Microbiome-Phytochemical Crosstalk Along the Gut-Brain Axis in Alzheimer and Parkinson's Disease

Gut-brain axis (GBA) has emerged as a bidirectional communication network linking the gut microbiota with central nervous system function and contributing to the pathogenesis of Alzheimer's disease (AD) and Parkinson's disease (PD). This study aimed to critically evaluate the current evidence on how phytochemicals modulate gut microbiota and GBA signaling to influence the progression of AD and PD. A systematic literature search was conducted using major scientific databases, and preclinical studies investigating microbiota-mediated mechanisms of phytochemicals were synthesized according to predefined inclusion criteria. The available evidence demonstrates that phytochemicals consistently remodel the gut microbiota by increasing beneficial taxa such as Lactobacillus, Bifidobacterium, Akkermansia, and short-chain fatty acid (SCFA)-producing bacteria while suppressing pro-inflammatory Gram-negative microorganisms. These microbial alterations were associated with reduced lipopolysaccharide (LPS) production, inhibition of TLR4/NF-κB and NLRP3 inflammasome signaling, enhancement of brain-derived neurotrophic factor (BDNF) activity, restoration of intestinal barrier integrity, attenuation of oxidative stress, and activation of autophagy-related pathways, including PI3K/AKT/mTOR and AMPK/mTOR, leading to reduced amyloid-β, tau, and α-synuclein pathology. A major contribution of this review is the integration of current evidence demonstrating the bidirectional crosstalk between phytochemicals and the gut microbiota as a central mechanism regulating GBA signaling in AD and PD. Available evidence suggests that phytochemical-mediated modulation of the gut microbiota represents a promising therapeutic strategy for slowing disease progression in AD and PD. However, further mechanistic investigations and well-designed clinical trials are required to validate these findings and facilitate their translation into clinical practice.