Abstract
Neurodegenerative protein conformational diseases (PCDs) are progressive, currently incurable disorders driven by toxic protein aggregation that leads to neuronal death. Emerging evidence supports a microbial role in PCDs, including the most prevalent: Alzheimer's and Parkinson's disease. While metagenomic studies consistently associate gut dysbiosis with these disorders, the mechanisms by which microbes influence host proteostasis remain poorly understood. In particular, considerable attention has been given to proteotoxic bacteria, whereas the mechanisms by which commensal microbes confer proteoprotection have received comparatively little attention. We previously employed Caenorhabditis elegans models to characterize the role of over 220 bacterial isolates from the Human Microbiome Project on host proteostasis. Strikingly, members of the Prevotella genus exhibited proteoprotective effects. Most notably, transient exposure to Prevotella corporis uniquely induced Hsp70, a critical molecular chaperone that maintains proteostasis, and significantly reduced aggregation of polyglutamine (polyQ), Aβ42, and α-synuclein. In the present study, we expand on these findings, demonstrating that among 13 Prevotella species tested, P. corporis robustly activates the heat shock response (HSR) and confers conserved aggregate-suppressing activity in Drosophila melanogaster. We further demonstrate that transient exposure to P. corporis results in the activation of protective stress pathways and promotes disaggregation of existing intestinal polyQ aggregates in C. elegans, leading to a general enhancement of global proteostasis. This is supported by significantly improved survival and enhanced thermotolerance. Together, our findings reveal a beneficial niche for P. corporis in activating the HSR to enhance organismal proteostasis and support a microbe-mediated gut-proteostasis axis. This work underscores the therapeutic potential of targeting the gut microbiota for the management of PCDs, highlights the importance of species-level resolution in microbiome studies, and supports the emerging view of the intestine as a proteostasis-modulating organ.
