Global compositional and functional states of the human gut microbiome in health and disease.

The human gut microbiota is of increasing interest, with metagenomics a key tool for analyzing bacterial diversity and functionality in health and disease. Despite increasing efforts to expand microbial gene catalogs and an increasing number of metagenome-assembled genomes, there have been few pan-metagenomic association studies and in-depth functional analyses across different geographies and diseases. Here, we explored 6014 human gut metagenome samples across 19 countries and 23 diseases by performing compositional, functional cluster, and integrative analyses. Using interpreted machine learning classification models and statistical methods, we identified Fusobacterium nucleatum and Anaerostipes hadrus with the highest frequencies, enriched and depleted, respectively, across different disease cohorts. Distinct functional distributions were observed in the gut microbiomes of both westernized and nonwesternized populations. These compositional and functional analyses are presented in the open-access Human Gut Microbiome Atlas, allowing for the exploration of the richness, disease, and regional signatures of the gut microbiota across different cohorts.

Viral antibody response predicts morbidity and mortality in alcohol-associated hepatitis.

BACKGROUND AND AIMS: Alcohol-associated hepatitis (AH) is associated with very high mortality despite abstinence from alcohol; up to 40% of patients die within 6 months of diagnosis. Patients with AH are especially prone to infections, which can lead to multiorgan dysfunction and poorer prognosis. APPROACH AND RESULTS: We performed comprehensive serological profiling of the viral and bacterial infection history of 36 healthy controls, 48 patients with alcohol use disorder, and 224 patients with AH from 2 multicenter observational studies. We used systematic viral and bacterial epitope scanning by VirScan, a phage-display immunoprecipitation and sequencing technology that detects the peptides recognized by antibodies in patient sera, to comprehensively analyze antiviral and antibacterial antibodies and identify serologic biomarkers to predict patient outcomes. We found significant differences in the serological profiles of the 3 populations. The number of serum antibody epitopes in patients with alcohol use disorder during abstinence was increased compared with during active alcohol use. A decreased number and diversity of viral and bacterial antibody targets were detected in the sera of patients with AH, particularly those with a higher Child-Pugh score. In patients with AH, a decrease in the serum antiviral, but not antibacterial, antibody repertoire was associated with decompensation and mortality. Ninety-day mortality in AH could be predicted using a serum viral epitope signature. CONCLUSIONS: Abstinence from alcohol is associated with a significant increase in serum viral and bacterial antibody response. Decreased serum antiviral antibody repertoire is predictive of decompensation of liver disease and mortality in patients with AH.

Serum aryl hydrocarbon receptor activity is associated with survival in patients with alcohol-associated hepatitis.

BACKGROUND AND AIMS: Patients with alcohol-associated hepatitis (AH) have an altered fecal metabolome, including reduced microbiota-derived tryptophan metabolites, which function as ligands for aryl hydrocarbon receptor (AhR). The aim of this study was to assess serum AhR ligand activity in patients with AH. APPROACH AND RESULTS: The study included 74 controls without AUD, 97 patients with AUD, and 330 patients with AH from 2 different multicenter cohorts (InTeam: 134, AlcHepNet: 196). Serum AhR activity was evaluated using an AhR reporter assay with HepG2-Lucia cells incubated with serum for 24 hours. Serum AhR activity was significantly higher in patients with AH compared with both controls (1.59 vs. 0.96-fold change, p < 0.001) and patients with AUD (1.59 vs. 0.93, p < 0.001). In both AH cohorts, patients with AhR activity ≥ 2.09 had significantly lower cumulative survival rates at 30, 60, 90, and 180 days compared to those with AhR activity < 2.09. When serum AhR activity was used to further stratify patients with severe AH, the cumulative 30, 60, 90, and 180-day survival rates for patients with severe AH and the AhR activity ≥ 2.09 group were all significantly lower than those with an AhR activity < 2.09 group. CONCLUSIONS: Serum AhR activity was significantly higher in patients with AH compared with controls and individuals with AUD, and this increased activity was associated with higher mortality. Consequently, serum AhR activity holds potential as a prognostic marker.

Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease.

Chronic liver disease due to alcohol-use disorder contributes markedly to the global burden of disease and mortality1-3. Alcoholic hepatitis is a severe and life-threatening form of alcohol-associated liver disease. The gut microbiota promotes ethanol-induced liver disease in mice4, but little is known about the microbial factors that are responsible for this process. Here we identify cytolysin-a two-subunit exotoxin that is secreted by Enterococcus faecalis5,6-as a cause of hepatocyte death and liver injury. Compared with non-alcoholic individuals or patients with alcohol-use disorder, patients with alcoholic hepatitis have increased faecal numbers of E. faecalis. The presence of cytolysin-positive (cytolytic) E. faecalis correlated with the severity of liver disease and with mortality in patients with alcoholic hepatitis. Using humanized mice that were colonized with bacteria from the faeces of patients with alcoholic hepatitis, we investigated the therapeutic effects of bacteriophages that target cytolytic E. faecalis. We found that these bacteriophages decrease cytolysin in the liver and abolish ethanol-induced liver disease in humanized mice. Our findings link cytolytic E. faecalis with more severe clinical outcomes and increased mortality in patients with alcoholic hepatitis. We show that bacteriophages can specifically target cytolytic E. faecalis, which provides a method for precisely editing the intestinal microbiota. A clinical trial with a larger cohort is required to validate the relevance of our findings in humans, and to test whether this therapeutic approach is effective for patients with alcoholic hepatitis.

Faecal proteomics links neutrophil degranulation with mortality in patients with alcohol-associated hepatitis.

OBJECTIVE: Patients with alcohol-associated hepatitis (AH) have a high mortality. Alcohol exacerbates liver damage by inducing gut dysbiosis, bacterial translocation and inflammation, which is characterised by increased numbers of circulating and hepatic neutrophils. DESIGN: In this study, we performed tandem mass tag (TMT) proteomics to analyse proteins in the faeces of controls (n=19), patients with alcohol-use disorder (AUD; n=20) and AH (n=80) from a multicentre cohort (InTeam). To identify protein groups that are disproportionately represented, we conducted over-representation analysis using Reactome pathway analysis and Gene Ontology to determine the proteins with the most significant impact. A faecal biomarker and its prognostic effect were validated by ELISA in faecal samples from patients with AH (n=70), who were recruited in a second and independent multicentre cohort (AlcHepNet). RESULT: Faecal proteomic profiles were overall significantly different between controls, patients with AUD and AH (principal component analysis p=0.001, dissimilarity index calculated by the method of Bray-Curtis). Proteins that showed notable differences across all three groups and displayed a progressive increase in accordance with the severity of alcohol-associated liver disease were predominantly those located in neutrophil granules. Over-representation and Reactome analyses confirmed that differentially regulated proteins are part of granules in neutrophils and the neutrophil degranulation pathway. Myeloperoxidase (MPO), the marker protein of neutrophil granules, correlates with disease severity and predicts 60-day mortality. Using an independent validation cohort, we confirmed that faecal MPO levels can predict short-term survival at 60 days. CONCLUSIONS: We found an increased abundance of faecal proteins linked to neutrophil degranulation in patients with AH, which is predictive of short-term survival and could serve as a prognostic non-invasive marker.

Oral-gut microbiome interactions in advanced cirrhosis: characterisation of pathogenic enterotypes and salivatypes, virulence factors and antimicrobial.

BACKGROUND & AIMS: Cirrhosis complications are often triggered by bacterial infections with multidrug-resistant organisms. Alterations in the gut and oral microbiome in decompensated cirrhosis (DC) influence clinical outcomes. We interrogated: (i) gut and oral microbiome community structures, (ii) virulence factors (VFs) and antimicrobial resistance genes (ARGs) and (iii) oral-gut microbial overlap in patients with differing cirrhosis severity. METHODS: 15 healthy controls (HC), 26 stable cirrhosis (SC), 46 DC, 14 acute-on-chronic liver failure (ACLF) and 14 with severe infection without cirrhosis (NLS) participated. Metagenomic sequencing was undertaken on paired saliva (S) and faecal (F) samples. 'Salivatypes' and 'enterotypes' based on genera clustering were assessed against cirrhosis severity and clinical parameters. VFs and ARGs were evaluated in oral and gut niches, and distinct resistotypes identified. RESULTS: Salivatypes and enterotypes revealed a greater proportion of pathobionts with concomitant reduction in autochthonous genera with increasing cirrhosis severity and hyperammonaemia. Increasing overlap between oral and gut microbiome communities was observed in DC and ACLF vs SC and HCs, independent of antimicrobial, beta-blocker and acid suppressant therapies. Two distinct gut microbiome clusters [ENT2/ENT3] harboured genes encoding for the phosphoenolpyruvate:sugar phosphotransferase system (PTS) system and other VFs in DC and ACLF. Substantial ARGs (oral: 1,218 and gut: 672) were detected [575 common to both sites]. The cirrhosis resistome was distinct, with three oral and four gut resistotypes identified, respectively. DISCUSSION: The degree of oral-gut microbial community overlap, frequency of VFs and ARGs all increment significantly with cirrhosis severity, with progressive dominance of pathobionts and loss of commensals. Despite similar antimicrobial exposure, patients with DC and ACLF have reduced microbial richness compared to NLS, supporting the additive pathobiological effect of cirrhosis. IMPACT AND IMPLICATIONS: This research underscores the crucial role of microbiome alterations in the progression of cirrhosis in an era of escalating multidrug resistant infections, highlighting the association and potential impact of increased oral-gut microbial overlap, virulence factors, and antimicrobial resistance genes on clinical outcomes. These findings are particularly significant for patients with decompensated cirrhosis and acute-on-chronic liver failure, as they reveal the intricate relationship between microbiome alterations and cirrhosis complications. This is relevant in the context of multidrug-resistant organisms and reduced oral-gut microbial diversity that exacerbate cirrhosis severity, drive hepatic decompensation and complicate treatment. For practical applications, these insights could guide for cirrhosis patients the development of targeted microbiome-based therapeutics and personalised antimicrobial regimens to mitigate infectious complications to improve their clinical outcomes.

Clinical Implications of Inflammation in Patients With Cirrhosis.

Cirrhosis-associated immune dysfunction refers to the concurrent systemic inflammation and immunoparesis evident across the disease spectrum of chronic liver disease, ranging from the low-grade inflammatory plasma milieu that accompanies compensated disease to the intense high-grade inflammatory state with coexistent severe immune paralysis that defines acute decompensation and acute-on-chronic liver failure. Systemic inflammation plays a crucial role in the disease course of cirrhosis and is a key driver for acute decompensation and the progression from compensated to decompensated cirrhosis. Severe systemic inflammation is fundamental to the development of organ dysfunction and failure and, in its most extreme form, acute-on-chronic liver failure. Systemic inflammation propagates the development of hepatic encephalopathy and hepatorenal syndrome-acute kidney injury. It may also be involved in the pathogenesis of further complications such as hepatocellular carcinoma and mental illness. Those patients with the most profound systemic inflammation have the worst prognosis. Systemic inflammation exerts its negative clinical effects through a number of mechanisms including nitric oxide-mediated increased splanchnic vasodilation, immunopathology, and metabolic reallocation.

Infection, inflammation and hepatic encephalopathy from a clinical perspective.

Hepatic encephalopathy (HE) is a syndrome that is associated with both acute and chronic liver injury. It manifests as a wide spectrum of neuropsychological abnormalities, ranging from subtle impairments in executive higher functions observed in cirrhosis, through to coma in acute liver failure. In acute liver failure, the central role of ammonia in the development of brain oedema has remained undisputed for 130 years. It latterly became apparent that infection and inflammation were profound determinants for the development of severe hepatic encephalopathy, associated with the development of cerebral oedema and intracranial hypertension. The relationship of the development of hepatic encephalopathy with blood ammonia levels in cirrhosis is less clear cut and the synergistic interplay of inflammation and infection with ammonia has been identified as being fundamental in the development and progression of hepatic encephalopathy. A perturbed gut microbiome and the presence of an impaired gut epithelial barrier that facilitates translocation of bacteria and bacterial degradation products into the systemic circulation, inducing systemic inflammation and innate and adaptive immune dysfunction, has now become the focus of therapies that treat hepatic encephalopathy in cirrhosis, and may explain why the prebiotic lactulose and rifaximin are efficacious. This review summarises the current clinical perspective on the roles of inflammation and infection in hepatic encephalopathy and presents the evidence base for existing therapies and those in development in the setting of acute and chronic liver failure.

Development and validation of the AMMON-OHE model to predict risk of overt hepatic encephalopathy occurrence in outpatients with cirrhosis.

BACKGROUND & AIMS: Neuropsychological and psychophysical tests are recommended to assess the risk of overt hepatic encephalopathy (OHE), but their accuracy is limited. Hyperammonaemia is central in the pathogenesis of OHE, but its predictive utility is unknown. In this study, we aimed to determine the role of neuropsychological or psychophysical tests and ammonia, and to develop a model (AMMON-OHE) to stratify the risk of subsequent OHE development in outpatients with cirrhosis. METHODS: This observational, prospective study included 426 outpatients without previous OHE from three liver units followed for a median of 2.5 years. Psychometric hepatic encephalopathy score (PHES) <-4 or critical flicker frequency (CFF) <39 was considered abnormal. Ammonia was normalized to upper limit of normal (AMM-ULN) at the respective reference laboratory. Multivariable frailty competing risk and random survival forest analyses were performed to predict future OHE and to develop the AMMON-OHE model. External validation was carried out using 267 and 381 patients from two independent units. RESULTS: Significant differences were found in time-to-OHE (log-rank p <0.001) according to PHES or CFF and ammonia, with the highest risk in patients with abnormal PHES plus high AMM-ULN (hazard ratio 4.4; 95% CI 2.4-8.1; p <0.001 compared with normal PHES and AMM-ULN). On multivariable analysis, AMM-ULN but not PHES or CFF was an independent predictor of the development of OHE (hazard ratio 1.4; 95% CI 1.1-1.9; p = 0.015). The AMMON-OHE model (sex, diabetes, albumin, creatinine and AMM-ULN) showed a C-index of 0.844 and 0.728 for the prediction of a first episode of OHE in two external validation cohorts. CONCLUSIONS: In this study, we developed and validated the AMMON-OHE model, comprising readily available clinical and biochemical variables that can be used to identify outpatients at the highest risk of developing a first episode of OHE. IMPACT AND IMPLICATIONS: In this study, we aimed to develop a model to predict which patients with cirrhosis are at risk of developing overt hepatic encephalopathy (OHE). Using data from three units and including 426 outpatients with cirrhosis, we developed the AMMON-OHE model - comprising sex, diabetes, albumin, creatinine and ammonia levels - which demonstrated good predictive ability. The AMMON-OHE model performs better than PHES and CFF to predict the first episode of OHE in outpatients with cirrhosis. This model was validated in 267 and 381 patients from two independent liver units. The AMMON-OHE model is available online for clinical use.

Management of Multidrug-Resistant Infections in Cirrhosis.

The World Health Organization describes antimicrobial resistance as one of the biggest threats to global health, food security, and development with indiscriminate use of antimicrobials globally driving the emergence of multidrug-resistant bacteria, resistant to 60% of antimicrobials in some countries. Infections with multidrug-resistant organisms (MDROs) have increased in recent decades in patients with cirrhosis, who are frequently prescribed antibiotics, regularly undergo invasive procedures such as large volume paracentesis, and have recurrent hospitalizations, posing a particular risk in this already immunocompromised cohort of patients. In this review, we explore mechanisms underlying this vulnerability to MDRO infection; the effect of bacterial infections on disease course in cirrhosis; prevalence of MDROs in patients with cirrhosis; outcomes following MDRO infection; fungal infections; antibiotics and their efficacy; and management of MDRO infections in terms of detection, antimicrobial and nonantimicrobial treatments, prophylaxis, antibiotic stewardship, the gut microbiome, and technological interventions.

Gut-derived systemic inflammation as a driver of depression in chronic liver disease.

Depression and chronic liver disease (CLD) are important causes of disability, morbidity and mortality worldwide and their prevalence continues to rise. The rate of depression in CLD is high compared to that of the general population and is comparable to the increased rates observed in other medical comorbidities and chronic inflammatory conditions. Notably, a comorbid diagnosis of depression has a detrimental effect on outcomes in cirrhosis. Systemic inflammation is pivotal in cirrhosis-associated immune dysfunction - a phenomenon present in advanced CLD (cirrhosis) and implicated in the development of complications, organ failure, disease progression, increased infection rates and poor outcome. The presence of systemic inflammation is also well-documented in a cohort of patients with depression; peripheral cytokine signals can result in neuroinflammation, behavioural change and depressive symptoms via neural mechanisms, cerebral endothelial cell and circumventricular organ signalling, and peripheral immune cell-to-brain signalling. Gut dysbiosis has been observed in both patients with cirrhosis and depression. It leads to intestinal barrier dysfunction resulting in increased bacterial translocation, in turn activating circulating immune cells, leading to cytokine production and systemic inflammation. A perturbed gut-liver-brain axis may therefore explain the high rates of depression in patients with cirrhosis. The underlying mechanisms explaining the critical relationship between depression and cirrhosis remain to be fully elucidated. Several other psychosocial and biological factors are likely to be involved, and therefore the cause is probably multifactorial. However, the role of the dysfunctional gut-liver-brain axis as a driver of gut-derived systemic inflammation requires further exploration and consideration as a target for the treatment of depression in patients with cirrhosis.

Plasma ammonia levels predict hospitalisation with liver-related complications and mortality in clinically stable outpatients with cirrhosis.

BACKGROUND & AIMS: Hyperammonaemia is central in the pathogenesis of hepatic encephalopathy. It also has pleiotropic deleterious effects on several organ systems, such as immune function, sarcopenia, energy metabolism and portal hypertension. This study was performed to test the hypothesis that severity of hyperammonaemia is a risk factor for liver-related complications in clinically stable outpatients with cirrhosis. METHODS: We studied 754 clinically stable outpatients with cirrhosis from 3 independent liver units. Baseline ammonia levels were corrected to the upper limit of normal (AMM-ULN) for the reference laboratory. The primary endpoint was hospitalisation with liver-related complications (a composite endpoint of bacterial infection, variceal bleeding, overt hepatic encephalopathy, or new onset or worsening of ascites). Multivariable competing risk frailty analyses using fast unified random forests were performed to predict complications and mortality. External validation was carried out using prospective data from 130 patients with cirrhosis in an independent tertiary liver centre. RESULTS: Overall, 260 (35%) patients were hospitalised with liver-related complications. On multivariable analysis, AMM-ULN was an independent predictor of both liver-related complications (hazard ratio 2.13; 95% CI 1.89-2.40; p <0.001) and mortality (hazard ratio 1.45; 95% CI 1.20-1.76; p <0.001). The AUROC of AMM-ULN was 77.9% for 1-year liver-related complications, which is higher than traditional severity scores. Statistical differences in survival were found between high and low levels of AMM-ULN both for complications and mortality (p <0.001) using 1.4 as the optimal cut-off from the training set. AMM-ULN remained a key variable for the prediction of complications within the random forests model in the derivation cohort and upon external validation. CONCLUSION: Ammonia is an independent predictor of hospitalisation with liver-related complications and mortality in clinically stable outpatients with cirrhosis and performs better than traditional prognostic scores in predicting complications. LAY SUMMARY: We conducted a prospective cohort study evaluating the association of blood ammonia levels with the risk of adverse outcomes in 754 patients with stable cirrhosis across 3 independent liver units. We found that ammonia is a key determinant that helps to predict which patients will be hospitalised, develop liver-related complications and die; this was confirmed in an independent cohort of patients.

Exaggerated inflammatory response to bacterial products in decompensated cirrhotic patients is orchestrated by interferons IL-6 and IL-8.

Cirrhosis-associated immune dysfunction (CAID) contributes to disease progression and organ failure development. We interrogated immune system function in nonseptic compensated and decompensated cirrhotic patients using the TruCulture whole blood stimulation system, a novel technique that allows a more accurate representation than traditional methods, such as peripheral blood mononuclear cell culture, of the immune response in vivo. Thirty cirrhotics (21 decompensated and 9 compensated) and seven healthy controls (HCs) were recruited. Whole blood was drawn directly into three TruCulture tubes [unstimulated to preloaded with heat-killed Escherichia coli 0111:B4 (HKEB) or lipopolysaccharide (LPS)] and incubated in dry heat blocks at 37°C for 24 h. Cytokine analysis of the supernatant was performed by multiplex assay. Cirrhotic patients exhibited a robust proinflammatory response to HKEB compared with HCs, with increased production of interferon-γ-induced protein 10 (IP-10) and IFN-λ1, and to LPS, with increased production of IFN-λ1. Decompensated patients demonstrated an augmented immune response compared with compensated patients, orchestrated by an increase in type I, II, and III interferons, and higher levels of IL-1ß, IL-6, and IL-8 post-LPS stimulation. IL-1ß, TNF-α, and IP-10 post-HKEB stimulation and IP-10 post-LPS stimulation negatively correlated with biochemical markers of liver disease severity and liver disease severity scores. Cirrhotic patients exposed to bacterial products exhibit an exaggerated inflammatory response orchestrated by IFNs, IL-6, and IL-8. Poststimulation levels of a number of proinflammatory cytokines negatively correlate with markers of liver disease severity raising the possibility that the switch to an immunodeficient phenotype in CAID may commence earlier in the course of advanced liver disease. NEW & NOTEWORTHY Decompensated cirrhotic patients, compared with compensated patients, exhibit a greater exaggerated inflammatory response to bacterial products orchestrated by interferons, IL-6, and IL-8. Postbacterial product stimulation levels of a number of pro-inflammatory cytokines negatively correlate with liver disease severity biomarkers and liver disease severity scores raising the possibility that the switch to an immunodeficient phenotype in cirrhosis-associated immune dysfunction may commence earlier in the course of advanced liver disease.

Implications and Management of Cirrhosis-Associated Immune Dysfunction Before and After Liver Transplantation.

Cirrhosis-associated immune dysfunction (CAID) describes a panacea of innate and adaptive deficits that result from the sequelae of cirrhotic portal hypertension that is similar in its manifestations regardless of etiology of chronic liver injury. CAID is associated with synchronous observations of dysregulated priming of innate immune effector cells that demonstrate a proinflammatory phenotype but are functionally impaired and unable to adequately prevent invading pathogens. CAID is mainly driven by gut-barrier dysfunction and is associated with deficits of microbial compartmentalization and homeostasis that lead to tonic activation, systemic inflammation, and exhaustion of innate-immune cells. CAID leads to a high frequency of bacterial and fungal infections in patients with cirrhosis that are often associated with acute decompensation of chronic liver disease and acute-on-chronic liver failure and carry a high mortality rate. Understanding the deficits of mucosal and systemic immunity in the context of chronic liver disease is essential to improving care for patients with cirrhosis, preventing precipitants of acute decompensation of cirrhosis, and improving morbidity and survival. In this review, we summarize the detailed dynamic immunological perturbations associated with advanced chronic liver disease and highlight the importance of recognizing immune dysregulation as a sequela of cirrhosis. Furthermore, we address the role of screening, prevention, and early treatment of infections in cirrhosis in improving patient outcomes in transplant and nontransplant settings.

Effect of rifaximin on infections, acute-on-chronic liver failure and mortality in alcoholic hepatitis: A pilot study (RIFA-AH).

BACKGROUND & AIMS: Alcoholic hepatitis (AH) is associated with a high incidence of infection and mortality. Rifaximin reduces bacterial overgrowth and translocation. We aimed to study whether the administration of rifaximin as an adjuvant treatment to corticosteroids decreases the number of bacterial infections at 90 days in patients with severe AH compared to a control cohort. METHODS: This was a multicentre, open, comparative pilot study of the addition of rifaximin (1200 mg/day/90 days) to the standard treatment for severe AH. The results were compared with a carefully matched historical cohort of patients treated with standard therapy and matching by age and model of end-stage liver disease (MELD). We evaluated bacterial infections, liver-related complications, mortality and liver function tests after 90 days. RESULTS: Twenty-one and 42 patients were included in the rifaximin and control groups respectively. No significant baseline differences were found between groups. The mean number of infections per patient was 0.29 and 0.62 in the rifaximin and control groups, respectively (p = .049), with a lower incidence of acute-on-chronic liver failure (ACLF) linked to infections within the treatment group. Liver-related complications were lower within the rifaximin group (0.43 vs. 1.26 complications/patient respectively) (p = .01). Mortality was lower in the treated versus the control groups (14.2% vs. 30.9, p = .15) without significant differences. No serious adverse events were associated with rifaximin treatment. CONCLUSIONS: Rifaximin is safe in severe AH with a significant reduction in clinical complications. A lower number of infections and a trend towards a lower ACLF and mortality favours its use in these patients.

The microbiota in cirrhosis and its role in hepatic decompensation.

Cirrhosis - the common end-stage of chronic liver disease - is associated with a cascade of events, of which intestinal bacterial overgrowth and dysbiosis are central. Bacterial toxins entering the portal or systemic circulation can directly cause hepatocyte death, while dysbiosis also affects gut barrier function and increases bacterial translocation, leading to infections, systemic inflammation and vasodilation, which contribute to acute decompensation and organ failure. Acute decompensation and its severe forms, pre-acute-on-chronic liver failure (ACLF) and ACLF, are characterised by sudden organ dysfunction (and failure) and high short-term mortality. Patients with pre-ACLF and ACLF present with high-grade systemic inflammation, usually precipitated by proven bacterial infection and/or severe alcoholic hepatitis. However, no precipitant is identified in 30% of these patients, in whom bacterial translocation from the gut microbiota is assumed to be responsible for systemic inflammation and decompensation. Different microbiota profiles may influence the rate of decompensation and thereby outcome in these patients. Thus, targeting the microbiota is a promising strategy for the prevention and treatment of acute decompensation, pre-ACLF and ACLF. Approaches include the use of antibiotics such as rifaximin, faecal microbial transplantation and enterosorbents (e.g. Yaq-001), which bind microbial factors without exerting a direct effect on bacterial growth kinetics. This review focuses on the role of microbiota in decompensation and strategies targeting microbiota to prevent acute decompensation.

PREDICT identifies precipitating events associated with the clinical course of acutely decompensated cirrhosis.

BACKGROUND & AIMS: Acute decompensation (AD) of cirrhosis may present without acute-on-chronic liver failure (ACLF) (AD-No ACLF), or with ACLF (AD-ACLF), defined by organ failure(s). Herein, we aimed to analyze and characterize the precipitants leading to both of these AD phenotypes. METHODS: The multicenter, prospective, observational PREDICT study (NCT03056612) included 1,273 non-electively hospitalized patients with AD (No ACLF = 1,071; ACLF = 202). Medical history, clinical data and laboratory data were collected at enrolment and during 90-day follow-up, with particular attention given to the following characteristics of precipitants: induction of organ dysfunction or failure, systemic inflammation, chronology, intensity, and relationship to outcome. RESULTS: Among various clinical events, 4 distinct events were precipitants consistently related to AD: proven bacterial infections, severe alcoholic hepatitis, gastrointestinal bleeding with shock and toxic encephalopathy. Among patients with precipitants in the AD-No ACLF cohort and the AD-ACLF cohort (38% and 71%, respectively), almost all (96% and 97%, respectively) showed proven bacterial infection and severe alcoholic hepatitis, either alone or in combination with other events. Survival was similar in patients with proven bacterial infections or severe alcoholic hepatitis in both AD phenotypes. The number of precipitants was associated with significantly increased 90-day mortality and was paralleled by increasing levels of surrogates for systemic inflammation. Importantly, adequate first-line antibiotic treatment of proven bacterial infections was associated with a lower ACLF development rate and lower 90-day mortality. CONCLUSIONS: This study identified precipitants that are significantly associated with a distinct clinical course and prognosis in patients with AD. Specific preventive and therapeutic strategies targeting these events may improve outcomes in patients with decompensated cirrhosis. LAY SUMMARY: Acute decompensation (AD) of cirrhosis is characterized by a rapid deterioration in patient health. Herein, we aimed to analyze the precipitating events that cause AD in patients with cirrhosis. Proven bacterial infections and severe alcoholic hepatitis, either alone or in combination, accounted for almost all (96-97%) cases of AD and acute-on-chronic liver failure. Whilst the type of precipitant was not associated with mortality, the number of precipitant(s) was. This study identified precipitants that are significantly associated with a distinct clinical course and prognosis of patients with AD. Specific preventive and therapeutic strategies targeting these events may improve patient outcomes.

Intestinal Virome in Patients With Alcoholic Hepatitis.

BACKGROUND AND AIMS: Alcoholic hepatitis (AH) is a severe manifestation of alcohol-associated liver disease (ALD) with high mortality. Although gut bacteria and fungi modulate disease severity, little is known about the effects of the viral microbiome (virome) in patients with ALD. APPROACH AND RESULTS: We extracted virus-like particles from 89 patients with AH who were enrolled in a multicenter observational study, 36 with alcohol use disorder (AUD), and 17 persons without AUD (controls). Virus-like particles from fecal samples were fractionated using differential filtration techniques, and metagenomic sequencing was performed to characterize intestinal viromes. We observed an increased viral diversity in fecal samples from patients with ALD, with the most significant changes in samples from patients with AH. Escherichia-, Enterobacteria-, and Enterococcus phages were over-represented in fecal samples from patients with AH, along with significant increases in mammalian viruses such as Parvoviridae and Herpesviridae. Antibiotic treatment was associated with higher viral diversity. Specific viral taxa, such as Staphylococcus phages and Herpesviridae, were associated with increased disease severity, indicated by a higher median Model for End-Stage Liver Disease score, and associated with increased 90-day mortality. CONCLUSIONS: In conclusion, intestinal viral taxa are altered in fecal samples from patients with AH and associated with disease severity and mortality. Our study describes an intestinal virome signature associated with AH.

Important Unresolved Questions in the Management of Hepatic Encephalopathy: An ISHEN Consensus.

Management of hepatic encephalopathy (HE) remains challenging from a medical and psychosocial perspective. Members of the International Society for Hepatic Encephalopathy and Nitrogen Metabolism recognized 5 key unresolved questions in HE management focused on (i) driving, (ii) ammonia levels in clinical practice, (iii) testing strategies for covert or minimal HE, (iv) therapeutic options, and (v) nutrition and patient-reported outcomes. The consensus document addresses these topical issues with a succinct review of the literature and statements that critically evaluate the current science and practice, laying the groundwork for future investigations.