January 14, 2020 -- Roundworms that were fed a commercially available dietary probiotic showed less buildup of proteins that form during the progression of Parkinson's disease in a new study, published in Cell Reports on January 14. The finding provides further evidence of a link between the gut microbiome and brain function.
Parkinson's disease is one of the most prevalent neurodegenerative diseases and is characterized by progressive loss of dopaminergic neurons in the substantia nigra region of the brain. The condition stems from the accumulation of proteins called alpha-synuclein (α-syn) that can aggregate in the brains of individuals. α-syn acquires neurotoxic properties when protein monomers progressively combine to form insoluble amyloid fibrils.
"Parkinson's is the fastest-growing neurological condition in the world," said Beckie Port, PhD, a research manager at Parkinson's UK, which cofunded the research. "Currently, there is no treatment that can slow, reverse, or protect someone from its progression but by funding projects like this; we're bringing forward the day when there will be."
Recent research provides evidence that signals peripheral to the central nervous system, particularly from the gastrointestinal tract and gut microbiota, are involved in the progression of Parkinson's disease. For example, α-syn pathology begins in peripheral tissues such as in the intestines and gradually spreads to multiple brain regions.
Gut microbiota has also been shown to impact brain function by producing metabolites that enter the bloodstream. However, how gut bacteria affect α-syn aggregation is still unclear.
To begin to investigate the effect of microbiota in Parkinson's, researchers from the University of Edinburgh and the University of Dundee used a roundworm model, Caenorhabditis elegans, to demonstrate α-syn aggregation. C. elegans is an ideal model because its gut microbiota can be precisely controlled to study physiological processes at both the single-species and single-gene levels, and C. elegans has been validated as a valuable model of studying molecular mechanisms of Parkinson's disease and protein aggregation.
The researchers showed that Bacillus subtilis PXN21, a probiotic strain of live bacteria that's available for human consumption, inhibits α-syn aggregation and removes aggregates in C. elegans model with expression of human α-syn. B. subtilis spores induce dietary restriction, which in turn activates the autophagy-lysosomal pathway, a main system of α-syn clearance in cells. This at least partially explains the mechanism of action.
Transcriptomics analysis performed by the researchers revealed that the probiotic effect was mediated by the upregulation of genes involved in the sphingolipid metabolic pathway, particularly the regulation of ceramide synthase, acid sphingomyelinase, and serine palmitoyltransferase. The imbalance of lipids contributes to aggregation propensity, which may be caused by direct interactions of α-syn and lipids. Loss-of-function analysis increased the number of α-syn aggregates in worms continuously grown on B. subtilis. Therefore, the researchers suggest that alterations in sphingolipid metabolism triggered by the B. subtilis diet resulted in a reduction of α-syn aggregation in C. elegans.
"The results provide an opportunity to investigate how changing the bacteria that make up our gut microbiome affects Parkinson's," said lead study author Maria Doitsidou, PhD, from the Centre for Discovery Brain Sciences at the University of Edinburgh. "The next steps are to confirm these results in mice, followed by fast-tracked clinical trials since the probiotic we tested is already commercially available."
Do you have a unique perspective on your research related to neurodegenerative diseases or nutrition? Contact the editor today to learn more.