Microbiome-modulated molecular chaperones: Gut-brain control of proteostasis and neurodegenerative risk

Abstract

The coordinated control of protein synthesis, folding/quality control, trafficking and degradation (UPS and autophagy-lysosome), is essential for neuronal function and survival. Emerging evidence reveals that the gut microbiome influences host proteostasis by modulating molecular chaperones and co-chaperones, constituting the protein quality control machinery. Microbial metabolites such as short-chain fatty acids, indoles, and bile acids, along with microbe-associated molecules including bacterial lipopolysaccharide (LPS) and even microbial heat shock proteins (HSPs), can trigger host stress pathways, epigenetically altering chaperone expression and post-translational modifications. This microbiota-chaperone crosstalk impacts autophagy, immune signalling, and neuroinflammation, thereby affecting the handling of misfolded proteins in the ageing brain. Dysbiosis and specific microbial taxa are linked to the protein aggregation pathologies of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. These insights highlight new therapeutic opportunities, engineered probiotics and prebiotic diets to boost beneficial metabolites, small-molecule chaperone co-inducers and targeted protein degraders (PROTACs) to enhance proteome stability, and metabolite mimetics. Ultimately, emerging multi-omics and spatial proteomic methodologies to PET imaging and proximity labelling are poised to accelerate discovery in this cross-disciplinary field and guide clinical strategies to modulate proteostasis in neurodegenerative diseases. © 2025