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

  • Ai Huey Tan
    Division of Neurology, Department of Medicine, Faculty of Medicine University of Malaya Kuala Lumpur Malaysia
  • Chun Wie Chong
    School of Pharmacy Monash University Malaysia Subang Jaya Malaysia
  • Shen‐Yang Lim
    Division of Neurology, Department of Medicine, Faculty of Medicine University of Malaya Kuala Lumpur Malaysia
  • Ivan Kok Seng Yap
    Sarawak Research and Development Council Kuching Malaysia
  • Cindy Shuan Ju Teh
    Department of Medical Microbiology, Faculty of Medicine University of Malaya Kuala Lumpur Malaysia
  • Mun Fai Loke
    Department of Medical Microbiology, Faculty of Medicine University of Malaya Kuala Lumpur Malaysia
  • Sze‐Looi Song
    China‐ASEAN College of Marine Sciences Xiamen University Malaysia Sepang Malaysia
  • Jiun Yan Tan
    Mah Pooi Soo and Tan Chin Nam Center for Parkinson's and Related Disorders, Faculty of Medicine University of Malaya Kuala Lumpur Malaysia
  • Ban Hong Ang
    Mah Pooi Soo and Tan Chin Nam Center for Parkinson's and Related Disorders, Faculty of Medicine University of Malaya Kuala Lumpur Malaysia
  • Yong Qi Tan
    Mah Pooi Soo and Tan Chin Nam Center for Parkinson's and Related Disorders, Faculty of Medicine University of Malaya Kuala Lumpur Malaysia
  • Mee Teck Kho
    School of Postgraduate Studies International Medical University Kuala Lumpur Malaysia
  • Jeff Bowman
    Integrative Oceanography Division Scripps Institution of Oceanography, University of California La Jolla CA USA
  • Sanjiv Mahadeva
    Division of Gastroenterology, Department of Medicine, Faculty of Medicine University Malaya Kuala Lumpur Malaysia
  • Hoi Sen Yong
    Institute of Biological Sciences University of Malaya Kuala Lumpur Malaysia
  • Anthony E. Lang
    Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic Toronto Western Hospital Toronto ON Canada

抄録

<jats:sec><jats:title>Objective</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Two hundred subjects (104 patients, 96 controls) underwent extensive clinical phenotyping. Stool samples were analyzed using <jats:italic>16S rRNA</jats:italic> gene sequencing. Fecal metabolomics were performed using two platforms, nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography–mass spectrometry.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Interpretation</jats:title><jats:p>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</jats:p></jats:sec>

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