Integrated Analyses of Microbiome and Longitudinal Metabolome Data Reveal Microbial-Host Interactions on Sulfur Metabolism in Parkinson’s Disease
Johannes Hertel,
Amy C. Harms,
Almut Heinken,
Federico Baldini,
Cyrille C. Thinnes,
Enrico Glaab,
Daniel A. Vasco,
Maik Pietzner,
Isobel D. Stewart,
Nicholas J. Wareham,
Claudia Langenberg,
Claudia Trenkwalder,
Rejko Krüger,
Thomas Hankemeier,
Ronan M.T. Fleming,
Brit Mollenhauer,
Ines Thiele
Affiliations
Johannes Hertel
School of Medicine, National University of Galway, Galway, Ireland; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg; Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
Amy C. Harms
Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Faculty of Science, Leiden University, Leiden, the Netherlands
Almut Heinken
School of Medicine, National University of Galway, Galway, Ireland; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg
Federico Baldini
Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg
Cyrille C. Thinnes
School of Medicine, National University of Galway, Galway, Ireland; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg
Enrico Glaab
Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg
Daniel A. Vasco
Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg
Maik Pietzner
MRC Epidemiology Unit, University of Cambridge, Cambridge CB2 0QQ, UK
Isobel D. Stewart
MRC Epidemiology Unit, University of Cambridge, Cambridge CB2 0QQ, UK
Nicholas J. Wareham
MRC Epidemiology Unit, University of Cambridge, Cambridge CB2 0QQ, UK
Claudia Langenberg
MRC Epidemiology Unit, University of Cambridge, Cambridge CB2 0QQ, UK
Claudia Trenkwalder
Paracelsus-Elena-Klinik, 34128 Kassel, Germany; Department of Neurosurgery, University Medical Center Goettingen, 37075 Goettingen, Germany
Rejko Krüger
Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg; Centre Hospitalier de Luxembourg (CHL), Luxembourg, Luxembourg
Thomas Hankemeier
Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Faculty of Science, Leiden University, Leiden, the Netherlands
Ronan M.T. Fleming
School of Medicine, National University of Galway, Galway, Ireland; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg; Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Faculty of Science, Leiden University, Leiden, the Netherlands
Brit Mollenhauer
Paracelsus-Elena-Klinik, 34128 Kassel, Germany; Department of Neurology, University Medical Center Goettingen, 37075 Goettingen, Germany
Ines Thiele
School of Medicine, National University of Galway, Galway, Ireland; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg; Division of Microbiology, National University of Galway, Galway, Ireland; APC Microbiome Ireland, Ireland; Corresponding author
Summary: Parkinson’s disease (PD) exhibits systemic effects on the human metabolism, with emerging roles for the gut microbiome. Here, we integrate longitudinal metabolome data from 30 drug-naive, de novo PD patients and 30 matched controls with constraint-based modeling of gut microbial communities derived from an independent, drug-naive PD cohort, and prospective data from the general population. Our key results are (1) longitudinal trajectory of metabolites associated with the interconversion of methionine and cysteine via cystathionine differed between PD patients and controls; (2) dopaminergic medication showed strong lipidomic signatures; (3) taurine-conjugated bile acids correlated with the severity of motor symptoms, while low levels of sulfated taurolithocholate were associated with PD incidence in the general population; and (4) computational modeling predicted changes in sulfur metabolism, driven by A. muciniphila and B. wadsworthia, which is consistent with the changed metabolome. The multi-omics integration reveals PD-specific patterns in microbial-host sulfur co-metabolism that may contribute to PD severity. : Hertel et al. demonstrate complex alterations in human and microbial sulfur metabolism in Parkinson’s disease by integrating longitudinal metabolomics and computational modeling of gut microbiomes. Then, potential clinical importance is revealed as secondary taurine-conjugated bile acids are shown to be associated with disease severity and Parkinson’s disease incidence. Keywords: metabolism, Parkinson's disease, neurodegenerative disease, microbiome, transsulfuration pathway, metabolomics, metagenomics, metabolic modeling, taurine metabolism, bile acid metabolism