Over 100,000 patients with alcohol use disorder develop sepsis annually in the United States. Patients with alcohol use disorder who develop sepsis are significantly more likely to die or have a complicated intensive care unit stay than septic patients without a history of alcohol use disorder. This proposal aims to understand why alcohol use disorder worsens outcomes in sepsis, as understanding this could lead to precision medicine approaches in this patient population. Using a model of chronic alcohol ingestion that does not result in detectable end organ damage followed by sepsis, we are able to identify possible mechanisms for why mortality is worse in alcohol/sepsis. While the majority of organs have similar function and histology between alcohol/septic and water/septic mice, both gut integrity and the adaptive immune system are severely dysregulated in alcohol/septic mice. Intestinal permeability is mediated through three different pathways that allow selective movement of gut luminal contents into the host. Each of these pathways is worsened in alcohol/sepsis, leading to gut hyperpermeability. The pore and leak pathways are mediated via the apical tight junction, allowing molecules of different sizes to pass through, although notably intact bacteria are too large to pass through either pathway. Increased gut permeability leads to altered host inflammation. CD103 is a key component in orchestrating immune responses in mucosal tissues, ensuring the body's defense against infections while preventing unwarranted immune reactions that could harm host tissues. Additionally, under normal conditions, Foxp3+ regulatory T cells are essential for maintaining immune homeostasis and preventing excessive inflammation. However, during sepsis, the balance between pro-inflammatory and anti-inflammatory responses becomes disrupted and impaired function of regulatory T cells allows for uncontrolled activation of effector T cells and other immune cells, thus contributing to the sepsis-induced cytokine storm and organ damage. Notably, CD103 is downregulated on CD4+ T cells and CD8+ T cells in alcohol/sepsis while regulatory T cells are increased within the CD4+ T cell compartment in alcohol/sepsis. This proposal seeks to understand the mechanisms underlying specific differences in alcohol/septic mice compared to water/septic mice with the ultimate goal of improving outcomes in septic patients with alcohol use disorder prior to hospital admission.