Project Summary This R35 MIRA renewal application is designed to investigate mechanisms responsible for the exaggerated effects of alcohol intoxication on the gut, lung, and brain after burn injury. Of the million people per year who suffer burn injuries in the United States, nearly half of the adult patients are intoxicated at the time of injury. Intoxicated burn patients have increased morbidity and mortality compared to those 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. Additionally, cognitive impairment is common among burn patients in the ICU, and it is associated with a breach of the blood-brain barrier (BBB) and neuroinflammation. Little is known about the mechanism by which alcohol intoxication upregulates the post-burn systemic inflammatory responses that lead to excessive pulmonary inflammation and increased susceptibility to lung infection nor is it known how cognitive dysfunction arises in this patient population. A common feature of these two critical organs is the aberrant activation of local populations of macrophages, alveolar macrophages (AM) in the lung and microglial cells in the brain. These cells are highly sensitive to stimulation by bacteria and bacterial products. Interestingly, both the post- burn pulmonary inflammation and the incidence of delirium in intoxicated burn patients follow a disruption in the integrity of the intestinal epithelial barrier secondary to burn. This, along with dysbiosis of the fecal microbiome, is critically involved in the systemic inflammation seen after alcohol intoxication and burn injury. To date, we know very little about how and when the intestinal microbiome recovers after remote injury, such as a cutaneous scald burn, and even less about how environmental factors, including alcohol intoxication prior to injury, alter that process. In this research program, we will use our clinically-relevant murine model of alcohol intoxication and burn injury along with clinical samples from burn patients, many of whom misuse alcohol, to address the following questions: 1) Can innate immunity be restored in the lung after alcohol and burn injury? 2) Do microglia play a role in the heightened cognitive impairment and neuroinflammation when alcohol proceeds burn injury? 3) Will restoring the gut barrier integrity and microbiome reduce systemic inflammation, improve the pulmonary response to infections, and lessen neuroinflammation and cognitive impairment? Taken together, these studies will expand the knowledge of how alcohol exposure alters the gut in the context of remote injury, such as burns, and may lead to the development of novel therapies to improve outcomes of patients with burns and other forms of trau...