Intestinal bacteria and epithelial barrier disruption after alcohol and burn injury

Loyola University Chicago, Maywood IL

Investigators

Linked publications, trials & patents

Abstract

Summary/Abstract Nearly one million burn injuries are reported every year in the United States. Many of these injuries occur under the influence of alcohol intoxication. Intoxication at the time of injury is associated with worse prognosis in burn patients resulting in more adverse outcomes. Gut dysfunction is a common hallmark in post-burn complications and thus studying ways to prevent gut dysfunction following burn injury bears strong clinical relevance. We and others have shown that severe burn or moderate burn injury combined with ethanol exposure disrupts the normal intestinal microbial structure and barrier integrity within 24 hours after injury, but how these changes in the microbiome contribute to intestine barrier disruption and subsequent development of post-burn complications remains to be established. An analysis of fecal samples from burn patients as well as from mice that have undergone ethanol and burn injury show a decrease in beneficial bacteria, including those involved in the production of helpful metabolites such as Short Chain Fatty Acids (SCFAs), and an increase in pathogenic bacteria involved in the production of harmful metabolites such as trimethylamine (TMA), a precursor of trimethylamine-N-oxide (TMAO) compared to controls. SCFAs such as butyrate play a key role in intestinal barrier maintenance. Moreover, TMAO has been linked with vascular inflammation, leakage, and poorer outcomes in patients suffering from cardiovascular diseases. Recently, we focused on microRNAs as they regulate many cellular processes. We have found the expression of several miRNAs is altered in intestinal epithelial cells (IECs) in mice receiving ethanol and burn injury. Together these findings led us to hypothesize that “gut dysbiosis and associated changes in microbial metabolites (SCFAs and TMAO) drive intestinal barrier disruption by altering miRNA homeostasis which can promote pathophysiological complications in alcohol and burn injury”. The hypothesis will be tested using samples generated from burn patients and a mouse model of ethanol and burn injury. Studies in Aim 1 will determine the changes in gut microbial structure and their metabolites in patients with burn injury and evaluate whether alcohol has any impact on these changes. Studies in Aim 2 will determine whether re-introduction of probiotics in mice re- establishes gut microbiota, prevents alteration in microRNA expression and restores gut barrier integrity following alcohol and burn injury. Finally, the focus of Aim 3 will be on whether a shift in microbiome derived metabolites (i.e., SCFAs and TMAO) alter microRNA expression and drive gut barrier disruption after alcohol and burn injury. Our findings will help in identifying novel therapeutic agents/targets to maintain intestine epithelial barrier and will be useful in developing therapeutic strategies for patients suffering from this devastating injury.