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| Name | Class |
|---|---|
| University of Copenhagen | OTHER |
| University of Southampton | OTHER |
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The goal of this pilot intervention trial is to investigate the biological effects of daily supplementation with different doses of indole-3-propionic acid (IPA) in healthy adults. The main scientific questions are:
Participants will:
Indole-3-propionic acid (IPA) is a gut bacterial metabolite with the amino acid tryptophan as substrate. In vitro and animal studies, suggest that IPA could contribute to regulating inflammation and metabolic function, preventing oxidative damage and upregulating expression of brain-derived neurotrophic factor. With this study we aim to investigate the biochemical effects of IPA at supraphysiological levels in humans.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo | Placebo Comparator | Placebo |
|
| 50 mg IPA | Experimental | 50 mg indole-3-propionic acid |
|
| 120 mg IPA | Experimental | 120 mg indole-3-propionic acid |
|
| 500 mg IPA | Experimental | 500 mg indole-3-propionic acid |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Indole-3-propionic acid | Dietary Supplement | A dosis of either 50 mg IPA, 120 mg IPA or 500 mg IPA (two capsules) will be taken orally, once daily in the morning after an overnight fast for 14 consecutive days. |
| Measure | Description | Time Frame |
|---|---|---|
| Regulatory T cells (first primary outcome) | FoxP3+CD25+CD127- regulatory T cells expressed as a percentage of single, live CD3+CD4+CD8- lymphocytes. Analysed in freshly isolated peripheral blood mononuclear cells using a Symphony A3 flowcytometer. | Results from fasting blood samples taken on day 15 and adjusted for results from day 1 (fasting just before first supplement/placebo dosis). |
| Brain-derived neurotrophic factor (second primary outcome) | Brain-derived neurotrophic factor measured in plasma samples using ELISA or mesoscale. | Results from fasting blood samples taken on day 15 and adjusted for results from day 1 (fasting just before first supplement/placebo dosis). |
| Measure | Description | Time Frame |
|---|---|---|
| Flowcytometric profiling of T cells | T cell profiling of freshly isolated peripheral blood mononuclear cells using a Symphony A3 flowcytometer. Panel antigens: CD3, CD4, CD8, CD45RA, CCR7, CXCR3, CCR6, CCR4, CCR10, CD25, CD127, FoxP3. Target populations Th1: CXCR3+CCR4-CCR6-CCR10- Th2: CXCR3-CCR4+CCR6-CCR10- Th17: CXCR3-CCR4+CCR6+CCR10- Th17.1: CXCR3+CCR4-CCR6+CCR10- Th22: CXCR3-CCR4+CCR6+CCR10+ all of the above expressed as a percentage of single, live CD3+CD4+CD8-CD45RA- lymphocytes. Furthermore, Th1/Th2 and Th17/Treg ratios will be calculated and the expression of CCR7 will be analysed within the target populations. In addition, the expression of the above chemokine receptors will be explored within the population of FoxP3+CD25+C1D127- T regulatory cells. This will allow for monitoring of newly identified T cells subsets such as Th1-like Tregs. Lastly, an untargetted approach may be employed to allow for unbiased identification of changes in novel, yet uncharacterized populations. |
| Measure | Description | Time Frame |
|---|---|---|
| Gastrointestinal comfort | Self-reported (questionnaire) gastrointestinal symptoms of bloating, pain, rumbling, flatulence, constipation, hard stools and diarrhea evaluated using a visual analogue scale as well as a question on the frequency of defecation. | Gastrointestinal symptoms are assessed on day 1 and day 15. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jette Lautrup Frederiksen, Prof, DMSc, MD | Jette Lautrup Frederiksen | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Optic Neuritis Clinic, Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet-Glostrup | Glostrup Municipality | 2600 | Denmark |
Individual participant data that underlie the results reported in published articles, after deidentification (text, tables, figures, and appendices).
Beginning 3 months and ending 5 years following publication of the article they are presented in.
Researchers who provide a methodologically sound proposal can access the IPD to achieve the aims of the approved proposal. Proposals should be directed to jette.lautrup.battistini@regionh.dk. To gain access, data requestors will need to sign a data access agreement. Data and explanatory files will be made available at a third party website.
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| SAP | No | Yes | No | Statistical Analysis Plan | Feb 25, 2025 | Mar 1, 2025 | SAP_000.pdf |
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Randomization is performed by external party. Each capsule bottle is named with a unique number (1-96) and no other identifier. Capsule bottles have already been randomized by the external party using block randomization with random block sizes of 4 or 8. Study participants receive the next available capsule bottle based on their order of recruitment. This way, everyone involved in the study is fully blinded and it is also impossible to guess which participants belong to the same group. Only after all study participants have been recruited and the collected data have been cleaned and quality checked, are the researchers performing the statistical analyses informed about which participants belong to the same group as well as the identity of the groups. This is a prerequisite for performance of statistical analyses, as the primary analysis is defined as the comparison between the group with the highest treatment dose and placebo.
| Placebo | Dietary Supplement | Two capsules of placebo will be taken orally, once daily in the morning after an overnight fast for 14 consecutive days. |
|
| Results from fasting blood samples taken on day 15 and adjusted for results from day 1 (fasting just before first supplement/placebo dosis). |
| CRP | C-reactive protein (CRP) measured in plasma (mg/L) as a biomarker of infection and systemic inflammation. Lower-limit of quantification: 0,4 mg/L. Values below 0,4 mg/L are imputed as 0,2 mg/L. | Results from blood samples taken on day 15 (just before last supplement/placebo dosis) and adjusted for results from day 1 (just before first supplement/placebo dosis). |
| Triglycerides | Plasma triglycerides (mmol/l). | Results from fasting blood samples taken on day 15 and adjusted for results from day 1 (fasting just before first supplement/placebo dosis). |
| non-HDL cholesterol | Non-HDL cholesterol calculated as total cholesterol minus HDL cholesterol (mmol/l) | Results from fasting blood samples taken on day 15 and adjusted for results from day 1 (fasting just before first supplement/placebo dosis). |
| C-peptide | Proinsulin C-peptide (pmol/l) measured in plasma. | Results from fasting blood samples taken on day 15 and adjusted for results from day 1 (fasting just before first supplement/placebo dosis). |
| Fasting glucose | Plasma glucose (mmol/l). Participants abstain from eating and drinking after 22.00 the day before. Only water is allowed. Fasting blood samples are taken between 8.00-10.00 in the morning. | Results from fasting blood samples taken on day 15 and adjusted for results from day 1 (fasting just before first supplement/placebo dosis). |
| Isoprostane-F2-alpha | Isoprostane-F2-alpha measured in blood or morningurine samples as a marker of lipid oxidation. | Results from samples taken on day 15 and adjusted for results from day 1. |
| 8-oxo-dG | 8-oxo-dG (8-Oxo-2'-deoxyguanosine) measured in blood or morningurine samples as a marker of DNA-related stress damage. | Results from samples taken on day 15 and adjusted for results from day 1. |
| Serum metabolomics | Targetted and untargetted liquid-chromatography mass-spectrometry-based metabolomics of serum samples. Targetted analyses aim to quantify indole-3-propionic acid and its metabolites (biomarker of compliance as well as absorptive and metabolic capacity), other bacterial- and host metabolites of tryptophan as well as short-chain fatty acids. | Four samples in total. Day 1 prior to and again 1.5 hour after intake of first capsule of IPA/ placeblo. Day 15 prior to and again 1.5 hour after intake of last capsule of IPA/ placebo. |
| Total cholesterol | Plasma cholesterol (mmol/l). | Results from fasting blood samples taken on day 15 and adjusted for results from day 1 (fasting just before first supplement/placebo dosis). |
| VLDL cholesterol | Plasma very low-density lipoproteins (mmol/l). | Results from fasting blood samples taken on day 15 and adjusted for results from day 1 (fasting just before first supplement/placebo dosis). |
| LDL cholesterol | Plasma low-density lipoprotein (LDL) (mmol/l). | Results from fasting blood samples taken on day 15 and adjusted for results from day 1 (fasting just before first supplement/placebo dosis). |
| HDL cholesterol | Plasma high-density lipoprotein (HDL) (mmol/l). | Results from fasting blood samples taken on day 15 and adjusted for results from day 1 (fasting just before first supplement/placebo dosis). |
| Malondialdehyde | Malondialdehyde measured in blood or morningurine samples as a marker of oxidative stress. | Results from samples taken on day 15 and adjusted for results from day 1. |
| Protein carbonyls | Protein carbonyls measured in blood or morningurine samples as a marker of protein oxidation. | Results from samples taken on day 15 and adjusted for results from day 1. |
| Glycated hemoglobin (HbA1c) | HbA1c (IFCC, mmol/mol) measured in whole blood. Estimated average glucose values (mmol/l) are also calculated automatically from HbA1c by our laboratory. | Results from fasting blood samples taken on day 15 and adjusted for results from day 1 (fasting just before first supplement/placebo dosis). |
| Changes in the gut microbiome | Characterization of the gut microbiome using molecular biology methods such as 16s rRNA sequencing. | Fecal samples are collected at three time points: prior to supplementation (earliest 48 hours prior to first visit (day 1)), short after initiation of supplementation (day 3 or soonest thereafter) and again earliest 48 hours prior to last visit. |
| Characterization of the metabolic activity of the gut microbiota | Targetted and untargetted liquid-chromatography mass-spectrometry-based metabolomics. Targetted analyses aim to quantify indole-3-propionic acid, other bacterial- and host metabolites of tryptophan as well as short-chain fatty acids. | Fecal samples are collected at three time points: prior to supplementation (earliest 48 hours prior to first visit (day 1)), short after initiation of supplementation (day 3 or soonest thereafter) and again earliest 48 hours prior to last visit. |
| Bacterial polysaccharides | Endotoxin, capsular polysaccharides or other bacterial polysaccharides measured in blood samples as biomarker of bacterial translocation across the intestinal epithelium. | Results from samples taken on day 15 and adjusted for results from day 1. |
| Pre-haptoglobin 2 | Measurement of pre-haptoglobin 2 in blood samples as a biomarker of intestinal permeability. | Results from samples taken on day 15 and adjusted for results from day 1. |
| Intestinal fatty acid binding protein | Measurements of intestinal fatty acid binding protein in blood samples as a biomarker of enterocyte damage. | Results from samples taken on day 15 and adjusted for results from day 1. |
| Citrulline | Measurement of citrulline in blood samples as a biomarker of intestinal function. | Results from samples taken on day 15 and adjusted for results from day 1. |
| Calprotectin | Calprotectin measured in fecal samples as a biomarker of intestinal inflammation. | Results from samples taken on day 15 and adjusted for results from day 1. |
| Neopterin | Neopterin measured in morningurine samples as a biomarker of systemic inflammation. | Results from samples taken on day 15 and adjusted for results from day 1. |
| suPAR | Soluble urokinase plasminogen activator receptor (suPAR) measured in blood samples. | Results from samples taken on day 15 and adjusted for results from day 1. |
| Microvesicles | Flow cytometric analyses of microvesicles/ microparticles in platelet-free plasma as biomarker of systemic inflammation. | Results from samples taken on day 15 and adjusted for results from day 1. |
| Endothelial progenitor cells | Flow cytometric analyses of endothelial progenitor cells measured in platelet-free plasma as biomarker of systemic inflammation | Results from samples taken on day 15 and adjusted for results from day 1. |
| Gastrointestinal transit time |
Measurement of transit time through the digestive system using a so-called maize test. Participants consume 100 grams of sweet maize in the morning between 5.30-10.00 while still in a fasting state. The exact date and time of consumption is registered and so is the exact date and time when maize is observed for the first time in feces. Transit time is expressed as the difference between the ingestion and fecal excretion timepoints in hours. |
| Maize is ingested five days before visit 1 and again five days before visit 2. |
| Stool consistency | Classification of stool consistency using the Bristol Stool Chart. Numerical scale ranging from 1 (separate hard lumps) to 7 (liquid consistency with no solid pieces) with one-unit increments. | Bristol stool chart is used in association with each maize test and collection of fecal samples (earliest 48 hours prior to first visit and day 3 or soonest thereafter and again earliest 48 hours prior to last visit (day 15)). |
| Fecal pH | pH of collected fecal samples | Fecal samples are collected at three time points: prior to supplementation (earliest 48 hours prior to first visit (day 1)), short after initiation of supplementation (day 3 or soonest thereafter) and again earliest 48 hours prior to last visit (day 15). |
| Antibody-coating of bacteria | Characterization of IgA, IgG and IgM-coating of bacteria from fecal samples using bacterial flow cytometry. | Fecal samples are collected at three time points: prior to supplementation (earliest 48 hours prior to first visit (day 1)), short after initiation of supplementation (day 3 or soonest thereafter) and again earliest 48 hours prior to last visit (day 15). |
| Immunoglobulin G | Plasma immunoglobulin G (g/l) | Results from fasting blood samples taken on day 15 and adjusted for results from day 1 (just before first supplement/placebo dosis). |
| Immunoglobulin A | Plasma immunoglobulin A (g/l) | Results from blood samples taken on day 15 (just before last supplement/placebo dosis) and adjusted for results from day 1 (just before first supplement/placebo dosis). |
| Leucocyte counts | Total leucocytes as well as basophils, eosinophils, lymphocytes, monocytes, neutrophils as well as the joint group of metamyelo-, myelo- and promyelocytes. All counted in whole blood samples (10^9/l). | Results from fasting blood samples taken on day 15 and adjusted for results from day 1 (just before first supplement/placebo dosis). |
| Hemoglobin | Hemoglobin measured in whole blood (mmol/l). | Results from blood samples taken on day 15 (just before last supplement/placebo dosis) and adjusted for results from day 1 (just before first supplement/placebo dosis). |
| Alanine transaminase | Plasma alanine transaminase (ALT, U/l) as a biomarker of liver function. | Results from fasting blood samples taken on day 15 and adjusted for results from day 1 (fasting just before first supplement/placebo dosis). |
| Alkaline phosphatase | Alkaline phosphatase (U/l) as a biomarker of liver function. | Results from blood samples taken on day 15 (just before last supplement/placebo dosis) and adjusted for results from day 1 (just before first supplement/placebo dosis). |
| Aspartate aminotransferase | Aspartate aminotransferase also known as aspartate transaminase measured in plasma (U/l) as a biomarker of liver damage. | Results from blood samples taken on day 15 (just before last supplement/placebo dosis) and adjusted for results from day 1 (just before first supplement/placebo dosis). |
| Bilirubin | Bilirubins measured in plasma (µmol/L) as a biomarker of liver function. | Results from blood samples taken on day 15 (just before last supplement/placebo dosis) and adjusted for results from day 1 (just before first supplement/placebo dosis). |
| Coagulation factors II + VII + X | Coagulation factors II + VII + X (INR: International Normalized Ratio) measured in plasma as a biomarker of liver function. | Results from blood samples taken on day 15 (just before last supplement/placebo dosis) and adjusted for results from day 1 (just before first supplement/placebo dosis). |
| Lactate dehydrogenase (LDH) | Lactate dehydrogenase measured in plasma (U/l). | Results from blood samples taken on day 15 (just before last supplement/placebo dosis) and adjusted for results from day 1 (just before first supplement/placebo dosis). |
| Creatinine | Plasma creatinine (µmol/L) as a biomarker of kidney function. | Results from blood samples taken on day 15 (just before last supplement/placebo dosis) and adjusted for results from day 1 (just before first supplement/placebo dosis) |
| eGFR | Estimated glomerular filtration rate (eGFR/ 1,73m² (ml/min)) as a biomarker of kidney function. | Results from blood samples taken on day 15 (just before last supplement/placebo dosis) and adjusted for results from day 1 (just before first supplement/placebo dosis). |
| Albumin | Albumin measured in plasma (g/l). | Results from blood samples taken on day 15 (just before last supplement/placebo dosis) and adjusted for results from day 1 (just before first supplement/placebo dosis). |
| 25-OH-vitamin D | Plasma 25-OH-vitamin D (D3+D2) (nmol/L) | Results from blood samples taken on day 15 (just before last supplement/placebo dosis) and adjusted for results from day 1 (just before first supplement/placebo dosis). |
| Blood pressure | Blood pressure (mm Hg) defined as the lowest value obtained across three measurements. | Measured on day 1 and then again on day 15 |