Ageing, proteostasis, and the gut: Insights into neurological health and disease

Recent research has illuminated the profound bidirectional communication between the gastrointestinal tract and the brain, furthering our understanding of neurological ailments facilitating possible therapeutic strategies. Technological advancements in high-throughput sequencing and multi-omics have unveiled significant alterations in gut microbiota and their metabolites in various neurological disorders. This review provides a thorough analysis of the role of microbiome-gut-brain axis in neurodegenerative disease pathology, linking it to reduced age-associated proteostasis. We discuss evidences that substantiate the existence of a gut-brain cross talk ranging from early clinical accounts of James Parkinson to Braak’s hypothesis. In addition to understanding of microbes, the review particularly entails specific metabolites which are altered in neurodegenerative diseases. The regulatory effects of microbial metabolites on protein clearance mechanisms, proposing their potential therapeutic implications, are also discussed. By integrating this information, we advocate for a combinatory therapeutic strategy that targets early intervention, aiming to restore proteostasis and ameliorate disease progression. This approach not only provides a new perspective on the pathogenesis of neurodegenerative diseases but also highlights innovative strategies to combat the increasing burden of these age-related disorders.