Natural Glycosides in Neurodegenerative Diseases: Multi‐Target Mechanisms via the Gut–Brain Axis

The multifactorial complexity of neurodegenerative diseases (NDs), including Alzheimer's and Parkinson's disease, limits the efficacy of single-target therapies. Natural glycosides exhibit promising neuroprotective potential, but their clinical translation is hindered by poor oral bioavailability and limited blood-brain barrier (BBB) penetration. The gut-brain axis offers a framework for understanding their potential biological effects beyond direct central exposure. This review explores the multi-target mechanisms of natural glycosides in NDs, focusing on their interactions with the gut-brain axis. A narrative literature search was conducted in PubMed, Web of Science, and ScienceDirect for studies published up to June 2026. Relevant literature on glycosides, NDs, gut microbiota, microbial biotransformation, pharmacokinetics, and neuroprotective mechanisms was critically reviewed. Natural glycosides may affect ND-related processes through gut-mediated and systemic/central mechanisms. Poorly absorbed glycosides can interact with intestinal microbiota, potentially modulating microbial composition, intestinal barrier integrity, and short-chain fatty acids (SCFAs) production. Microbial biotransformation may generate metabolites with altered physicochemical properties and systemic exposure, potentially enhancing central nervous system accessibility in a compound-specific manner. Experimental evidence also suggests effects on neuroinflammation, mitochondrial homeostasis, autophagy, and synaptic function. However, most findings remain preclinical, with limited direct human evidence. The gut-brain axis provides a valuable perspective for understanding the biological activities of natural glycosides despite their limited oral bioavailability and BBB penetration. Further pharmacokinetic studies, causal investigations of microbiota-mediated effects, and controlled clinical trials are needed to establish their therapeutic potential in NDs.