The microbiota–proteostasis axis: implications in neurodegenerative diseases

Abstract Disruption of protein homoeostasis, or proteostasis, is a hallmark of protein conformational diseases (PCDs), including Alzheimer's and Parkinson's disease. These disorders are characterized by progressive protein aggregation and cellular dysfunction, yet no effective therapies exist. Emerging evidence indicates that microbial communities influence host proteostasis, giving rise to the concept of the microbiota–proteostasis axis. Microbes and their products can modulate host proteins by engaging with host proteostasis. As such, microbial dysbiosis has been linked to proteostasis disruption through the production of metabolites, extracellular vesicles, functional amyloids, and toxins or effector proteins capable of seeding or destabilizing host proteins associated with PCDs. These microbial factors have been shown in experimental models to converge on key proteostasis pathways, including protein synthesis, folding and clearance, thereby potentially reducing cellular buffering capacity and lowering the threshold for proteotoxic collapse. In parallel, microbiota-driven influence on inflammatory responses and immune signalling further amplifies systemic proteostasis disruption. In this review, we synthesize emerging evidence defining the microbiota–proteostasis axis and highlight how microbial factors influence host proteostasis. Importantly, these host–microbe interactions often precede neurodegeneration, suggesting potential for early detection and intervention. Together, these insights support targeting the microbiota as a potential strategy to enhance proteostasis and delay or prevent neurodegenerative disease. This article is part of the Theo Murphy meeting issue ‘ProteostaSys: a systems view of proteostasis’.