Acetate modulates host physiology and bacterial energetics to improve antibiotic efficacy during obesity-associated infection.

Antibiotic efficacy is conventionally attributed to the susceptibility of the infecting pathogen. However, obese patients experience disproportionately poor infection outcomes despite receiving antibiotics to which pathogens remain genetically susceptible. These observations suggest that host-associated factors can influence treatment outcomes independently of the bacterial genotype, although the underlying mechanisms remain poorly understood. Using a mechanistic comparison of diet-induced obese and healthy mice infected with IMPORTANCE: Antibiotic treatment failure in obese patients remains poorly understood and therapeutically unaddressed. This study reveals that host metabolic state can control antibiotic response through a gut microbiota-derived metabolite that acts on both host defense and bacterial physiology. We identify obesity-driven depletion of microbiota-derived acetate as a previously unrecognized determinant of antibiotic failure, operating independently of bacterial resistance. By simultaneously restoring gut microbial balance, rescuing impaired innate immunity, and directly sensitizing pathogens to aminoglycoside killing through bacterial membrane alteration, acetate supplementation addresses the host-pathogen-microbiome axis through a single intervention. Given its established clinical safety, acetate represents a compelling combination therapy alongside aminoglycosides in obesity-associated gram-negative infections in a population for which host-directed treatment strategies are currently limited.