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Alcohol-related liver disease (ALD) is a major cause of liver-related death worldwide, yet understanding of the three key pathological features of the disease—fibrosis, inflammation and steatosis—remains incomplete. Here, we present a paired liver–plasma proteomics approach to infer molecular pathophysiology and to explore the diagnostic and prognostic capability of plasma proteomics in 596 individuals (137 controls and 459 individuals with ALD), 360 of whom had biopsy-based histological assessment. We analyzed all plasma samples and 79 liver biopsies using a mass spectrometry (MS)-based proteomics workflow with short gradient times and an enhanced, data-independent acquisition scheme in only 3 weeks of measurement time. In plasma and liver biopsy tissues, metabolic functions were downregulated whereas fibrosis-associated signaling and immune responses were upregulated. Machine learning models identified proteomics biomarker panels that detected significant fibrosis (receiver operating characteristic–area under the curve (ROC–AUC), 0.92, accuracy, 0.82) and mild inflammation (ROC–AUC, 0.87, accuracy, 0.79) more accurately than existing clinical assays (DeLong’s test, P  < 0.05). These biomarker panels were found to be accurate in prediction of future liver-related events and all-cause mortality, with a Harrell’s C -index of 0.90 and 0.79, respectively. An independent validation cohort reproduced the diagnostic model performance, laying the foundation for routine MS-based liver disease testing. Interogation of mass-spectrometry-based proteomics of liver and plasma from a cohort of patients with alcohol-related liver disease identifies noninvasive biomarkers associated with early stages of disease progression, including significant fibrosis, inflammation and steatosis.

Chronic liver disease due to alcohol-use disorder contributes markedly to the global burden of disease and mortality 1 – 3 . Alcoholic hepatitis is a severe and life-threatening form of alcohol-associated liver disease. The gut microbiota promotes ethanol-induced liver disease in mice 4 , 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 faecalis 5 , 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. In patients with alcoholic hepatitis, cytolysin-positive Enterococcus faecalis strains are correlated with liver disease severity and increased mortality, and in mouse models these strains can be specifically targeted by bacteriophages.

Alcoholic liver disease, which ranges from mild disease to alcoholic hepatitis and cirrhosis, is a leading cause of morbidity and mortality worldwide. Alcohol intake can lead to changes in gut microbiota composition, even before liver disease development. These alterations worsen with advancing disease and could be complicit in disease progression. Microbial function, especially related to bile acid metabolism, can modulate alcohol-associated injury even in the presence of cirrhosis and alcoholic hepatitis. Microbiota changes might also alter brain function, and the gut–brain axis might be a potential target to reduce alcoholic relapse risk. Gut microbiota manipulation including probiotics, faecal microbial transplant and antibiotics has been studied in alcoholic liver disease with varying success. Further investigation of the modulation of the gut–liver axis is relevant, as most of these patients are not candidates for liver transplantation. This Review focuses on clinical studies involving the gut microbiota in patients with alcoholic liver disease across the spectrum from alcoholic fatty liver to cirrhosis and alcoholic hepatitis. Specific alterations in the gut–liver–brain axis that are complicit in the interactions between the gut microbiota and alcohol addiction are also reviewed.Alcoholic liver disease (ALD) is a leading cause of morbidity and mortality worldwide. Here, Bajaj discusses clinical studies on the gut microbiota in individuals with ALD and explores the specific alterations in the gut–liver–brain axis that might alter patient outcomes.

Felix Stickel and colleagues report the results of a genome-wide association study of alcohol-related cirrhosis. They confirm PNPLA3 as a susceptibility locus and identify new association signals in MBOAT7 and TM6SF2 . Alcohol misuse is the leading cause of cirrhosis and the second most common indication for liver transplantation in the Western world 1 , 2 , 3 . We performed a genome-wide association study for alcohol-related cirrhosis in individuals of European descent (712 cases and 1,426 controls) with subsequent validation in two independent European cohorts (1,148 cases and 922 controls). We identified variants in the MBOAT7 ( P = 1.03 × 10 −9 ) and TM6SF2 ( P = 7.89 × 10 −10 ) genes as new risk loci and confirmed rs738409 in PNPLA3 as an important risk locus for alcohol-related cirrhosis ( P = 1.54 × 10 −48 ) at a genome-wide level of significance. These three loci have a role in lipid processing, suggesting that lipid turnover is important in the pathogenesis of alcohol-related cirrhosis.

Chronic alcohol consumption is a leading cause of chronic liver disease worldwide, leading to cirrhosis and hepatocellular carcinoma. Currently, the most widely used model for alcoholic liver injury is ad libitum feeding with the Lieber-DeCarli liquid diet containing ethanol for 4–6 weeks; however, this model, without the addition of a secondary insult, only induces mild steatosis, slight elevation of serum alanine transaminase (ALT) and little or no inflammation. Here we describe a simple mouse model of alcoholic liver injury by chronic ethanol feeding (10-d ad libitum oral feeding with the Lieber-DeCarli ethanol liquid diet) plus a single binge ethanol feeding. This protocol for chronic-plus-single-binge ethanol feeding synergistically induces liver injury, inflammation and fatty liver, which mimics acute-on-chronic alcoholic liver injury in patients. This feeding protocol can also be extended to chronic feeding for longer periods of time up to 8 weeks plus single or multiple binges. Chronic-binge ethanol feeding leads to high blood alcohol levels; thus, this simple model will be very useful for the study of alcoholic liver disease (ALD) and of other organs damaged by alcohol consumption.

Complement receptor of immunoglobulin superfamily (CRIg) is expressed on liver macrophages and directly binds complement component C3b or Gram-positive bacteria to mediate phagocytosis. CRIg plays important roles in several immune-mediated diseases, but it is not clear how its pathogen recognition and phagocytic functions maintain homeostasis and prevent disease. We previously associated cytolysin-positive Enterococcus faecalis with severity of alcohol-related liver disease. Here, we demonstrate that CRIg is reduced in liver tissues from patients with alcohol-related liver disease. CRIg-deficient mice developed more severe ethanol-induced liver disease than wild-type mice; disease severity was reduced with loss of toll-like receptor 2. CRIg-deficient mice were less efficient than wild-type mice at clearing Gram-positive bacteria such as Enterococcus faecalis that had translocated from gut to liver. Administration of the soluble extracellular domain CRIg–Ig protein protected mice from ethanol-induced steatohepatitis. Our findings indicate that ethanol impairs hepatic clearance of translocated pathobionts, via decreased hepatic CRIg, which facilitates progression of liver disease. CRIg is expressed on liver macrophages and binds Gram-positive bacteria to mediate phagocytosis, but it is not clear how its phagocytic functions contribute to liver homeostasis or disease. Here the authors report that ethanol impairs hepatic clearance of translocated pathobionts, via decreased hepatic CRIg, which facilitates progression of alcoholic liver disease.

Disturbed lipid metabolism precedes alcoholic liver injury. Whether and how AhR alters degradation of lipids, particularly phospho-/sphingo-lipids during alcohol exposure, was not explored. Here, we show that alcohol consumption in mice results in induction and activation of aryl hydrocarbon receptor (AhR) in the liver, and changes the hepatic phospho-/sphingo-lipids content. The levels of kynurenine, an endogenous AhR ligand, are elevated with increased hepatic tryptophan metabolic enzymes in alcohol-fed mice. Either alcohol or kynurenine treatment promotes AhR activation with autophagy dysregulation via AMPK. Protein Phosphatase 2 Regulatory Subunit-Bdelta ( Ppp2r2d) is identified as a transcriptional target of AhR. Consequently, PPP2R2D-dependent AMPKα dephosphorylation causes autophagy inhibition and mitochondrial dysfunction. Hepatocyte-specific AhR ablation attenuates steatosis, which is associated with recovery of phospho-/sphingo-lipids content. Changes of AhR targets are corroborated using patient specimens. Overall, AhR induction by alcohol inhibits autophagy in hepatocytes through AMPKα, which is mediated by Ppp2r2d gene transactivation, revealing an AhR-dependent metabolism of phospho-/sphingo-lipids. Alcohol consumption promotes neutral fat accumulation in the liver. Here, the authors report that alcohol induces aryl hydrocarbon receptor AhR in the liver, and hepatocyte-specific AhR deletion protects against alcohol induced accumulation potentially via transcriptional regulation of Protein phosphatase 2 regulatory subunit Bdelta and subsequent effects on autophagy.

It is elusive why some heavy drinkers progress to severe alcohol-related liver disease (ALD) while others do not. This study aimed to investigate if the association between alcohol consumption and severe ALD is modified by diet. This prospective study included 303,269 UK Biobank participants. Alcohol consumption and diet were self-reported. The diet score was created from 4 items selected using LASSO. Cox proportional hazard model showed that the diet score was monotonically associated with severe ALD risk, adjusted for sociodemographics, lifestyle factors, and alcohol consumption. Relative excess risk due to interaction analysis indicated that having a higher ALD diet score and a higher alcohol consumption simultaneously confers to 2.44 times (95% CI: 1.06-3.83) higher risk than the sum of excess risk of each factor. In this work, we show that people who have a poor diet might be more susceptible to severe ALD due to alcohol consumption. It is elusive why some heavy drinkers progress to severe alcohol-related liver disease (ALD) while others do not. Here we show that people who have a poor diet, as indicated with a data-driven score, might be more susceptible to severe ALD due to alcohol consumption.

Alcoholic liver disease (ALD) causes significant morbidity and mortality, and pharmacological treatment options are limited. In this study, we evaluated the PCSK9 inhibitor alirocumab, a monoclonal antibody that robustly reduces low-density lipoprotein cholesterol (LDL-C), for the treatment of ALD using a rat model of chronic alcohol exposure. Alirocumab (50 mg/kg) or vehicle was administered weekly for 6 weeks to rats receiving a 12% alcohol liquid diet or an isocaloric control diet. At the end of the alcohol exposure protocol, serum and liver samples were obtained for molecular characterization and histopathological analysis. PCSK9 inhibition with alirocumab attenuated alcohol-induced hepatic triglyceride accumulation through regulation of lipid metabolism (mRNA expression of modulators of fatty acid synthesis (FAS) and catabolism (PPARα and CPT1)), hepatocellular injury (ALT), hepatic inflammation (mRNA expression of pro-inflammatory cytokines/chemokines (TNFa, IL-1β, IL-22, IL-33, IL-17α, IL-2, MIP-2, and MCP-1), and neutrophil infiltration (myeloperoxidase staining)). Alirocumab treatment also attenuated alcohol-induced PCSK9 mRNA elevation and upregulated LDL-receptor (LDL-R) via modulation of the transcription factors (SREBP-1, SREBP-2, and E2F1) in liver. We demonstrated that chronic anti-PCSK9 treatment using the monoclonal antibody alirocumab attenuated alcohol-induced steatohepatitis in the rat model. Given the large unmet clinical need for effective and novel treatments for ALD, anti-PCSK9 treatment with the monoclonal antibody that spares liver metabolism is a viable new therapeutic possibility. Future studies are needed to elucidate the exact role of PCSK9 in ALD and alcohol use disorder (AUD) and to evaluate efficacy and safety of anti-PCSK9 treatment in clinical populations with ALD/AUD.

BackgroundThe incidence of both non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (ALD) are expected to grow as a consequence of the ongoing obesity and alcohol consumption trends.ObjectiveWe examined the joint associations of adiposity (body mass index (BMI) and waist circumference (WC)) and alcohol consumption on ALD, NAFLD and liver disease incidence and mortality (n = 465,437).MethodsAlcohol consumption was categorised based on current UK guidelines (14 units/week). Data were analysed using Cox proportional hazard models. A total of 1090 liver disease deaths, 230 ALD deaths and 192 NAFLD deaths occurred over an average follow-up length of 10.5 ± 1.7 years.ResultsIn multivariate models, we observed greater point estimates for risk of ALD, NAFLD and liver disease incidence and mortality among overweight/obese participants who consumed alcohol at the same level as normal weight participants. We found that overweight/obese participants who reported alcohol consumption above the guidelines had a greater HR for liver disease incidence and mortality (HR 1.52, 95% CI 1.32, 1.75 and HR 2.20, 95% CI 1.41, 3.44, respectively) than normal weight individuals (HR 0.95, 95% CI 0.83, 1.09 and HR 1.24, 95% CI 0.8, 1.93, respectively). The results for the associations of alcohol consumption and WC with ALD, NAFLD and liver disease mortality were similar. Participants with high WC who reported alcohol consumption above the guidelines had a greater HR for liver disease incidence (HR 1.59, 95% CI 1.35, 1.87) than normal WC individuals (HR 0.85, 95% CI 0.72, 1.01).ConclusionsWe found evidence that being overweight/obese amplified the harmful effect of alcohol on the liver incidence and mortality.