The Intricate Interplay: Microbial Metabolites and the Gut‐Liver‐Brain Axis in Parkinson's Disease

Parkinson's Disease (PD) is a neurodegenerative disorder marked by the depletion of dopaminergic neurons. Recent studies highlight the gut-liver-brain (GLB) axis and its role in PD pathogenesis. The GLB axis forms a dynamic network facilitating bidirectional communication between the gastrointestinal tract, liver, and central nervous system. Dysregulation within this axis, encompassing gut dysbiosis and microbial metabolites, is emerging as a critical factor influencing PD progression. Our understanding of PD was traditionally centered on neurodegenerative processes within the brain. However, examining PD through the lens of the GLB axis provides new insights. This review provides a comprehensive analysis of microbial metabolites, such as short-chain fatty acids (SCFAs), trimethylamine-N-oxide (TMAO), kynurenine, serotonin, bile acids, indoles, and dopamine, which are integral to PD pathogenesis by modulation of the GLB axis. Our extensive research included a comprehensive literature review and database searches utilizing resources such as gutMGene and gutMDisorder. These databases have been instrumental in identifying specific microbes and their metabolites, shedding light on the intricate relationship between the GLB axis and PD. This review consolidates existing knowledge and underscores the potential for targeted therapeutic interventions based on the GLB axis and its components, which offer new avenues for future PD research and treatment strategies. While the GLB axis is not a novel concept, this review is the first to focus specifically on its role in PD, highlighting the importance of integrating the liver and microbial metabolites as central players in the PD puzzle.