Alcoholic hepatitis, characterized by liver inflammation and hepatocyte injury, occurs in 10-20% of patients with alcohol use disorder and accounts for significant mortality and financial burden to the VA healthcare system. Currently, there is no FDA-approved therapy for such patients and treatment options remain as it was 40 years ago. Therefore, it is imperative to develop new therapeutic strategies for which a better understanding of the disease progression is required. There is robust evidence that gut microbial-derived components, such as endotoxins, are the necessary cofactors for development of alcohol-associated liver disease (ALD) and their increased serum levels correlate with disease severity. Further studies have demonstrated that elevated serum levels of the gut luminal antigens occur through two main mechanisms: (i) compromised gut epithelial barrier integrity that allows for increased paracellular translocation; and (ii) qualitative and quantitative changes in the gut microbiota associated with an increased production of pathogenic antigens. These antigens normally penetrate the intestinal epithelium in only trace amounts due to tightly regulated barrier integrity. The barrier is mainly provided by the highly specialized intercellular multiprotein junctional complex, tight junctions (TJ), located at the apical end of epithelial cells. Several studies have documented that ethanol disrupts the structural integrity of TJ. The consequent loss of mucosal barrier allows for increased paracellular translocation of gut luminal pathogenic molecules to travel through portal circulation and initiate a necroinflammatory cascade in the liver. However, the molecular mechanism by which ethanol compromises TJ integrity is incompletely understood. We have previously shown that ethanol consumption alters the methionine metabolic pathway in the liver. The consequent decline in the methylation index impairs crucial methylation reactions, leading to the generation of many hallmark features of early alcohol-associated liver injury. We now present novel evidence that ethanol administration alters the intestinal methionine metabolic pathway and lowers the methylation index in a manner analogous to the liver. Further compelling evidence demonstrates that the consequent reduction in the intestinal methylation reactions causes TJ disruption to promote paracellular leakage, endotoxemia and progressive liver injury. Furthermore, associated with the alcohol-induced disruption of the gut barrier integrity is gut microbial dysbiosis, marked by an increase in the Proteobacteria phylum and Gram-negative bacteria that contribute to endotoxemia. More importantly, we show that co-treatment with betaine, a safe, bioavailable, highly soluble, and naturally occurring methyl group donor, preserves intestinal barrier function and prevents pathogenic gut microbiome changes to mitigate alcohol-induced endotoxemia and liver inflammation. Based on these considerations, we put ...