Differential disease tolerance mediates sex-biased illness severity in sepsis.

Summary

Using murine sepsis models, the authors show that male-biased severity stems from impaired disease tolerance driven by deficient mitochondrial oxidative metabolic shifts, independent of pathogen control and canonical inflammation. Pharmacologic enhancement of mitochondrial tolerance with doxycycline abrogated sex differences by preferentially improving outcomes in males.

Key Findings

• Male mice exhibited greater illness severity and organ dysfunction due to impaired disease tolerance, linked to blunted tolerogenic shifts in mitochondrial oxidative metabolism.
• Sex differences in outcomes were independent of pathogen resistance and canonical immune/inflammatory dysregulation.
• Doxycycline enhanced mitochondrial tolerance and preferentially reduced illness severity and organ dysfunction in males, eliminating sexual dimorphism.

Clinical Implications

Sepsis trials and care pathways should incorporate sex-stratified analyses and consider therapeutics that enhance mitochondrial tolerance (e.g., doxycycline), with careful dose–response and safety assessment.

Limitations

• Preclinical murine models limit direct human translatability
• Doxycycline’s pleiotropy and optimal dosing/safety in sepsis remain undefined in humans

Future Directions

Validate mitochondrial tolerance biomarkers and test sex-stratified, dose-finding trials of tolerance-enhancing agents (e.g., tetracyclines) in human sepsis.