Weight loss and metabolic improvements dominate the microbiome response in the MIND diet intervention: a randomized controlled trial

Abstract INTRODUCTION Observational studies link the MIND diet to reduced risk of Alzheimer's disease (AD) and slower cognitive decline. However, a recent randomized controlled trial found no differential cognitive benefit of the MIND diet over a control diet in the context of shared caloric restriction. Given that both groups achieved significant weight loss and metabolic improvements, this study aimed to disentangle the impact of the MIND diet and host metabolic improvements on the intestinal microbiome. METHODS A subset of participants ( n = 213) from the MIND trial were analyzed in this study. Clinical data and stool samples were collected at baseline, Year 1, Year 2, and Year 3, and longitudinal changes in microbiome composition were assessed via shotgun metagenomics. RESULTS Both groups exhibited significant, transient microbiome remodeling at Year 1 (the period of most active weight loss). The control group demonstrated a broad range of altered metabolic pathways, whereas the MIND diet group showed only one, suggesting a functional buffering effect of the MIND diet. Prospective modeling independent of diet group revealed that a poorer cognitive trajectory was significantly associated with increased inositol degradation (PWY‐7237) and purine nucleotide salvage (PWY66‐409); conversely, a better cognitive trajectory was associated with increased degradation of deoxy sugars (FUC‐RHAMCAT‐PWY). DISCUSSION Caloric restriction, weight loss, and host metabolic improvement are the dominant factors shaping the intestinal microbiome, overshadowing diet‐specific taxonomic shifts. The MIND diet appeared to provide a modest stabilizing effect on the microbial functional profile against perturbations during active weight loss; however, these dietary associations did not persist in covariate‐adjusted models, suggesting that host metabolic improvements remained the primary driver of functional shifts.