The engineered probiotic strain Lactococcus lactis MG1363-pMG36e-GLP-1 regulates microglial polarization and gut dysbiosis in a transgenic mouse model of Parkinson's disease.

JOURNAL/nrgr/04.03/01300535-202603000-00044/figure1/v/2025-06-16T082406Z/r/image-tiff Parkinson's disease is characterized by synucleinopathy-associated neurodegeneration. Previous studies have shown that glucagon-like peptide-1 (GLP-1) has beneficial effects in a mouse model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. However, the effect of GLP-1 on intrinsic synuclein malfunction remains unclear. In this study, we investigated the effect of Lactococcus lactis MG1363-pMG36e-GLP-1 on parkinsonism in SncaA53T transgenic mice and explored the underlying mechanisms. Our data showed that Lactococcus lactis MG1363-pMG36e-GLP-1 inhibited dopaminergic neuronal death, reduced pathological aggregation of α-synuclein, and decreased movement disorders in SncaA53T transgenic mice. Furthermore, Lactococcus lactis MG1363-pMG36e-GLP-1 downregulated lipopolysaccharide-related inflammation, reduced cerebral activation of microglia and astrocytes, and promoted cell survival via the GLP-1 receptor/PI3K/Akt pathway in the substantia nigra. Additionally, Lactococcus lactis MG1363-pMG36e-GLP-1 decreased serum levels of pro-inflammatory molecules including lipopolysaccharide, lipopolysaccharide binding protein, interleukin-1β, and interleukin-6. Gut histopathology and western blotting further revealed that Lactococcus lactis MG1363-pMG36e-GLP-1 increased the expression of gut integrity-related proteins and reduced lipopolysaccharide-related inflammation by reversing gut dysbiosis in SncaA53T transgenic mice. Our findings showed that the beneficial effect of Lactococcus lactis MG1363-pMG36e-GLP-1 on parkinsonism traits in SncaA53T transgenic mice is mediated by microglial polarization and the reversal of dysbiosis. Collectively, our findings suggest that Lactococcus lactis MG1363-pMG36e-GLP-1 is a promising therapeutic agent for the treatment of Parkinson's disease.