The ExpoBiome project will analyze the impact of fasting on patients with Parkinsons's Disease (PD) or rheumatoid arthritis (RA) on a clinical level as well as the effect of fasting on their immune system and gut microbiota. ExpoBiome will combine metagenomics and other "omics" \[meta-transcriptomics, meta-proteomics and (meta-)metabolomics\], bioinformatic analyses and biostatistics under a systems biology framework to gain new mechanistic insights into microbiome-immune system interactions in the context of chronic diseases with inflammatory signatures. Besides a one time crossectional study of healthy participants, patients with RA and PD a longitudinal fasting study with two arms (RA and PD) is planned.
The human gut microbiome is a complex ecosystem, which contributes essential functions to human physiology. Changes to the microbiome are associated with several chronic diseases characterised by inflammation, including neurodegenerative and autoimmune diseases. Microbiome-derived effector molecules comprising nucleic acids, (poly)peptides and metabolites are present at high levels in the gut but have so far eluded systematic study. This gap in knowledge is limiting mechanistic understanding of the microbiome's functional impact on chronic diseases such as Parkinson's Disease (PD) and rheumatoid arthritis (RA). Here, for the first time a combination of advanced high-resolution methodologies will be integrated to comprehensively identify the constituents of this molecular complex and their impact on the human immune system. First, a quantitative, integrated multi-omic analysis on microbiome samples collected from healthy individuals and patients with newly diagnosed PD or RA will be performes. Using contextualised prior knowledge (ExpoBiome Map) and machine learning methods, we will identify microbial molecules associated with condition-specific immunophenotypes. Second, the biomarker signature during a model clinical intervention (therapeutic fasting) will be validated and tracked to predict treatment outcomes. Third, microbes and molecules will be screened in personalised HuMiX gut-on-chip models to identify novel anti-inflammatory compounds. By providing mechanistic insights into the molecular basis of human-microbiome interactions, the project will generate essential new knowledge about causal relationships between the gut microbiome and the immune system in health and disease. By facilitating the elucidation of currently unknown microbiome-derived molecules, it will identify new genes, proteins,metabolites and host pathways for the development of future diagnostic and therapeutic applications.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
HEALTH_SERVICES_RESEARCH
Masking
NONE
Enrollment
183
Patients undergo a 5-10 day fasting period with a dietary energy supply 350-400kcal per day with fruit and vegetable juices or, if not feasible, an established fasting-mimicking diet of 600-800 kcal according to Longo et al.
Paracelsus-Elena-Klinik Kassel
Kassel, Hesse, Germany
Charité Hochschulambulanz für Naturheilkunde am Immanuel Krankenhaus
Berlin, Germany
Gut microbiota Characterization
Molecular typing of the gut microbiota using sequencing and high-throughput analysis from stool samples (metagenomics, metatranscriptomics, metaproteomics, metabolomics)
Time frame: Change over baseline to 12 months
Resting blood pressure
Time frame: Change over baseline to 12 months
Heart rate
Time frame: Change over baseline to 12 months
Abdominal circumference
Time frame: Change over baseline to 12 months
Waist to Hip Ratio
Time frame: Change over baseline to 12 months
Body Mass Index (kg/m2)
Time frame: Change over baseline to 12 months
Disease Activity Score 28 (DAS-28-CRP)
Change from Baseline in the DAS-28-CRP, range from 2.0 to 10.0 while higher values meaning a higher disease activity and below of 2.6 meaning remission
Time frame: Change over baseline to 12 months
Health Assessement Questionnaire (HAQ)
Change from Baseline in the HAQ, range from 0 to 3 while higher values meaning a higher grade of disability
Time frame: Change over baseline to 12 months
Simplified Disease Activity Index Score (SDAI)
Change from Baseline in the SDAI, range from 0 to 86 with assumed range from 0.1 to 10mg/dL for CRP. Higher values mean a higher disease activity and below of 34 meaning remission.
Time frame: Change over baseline to 12 months
Hannover Functional Ability Questionnaire (Funktionsfragebogen Hannover, FFbH-R)
Change from Baseline in the FFbH-R, range from 0 to 100 % while higher values meaning a higher grade of functional capacity
Time frame: Change over baseline to 12 months
MDS-UPDRS
Movement Disorders Society-sponsored revision of the Unified Parkinson's Disease Rating Scale part I, II, IV (MDS-UPDRS part I, II, IV). Total score range: 0-260 (including the MDS-UPDRS part III), including 4 subcategories. Subcategories are summed to compute the total score. A lower score means a better outcome.
Time frame: Change over baseline to 12 months
Parkinson's Disease Sleep Scale-2 (PDSS-2)
The Parkinson's Disease Sleep Scale 2 (PDSS-2) is designed to assess nocturnal disability in Parkinson's disease. The PDSS-2 is a 15 question analog scale that ranks answers from 0 - 4, with 4 being worse. (Question 1 is an exception, where 4 is better and 0 is worse). In addition to an overall assessment of sleep disability three aspects of sleep problems can be obtained; disturbed sleep (total of questions 1-3, 8 and 14), PD-specific nocturnal motor symptoms (total of questions 4-6, 12 and 13), and PD-specific nocturnal symptoms (Total of questions 7, 9-11 and 15).
Time frame: Change over baseline to 12 months
Parkinson's Disease Questionnaire-39 (PDQ-39)
The 39 question Parkinson's Disease Questionnaire (PDQ-39) is a patient-reported rating scale for quality of life in Parkinson's disease. Respondents affirm if they have experienced problems due to their disease using a five point scale from never (0 points) to always (4 points, or worse) in doing common activities. The PDQ-39 is comprised of 8 domains: mobility, emotion, activities of daily living, cognition, stigma, social support, communication, bodily discomfort. Total possible range of scores = 0 - 156, with higher scores representing worse severity.
Time frame: Change over baseline to 12 months
Non-motor symptoms questionnaire (NMSQ)
The non-motor symptoms (NMS) questionnaire can be given to people affected by Parkinson's in order to aid health and social care professionals to assess their non-motor symptoms.The non-motor symptoms questionnaire is a 30-point, patient-based questionnaire used to determine the non-motor symptoms experienced by the patient during the past month. The points should be totalled to give a score out of 30. A score of under 10 is mild, 10-20 moderate and over 20, severe.
Time frame: Change over baseline to 12 months
Non Motor Symptoms Scale (NMSS)
The Non-Motor Symptoms Scale (NMSS) measures the frequency and severity of a range of non-motor symptoms in Parkinson's Disease, through 30 questions grouped into 9 domains: cardiovascular, sleep/fatigue, mood/cognition, perceptual problems/hallucinations, attention/memory, gastro-intestinal tract, urinary, sexual function, and miscellaneous (pain, taste/smell, weight change, excessive sweating). Severity is rated on a scale from 0 (none) to 3 (severe). Frequency is rated on a scale from 1 (rarely) to 4 (very frequent). Item scores are calculated as the product of severity and frequency; the total score is obtained by summing the item scores. The NMSS total score ranges from 0 to 360 with a lower score indicating fewer symptoms. A negative change from baseline indicates improvement in symptoms (reduced score).
Time frame: Change over baseline to 12 months
Stress questionnaire (Cohen Perceived Stress Scale, CPSS)
Change from Baseline in the CPSS, range from 0 to 4 in each item. Scores are obtained by reversing responses (e.g., 0 = 4, 1 = 3, 2 = 2, 3 = 1 \& 4 = 0) to the positively stated items and then summing across all scale items, higher values meaning a higher grade of perceived stress.
Time frame: Change over baseline to 12 months
Quality of Life questionnaire (WHO-5)
Change from Baseline in the WHO-5, range from 0 to 100 %, higher values meaning a higher grade of well-being
Time frame: Change over baseline to 12 months
Hospital Anxiety and Depression Scale (HADS)
Assessing full scale, range 0-42, lower score meaning a better outcome
Time frame: Change over baseline to 12 months
Mood questionnaire (Profile of Mood States, POMS)
Change from Baseline in Emotional Distress will be measured using the German Version of the Profile of Mood States (ASTS) short version (19 items, 7-point Likert scale; 0=not at all, 6=extremely). Lower scores indicate more stable mood profiles.
Time frame: Change over baseline to 12 months
Sociodemographic Measurements
Age, gender, education level, household income, employment status, marital status, language spoken, complete family history, current and previous illness and co-morbidities, and current medications
Time frame: Baseline
Behavioral Factors
Physical inactivity, coffee, health promoting activities via Likert Scales, range from 0 to 5 while higher values meaning a higher grade of agreement
Time frame: Change over baseline to 12 months
Dietary Behaviour
Modified FFQ recording dietary behaviour such as mealtimes, frequency of food intake, food preferences, fasting experiences
Time frame: Change over baseline to 12 months
Behavioral Factors: alcohol consumption
Number of alcoholic beverages on average per week in the last month
Time frame: Change over baseline to 12 months
Behavioral Factors: smoking
Smoking status in packyears
Time frame: Baseline
Expectation questions
For fasting on a 5-point likert scale from 1 (nothing at all) to 5 (very strong)
Time frame: Baseline
Differential blood count
Time frame: Change over baseline to 12 months
Hepatic transaminases (GPT, GOT) and Gamma glutamyl transpeptidase (y-GT)
GPT in units per liter (U/L) GOT (U/L) y-GT (U/L)
Time frame: Change over baseline to 12 months
Bilirubine (total, direct, indirect in mg/dL)
Time frame: Change over baseline to 12 months
Total protein in grams per liter (g/L)
Time frame: Change over baseline to 12 months
Albumine in grams per liter (g/L)
Time frame: Change over baseline to 12 months
Creatinine in µmol per liter (µmol/L)
Time frame: Change over baseline to 12 months
Estimated glomerular filtration rate (eGFR) in milliliter per minute (mL/min)
Time frame: Change over baseline to 12 months
Alcalic Phosphatase in units per liter (U/L)
Time frame: Change over baseline to 12 months
Urea in milligrams per deciliter (mg/dL)
Time frame: Change over baseline to 12 months
Blood lipids and fasting glucose
* triglycerides (mmol/L) * total cholesterol (mmol/L) * LDL (mmol/L) * HDL (mmol/L) * fasting glucose (mmol/L)
Time frame: Change over baseline to 12 months
HbA1C (mmol/mol Hb, %)
Time frame: Change over baseline to 12 months
TSH (mU/L)
Time frame: Change over baseline to 12 months
IGF-1 (ng/mL)
Time frame: Change over baseline to 12 months
Insulin (mU/L)
Time frame: Change over baseline to 12 months
High sensitive CrP (mg/L)
Evaluate change in hs-CrP levels in participants with RA
Time frame: Change over baseline to 12 months
Rheumatoid factor (RF, IgM) (U/mL)
Evaluate RF status in participants with RA
Time frame: Baseline
Anti-cyclic citrullinated peptide (ACPA) (U/mL)
Evaluate change in ACPA levels in participants with RA
Time frame: Change over baseline to 12 months
Zonulin (ng/mL)
Time frame: Change over baseline to 12 months
Fatty acid binding protein 2 (FABP2) (pg/mL)
Time frame: Change over baseline to 12 months
Plasma Calprotectin (µg/g)
Time frame: Change over baseline to 12 months
Fecal Calprotectin (µg/g)
Time frame: Change over baseline to 12 months
Phenotyping of immune cells
Determination of cytometric parameters that indicate changes in cell activation or quantitative changes in the absolute and/or relative size of subpopulations (e.g. classical/intermediate/non-classical monocytes, naïve and memory T-cells, B-cell differentiation to plasmablasts/-cells) Gene expression analysis of immune cells with Affymetrix whole genome microarrays and RNAseq to search for transcriptional patterns and markers that help to identify relevant immune cell (sub-)populations, which are not yet included in the cytometric phenotyping screen
Time frame: Change over baseline to 12 months
Urine metabolomics (10 ml midstream urine)
Time frame: Change over baseline to 12 months
Oral microbiota analysis in saliva
Time frame: Change over baseline to 12 months
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