[
International Worm Meeting,
2021]
Recent discoveries have implicated the gut microbiome in the progression and severity of Parkinson's disease. However, how gut bacteria affect neurodegenerative disorders remains unclear. We previously showed that a probiotic Bacillus subtilis strain inhibits alpha-synuclein aggregation and clears preformed aggregates in an established Caenorhabditis elegans model of synucleinopathy (Goya et al, 2020). The reduction in aggregates can be triggered by multiple B. subtilis strains and correlates with improved locomotion in alpha-synuclein-expressing worms. We provide evidence for distinct contributions of spores and vegetative cells in inhibiting alpha-synuclein aggregation, and a role of biofilm formation in the gut for maintaining low levels of aggregation during aging. We are taking genetics and metabolomics approaches to uncover bacterial metabolic pathways that mediate the protective effect, and host response mechanisms triggered by the B. subtilis diet. Our findings provide a basis for exploring the disease-modifying potential of B. subtilis and its metabolic products in synucleinopathies.
[
International Worm Meeting,
2019]
The recent discovery that the composition of gut microbiota can influence the symptoms of neurodegenerative disease is a paradigm shift in how we view these conditions. Understanding the molecular mechanisms by which gut bacteria interact with the host to alter physiology in remote tissues, including protein homeostasis, can lead to novel prognostic and therapeutic interventions. Despite the clinical importance, little is known about how gut microbiota can affect the development and progression of neurodegenerative disorders. To address this gap of knowledge, we tested probiotic bacterial strains on C. elegans protein aggregation-based models of neurodegenerative disease. We identified a bacterial strain appropriate for human consumption that, when fed to the worms, prevents the formation of toxic protein aggregates, compared to a regular OP50 diet. This effect can be seen as early as larval stages, early adulthood, as well as during ageing, and is shared by different strains of the same bacterial species. The probiotic bacterial diet is not only able to prevent protein aggregate formation, it is also able to reverse already formed aggregates. In addition, the bacterial-induced reduction of protein aggregation correlates with improved locomotion. We performed comparative transcriptomics analysis by RNAseq and identified host metabolic pathways that are differentially regulated by the probiotic, such as, innate immune response, redox processes and lipid metabolism. Functional validation of the differentially regulated genes led us to the identification of key molecular components of the host response mechanism that contribute to the protection from protein aggregation. Finally, by genetically manipulating the bacteria, we identified bacterial pathways important for the protective effect. The requirement for live, metabolically active bacteria for the observed effects, and the efficacy of bacterial extracts against protein aggregation will be discussed. Our findings open possibilities for disease-modifying strategies through dietary interventions that alter gut microbiota composition.