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Development of a synbiotic product to modulate the Parkinson’s disease associated microbiome

Periodic Reporting for period 1 - SyMPaBiome (Development of a synbiotic product to modulate the Parkinson’s disease associated microbiome)

Reporting period: 2022-01-01 to 2023-12-31

Parkinson’s Disease (PD) is a neurodegenerative disease affecting approximately 2 % of adults over 65 years old and is characterized by plaques of wrongly folded proteins, called α-synuclein protein aggregates, and death of nerve cells that produce dopamine, called dopaminergic neurons, in the area of the brain responsible for movement, resulting in the typical PD motor symptoms (tremor, rigidity of gait). Approximately 50 % of cases are “body first PD”, in which the central nervous system disorder potentially initiates in the part of the nervous system that lies outside the brain and spinal cord, in particular in the nervous system of the intestine, and intestinal symptoms can appear years to decades prior to the onset of the typical motor symptoms of the disease. Pro- and prebiotics can have beneficial effects through reduction of (mainly) non-motor symptoms such as intestinal inflammation and constipation, as well as via protective effects on dopaminergic neurons and interference with α-synuclein aggregation. Research has shown that the collection of the microorganisms and their genomes in the intestine of PD patients, called the intestinal microbiome, has a different composition and changed function, importantly less fibre-degrading bacteria and reduced production of short chain fatty acids, compounds that are an important energy source for the cells that line the intestine. These cells, intestinal epithelial cells, form a barrier between the gut content and the underlying tissues, regulating the entrance of microorganisms and their products in our bodies. In PD patients, this barrier can be compromised. While currently used probiotics can help protect against certain pathogenic bacteria and can help the immune system, they typically do not address the changed composition and function of the intestinal microbiome observed in PD.
The H2020 Widening Fellowship SyMPaBiome set out to develop a synbiotic product to modulate PD patient gut microbiome. A synbiotic is a mixture comprising live microorganisms and substrate(s) selectively utilized by host microorganisms that confers a health benefit to the host. The aim of the SyMPaBiome synbiotic was to increase short chain fatty acid production and reduce inflammation and increase the intestinal barrier function, as well as to restore the compromised microbiome observed in PD patients. The objectives of the action were to assemble the synbiotic, test its efficacy and mode of action, and finally perform in vitro validation of the synbiotic in a device, called neuroHuMiX, that mimics the intestine, specifically the lining of the intestinal wall and the intestinal nerves, and allows culturing of microorganisms present in the intestine inside. By introducing this synbiotic in neuroHuMiX and computationally analyzing the interactions between the different cell types in this model, novel interactions and disease influencing mechanisms on the interplay between microbiome and human host could be identified, and mechanisms for therapeutic applicability could be validated.
During this action, a novel synbiotic product was developed, containing four probiotic bacteria and two types of prebiotic fibre. A safety screening, based on the genome of the bacteria, for antimicrobial resistance genes, toxins, virulence factors, and genes interfering with common PD medication was performed for the four strains. This showed that some bacteria in the mixture could potentially have resistance to certain antibiotics which could be transferred to other bacteria, which needs to experimentally tested. The effect of the synbiotic on inflammation and epithelial barrier function was tested in cell culture models containing intestinal epithelial cells and nerve cells, as well as in neuroHuMiX. The synbiotic demonstrated a beneficial effect on intestinal epithelial barrier function and inflammation, and was not toxic to the cells in these models.
In work package (WP) 1, candidate probiotic strains and prebiotics were identified based on literature and recent research of the host institution’s research group. Four species were selected based on their metabolic properties and reported reduced abundance in PD. Two prebiotic substrates were selected to selectively stimulate bacterial taxa underrepresented in PD, as well as the selected probiotic species. An initial qualified presumption of safety screening was performed based on available literature no major safety concerns regarding pathogenicity, safety concerns, or safety concerns for the environment exist for the strains selected for the synbiotic. The initial safety screening was continued with an in silico safety screening for virulence factors and antimicrobial resistance genes. Then, a growth medium was selected that could support the growth of the selected probiotic bacteria with or without the addition of prebiotic substrates. A further selection of the microbial growth medium was performed to assess cytotoxic effects and effects on metabolic activity on intestinal epithelial or neuronal cells, which were to be used in subsequent in vitro models.

In WP2, the synbiotic’s ability to reduce inflammation and reinforce epithelial barrier function was examined. This was assessed using intestinal epithelial cells and intestinal nerve cells. The assay showed that the synbiotic mixture increased epithelial barrier function in an intestinal epithelial cell model, yet in combinations of intestinal epithelial cells and intestinal nerve cells, this increase was not statistically significant. The synbiotic mixture did not cause inflammation, nor had toxic effects on intestinal epithelial cells and intestinal nerve cells. In a combined culture of intestinal epithelial cells and nerve cells, the probiotic mixture could reduce simulated inflammation, and increase the release of specific neurotransmitters.

During WP3, the efficacy of the synbiotic product was assessed in the neuroHuMiX model with or without simulated inflammation. Due to technical issues, WP4-5 were not started.

Dissemination: The results of this project have been presented at two international conferences in the field of microbial ecology and host-microbe interaction.
This action will lead to follow-up projects in the host institution’s group, in particular the further optimization of culturing stool samples in neuroHuMiX, and several grant proposals in collaboration with private partners have been submitted.
This action enabled novel research on the use of next-generation probiotics, in combination with prebiotic fibres, with disease-modifying anti-inflammatory and neuroprotective properties for Parkinson’s Disease, with prophylactic potential for at-risk individuals. Beneficial effects of the synbiotic mixture on inflammation and intestinal barrier function were demonstrated and additional beneficial properties are being explored. Methods were developed to culture a mixed microbial community in neuroHuMiX, a laboratory model of the human intestine, allowing the co-culture in close proximity of intestinal nerve cells, intestinal epithelial cells, and microorganisms, which enables detailed research on the interaction between the different cell types in this model, which is not possible in other laboratory models. Further research and development of the synbiotic mixture could lead to a new product to be used as an add-on therapy for PD patients, or as a prophylactic product for at-risk individuals.
Schematic overview of the neuroHuMix gut-on-chip used during the SyMPaBiome project.