Burn is a form of traumatic injury that affects more than just the skin and can cause damage to multiple organ systems. Of the one million people per year who suffer burn injuries in the United States, 40,000 are admitted to hospitals. Remarkably, about half of those patients are intoxicated at the time of injury. Burn patients who were intoxicated when they sustained their injuries have increased morbidity and mortality compared to burn patients who had not been drinking. The lung is the most frequent organ to fail after a remote injury such as cutaneous burn, with 45% of burn patients showing some form of lung damage even in the absence of inhalation injury. Pneumonia and acute respiratory distress syndrome (ARDS) are among the major complications seen in intoxicated burn patients. However, little is known about the mechanism by which alcohol intoxication modulates systemic inflammatory responses that lead to excessive pulmonary inflammation and increased susceptibility to lung infection and damage in burn victims. Evidence suggests that reduced integrity of the epithelial barrier of the gut secondary to burn injury plays a critical role in this process. Burn trauma and alcohol intoxication independently reduce the intestinal barrier integrity by altering the localization of epithelial tight junction proteins. Following the dual insult of alcohol intoxication and burn injury, the responses are compounded (additively, if not synergistically). The result is a more dramatic release of bacterial products and endotoxins into the portal and systemic circulation, triggering the so-called “cytokine storm” characteristic of injury-induced systemic inflammation. From these observations, we hypothesize that after burn injury, 1) intestinal dysfunction, including a breach in the integrity of the intestinal epithelial barrier, mediates the observed multi-organ complications, 2) that these changes can be monitored by measuring biomarkers of intestinal damage and inflammation in the blood, and that 3) gut-directed therapies will restore intestinal and systemic homeostasis improving the function of distal organs such as the lung. To test this hypothesis, first, in Aim 1, we will examine whether intestinal barrier dysregulation in the setting of alcohol intoxication and burn injury precedes pulmonary inflammation and if the intestinal barrier changes can be followed over time using a panel of blood-borne biomarkers. In Aim 2, we will investigate whether restoration of intestinal barrier integrity attenuates systemic and pulmonary indices of inflammation in our mouse model of alcohol intoxication and burn injury and whether repairing the intestinal barrier improves the pulmonary response to an infection. Lastly, in Aim 3, we will study burn patients, with and without recent alcohol intoxication, longitudinally to determine if the superimposed impact of burn injury with alcohol abuse alters intestinal barrier dysregulation to a greater extent than burn or alcohol...