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

Summary

Using bacterial sepsis models, the authors show that males exhibit impaired disease tolerance driven by deficient mitochondrial oxidative metabolic shifts, independent of pathogen control or canonical inflammation. Augmenting mitochondrial tolerance with doxycycline abrogated male-biased illness severity and organ dysfunction, highlighting sex as a determinant of treatment responsiveness.

Key Findings

• Male mice show impaired disease tolerance via deficient mitochondrial oxidative metabolic shifts during sepsis.
• Sex-biased tolerance is independent of pathogen resistance and canonical immune/inflammatory dysregulation.
• Doxycycline enhanced mitochondrial tolerance and neutralized male-predominant illness severity and organ dysfunction.

Clinical Implications

Encourages sex-stratified sepsis trials and consideration of tolerance-targeting adjuncts (e.g., doxycycline) particularly in males; prompts incorporation of sex as a key biological variable in sepsis therapeutics development.

Limitations

• Findings are based on animal models with limited direct human validation.
• Potential translational uncertainties around dosing, timing, and antibiotic confounding effects.

Future Directions

Sex-stratified early-phase clinical trials of tolerance-enhancing agents; development of biomarkers for mitochondrial tolerance to enable patient selection.