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

Abstract

The proper communication between gut and brain is pivotal for maintenance of health and dysregulation of the gut-brain axis can lead to several clinical disorders. Also, in Parkinson's disease (PD) 85% 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. DJ-1 is a chaperon 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 DJ-1 modifies the PD risk remains incompletely understood. In the present study we provide evidence that DJ-1 is implicated in shaping the gut microbiome including their metabolite production or innate immune cells (ILCs) development. We revealed that in 4 months old mice genetic deficiency of DJ-1 leads to significantly decrease in several bacterial genera and significantly increase in two specific genera, namely Alistipes and Rikenella. DJ-1 deficient mice have a higher production of calprotectin/MCP-1 inflammatory protein -a known protein involved in colonic inflammation -and significantly higher expression of glial fibrillary acidic protein (GFAP) than control littermates. Expression of a-Synuclein, a key protein in Lewy bodies, in the colon was not significantly different between genotypes. Metabolic profiles of feces extracts analysed by H 1 -NMR spectroscopy showed increased short chain fatty acids (SCFAs) and decreased amino acid levels, suggesting a general switch from protein towards fibre degrading strains in DJ-1 deficient mice. We observed that Malonate -which is known to influence the immune system -has significantly higher concentrations in DJ-1 deficient mice. Moreover, DJ-1 deficient mice have high levels of the phenol derivate 3-(3-Hydroxyphenyl) propanoic acid (3-HPPA) which is a breakdown product of aromatic substrates like tyrosine, phenylalanine and polyphenols. DJ-1 deficient mice also showed significantly reduced percentage of ILCs. Thus, our data suggests that absence of DJ-1 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 brain during disease progression.

Quantifying mediation between omics layers and complex traits

“…While the exact role of the protein in the disease remains debated, reduced intestinal expression of PARK7 was observed in patients and mouse models for IBD [53]. Moreover, Park7 knockout mice were shown to have increased levels of pro-colitis bacterial species in their microbiome [54,52] and experience aggravated symptoms of experimental-induced colitis [53]. In line with these observations, DNAm of the PARK7…”

“…In addition to providing insights into global patterns governing the mediation between different intermediate phenotypic layers and functional traits, our analyses generated plausible hypotheses regarding specific biological pathways. Recently, the involvement of the anti-oxidant and anti-inflammatory protein PARK7 in inflammatory bowel disease (IBD) has been brought to light [50,51,52,53]. While the exact role of the protein in the disease remains debated, reduced intestinal expression of PARK7 was observed in patients and mouse models for IBD [53].…”

Quantifying the role of transcript levels in mediating DNA methylation effects on complex traits and diseases

“…Involvement of the anti-oxidant and anti-inflammatory protein PARK7 in inflammatory bowel disease (IBD) has recently been brought to light [40][41][42][43] . While the exact role of the protein in the disease remains debated, reduced intestinal expression of PARK7 was observed in patients and mouse models for IBD 43 .…”

“…While the exact role of the protein in the disease remains debated, reduced intestinal expression of PARK7 was observed in patients and mouse models for IBD 43 . Moreover, Park7 knockout mice were shown to have increased levels of pro-colitis bacterial species in their microbiome 42,44 and experience aggravated symptoms of experimentally-induced colitis 43 . In line with these observations, DNAm of the PARK7 promoter probe cg10385390 (chr1:8'022'505) decreased PARK7 transcript expression (α EM = −0.675, P = 2.7e-4; MP of DNAmtrait pairs stratified according to the number of mediators.…”