Dynamic Modulation of the Gut Microbiome in Neurodegenerative Diseases: Mechanisms, Therapeutic Potential, and Clinical Perspective

The gut and brain communicate bidirectionally through the gut microbiota, forming a complex network often referred to as the "microbiota-gut-brain axis." The gastrointestinal microbiome produces various metabolites, including short-chain fatty acids (SCFAs), tryptophan-derived compounds, and secondary bile acids. Research indicates that disruptions in the intestinal microbiota (dysbiosis) and impaired gut-brain axis are associated with various neurological conditions. The central nervous system (CNS) influences digestive processes via the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS). On the other hand, the gut reciprocally affects brain function through microbial metabolites, neuroactive substances, and intestinal hormones via multiple pathways, including neural (vagal), immune, and endocrine signaling; however, only a subset of metabolites can directly access the CNS due to blood-brain barrier (BBB) selectivity. These microbial metabolites can directly or indirectly influence the CNS and modulate neuro-immune signaling by activating receptors, such as the aryl hydrocarbon receptor (AhR) and G protein-coupled receptors (GPCRs). By acting as ligands for these receptors, metabolites modulate neural signaling and exert neuroprotective effects. This review discusses how probiotic-derived metabolites modulate the gut-brain axis and provide neuroprotective effects, focusing on the receptors they activate and their downstream signaling pathways involved in neuroprotection.