Protocol for a multicentre cross-sectional, longitudinal ambulatory clinical trial in rheumatoid arthritis and Parkinson's disease patients analysing the relation between the gut microbiome, fasting and immune status in Germany (ExpoBiome).
Clinical trials; IMMUNOLOGY; MICROBIOLOGY; NUTRITION & DIETETICS; Parkinson-s disease; Rheumatology; Humans; Cross-Sectional Studies; Longitudinal Studies; Fasting; Germany; Ethics Committees, Research; Multicenter Studies as Topic; Gastrointestinal Microbiome; Parkinson Disease/therapy; Arthritis, Rheumatoid/therapy; Arthritis, Rheumatoid; Parkinson Disease; Medicine (all); General Medicine
Abstract :
[en] [en] INTRODUCTION: Chronic inflammatory diseases like rheumatoid arthritis (RA) and neurodegenerative disorders like Parkinson's disease (PD) have recently been associated with a decreased diversity in the gut microbiome, emerging as key driver of various diseases. The specific interactions between gut-borne microorganisms and host pathophysiology remain largely unclear. The microbiome can be modulated by interventions comprising nutrition.The aim of our clinical study is to (1) examine effects of prolonged fasting (PF) and time-restricted eating (TRE) on the outcome parameters and the immunophenotypes of RA and PD with (2) special consideration of microbial taxa and molecules associated with changes expected in (1), and (3) identify factors impacting the disease course and treatment by in-depth screening of microorganisms and molecules in personalised HuMiX gut-on-chip models, to identify novel targets for anti-inflammatory therapy.
METHODS AND ANALYSIS: This trial is an open-label, multicentre, controlled clinical trial consisting of a cross-sectional and a longitudinal study. A total of 180 patients is recruited. For the cross-sectional study, 60 patients with PD, 60 patients with RA and 60 healthy controls are recruited at two different, specialised clinical sites. For the longitudinal part, 30 patients with PD and 30 patients with RA undergo 5-7 days of PF followed by TRE (16:8) for a period of 12 months. One baseline visit takes place before the PF intervention and 10 follow-up visits will follow over a period of 12 months (April 2021 to November 2023).
ETHICS AND DISSEMINATION: Ethical approval was obtained to plan and conduct the trial from the institutional review board of the Charité-Universitätsmedizin Berlin (EA1/204/19), the ethics committee of the state medical association (Landesärztekammer) of Hessen (2021-2230-zvBO) and the Ethics Review Panel (ERP) of the University of Luxembourg (ERP 21-001 A ExpoBiome). The results of this study will be disseminated through peer-reviewed publications, scientific presentations and social media.
TRIAL REGISTRATION NUMBER: NCT04847011.
Disciplines :
Life sciences: Multidisciplinary, general & others
Author, co-author :
HANSEN, Bérénice ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Medical Translational Research
LACZNY, Cedric Christian ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Systems Ecology
AHO, Velma ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Systems Ecology > Team Paul WILMES
Frachet-Bour, Audrey; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
Habier, Janine; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
OSTASZEWSKI, Marek ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
Michalsen, Andreas; Institute for Social Medicine, Epidemiology and Health Economics, Charité Universitätsmedizin Berlin, Berlin, Germany ; Department of Internal and Integrative Medicine, Immanuel Hospital Berlin-Wannsee Branch, Berlin, Germany
Hanslian, Etienne; Institute for Social Medicine, Epidemiology and Health Economics, Charité Universitätsmedizin Berlin, Berlin, Germany ; Department of Internal and Integrative Medicine, Immanuel Hospital Berlin-Wannsee Branch, Berlin, Germany
Koppold, Daniela A; Institute for Social Medicine, Epidemiology and Health Economics, Charité Universitätsmedizin Berlin, Berlin, Germany ; Department of Internal and Integrative Medicine, Immanuel Hospital Berlin-Wannsee Branch, Berlin, Germany
Hartmann, Anika M ; Institute of Social Medicine, Epidemiology and Health Economics, Charité Universitätsmedizin Berlin, Berlin, Germany ; Department of Dermatology, Venereology and Allergology, Charité Universitätsmedizin Berlin, Berlin, Germany
Steckhan, Nico; Institute for Social Medicine, Epidemiology and Health Economics, Charité Universitätsmedizin Berlin, Berlin, Germany ; Digital Health-Connected Healthcare, Hasso Plattner Institute, University of Potsdam, Potsdam, Germany
Mollenhauer, Brit; Neurosurgery, University Medical Center Göttingen, Gottingen, Germany ; Movement disorders and Parkinson's Disease, Paracelsus-Kliniken Deutschland GmbH, Osnabruck, Germany
Schade, Sebastian ; Neurosurgery, University Medical Center Göttingen, Gottingen, Germany ; Movement disorders and Parkinson's Disease, Paracelsus-Kliniken Deutschland GmbH, Osnabruck, Germany
RUMP, Kirsten ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
SCHNEIDER, Jochen ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Medical Translational Research ; Department of Internal Medicine and Psychiatry, Saarland University Hospital and Saarland University Faculty of Medicine, Homburg, Germany
WILMES, Paul ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Systems Ecology
Protocol for a multicentre cross-sectional, longitudinal ambulatory clinical trial in rheumatoid arthritis and Parkinson's disease patients analysing the relation between the gut microbiome, fasting and immune status in Germany (ExpoBiome).
H2020 - 863664 - ExpoBiome - Deciphering the impact of exposures from the gut microbiome-derived molecular complex in human health and disease
FnR Project :
FNR11823097 - Microbiomes In One Health, 2017 (01/09/2018-28/02/2025) - Paul Wilmes
Funders :
H2020 European Research Council Union Européenne
Funding text :
This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement number 863664). This work was supported by the Luxembourg National Research Fund (FNR) under grant PRIDE/11823097.
Wilmes P, Martin-Gallausiaux C, Ostaszewski M, et al. The gut microbiome molecular complex in human health and disease. Cell Host Microbe 2022; 30: 1201-6.
De Saedeleer B, Malabirade A, Ramiro-Garcia J, et al. Systematic characterization of human gut microbiome-secreted molecules by integrated multi-omics. ISME Commun 2021; 1: 82.
Greenhalgh K, Meyer KM, Aagaard KM, et al. The human gut microbiome in health: establishment and resilience of microbiota over a lifetime. Environ Microbiol 2016; 18: 2103-16.
Hall AB, Tolonen AC, Xavier RJ. Human genetic variation and the gut microbiome in disease. Nat Rev Genet 2017; 18: 690-9.
Baldini F, Hertel J, Sandt E, et al. Parkinson's disease-associated alterations of the gut microbiome predict disease-relevant changes in metabolic functions. BMC Biol 2020; 18: 62.
Yoo J, Groer M, Dutra S, et al. Gut microbiota and immune system interactions. Microorganisms 2020; 8: 1587.
Sonnenburg JL, Bäckhed F. Diet-microbiota interactions as moderators of human metabolism. Nature 2016; 535: 56-64.
Zmora N, Suez J, Elinav E. You are what you eat: diet, health and the gut microbiota. Nat Rev Gastroenterol Hepatol 2019; 16: 35-56.
Guo Q, Wang Y, Xu D, et al. Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies. Bone Res 2018; 6: 15.
Healthline VL. Rheumatoid arthritis by the numbers: facts, statistics, and you; 2021.
Scherer HU, Häupl T, Burmester GR. The etiology of rheumatoid arthritis. J Autoimmun 2020; 110: 102400.
Bodkhe R, Balakrishnan B, Taneja V. The role of microbiome in rheumatoid arthritis treatment. Ther Adv Musculoskelet Dis 2019; 11: 1759720X19844632.
Chen J, Wright K, Davis JM, et al. An expansion of rare lineage intestinal microbes characterizes rheumatoid arthritis. Genome Med 2016; 8: 43.
Kitamura K, Shionoya H, Suzuki S, et al. Oral and intestinal bacterial substances associated with disease activities in patients with rheumatoid arthritis: a cross-sectional clinical study. J Immunol Res 2022; 2022: 6839356.
Wu H-J, Ivanov II, Darce J, et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 2010; 32: 815-27.
Scher JU, Sczesnak A, Longman RS, et al. Expansion of intestinal prevotella copri correlates with enhanced susceptibility to arthritis. Elife 2013; 2: e01202.
Zhang X, Zhang D, Jia H, et al. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat Med 2015; 21: 895-905.
Lubomski M, Tan AH, Lim S-Y, et al. Parkinson's disease and the gastrointestinal microbiome. J Neurol 2020; 267: 2507-23.
Opara J, Małecki A, Małecka E, et al. Motor assessment in Parkinson's disease. Ann Agric Environ Med 2017; 24: 411-5.
Tysnes OB, Storstein A. Epidemiology of Parkinson's disease. J Neural Transm (Vienna) 2017; 124: 901-5.
Garcia P, Jürgens-Wemheuer W, Uriarte Huarte O, et al. Neurodegeneration and neuroinflammation are linked, but independent of alpha-synuclein inclusions, in a seeding/spreading mouse model of Parkinson's disease. Glia 2022; 70: 935-60.
Heintz-Buschart A, Wilmes P. Human gut microbiome: function matters. Trends Microbiol 2018; 26: 563-74.
Romano S, Savva GM, Bedarf JR, et al. Meta-analysis of the Parkinson's disease gut microbiome suggests alterations linked to intestinal inflammation. NPJ Parkinsons Dis 2021; 7: 27.
Becker A, Schmartz GP, Gröger L, et al. Effects of resistant starch on symptoms, fecal markers, and gut microbiota in Parkinson's disease-the RESISTA-PD trial. Genom Proteom Bioinform 2022; 20: 274-87.
Hall DA, Voigt RM, Cantu-Jungles TM, et al. An open label, non-randomized study assessing a Prebiotic fiber intervention in a small cohort of Parkinson's disease participants. Nat Commun 2023; 14: 926.
Mertsalmi TH, Aho VTE, Pereira PAB, et al. More than constipation-bowel symptoms in Parkinson's disease and their connection to gut microbiota. Eur J Neurol 2017; 24: 1375-83.
Dogra N, Mani RJ, Katare DP. The gut-brain axis: two ways signaling in Parkinson's disease. Cell Mol Neurobiol 2022; 42: 315-32.
Forsyth CB, Shannon KM, Kordower JH, et al. Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson's disease. PLoS One 2011; 6: e28032.
Devos D, Lebouvier T, Lardeux B, et al. Colonic inflammation in Parkinson's disease. Neurobiol Dis 2013; 50: 42-8.
Britannica. "The editors of encyclopaedia. "fasting". encyclopedia Britannica". Available: https://www.britannica.com/topic/fasting [Accessed. 03 Oct 2022].
Hartmann AM, Dell'Oro M, Kessler CS, et al. Efficacy of therapeutic fasting and plant-based diet in patients with rheumatoid arthritis (Nutrifast): study protocol for a randomised controlled clinical trial. BMJ Open 2021; 11: e047758.
Michalsen A. Prolonged fasting as a method of mood enhancement in chronic pain syndromes: a review of clinical evidence and mechanisms. Curr Pain Headache Rep 2010; 14: 80-7.
Vargas-Molina S, Carbone L, Romance R, et al. Effects of a low-carbohydrate Ketogenic diet on health parameters in resistance-trained women. Eur J Appl Physiol 2021; 121: 2349-59.
Mattison JA, Colman RJ, Beasley TM, et al. Caloric restriction improves health and survival of rhesus monkeys. Nat Commun 2017; 8: 14063.
Maifeld A, Bartolomaeus H, Löber U, et al. Fasting alters the gut microbiome reducing blood pressure and body weight in metabolic syndrome patients. Nat Commun 2021; 12: 1970.
Choi IY, Piccio L, Childress P, et al. A diet mimicking fasting promotes regeneration and reduces autoimmunity and multiple sclerosis symptoms. Cell Reports 2016; 15: 2136-46.
Jordan S, Tung N, Casanova-Acebes M, et al. Dietary intake regulates the circulating inflammatory monocyte pool. Cell 2019; 178: 1102-14.
Neth BJ, Bauer BA, Benarroch EE, et al. The role of intermittent fasting in Parkinson's disease. Front Neurol 2021; 12: 682184.
Cignarella F, Cantoni C, Ghezzi L, et al. Intermittent fasting confers protection in CNS autoimmunity by altering the gut microbiota. Cell Metab 2018; 27: 1222-35.
Mesnage R, Grundler F, Schwiertz A, et al. Changes in human gut microbiota composition are linked to the energy metabolic switch during 10 d of Buchinger fasting. J Nutr Sci 2019; 8: e36.
Magne F, Gotteland M, Gauthier L, et al. The Firmicutes/Bacteroidetes ratio: a relevant marker of gut dysbiosis in obese patients Nutrients 2020; 12: 1474.
Purchiaroni F, Tortora A, Gabrielli M, et al. The role of intestinal microbiota and the immune system. Eur Rev Med Pharmacol Sci 2013; 17: 323-33.
Leeming ER, Johnson AJ, Spector TD, et al. Effect of diet on the gut microbiota: Rethinking intervention duration. Nutrients 2019; 11: 2862.
Heintz-Buschart A, May P, Laczny CC, et al. Integrated multi-omics of the human gut microbiome in a case study of familial type 1 diabetes. Nat Microbiol 2016; 2: 16227.
Narayanasamy S, Jarosz Y, Muller EEL, et al. IMP: a pipeline for reproducible reference-independent integrated metagenomic and metatranscriptomic analyses. Genome Biol 2016; 17: 260.
Wilmes P, Heintz-Buschart A, Bond PL. A decade of metaproteomics: where we stand and what the future holds. Proteomics 2015; 15: 3409-17.
Gabel K, Hoddy KK, Haggerty N, et al. Effects of 8-hour time restricted feeding on body weight and metabolic disease risk factors in obese adults: a pilot study. Nutr Healthy Aging 2018; 4: 345-53.
Hughes AJ, Daniel SE, Blankson S, et al. A clinicopathologic study of 100 cases of Parkinson's disease. Arch Neurol 1993; 50: 140-8.
Hoehn MM, Yahr MD. Parkinsonism. onset, progression, and mortality. Neurology 1967; 17: 427-42.
Kay J, Upchurch KS. ACR/EULAR 2010 rheumatoid arthritis classification criteria. Rheumatology (Oxford) 2012; 51 Suppl 6: vi5-9.
Feng X, Xu X, Shi Y, et al. Body mass index and the risk of rheumatoid arthritis: an updated dose-response meta-analysis. Biomed Res Int 2019; 2019: 3579081.
Harris PA, Taylor R, Thielke R, et al. Research electronic data capture (Redcap)-A metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009; 42: 377-81.
Wilmes P, Roume H, Hiller K, et al. Method and kit for the isolation of genomic DNA, RNA, proteins and metabolites from a single biological sample. In: World intellectual property organization. Switzerland: C.D.R.P.-G.L. Université Du Luxembourg, 2014.
Roume H, EL Muller E, Cordes T, et al. A biomolecular isolation framework for ECO-systems biology. ISME J 2013; 7: 110-21.
Locati MD, Terpstra I, de Leeuw WC, et al. Improving small RNA-Seq by using a synthetic spike-in set for size-range quality control together with a set for data normalization. Nucleic Acids Res 2015; 43: e89.
Wampach L, Heintz-Buschart A, Fritz JV, et al. Birth mode is associated with earliest strain-conferred gut microbiome functions and Immunostimulatory potential. Nat Commun 2018; 9: 5091.
Albanese D, Donati C. Strain profiling and epidemiology of bacterial species from metagenomic sequencing. Nat Commun 2017; 8: 2260.
Vandeputte D, Kathagen G, D'hoe K, et al. Quantitative microbiome profiling links gut community variation to microbial load. Nature 2017; 551: 507-11.
Tang H, Li S, Ye Y. A graph-centric approach for metagenome-guided peptide and protein identification in metaproteomics. PLoS Comput Biol 2016; 12: e1005224.
Tabb DL, Fernando CG, Chambers MC. Myrimatch: highly accurate tandem mass spectral peptide identification by multivariate hypergeometric analysis. J Proteome Res 2007; 6: 654-61.
Heintz-Buschart A, Pandey U, Wicke T, et al. The nasal and gut microbiome in Parkinson's disease and idiopathic rapid eye movement sleep behavior disorder. Mov Disord 2018; 33: 88-98.
Chen SG, Stribinskis V, Rane MJ, et al. Exposure to the functional bacterial Amyloid protein Curli enhances alpha-Synuclein aggregation in aged Fischer 344 rats and Caenorhabditis Elegans. Sci Rep 2016; 6: 34477.
Wilmes P, Bowen BP, Thomas BC, et al. Metabolome-proteome differentiation coupled to microbial divergence. mBio 2010; 1: e00246-10.
Kim D-H, Achcar F, Breitling R, et al. LC-MS-based absolute metabolite quantification: application to metabolic flux measurement in trypanosomes. Metabolomics 2015; 11: 1721-32.
Lei Z, Huhman DV, Sumner LW. Mass spectrometry strategies in metabolomics. J Biol Chem 2011; 286: 25435-42.
IMPACC Manuscript Writing Team, IMPACC Network Steering Committee. Immunophenotyping assessment in a COVID-19 cohort (IMPACC): a prospective longitudinal study. Sci Immunol 2021; 6: eabf3733.
Shah P, Fritz JV, Glaab E, et al. A microfluidics-based in vitro model of the gastrointestinal human-microbe interface. Nat Commun 2016; 7: 11535.
Aho VTE, Ostaszewski M, Martin-Gallausiaux C, et al. Snapshot: the expobiome map. Cell Host Microbe 2022; 30: 1340.
Tusher VG, Tibshirani R, Chu G. Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci U S A 2001; 98: 5116-21.
Finnell JS, Saul BC, Goldhamer AC, et al. Is fasting safe? A chart review of adverse events during medically supervised, water-only fasting. BMC Complement Altern Med 2018; 18: 67.
Chan A-W, Tetzlaff JM, Gøtzsche PC, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ 2013; 346: e7586.
Wells G, Becker J-C, Teng J, et al. Validation of the 28-joint disease activity score (Das28) and European league against rheumatism response criteria based on C-reactive protein against disease progression in patients with rheumatoid arthritis, and comparison with the DAS28 based on Erythrocyte sedimentation rate. Ann Rheum Dis 2009; 68: 954-60.
Trenkwalder C, Kohnen R, Högl B, et al. Parkinson's disease sleep scale-validation of the revised version PDSS-2. Mov Disord 2011; 26: 644-52.
Bushnell DM, Martin ML. Quality of life and Parkinson's disease: translation and validation of the US Parkinson's disease questionnaire (PDQ-39). Qual Life Res 1999; 8: 345-50.
Smolen JS, Breedveld FC, Schiff MH, et al. A simplified disease activity index for rheumatoid arthritis for use in clinical practice. Rheumatology (Oxford) 2003; 42: 244-57.
Raspe HH, Hagedorn U, Kohlmann T, et al. Der Funktionsfragebogen Hannover (FFbH): ein instrument Zur Funktionsdiagnostik BEI Polyartikulären Gelenkerkrankungen. In: Ergebnisse sozialwissenschaftlicher Evaluation eines Modellversuchs. Schattauer Verlag, 1990: 164-82.
Goetz CG, Fahn S, Martinez-Martin P, et al. Movement disorder society-sponsored revision of the unified Parkinson's disease rating scale (MDS-UPDRS): process, format, and clinimetric testing plan. Mov Disord 2007; 22: 41-7.
Chaudhuri KR, Martinez-Martin P, Schapira AHV, et al. International multicenter pilot study of the first comprehensive self-completed nonmotor symptoms questionnaire for Parkinson's disease: the NMSQuest study. Mov Disord 2006; 21: 916-23.
Chaudhuri KR, Martinez-Martin P, Brown RG, et al. The metric properties of a novel non-motor symptoms scale for Parkinson's disease: results from an international pilot study. Mov Disord 2007; 22: 1901-11.
Wolfe F. A brief clinical health assessment instrument Clinhaq, 32. Arthritis and Rheumatism, 1989: S99.
Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol 1997; 32: 920-4.
Topp CW, Østergaard SD, Søndergaard S, et al. The WHO-5 well-being index: a systematic review of the literature. Psychother Psychosom 2015; 84: 167-76.
Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983; 67: 361-70.
McNair DM, Lorr M, Droppleman LF. Edits manual for the profile of mood states (Poms), Rev ed. San Diego: Educational and Industrial Testing Service, 1992.
