A multi-omics approach exploring the gut-liver axis following combined radiation exposure and burn injury in a Sinclair minipig model

While radiation and burn injury have distinct local and systemic effects, they both negatively impact intestinal permeability/function. In a nuclear attack, combined thermal burns and radiation exposure (e.g., combined injury (CI)) would be a dominant injury pattern. Despite this, how burns affect gastrointestinal acute radiation syndrome, and vice versa, has been largely unstudied. Next-generation sequencing has revealed a strong bidirectional link between the liver and gut. Here, we used a porcine model to evaluate the impact of burn, radiation, and CI on the gut microbiota and liver transcriptomics to determine if this link exists in these injury patterns. Sinclair minipigs were randomly divided into three groups: burn (n = 8), hemibody radiation (n = 7), and CI (n = 8). Animals were monitored for 14 days with longitudinal rectal swab and blood collection. CI increased weight loss, diarrhea, inappetence and lethargy compared to either injury pattern alone. Jejunum histology revealed increased mucosal apoptosis in burn and CI groups compared to radiation. CI led to elevated levels of NLRP3 and IL1β in the jejunum. Intestinal barrier disruption was indicated by decreasing circulating l-citrulline in CI which correlated inversely with intestinal-Fatty Acid Binding Protein. Bacteremia was elevated post-burn on day 1 and again from day 7-14 in burn and CI groups. Microbiome analysis showed phylogenetic shifts and differential abundance across groups with CI animals exhibiting distinct microbial signatures linked to intestinal dysfunction and liver injury. Liver RNA-seq revealed group-specific gene expression changes, with CI-altered pathways implicating immune responses and lipid metabolism, which were correlated with gut microbiota such as Bacteroidaceae and Lachnospiraceae. Taken together, we present a first-of-its kind large animal model of radiation combined injury to highlight the interplay between gut-liver axis disruptions and systemic injury responses.