of nonvariceal upper gastrointestinal hemorrhage in patients with chronic kidney disease.

AIM: To evaluate the clinical characteristics of nonvariceal upper gastrointestinal hemorrhage (NGIH) in patients with chronic kidney disease (CKD). METHODS: From 2003 to 2010, a total of 72 CKD patients (male n = 52, 72.2%; female n = 20, 27.8%) who had undergone endoscopic treatments for NGIH were retrospectively identified. Clinical findings, endoscopic features, prognosis, rebleeding risk factors, and mortality-related factors were evaluated. The characteristics of the patients and rebleeding-related data were recorded for the following variables: gender, age, alcohol use and smoking history, past hemorrhage history, endoscopic findings (the cause, location, and size of the hemorrhage and the hemorrhagic state), therapeutic options for endoscopy, endoscopist experience, clinical outcomes, and mortality. RESULTS: The average size of the hemorrhagic site was 13.7 ± 10.2 mm, and the most common hemorrhagic site in the stomach was the antrum (n = 21, 43.8%). The most frequent method of hemostasis was combination therapy (n = 32, 44.4%). The incidence of rebleeding was 37.5% (n = 27), and 16.7% (n = 12) of patients expired due to hemorrhage. In a multivariate analysis of the risk factors for rebleeding, alcoholism (OR = 11.19, P = 0.02), the experience of endoscopists (OR = 0.56, P = 0.03), and combination endoscopic therapy (OR = 0.06, P = 0.01) compared with monotherapy were significantly related to rebleeding after endoscopic therapy. In a risk analysis of mortality after endoscopic therapy, only rebleeding was related to mortality (OR = 7.1, P = 0.02). CONCLUSION: Intensive combined endoscopic treatments by experienced endoscopists are necessary for the treatment of NGIH in patients with CKD, especially when a patient is an alcoholic.

Clinical characteristics and pituitary dysfunction in patients with metastatic cancer to the sella.

OBJECTIVE: Metastatic disease to the sella is uncommon and there are limited available data regarding the clinical aspects of this disease. We therefore sought to characterize the clinical demographics of sellar metastases. METHODS: Retrospective chart review of adults treated at Stanford University Medical Center from 1980 to 2011 with metastatic disease to the sella. RESULTS: A total of 13 subjects were identified (9 females). The mean age at diagnosis was 55 years (range, 25 to 73 years). A total of 6 patients (46%) had breast carcinoma, 3 (23%) had renal cell carcinoma, 2 (15%) had squamous cell carcinoma of the head and neck, 1 had bronchoalveolar carcinoma of the lung, and 1 had nodular sclerosing Hodgkin's lymphoma. The most common presenting signs and symptoms were headache (58%), followed by fatigue (50%), polyuria (50%), visual field defects (42%), and ophthalmoplegia (42%). Seventy-five percent of patients presented with at least one pituitary hormone insufficiency, which included 6 patients (50%) with diabetes insipidus (DI). Eight (67%) subjects had secondary hypothyroidism and 5 (45%) had secondary adrenal insufficiency. Of the patients with stalk involvement, 86% had DI. All patients had a prior diagnosis of malignancy, with a mean duration of 95 months. CONCLUSION: The most common neoplastic sources to the sella were breast and renal cell carcinomas. Secondary hypothyroidism was the most common endocrine abnormality, followed by DI and adrenal insufficiency. New-onset central hypothyroidism and DI along with known malignancy in a patient with a sellar lesion should raise the suspicion of a metastatic source.