(PTFS08-01-25) Distinct Gut Microbiome and Metabolomic Signatures Linked to Cognitive Improvement in Older Adults After Mediterranean and Modified Mediterranean-Ketogenic Diets

Objectives: Dietary patterns tightly regulate the gut microbiome. A Mediterranean diet (MED) fosters microbial diversity and fiber-fermenting bacteria, producing metabolites that regulate the gut-brain axis. This study assessed gut microbiome and fecal/plasma metabolomes in older adults with mild cognitive impairment (MCI) and cognitively normal (CN) counterparts following a 10-week MED or modified Mediterranean-ketogenic diet (MKD) intervention, in relation to cognitive performance.

Methods: In this randomized parallel-arm clinical trial, 31 participants (24/7 F/M; age 55–85 yrs; mean BMI 31.6±8.7 kg/m²) with MoCA scores of 17–26 (MCI) or >27 (CN) were randomized to a MED (n=16; 8 MCI) or an MKD (n=15; 9 MCI) group. Weekly 1-hour dietitian-led meetings provided tailored nutrition education and lifestyle strategies. Measures included body-composition, 3-day food logs, NIH Toolbox Cognition Battery, and fecal/plasma samples. Gut microbiome was assessed via 16S sequencing, and metabolomics via untargeted NMR spectroscopy. Statistical analyses utilized Wilcoxon Signed-Rank for pre/post-tests and Mann-Whitney U and Fisher's Exact tests in SPSS 28.0.

Results: At baseline, gut profiles were similar between MCI and CN, though obesity (p=0.05) and lower dietary magnesium and copper (p < 0.05) correlated with MCI. After 10-wks, MCI subjects on MED had higher microbial diversity than MKD (p=0.02). MED group had increases in Christensenellaceae (p=0.042), Oscillospiraceae (p=0.046), Ruminococcaceae(p=0.02), fecal adenine, butyrate, propionate, and plasma citrate and glutamine (p < 0.05). Among MED subjects with cognitive gains, fecal histamine (p=0.004) and Faecalibacterium (p=0.009) were elevated. In MKD, cognitive gains correlated with higher fecal propionate (p=0.034). Across all groups, cognitive gains correlated with reduced fecal tyrosine and beta-alanine (p < 0.01) and weight loss (p=0.028). Cognitive decline correlated with increased fecal cholate (p=0.026) and reduced plasma isoleucine (p=0.031).

Conclusions: Nutrition education interventions modulate gut microbiome and metabolome in older adults and these modulations correlate with cognitive health differently based on body-weight and adherence rate, calling for further studies elucidating these intricate relationships.

Funding Sources: Florida Department of Health