Dynamic changes in the gut microbiota play a critical role in age-associated cognitive dysfunction via SCFAs and LPS synthesis metabolic pathways during brain aging.

Background: Gut microbiota plays an essential role in cognitive dysfunction during aging. The aim of this study was to investigate the dynamic alterations in the gut microbiota and screen for key gut bacterial taxa correlated with age-associated cognitive dysfunction during natural aging.

Methods: 16S rRNA gene sequencing was performed to determine the composition of the gut microbiota in faecal samples from SAMR1 and SAMP8 mice, cognitively normal controls (NC), and patients with amnestic mild cognitive impairment (aMCI). Faecal microbiota transplantation (FMT) and GMrepo database were used to screen key gut microbiota associated with cognitive decline in aging mice and humans.

Results: The composition of the gut microbiota dynamically changed during natural aging in SAMR1 and SAMP8 mice, as well as in healthy subjects of different ages extracted from the GMrepo database. FMT from SAMR1 to SAMP8 mice altered the gut microbiota composition and improved the cognitive impairment in SAMP8 mice. Key gut bacterial taxa, including Lactobacillus, Akkermansia, Clostridium, Oscillospira and Dorea, were screened and validated to correlate with aging-associated cognitive decline. The function of the key gut bacterial taxa predicted by PICRUSt2 indicated that the metabolic pathways related to short-chain fatty acids (SCFAs) and lipopolysaccharide (LPS) synthesis were involved in age-associated cognitive dysfunction during natural aging.

Conclusion: These results demonstrate that the composition of the gut microbiota changes dynamically during brain aging, with some key gut bacterial taxa playing critical roles in age-associated cognitive dysfunction through SCFAs and LPS synthesis metabolic pathways.