Microbiota-Gut-Brain Axis in Neurodegenerative Diseases: The Role of Bacterial Amyloids

Neurodegenerative diseases are proteinopathies, characterized by misfolded protein aggregation in the brain that drives neuronal dysfunctions. Neurodegenerative diseases are also increasingly recognized as multi-organ disorders in which the gut plays a pivotal role. Indeed, recent advances in the research field of neurodegenerative diseases suggest that the gut is not merely a passive bystander, given the high prevalence of gastrointestinal symptoms, but a critical contributor to disease etiology, with evidence supporting a direct role in initiating and driving disease progression. Among environmental factors increasingly recognized as modulators of neurodegenerative disease progression, the gut microbiota has gained prominence. Beyond the impact of altered bacterial metabolites, growing evidence indicate a potential role of gut microbiota-derived amyloids in neurodegenerative diseases. For instance, gut microbial amyloids such as curli can cross-seed host proteins like α-synuclein and β-amyloid promoting aggregation, gut-to-brain propagation, and exacerbating neurodegeneration, revealing a novel mechanism linking the microbiome to neurodegenerative diseases. This conceptual shift opens promising avenues for strategies targeting the gut microbiota, including therapeutic and preventive interventions aimed at reshaping microbial communities or limiting exposure to pathogenic amyloids to reduce risk of neurodegenerative diseases. Here, we review recent discoveries to elucidate the complex interplay between gut microbiota and host amyloids, offering insights for enhancing gut and brain health and potentially preventing or reversing neurodegenerative disease progression.