Anaerobic gut bacterial metabolites alter morphology and survival of neurons and glia in a hippocampal culture model of Parkinson’s Disease

Background : Parkinson’s disease (PD) is associated with alpha-synuclein (α-syn) accumulation and spread. Recent evidence suggests a connection between PD and gastrointestinal changes early in the disease process due to host-bacterial interactions and association between the microbiome and PD pathology. Methods : Supernatants (SNs) from 16 bacterial strains, characterised via HPLC and GC, were tested on rat hippocampal cultures. PD pathology was modelled via viral gene delivery targeting neurons with human mutated A53T α-synuclein (hA53T-αsyn). Cell viability was assessed +/- SNs and hA53T-αsyn. Immunohistochemistry combined with semi-automated image analyses was developed to determine neuronal and glial density and morphology. Results : A microbiome panel of 16 different species yielded a range of SN-specific fermentation products (e.g. acetate, formate and lactate). HA53T-αsyn transfection created an in vitro synucleinopathy model with ~-50% viability after 6 days. Most bacterial SNs ameliorated gross viability loss caused by hA53T-αsyn. Segmentation of cell types identified microglia as most impacted by hA53T-αsyn, with an increased size indicative of activation. Some SN treatments boosted neurone and microglia numbers per se , and reduced hA53T-αsyn toxicity , with partial neuro-protection detected for B. subtilis and B. hansenii , while A. mucinipila, E. rectale and R. intestinalis offered some protection for glia. Conclusions : Specific SNs improved viability per se and affected hA53T-αsyn toxicity. Actions were highly cell type specific with some improving neuronal or glia morphology changes. The observed CNS-modulatory effects indicate that therapeutic routes targeting the microbiome may ameliorate PD pathology.