Shuxin Zhou, Yuke Huang, Weihua Chu
Medicine-food homology (MFH) substances constitute a distinctive category of functional food ingredients deeply rooted in traditional dietary wisdom. Although their therapeutic potential is increasingly acknowledged, a comprehensive framework that mechanistically links their ecological roles in the gut to systemic health benefits remains necessary to advance modern food science and precision nutrition. This review synthesizes evidence from multi-omics studies, in vitro models, and animal and human research to establish MFH substances as dietary-derived ecological engineers of the gut microbiota. We focus on three core mechanisms of action: niche construction, metabolic reprogramming, and symbiosis induction. Furthermore, we evaluate emerging strategies—such as AI-driven formulation, phage-assisted delivery, and CRISPR-engineered probiotics—designed to overcome bioavailability challenges and enable personalized applications. Our analysis confirms that MFH substances reshape the gut ecosystem, enriching keystone taxa (e.g., Akkermansia , Bifidobacterium ) and stimulating bioactive metabolites (SCFAs, indoles, secondary bile acids). These metabolites activate host receptors (GPR43, AhR, FXR) to orchestrate multi-organ homeostasis, explaining their beneficial roles in metabolic disorders (e.g., obesity, NAFLD) via the gut–liver axis and neurological conditions (e.g., cognitive decline, depression) via the gut–brain axis. This provides a scientific basis for the ancient "preventive treatment" principle. Integrating this ecological insight with modern food technology positions MFH as a cornerstone for next-generation, microbiota-targeted functional foods, shifting dietary practice from passive intake to active health management. Beyond enriching well-recognized keystone taxa such as Akkermansia and Bifidobacterium , MFH interventions consistently modulate a broader spectrum of beneficial commensals, including Lactobacillus , Lachnospiraceae , Blautia , Romboutsia , and Prevotella , thereby supporting a more resilient and functionally diverse gut ecosystem. • Repositions MFH as dietary ecological engineers of gut microbiota. • Proposes AI/phage/CRISPR tools to boost MFH bioavailability. • Mechanistically links ancient preventive wisdom to food science. • Orchestrates multi-organ health via microbiota-derived metabolites. • Establishes a scientific basis for the "preventive treatment" principle.