TMAO Correlates with Transcriptomic Signatures of Leukocyte Activation and Systemic Inflammation Following Burn Injury.

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 to 36 hours 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.