Project Summary The proposed studies will examine mechanisms by which morbidity and mortality are greater in older burn patients. Regardless of age, most burn patients do not die from primary injuries but rather from complications, such as pneumonia and multiple organ failure (MOF). Clinical and experimental evidence reveal that healthy aged subjects are in an elevated basal inflammatory state, referred to as “inflamm-aging,” which can slow the immune system's response to invading pathogens. We and others believe that inflamm-aging is caused by translocation of bacterial products from the intestinal lumen and that continuous exposure to these products triggers the production of pro-inflammatory cytokines, including interleukin (IL)-1β and IL-6. In addition, shifts in the intestinal microbiota in the aged can promote systemic inflammation and these shifts are much more dramatic after burns. Novel preliminary data in our clinically-relevant mouse model of burn injury confirm that aged burn-injured mice have heightened circulating levels of danger-associated molecular patterns (DAMPs), a greater breach in intestinal epithelial barrier integrity, and more dramatic dysbiosis of the fecal microbiome relative to their young counterparts. Moreover, we know from our recent work on burn patients that advanced age upregulates pro-inflammatory mediators in the lungs and blood, which parallels our mouse studies. From these observations, we hypothesize that, relative to young, older subjects who sustain a burn injury have greater 1) breach in the integrity of the intestinal epithelial barrier and 2) shift in the intestinal microbiome, leading to excessive systemic inflammation and damage to critical organs, like the lung. To test the concept of the post-burn “gut-lung axis,” in Aim 1, we will examine intestinal barrier integrity in burn-injured young and aged mice over time using blood-borne and fecal biomarkers of intestinal damage and determine if restoring the intestinal barrier reduces inflammation and improves function of distant organs, including the lung. In Aim 2, we will examine levels of a subset of gut and lung antimicrobial peptides (AMPs), determine the extent of fecal microbiome dysbiosis, and investigate whether modulating AMP levels restores normal intestinal and pulmonary parameters in young and aged burned mice. Lastly, in Aim 3, we will study burn patients longitudinally to determine if the superimposed impact of burn injury with advanced age alters intestinal barrier integrity and fecal microbiota to a greater extent than seen in younger subjects with equivalent size burns. Moreover, we will see if there is a relationship between intestinal dysregulation and systemic/pulmonary inflammation by assessing blood-borne and fecal biomarkers of intestinal damage and microbial dysbiosis and determine if these biomarkers can be used to predict acute hypoxic respiratory failure and poor immune response following pulmonary infections. These studies wi...