Deciphering the Impact of Exposures From the Gut Microbiome-derived Molecular Complex in Human Health and Disease

Healthy Clinical Trial

— ExpoBiome  

Official title:

Deciphering the Impact of Exposures From the Gut Microbiome-derived Molecular Complex in Human Health and Disease

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04847011
• Other study ID #: ExpoBiome
• Status: Completed
• Phase: N/A
• Start date: April 21, 2021
• Est. completion date: September 26, 2023

Study information

• Verified date: January 2024
• Source: Charite University, Berlin, Germany
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 183
• Est. completion date: September 26, 2023
• Est. primary completion date: September 26, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 79 Years

Eligibility

Inclusion Criteria:

• One of the following diagnoses: rheumatoid arthritis (first diagnosis >6 weeks ago and <8 years), parkinson's disease OR healthy volunteer
• Control ("healthy") individuals must be without any evidence of active, known or treated RA, without any evidence of active, known or treated central nervous system disease, and without a known family history of idiopathic PD
• Arthritis in at least one joint
• Control individuals should match the RA or PD individuals as closely as possible, especially their age, sex, and education
• Present written declaration of consent
• Consent to specimen collection and specimen use
• Ability to understand the patient information and willingness to sign the consent form

Exclusion Criteria:

• gout or proven bacterial arthritis
• Psychiatric illness that limits understanding of the examination protocol (unable to consent)
• BMI < 18.5
• Pre-existing/current eating disorders (bulimia nervosa, anorexia nervosa) within the past 5 years.
• Severe internal diseases (e.g. renal insufficiency with creatinine > 2mg/dl)
• Participation in another study
• Existing vegan diet or fasting within the past 6 months
• Pregnancy or breastfeeding
• Chronic inflammatory bowel disease
• Use of antibiotics within the past 12 months
• Presence of anemia

Related Conditions & MeSH terms

• Healthy
• Parkinson Disease
• Rheumatoid Arthritis

Intervention

Other:
• Fasting
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.

Locations

Country	Name	City	State
Germany	Charité Hochschulambulanz für Naturheilkunde am Immanuel Krankenhaus	Berlin
Germany	Paracelsus-Elena-Klinik Kassel	Kassel	Hessen

Sponsors (3)

Lead Sponsor	Collaborator
Andreas Michalsen	Luxembourg Centre for Systems Biomedicine, Paracelsus-Elena-Klinik Kassel

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Gut microbiota Characterization	Molecular typing of the gut microbiota using sequencing and high-throughput analysis from stool samples (metagenomics, metatranscriptomics, metaproteomics, metabolomics)	Change over baseline to 12 months
Secondary	Resting blood pressure		Change over baseline to 12 months
Secondary	Heart rate		Change over baseline to 12 months
Secondary	Abdominal circumference		Change over baseline to 12 months
Secondary	Waist to Hip Ratio		Change over baseline to 12 months
Secondary	Body Mass Index (kg/m2)		Change over baseline to 12 months
Secondary	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	Change over baseline to 12 months
Secondary	Health Assessement Questionnaire (HAQ)	Change from Baseline in the HAQ, range from 0 to 3 while higher values meaning a higher grade of disability	Change over baseline to 12 months
Secondary	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.	Change over baseline to 12 months
Secondary	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	Change over baseline to 12 months
Secondary	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.	Change over baseline to 12 months
Secondary	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).	Change over baseline to 12 months
Secondary	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.	Change over baseline to 12 months
Secondary	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.	Change over baseline to 12 months
Secondary	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).	Change over baseline to 12 months
Secondary	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.	Change over baseline to 12 months
Secondary	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	Change over baseline to 12 months
Secondary	Hospital Anxiety and Depression Scale (HADS)	Assessing full scale, range 0-42, lower score meaning a better outcome	Change over baseline to 12 months
Secondary	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.	Change over baseline to 12 months
Secondary	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	Baseline
Secondary	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	Change over baseline to 12 months
Secondary	Dietary Behaviour	Modified FFQ recording dietary behaviour such as mealtimes, frequency of food intake, food preferences, fasting experiences	Change over baseline to 12 months
Secondary	Behavioral Factors: alcohol consumption	Number of alcoholic beverages on average per week in the last month	Change over baseline to 12 months
Secondary	Behavioral Factors: smoking	Smoking status in packyears	Baseline
Secondary	Expectation questions	For fasting on a 5-point likert scale from 1 (nothing at all) to 5 (very strong)	Baseline
Secondary	Differential blood count		Change over baseline to 12 months
Secondary	Hepatic transaminases (GPT, GOT) and Gamma glutamyl transpeptidase (y-GT)	GPT in units per liter (U/L) GOT (U/L) y-GT (U/L)	Change over baseline to 12 months
Secondary	Bilirubine (total, direct, indirect in mg/dL)		Change over baseline to 12 months
Secondary	Total protein in grams per liter (g/L)		Change over baseline to 12 months
Secondary	Albumine in grams per liter (g/L)		Change over baseline to 12 months
Secondary	Creatinine in µmol per liter (µmol/L)		Change over baseline to 12 months
Secondary	Estimated glomerular filtration rate (eGFR) in milliliter per minute (mL/min)		Change over baseline to 12 months
Secondary	Alcalic Phosphatase in units per liter (U/L)		Change over baseline to 12 months
Secondary	Urea in milligrams per deciliter (mg/dL)		Change over baseline to 12 months
Secondary	Blood lipids and fasting glucose	triglycerides (mmol/L); total cholesterol (mmol/L); LDL (mmol/L); HDL (mmol/L); fasting glucose (mmol/L)	Change over baseline to 12 months
Secondary	HbA1C (mmol/mol Hb, %)		Change over baseline to 12 months
Secondary	TSH (mU/L)		Change over baseline to 12 months
Secondary	IGF-1 (ng/mL)		Change over baseline to 12 months
Secondary	Insulin (mU/L)		Change over baseline to 12 months
Secondary	High sensitive CrP (mg/L)	Evaluate change in hs-CrP levels in participants with RA	Change over baseline to 12 months
Secondary	Rheumatoid factor (RF, IgM) (U/mL)	Evaluate RF status in participants with RA	Baseline
Secondary	Anti-cyclic citrullinated peptide (ACPA) (U/mL)	Evaluate change in ACPA levels in participants with RA	Change over baseline to 12 months
Secondary	Zonulin (ng/mL)		Change over baseline to 12 months
Secondary	Fatty acid binding protein 2 (FABP2) (pg/mL)		Change over baseline to 12 months
Secondary	Plasma Calprotectin (µg/g)		Change over baseline to 12 months
Secondary	Fecal Calprotectin (µg/g)		Change over baseline to 12 months
Secondary	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	Change over baseline to 12 months
Secondary	Urine metabolomics (10 ml midstream urine)		Change over baseline to 12 months
Secondary	Oral microbiota analysis in saliva		Change over baseline to 12 months