Abstract
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.
Original language | English |
---|---|
Pages (from-to) | 1767-1777.e8 |
Journal | Cell Reports |
Volume | 29 |
Issue number | 7 |
DOIs | |
Publication status | Published - 12 Nov 2019 |
Externally published | Yes |
Keywords
- Parkinson's disease
- bile acid metabolism
- metabolic modeling
- metabolism
- metabolomics
- metagenomics
- microbiome
- neurodegenerative disease
- taurine metabolism
- transsulfuration pathway
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Integrated Analyses of Microbiome and Longitudinal Metabolome Data Reveal Microbial-Host Interactions on Sulfur Metabolism in Parkinson's Disease. / Hertel, Johannes; Harms, Amy C.; Heinken, Almut et al.
In: Cell Reports, Vol. 29, No. 7, 12.11.2019, p. 1767-1777.e8.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Integrated Analyses of Microbiome and Longitudinal Metabolome Data Reveal Microbial-Host Interactions on Sulfur Metabolism in Parkinson's Disease
AU - Hertel, Johannes
AU - Harms, Amy C.
AU - Heinken, Almut
AU - Baldini, Federico
AU - Thinnes, Cyrille C.
AU - Glaab, Enrico
AU - Vasco, Daniel A.
AU - Pietzner, Maik
AU - Stewart, Isobel D.
AU - Wareham, Nicholas J.
AU - Langenberg, Claudia
AU - Trenkwalder, Claudia
AU - Krüger, Rejko
AU - Hankemeier, Thomas
AU - Fleming, Ronan M.T.
AU - Mollenhauer, Brit
AU - Thiele, Ines
N1 - Funding Information: Computational analyses presented in this paper were carried out in part using the high-performance computing (HPC) facilities of the University of Luxembourg (see https://hpc.uni.lu/ ). The authors thank Mr. P. Queiros for helping with the mapping of the metabolites onto the VMH database identifiers, Dr. P. Banda and Dr. K. Roomp for helping with clinical metadata access, and Dr. Fay Betsou and Estelle Sandt from the Integrated BioBank of Luxembourg for sample handling. This study was funded by Luxembourg National Research Fund (FNR) through the ATTRACT programme grant ( FNR/A12/01 to I.T.), the National Centre of Excellence in Research (NCER) on Parkinson’s disease, and by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 757922 ). The EPIC-Norfolk study ( https://doi.org/10.22025/2019.10.105.00004 ) has received funding from the Medical Research Council ( MR/N003284/1 and MC-UU_12015/1 ) and Cancer Research UK ( C864/A14136 ). Metabolite measurements in the EPIC-Norfolk study were supported by the MRC Cambridge Initiative in Metabolic Science ( MR/L00002/1 ) and the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no. 115372 . We are grateful to all the participants who have been part of the project and to the many members of the study teams at the University of Cambridge who have enabled this research. Furthermore, we acknowledge the joint effort of the NCER-PD consortium members generally contributing to the Luxembourg Parkinson’s Study as listed below: Aguayo, Gloria; Allen, Dominic; Ammerlann, Wim; Aurich, Maike; Balling, Rudi; Banda, Peter; Beaumont, Katy; Becker, Regina; Berg, Daniela; Betsou, Fay; Binck, Sylvia; Bisdorff, Alexandre; Bobbili, Dheeraj; Brockmann, Kathrin; Calmes, Jessica; Castillo, Lorieza; Diederich, Nico; Dondelinger, Rene; Esteves, Daniela; Ferrand, Jean-Yves; Gantenbein, Manon; Gasser, Thomas; Gawron, Piotr; Geffers, Lars; Giarmana, Virginie; Gomes, Clarissa P.C.; Goncharenko, Nikolai; Graas, Jérôme; Graziano, Mariela; Groues, Valentin; Grünewald, Anne; Gu, Wei; Hammot, Gaël; Hanff, Anne-Marie; Hansen, Linda; Hansen, Maxime; Haraldsdöttir, Hulda; Heirendt, Laurent; Herbrink, Sylvia; Herzinger, Sascha; Heymann, Michael; Hiller, Karsten; Hipp, Geraldine; Hu, Michele; Huiart, Laetitia; Hundt, Alexander; Jacoby, Nadine; Jarosław, Jacek; Jaroz, Yohan; Kolber, Pierre; Kutzera, Joachim; Landoulsi, Zied; Larue, Catherine; Lentz, Roseline; Liepelt, Inga; Liszka, Robert; Longhino, Laura; Lorentz, Victoria; Mackay, Clare; Maetzler, Walter; Marcus, Katrin; Marques, Guilherme; Martens, Jan; Mathay, Conny; Matyjaszczyk, Piotr; May, Patrick; Meisch, Francoise; Menster, Myriam; Minelli, Maura; Mittelbronn, Michel; Mommaerts, Kathleen; Moreno, Carlos; Mühlschlegel, Friedrich; Nati, Romain; Nehrbass, Ulf; Nickels, Sarah; Nicolai, Beatrice; Nicolay, Jean-Paul; Noronha, Alberto; Oertel, Wolfgang; Ostaszewski, Marek; Pachchek, Sinthuja; Pauly, Claire; Pavelka, Lukas; Perquin, Magali; Reiter, Dorothea; Rosety, Isabel; Rump, Kirsten; Sandt, Estelle; Satagopam, Venkata; Schlesser, Marc; Schmitz, Sabine; Schmitz, Susanne; Schneider, Reinhard; Schwamborn, Jens; Schweicher, Alexandra; Simons, Janine; Stute, Lara; Trefois, Christophe; Trezzi, Jean-Pierre; Vaillant, Michel; Vyas, Maharshi; Wade-Martins, Richard; Wilmes, Paul. Funding Information: Computational analyses presented in this paper were carried out in part using the high-performance computing (HPC) facilities of the University of Luxembourg (see https://hpc.uni.lu/). The authors thank Mr. P. Queiros for helping with the mapping of the metabolites onto the VMH database identifiers, Dr. P. Banda and Dr. K. Roomp for helping with clinical metadata access, and Dr. Fay Betsou and Estelle Sandt from the Integrated BioBank of Luxembourg for sample handling. This study was funded by Luxembourg National Research Fund (FNR) through the ATTRACT programme grant (FNR/A12/01 to I.T.), the National Centre of Excellence in Research (NCER) on Parkinson's disease, and by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement no. 757922). The EPIC-Norfolk study (https://doi.org/10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1 and MC-UU_12015/1) and Cancer Research UK (C864/A14136). Metabolite measurements in the EPIC-Norfolk study were supported by the MRC Cambridge Initiative in Metabolic Science (MR/L00002/1) and the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no. 115372. We are grateful to all the participants who have been part of the project and to the many members of the study teams at the University of Cambridge who have enabled this research. Furthermore, we acknowledge the joint effort of the NCER-PD consortium members generally contributing to the Luxembourg Parkinson's Study as listed below: Aguayo, Gloria; Allen, Dominic; Ammerlann, Wim; Aurich, Maike; Balling, Rudi; Banda, Peter; Beaumont, Katy; Becker, Regina; Berg, Daniela; Betsou, Fay; Binck, Sylvia; Bisdorff, Alexandre; Bobbili, Dheeraj; Brockmann, Kathrin; Calmes, Jessica; Castillo, Lorieza; Diederich, Nico; Dondelinger, Rene; Esteves, Daniela; Ferrand, Jean-Yves; Gantenbein, Manon; Gasser, Thomas; Gawron, Piotr; Geffers, Lars; Giarmana, Virginie; Gomes, Clarissa P.C.; Goncharenko, Nikolai; Graas, J?r?me; Graziano, Mariela; Groues, Valentin; Gr?newald, Anne; Gu, Wei; Hammot, Ga?l; Hanff, Anne-Marie; Hansen, Linda; Hansen, Maxime; Haraldsd?ttir, Hulda; Heirendt, Laurent; Herbrink, Sylvia; Herzinger, Sascha; Heymann, Michael; Hiller, Karsten; Hipp, Geraldine; Hu, Michele; Huiart, Laetitia; Hundt, Alexander; Jacoby, Nadine; Jaros?aw, Jacek; Jaroz, Yohan; Kolber, Pierre; Kutzera, Joachim; Landoulsi, Zied; Larue, Catherine; Lentz, Roseline; Liepelt, Inga; Liszka, Robert; Longhino, Laura; Lorentz, Victoria; Mackay, Clare; Maetzler, Walter; Marcus, Katrin; Marques, Guilherme; Martens, Jan; Mathay, Conny; Matyjaszczyk, Piotr; May, Patrick; Meisch, Francoise; Menster, Myriam; Minelli, Maura; Mittelbronn, Michel; Mommaerts, Kathleen; Moreno, Carlos; M?hlschlegel, Friedrich; Nati, Romain; Nehrbass, Ulf; Nickels, Sarah; Nicolai, Beatrice; Nicolay, Jean-Paul; Noronha, Alberto; Oertel, Wolfgang; Ostaszewski, Marek; Pachchek, Sinthuja; Pauly, Claire; Pavelka, Lukas; Perquin, Magali; Reiter, Dorothea; Rosety, Isabel; Rump, Kirsten; Sandt, Estelle; Satagopam, Venkata; Schlesser, Marc; Schmitz, Sabine; Schmitz, Susanne; Schneider, Reinhard; Schwamborn, Jens; Schweicher, Alexandra; Simons, Janine; Stute, Lara; Trefois, Christophe; Trezzi, Jean-Pierre; Vaillant, Michel; Vyas, Maharshi; Wade-Martins, Richard; Wilmes, Paul. Manuscript ? Main Text, J.H. I.T. and A.H.; Methods, J.H. I.T. F.B. A.C.H. and E.G.; Statistical Analyses, J.H. A.H. D.A.V. M.P. and I.D.S.; Metagenomic Data Processing, F.B.; Computational Modeling, F.B. and A.H.; Study Design, I.T. R.M.T.F. C.C.T. C.T. B.M. E.G. R.K. and C.L.; Metabolomic Measurements, A.C.H. and T.H. All of the authors read, reviewed, and approved the final version of the manuscript. The authors declare no competing interests. Publisher Copyright: © 2019 The Authors
PY - 2019/11/12
Y1 - 2019/11/12
N2 - 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.
AB - 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.
KW - Parkinson's disease
KW - bile acid metabolism
KW - metabolic modeling
KW - metabolism
KW - metabolomics
KW - metagenomics
KW - microbiome
KW - neurodegenerative disease
KW - taurine metabolism
KW - transsulfuration pathway
UR - http://www.scopus.com/inward/record.url?scp=85074641473&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2019.10.035
DO - 10.1016/j.celrep.2019.10.035
M3 - Article
C2 - 31722195
AN - SCOPUS:85074641473
SN - 2211-1247
VL - 29
SP - 1767-1777.e8
JO - Cell Reports
JF - Cell Reports
IS - 7
ER -