Melatonin Confers Protection Against Multidrug‐Resistant Bacterial Infections in Aged Mice Via Microbiota‐Derived Butyrate

Aging is associated with increased susceptibility to bacterial infections, particularly multidrug-resistant (MDR) strains, which often result in antibiotic treatment failure and high mortality rates in the elderly. However, effective preventive and therapeutic strategies remain limited. Herein, we showed that aged mice exhibited higher susceptibility to colistin-resistant Salmonella enterica serotype Typhimurium and methicillin-resistant Staphylococcus aureus compared to young mice. Notably, pre-supplementation with melatonin, a hormone markedly reduced in the aging gut, effectively restricted MDR bacterial infections in aged mice by enhancing microbial colonization resistance. Mechanistically, melatonin-induced alterations in the gut microbiota, particularly the enrichment of butyrate-producing bacteria including Faecalibaculum, Muribaculaceae, and Ruminococcus, played a pivotal role in enhancing resistance to pathogenic bacteria. Elevated gut butyrate levels following melatonin pre-supplementation not only preserved intestinal barrier integrity and mitigated inflammaging, but also directly inhibited pathogenic bacterial growth by disrupting intracellular pH homeostasis, leading to proton motive force dissipation and metabolic disturbances. These findings underscore melatonin and its metabolite, butyrate, as promising candidates for the prevention of MDR bacterial infections in the aging population.