Effects of a Colon-delivered Multivitamin Supplement on Brain Functioning, Immunometabolic- and Intestinal Markers in Ageing

Study Overview
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Brief Summary
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COMBI is a multi-center, randomized controlled trial among 70 older adults at risk of cognitive decline. The main goal is to investigate the effect of a 6-week colon-delivered multivitamin supplementation on the gut-brain axis in older adults, by assessing changes in brain function as well as intestinal changes compared to placebo.

Detailed Description
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Growing evidence indicates an important role for intestinal health in development of cognitive decline in ageing. Intestinal health, and especially the gut microbiome, is assumed to affect brain health and functioning via immunometabolic pathways captured in the gut-brain axis. However, it is unclear whether changes in intestinal health markers causally relate to cognitive decline in older adults and how. Nutritional interventions specifically targeting the gut were found beneficial for human cognition and brain function. An intervention based on colon-delivered vitamins (B2, B3, B6, B9, C, D3) is proposed to affect gut health using microbiome-dependent and independent pathways. In this study, it will be investigated whether this intervention affects neurocognition in ageing humans, to reveal causal gut-brain relationships in aging.Therefore, the primary goal of the COMBI study is to investigate the effect of a 6-week colon-delivered multivitamin supplementation on the gut-brain axis in older adults, by assessing changes in brain function as well as intestinal changes compared to placebo. Secondary, the effects of this 6-week colon-delivered multivitamin supplementation in older adults on the following parameters related to potential gut-brain pathways will also be investigated: (1) other relevant brain parameters, (2) other relevant intestinal parameters, (3) immunometabolic parameters related to gut-brain pathways, and (4) neuropsychological test battery scoring.

Official Title
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The Effects of a Colon-delivered Multivitamin Supplement on Brain Functioning and Its Relation With Immunometabolic and Intestinal Markers in Ageing: the COMBI Study

Conditions
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Aging, Cognitive Decline

Intervention / Treatment
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* Dietary Supplement: Colon-delivered multivitamin supplement
* Dietary Supplement: Placebo capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Age between 60-75 years (at pre-screening) Fluency in Dutch (speaking, reading and writing) Score ≥2 points on the risk factor scale below based on self report: BMI≥25 (1 point) Physical inactivity (according to WHO guidelines) (1 point) Hypertension (1 point) Hypertension without medication (1 point) Hypercholesterolemia (1 point) Diabetes type II (1 point) Mild cardiovascular disease (1 point) Exclusion Criteria: Food allergies or other issues with the vitamins included in the supplement Concurrent participation in other intervention trials Clinical diagnosis of ≥1 of the following: Stroke; Neurological disease(s) (e.g. MCI, dementia, MS, Parkinson's, epilepsy); Current malignant disease(s), with or without treatment; Current psychiatric disorder(s) (e.g. depression, psychosis, bipolar episodes, eating disorder); Symptomatic cardiovascular disease (e.g. stroke, angina pectoris, heart failure, myocardial infarction); Revascularisation surgery in the last 12 months at pre-screening; Gastrointestinal diseases (i.e., diarrhoea, Crohn's disease, ulcerative colitis, diverticulosis, stomach or duodenal ulcers) or having a history of gastrointestinal surgical events (e.g. stoma) that may influence the results of the study, as determined by the study team; Visual impairment (e.g. blindness); Hearing or communicative impairment. Use of antibiotics within the previous 3 months before the study start. Use of protonpump inhibitors within the study period (esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole) Not willing to refrain from taking other supplements (containing vitamin B2, B3, B6, B9, or C, prebiotic, or probiotic) that can interfere with the study outcomes, from at least 2 weeks before start of the intervention till the end of the intervention period. Answering Yes on ≥1 of the Donders Institute MRI safety screening protocol questions (see the 8 questions below): Are there metal objects located in your upper body? Exception: tooth-fillings and/or dental crowns. Are there metal splinters in your body, in particular within the eyes? For example: through labour work in the metal industry. Are there jewellery items or piercings that you are unable to take off? Have you had a brain surgery in the past? Are there active implants present? For example: pacemaker, neurostimulator, insulin pump, hearing aid (that is unable to be removed). Are there any medical plasters or patches that you can't or may not take off? For example: nicotine patch. Do you suffer from epilepsy? Do you suffer from claustrophobia? Cognitive impairment as determined by Telephone Interview for Cognitive Status (TICS-M1), performed during pre-screening before inclusion and defined as a score <23.

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This randomized controlled trial has two parallel intervention arms. One group will daily consume a colon-delivered multivitamin supplement for 6 weeks. The other group will daily consume a placebo tablet for 6 weeks. Participants will we randomly assigned to one of the two groups.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Colon-delivered multivitamin supplement<br>Within this arm, study subjects will consume a colon-delivered multivitamin supplement for 6 weeks. Subjects are instructed to consume the capsule daily during breakfast. The capsule must be taken orally with a glass of water. | Dietary Supplement: Colon-delivered multivitamin supplement<br>* Colon-delivered multivitamin supplement containing the following dose of the indicated vitamin: vitamin B2 (10 mg), vitamin B3 (4.0 mg), vitamin B6 (1.4 mg), vitamin B9 (400 μg), vitamin C (200 mg) and vitamin D3 (15ug). Vitamin capsules are filled with microcrystalline cellulose and magnesium stearate up to 200 mg. Control of release in the colon is achieved by the Eudragit S 100 coating layer technology that surrounds the vitamins contained in the core capsules.<br>|
| Placebo Comparator: Placebo<br>Within this arm, study subjects will consume a placebo capsule for 6 weeks. Subjects are instructed to consume the capsule daily during breakfast. The capsule must be taken orally with a glass of water. | Dietary Supplement: Placebo capsule<br>* Placebo capsule containing microcrystalline cellulose and magnesium stearate up to 200 mg. Placebo capsules are coated with the Eudragit S 100 coating layer.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in brain activity during working memory | Blood-oxygen level dependent activity in dlPFC and hippocampus during N-back fMRI task | Change between Baseline (T0), Follow-up after 6 weeks (T1) | 
| Change in working memory performance | Task accuracy during N-back fMRI task | Change between Baseline (T0), Follow-up after 6 weeks (T1) | 
| Change in faecal short-chain fatty acids | Total faecal short-chain fatty acid concentration measured by gas chromatograph mass spectrometry | Change between Baseline (T0), Follow-up after 6 weeks (T1) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in brain myo-inositol levels (neuroimaging) | Brain myo-inositol levels reflecting neuroinflammation in dlPFC and hippocampus, measured by magnetic resonance spectroscopy | Change between Baseline (T0), Follow-up after 6 weeks (T1) | 
| Change in cerebral perfusion levels (neuroimaging) | Cerebral perfusion levels measured by arterial spin labelling | Change between Baseline (T0), Follow-up after 6 weeks (T1) | 
| Change in neuropsychological test-battery scoring | Z-scoring on cognitive domains predominantly affected by cognitive ageing: executive function (incl. working memory), episodic memory and processing speed. | Change between Baseline (T0), Follow-up after 6 weeks (T1) | 
| Change in microbiota profile (faecal) | 16S rRNA based profile of gut microbiota in faeces | Change between Baseline (T0), Follow-up after 6 weeks (T1) | 
| Change in individual short-chain fatty acids profile (faecal) | GCMS measurement to assess profile of individual SCFAs in faeces (acetic acid, formic acid, propionic acid, isobutyric acid, butyric acid, isovaleric acid, valeric acid, 4-methyl valeric acid, hexanoic acid, heptanoic acid) | Change between Baseline (T0), Follow-up after 6 weeks (T1) | 
| Change in stool water content (faecal) | Water content of stool, based on wet- and dry weight. | Change between Baseline (T0), Follow-up after 6 weeks (T1) | 
| Change in stool pH (faecal) | Faecal pH will be measured with a pH/redox meter in faeces | Change between Baseline (T0), Follow-up after 6 weeks (T1) | 
| Change in stool redox potential (faecal) | Redox potential will be measured with a pH/redox meter in faeces | Change between Baseline (T0), Follow-up after 6 weeks (T1) | 
| Change in intestinal inflammation profile (faecal) | Assay-based profile of intestinal inflammation measured in faeces | Change between Baseline (T0), Follow-up after 6 weeks (T1) | 
| Change in C-reactive protein concentration (blood) | hsCRP measured via finger prick analysis | Change between Baseline (T0), Follow-up after 6 weeks (T1) | 
| Change in white blood cell count (blood) | White blood cell count measured via finger prick analysis | Change between Baseline (T0), Follow-up after 6 weeks (T1) | 
| Change in inflammation profile (blood) | Assay-based profile of systemic inflammation measured in plasma | Change between Baseline (T0), Follow-up after 6 weeks (T1) | 
| Change in intestinal integrity profile (blood) | Assay-based profile of intestinal integrity measured in plasma | Change between Baseline (T0), Follow-up after 6 weeks (T1) | 
| Change in anti-oxidant status profile (blood) | Assay-based profile of anti-oxidant status and oxidative stress measured in plasma | Change between Baseline (T0), Follow-up after 6 weeks (T1) | 
| Change in metabolic profile (blood) | Assay-based profile of (energy) metabolism measured in plasma | Change between Baseline (T0), Follow-up after 6 weeks (T1) | 
| Change in brain health profile (blood) | Assay-based profile of brain health measured in plasma | Change between Baseline (T0), Follow-up after 6 weeks (T1) | 
| Change in vitamin profile (blood) | Assay-based profile of circulating vitamins from supplement measured in plasma | Change between Baseline (T0), Follow-up after 6 weeks (T1) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Intestinal health, Gut-brain axis