Investigating protective mechanisms of gut bacteria in C. elegans models of Parkinson’s disease

Informations projet

Gut_Fights_PD

N° de convention de subvention: 798650

DOI

10.3030/798650

Projet clôturé

Date de signature de la CE 28 Mars 2018

Date de début 1 Septembre 2019

Date de fin 31 Août 2021

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 183 454,80

Contribution de l’UE

€ 183 454,80

Coordonné par

THE UNIVERSITY OF EDINBURGH
United Kingdom

Periodic Reporting for period 1 - Gut_Fights_PD (Investigating protective mechanisms of gut bacteria in C. elegans models of Parkinson’s disease)

Période du rapport: 2019-09-01 au 2021-08-31

Résumé du contexte et des objectifs généraux du projet

In the past years, the collective community of microorganisms found in the human gut (the gut microbiome), has emerged as a new important player influencing Parkinson’s Disease (PD). Specifically, the composition of the gut microbiome was shown to differ between PD patients and healthy individuals and these differences correlate with the severity of the symptoms. Understanding the molecular mechanisms by which gut bacteria interact with the host to alter physiology in remote tissues, can lead to novel prognostic and therapeutic interventions for PD. However, how single species of the gut microbiome affect manifestations of the disease remains unclear.
In people with Parkinson’s, the protein alpha-synuclein (α-syn) builds up and forms toxic clumps which induce the degeneration of specific dopamine-producing neurons. Using a worm model of PD expressing the α-syn, we tested the effect of commercially available probiotic bacteria in the formation of toxic protein aggregates. We identified a strongly protective effect when worms were fed the strain Bacillus subtilis PXN21 (isolated from Bio-Kult), in comparison to the regular worm’s diet. The main goal of this project was to study how this probiotic induces the protective effect, at the molecular level. We proposed to elucidate this by focusing on both organisms in the interaction: the bacteria and the worms. We aimed to explore the physiological changes induced by B. subtilis in the worms by studying the overall gene expression in the host. From the bacterial side, we proposed to identify specific genes and metabolic pathways used by B. subtilis to reduce protein aggregates by doing a single-gene deletion library screening.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

We first fully characterized all the biological aspects of B. subtilis protection. We found that the probiotic prevents the formation of α-syn aggregates in early adulthood and during aging and it is able to extend the lifespan of the worms. We also showed that the protective effect is conserved among different B. subtilis strains. This diet is not only able to prevent aggregate formation, but also to clear already formed aggregates. Moreover, we found that the protection against α-syn aggregation correlates with improved healthspan (locomotion). Using comparative transcriptomics analysis, we identified host metabolic pathways that are differentially regulated by the probiotic, such as, innate immune response, redox processes, and lipid metabolism. Functional validation led us to the identification of the sphingolipid metabolism pathway as a key host mechanism that is altered by the bacteria to induce protection. Finally, by genetically manipulating the bacteria, we identified that biofilm formation and nitric oxide (NO) production are important for the protective effect during aging. Live bacteria and gut colonization aren’t required for early protection, which is partly mediated by additional protective metabolites. We are currently trying to fully identify the protective bacterial metabolic pathways.
The main results from this project were published in Goya et al, 2020 (https://doi.org/10.1016/j.celrep.2019.12.078). We have extensively communicated our research findings in numerous scientific meetings such us the International C. elegans GSA meeting (2019 and 2021), the UK worm meeting (2019), the Second Latin American Worm Meeting (2020), the European worm meeting (2020), the XXXV Argentinean Society for Research in Neuroscience meeting (2020) and the Ageing in Isolation online seminar series.
As for public dissemination, following our press release from The University of Edinburgh (https://www.ed.ac.uk/biomedical-sciences/news/2018/probiotic-hope-for-parkinsons-disease) our work was featured in Parkinson’s UK, Herald Scotland, Daily Mail UK, Neuroscience News, and iNews, among others. The lab has been involved in multiple events organized by the Edinburgh branch of Parkinson’s UK, which has given further dissemination to our research: https://www.parkinsons.org.uk/news/gut-bacteria-could-guard-against-parkinsons https://www.edinburghparkinsons.org/towards-a-clinical-trial-to-assess-the-ability-of-a-probiotic-bacterium-to-protect-against-%CE%B1-synuclein-aggregation-in-parkinsons/.
All the relevant information about the project can be found in our lab webpage: https://www.ed.ac.uk/discovery-brain-sciences/our-staff/research-groups/maria-doitsidou

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

B. subtilis PXN21 is a commercially available probiotic strain, safe for human consumption, with major potential to modify PD-related symptomatology in other models. Our findings have made new contributions to the exciting field of gut-brain interactions in PD and provided the functional basis for disease-modifying strategies through dietary interventions that alter gut microbiome composition.
More broadly, this project established a worm-bacteria dual model system to study proteostasis and PD that can be extended to find new protective species of the human gut microbiome. In this sense, this project has pioneered the use of C. elegans for microbiome studies and has demonstrated that the potential of this model to help elucidate single-bacterial species effects at the molecular level is endless.

B. subtilis inhibits α-synucleing aggregation in C. elegans

Team from the Doitsidou lab involved in the project. From left to right, upper row: Dr. Feng Xue, Ai