Fasting-induced ketogenesis sensitizes bacteria to antibiotic treatment.

Summary

In multiple murine sepsis models, fasting-induced ketogenesis markedly enhanced antibiotic efficacy, boosting bacterial clearance and survival. Mechanistically, the ketone body acetoacetate increased bacterial membrane permeability, depleted positively charged amino acids and putrescine, and amplified antibiotic lethality.

Key Findings

• Fasting potentiated antibiotic treatment in murine sepsis due to Salmonella Typhimurium, Klebsiella pneumoniae, and Enterobacter cloacae, improving bacterial clearance and survival.
• Fasting-induced ketogenesis, specifically acetoacetate, increased outer and inner bacterial membrane permeability and antibiotic lethality.
• Acetoacetate depleted bacterial positively charged amino acids and putrescine, causing membrane malfunctions and redox-related lethality; antibiotic–ketone body combination therapy recapitulated fasting benefits.

Clinical Implications

Suggests potential adjunct strategies: short-term metabolic modulation (e.g., ketone body supplementation) to enhance antibiotic killing in bacterial sepsis. Human safety, dosing, and patient selection require rigorous clinical trials.

Limitations

• Preclinical mouse and bacterial models; no human clinical data.
• Safety and feasibility of fasting or ketone body supplementation in acutely ill septic patients remain untested.

Future Directions

Phase I/II trials to evaluate safety and pharmacodynamics of ketone body supplementation with antibiotics; patient stratification by pathogen and metabolic status; exploration of optimal dosing and timing.