Background: Pneumonia contributes to post-burn morbidity and mortality. Understanding the mechanisms that predispose burn patients to pneumonia is crucial to both stratifying patients at increased risk and developing targeted interventions. Methods: A prospective observational study was conducted with 47 human patients who sustained large burn injuries with serum collected on days 2 and 3 post-burn and assessed for Angiopoietin-1 (Ang-1) and -2 (Ang-2). C57BL/6 mice were subjected to either sham injury or a 12.5% total body surface area (TBSA) scald burn injury, and plasma and lungs were assessed. Results: Patients who developed pneumonia within 30 days of injury had higher serum Ang-2 and Ang-2/1 ratio on post-injury days 2 and 3. Similar to patient findings, we observed an increase in Ang-2 in burn mice compared to sham. Within the lungs of burn mice, we found significant increases in Tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2 (TIE2) receptor transcript Tek, downstream mediators TNFAIP3 Interacting Protein 2 (Tnip2) and phosphoinositide-3-kinase regulatory subunit 1 (Pik3r1), in addition to endothelial adhesion molecules intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), along with neutrophil infiltration and markers compared to sham. Conclusions: These findings suggest that burn injury increases Angiopoetin-2 and downstream signaling in the lungs, which may contribute to post-burn pulmonary dysfunction. Further studies are necessary to understand if modulating the Ang–TIE2 axis can protect against pneumonia post-burn.

Background: Severe burn injury induces gastrointestinal dysfunction and bacterial dysbiosis, yet the systemic impact of altered bacterial metabolites remains poorly understood. We assessed whether changes in plasma levels of trimethylamine N-oxide (TMAO), a gut-derived metabolite, have a relationship with changes in the whole blood transcriptomic profile following burn injury. Methods: Using previously harvested plasma from 67 burn patients, we quantified circulatory levels of TMAO via ELISA. To assess TMAO’s impact on the blood transcriptome, we applied a linear model to previously published whole blood microarray data from a subset of these patients (n = 22) with paired TMAO measurements. Results: While initial TMAO levels were comparable across small and larger burns, concentrations significantly increased 24-36 h post-admission in patients with >10% total body surface area (TBSA) burns, independent of age or sex. Elevated TMAO positively correlated with both burn size and Baux score. Furthermore, transcriptomic analysis revealed that high TMAO levels were strongly associated with the enrichment of inflammatory and leukocyte activation pathways, despite a lack of association between TMAO levels and imputed fractions of immune cells. Conclusion: Burn injury is associated with a delayed, severity-dependent elevation in circulating TMAO. This increase in TMAO correlates with transcriptomic signatures of robust immune activation and systemic inflammation, suggesting that targeting the gut microbiome and its metabolites may offer a novel therapeutic avenue to address post-burn inflammatory complications.