Aged sepsis patients harbor increased levels of Klebsiella aerogenes bacteria that produce histamine through a histidine decarboxylase gene variant. This bacterial histamine disrupts intestinal barrier function by suppressing Nlrp6 expression and preventing its binding to LC3, ultimately impairing autophagy—the cellular cleanup mechanism critical for removing damaged components during infection. Fecal transplant experiments confirmed this age-related microbiome shift directly causes barrier dysfunction in young recipients. The discovery of the histamine-Nlrp6-LC3 axis represents a significant mechanistic breakthrough connecting aging, microbiome composition, and sepsis severity. This pathway offers concrete therapeutic targets beyond current sepsis treatments that focus primarily on antibiotics and supportive care. The finding is particularly compelling because it explains why elderly patients consistently experience worse sepsis outcomes through a specific bacterial-metabolite-host interaction. However, the research was conducted in mice with human validation limited to microbiome analysis, requiring clinical trials to confirm therapeutic potential. The identification of genetically distinct K. aerogenes strains as histamine producers suggests precision medicine approaches could target specific bacterial variants rather than broad-spectrum interventions.