Gut bacterial supernatants modulate neuronal survival and neuron–glia morphology in a hippocampal culture model of Parkinson’s disease

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Abstract Background: Parkinson's disease (PD) is characterised by the accumulation and spread of α-synuclein (α-syn). Increasing evidence suggests that alterations in the gut microbiome occur early in PD and that microbiome-derived factors may contribute to disease pathogenesis through the gut–brain axis. Methods: Supernatants (SNs) from 16 bacterial strains were characterised by high-performance liquid chromatography (HPLC) and gas chromatography (GC) and tested in primary mixed hippocampal cultures from Sprague Dawley rats. PD-like pathology was modelled by neuronal expression of human A53T α-synuclein (hA53T-αsyn). Metabolic viability was assessed in the presence or absence of bacterial SNs and hA53T-αsyn, while immunocytochemistry combined with semi-automated image analysis (CellProfiler) quantified neuronal, microglial and astrocytic cell numbers and morphology. Associations between major bacterial metabolites and cellular phenotypes were examined by correlation analysis. Results: Bacterial strains generated distinct fermentation profiles containing varying concentrations of metabolites including acetate, propionate, butyrate, formate and lactate. hA53T-αsyn expression reduced metabolic viability by approximately 50% after six days, which was partially ameliorated by most bacterial SNs. Microglia showed particularly pronounced morphological responses, including increased cell size and changes consistent with reactive phenotypes. Several bacterial SNs preserved neuronal or microglial cell numbers. Bacillus subtilis partially rescued hA53T-αsyn-induced neuronal loss, whereas Blautia hansenii predominantly modified neuronal morphology. Akkermansia muciniphila and Roseburia intestinalis partially normalised selected astrocytic morphological changes, while Eubacterium rectale ameliorated selected microglial abnormalities. Metabolite–phenotype correlations revealed distinct associations, with butyrate showing the strongest positive relationship with metabolic viability and acetate and propionate associating with neuronal abundance, whereas relationships with most morphological parameters were comparatively weak. Conclusions: Defined bacterial secretomes exert distinct, cell type-specific effects on neuronal and glial responses in an in vitro model of α-syn toxicity. The limited correspondence between individual SCFAs and cellular morphology suggests that these effects cannot be attributed to a single fermentation product. Together, the findings identify bacterial species and metabolites for targeted mechanistic investigation and support further investigation of microbiome-derived secretomes as modulators of PD-relevant cellular pathology.

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