Gut Microbial Ecosystem in Parkinson Disease: New Clinicobiological Insights from Multi-Omics

Tan AH 1 , Chong CW 2 , Lim SY 1 , Yap IKS 3 , Teh CSJ 4 , Loke MF 4 Show all authors , Song SL 5 , Tan JY 6 , Ang BH 6 , Tan YQ 6 , Kho MT 7 , Bowman J 8 , Mahadeva S 9 , Yong HS 10 , Lang AE 11

Affiliations 

  • 1 Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 2 School of Pharmacy, Monash University Malaysia, Subang Jaya, Malaysia
  • 3 Sarawak Research and Development Council, Kuching, Malaysia
  • 4 Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 5 China-ASEAN College of Marine Sciences, Xiamen University Malaysia, Sepang, Malaysia
  • 6 Mah Pooi Soo and Tan Chin Nam Center for Parkinson's and Related Disorders, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 7 School of Postgraduate Studies, International Medical University, Kuala Lumpur, Malaysia
  • 8 Integrative Oceanography Division, Scripps Institution of Oceanography, University of California, La Jolla, CA, USA
  • 9 Division of Gastroenterology, Department of Medicine, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
  • 10 Institute of Biological Sciences, University of Malaya, Kuala Lumpur, Malaysia
  • 11 Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, ON, Canada
Ann Neurol, 2021 03;89(3):546-559.
PMID: 33274480 DOI: 10.1002/ana.25982

Abstract

OBJECTIVE: Gut microbiome alterations in Parkinson disease (PD) have been reported repeatedly, but their functional relevance remains unclear. Fecal metabolomics, which provide a functional readout of microbial activity, have scarcely been investigated. We investigated fecal microbiome and metabolome alterations in PD, and their clinical relevance.

METHODS: Two hundred subjects (104 patients, 96 controls) underwent extensive clinical phenotyping. Stool samples were analyzed using 16S rRNA gene sequencing. Fecal metabolomics were performed using two platforms, nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-mass spectrometry.

RESULTS: Fecal microbiome and metabolome composition in PD was significantly different from controls, with the largest effect size seen in NMR-based metabolome. Microbiome and NMR-based metabolome compositional differences remained significant after comprehensive confounder analyses. Differentially abundant fecal metabolite features and predicted functional changes in PD versus controls included bioactive molecules with putative neuroprotective effects (eg, short chain fatty acids [SCFAs], ubiquinones, and salicylate) and other compounds increasingly implicated in neurodegeneration (eg, ceramides, sphingosine, and trimethylamine N-oxide). In the PD group, cognitive impairment, low body mass index (BMI), frailty, constipation, and low physical activity were associated with fecal metabolome compositional differences. Notably, low SCFAs in PD were significantly associated with poorer cognition and low BMI. Lower butyrate levels correlated with worse postural instability-gait disorder scores.

INTERPRETATION: Gut microbial function is altered in PD, characterized by differentially abundant metabolic features that provide important biological insights into gut-brain pathophysiology. Their clinical relevance further supports a role for microbial metabolites as potential targets for the development of new biomarkers and therapies in PD. ANN NEUROL 2021;89:546-559.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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