(P02-038-23) Multi-Omics Analyses Reveal Ameliorative Effects of a Mediterranean-Ketogenic Diet on Gut Microbiome and Neurocognitive Health in a Preclinical Alzheimer’s Model

Objectives: To explore the effects of a Mediterranean-ketogenic diet (MKD) versus a western-style diet (WD) pattern on the gut microbiome, mycobiome, metabolome, and neurocognitive function in a transgenic murine model of Alzheimer’s disease (AD).

Methods: Wild-type (WT) and double-transgenic (APP/PS1) mice (AD) were fed either a WD or MKD diet for 8-weeks. Gut microbiome and mycobiome were measured using the 16S and ITS sequencing, respectively; fecal and serum metabolome were quantified with NMR spectroscopy; and neurocognitive and motor behavioral tests were performed at the end of the dietary intervention. Gut permeability and inflammatory markers were measured in gut and brain tissues using RT-PCR-based assays of mRNA expression of genes.

Results: After 8 weeks of intervention, both diets induced significant changes in AD and WT mice. The microbiome structure of MKD groups appeared to deviate away from WD groups. The genus Dubosiella increased in all groups, but more notably in WD groups. Beneficial genus Lactobacillus was most predominant and significantly more abundant in MD groups than in WD groups, whereas Bifidobacterium was depleted. In the fungal microbiome, the Saccaromycetales order and Wicherhamomyces genus were abundant in all groups by the time, but no distinctive genotypical differences or dietary effects were observed. The fecal metabolome also showed distinct arrays according to the two diet groups. MKD intervention in both AD and WT groups enriched metabolites associated with intestinal repair and function like lysine, threonine, and glutamine while diminishing total bile acids and succinate. Additionally, MKD diet improved gut permeability and neurocognitive function and reduced anxiety-like behavior and the inflammatory markers in gut as well as brain tissues in AD mice.

Conclusions: These findings indicate that MKD ameliorates gut epithelial integrity and inflammation by modulating the gut microbiome and metabolome, leading to improvements in AD-related neurocognitive function via the gut-biome-brain axis.

Funding Sources: The study was supported by funds from the Florida State University Council on Research & Creativity and the startup funds from the FSU College of Health & Human Sciences to RN.