Aging-caused the changes of the gut microbiota drive intestinal barrier dysfunction and increase sepsis susceptibility.

Aged septic patients and mice harbor distinct gut microbiota compositions compared to young septic counterparts, with increased abundance of Klebsiella aerogenes in aged hosts.

• Fecal samples were collected from both aged and young septic patients and mice for comparison.
• 16S rDNA sequencing was used to characterize gut microbiota composition.
• K. aerogenes was identified as a differentially abundant taxon enriched in aged hosts.
• Fecal microbiota transplantation (FMT) into young pseudo-germ-free mice was used to establish causal relationships.

Fecal microbiota from aged septic hosts, when transplanted into young pseudo-germ-free mice, increased intestinal barrier dysfunction compared to transplantation of young septic host microbiota.

• Young pseudo-germ-free recipient mice received FMT from aged or young septic patients and mice.
• Intestinal permeability was assessed using FITC-dextran assay.
• Histopathological examination of colon tissue was performed to assess gut injury.
• ELISA was used to measure inflammatory markers in blood and tissue samples.

Klebsiella aerogenes strains carrying a histidine decarboxylase gene variant were identified as major histamine producers in aged septic hosts.

• Nontargeted and targeted metabolomics were used to identify differential metabolites in feces of aged versus young septic mice.
• Histamine (HA) was identified as a key differentially produced metabolite elevated in aged septic conditions.
• A specific variant of the histidine decarboxylase gene in K. aerogenes was linked to elevated histamine production.
• Genetically engineered bacteria were used in both in vivo and in vitro experiments to validate the role of K. aerogenes and its histidine decarboxylase variant.

Histamine drives intestinal barrier dysfunction by inhibiting Nlrp6 expression and its subsequent binding to LC3, thereby impairing autophagy.

• Mechanistic experiments demonstrated that histamine suppressed Nlrp6 expression in intestinal tissue.
• Reduced Nlrp6 expression impaired the binding of Nlrp6 to LC3, a key component of the autophagy pathway.
• Impaired Nlrp6-LC3 interaction led to defective autophagy and exacerbated intestinal barrier dysfunction.
• This HA-Nlrp6-LC3 axis was identified as a mechanistic pathway linking microbiota changes to gut barrier failure in sepsis.

Modulation of histamine levels or overexpression of Nlrp6 ameliorated inflammation and intestinal barrier dysfunction in septic mice.

• Treatments that reduced histamine levels improved intestinal barrier function in septic mouse models.
• Overexpression of Nlrp6 similarly ameliorated inflammation in septic mice.
• Both interventions targeted the HA-Nlrp6-LC3 axis.
• These findings were validated using in vivo experiments in septic mouse models.

Aging-associated gut microbiota changes contribute to deteriorating sepsis prognosis through increased intestinal permeability and systemic inflammation.

• Physiological and pathological changes associated with aging were identified as contributing factors to worsened sepsis outcomes.
• The study used both clinical samples (aged and young septic patients) and animal models to establish these associations.
• Gut barrier dysfunction was assessed through histopathological examination, ELISA, and FITC-dextran intestinal permeability assay.
• The study suggests that targeting the HA-Nlrp6-LC3 axis could offer a novel therapeutic approach for managing sepsis particularly in aged populations.