Background: Animal data suggest a role of the gut-liver axis in progression of alcoholic liver disease (ALD), but human data are scarce especially for early disease stages. Methods: We included patients with alcohol use disorder (AUD) who follow a rehabilitation program and matched healthy controls. We determined intestinal epithelial and vascular permeability (IP) (using urinary excretion of 51 Cr-EDTA, fecal albumin content, and immunohistochemistry in distal duodenal biopsies), epithelial damage (histology, serum iFABP, and intestinal gene expression), and microbial translocation (Gram-and Gram + serum markers by ELISA). Duodenal mucosaassociated microbiota and fecal microbiota were analyzed by 16 S rRNA sequencing. ALD was staged by Fibroscan® (liver stiffness, controlled attenuation parameter) in combination with serum AST, ALT, and CK18-M65. Results: Only a subset of AUD patients had increased 51 Cr-EDTA and fecal albumin together with disrupted tight junctions and vasculature expression of plasmalemma Vesicle-Associated Protein-1. The so-defined increased intestinal permeability was not related to changes of the duodenal microbiota or alterations of the intestinal epithelium but associated with compositional changes of the fecal microbiota. Leaky gut alone did not explain increased microbial translocation in AUD patients. By contrast, duodenal dysbiosis with a dominance shift toward specific potential pathogenic bacteria genera (Streptococcus, Shuttleworthia, Rothia), increased IP and elevated markers of microbial translocation characterized AUD patients with progressive ALD (steato-hepatitis, steatofibrosis). Conclusion: Progressive ALD already at early disease stages is associated with duodenal mucosaassociated dysbiosis and elevated microbial translocation. Surprisingly, such modifications were not linked with increased IP. Rather, increased IP appears related to fecal microbiota dysbiosis.

Mechanisms underlying alcohol‐induced liver injury and its progression still remain incompletely understood. Animal models can only address some aspects of the pathophysiology that requires studies directly in humans, which are scarce. We assessed liver inflammatory and immune responses at early stages of alcoholic liver disease in a unique cohort of alcohol‐dependent patients undergoing a highly standardized alcohol withdrawal program. In active drinkers, quantitative real‐time polymerase chain reaction revealed alcohol‐induced activation of tumor necrosis factor alpha, interleukin (IL)‐1β, and nuclear factor kappa B in liver tissue already at early disease stages. Double immunofluorescence staining indicated that this proinflammatory response was restricted to activated, CD68‐positive macrophages. In parallel, down‐regulation of IL‐6, inhibition of the signal transducer and activator of transcription 3 (Stat3) pathway, as well as blunted cyclin D expression in hepatocytes, reduced proliferation and favored hepatocyte apoptosis. In addition, immunofluorescence and quantitative real‐time polymerase chain reaction of liver tissue showed that alcohol also activated the toll‐like receptor (TLR) 7–interferon (IFN) axis in hepatocytes, which was confirmed in alcohol‐stimulated primary human hepatocytes and precision‐cut liver slices in vitro . Activation of the TLR7–IFN axis strongly correlated with liver fibrosis markers and disease progression. Two weeks of abstinence attenuated the inflammatory response but did not allow recovery of the defective Stat3 pathway or effect on fibrosis‐associated factors. Conclusion : In humans, inflammation, activation of the TLR7–IFN axis, and inhibition of Stat3‐dependent repair mechanisms in early alcoholic liver disease pave the way for fibrosis development and ultimately disease progression.

Alcohol-related liver disease is a public health care burden globally. Only 10–20% of patients with alcohol use disorder have progressive liver disease. This study aimed to identify lipid biomarkers for the early identification of progressive alcohol-related liver disease, which is a key step for early intervention. We performed untargeted lipidomics analysis in serum and fecal samples for a cohort of 49 subjects, including 17 non-alcoholic controls, 16 patients with non-progressive alcohol-related liver disease, and 16 patients with progressive alcohol-related liver disease. The serum and fecal lipidome profiles in the two patient groups were different from that in the controls. Nine lipid biomarkers were identified that were significantly different between patients with progressive liver disease and patients with non-progressive liver disease in both serum and fecal samples. We further built a random forest model to predict progressive alcohol-related liver disease using nine lipid biomarkers. Fecal lipids performed better (Area Under the Curve, AUC = 0.90) than serum lipids (AUC = 0.79). The lipid biomarkers identified are promising candidates for the early identification of progressive alcohol-related liver disease.

Alcohol-associated liver disease (ALD) encompasses a spectrum of injury, ranging from benign, generally asymptomatic fatty liver (steatosis), to advanced stages including cirrhosis, severe alcoholassociated hepatitis, and eventually hepatocellular carcinoma (O'Shea et al., 2010). Although around 90% of heavy drinkers (>60 g/day of alcohol) develop steatosis, only a subset of alcohol

Chronic alcohol consumption and alcohol-associated liver disease (ALD) represent a major public health problem worldwide. Only a minority of patients with an alcohol-use disorder (AUD) develop severe forms of liver disease (e.g., steatohepatitis and fibrosis) and finally progress to the more advanced stages of ALD, such as severe alcohol-associated hepatitis and decompensated cirrhosis. Emerging evidence suggests that gut barrier dysfunction is multifactorial, implicating microbiota changes, alterations in the intestinal epithelium, and immune dysfunction. This failing gut barrier ultimately allows microbial antigens, microbes, and metabolites to translocate to the liver and into systemic circulation. Subsequent activation of immune and inflammatory responses contributes to liver disease progression. Here we review the literature about the disturbance of the different host defense mechanisms linked to gut barrier dysfunction, increased microbial translocation, and impairment of liver and systemic inflammatory responses in the different stages of ALD.