An intestine-centric view of neurodegeneration: How intestine-derived signals mediate the intestine-brain axis to impact Alzheimer's disease.

Abstract

Alzheimer's disease (AD) has emerged as an increasingly prevalent and burdensome public health challenge with global aging, underscoring the urgent need to clarify the key factors involved in its pathogenesis for effective prevention and management. Mounting evidence suggests that disrupted crosstalk between the intestine and brain may contribute to aging-related neurodegeneration, including AD. Acting as a peripheral modulatory hub of the intestine-brain axis, the intestine releases a variety of bioactive substances that regulate brain function. This narrative review synthesizes current evidence on intestine-derived signaling molecules and immune mediators implicated in AD pathogenesis, with a focus on two primary communication routes: the vagus nerve and systemic circulation. In addition, intestine-targeted interventions-including dietary modification, probiotic supplementation, and fecal microbiota transplantation-are summarized. Notably, metagenomics-based intestinal microbiota aging clocks represent an emerging non-invasive strategy for AD risk prediction. Although preclinical findings are encouraging, the translational limitations and heterogeneity of current intestine-brain research remain noteworthy. In summary, this narrative review integrates substantial evidence on the correlation between intestine-derived mediators and AD and provides potential insights for the development of intestine-targeted preventive strategies.