Multi-Omics and -Organ Insights into Energy Metabolic Adaptations in Early Sepsis Onset.

Summary

This translational study integrates human serum metabolomics/lipidomics with mouse single-nucleus RNA-seq to reveal early serine-centered energy metabolic adaptations that distinguish uncomplicated infection from sepsis. Mitochondrial gene modules (Cox4i1, Cox8a, Ndufa4) are down-regulated across tissues, with liver-specific serine-dependent shifts. Findings suggest feasible early biomarkers and mitochondrial-metabolic targets for risk stratification.

Key Findings

• Untargeted serum metabolomics/lipidomics in 152 presymptomatic surgical patients identified serine and aminoadipic acid as discriminators between postoperative uncomplicated infection and sepsis.
• Single-nucleus RNA-seq in a mouse sepsis model showed tissue-independent down-regulation of serine and energy-related genes with key roles for mitochondrial genes Cox4i1, Cox8a, and Ndufa4.
• Liver-specific serine-dependent metabolic shifts were highlighted, linking systemic metabolite signatures to organ-level energy metabolism.
• Integrative multi-omics across species indicates early bioenergetic failure as a unifying feature preceding sepsis onset.

Clinical Implications

Supports development of early risk-stratification assays using serine-centered metabolite panels and suggests evaluating mitochondrial bioenergetic pathways as therapeutic targets, particularly hepatic serine metabolism.

Limitations

• Moderate human sample size from a surgical cohort may limit generalizability.
• External validation cohorts and prospective diagnostic performance metrics are needed.

Future Directions

Validate metabolite panels in multicenter cohorts, define predictive thresholds, and test serine/mitochondrial pathway modulation in preclinical and early-phase interventional studies.