Chronic liver disease due to alcohol use disorder contributes markedly to the global burden of disease and mortality 1-3. Alcoholic hepatitis is a severe and life-threatening form of alcohol-Duan et al.

The spectrum of non-alcoholic fatty liver disease (NAFLD) ranges from simple hepatic steatosis, commonly associated with obesity, to non-alcoholic steatohepatitis, which can progress to fibrosis, cirrhosis and hepatocellular carcinoma. NAFLD pathophysiology involves environmental, genetic and metabolic factors, as well as changes in the intestinal microbiota and their products. Dysfunction of the intestinal barrier can contribute to NAFLD development and progression. Although there are technical limitations in assessing intestinal permeability in humans and the number of patients in these studies is rather small, fewer than half of the patients have increased intestinal permeability and translocation of bacterial products. Microbe-derived metabolites and the signalling pathways they affect might play more important roles in development of NAFLD. We review the microbial metabolites that contribute to the development of NAFLD, such as trimethylamine, bile acids, short-chain fatty acids and ethanol. We discuss the mechanisms by which metabolites produced by microbes might affect disease progression and/or serve as therapeutic targets or biomarkers for NAFLD.

Objective. To acquire more data about the epidemiologic characteristics of constipation in different kinds of populations in China. Methods. Using “constipation” and “China” as search terms; relevant papers were searched from January 1995 to April 2014. Data on prevalence, gender, diagnostic criteria, geographical area, educational class, age, race, and physician visit results were extracted and analyzed. Results. 36 trials were included. Prevalence rates of constipation in elderly population (18.1%) and pediatric population (18.8%) were significantly higher than that in general population (8.2%). Prevalence of constipation defined by non-Rome criteria was higher than that by Rome criteria in general population. Prevalence rates of constipation were different for different geographical area. People with less education were predisposed to constipation. In pediatric population, prevalence of constipation was the lowest in children aged 2–6 years. Prevalence of constipation in ethnic minorities was higher than that in Han people. People with constipation were predisposed to FD, haemorrhoid, and GERD. Only 22.2% patients seek medical advice in general population. Conclusions. In China, prevalence of constipation was lower compared with most of other countries. The factors including female gender, diagnostic criteria, geographical area, age, educational class, and race seemed to have major effects on prevalence of constipation.

Background & Aims: Alcohol-associated liver disease is a leading indication for liver transplantation and a leading cause of mortality. Alterations to the gut microbiota contribute to the pathogenesis of alcohol-associated liver disease. Patients with alcohol-associated liver disease have increased proportions of Candida spp. in the fecal mycobiome, yet little is known about the effect of intestinal Candida on the disease. Herein, we evaluated the contributions of Candida albicans and its exotoxin candidalysin in alcohol-associated liver disease. Methods: C. albicans and the extent of cell elongation 1 (ECE1) were analyzed in fecal samples from controls, patients with alcohol use disorder and those with alcoholic hepatitis. Mice colonized with different and genetically manipulated C. albicans strains were subjected to the chronic-plus-binge ethanol diet model. Primary hepatocytes were isolated and incubated with candidalysin.Results: The percentages of individuals carrying ECE1 were 0%, 4.76% and 30.77% in non-alcoholic controls, patients with alcohol use disorder and patients with alcoholic hepatitis, respectively. Candidalysin exacerbates ethanol-induced liver disease and is associated with increased mortality in mice. Candidalysin enhances ethanol-induced liver disease independently of the bglucan receptor C-type lectin domain family 7 member A (CLEC7A) on bone marrow-derived cells, and candidalysin does not alter gut barrier function. Candidalysin can damage primary hepatocytes in a dose-dependent manner in vitro and is associated with liver disease severity and mortality in patients with alcoholic hepatitis. Conclusions: Candidalysin is associated with the progression of ethanol-induced liver disease in preclinical models and worse clinical outcomes in patients with alcoholic hepatitis.Lay summary: Candidalysin is a peptide toxin secreted by the commensal gut fungus Candida albicans. Candidalysin enhances alcohol-associated liver disease independently of the b-glucan receptor CLEC7A on bone marrow-derived cells in mice without affecting intestinal permeability. Candidalysin is cytotoxic to primary hepatocytes, indicating a direct role of candidalysin on ethanol-induced liver disease. Candidalysin might be an effective target for therapy in patients with alcohol-associated liver disease.Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.

The gut-liver axis is associated with the progression of non-alcoholic fatty liver disease (NAFLD). Targeting the gut-liver axis and bile acid-based pharmaceuticals are potential therapies for NAFLD. The effect of tauroursodeoxycholic acid (TUDCA), a candidate drug for NAFLD, on intestinal barrier function, intestinal inflammation, gut lipid transport and microbiota composition was analysed in a murine model of NAFLD. EXPERIMENTAL APPROACHThe NAFLD mouse model was established by feeding mice a high-fat diet (HFD) for 16 weeks. TUDCA was administered p.o. during the last 4 weeks. The expression levels of intestinal tight junction genes, lipid metabolic and inflammatory genes were determined by quantitative PCR. Tissue inflammation was evaluated by haematoxylin and eosin staining. The gut microbiota was analysed by 16S rRNA gene sequencing. KEY RESULTSTUDCA administration attenuated HFD-induced hepatic steatosis, inflammatory responses, obesity and insulin resistance in mice. Moreover, TUDCA attenuated gut inflammatory responses as manifested by decreased intestinal histopathology scores and inflammatory cytokine levels. In addition, TUDCA improved intestinal barrier function by increasing levels of tight junction molecules and the solid chemical barrier. The components involved in ileum lipid transport were also reduced by TUDCA administration in HFD-fed mice. Finally, the TUDCA-treated mice showed a different gut microbiota composition compared with that in HFD-fed mice but similar to that in normal chow diet-fed mice. CONCLUSIONS AND IMPLICATIONSTUDCA attenuates the progression of HFD-induced NAFLD in mice by ameliorating gut inflammation, improving intestinal barrier function, decreasing intestinal fat transport and modulating intestinal microbiota composition. Abbreviations ACOX1, peroxisomal acyl-CoA oxidase 1; ANOSIM, analysis of similarities; C3GNT, core 3β1,3-N-acetyl glucosaminyltransferase; CYP7a, cholesterol 7α-hydroxylase; ER, endoplasmic reticulum; FABP, fatty acid-binding protein; FATP4, fatty acid transport protein 4; FAR3, fatty acid receptor 3; H&E, haematoxylin and eosin; HFD, high-fat diet; HOMA-IR, homeostasis model assessment of the insulin resistance index; Iap, intestinal alkaline phosphatase; ICAM1, intercellular cell adhesion molecule-1; IPGTT, i.p. glucose tolerance test; IPITT, i.p. insulin tolerance test; Irak4, IL-1 receptor-associated kinase 4; JAM, junctional adhesion molecule; Lcad, long-chain acyl-CoA dehydrogenase; NAFLD, non-alcoholic fatty liver disease; NAS, non-alcoholic fatty liver disease activity score; NASH, non-alcoholic steatohepatitis; NCD, normal chow diet; OTU, operational taxonomic unit; PCoA, principal coordinates analysis; Tab1, TGF-β activated kinase 1 mitogen-activated protein kinase kinase kinase 7-binding protein 1; TC, total cholesterol; TEERs, transepithelial electrical resistances; TGs, triglycerides; TLR, toll-like receptor; Tram, toll or IL-1 receptor domain-containing adaptor inducing IFN-β-related adaptor molecule; TUDCA, tauroursodeoxycholic acid; UDCA...

Intestinal bacteria contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Recently developed microbial profiling techniques are beginning to shed light on the nature of the changes in the gut microbiota that accompany NAFLD and non-alcoholic steatohepatitis (NASH). In this review, we summarize the role of gut microbiota in the development of NAFLD, NASH, and hepatocellular carcinoma (HCC). We highlight the mechanisms by which gut microbiota contribute to NAFLD/NASH, including through alterations in gut epithelial permeability, choline metabolism, endogenous alcohol production, release of inflammatory cytokines, regulation of hepatic Toll-like receptor (TLR), and bile acid metabolism. In addition, we analyze possible mechanisms for enhanced hepatic carcinogenesis, including alterations in bile acid metabolism, release of inflammatory cytokines, and expression of TLR-4. Finally, we describe therapeutic approaches for NAFLD/NASH and preventive strategies for HCC involving modulation of the intestinal microbiota or affected host pathways. Although recent studies have provided useful information, large-scale prospective studies are required to better characterize the intestinal microbiota and metabolome, in order to demonstrate a causative role for changes in the gut microbiota in the etiology of NAFLD/NASH, to identify new therapeutic strategies for NAFLD/NASH, and to develop more effective methods of preventing HCC.

The intestinal microbiome plays a major role in the pathogenesis of liver disease, with a hallmark event being dysbiosis, or an imbalance of pathobionts and beneficial bacteria with the associated deleterious effects on their host. Reducing the number of intestinal bacteria with antibiotic treatment is generally advantageous in experimental liver diseases. Complete absence of intestinal microbiota as in germ-free rodents can be protective in autoimmune hepatitis and hepatic tumors induced by chemicals, or it can exacerbate disease as in acute toxic liver injury and liver fibrosis/cirrhosis. In alcoholic liver disease, nonalcoholic fatty liver disease, and autoimmune cholangiopathies, germ-free status can be associated with worsened or improved hepatic phenotype depending on the experimental model and type of rodent. Some of the unexpected outcomes can be explained by the limitations of rodents raised in a germ-free environment including a deficient immune system and an altered metabolism of lipids, cholesterol, xenobiotics/toxins, and bile acids. Given these limitations and to advance understanding of the interactions between host and intestinal microbiota, simplified model systems such as humanized gnotobiotic mice, or gnotobiotic mice monoassociated with a single bacterial strain or colonized with a defined set of microbes, are unique and useful models for investigation of liver disease in a complex ecosystem.

Background and Aims: The aim of this study was to assess the effects of gastric electrical stimulation (GES) on symptoms and gastric emptying in patients with gastroparesis, and the effects of GES on the three subgroups of gastroparesis. Methods: A literature search of clinical trials using high-frequency GES to treat patients with gastroparesis from January 1995 to January 2011 was performed. Data on the total symptom severity score (TSS), nausea severity score, vomiting severity score, and gastric emptying were extracted and analyzed. The statistic effect index was weighted mean differences. Results: Ten studies (n = 601) were included in this study. In the comparison to baseline, there was significant improvement of symptoms and gastric emptying (P < 0.00001). It was noted that GES significantly improved both TSS (P < 0.00001) and gastric retention at 2 h (P = 0.003) and 4 h (P < 0.0001) in patients with diabetic gastroparesis (DG), while gastric retention at 2 h (P = 0.18) in idiopathic gastroparesis (IG) patients, and gastric retention at 4 h (P = 0.23) in postsurgical gastroparesis (PSG) patients, did not reach significance. Conclusions: Based on this meta-analysis, the substantial and significant improvement of symptoms and gastric emptying, and the good safety we observed, indicate that highfrequency GES is an effective and safe method for treating refractory gastroparesis. DG patients seem the most responsive to GES, both subjectively and objectively, while the IG and PSG subgroups are less responsive and need further research.