Politechnika Gdanska

Urinary Tract Infections (UTIs) and urosepsis represent significant challenges in clinical medicine, necessitating a deeper understanding of the molecular intricacies underlying these conditions. In this study, we employed a multi-omics approach to elucidate the molecular landscape associated with UTIs and urosepsis, with a specific focus on ferroptosis and oxidative stress. Through integrative analysis of metabolomic, proteomic, and genetic data, we identified potential bacterial and human biomarkers linked to iron sequestration, oxidative damage, and dysregulated pathways associated with the progression and severity of UTIs and urosepsis. Elevated levels of glutathione, iron-handling proteins, and pro-inflammatory cytokines: Interleukin-6, Interleukin-8 suggest a mechanistic link between oxidative stress and ferroptosis in urosepsis. Importantly, our study highlights the role of oxidative damage in exacerbating tissue injury and systemic dysfunction during the progression of sepsis. We also identified 5,6-Dihydroxyindole-2-carboxylic acid as a novel biomarker for urosepsis, indicating that oxidative stress and iron metabolism dysregulation may extend beyond standard organs to influence broader systemic responses. This metabolite may serve as an early indicator for detecting and differenting of urosepsis from uncomplicated UTIs, providing a valuable tool to improve diagnostic precision and patient outcomes.

Urinary tract infections (UTIs) and urosepsis necessitate a deeper understanding of host-pathogen interactions at the metabolic level. We use LC-MS and GC-MS techniques to characterize metabolic pathway alterations in patients and Escherichia coli isolates during UTI and urosepsis. Our findings reveal substantial metabolic adaptations in the human host, including increased porphyrin metabolism, suggesting oxidative stress response or tissue damage. Activation of the pentose phosphate pathway (PPP) and tricarboxylic acid cycle (TCA) highlights the host's heightened immune and energy demands during infection. Additionally, enhanced malate-aspartate shuttle activity suggests a greater reliance on glycolysis for energy production, while increased pyruvaldehyde degradation indicates active detoxification of harmful metabolic byproducts. In E. coli, distinct metabolic shifts depended on the extracellular/intracellular niche and infection stage. Intracellular metabolites of E. coli during urosepsis exhibited upregulated purine and biotin metabolism, reflecting a focus on replication and essential metabolic functions. Conversely, intracellular metabolites of E. coli during UTI displayed increased aspartate metabolism, TCA cycle activity, Warburg effect, fatty acid biosynthesis, and glycine/serine metabolism, indicative of urinary tract adaptation. Extracellular metabolites of E. coli during urosepsis exhibited a broad activation of sugar metabolism, highlighting its ability to exploit diverse nutrient sources in systemic infection. In contrast, extracellular metabolites of E. coli during UTI demonstrated specific metabolic changes, including propanoate metabolism activation and homocysteine dysregulation, reflecting unique urinary tract conditions. These findings provide insights into the metabolic pathways employed by host and pathogen during UTI and urosepsis, uncovering potential metabolic vulnerabilities in E. coli.