Early gut microbiota dysbiosis in c-Rel deficient mice, a model of Parkinson’s disease

Parkinson’s disease (PD), the most common neurodegenerative movement disorder, is characterized by dopaminergic nigrostriatal neuron loss and α-synuclein accumulation. Besides classical motor symptoms, PD patients can manifest a broad spectrum of non-motor symptoms, including constipation, that usually occur years before the onset of motor symptoms. In accordance with the early onset of gastrointestinal dysfunction, the enteric nervous system (ENS) is among the structures earliest and most frequently affected by α-synuclein pathology. Recent research has shown that gut microbiota is altered in PD patients and could be involved in the disease onset and progression interacting with ENS.

We previously showed that male mice lacking the NF-kB/c-Rel subunit (c-rel^-/- male mice) reproduce a pattern of ascending α-synuclein deposition in the olfactory bulbs and brainstem nuclei. The pathology progression is accompanied by the appearance of both non-motor and motor symptoms, including hyposmia at 2 months, anxiety- and depressive-like behaviour at 12 months, and motor deficits at 18 months. Of note, c-rel^-/- male mice display early and progressive intestinal α-synuclein accumulation and inflammation starting at 2 months, paralleled by reduced colon motility.

Here we determined whether gut dysfunction and pathology in c-rel^-/- male mice were coupled with an altered microbiota composition. Stool pellets collected from wt and c-rel^-/- male mice at early (0.5 and 1 months) and later (6-8 and 18-20 months) phases of the pathology were subjected to culturomics and Next Generation Sequencing (NGS) analyses. The complementary culturomics and metagenomic approaches indicated a remarkable difference between wt and c-rel^-/- male mice particularly at 0.5 months. Indeed, young c-rel^-/- male mice displayed a pro-inflammatory microbiota characterized by the reduction of Verrucomicrobiacae and Enterobacteriaceae bacteria families, and the increase of Prevotellacae. This microbiota profile, deriving from young c-rel^-/- mice in an extremely early phase of the pathology, may be involved in the pathogenesis of the disease.