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BACKGROUND AND AIMS: IgG4 sclerosing cholangitis (IgG4-SC) is the biliary component of the multisystem IgG4-related disease. We aimed to investigate the clinical features, demographics, treatment response and outcomes of IgG4-SC in a large Australian cohort. METHODS: We conducted nationwide retrospective cohort via the Australian Liver Association Clinical Trials Network (ALA-CRN). 39 sites were invited to participate. IgG4-SC was defined by the clinical diagnostic criteria established by the Japanese Biliary Association in 2012. Data were collected on patient demographic, clinical and laboratory information, presenting features, response to therapy and clinical outcomes. RESULTS: 67 patients meet inclusion criteria from 22 sites. 76% were male with mean age of 63.3 ± 14.5 years and a median IgG4 level of 3.6 g/L [0.09-67.1]. The most frequent presenting symptom was jaundice (62%) and abdominal pain (42%) and Type 1 biliary stricturing (52%) at the distal common bile duct was the most frequent biliary tract finding. Prednisolone was used as a primary treatment in 61 (91%) and partial or complete response occurred in 95% of subjects. Relapse was common (42%) in those who ceased medical therapy. After a median follow up of 3.9 years there was one hepatocellular carcinoma and no cholangiocarcinomas. CONCLUSIONS: Our study confirms the preponderance of IgG4-SC in males and highlights the steroid response nature of this condition although relapse is common after steroid cessation. Progression to malignancy was uncommon.

Little is known of the relationships among paediatric upper gastrointestinal microbiotas, and the impact of medication use and disease on their diversity. Here, we investigated the diversity of three microbiotas in the upper gastrointestinal tract of paediatric patients in relation to each other and to host factors. Oral, oesophageal and gastric microbiotas from a prospective paediatric cohort (n=54) were profiled using the 16S rRNA gene and ITS2 amplicon sequencing. 16S rRNA gene amplicon sequencing of oesophageal biopsies from a retrospective paediatric cohort (n=96) and shotgun metagenomics data from oesophageal brushings (n=88) were employed for genomic signature validation. Bacterial diversity and composition showed substantial differences across oral, oesophageal and gastric fluid samples that were not replicated for fungi, and the presence of reflux led to increased homogeneity in the bacterial component of these three microbiotas. The oral and oesophageal microbiotas were associated with age, sex, history of oesophageal atresia and presence of oesophageal metaplasia, with the latter characterized by Prevotella enrichment. Proton pump inhibitor use was associated with increased oral bacterial richness in the gastric fluid, and this correlated with increased levels of gastric pro-inflammatory cytokines. Profiling of oesophageal biopsies from a retrospective paediatric cohort confirmed an increased Prevotella prevalence in samples with metaplasia. Analysis of metagenome-derived oesophageal Prevotella melaninogenica genomes identified strain-specific features that were significantly increased in prevalence in samples with metaplasia. Prevotella enrichment is a signature associated with paediatric oesophageal metaplasia, and proton pump inhibitor use substantially alters the paediatric gastric microenvironment.

Campylobacteriosis is a gastroenteritis caused by pathogenicCampylobacterspecies and an important topic in public health. Here we review the global epidemiology of campylobacteriosis in the last eight years between 2014-2021, providing comprehensive and updated information on the reported incidence and outbreaks ofCampylobacterinfections. The government public health website of each of the 195 countries and publications from 2014 to September 2022 in public databases were searched. The reported incidence of campylobacteriosis in pre-COVID-19 years was compared to that during the COVID-19 pandemic in countries where data were available. Czech Republic had the highest reported incidence of campylobacteriosis worldwide (215 per 100,000 in 2019), followed by Australia (146.8 per 100,000 in 2016) and New Zealand (126.1 per 100,000 in 2019).Campylobacterwas one of the most common human enteric pathogens in both developed and developing countries. About 90% of cases of campylobacteriosis were caused byCampylobacter jejuni, whereas less than 10% of cases were caused byCampylobacter coli. OtherCampylobacterspecies were also isolated. The reported incidence and case numbers of campylobacteriosis in developed nations have remained steadily high prior to the COVID-19 pandemic, whilst some countries reported an increasing trend such as France and Japan. While outbreaks were more frequently reported in some countries,Campylobacterinfections were mainly sporadic cases in most of the developed countries.Campylobacterinfection was more common in summer in some but not all countries.Campylobacterinfection was more common in males than females. The COVID-19 pandemic has reduced the reported incidence of campylobacteriosis in most countries where 2020 epidemiology data were available. In conclusion,Campylobacterinfection remains a global health concern. Increased research and improved strategies are needed for prevention and reduction ofCampylobacterinfection.

BackgroundThe enrichment of Gram-negative bacteria of oral origin in the esophageal microbiome has been associated with the development of metaplasia. However, to date, no study has comprehensively assessed the relationships between the esophageal microbiome and the host.MethodsHere, we examine the esophageal microenvironment in gastro-esophageal reflux disease and metaplasia using multi-omics strategies targeting the microbiome and host transcriptome, followed by targeted culture, comparative genomics, and host-microbial interaction studies of bacterial signatures of interest.ResultsProfiling of the host transcriptome from esophageal mucosal biopsies revealed profound changes during metaplasia. Importantly, five biomarkers showed consistent longitudinal changes with disease progression from reflux disease to metaplasia. We showed for the first time that the esophageal microbiome is distinct from the salivary microbiome and the enrichment ofCampylobacterspecies as a consistent signature in disease across two independent cohorts. Shape fitting and matrix correlation identified associations between the microbiome and host transcriptome profiles, with a novel co-exclusion relationship found betweenCampylobacterand napsin B aspartic peptidase. Targeted culture ofCampylobacterspecies from the same cohort revealed a subset of isolates to have a higher capacity to survive within primary human macrophages. Comparative genomic analyses showed these isolates could be differentiated by specific genomic features, one of which was validated to be associated with intracellular fitness. Screening for theseCampylobacterstrain-specific signatures in shotgun metagenomics data from another cohort showed an increase in prevalence with disease progression. Comparative transcriptomic analyses of primary esophageal epithelial cells exposed to theCampylobacterisolates revealed expression changes within those infected with strains with high intracellular fitness that could explain the increased likelihood of disease progression.ConclusionsWe provide a comprehensive assessment of the esophageal microenvironment, identifying bacterial strain-specific signatures with high relevance to progression of metaplasia.

Campylobacter concisus is an emerging bacterial pathogen that may play a role in the development of inflammatory bowel disease and oral inflammatory conditions such as periodontal disease. To elucidate the role and pathogenic mechanisms of C. concisus in contributing to oral inflammation, this study examined the production of IL-1 family proinflammatory cytokines IL-18 and IL-1β in oral epithelial cells induced by C. concisus strains using enzyme-linked immunosorbent assay (ELISA), Western-blot and quantitative real-time PCR. C. concisus increased the mRNA levels of IL-18 and IL-1β in oral epithelial cells. Furthermore, a large amount of IL-18 in the supernatants of oral epithelial cells infected with C. concisus strains was detected by ELISA, and various experiments demonstrated that this positive signal was derived from C. concisus bacterium. The findings that C. concisus upregulated IL-18 and IL-1β in oral epithelial cells from this study support a role of C. concisus in oral inflammatory diseases. Furthermore, the finding that C. concisus released a molecule that was strongly cross-reactive to anti-human IL-18 monoclonal antibodies suggests that in future studies examining cytokines induced by bacterial microbes, a bacterium control should be included.

Programmed cell death ligand-1 (PD-L1) is an immune checkpoint protein, which is used by tumor cells for immune evasion. PD-L1 is upregulated in inflamed intestinal tissues. The intestinal tract is colonized by millions of bacteria, most of which are commensal bacterial species. We hypothesize that under inflammatory conditions, some commensal bacterial species contribute to increased PD-L1 expression in intestinal epithelium and examined this hypothesis. Human intestinal epithelial HT-29 cells with and without interferon (IFN)-γ sensitization were incubated with six strains of four enteric bacterial species. The mRNA and protein levels of PD-L1 in HT-29 cells were examined using quantitative real-time PCR and flow cytometry, respectively. The levels of interleukin (IL)-1β, IL-18, IL-6, IL-8 and tumor necrosis factor (TNF)-α secreted by HT-29 cells were measured using enzyme-linked immunosorbent assay. Apoptosis of HT-29 was measured using caspase 3/7 assay. We found that Escherichia coli (E. coli) K12 significantly upregulated both PD-L1 mRNA and protein in IFN-γ sensitized HT-29 cells. E. coli K12 induced the production of IL-8 in HT-29 cells, however, IL-8 did not affect HT-29 PD-L1 expression. Inhibition of the nuclear factor-kappa B pathway significantly reduced E. coli K12 induced PD-L1 expression in HT-29 cells. The other two E. coli strains and two enteric bacterial species did not significantly affect PD-L1 expression in HT-29 cells. Enterococcus faecalis significantly inhibited PD-L1 expression due to induction of cell death. Data from this study suggest that some gut bacterial species have the potential to affect immune function under inflammatory conditions via upregulating epithelial PD-L1 expression.

Campylobacter concisusis an emerging enteric pathogen that is associated with several gastrointestinal diseases, such as inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC). Currently, only three completeC. concisusgenomes are available and more completeC. concisusgenomes are needed in order to better understand the genomic features and pathogenicity of this emerging pathogen. DNA extracted from 22C.concisusstrains were subjected to Oxford Nanopore genome sequencing. Complete genome assembly was performed using Nanopore genome data in combination with previously reported short-read Illumina data. Genome features of completeC. concisusgenomes were analysed using bioinformatic tools. The enteric disease associations ofC. concisusplasmids were examined using 239C.concisusstrains and confirmed using PCRs. Proteomic analysis was used to examine T6SS secreted proteins. We successfully obtained 13 completeC. concisusgenomes in this study. Analysis of 16 completeC. concisusgenomes (3 from public databases) identified multiple novel plasmids. pSma1 plasmid was found to be associated with severe UC. Sec-SRP, Tat and T6SS were found to be the main secretion systems inC. concisusand proteomic data showed a functional T6SS despite the lack of ClpV. T4SS was found in 25% of completeC. concisusgenomes. This study also found that GS2 strains had larger genomes and higher GC content than GS1 strains and more often had plasmids. In conclusion, this study provides fundamental genomic data for understandingC. concisusplasmids, genomospecies features, evolution, secretion systems and pathogenicity.

Background The esophageal microbiome has been proposed to be involved in a range of diseases including the esophageal adenocarcinoma cascade; however, little is currently known about its function and relationship to the host. Here, the esophageal microbiomes of 106 prospectively recruited patients were assessed using 16S rRNA and 18S rRNA amplicon sequencing as well as shotgun sequencing, and associations with age, gender, proton pump inhibitor use, host genetics, and disease were tested. Results The esophageal microbiome was found to cluster into functionally distinct community types (esotypes) defined by the relative abundances of Streptococcus and Prevotella. While age was found to be a significant factor driving microbiome composition, bacterial signatures and functions such as enrichment with Gram-negative oral-associated bacteria and microbial lactic acid production were associated with the early stages of the esophageal adenocarcinoma cascade. Non-bacterial microbes such as archaea, Candida spp., and bacteriophages were also identified in low abundance in the esophageal microbiome. Specific host SNPs in NOTCH2, STEAP2-AS1, and NREP were associated with the composition of the esophageal microbiome in our cohort. Conclusions This study provides the most comprehensive assessment of the esophageal microbiome to date and identifies novel signatures and host markers that can be investigated further in the context of esophageal adenocarcinoma development. Electronic supplementary material The online version of this article (10.1186/s40168-018-0611-4) contains supplementary material, which is available to authorized users.

Anti-cytokine antibodies are used in treating chronic inflammatory diseases and autoimmune diseases such as inflammatory bowel disease and rheumatic diseases. Patients with these diseases often have a compromised gut barrier function, suggesting that anti-cytokine antibodies may contribute to the re-establishment of gut barrier integrity, in addition to their immunomodulatory effects. This paper reviews the effects of anti-cytokine antibodies on gut barrier function and their mechanisms.

Drugs used for sedation/analgesia during gastrointestinal (GI) endoscopy, including midazolam, fentanyl, and propofol, result in short-term, reversible decline in cognitive function. This prospective cohort trial aimed to identify the sedative/analgesic regimen associated with the least impairment of cognition at the time of discharge.Patients undergoing elective GI endoscopy were included. Patients investigated at the Prince of Wales Hospital, Sydney, received midazolam/fentanyl (M/F), whereas patients investigated at the Prince of Wales Private Hospital, Sydney, received midazolam/fentanyl/propofol (M/F/P) or midazolam/propofol (M/P). Patients underwent a computerized neurocognitive test, the CogState Brief Battery, before sedation and at discharge.Patients in the M/F group who received gastroscopy (n=22) were administered midazolam 3.36 mg (±0.79 mg) and fentanyl 61.36 μg (±16.77 μg), those who received colonoscopy (n=50) were administered midazolam 3.98 mg (±1.06 mg) and fentanyl 74.50 μg (±24.48 μg), and those who received gastroscopy/colonoscopy (n=28) were administered midazolam 4.82 mg (±1.41 mg) and fentanyl 94.64 μg (±24.35 μg). Patients in the M/F/P group who received colonoscopy (n=45) were administered midazolam 2.77 mg (±0.55 mg), fentanyl 45.11 μg (±25.78 μg), and propofol 148.64 mg (±57.65 mg), and those who received gastroscopy/colonoscopy (n=36) were administered midazolam 2.64 mg (±0.472 mg), fentanyl 35.28 μg (±19.16 μg), and propofol 168.06 mg (±60.75 mg). Nineteen patients in the M/P group who received gastroscopy (n=19) were administered midazolam 2.37 mg (±0.04 mg) and propofol 13.68 mg (±37.74 mg). Neurocognitive scores were significantly lower in the postprocedure test compared with baseline scores for detection, identification, and one card learning (P0.001). Postprocedure detection test scores were significantly impaired in the M/F group compared with the M/F/P and M/P groups. Predictors of poorer neurocognitive function were midazolam dosage3 mg (P0.006) and fentanyl dosage50 μg (P0.009).The use of propofol in GI endoscopy allows for less exposure to midazolam and fentanyl and is associated with improved cognition at the time of discharge.

International Liver Disease Genetics Consortium (ILDGC)., Hepatocarcinogenesis is tightly linked to liver fibrosis. Recently, two GWAS variants, MICA rs2596542 and DEPDC5 rs1012068 were identified as being associated with the development of HCV-induced hepatocellular carcinoma (HCC) in Japanese patients. The role of these variants on hepatic inflammation and fibrosis that are closely associated with HCC development is not known, nor are the biological mechanisms underlying their impact on the liver. Here, we demonstrate in 1689 patients with chronic hepatitis C (CHC) (1,501 with CHC and 188 with HCV-related HCC), that the MICA (T) allele, despite not being associated with HCC susceptibility, is associated with increased fibrosis stage (OR: 1.47, 95% CI: 1.05–2.06, p = 0.02) and fibrosis progression rate (hazards ratio: 1.41, 95% CI: 1.04–1.90, p = 0.02). The DEPDC5 variant was not associated with any of these phenotypes. MICA expression was down-regulated in advanced fibrosis stages. Further, (T) allele carriage was associated with lower MICA expression in liver and serum. Transforming growth factor-β1 (TGF-β1) expression suppresses MICA expression in hepatic stellate cells. Our findings suggest a novel mechanism linking susceptibility to advanced fibrosis and subsequently indirectly to HCC, to the level of MICA expression through TGF-β1-dependent mechanisms., M.E., C.L., M.D. and J.G. are supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney; a National Health and Medical Research Council of Australia (NHMRC) Program Grant (APP1053206, APP1149976) and Project grants (APP1107178 and APP1108422). G.D. is supported by an NHMRC Fellowship (1028432). U.S. and J.N. are supported by DFG SFB-TR57 and the Hector-Foundation (M63). R.E. and K.T. are supported by a scholarship from the Egyptian government. A.B. is supported by an Australian Government Research Training Program (RTP) scholarship.

INTRODUCTION Achievement of the 2030 World Health Organisation (WHO) global hepatitis C virus (HCV) elimination targets will be underpinned by scale-up of testing and use of direct-acting antiviral treatments. In Australia, despite publically-funded testing and treatment, less than 15% of patients were treated in the first year of treatment access, highlighting the need for greater efficiency of health service delivery. To this end, non-invasive fibrosis algorithms were examined to reduce reliance on transient elastography (TE) which is currently utilised for the assessment of cirrhosis in most Australian clinical settings. MATERIALS AND METHODS This retrospective and prospective study, with derivation and validation cohorts, examined consecutive patients in a tertiary referral centre, a sexual health clinic, and a prison-based hepatitis program. The negative predictive value (NPV) of seven non-invasive algorithms were measured using published and newly derived cut-offs. The number of TEs avoided for each algorithm, or combination of algorithms, was determined. RESULTS The 850 patients included 780 (92%) with HCV mono-infection, and 70 (8%) co-infected with HIV or hepatitis B. The mono-infected cohort included 612 men (79%), with an overall prevalence of cirrhosis of 16% (125/780). An 'APRI' algorithm cut-off of 1.0 had a 94% NPV (95%CI: 91-96%). Newly derived cut-offs of 'APRI' (0.49), 'FIB-4' (0.93) and 'GUCI' (0.5) algorithms each had NPVs of 99% (95%CI: 97-100%), allowing avoidance of TE in 40% (315/780), 40% (310/780) and 40% (298/749) respectively. When used in combination, NPV was retained and TE avoidance reached 54% (405/749), regardless of gender or co-infection. CONCLUSIONS Non-invasive algorithms can reliably exclude cirrhosis in many patients, allowing improved efficiency of HCV assessment services in Australia and worldwide.

The morbidity and mortality resulting from acute gastroenteritis and associated chronic sequelae represent a substantial burden on health care systems worldwide. Few studies have investigated changes in the gut microbiome following an episode of acute gastroenteritis. By using nondirected 16S rRNA gene amplicon sequencing, the fecal microbiota of 475 patients with acute gastroenteritis was examined. Patient age was correlated with the overall microbial composition, with a decrease in the abundance of Faecalibacterium being observed in older patients. We observed the emergence of a potential Escherichia-Shigella -dominated enterotype in a subset of patients, and this enterotype was predicted to be more proinflammatory than the other common enterotypes, with the latter being dominated by Bacteroides or Faecalibacterium . The increased abundance of Escherichia-Shigella did not appear to be associated with infection with an agent of a similar sequence similarity. Stool color and consistency were associated with the diversity and composition of the microbiome, with deviations from the norm (not brown and solid) showing increases in the abundances of bacteria such as Escherichia-Shigella and Veillonella . Analysis of enriched outliers within the data identified a range of genera previously associated with gastrointestinal diseases, including Treponema , Proteus , Capnocytophaga , Arcobacter , Campylobacter , Haemophilus , Aeromonas , and Pseudomonas . Our data represent the first in-depth analysis of gut microbiota in acute gastroenteritis. Phenotypic changes in stool color and consistency were associated with specific changes in the microbiota. Enriched bacterial taxa were detected in cases where no causative agent was identified by using routine diagnostic tests, suggesting that in the future, microbiome analyses may be utilized to improve diagnostics.

Campylobacter concisus is an oral bacterium that is associated with inflammatory bowel disease (IBD) including Crohn’s disease (CD) and ulcerative colitis (UC). C. concisus consists of two genomospecies (GS) and diverse strains. This study aimed to identify molecular markers to differentiate commensal and IBD-associated C. concisus strains. The genomes of 63 oral C. concisus strains isolated from patients with IBD and healthy controls were examined, of which 38 genomes were sequenced in this study. We identified a novel secreted enterotoxin B homologue, Csep1. The csep1 gene was found in 56% of GS2 C. concisus strains, presented in the plasmid pICON or the chromosome. A six-nucleotide insertion at the position 654–659 bp in csep1 (csep1-6bpi) was found. The presence of csep1-6bpi in oral C. concisus strains isolated from patients with active CD (47%, 7/15) was significantly higher than that in strains from healthy controls (0/29, P = 0.0002), and the prevalence of csep1-6bpi positive C. concisus strains was significantly higher in patients with active CD (67%, 4/6) as compared to healthy controls (0/23, P = 0.0006). Proteomics analysis detected the Csep1 protein. A csep1 gene hot spot in the chromosome of different C. concisus strains was found. The pICON plasmid was only found in GS2 strains isolated from the two relapsed CD patients with small bowel complications. This study reports a C. concisus molecular marker (csep1-6bpi) that is associated with active CD.

Campylobacter concisus is an oral bacterium that is associated with inflammatory bowel disease (IBD). This study examined the impact of pH and bile on the growth of oral C. concisus strains isolated from patients with IBD and controls. The growth of 58 C. concisus strains on horse blood agar (HBA) plates following exposure to media with various pH values for different time points was examined. Furthermore, the growth of C. concisus strains on HBA plates containing different concentrations of ox bile was investigated. Following exposure to pH 2 for 30 min, none of the 58 oral C. concisus strains grew on HBA plates. Following exposure to pH 3.5 for 30 min, only four of 20 oral strains examined grew on HBA plates, with a log10 c.f.u. reduction of 0.7–2.5 compared to the same strains without low pH exposure. Exposure to pH 5 for 120 min had minimal effects on C. concisus growth. Approximately half of the oral strains (55.2 %, 32/58) grew on HBA containing 2 % bile. Bile inhibited the growth of C. concisus in a dose- and strain-dependent manner. These data suggest that both bacterial and intestinal environmental factors may play a role in the determination of C. concisus colonization in the different parts of the gastrointestinal tract and that increased gastric pH and reduced intestinal bile may be risk factors for increased gastric and intestinal C. concisus colonization.

Background Hepatic encephalopathy is a disorder of brain function as a result of liver failure or portosystemic shunt or both. Both hepatic encephalopathy (clinically overt) and minimal hepatic encephalopathy (not clinically overt) significantly impair patient’s quality of life and daily functioning, and represent a significant burden on healthcare resources. Probiotics are live micro-organisms, which when administered in adequate amounts, may confer a health benefit on the host. Objectives To determine the beneficial and harmful effects of probiotics in any dosage, compared with placebo or no intervention, or with any other treatment for people with any grade of acute or chronic hepatic encephalopathy. This review did not consider the primary prophylaxis of hepatic encephalopathy. Search methods We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, conference proceedings, reference lists of included trials, and the World Health Organization International Clinical Trials Registry Platform until June 2016. Selection criteria We included randomised clinical trials that compared probiotics in any dosage with placebo or no intervention, or with any other treatment in people with hepatic encephalopathy. Data collection and analysis We used standard methodological procedures expected by The Cochrane Collaboration. We conducted random-effects model meta-analysis due to obvious heterogeneity of participants and interventions. We defined a P value of 0.05 or less as significant. We expressed dichotomous outcomes as risk ratio (RR) and continuous outcomes as mean difference (MD) with 95% confidence intervals (CI). Main results We included 21 trials with 1420 participants, of these, 14 were new trials. Fourteen trials compared a probiotic with placebo or no treatment, and seven trials compared a probiotic with lactulose. The trials used a variety of probiotics; the most commonly used group of probiotic was VSL#3, a proprietary name for a group of eight probiotics. Duration of administration ranged from 10 days to 180 days. Eight trials declared their funding source, of which six were independently funded and two were industry funded. The remaining 13 trials did not disclose their funding source. We classified 19 of the 21 trials at high risk of bias. We found no effect on all-cause mortality when probiotics were compared with placebo or no treatment (7 trials; 404 participants; RR 0.58, 95% CI 0.23 to 1.44; low-quality evidence). No-recovery (as measured by incomplete resolution of symptoms) was lower for participants treated with probiotic (10 trials; 574 participants; RR 0.67, 95% CI 0.56 to 0.79; moderate-quality evidence). Adverse events were lower for participants treated with probiotic than with no intervention when considering the development of overt hepatic encephalopathy (10 trials; 585 participants; RR 0.29, 95% CI 0.16 to 0.51; low-quality evidence), but effects on hospitalisation and change of/or withdrawal from treatment were uncertain (hospitalisation: 3 trials, 163 participants; RR 0.67, 95% CI 0.11 to 4.00; very low-quality evidence; change of/or withdrawal from treatment: 9 trials, 551 participants; RR 0.70, 95% CI 0.46 to 1.07; very low-quality evidence). Probiotics may slightly improve quality of life compared with no intervention (3 trials; 115 participants; results not meta-analysed; low-quality evidence). Plasma ammonia concentration was lower for participants treated with probiotic (10 trials; 705 participants; MD -8.29 μmol/L, 95% CI -13.17 to -3.41; low-quality evidence). There were no reports of septicaemia attributable to probiotic in any trial. When probiotics were compared with lactulose, the effects on all-cause mortality were uncertain (2 trials; 200 participants; RR 5.00, 95% CI 0.25 to 102.00; very low-quality evidence); lack of recovery (7 trials; 430 participants; RR 1.01, 95% CI 0.85 to 1.21; very low-quality evidence); adverse events considering the development of overt hepatic encephalopathy (6 trials; 420 participants; RR 1.17, 95% CI 0.63 to 2.17; very low-quality evidence); hospitalisation (1 trial; 80 participants; RR 0.33, 95% CI 0.04 to 3.07; very low-quality evidence); intolerance leading to discontinuation (3 trials; 220 participants; RR 0.35, 95% CI 0.08 to 1.43; very low-quality evidence); change of/or withdrawal from treatment (7 trials; 490 participants; RR 1.27, 95% CI 0.88 to 1.82; very low-quality evidence); quality of life (results not meta-analysed; 1 trial; 69 participants); and plasma ammonia concentration overall (6 trials; 325 participants; MD -2.93 μmol/L, 95% CI -9.36 to 3.50; very low-quality evidence). There were no reports of septicaemia attributable to probiotic in any trial. Authors' conclusions The majority of included trials suffered from a high risk of systematic error (‘bias’) and a high risk of random error (‘play of chance’). Accordingly, we consider the evidence to be of low quality. Compared with placebo or no intervention, probiotics probably improve recovery and may lead to improvements in the development of overt hepatic encephalopathy, quality of life, and plasma ammonia concentrations, but probiotics may lead to little or no difference in mortality. Whether probiotics are better than lactulose for hepatic encephalopathy is uncertain because the quality of the available evidence is very low. High-quality randomised clinical trials with standardised outcome collection and data reporting are needed to further clarify the true efficacy of probiotics.

IL28B polymorphisms strongly predict spontaneous and treatment-induced clearance of hepatitis C virus (HCV) infection. A recent study proposed a 32-base pair deletion in the CC-chemokine receptor 5 (CCR5) gene (CCR5-D32) interacting with the IL28B polymorphisms to influence spontaneous HCV clearance. The aim of this study was to clarify the role of CCR5-D32 in treatmentinduced clearance of chronic hepatitis C (CHC). A cross-sectional cohort of 813 Caucasian patients with CHC genotype 1 (365 responders and 448 non-responders) who had received standard of care dual therapy with interferon (IFN)-a and ribavirin (RBV) was genotyped for the CCR5-D32 and IL28B polymorphisms to examine their interaction with respect to treatment response. CCR5-D32 did not influence treatment-induced recovery to IFN-a/RBV in CHC, and did not improve prediction of sustained virological response in the context of the IL28B polymorphisms in a multivariate model. CCR5-D32 homozygotes were significantly more frequent in those with CHC than healthy controls in the European cohorts (2.9% vs 0.4%, Po0.0001), but not in Australians of European ancestry. In conclusion, CCR5-D32 does not influence treatment response in the context of IL28B polymorphisms. Although CCR5-D32 may affect viral clearance within closely controlled geographical and genetic environments, we found no effect in larger cohorts treated with dual therapy. Refereed/Peer-reviewed

Campylobacter concisus is an oral bacterium that is associated with inflammatory bowel disease. C. concisus has two major genomospecies, which appear to have different enteric pathogenic potential. Currently, no studies have compared the genomes of C. concisus strains from different genomospecies. In this study, a comparative genome analysis of 36 C. concisus strains was conducted including 27 C. concisus strains sequenced in this study and nine publically available C. concisus genomes. The C. concisus core-genome was defined and genomospecies-specific genes were identified. The C. concisus core-genome, housekeeping genes and 23S rRNA gene consistently divided the 36 strains into two genomospecies. Two novel genomic islands, CON_PiiA and CON_PiiB, were identified. CON_PiiA and CON_PiiB islands contained proteins homologous to the type IV secretion system, LepB-like and CagA-like effector proteins. CON_PiiA islands were found in 37.5% of enteric C. concisus strains (3/8) isolated from patients with enteric diseases and none of the oral strains (0/27), which was statistically significant. This study reports the findings of C. concisus genomospecies-specific genes, novel genomic islands that contain type IV secretion system and putative effector proteins, and other new genomic features. These data provide novel insights into understanding of the pathogenicity of this emerging opportunistic pathogen.

Acute liver failure (ALF) remains a potentially devastating syndrome with a high mortality rate. Much interest continues to center upon the possibility of providing effective liver support through various artificial and bioartificial extracorporeal devices. The development of purpose-designed intensive care units for the treatment of ALF allowed a better understanding of the clinical syndrome and its best management, through the ability to conduct detailed clinical observation and clinical trials of new interventions. Survival rates are substantially improved today compared with the mortality rate that approximated 100% when the syndrome was first described nearly five decades ago. Nonetheless, these have plateaued in recent years, prompting one to consider whether major new advances in disease understanding are needed to further improve the overall outcome. A major challenge to a broader understanding of disease pathogenesis and the ability to direct appropriate therapy remains the substantial number of cases of ALF for which no specific etiology can be identified. Much is now known about the basic molecular mechanisms underlying hepatocyte cell death in ALF and an important issue is whether these cell death pathways can, in the future, be interrupted for therapeutic gain. Such considerations would seem most relevant in the early stages of the clinical course, when damage to the liver is not so severe but perhaps programmed to so evolve. A particular challenge will be to reduce hepatocellular death without inhibiting the liver's regenerative potential, given the pleiotropic functions of some of the molecules involved in both processes.

The prevalence of lactose malabsorption (LM) is increased in the elderly, although the mechanisms responsible are still a matter of speculation. The objective of this study was to investigate the possible roles of reduced functional small intestinal absorptive area, lactase deficiency and small intestinal bacterial overgrowth (SIBO).Twenty Caucasian (Anglo-Celtic), asymptomatic, well-nourished, elderly volunteers (median age 79 years, range 70-94 years) with no clinically apparent predisposition to SIBO underwent a 50 g lactose breath hydrogen test (LBHT) and mannitol absorption test, the latter as an index of functional small intestinal absorptive area. Those with LM additionally underwent bacteriological assessment of small intestinal secretions and mucosal biopsy, to assess the contribution of SIBO and lactase deficiency, respectively, to the pathogenesis of LM in individual cases. The prevalence of SIBO was also determined in elderly subjects without LM. Twenty asymptomatic younger subjects (median age 29 years, age range 18-35 years) served as controls. All subjects were "hydrogen producers" in response to lactulose.LM was evident in 10/20 (50%) elderly subjects and 1/20 (5%) younger subjects (p=0.003). Mannitol absorption did not differ significantly in elderly and younger subjects or in elderly subjects with and without LM. SIBO was documented in 9/10 (90%) elderly subjects with LM; eradication was associated with resolution of LM. Lactase deficiency was evident in only one elderly subject with LM. SIBO was evident in 2/10 (20%) elderly subjects without LM (p=0.005 compared to those with LM). Lactulose breath hydrogen test identified only 2/11 (18%) elderly subjects with SIBO.Increased prevalence of LM in the elderly is mostly due to clinically non-apparent SIBO, rather than mucosal factors. The lactulose breath hydrogen test cannot be relied upon to identify elderly subjects with SIBO, even in those without an anatomical predisposition.

Properly assessing the safety of pharmacological therapies for gastrointestinal conditions encountered during pregnancy is a challenge on account of both the often limited controlled data available and the potentially confounding effect of the underlying disorders requiring treatment on fetal outcomes. Here, the available data with regard to gastrointestinal disorders specific to pregnancy, those that may be precipitated or exacerbated by pregnancy and those that may be pre-existing or arise concurrently during pregnancy are reviewed.

On the basis of limited experimental and clinical studies, increased activity of the vasodilatory nitric oxide-cyclic guanosine monophosphate pathway is considered to play a key role in the pathogenesis of hepatopulmonary syndrome. We report a 46-year-old woman with Child-Pugh class C cirrhosis and progressive dyspnoea for 12 months. Investigations revealed elevated circulating concentrations of nitric oxide metabolites and exhaled nitric oxide levels, an hyperdynamic circulation with low systemic vascular resistance and mean arterial pressure, a large right to left intrapulmonary shunt fraction on radiolabelled macroaggregated albumin perfusion scanning, positive contrast-enhanced echocardiography, reduced diffusion capacity of carbon monoxide, hypoxaemia and orthodeoxyia, all in keeping with severe hepatopulmonary syndrome. Sequential inhibition of the nitric oxide-cyclic guanosine monophosphate pathway using curcumin (diferuloylmethane), terlipressin and methylene blue was associated with substantial improvements in vascular tone and the hyperdynamic circulation. No improvement, however, in the intrapulmonary shunt was demonstrated. Both hypoxaemia and orthodeoxia were substantially, reproducibly and reversibly worsened with all three treatments. Our findings argue against the contention that intrapulmonary shunting and impairment in arterial oxygenation in hepatopulmonary syndrome are necessarily the consequence of on-going, nitric oxide-cyclic guanosine monophosphate-mediated vasodilatation, at least in the chronic stage, and, given the possibility of substantial worsening of pulmonary oxygen exchange, suggest that inhibition of the nitric oxide-cyclic guanosine monophosphate pathway should be avoided in this setting.

Given that Campylobacter jejuni is recognized as the most common cause of bacterial gastroenteritis worldwide, recent findings showing comparable levels of Campylobacter concisus in patients with gastroenteritis would suggest that this bacterium is clinically important. The prevalence and abundance of Campylobacter concisus in stool samples collected from patients with acute gastroenteritis was examined using quantitative real-time PCR. The associated virulence determinants exotoxin 9 and zonula occludens toxin DNA were detected for Campylobacter concisus-infected samples using real-time PCR. Campylobacter concisus was detected at high prevalence in patients with gastroenteritis (49.7 %), higher than that observed for Campylobacter jejuni (∼5 %). The levels of Campylobacter concisus were putatively classified into clinically relevant and potentially transient subgroups based on a threshold developed using Campylobacter jejuni levels, as the highly sensitive real-time PCR probably detected transient passage of the bacterium from the oral cavity. A total of 18 % of patients were found to have clinically relevant levels of Campylobacter concisus, a significant number of which also had high levels of one of the virulence determinants. Of these patients, 78 % were found to have no other gastrointestinal pathogen identified in the stool, which strongly suggests a role for Campylobacter concisus in the aetiology of gastroenteritis in these patients. These results emphasize the need for diagnostic laboratories to employ identification protocols for emerging Campylobacter species. Clinical follow-up in patients presenting with high levels of Campylobacter concisus in the intestinal tract is needed, given that it has been associated with more chronic sequelae.

Campylobacter concisus is an oral bacterium that has been shown to be associated with inflammatory bowel disease (IBD). In this study we examined clusters of oral C. concisus strains isolated from patients with IBD and healthy controls by analysing six housekeeping genes. In addition, we investigated the population structure of C. concisus strains. Whether oral and enteric strains form distinct clusters based on the sequences of these housekeeping genes was also investigated. The oral C. concisus strains were found to contain two genomospecies, which belong to the two genomospecies previously found in enteric C. concisus strains. C. concisus clusters formed based on the sequences of a single aspA gene were the same as that formed by using previously reported MLST schemes. The analysis of combined oral and enteric C. concisus strains found that enteric C. concisus strains did not form distinct clusters. Genetic structure analysis identified five subpopulations of C. concisus and showed that genetic recombination between C. concisus strains was common. However, genetic recombination was significantly less in oral strains isolated from patients with IBD than from healthy individuals. Previously reported oral and enteric intestinal epithelial invasive C. concisus strains were in cluster II and subpopulation III. Furthermore, this study shows that there are no distinct enteric C. concisus strain clusters or subpopulations.

Tissue fibrosis is a core pathologic process that contributes to mortality in ~45% of the population and is likely to be influenced by the host genetic architecture. Here we demonstrate, using liver disease as a model, that a single-nucleotide polymorphism (rs12979860) in the intronic region of interferon-λ4 (IFNL4) is a strong predictor of fibrosis in an aetiology-independent manner. In a cohort of 4,172 patients, including 3,129 with chronic hepatitis C (CHC), 555 with chronic hepatitis B (CHB) and 488 with non-alcoholic fatty liver disease (NAFLD), those with rs12979860CC have greater hepatic inflammation and fibrosis. In CHC, those with rs12979860CC also have greater stage-constant and stage-specific fibrosis progression rates (P, Tissue fibrosis is a major contributor to mortality in the developed world. Here, the authors identify a genetic variant in the intronic region of interferon-λ4 that is a strong predictor of hepatic inflammation and fibrosis, independent of liver disease aetiology

In patients with cirrhosis and hepatocellular carcinoma (HCC), orthotopic liver transplantation (OLT) offers hope for cure of both the complicating HCC and the underlying chronic liver disease. Excellent 5 year survival has been reported when the restrictive Milan criteria are used to select transplant candidates. Alternative recommendations have recently been proposed by groups at University of California San Francisco, University of Pittsburgh and Mount Sinai. We review current and evolving concepts regarding selection criteria for OLT in patients with HCC, along with strategies to reduce waiting times, such as the impact of the implementation of the model for end-stage liver disease (MELD) scoring system on organ distribution and the role of living donor OLT for this indication. The possible efficacy of adjuvant anti-tumour therapies in limiting HCC growth while waiting for OLT, along with factors influencing the risk of HCC recurrence post-OLT, the major cause of death in this setting, are also discussed.

Minimal hepatic encephalopathy (MHE) is an important disorder that may seriously impair daily functioning and quality of life in patients with cirrhosis. Treatment with lactulose is of benefit. The possible role of synbiotics (probiotics and fermentable fiber) has not been assessed. We screened 97 consecutive cirrhotic patients without overt hepatic encephalopathy for MHE using the number connection test and measurement of brainstem auditory evoked potentials. MHE, defined by abnormality on at least one test modality, was present in 58 (60%) patients. Fifty-five of these patients with MHE were randomized to receive a synbiotic preparation (n = 20), fermentable fiber alone (n = 20), or placebo (n = 15) for 30 days. Cirrhotic patients with MHE were found to have substantial derangements in the gut microecology, with significant fecal overgrowth of potentially pathogenic Escherichia coli and Staphylococcal species. Synbiotic treatment significantly increased the fecal content of non-urease-producing Lactobacillus species at the expense of these other bacterial species. Such modulation of the gut flora was associated with a significant reduction in blood ammonia levels and reversal of MHE in 50% of patients. Synbiotic treatment was also associated with a significant reduction in endotoxemia. The Child-Turcotte-Pugh functional class improved in nearly 50% of cases. Treatment with fermentable fiber alone was also of benefit in a substantial proportion of patients. In conclusion, treatment with synbiotics or fermentable fiber is an alternative to lactulose for the management of MHE in patients with cirrhosis.

Acute liver failure (ALF) occurs when the rate and extent of liver cell death are not adequately balanced by regenerative activity. Two forms of liver cell death are recognized: apoptosis and necrosis. A number of causes of ALF have been shown, predominantly in experimental animal models, to induce one or the other form of liver cell death. Nonetheless, an insult capable of inducing apoptosis may cause cell death by necrosis, particularly if the degree of mitochondrial damage is sufficient to exhaust stores of adenosine triphosphate. Here we consider mechanisms of liver cell injury in ALF, including evolving knowledge of signaling pathways leading to hepatocellular apoptosis and necrosis. Factors that have an impact on the adequacy of hepatic regeneration along with the pathophysiology of complicating multiorgan failure are also reviewed. Prognostic criteria are discussed, especially in relation to current concepts of mechanisms of liver cell death and multiorgan dysfunction.

The presence of Campylobacter concisus in the saliva of healthy individuals and patients with inflammatory bowel disease (IBD) was examined. C . concisus was detected in 97% of the healthy individuals and 100% of the patients with IBD tested. The C . concisus culture positivity rate in younger children was significantly lower than that in the other age groups.

Any virus that can cause an acute hepatitis will, on occasion, give rise to acute liver failure. Such infections can be separated into those due to the primary hepatitis viral infections A to E and those where hepatitis occurs as part of a systemic viral infection, as with infection with, for instance, Epstein-Barr virus, cytomegalovirus, Varicella zoster virus, adenovirus and Herpes simplex virus. In general, the frequency with which the different hepatitis viruses are responsible for acute liver failure is related to their underlying prevalence in particular countries. An apparent exception is the striking geographical variation in the reported prevalence of acute liver failure due to hepatitis C virus infection, with a much higher proportion of cases generally attributed to this agent in Japan and Taiwan than in Western countries. Recent work has focused on the possible importance of mutant hepatitis B viral strains, co- and super-infection with known hepatitis viruses and certain newly described agents that may account for otherwise unexplained cases of acute liver failure. Despite an improved understanding of the pathogenesis of complicating cerebral oedema and advances in general supportive care, it is likely that the most severely affected patients with acute liver failure due to viral causes will survive only with liver transplantation, at least until approaches for promoting adequate liver regeneration are successfully developed and implemented.

OBJECTIVES: The aims of this study were 1) to document the sensitivity, specificity, and predictive values of the rice breath hydrogen test for small intestinal bacterial overgrowth; 2) to determine the possible influence of concurrent gastric bacterial overgrowth and gastroduodenal pH on the efficacy of this test; and 3) to investigate whether reliability is limited by an inability of small intestinal luminal flora to ferment rice or its product of hydrolysis, maltose. METHODS: Twenty adult subjects were investigated with microbiological culture of proximal small intestinal aspirate and a 3-g/kg rice breath hydrogen test. Gastroduodenal pH, the presence or absence of gastric bacterial overgrowth, and the in vitro capability of small intestinal luminal flora to ferment rice and maltose, its product of hydrolysis, were determined. RESULTS: Sensitivity of the rice breath hydrogen test for small intestinal bacterial overgrowth was 33% and remained low even when subjects with small intestinal overgrowth with oropharyngeal-type (38%) and colonic-type flora (20%) and those with concurrent small intestinal and gastric bacterial overgrowth (40%) were considered separately. Sensitivity remained suboptimal despite favorable gastroduodenal luminal pH and documented ability of bacterial isolates to ferment rice and maltose in vitro. Specificity of the rice breath hydrogen test for small intestinal bacterial overgrowth was 91%. Positive predictive value, negative predictive value, and predictive accuracy were 75%, 63%, and 65%, respectively. CONCLUSIONS: Clinical value of the rice breath hydrogen test for detecting small intestinal bacterial overgrowth is limited. The rice breath hydrogen test is not a suitable alternative to small intestinal intubation and culture of secretions for the detection of small intestinal bacterial overgrowth.

Acute liver failure (ALF) still represents a major therapeutic challenge for hepatologists due to its high mortality rate as a result of multiorgan failure. Although emergency orthotopic liver transplantation represents a major advance in the management of selected patients, it is not applicable to all candidates due to limited organ availability. Therefore, new therapeutic options should be developed to bridge selected patients to transplantation or to treat patients not candidates for liver transplantation. Although new techniques for cell culture and perfusion have resulted in a number of promising devices for the provision of temporary liver support in acute liver failure, their clinical efficacy is as yet uncertain. Controlled trials on a multi-centre basis in well-defined patient groups and with standardised outcome measures, including the extent to which treatment influences cell damage and regeneration and prevents or reverses multiorgan failure, will be essential to properly evaluate the clinical value of current and evolving artificial and bioartificial devices. The same considerations must also apply to the assessment of therapeutic efficacy of hepatocyte transplantation. A better understanding of mechanisms responsible for the development of liver cell death, along with cellular and molecular mechanisms allowing surviving cells to proliferate in a hostile environment, will be required if a more targeted therapeutic approach to decreasing hepatocellular injury and enhancing liver regeneration is to be achieved. Whether extracorporeal devices or the transplantation of primary hepatocytes, stem cells or cells genetically engineered to over-express key metabolic functions, a proliferative phenotype and/or cytoprotective pathways will be best suited to meeting these demanding challenges remains to be determined.

The relative shortage of donor organs and lack of immediate availability mean that many patients with acute liver failure die before orthotopic liver transplantation can be performed. An effective temporary liver support system could improve the chance of survival with or without a transplant being ultimately carried out. Recent technological advances resulting in improved maintenance of hepatocyte viability and function in culture and bioreactor designs which facilitate adequate perfusion of the cellular component and removal of products of cellular metabolism have led to the development of a number of bioartificial devices for liver support. Three such devices have undergone preliminary clinical evaluation in the setting of acute liver failure, with a statistically significant reduction in raised intracerebral pressure along with improvements in consciousness level and some biochemical parameters associated with treatment with one of these. Several other devices with different characteristics have shown promise in vitro and/or in animal models but await clinical evaluation. Several new totally artificial systems have also been described, along with the emergence of isolated hepatocyte transplantation, with reports of successful 'bridging' to liver transplantation. Controlled trials on a multicentre basis in well-defined patient groups and with standardized outcome measures will be required to properly evaluate the clinical value of each of these approaches to providing liver support in acute liver failure and cirrhosis. A better understanding of mechanisms underlying multiorgan failure and of factors inhibiting liver regeneration, thereby allowing a more targeted approach, will be essential to the further development of effective liver support strategies in these settings.

Hepatitis C virus (HCV) infection usually recurs after orthotopic liver transplantation (OLT), and most patients develop graft damage. This study compared the efficacy of interferon alfa (IFN-alpha) and ribavirin monotherapies in liver transplant recipients with chronic hepatitis C in the graft. Thirty OLT recipients with chronic hepatitis C were randomized to receive either IFN-alpha (3 MU three times a week) or ribavirin (up to 1.2 g daily) for 24 weeks. Virological, biochemical, and histological responses to treatment were assessed. Twenty-eight patients completed the treatment regimen, two ribavirin-treated patients being withdrawn because of severe hemolysis. Normalization of serum aspartate aminotransferase was achieved in 13 of 14 patients receiving ribavirin (93%) and 6 of 14 patients receiving IFN-alpha (43%; P=.01). Lobular inflammation was reduced in 9/14 ribavirin-treated (64%) and 3 of 14 IFN-alpha-treated patients (21%; P=.05), each of whom had a biochemical response. However, the total histological activity index did not improve in either the interferon (P=.43) or the ribavirin (P=.96) group. Posttreatment viremia levels were significantly reduced in IFN-alpha-treated (P=.05) but not in ribavirin-treated (P=.88) patients. Hemolysis occurred in all ribavirin-treated patients, with serum hemoglobin decreasing to < 10 g/dL in 50%. Total leukocyte and lymphocyte counts decreased significantly during ribavirin treatment (P=.02 and P=.004, respectively). We concluded that in patients with chronic hepatitis C after OLT, IFN-alpha retains an antiviral effect whereas ribavirin is superior in achieving normalization of serum aspartate aminotransferase levels and reducing lobular inflammation, but not the total histological activity index. These findings provide a rationale for combination therapy in the post-OLT setting, although patients must be carefully monitored for hemolysis.

Objective: Some rodent strains with experimental small intestinal bacterial overgrowth (SIBO) unrelated to jejunoileal bypass are susceptible to hepatic damage, possibly because of increased small intestinal permeability to proinflammatory bacterial polymers. However, data on the prevalence of hepatic damage in human subjects with SIBO in this setting are lacking. This study addressed this issue. Methods: Seventy adult subjects were investigated for possible SIBO and hepatic damage with bacteriological analysis of small intestinal aspirates and measurement of serum concentrations of alkaline phosphatase, gamma-glutamyl transpeptidase, aspartate aminotransferase, and alanine aminotransferase. Nutritional indices (serum albumin and anthropometry) and the urinary lactulose/mannitol ratio, an index of small intestinal permeability, were measured in all subjects with SIBO and liver damage. Results: SIBO was present in 40 of 70 subjects (57.1%). Overgrowth flora included salivary-type bacteria alone in 11 subjects and colonictype bacteria in 29 subjects (facultative anaerobes [Enterobacteriaceae] alone in 21 subjects and both facultative and obligate anaerobes [Enterobacteriaceae and Bacteroides spp]in eight subjects). Biochemical evidence of liver damage was found in zero of 30 subjects without SIBO, zero of 11 subjects with SIBO with salivary-type bacteria alone, zero of 21 subjects with SIBO with facultative but not obligate anaerobic colonic-type bacteria, and in one of eight subjects (12.5%) with SIBO with obligate anaerobic colonic-type bacteria, in whom serum alkaline phosphatase and gamma-glutamyl transpeptidase levels were elevated. Nutritional indices were normal in this patient. Small intestinal permeability was increased and, along with liver enzyme abnormalities, normalized after eradication of SIBO. Small intestinal permeability was also increased in three of six patients (50.0%) with SIBO with obligate anaerobic colonic-type bacteria who had no evidence of liver damage. Conclusions: SIBO per se is not a major risk factor for liver damage in humans, even when the overgrowth flora includes obligate anaerobes. Liver damage is not a necessary consequence of increased small intestinal permeability in this setting.

Hepatic encephalopathy is a complex neuropsychiatric syndrome that may occur in such diverse clinical situations as inherited errors of the urea cycle, acute or chronic liver disease, and spontaneous or iatrogenic portosystemic venous shunting, including that following procedures to establish a transjugular intrahepatic portosystemic shunt. The clinical manifestations of this syndrome range from subtle abnormalities detectable only by psychometric testing to deep coma. Several grading systems have been proposed; one based on clinical and electroencephalographic abnormalities is shown in Table 1.1 Hepatic encephalopathy may be present in 50 to 70 percent of all patients with cirrhosis, including those with abnormalities demonstrable . . .

Bioartificial liver devices aim to support patients with acute liver failure (ALF) until orthotopic liver transplantation (OLT) or spontaneous recovery due to hepatic regeneration can occur. However, initial clinical experiences with two devices have indicated that functional efficacy in this setting may be less than in the experimental situation. Several fundamental issues remain unresolved, including the cell mass required to provide meaningful support and which of those hepatocyte components and bioreactor designs so far proposed is best able to do this. In particular, further studies of the efficacy of devices incorporating human hepatocyte lines transformed by either cultural conditions or genetic engineering and those based on multi-channel or flat bed bioreactor designs in which hepatocytes are co-cultured with non-parenchymal cells are awaited. Controlled trials on a multicentre basis in well-defined patient groups and with standardised outcome measures will be required to properly evaluate the clinical value of these devices. A better understanding of factors promoting recovery and regeneration of the native liver and to what extent these can be provided by extracorporeal devices will be essential to the further development of effective bioartificial liver support systems.

The influence of luminal bacteria on small-intestinal permeability has not been fully assessed. This study addressed this issue.Thirty-four subjects (mean age 64 years; range 22-95 years) were investigated for possible small-intestinal bacterial overgrowth (SIBO) with culture of a small-intestinal aspirate. A lactulose/mannitol small-intestinal permeability test was performed, small-intestinal histology assessed and serum vitamin B12 concentrations measured in all subjects. Permeability was also assessed in a control group of 34 asymptomatic volunteers.Urinary lactulose/mannitol ratios were significantly increased in subjects with SIBO with colonic-type flora (P0.0005), even in the absence of villous atrophy. Urinary lactulose/mannitol ratios were increased in this group due to significantly increased urinary lactulose concentrations (P0.0005) rather than reduced urinary mannitol levels, after correcting for inter-subject variations in renal function. Counts of intraepithelial lymphocytes of CD8 phenotype were significantly increased in this group (P = 0.003). Although a significant correlation was found between intraepithelial lymphocyte counts and small-intestinal permeability overall (P0.002), these counts were not significantly different in subjects with SIBO with colonic-type flora whose permeability values wereor =0.028, the upper limit of normal in asymptomatic controls. Serum vitamin B12 concentrations did not differ significantly between groups (P0.5). Ageing did not independently influence small-intestinal permeability (P0.5).Small-intestinal permeability is increased in subjects with SIBO with colonic-type bacteria. This effect is independent of ageing and not mediated by vitamin B12 deficiency. Although counts of intraepithelial lymphocytes of CD8 phenotype are increased in this disorder, it is also unlikely that these cells play an important causative role in this process. Routine light microscopic assessment underestimates the prevalence of small-intestinal functional disturbance in this disorder.

Culture-independent molecular techniques have demonstrated that the majority of the gut microbiota is uncultivable. Application of these molecular techniques to more accurately identify the indigenous gut microbiome has moved with great pace over recent years, leading to a substantial increase in understanding of gut microbial communities in both health and a number of disorders, including irritable bowel syndrome (IBS). Use of culture-independent molecular techniques already employed to characterise faecal and, to a lesser extent, colonic mucosal microbial populations in IBS, without reliance on insensitive, traditional microbiological culture techniques, has the potential to more accurately determine microbial composition in the small intestine of patients with this disorder, at least that occurring proximally and within reach of sampling. Current data concerning culture-based and culture-independent analyses of the small intestinal microbiome in IBS are considered here.

Campylobacter concisus, a Gram-negative bacterium that colonizes the human oral cavity, has been shown to be associated with inflammatory bowel diseases (IBD). The effects of different C. concisus strains on intestinal epithelial expression of Toll like receptors (TLR) have not been investigated. This study examined the effects of C. concisus strains isolated from patients with IBD and controls on expression of TLR4, its co-receptor myeloid differentiation factor (MD)-2; TLR2, TLR5, cyclooxygenase-2 (COX-2) and interleukin (IL)-8 in HT-29 cells. Fourteen oral and enteric C. concisus strains isolated from patients with IBD and healthy controls were co-incubated with HT-29 cells. Expression of TLR4, MD-2, TLR2, TLR5 and COX-2 in HT-29 cells in response to C. concisus infection was examined by Western blot, flow cytometry analysis and immunofluorescent staining visualized by confocal microscope. Production of IL-8 was evaluated by enzyme-linked immunosorbent assay. Both oral and enteric C. concisus strains upregulated expression of TLR4 in HT-29 cells. The levels of glycosylated TLR4 (Gly-TLR4) and surface TLR4 induced by C. concisus strains isolated from patients with IBD were significantly higher than those induced by C. concisus strains isolated from the healthy controls. Four C. concisus strains isolated from patients with IBD induced more than two-fold increase of surface expression of MD-2. C. concisus did not affect expression of TLR2 and TLR5. All C. concisus strains induced production of IL-8 and COX-2 in HT-29 cells. This study shows that some C. concisus strains, most from patients with IBD, upregulate surface expression of TLR4 and MD-2 in HT-29 cells. These data suggest that a potential role of specific C. concisus strains in modulating the intestinal epithelial responses to bacterial LPS needs to be investigated.

BACKGROUND: Hepatic encephalopathy is a disorder of brain function as a result of liver failure or portosystemic shunt or both. Both hepatic encephalopathy (clinically overt) and minimal hepatic encephalopathy (not clinically overt) significantly impair patient’s quality of life and daily functioning, and represent a significant burden on healthcare resources. Probiotics are live micro‐organisms, which when administered in adequate amounts, may confer a health benefit on the host. OBJECTIVES: To determine the beneficial and harmful effects of probiotics in any dosage, compared with placebo or no intervention, or with any other treatment for people with any grade of acute or chronic hepatic encephalopathy. This review did not consider the primary prophylaxis of hepatic encephalopathy. SEARCH METHODS: We searched The Cochrane Hepato‐Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, conference proceedings, reference lists of included trials, and the World Health Organization International Clinical Trials Registry Platform until June 2016. SELECTION CRITERIA: We included randomised clinical trials that compared probiotics in any dosage with placebo or no intervention, or with any other treatment in people with hepatic encephalopathy. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. We conducted random‐effects model meta‐analysis due to obvious heterogeneity of participants and interventions. We defined a P value of 0.05 or less as significant. We expressed dichotomous outcomes as risk ratio (RR) and continuous outcomes as mean difference (MD) with 95% confidence intervals (CI). MAIN RESULTS: We included 21 trials with 1420 participants, of these, 14 were new trials. Fourteen trials compared a probiotic with placebo or no treatment, and seven trials compared a probiotic with lactulose. The trials used a variety of probiotics; the most commonly used group of probiotic was VSL#3, a proprietary name for a group of eight probiotics. Duration of administration ranged from 10 days to 180 days. Eight trials declared their funding source, of which six were independently funded and two were industry funded. The remaining 13 trials did not disclose their funding source. We classified 19 of the 21 trials at high risk of bias. We found no effect on all‐cause mortality when probiotics were compared with placebo or no treatment (7 trials; 404 participants; RR 0.58, 95% CI 0.23 to 1.44; low‐quality evidence). No‐recovery (as measured by incomplete resolution of symptoms) was lower for participants treated with probiotic (10 trials; 574 participants; RR 0.67, 95% CI 0.56 to 0.79; moderate‐quality evidence). Adverse events were lower for participants treated with probiotic than with no intervention when considering the development of overt hepatic encephalopathy (10 trials; 585 participants; RR 0.29, 95% CI 0.16 to 0.51; low‐quality evidence), but effects on hospitalisation and change of/or withdrawal from treatment were uncertain (hospitalisation: 3 trials, 163 participants; RR 0.67, 95% CI 0.11 to 4.00; very low‐quality evidence; change of/or withdrawal from treatment: 9 trials, 551 participants; RR 0.70, 95% CI 0.46 to 1.07; very low‐quality evidence). Probiotics may slightly improve quality of life compared with no intervention (3 trials; 115 participants; results not meta‐analysed; low‐quality evidence). Plasma ammonia concentration was lower for participants treated with probiotic (10 trials; 705 participants; MD ‐8.29 μmol/L, 95% CI ‐13.17 to ‐3.41; low‐quality evidence). There were no reports of septicaemia attributable to probiotic in any trial. When probiotics were compared with lactulose, the effects on all‐cause mortality were uncertain (2 trials; 200 participants; RR 5.00, 95% CI 0.25 to 102.00; very low‐quality evidence); lack of recovery (7 trials; 430 participants; RR 1.01, 95% CI 0.85 to 1.21; very low‐quality evidence); adverse events considering the development of overt hepatic encephalopathy (6 trials; 420 participants; RR 1.17, 95% CI 0.63 to 2.17; very low‐quality evidence); hospitalisation (1 trial; 80 participants; RR 0.33, 95% CI 0.04 to 3.07; very low‐quality evidence); intolerance leading to discontinuation (3 trials; 220 participants; RR 0.35, 95% CI 0.08 to 1.43; very low‐quality evidence); change of/or withdrawal from treatment (7 trials; 490 participants; RR 1.27, 95% CI 0.88 to 1.82; very low‐quality evidence); quality of life (results not meta‐analysed; 1 trial; 69 participants); and plasma ammonia concentration overall (6 trials; 325 participants; MD ‐2.93 μmol/L, 95% CI ‐9.36 to 3.50; very low‐quality evidence). There were no reports of septicaemia attributable to probiotic in any trial. AUTHORS' CONCLUSIONS: The majority of included trials suffered from a high risk of systematic error (‘bias’) and a high risk of random error (‘play of chance’). Accordingly, we consider the evidence to be of low quality. Compared with placebo or no intervention, probiotics probably improve recovery and may lead to improvements in the development of overt hepatic encephalopathy, quality of life, and plasma ammonia concentrations, but probiotics may lead to little or no difference in mortality. Whether probiotics are better than lactulose for hepatic encephalopathy is uncertain because the quality of the available evidence is very low. High‐quality randomised clinical trials with standardised outcome collection and data reporting are needed to further clarify the true efficacy of probiotics.

IntroductionCrohn's disease (CD) and ulcerative colitis (UC) are the two major forms of inflammatory bowel disease (IBD). A high prevalence of Campylobacter concisus was previously detected in paediatric CD and adult UC. Currently, the prevalence of C. concisus in adult CD and the preferential colonization sites of Campylobacter species in the human intestine are unknown. In this study, we examined the prevalence of Campylobacter species in biopsies collected from multiple anatomic sites of adult patients with IBD and controls.MethodsThree hundred and one biopsies collected from ileum, caecum, descending colon and rectum of 28 patients IBD (15 CD and 13 UC) and 33 controls were studied. Biopsies were used for DNA extraction and detection of Campylobacter species by PCR-sequencing and Campylobacter cultivation.ResultsA significantly higher prevalence of C. concisus in colonic biopsies of patients with CD (53%) was detected as compared with the controls (18%). Campylobacter genus-PCR positivity and C. concisus positivity in patients with UC were 85% and 77% respectively, being significantly higher than that in the controls (48% and 36%). C. concisus was more often detected in descending colonic and rectal biopsies from patients with IBD in comparison to the controls. C. concisus was isolated from patients with IBD.ConclusionThe high intestinal prevalence of C. concisus in patients with IBD, particularly in the proximal large intestine, suggests that future studies are needed to investigate the possible involvement of C. concisus in a subgroup of human IBD. To our knowledge, this is the first report of the association between adult CD and C. concisus as well as the first study of the preferential colonization sites of C. concisus in the human intestine.

Vijayaprakash Suppiah and colleagues show that genotyping hepatitis C patients for the IL28B, HLA-C, and KIR genes improves the ability to predict whether or not patients will respond to antiviral treatment., Background To date, drug response genes have not proved as useful in clinical practice as was anticipated at the start of the genomic era. An exception is in the treatment of chronic hepatitis C virus (HCV) genotype 1 infection with pegylated interferon-alpha and ribavirin (PegIFN/R). Viral clearance is achieved in 40%–50% of patients. Interleukin 28B (IL28B) genotype predicts treatment-induced and spontaneous clearance. To improve the predictive value of this genotype, we studied the combined effect of variants of IL28B with human leukocyte antigen C (HLA-C), and its ligands the killer immunoglobulin-like receptors (KIR), which have previously been implicated in HCV viral control. Methods and Findings We genotyped chronic hepatitis C (CHC) genotype 1 patients with PegIFN/R treatment-induced clearance (n = 417) and treatment failure (n = 493), and 234 individuals with spontaneous clearance, for HLA-C C1 versus C2, presence of inhibitory and activating KIR genes, and two IL28B SNPs, rs8099917 and rs12979860. All individuals were Europeans or of European descent. IL28B SNP rs8099917 “G” was associated with absence of treatment-induced clearance (odds ratio [OR] 2.19, p = 1.27×10−8, 1.67–2.88) and absence of spontaneous clearance (OR 3.83, p = 1.71×10−14, 2.67–5.48) of HCV, as was rs12979860, with slightly lower ORs. The HLA-C C2C2 genotype was also over-represented in patients who failed treatment (OR 1.52, p = 0.024, 1.05–2.20), but was not associated with spontaneous clearance. Prediction of treatment failure improved from 66% with IL28B to 80% using both genes in this cohort (OR 3.78, p = 8.83×10−6, 2.03–7.04). There was evidence that KIR2DL3 and KIR2DS2 carriage also altered HCV treatment response in combination with HLA-C and IL28B. Conclusions Genotyping for IL28B, HLA-C, and KIR genes improves prediction of HCV treatment response. These findings support a role for natural killer (NK) cell activation in PegIFN/R treatment-induced clearance, partially mediated by IL28B. Please see later in the article for the Editors' Summary, Editors' Summary Background About 170 million people harbor long-term (chronic) infections with the hepatitis C virus (HCV) and 3–4 million people are newly infected with the virus every year. HCV—a leading cause of chronic hepatitis (inflammation of the liver)—is spread though contact with infected blood. Transmission can occur during medical procedures (for example, transfusions with unscreened blood or reuse of inadequately sterilized medical instruments) but in developed countries, where donated blood is routinely screened for HCV, the most common transmission route is needle-sharing among intravenous drug users. HCV infection can cause a short-lived illness characterized by tiredness and jaundice (yellow skin and eyes) but 70%–80% of newly infected people progress to a symptom-free, chronic infection that can eventually cause liver cirrhosis (scarring) and liver cancer. HCV infections can be treated with a combination of two drugs—pegylated interferon-alpha and ribavirin (PegIFN/R). However, PegIFN/R is expensive, causes unpleasant side-effects, and is ineffective in about half of people infected with HCV genotype 1, the commonest HCV strain. Why Was This Study Done? It would be extremely helpful to be able to identify which patients will respond to PegIFN/R before starting treatment. An individual's genetic make-up plays a key role in the safety and effectiveness of drugs. Thus, pharmacogenomics—the study of how genetic variants affects the body's response to drugs—has the potential to alter the clinical management of many diseases by allowing clinicians to provide individually tailored drug treatments. In 2009, scientists reported that certain single nucleotide polymorphisms (SNPs, a type of genetic variant) lying near the IL28B gene (which encodes an immune system protein made in response to viral infections) strongly influence treatment outcomes and spontaneous clearance in HCV-infected people. This discovery is now being used to predict treatment responses to PegIFN/R in clinical practice but genotyping (analysis of variants of) IL28B only correctly predicts treatment failure two-thirds of the time. Here, the researchers investigate whether genotyping two additional regions of the genome—the HLA-C and KIR gene loci—can improve the predictive value of IL28B genotyping. Human leukocyte antigen C (HLA-C) and the killer immunoglobulin-like receptors (KIRs) are interacting proteins that have been implicated in HCV viral control. What Did the Researchers Do and Find? The researchers genotyped 417 patients chronically infected with HCV genotype 1 whose infection had been cleared by PegIFN/R treatment, 493 patients whose infection had not responded to treatment, and 234 patients whose infection had cleared spontaneously for two HLA-C variants (C1 and C2), the presence of several KIR genes (individuals carry different combinations of KIR genes), and two IL28B SNPs (rs8099917 and rs12979860). Carriage of “variants” of either IL28B SNP was associated with absence of treatment-induced clearance and absence of spontaneous clearance. That is, these variant SNPs were found more often in patients who did not respond to treatment than in those who did respond, and more often in patients who did not have spontaneous clearance of their infection than those who did. The HLA-C C2C2 genotype (there are two copies of most genes in the genome) was also more common in patients who failed treatment than in those who responded but was not associated with spontaneous clearance. The rate of correct prediction of treatment failure increased from 66% with IL28B genotyping alone to 80% with combined IL28B and HLA-C genotyping. Finally, carriage of specific KIR genes in combination with specific HLA-C and IL28B variants was also associated with an altered HCV treatment response. What Do These Findings Mean? These findings show that the addition of HCL-C and KIR genotyping to IL28B genotyping improved the prediction of HCV treatment response in the patients investigated in this study. Because all these patients were European or of European descent, these findings need confirming in people of other ethnic backgrounds. They also need confirming in other groups of Europeans before being used in a clinical setting. However, the discovery that the addition of HLA-C genotyping to IL28B genotyping raises the rate of correct prediction of PegIFN/R treatment failure to 80% is extremely promising and should improve the clinical management of patients infected with HCV genotype 1. In addition, these results provide new insights into how PegIFN/R clears HCV infections that may lead to improved therapies in the future. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001092. The World Health Organization provides detailed information about hepatitis C (in several languages) The US Centers for Disease Control and Prevention provides information on hepatitis C for the public and for health professionals (information is also available in Spanish) The US National Institute of Diabetes and Digestive and Kidney Diseases provides basic information on hepatitis C (in English and Spanish) The Hepatitis C Trust is a patient-led, patient-run UK charity that provides detailed information about hepatitis C and support for patients and their families; a selection of personal stories about patients' experiences with hepatitis C is available, including Phil's treatment story, which details the ups and downs of treatment with PegIFN/R MedlinePlus provides links to further resources on hepatitis C The Human Genome Project provides information about medicine and the new genetics, including a primer on pharmacogenomics

OBJECTIVES: Available data regarding whether appendicectomy performed after the onset of ulcerative colitis can modulate its clinical course are currently limited. This study aimed at addressing this issue. METHODS: In this study, we report a prospective case series of 30 adult patients (median age 35 years, range 17-70 years; male/female: 11/19) with ulcerative proctitis (median duration of symptoms 5 years, range 8 months to 30 years; median Simple Clinical Colitis Activity Index score 9, range 7-12), who underwent appendicectomy in the absence of any history suggestive of previous appendicitis. Patients were subsequently followed up clinically with the assessment of the Simple Clinical Colitis Activity Index for a median of 14 months (range 9-32 months). RESULTS: After appendicectomy, the clinical activity index improved significantly to a median score of 2 (range 0-12) (P

Background/Aims The human equivalent of mouse mammary tumour virus (MMTV-LV) may have a role in the pathogenesis of primary biliary cirrhosis (PBC) and breast carcinogenesis. We investigated MMTV-LV prevalence in patients with liver disease of diverse aetiology and associations with hepatic expression of hormonal receptors, p53 protein and complicating hepatocarcinogenesis. Methods Nested PCR for MMTV-LV envelope was performed using tissue from 210 patients with liver disease and 20 patients with histologically normal liver. Hepatic expression of estrogen receptor-alpha (ER-α), progesterone receptor (PgR) and p53 protein was determined by immunohistochemistry. MMTV-LV expression was also determined in hepatocellular carcinoma (HCC) tissue from 21 patients, in 11 of whom paired non-tumourous liver tissue was available for comparison. Results MMTV-LV envelope sequences were present in 25% (53/210) of liver disease biopsies but not in histologically normal liver (0/20) ( P =0.02). There was no association between MMTV-LV presence and hepatic expression of ER-α or p53 protein. No liver sections were PgR positive. MMTV-LV prevalence was not significantly different in HCC tissue, paired non-tumourous chronic liver disease tissue from the same patients and liver disease tissue from patients without complicating HCC. Conclusions Hepatic expression of MMTV-LV is evident in a wide range of non-cirrhotic and cirrhotic liver diseases, irrespective of ER-α, PgR or p53 status, and unrelated to complicating HCC.

Toll-like receptors (TLRs) play a key role in the innate immune response. The aim of this study was to examine the expression of TLR2 and TLR4 in chronic hepatitis B (CHB). The TLR2 and TLR4 expression on hepatocytes and Kupffer cells from fresh liver biopsies was measured from 21 patients with untreated hepatitis B e antigen (HBeAg)-positive and HBeAg-negative CHB. Parallel studies were also undertaken on monocytes from their peripheral blood. Expression of TLR2 on hepatocytes, Kupffer cells, and peripheral monocytes was significantly reduced in patients with HBeAg-positive CHB in comparison with HBeAg-negative CHB and controls, whereas it was significantly increased in HBeAg-negative CHB compared with controls. The level of TLR4 expression did not differ significantly between the groups. These results were confirmed in vitro using hepatic cell lines transduced with recombinant HBV baculovirus expressing wild-type HBV (HBeAg-positive), precore stop codon (G1896A) mutant HBV (HBeAg-negative). The functional relevance of these findings was established by the demonstration of significantly reduced cytokine production (TNF-α) and phospho-p38 kinase expression in the presence of the HBeAg. In the absence of HBeAg, HBV replication was associated with up-regulation of the TLR2 pathway leading to increased TNF-α production. Conclusion: This study demonstrates a potentially important interaction between HBeAg, HBV, and the innate immune response. (HEPATOLOGY 2007;45:102–110.)

Bacterial infection, especially with intestinal-type bacterial flora, is a common complication in patients with cirrhosis [1–4]. Spontaneous bacterial peritonitis (SBP), urinary tract infection, pneumonia, spontaneous bacterial empyema and bacteraemia are the most frequent infective complications in this group. The incidence of infection with Gram-positive cocci, in particular, has increased in recent years, with such flora now the most frequent isolates in hospitalised cirrhotics with nosocomial infection, especially those admitted to intensive care units, presumably due to the high rate of requirement for invasive procedures in this group [4]. Recent data suggest that between 15% and 35% of cirrhotic patients admitted to hospital develop nosocomial bacterial infection, substantially higher than the infection rate in the order of 5% to 7% in the general hospital patient setting [5]. Excluding sepsis related to invasive procedures in hospitalised patients, several factors likely predispose to the increased potential for bacterial infection in patients with cirrhosis. Increasing evidence points to a key role for bacterial translocation of intestinal flora from the intestinal lumen, in combination with failure of anti-bacterial defence mechanisms to efficiently clear these translocating microorganisms [6]. The latter defences include reduced opsonic activity due to low hepatic synthesis of complement, deranged function of macrophage Fc gamma receptors and reduced phagocytic and killing capacity of neutrophils [7–10]. The high prevalence of associated malnutrition in cirrhotic patients [11] exacerbates the potential for infection. Impairment of mucosal immunity may also be important [12]. Complicating bacterial infection may have severe adverse clinical consequences in cirrhotic patients.