Heterogeneity in gut microbiota drive polyphenol metabolism that influences α-synuclein misfolding and toxicity

Lap Ho, Danyue Zhao, Kenjiro Ono, Kai Ruan, Ilaria Mogno, Mayumi Tsuji, Eileen Carry, Justin Brathwaite, Steven Sims, Tal Frolinger, Susan Westfall, Paolo Mazzola, Qingli Wu, Ke Hao, Thomas E. Lloyd, James E. Simon, Jeremiah Faith, Giulio M. Pasinetti

Research output: Journal article publicationJournal articleAcademic researchpeer-review

20 Citations (Scopus)

Abstract

The intestinal microbiota actively converts dietary flavanols into phenolic acids, some of which are bioavailable in vivo and may promote resilience to select neurological disorders by interfering with key pathologic mechanisms. Since every person harbors a unique set of gut bacteria, we investigated the influence of the gut microbiota's interpersonal heterogeneity on the production and bioavailability of flavonoid metabolites that may interfere with the misfolding of alpha (α)-synuclein, a process that plays a central role in Parkinson's disease and other α-synucleinopathies. We generated two experimental groups of humanized gnotobiotic mice with compositionally diverse gut bacteria and orally treated the mice with a flavanol-rich preparation (FRP). The two gnotobiotic mouse groups exhibited distinct differences in the generation and bioavailability of FRP-derived microbial phenolic acid metabolites that have bioactivity towards interfering with α-synuclein misfolding or inflammation. We also demonstrated that these bioactive phenolic acids are effective in modulating the development and progression of motor dysfunction in a Drosophila model of α-synucleinopathy. Lastly, through in vitro bacterial fermentation studies, we identified select bacteria that are capable of supporting the generation of these bioavailable and bioactive phenolic acids. Outcomes from our studies provide a better understanding of how interpersonal heterogeneity in the gut microbiota differentially modulates the efficacy of dietary flavanols to protect against select pathologic mechanisms. Collectively, our findings provide the basis for future developments of probiotic, prebiotic, or synbiotic approaches for modulating the onset and/or progression of α-synucleinopathies and other neurological disorders involving protein misfolding and/or inflammation.

Original languageEnglish
Pages (from-to)170-181
Number of pages12
JournalJournal of Nutritional Biochemistry
Volume64
DOIs
Publication statusPublished - Feb 2019
Externally publishedYes

Keywords

  • Drosophila
  • Humanized gnotobiotic mice
  • Microbiome
  • Phenolic acids
  • Polyphenol metabolism
  • α-Synucleinopathy

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Nutrition and Dietetics
  • Clinical Biochemistry

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