Objective: To search for molecular links between Parkinson’s disease (PD) pathogenesis and gut microbes based on integrated multi-omic analyses of fecal samples from patients with PD or idiopathic REM sleep behavior disorder (iRBD) and healthy controls.

Background: A growing number of studies are reporting differences between the gut microbial communities of PD patients and healthy subjects [1, 2]. So far, research has mainly focused on cataloguing microbes with altered abundances in PD. Therefore, a more comprehensive methodology is required for mechanistic understanding of the role of microbes in PD pathogenesis. Potential connections include microbial molecules that influence alpha-synuclein (aSyn) aggregation, inflammation, or both [2].

Method: We performed integrated multi-omic analyses of DNA, RNA, proteins and metabolite fractions from stool collected from patients with PD (n=47) or iRBD (n=27) and healthy control subjects (n=49) representing two German cohorts. We then focused on the most promising molecule from this screening, testing for toxicity as well as effects on aSyn aggregation and inflammation. We used several experimental models, including aSyn expressing transgenic yeast, enteric neurons derived from human induced pluripotent stem cells, murine bone-marrow-derived macrophages as well as aSyn-overexpressing mice.

Results: Our comparisons revealed that an unknown metabolite was significantly increased in stool samples of patients with PD or iRBD compared to healthy controls. It was identified as 2-hydroxypyridine (2-HP), a molecule associated with archaeal metabolism [3]. Experimental assays showed that 2-HP is toxic to human aSyn expressing yeast and enhances aSyn aggregation in enteric neurons. It also upregulates interleukin 1 beta (IL-1b) expression in murine macrophages, indicating that it can activate the NLRP3 inflammasome, which has been implicated in PD pathogenesis and microbiota-gut-brain interactions [4]. Finally, an in vivo mouse experiment with intrastriatal injections of 2-HP suggests that this molecule can affect motor symptoms.

Conclusion: 2-hydroxypyridine is a novel microbial molecule which is likely to be involved in PD pathogenesis, capable of affecting aSyn aggregation, inflammation and motor symptom development.

References: 1. Boertien JM, Pereira PAB, Aho VTE, Scheperjans F. Increasing Comparability and Utility of Gut Microbiome Studies in Parkinson’s Disease: A Systematic Review. J Parkinsons Dis. 2019;9(s2):S297-S312. 2. Fang P, Kazmi SA, Jameson KG, Hsiao EY. The Microbiome as a Modifier of Neurodegenerative Disease Risk. Cell Host Microbe. 2020 Aug 12;28(2):201-222. 3. Shima S, Chen D, Xu T, Wodrich MD, Fujishiro T, Schultz KM, Kahnt J, Ataka K, Hu X. Reconstitution of [Fe]-hydrogenase using model complexes. Nat Chem. 2015 Dec;7(12):995-1002. 4. Pellegrini C, Antonioli L, Calderone V, Colucci R, Fornai M, Blandizzi C. Microbiota-gut-brain axis in health and disease: Is NLRP3 inflammasome at the crossroads of microbiota-gut-brain communications? Prog Neurobiol. 2020 Aug;191:101806.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/integrated-multi-omics-of-the-gut-microbiome-reveal-2-hydroxypyridine-as-a-novel-molecule-relevant-to-parkinsons-disease-pathogenesis/