DJ-1 (Park7) affects the gut microbiome, metabolites, and development of Innate Lymphoid Cells (ILCs)

The proper communication between gut and brain is pivotal for the maintenance of health and dysregulation of the gut brain axis can lead to several clinical disorders. Also, in Parkinson9s disease (PD) 85 percentage of all patients experienced constipation long before showing any signs of motor phenotypes. For differential diagnosis and when it comes to preventive treatment, there is an urgent need for the identification of biomarkers indicating early disease stages long before the disease phenotype manifests. DJ1 is a chaperone protein involved in the protection against PD and genetic mutations in this protein have been shown to cause familial PD. However, how the deficiency of DJ1 modifies the PD risk remains incompletely understood. In the present study, we provide evidence that DJ1 is implicated in shaping the gut microbiome including their metabolite production or innate immune cells (ILCs) development. We revealed that in four months old mice genetic deficiency of DJ1 leads to a significant decrease in several bacterial genera and significantly increase in two specific genera, namely Alistipes and Rikenella. DJ1 deficient mice have a higher production of calprotectin and MCP1 inflammatory protein, a known protein involved in colonic inflammation, and significantly higher expression of the glial fibrillary acidic protein (GFAP) than control littermates. Expression of alpha-Synuclein, a key protein in Lewy bodies, in the colon was not significantly different between genotypes. Metabolic profiles of feces extracts analyzed by H1NMR spectroscopy showed increased short chain fatty acids (SCFAs) and decreased amino acid levels, suggesting a general switch from protein towards fiber degrading strains in DJ1 deficient mice. We observed that Malonate, which is known to influence the immune system, has significantly higher concentrations in DJ1 deficient mice. Moreover, DJ1 deficient mice have high levels of the phenol derivate 3(3Hydroxyphenyl) propanoic acid (3HPPA) which is a breakdown product of aromatic substrates like tyrosine, phenylalanine, and polyphenols. DJ1 deficient mice also showed significantly reduced the percentage of ILCs. Thus, our data suggest that absence of DJ1 leads to increase in gut inflammatory bacteria composition, deregulated metabolites and dysregulated innate immunity which could be a key factor in the initiation of PD disease in the gut, and potentially also in the brain during disease progression.