Polymannuronic acid prevents dopaminergic neuronal loss via brain-gut-microbiota axis in Parkinson’s disease model

Authors: DONG, XIAO-LI - The Hong Kong Polytechnic University Shenzhen Institute; WANG, XIONG - Ocean University Of China; LIU, FANG - Ocean University Of China; Li, Robert; XUE, CHANG-HU - Ocean University Of China; WONG, KA-HING - The Hong Kong Polytechnic University Shenzhen Institute; WONG, WING-TAK - The Hong Kong Polytechnic University Shenzhen Institute; TANG, QING-JUAN - Ocean University Of China

Submitted to: International Journal of Biological Macromolecules
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/16/2020
Publication Date: 7/22/2020
Citation: Dong, X., Wang, X., Liu, F., Li, R.W., Xue, C., Wong, K., Wong, W., Tang, Q. 2020. Polymannuronic acid prevents dopaminergic neuronal loss via brain-gut-microbiota axis in Parkinson’s disease model. International Journal of Biological Macromolecules. 164:994-1005. https://doi.org/10.1016/j.ijbiomac.2020.07.180.
DOI: https://doi.org/10.1016/j.ijbiomac.2020.07.180

Interpretive Summary: Parasitic infections, and ensuing changes in gut microbiome and metabolites, have a profound impact on intestinal inflammation and host immunity. However, the mechanism by which parasites evade host immune surveillance and modulate gut inflammation remains elusive. Using murine models to identify natural products to dampen parasite-induced intestine inflammation will accelerate the development of alternative parasite control strategies for farm animals. In this study, we took advantage of a well-established mouse model for Parkinson's disease (PD), one of the most important age-related neurodegenerative disorder with a significant manifestation of gastrointestinal dysfunction, to screen for natural products with potent anti-inflammatory properties. Our results demonstrate that oral administration of polymannuronic acid, one of bioactive polysaccharides, resulted in notable neuroprotective effects in a PD mouse model by affecting several key targets along the brain-gut-microbiota axis, including alleviating intestinal inflammation. Our findings will aid the development of polymannuronic acid as an alternative therapeutic agent for preventing dopaminergic neuronal loss in PD patients and may result in potential countermeasures for animal parasitism.

Technical Abstract: Background and Purpose: The pathological process of the brain-gut-microbiota axis might spread from the gut to the brain and contribute to the pathogenesis of Parkinson's disease (PD). Novel preventative or therapeutic options that aim at modifying gut microbiome and alleviating intestinal inflammation might influence the initial step of the cascade of events that lead to PD neurodegeneration. Experimental Approach: 48 eight-week-old male C57BL/6J mice were randomly and evenly assigned to one normal control and five PD model groups. The preventative effects of three bioactive polysaccharides, including alginate (Alg) and its two components polymannuronic acid (PM) and polyguluronic acid (PG), against MPTP toxins and underlying mechanisms were explored. Key Results: PM pretreatment for 4 weeks provided better neuroprotection than Alg and PG by significantly improving motor functions; increasing tyrosine hydroxylase expressions in the substantia nigra and cortex; enhancing contents of several neurotransmitters (Homovanillic acid, 5-HT, 5-hydroxyindole acetic acid, GABA) in the striatum of PD mice. Mechanism results implied Alg, PM and PG reshaped gut microbiota and impacted microbial pathways in different ways; and only PM administration led to positive impacts against PD pathogenesis. PM treatment induced gene transcripts benefiting neuroprotection, but suppressed genes aggravating neurodegeneration in the colon of PD mice. In particular, only PM alleviated intestinal and systematic inflammation. Conclusion and Implications: PM prevented dopaminergic neuronal loss in PD mice mainly by acting on multiple targets along the brain-gut-microbiota axis. Key words: Parkinson’s disease; Alginate; Polymannuronic acid; Polyguluronic acid; Brain-gut-microbiota axis; Metagenomic sequencing; RNA sequencing Abbreviations used: Alg, alginate; ANS, autonomic nervous system; aSyn, alpha synuclein; DA, dopamine; DAB, 3’-diaminobenzidine; DOPAC, 3,4-dihydroxyphenylacetic acid; ENS, enteric nervous system; FDR, false discovery rate; G, a-L-guluronic acid; GI, gastrointestinal; GO, gene ontology; 5-HIAA, 5-hydroxyindole acetic acid; HVA, homovanillic acid; IHC, immunohistochemistry; IL-6, interleukin 6; KEGG, Kyoto Encyclopedia of Genes and Genomes; LDA, linear discriminant analysis; L-Dopa, levodopa; LEfSe, Linear discriminant analysis Effect Size; M, ß-D-mannuronic acid; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; OTU, operational taxonomic unit; PD, Parkinson’s disease; PG, polyguluronic acid; PICRUSt, Phylogenetic Investigation of Communities by Reconstruction of Unobserved States; PM, polymannuronic acid; PS, polysaccharides; SNpc, substantia nigra pars compacta; TH, tyrosine hydroxylase; TH-IR, tyrosine hydroxylase immunoreactive.