Changes in the Gut Microbiome Drive Age-Related Intestinal Barrier Dysfunction
The balance of microbial species making up the gut microbiome changes with age in ways that promote inflammation and other harms. Researchers can accurately map the composition of the gut microbiome using sequencing approaches, and are steadily identifying specific microbial species and mechanisms that contribute to the dysfunctions of age. A number of approaches exist to restore a more youthful gut microbiome composition, such as fecal microbiota transplantation from a young donor or flagellin immunization, but none are yet very widely used in the context of attempting to improve late life health.
Physiological and pathological changes associated with aging contribute to deteriorating disease prognosis in sepsis. However, the mechanisms by which these disturbances exacerbate inflammation remain underexplored. In this study, fecal samples were collected from aged and young septic patients and mice and subsequently transplanted into young pseudo-germ-free mice via fecal microbiota transplantation. Fecal, colon tissue, and blood samples were collected to be used 16S rDNA sequencing to characterize the gut microbiota, histopathological examination, enzyme-linked immunosorbent assay and FITC-dextran intestinal permeability assay to assess gut injury and gut barrier function.
Additionally, nontargeted and targeted metabolomics were used to identify differential metabolites in the feces of aged and young septic mice. To further validate the roles of specific bacterial strains and their metabolites in sepsis, genetically engineered bacteria were used in both in vivo and in vitro experiments.
The results showed an increased abundance of Klebsiella aerogenes (K. aero) in aged hosts, which led to elevated histamine (HA) production and exacerbated intestinal barrier dysfunction. Importantly, K. aero strains carrying a histidine decarboxylase gene variant were identified as major HA producers. Mechanistically, HA was shown to drive intestinal barrier dysfunction by inhibiting Nlrp6 expression and its subsequent binding to LC3, thereby impairing autophagy. Treatments that modulated HA levels or overexpressed Nlrp6 ameliorated inflammation in septic mice. These findings suggest that targeting the HA-Nlrp6-LC3 axis could offer a novel therapeutic approach for managing sepsis, particularly in aged populations.