Research Project
10180982
Alcohol-related traumatic and burn injuries remain a considerable health and economic burden to the American society. Studies have shown that patients who are intoxicated at the time of injury are more susceptible to infection and exhibit significantly higher morbidity and mortality compared to burn patients who are not intoxicated at the time of injury. Yet, the mechanism by which alcohol (ethanol) enhances post burn pathogenesis remains largely unclear. Gut barrier dysfunction is frequently associated with ethanol exposure and major injury. We have shown that the ethanol intoxication combined with moderate burn injury causes intestinal tissue damage, leakiness, and a significant increase in bacterial translocation within 24 hours after injury. We further observed a decrease in the expression of microRNA (miR-7a and miR-150) and microRNA biogenesis components Drosha and Argonaute-2 in intestinal epithelial cells (IEC) one day following alcohol and burn injury. Moreover, ethanol combined with burn injury increases bacterial load (Enterobacteriaceae) in the small intestine. Such an increase in Enterobacteriaceae may disrupt the bacteria/host interactions and potentiate the inflammatory response by activating pattern recognition receptors (PRR) expressed on IECs leading to intestine tissue damage and leakiness following ethanol and burn injury. Our hypothesis is that accumulation of Gram-negative bacteria (i.e. Enterobacteriaceae) in intestine following ethanol and burn injury perturbs gut microbiota-epithelial interactions, which become exacerbated by altered microRNA homeostasis, thus, culminating in gut inflammation and barrier disruption. The hypothesis will be tested in 3 Aims in a well-established mouse model of ethanol intoxication and burn injury. Studies in Aim 1 are designed to delineate the mechanism by which ethanol and burn induced changes in intestinal bacteria influence intestine barrier integrity following injury. Aim 2 will determine whether changes in gut bacteria alone or in combination with an increase in HIF-1? influence the expression of miR-150 and miR-7a and whether restoration of miR-150 and/or miR-7a in intestinal epithelial cells following alcohol and burn injury reduces gut inflammation and improves barrier integrity. Furthermore studies in Aim 3 will determine whether treatment of animals with probiotics reestablishes gut microbiota and intestine barrier integrity following alcohol and burn injury. The findings from these studies will reveal a novel role for gut microbiota in gut leakiness following ethanol intoxication and burn injury and in turn may help in developing new therapeutic strategies for patients suffering from a combined insult of ethanol and burn injury.
