The synergistic interplay between vitamin A, dietary fiber, and the microbiota-gut-brain axis: a potential mechanism for preventing Alzheimer’s disease

The human gastrointestinal tract harbors a vast and diverse microbial community, with the gut microbiome playing a fundamental role in numerous biological processes that influence overall health and disease progression. Emerging evidence has identified bacterial lipopolysaccharides in the hippocampus of patients with Alzheimer's disease (AD), highlighting the intricate relationship between the gastrointestinal tract, gut microbiome, and the central and enteric nervous systems-commonly referred to as the "microbiota-gut-brain axis." In this review, we explore the mechanisms by which the microbiota-gut-brain axis contributes to AD pathogenesis. We propose that sufficient levels of all-trans retinoic acid (ATRA), the bioactive form of vitamin A, enhance intestinal barrier integrity by upregulating tight junction proteins and modulating immune function through the induction of regulatory T-cell differentiation, thereby mitigating inflammation. Furthermore, dietary fiber complements this process by promoting the production of short-chain fatty acids, such as butyrate, via bacterial fermentation. Butyrate, in turn, acts as a histone deacetylase inhibitor, upregulating ATRA bioavailability by elevating aldehyde dehydrogenase gene expression. Our mechanistic framework is supported by the endotoxin hypothesis of AD, which maintains that the movement of infectious pathogens across the blood-brain barrier causes a vicious cycle of inflammation, a key factor of AD pathogenesis, leading to amyloid-β deposition, microglial activation, and CYP26A1-mediated ATRA degradation. Finally, we discuss microbiome-based therapeutic strategies and dietary interventions, including prebiotic compounds, probiotic bacteria, fecal microbiota transplantation, the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet, and a combined approach featuring vitamins A/D and dietary fiber, as potential approaches to prevent progression to AD via the microbiota-gut-brain axis.