Precision prebiotics: Engineering food-derived polysaccharides to target specific SCFA-producing taxa for neuroprotection via the microbiota-gut-brain axis

Neurodegenerative and neuropsychiatric disorders lack disease-modifying therapies. The microbiota-gut-brain (MGB) axis, particularly short-chain fatty acid (SCFA)-producing microbiota dysbiosis, has emerged as a conserved driver of neuroinjury pathogenesis. Natural food-derived polysaccharides have been explored as prebiotic substrates, but their clinical translation is hindered by poor target specificity, high interindividual heterogeneity, and low bioavailability. Engineered food-derived polysaccharides, as a next-generation precision prebiotic platform, enable rational tailoring of molecular fine structures via targeted physical, chemical, biological, and combinatorial modification technologies, aiming for strain-specific directional modulation of intestinal SCFA-producing microbiota and multi-pathway neuroprotection through the MGB axis. In this review, we systematically delineate the bidirectional regulatory mechanisms between SCFA-producing microbiota and neural homeostasis, dissect disease-specific pathological cascades driven by SCFA-producing microbiota dysbiosis, and discuss conflicting findings on the dual effects of SCFAs. We further propose a full-chain framework of the structure-activity relationship of engineered polysaccharides, dissecting core modification strategies, strain-specific targeting mechanisms, and a multi-dimensional efficacy evaluation system for these precision prebiotics. Additionally, we assess safety evaluation status, major global regulatory differences, and core clinical translation bottlenecks. Finally, we outline key unresolved challenges and propose a conceptual roadmap for AI-assisted rational design of precision prebiotics, personalized microbiota-adapted intervention strategies, and multicenter clinical translation directions. This review provides a mechanism-driven theoretical framework and practical guidance for developing engineered food-derived polysaccharides as precision nutrition interventions for neuroinjury-related disorders.