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Liver transplantation as a treatment option for end-stage liver diseases is associated with a relevant risk for complications. On the one hand, immunological factors and associated chronic graft rejection are major causes of morbidity and carry an increased risk of mortality due to liver graft failure. On the other hand, infectious complications have a major impact on patient outcomes. In addition, abdominal or pulmonary infections, and biliary complications, including cholangitis, are common complications in patients after liver transplantation and can also be associated with a risk for mortality. Thereby, these patients already suffer from gut dysbiosis at the time of liver transplantation due to their severe underlying disease, causing end-stage liver failure. Despite an impaired gut-liver axis, repeated antibiotic therapies can cause major changes in the gut microbiome. Due to repeated biliary interventions, the biliary tract is often colonized by several bacteria with a high risk for multi-drug resistant germs causing local and systemic infections before and after liver transplantation. Growing evidence about the role of gut microbiota in the perioperative course and their impact on patient outcomes in liver transplantation is available. However, data about biliary microbiota and their impact on infectious and biliary complications are still sparse. In this comprehensive review, we compile the current evidence for the role of microbiome research in liver transplantation with a focus on biliary complications and infections due to multi-drug resistant germs. more...

The impact of invasive candidiasis (IC) on the outcomes in the non-conventional high-risk cirrhosis population is poorly characterized. Therefore, we reviewed the outcomes and their influencing factors in cirrhosis patients with IC. PubMed, Embase, Ovid, CINHAL, and Web of Science were searched for full-text observational studies describing mortality due to IC in cirrhosis. We did a systematic review and random-effects meta-analysis to pool the point-estimate and comparative-odds of mortality. The estimate's heterogeneity was explored on sub-groups, outliers-test, and meta-regression. We evaluated the asymmetry in estimates on funnel plot and Eggers regression. Quality of studies was assessed on the New-Castle Ottawa scale. Of 3143 articles, 13 studies (611 patients) were included (good/fair quality: 6/7). IC patients were sick with a high model for end-stage liver disease (MELD: 27.0) and long hospital stay (33.2 days). The pooled-mortality was 54.7% (95% CI: 41.3--67.5), I2: 80%, P < 0.01. Intensive care unit (ICU) admission (P < 0.001), site of infection; viz. peritonitis and candidemia (P = 0.014) and high MELD of cases (P = 0.029) were predictors of high mortality. The odds of mortality due to IC was 4.4 times higher than controls and was 8.5 and 3.3 times higher than non-infected, and bacterially-infected controls. Studies in ICU-admitted (OR: 5.0) or acute-on-chronic liver failure (ACLF, OR: 6.3) patients had numerically higher odds of mortality than all-hospitalized cirrhosis patients (OR: 4.0). In conclusion, substantially high mortality is reported in cirrhosis patients with IC. ICU admission, ACLF, high MELD, peritonitis, and candidemia are key factors determining high mortality in cirrhosis patients with IC., Lay Summary: We report a high mortality rate of 55% in patients with liver cirrhosis and invasive candidiasis. Higher odds (4.4 times) of death, especially in patients with ACLF (6.3 times) or ICU admission (5.0 times) were seen. Candida peritonitis and candidemia are associated with high mortality in cirrhosis., (© The Author(s) 2021. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.) more...

Recent investigations of gut microbiota have contributed to understanding of the critical role of microbial community in pathophysiology. Dysbiosis not only causes disturbance directly to the gastrointestinal tract but also affects the liver through gut-liver axis. Various types of dysbiosis have been documented in alcoholic liver disease (ALD), nonalcoholic fatty liver disease, autoimmune hepatitis (AIH), primary sclerosing cholangitis, and may be crucial for the initiation, progression, or deterioration to end-stage liver disease. A few microbial species have been identified as the causal factors leading to these chronic illnesses that either do not have clear etiologies or lack effective treatment. Notably, cytolysin-producing Enterococcus faecalis, Klebsiella pneumoniae and Enterococcus gallinarum were defined for ALD, NASH, and AIH, respectively. These groundbreaking discoveries drive a rapid development in innovative therapeutics, such as fecal microbial transplantation and implementation of specific bacteriophages in addition to prebiotics, probiotics, or synbiotics for intervention of dysbiosis. Although most emerging interventions are in preclinical development or early clinical trials, a better delineation of specific dysbiosis in these disorders at metabolic, immunogenic, or molecular levels in establishing particular causal effects aids in modulating or correcting the microbial community which is the part of daily life for human being., (© 2021 Federation of American Societies for Experimental Biology.) more...

In chronic liver disease, the causative factor is important; however, recently, the intestinal microbiome has been associated with the progression of chronic liver disease and the occurrence of side effects. The immune system is affected by the metabolites of the microbiome, and diet is the primary regulator of the microbiota composition and function in the gut-liver axis. These metabolites can be used as therapeutic material, and postbiotics, in the future, can increase or decrease human immunity by modulating inflammation and immune reactions. Therefore, the excessive intake of nutrients and the lack of nutrition have important effects on immunity and inflammation. Evidence has been published indicating that microbiome-induced chronic inflammation and the consequent immune dysregulation affect the development of chronic liver disease. In this research paper, we discuss the overall trend of microbiome-derived substances related to immunity and the future research directions. more...

Objective: Altered bacterial composition is associated with disease progression in cirrhosis but the role of virome, especially phages, is unclear., Design: Cross-sectional and pre/post rifaximin cohorts were enrolled. Cross-sectional: controls and cirrhotic outpatients (compensated, on lactulose (Cirr-L), on rifaximin (Cirr-LR)) were included and followed for 90-day hospitalisations. Pre/post: compensated cirrhotics underwent stool collection pre/post 8 weeks of rifaximin. Stool metagenomics for bacteria and phages and their correlation networks were analysed in controls versus cirrhosis, within cirrhotics, hospitalised/not and pre/post rifaximin., Results: Cross-sectional: 40 controls and 163 cirrhotics (63 compensated, 43 Cirr-L, 57 Cirr-LR) were enrolled. Cirr-L/LR groups were similar on model for end-stage liver disease (MELD) score but Cirr-L developed greater hospitalisations versus Cirr-LR (56% vs 30%, p=0.008). Bacterial alpha/beta diversity worsened from controls through Cirr-LR. While phage alpha diversity was similar, beta diversity was different between groups. Autochthonous bacteria linked negatively, pathobionts linked positively with MELD but only modest phage-MELD correlations were seen. Phage-bacterial correlation network complexity was highest in controls, lowest in Cirr-L and increased in Cirr-LR. Microviridae and Faecalibacterium phages were linked with autochthonous bacteria in Cirr-LR, but not Cirr-L hospitalised patients had greater pathobionts, lower commensal bacteria and phages focused on Streptococcus, Lactococcus and Myoviridae. Pre/post: No changes in alpha/beta diversity of phages or bacteria were seen postrifaximin. Phage-bacterial linkages centred around urease-producing Streptococcus species collapsed postrifaximin., Conclusion: Unlike bacteria, faecal phages are sparsely linked with cirrhosis characteristics and 90-day outcomes. Phage and bacterial linkages centred on urease-producing, ammonia-generating Streptococcus species were affected by disease progression and rifaximin therapy and were altered in patients who experienced 90-day hospitalisations., Competing Interests: Competing interests: DK, EH, TSR and TW are employees of Diversigen, where the metagnomic and virome analysis was performed., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.) more...

Chronic liver disease is reaching epidemic proportions with the increasing prevalence of obesity, nonalcoholic liver disease, and alcohol overuse worldwide. Most patients are not candidates for liver transplantation even if they have end-stage liver disease. There is growing evidence of a gut microbial basis for many liver diseases, therefore, better diagnostic, prognostic, and therapeutic approaches based on knowledge of gut microbiota are needed. We review the questions that need to be answered to successfully translate our knowledge of the intestinal microbiome and the changes associated with liver disease into practice., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.) more...

Background and Aims: Alcoholic hepatitis is the most severe form of alcohol-related liver disease. While the gut microbiome is known to play a role in disease development and progression, less is known about specific compositional changes of the gut bacterial microbiome associated with disease severity. Therefore, the aim of our study was to correlate gut microbiota features with disease severity in alcoholic hepatitis patients., Methods: We used 16S rRNA gene sequencing on fecal samples from 74 alcoholic hepatitis patients, which were enrolled at 9 centers in Europe, the United States, and Mexico in a multi-center observational study. The relative abundance of gut bacterial taxa on genus level, as well as the microbiome diversity, was correlated to various clinical, laboratory, and histologic parameters., Results: We observed a negative correlation between the model for end-stage liver disease score and Shannon diversity, independent of potentially confounding factors (P adjust  = 0.046). Alcoholic hepatitis patients with more severe disease had significantly decreased relative abundances of Akkermansia while the relative abundance of Veillonella was increased. We observed a reduction in the Bacteroides abundance (P adjust  = 0.048) and Shannon diversity (P adjust  = 0.018) in antibiotic-treated patients and patients receiving steroids had an increase in Veillonella abundance (P adjust  = 0.005), which was both independent of potentially confounding factors., Conclusion: We observed distinct changes in the gut bacterial microbiome of alcoholic hepatitis patients with more severe disease. The gut bacterial microbiome might be an attractive target to prevent and treat this deadly disease. more...

The presence of advanced fibrosis is an important measure of the severity of chronic liver disease. Prior works that have examined the gut microbiome as a novel biomarker for advanced fibrosis have only examined patients with nonalcoholic fatty liver disease. Therefore, our goal was to examine the gut microbiome across varying etiologies of liver disease to create a predictive model for liver fibrosis based upon a microbial signature. Stool samples were obtained from patients with chronic liver disease (n = 50) undergoing FibroScan (ultrasound elastography) at the VA Greater Los Angeles Healthcare System. Healthy control patients (n = 25) were also recruited as a reference population. Fecal samples underwent 16S ribosomal RNA sequencing. Using differentially abundant microbes, a random forest classifier model was created to distinguish advanced fibrosis from mild/moderate fibrosis. The findings were then validated in a separate cohort of chronic liver disease patients (n = 37). Etiologies for liver disease included non-alcoholic liver disease (58.0%), hepatitis C (26.0%), hepatitis B (10.0%), and alcohol (6.0%). Microbiome composition was distinct in liver patients with advanced fibrosis compared to those with minimal fibrosis and healthy controls (p = 0.003). In multivariate negative binomial modeling, 26 bacterial taxa were differentially abundant in patients with advanced fibrosis as compared to those with minimal/moderate fibrosis (q-value < 0.05). A random forests classifier based on these taxa had an AUROC of 0.90 to predict advanced fibrosis. Prevotella copri, which was enriched in patients with advanced fibrosis, was the most strongly predictive microbe in the classifier. The classifier had an AUROC of 0.82 for advanced fibrosis in the validation cohort and Prevotella copri remained the strongest predictive microbe for advanced fibrosis. There is a distinct microbial signature for patients with advanced fibrosis independent of liver disease etiology and other comorbidities. These results suggest that microbial profiles can be used as a non-invasive marker for advanced fibrosis and support the hypothesis that microbes and their metabolites contribute to hepatic fibrosis. more...

Infections by multidrug-resistant bacteria (MDRB) remain a leading cause of morbidity and mortality after liver transplantation (LT). Gut dysbiosis characteristic of end-stage liver disease may predispose patients to intestinal MDRB colonization and infection, in turn exacerbating dysbiosis. However, relationships between MDRB colonization and dysbiosis after LT remain unclear. We prospectively recruited 177 adult patients undergoing LT at a single tertiary care center. 16 S V3-V4 rRNA sequencing was performed on 723 fecal samples collected pre-LT and periodically until one-year post-LT to test whether MDRB colonization was associated with decreased microbiome diversity. In multivariate linear mixed-effect models, MDRB colonization predicts reduced Shannon α-diversity, after controlling for underlying liver disease, antibiotic exposures, and clinical complications. Importantly, pre-LT microbial markers predict subsequent colonization by MDRB. Our results suggest MDRB colonization as a major, previously unrecognized, marker of persistent dysbiosis. Therapeutic approaches accounting for microbial and clinical factors are needed to address post-transplant microbiome health. more...

Background: Multidrug-resistant (MDR) pathogens represent an emerging challenge in end-stage liver disease and in liver transplant recipients., Methods: We evaluated the impact of MDR bacteria upon clinical outcomes in patients with end-stage liver disease (n = 777) at the time of enrollment on the liver transplant (LTx) waiting list, after first LTx (n = 645), and after second LTx (n = 128)., Results: Colonization/infection with MDR bacteria was present in 72/777 patients on the waiting list, in 98/645 patients at first LTx, and in 46/128 patients at second LTx. While on the LTx waiting list, the time until first hydropic decompensation (p = 0.021), hepatic encephalopathy (p < 0.001) and hepatorenal syndrome (p < 0.001) was reduced in the presence of MDR bacteria, which remained an independent risk factor of poor survival in multivariate analysis (p < 0.001). Following first and second liver transplant, MDR bacteria were associated with an increased risk of infection-related deaths (first LTx: p < 0.001; second LTx: p = 0.037) and reduced actuarial survival (first LTx: p < 0.001; second LTx: p = 0.046)., Conclusions: We showed that MDR pathogens are associated with poor outcomes before, after first and after recurrent LTx. more...

ABSTRACT Microbial infection is an important cause of acute-on-chronic liver failure (ACLF), which is a syndrome that results in multiple organ dysfunction or failure and is accompanied by an increased short-term risk of mortality. Early detection and treatment of microbial infection can effectively reduce the mortality of patients with ACLF. However, antimicrobial resistance has recently increased due to the increased use of antimicrobial agents. Therefore, it is important to choose appropriate antibiotics and antifungal agents for early prevention or treatment of patients with microbial infection and ACLF to reduce the occurrence of drug resistance and to reduce patient mortality. This review summarizes the current status in the understanding of the epidemiology, pathogenesis, early diagnosis, treatment, and strategies for prevention of microbial infection in patients with ACLF. more...

Background: Patients with end-stage liver disease (ESLD) have a compromised nutritional status because of the liver crucial role in regulating metabolic homeostasis and energy balance., Data Sources: A systematic review of literature based on extensive relevant articles published from 2001 to 2017 in English in PubMed database was performed by searching keywords such as liver disease, non-alcoholic liver disease, alcoholic liver disease, malnutrition, epigenetics, gut microbiota, and probiotics., Results: Liver transplantation would be one eligible therapy for ESLD patients, even if, the clinical outcome is negatively influenced by malnutrition and/or infections. The malnutrition is a condition of nutrient imbalance with a high incidence in ESLD patients. An accurate evaluation of nutritional status could be fundamental for reducing complications and prolonging the survival of ESLD patients including those undergoing liver transplantation. In addition, the interaction among nutrients, diet and genes via epigenetics has emerged as a potential target to reduce the morbidity and mortality in ESLD patients. The malnutrition induces changes in gut microbiota causing dysbiosis with a probable translocation of bacteria and/or pathogen-derived factors from the intestine to the liver. Gut microbiota contribute to the progression of chronic liver diseases as well as hepatocellular carcinoma. The administration of probiotics modulating gut microbiota could improve all chronic liver diseases., Conclusions: This review provides an update on malnutrition status linked to epigenetics and the potential benefit of some probiotics on the management of ESLD patients. In support of this view and to reveal the constant and growing interest in this field, some clinical trials are reported., (Copyright © 2018 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.) more...

Background & Aims: Variants at the ABCB4 or MDR2 locus, which encodes a biliary transport protein, are associated with a spectrum of cholestatic liver diseases. Exacerbation of liver disease has been linked to increased hepatic levels of interleukin (IL) 17, yet the mechanisms of this increase are not understood. We studied mice with disruption of Mdr2 to determine how defects in liver and alteration in the microbiota contribute to production of IL17 by intrahepatic γδ T cells., Methods: We performed studies with Mdr2 -/- and littermate FVB/NJ (control) mice. IL17 was measured in serum samples by an enzyme-linked immunosorbent assay. Mice were injected with neutralizing antibodies against the γδ T-cell receptor (TCR; anti-γδ TCR) or mouse IL17A (anti-IL17A). Livers were collected and bacteria were identified in homogenates by culture procedures; TCRγδ + cells were isolated by flow cytometry. Fecal samples were collected from mice and analyzed by 16S ribosomal DNA sequencing. Cells were stimulated with antibodies or bacteria, and cytokine production was measured. We obtained tissues from 10 patients undergoing liver transplantation for primary sclerosing cholangitis or chronic hepatitis C virus infection. Tissues were analyzed for cytokine production by γδ TCR + cells., Results: Mdr2 -/- mice had collagen deposition around hepatic bile ducts and periportal-bridging fibrosis with influx of inflammatory cells and increased serum levels of IL17 compared with control mice. Administration of anti-IL17A reduced hepatic fibrosis. Livers from Mdr2 -/- mice had increased numbers of IL17A + γδTCR + cells-particularly of IL17A + Vγ6Jγ1 γδ TCR + cells. Fecal samples from Mdr2 -/- mice were enriched in Lactobacillus, and liver tissues were enriched in Lactobacillus gasseri compared with control mice. Mdr2 -/- mice also had increased intestinal permeability. The γδ TCR + cells isolated from Mdr2 -/- livers produced IL17 in response to heat-killed L gasseri. Intraperitoneal injection of control mice with L gasseri led to increased serum levels of IL17 and liver infiltration by inflammatory cells; injection of these mice with anti-γδ TCR reduced serum level of IL17. Intravenous injections of Mdr2 -/- mice with anti-γδ TCR reduced fibrosis; liver levels of IL17, and inflammatory cells; and serum levels of IL17. γδTCR + cells isolated from livers of patients with primary sclerosing cholangitis, but not hepatitis C virus infection, produced IL17., Conclusions: In Mdr2 -/- mice, we found development of liver fibrosis and inflammation to require hepatic activation of γδ TCR + cells and production of IL17 mediated by exposure to L gasseri. This pathway appears to contribute to development of cholestatic liver disease in patients., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.) more...

Liver transplantation (LT) improves daily function and ameliorates gut microbial composition. However, the effect of LT on microbial functionality, which can be related to overall patient benefit, is unclear and could affect the post-LT course. The aims were to determine the effect of LT on gut microbial functionality focusing on endotoxemia, bile acid (BA), ammonia metabolism, and lipidomics. We enrolled outpatient patients with cirrhosis on the LT list and followed them until 6 months after LT. Microbiota composition (Shannon diversity and individual taxa) and function analysis (serum endotoxin, urinary metabolomics and serum lipidomics, and stool BA profile) and cognitive tests were performed at both visits. We enrolled 40 patients (age, 56 ± 7 years; mean Model for End-Stage Liver Disease score, 22.6). They received LT 6 ± 3 months after enrollment and were re-evaluated 7 ± 3 months after LT with a stable course. A significant improvement in cognition with increase in microbial diversity, increase in autochthonous and decrease in potentially pathogenic taxa, and reduced endotoxemia were seen after LT compared with baseline. Stool BAs increased significantly after LT, and there was evidence of greater bacterial action (higher secondary, oxo and iso-BAs) after LT although the levels of conjugated BAs remained similar. There was a reduced serum ammonia and corresponding rise in urinary phenylacetylglutamine after LT. There was an increase in urinary trimethylamine-N-oxide, which was correlated with specific changes in serum lipids related to cell membrane products. The ultimate post-LT lipidomic profile appeared beneficial compared with the profile before LT. In conclusion, LT improves gut microbiota diversity and dysbiosis, which is accompanied by favorable changes in gut microbial functionality corresponding to BAs, ammonia, endotoxemia, lipidomic, and metabolomic profiles. Liver Transplantation 24 752-761 2018 AASLD., (© 2018 by the American Association for the Study of Liver Diseases.) more...

Background: Portal hypertension (PHT) is defined as a portal venous pressure gradient (PVPG) exceeding 5 mm Hg, which results in severe clinical manifestations. However, the validity of intraoperative PVPG monitoring and the association between PHT and bacterial translocation after liver transplantation remain unclear., Methods: In this retrospective study, 223 patients who underwent primary adult-to-adult living donor liver transplantation from 2008 to 2015 were divided into 2 groups based on the PVPG at the end of the operation: high PVPG (>5 mm Hg, n = 69) and low PVPG (≤5 mm Hg, n = 154). The clinical factors were compared between the groups, and the association between a high PVPG and posttransplant bacteremia/bacterial infections was investigated., Results: The high PVPG group had a significantly higher incidence of bacteremia (46% vs 24%, P < 0.001), higher 90-day mortality rate (20% vs 7%, P = 0.002), and poorer 1-year survival (71% vs 86%, P = 0.006). The high PVPG group had a particularly higher incidence of bacteremia caused by "gut bacteria" including Enterobacteriaceae, Bacteroides spp., and Enterococcus spp. (29% vs 12%, P = 0.003). Multivariate analysis showed that a PVPG greater than 5 mm Hg (odds ratio, 2.55; 95% confidence interval, 1.18-5.55; P = 0.017) was an independent predictor of bacteremia due to gut bacteria., Conclusions: Monitoring of the PVPG is clinically meaningful for predicting patients' prognosis. In particular, a high PVPG with a threshold of 5 mm Hg at the end of adult-to-adult living donor liver transplantation may increase gut-related bacteremia through the mechanism of bacterial translocation, resulting in early mortality. more...

Patients with end-stage liver disease complicated by invasive fungal infection have poor tolerance, difficulties in pharmacotherapy, and high mortality. Invasive fungal infection in patients with end-stage liver disease should be taken seriously in clinical practice. Pathogen test should be performed as early as possible, and standard antifungal treatment should be started at the right time to improve prognosis. more...

Candida species are the leading cause of invasive fungal infections and a common cause of hospital-acquired bloodstream infections. Invasive candidiasisis a highly lethal infection associated with mortality rates between 40 and 60 %. This study was conducted with aim of assessing the role of Candida albicans germ tube antibody (CAGTA) level in the early diagnosis of invasive candidiasis and in monitoring the efficacy of antifungal drugs in patients with end stage liver disease. Sixty two end stage liver disease patients were included in this study. Candida albicans germ tube antibody (CAGTA) test was done for all cases by indirect immunofluorescence technique, and it was positive with (titre ≥ 1/160) in 18 cases including the 10 blood culture positive cases. Compared to positive blood culture, the sensitivity, specificity, negative predictive value, positive predictive value and accuracy of CAGTA test were 100%, 84.6 %, 55.6 %, 100 % and 73.3 % respectively. Candida albicans germ tube antibody (CAGTA) test is sensitive and specific test, that can be used for early diagnosis of invasive candidiasis and in monitoring the effect of treatment with antifungal drugs in end stage liver disease patients., (Copyright© by the Egyptian Association of Immunologists.) more...

Background: Mortality from chronic liver disease is rising exponentially. The liver is intimately linked to the gut via the portal vein, and exposure to gut microbiota and their metabolites translocating across the gut lumen may impact upon both the healthy and diseased liver. Modulation of gut microbiota could prove to be a potential therapeutic target., Aim: To characterise the changes in the gut microbiome that occur in chronic liver disease and to assess the impact of manipulation of the microbiome on the liver., Methods: We conducted a PubMed search using search terms including 'microbiome', 'liver' and 'cirrhosis' as well as 'non-alcoholic fatty liver disease', 'steatohepatitis', 'alcohol' and 'primary sclerosing cholangitis'. Relevant articles were also selected from references of articles and review of the ClinicalTrials.gov website., Results: Reduced bacterial diversity, alcohol sensitivity and the development of gut dysbiosis are seen in several chronic liver diseases, including non-alcoholic fatty liver disease, alcohol-related liver disease and primary sclerosing cholangitis. Perturbations in gut commensals could lead to deficient priming of the immune system predisposing the development of immune-mediated diseases. Furthermore, transfer of stool from an animal with the metabolic syndrome may induce steatosis in a healthy counterpart. Patients with cirrhosis develop dysbiosis, small bowel bacterial overgrowth and increased gut wall permeability, allowing bacterial translocation and uptake of endotoxin inducing hepatic and systemic inflammation., Conclusions: Manipulation of the gut microbiota with diet, probiotics or faecal microbiota transplantation to promote the growth of "healthy" bacteria may ameliorate the dysbiosis and alter prognosis., (© 2017 John Wiley & Sons Ltd.) more...

The characteristics of intestinal microbial communities may be affected by changes in the pathophysiology of patients with end-stage liver disease. Here, we focused on the characteristics of intestinal fecal microbial communities in post-liver transplantation (LT) patients in comparison with those in the same individuals pre-LT and in healthy individuals. The fecal microbial communities were analyzed via MiSeq-PE250 sequencing of the V4 region of 16S ribosomal RNA and were then compared between groups. We found that the gut microbiota of patients with severe liver disease who were awaiting LT was significantly different from that of healthy controls, as represented by the first principal component (p = 0.0066). Additionally, the second principal component represented a significant difference in the gut microbiota of patients between pre-LT and post-LT surgery (p = 0.03125). After LT, there was a significant decrease in the abundance of certain microbial species, such as Actinobacillus, Escherichia, and Shigella, and a significant increase in the abundance of other microbial species, such as Micromonosporaceae, Desulfobacterales, the Sarcina genus of Eubacteriaceae, and Akkermansia. Based on KEGG profiles, 15 functional modules were enriched and 21 functional modules were less represented in the post-LT samples compared with the pre-LT samples. Our study demonstrates that fecal microbial communities were significantly altered by LT. more...

Alcoholic liver disease is a major medical burden. Alcohol abuse is the cause for end-stage liver disease in approximately 50% of all patients with cirrhosis. Chronic alcohol consumption is associated with changes in the composition of the intestinal microbiota and gut barrier dysfunction. The portal vein is the major communication route between the intestine and the liver. Increased intestinal permeability allows microbial components, bacteria, and metabolites to translocate to the liver. The liver communicates with the intestine via mediators in the systemic circulation and the biliary system. In this review, the authors describe the changes that occur in the intestinal microbiota with chronic alcohol consumption. They further review the bilateral communication between the liver and the gut, and discuss how this interaction affects the progression of alcoholic liver disease., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.) more...

Background: The gut microbial ecosystem plays an important role in the pathogenesis of liver diseases. However, the association of microbial community structure with the severity of liver dysfunction is not completely understood., Methods: Fecal microflora was assessed in 40 patients with liver cirrhosis listed for primary liver transplantation (LT). Independent associations between fecal microbial counts and serum bilirubin, serum creatinine, international normalized ratio (INR), and the Model for End-stage Liver Disease (MELD) score were established in multiple linear regression models., Results: Bifidobacterium (standardized regression coefficient [sβ] = -0.549; P < 0.001), Enterococcus (sβ = 0.369; P = 0.004), and yeast (sβ = 0.315; P = 0.018) numbers were independently associated with serum bilirubin, while Escherichia coli counts (sβ = 0.318; P = 0.046) correlated with INR, and Bifidobacterium counts (sβ = 0.410; P = 0.009) with serum creatinine. Only Bifidobacterium (sβ = -0.468; P = 0.003) and Enterococcus (sβ = 0.331; P = 0.029) counts were independent predictors of the MELD score. Bifidobacterium/Enterococcus ratio, proposed as a measure of pre-LT gut dysbiosis, was significantly related to the MELD score following the adjustment for the absolute Bifidobacterium (sβ = -0.333; P = 0.029) and Enterococcus (sβ = -0.966; P = 0.003) numbers. This pre-transplant dysbiosis ratio (PTDR) was significantly correlated with Enterococcus (R = -0.897; P < 0.001) but not with Bifidobacterium (R = 0.098; P = 0.546) counts. Among the other components of gut microflora, only hydrogen peroxide (H2 O2 )-producing Lactobacillus strains significantly influenced Enterococcus counts (sβ = 0.349; P = 0.028) and PTDR (sβ = -0.318; P = 0.046)., Conclusion: While the abundance of both Bifidobacterium and Enterococcus is related to liver dysfunction, the size of the Enterococcus population seems to be the most important determinant of pre-LT gut dysbiosis in cirrhotic patients. The H2 O2 -producing Lactobacillus strains potentially ameliorate this dysbiotic state., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.) more...

Background: Nearly 20% of tuberculosis (TB) patients die within one year, and TB-related mortality rates remain high in Taiwan. The study aimed to identify factors correlated with TB-specific deaths versus non-TB-specific deaths in different age groups among TB-related mortalities., Methods: A retrospective cohort study was conducted from 2006-2008 with newly registered TB patients receiving follow-up for 1 year. The national TB database from the Taiwan-CDC was linked with the National Vital Registry System and the National Health Insurance database. A chi-squared test and logistic regression were used to analyse the correlated factors related to TB-specific and non-TB-specific deaths in different age groups., Results: Elderly age (odds ratio [OR] 2.68-8.09), Eastern residence (OR 2.01), positive sputum bacteriology (OR 2.54), abnormal chest X-ray (OR 2.28), and comorbidity with chronic kidney disease (OR 2.35), stroke (OR 1.74) or chronic liver disease (OR 1.29) were most likely to be the cause of TB-specific deaths, whereas cancer (OR 0.79) was less likely to be implicated. For non-TB-specific deaths in patients younger than 65 years of age, male sex (OR 2.04) and comorbidity with HIV (OR 5.92), chronic kidney disease (OR 8.02), stroke (OR 3.75), cancer (OR 9.79), chronic liver disease (OR 2.71) or diabetes mellitus (OR 1.38) were risk factors., Conclusions: Different factors correlated with TB-specific deaths compared with non-TB-specific deaths, and the impact of comorbidities gradually decreased as age increased. To reduce TB-specific mortality, special consideration for TB patients with old age, Eastern residence, positive sputum bacteriology and comorbidity with chronic kidney disease or stroke is crucial. In particular, Eastern residence increased the risk of TB-specific death in all age groups. In terms of TB deaths among patients younger than 65 years of age, patients with HIV, chronic kidney disease or cancer had a 6-10 times increased risk of non-TB-specific deaths. more...

Clostridium difficile infection (CDI) occurs in 3-7% of liver transplant recipients (LTR). However, few data exist on the recent epidemiology, predictors and outcomes of CDI in LTR. A cohort study was performed including LTR from 2000 to 2010 at a tertiary care hospital in Detroit. CDI was defined as diarrhea with a stool C. difficile positive test. Data analyzed included demographics, comorbidities, length of stay (LOS), severity of CDI, rates of recurrence (<12 weeks), relapse (<4 weeks) and overall mortality. Predictors of CDI were calculated using Cox proportional hazard model; 970 LTR were followed for years. Overall prevalence of CDI was 18.9%. Incidence of CDI within 1 year of transplant was 12.4%. Severe CDI occurred in 29.1%. CDI recurrence and relapse rates were 16.9% and 9.7%, respectively. Independent predictors of CDI were year of transplant (hazard ratio [HR] 1.137, 95% confidence interval [CI] 1.06-1.22; p < 0.001), white race (105/162 whites, HR 1.47, 95% CI 1.03-2.1; p = 0.035), Model for End-Stage Liver Disease score (HR 1.03, 95% CI 1.01-1.045, p = 0.003) and LOS (HR 1.01, 95% CI 1.005-1.02, p < 0.001). Significant mortality was observed among LTR with CDI compared to those without CDI (p = 0.003). We concluded that CDI is common among LTR and is associated with higher mortality., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.) more...

Background: The term 'zero tolerance' has recently been applied to healthcare-associated infections, implying that such events are always preventable. This may not be the case for healthcare-associated infections such as methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia., Methods: We combined information from an epidemiological investigation and bacterial whole-genome sequencing to evaluate a cluster of five MRSA bacteraemia episodes in four patients in a specialist hepatology unit., Results: The five MRSA bacteraemia isolates were highly related by multilocus sequence type (ST) (four isolates were ST22 and one isolate was a single-locus variant, ST2046). Whole-genome sequencing demonstrated unequivocally that the bacteraemia cases were unrelated. Placing the MRSA bacteraemia isolates within a local and global phylogenetic tree of MRSA ST22 genomes demonstrated that the five bacteraemia isolates were highly diverse. This was consistent with the acquisition and importation of MRSA from the wider referral network. Analysis of MRSA carriage and disease in patients within the hepatology service demonstrated a higher risk of both initial MRSA acquisition compared with the nephrology service and a higher risk of progression from MRSA carriage to bacteraemia, compared with patients in nephrology or geriatric services. A root cause analysis failed to reveal any mechanism by which three of five MRSA bacteraemia episodes could have been prevented., Conclusions: This study illustrates the complex nature of MRSA carriage and bacteraemia in patients in a specialized hepatology unit. Despite numerous ongoing interventions to prevent MRSA bacteraemia in healthcare settings, these are unlikely to result in a zero incidence in referral centres that treat highly complex patients., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.) more...

Background: End-stage liver disease (ESLD) is associated with dysregulation of the immune system and increased susceptibility to infections. Although invasive fungal infection (IFI) is a growing public health problem, studies of IFI in ESLD are lacking. The aims of this study were to screen for IFI in ESLD and to assess risk factors and serum interleukin 17 (IL-17) as a marker of the cellular immune response., Methods: Both blood and ascitic fluid samples were collected from 46 patients with ESLD for fungal culture and PCR. Serum IL-17 levels were determined., Results: Seven patients had isolated IFI (four had spontaneous fungal peritonitis, two had fungemia, and one had a disseminated fungal infection) and five cases had combined fungal and bacterial infections. Spontaneous fungal peritonitis was attributed to Candida species, while fungemia was caused by Aspergillus species. Patients with IFI had higher serum IL-17 levels and increased mortality compared to patients without IFI. A history of antibiotic use (p = 0.002), higher model for end-stage liver disease (MELD) scores (p = 0.04), and hepatorenal syndrome (p = 0.006) were risk factors for IFI., Conclusions: Patients with ESLD had a low frequency of IFI; however, in patients with these infections, delayed diagnosis and treatment may contribute to a high fatality rate. Thus, clinicians should have a high index of suspicion for this unusual but lethal entity, as prompt detection and appropriate treatment can improve the outcome., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.) more...

Background & Aims: The gut microbiome is altered in cirrhosis; however its evolution with disease progression is only partly understood. We aimed to study changes in the microbiome over cirrhosis severity, its stability over time and its longitudinal alterations with decompensation., Methods: Controls and age-matched cirrhotics (compensated/decompensated/hospitalized) were included. Their stool microbiota was quantified using multi-tagged pyrosequencing. The ratio of autochthonous to non-autochthonous taxa was calculated as the cirrhosis dysbiosis ratio (CDR); a low number indicating dysbiosis. Firstly, the microbiome was compared between controls and cirrhotic sub-groups. Secondly, for stability assessment, stool collected twice within 6months in compensated outpatients was analyzed. Thirdly, changes after decompensation were assessed using (a) longitudinal comparison in patients before/after hepatic encephalopathy development (HE), (b) longitudinal cohort of hospitalized infected cirrhotics MELD-matched to uninfected cirrhotics followed for 30days., Results: 244 subjects [219 cirrhotics (121 compensated outpatients, 54 decompensated outpatients, 44 inpatients) and 25 age-matched controls] were included. CDR was highest in controls (2.05) followed by compensated (0.89), decompensated (0.66), and inpatients (0.32, p<0.0001) and negatively correlated with endotoxin. Microbiota and CDR remained unchanged in stable outpatient cirrhotics (0.91 vs. 0.86, p=0.45). In patients studied before/after HE development, dysbiosis occurred post-HE (CDR: 1.2 to 0.42, p=0.03). In the longitudinal matched-cohort, microbiota were significantly different between infected/uninfected cirrhotics at baseline and a low CDR was associated with death and organ failures within 30days., Conclusions: Progressive changes in the gut microbiome accompany cirrhosis and become more severe in the setting of decompensation. The cirrhosis dysbiosis ratio may be a useful quantitative index to describe microbiome alterations accompanying cirrhosis progression., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.) more...

Purpose: To assess the impact of chronic liver disease (CLD) on ICU-acquired pneumonia., Methods: This was a prospective, observational study of the characteristics, microbiology, and outcomes of 343 consecutive patients with ICU-acquired pneumonia clustered according to the presence of CLD., Results: Sixty-seven (20%) patients had CLD (67% had liver cirrhosis, LC), MELD score 26 ± 9, 20% Child-Pugh class C). They presented higher severity scores than patients without CLD both on admission to the ICU (APACHE II, LC 19 ± 6 vs. other CLD 18 ± 6 vs. no CLD 16 ± 6; p < 0.001; SOFA, 10 ± 3 vs. 8 ± 4 vs. 7 ± 3; p < 0.001) and at onset of pneumonia (APACHE II, 19 ± 6 vs. 17 ± 6 vs. 16 ± 5; p = 0.001; SOFA, 11 ± 4 vs. 9 ± 4 vs. 7 ± 3; p < 0.001). Levels of CRP were lower in patients with LC than in the other two groups (day 1, 6.5 [2.5-11.5] vs. 13 [6-23] vs. 15.5 [8-24], p < 0.001, day 3, 6 [3-12] vs. 16 [9-21] vs. 11 [5-20], p = 0.001); all the other biomarkers were higher in LC and other CLD patients. LC patients had higher 28- and 90-day mortality (63 vs. 28%, p < 0.001; 72 vs. 38%, p < 0.001, respectively) than non-CLD patients. Presence of LC was independently associated with decreased 28- and 90-day survival (95% confidence interval [CI], 1.982-17.250; p = 0.001; 95% confidence interval [CI], 2.915-20.699, p = 0.001, respectively)., Conclusions: In critically ill patients with ICU-acquired pneumonia, CLD is associated with a more severe clinical presentation and poor clinical outcomes. Moreover, LC is independently associated with 28- and 90-day mortality. The results of this study are important for future trials focused on mortality. more...

Aim: To investigate optimal timing for therapeutic efficacy of entecavir for acute-on-chronic hepatitis B liver failure (ACLF-HBV) in hepatitis B e antigen (HBeAg)-negative patients., Methods: A total of 109 inpatients with ACLF-HBV were recruited from the Department of Infectious Diseases of the Third Affiliated Hospital, Sun Yat-sen University from October 2007 to October 2010. Entecavir 0.5 mg/d was added to each patient's comprehensive therapeutic regimen. Patients were divided into three groups according to model for end-stage liver disease (MELD) score: high (≥ 30, 20 males and 4 females, mean age 47.8 ± 13.5 years); intermediate (22-30, 49 males and 5 females, 45.9 ± 12.4 years); and low (≤ 22, 28 males and 3 females, 43.4 ± 9.4 years). Statistical analysis were performed using SPSS 11.0 software. Data with normal distribution were expressed as mean ± SD and comparisons were made with Student's t tests. A value of P < 0.05 was considered statistically significant. Viral loads were related exponentially and logarithmic data were used for analysis., Results: For 24 patients with MELD score ≥ 30, treatment lasted 17.2 ± 16.5 d. Scores before and after treatment were significantly different (35.97 ± 4.87 and 40.48 ± 8.17, respectively, t = -2.762, P = 0.011); HBV DNA load was reduced (4.882 ± 1.847 copies log(10)/mL to 3.685 ± 1.436 copies log(10)/mL); and mortality rate was 95.83% (23/24). Of 54 patients with scores of 22-30, treatment lasted for 54.0 ± 43.2 d; scores before and after treatment were 25.87 ± 2.33 and 25.82 ± 13.92, respectively (t = -0.030, P = 0.976); HBV DNA load decreased from 6.308 ± 1.607 to 3.473 ± 2.097 copies log(10)/mL; and mortality was 51.85% (28/54). Of 31 patients with scores ≤ 22, treatment lasted for 66.1 ± 41.9 d; scores before and after treatment were 18.88 ± 2.44 and 12.39 ± 7.80, respectively, (t = 4.860, P = 0.000); HBV DNA load decreased from 5.841 ± 1.734 to 2.657 ± 1.154 copies log(10)/mL; and mortality was 3.23% (1/31)., Conclusion: For HBeAg-negative patients with ACLF-HBV, when entecavir was added to comprehensive therapy, a MELD score ≥ 30 predicted very poor prognosis due to fatal liver failure. more...

About 6500-7000 people/year die in Hungary due to liver cirrhosis which is often complicated with hepatic encephalopathy (HE). While conventional interpretation is that hepatic encephalopathy is a consequence of high blood ammonia level, recent data indicate that the degree of encephalopathy is related to systemic inflammatory response during decompensation. In this review the authors overview and analyze the latest treatment modalities of hepatic encephalopathy based on most recent findings. They found that frequently used evidence based treatment which apply metronidazole, neomycine or disaccharides was only partially effective in clinical studies. Use of rifaximine only is supported by grade I evidence, however it is quite a costly drug. The authors could not identify a generally accepted guideline for the treatment of HE with a systematic literature review, although it has significant effect on survival after liver transplantation. Therefore, the authors urge to develop a consensus guideline for the treatment of HE. more...

Background & Aims: Chronic infection with hepatitis B or C virus (HBV or HCV) is a leading cause of cirrhosis by unknown mechanisms of pathogenesis. Translocation of gut microbial products into the systemic circulation might increase because of increased intestinal permeability, bacterial overgrowth, or impaired clearance of microbial products by Kupffer cells. We investigated whether the extent and progression of liver disease in patients with chronic HBV or HCV infection are associated with microbial translocation and subsequent activation of monocytes., Methods: In a retrospective study, we analyzed data from 16 patients with minimal fibrosis, 68 with cirrhosis, and 67 uninfected volunteers. We analyzed plasma levels of soluble CD14 (sCD14), intestinal fatty acid binding protein, and interleukin-6 by enzyme-linked immunosorbent assay, and lipopolysaccharide (LPS) by the limulus amebocyte lysate assay, at presentation and after antiviral treatment., Results: Compared with uninfected individuals, HCV- and HBV-infected individuals had higher plasma levels of LPS, intestinal fatty acid binding protein (indicating enterocyte death), sCD14 (produced upon LPS activation of monocytes), and interleukin-6. Portal hypertension, indicated by low platelet counts, was associated with enterocyte death (P=.045 at presentation, P<.0001 after therapy). Levels of sCD14 correlated with markers of hepatic inflammation (P=.02 for aspartate aminotransferase, P=.002 for ferritin) and fibrosis (P<.0001 for γ-glutamyl transpeptidase, P=.01 for alkaline phosphatase, P<.0001 for α-fetoprotein). Compared to subjects with minimal fibrosis, subjects with severe fibrosis at presentation had higher plasma levels of sCD14 (P=.01) and more hepatic CD14+ cells (P=.0002); each increased risk for disease progression (P=.0009 and P=.005, respectively)., Conclusions: LPS-induced local and systemic inflammation is associated with cirrhosis and predicts progression to end-stage liver disease in patients with HBV or HCV infection., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.) more...