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

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

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.

Study Overview

• Status: Completed
• Conditions: Aging; Cognitive Decline
• Intervention / Treatment: Dietary supplement: Colon-delivered multivitamin supplement; Dietary supplement: Placebo capsule

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 75
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6525 EN
      • Radboud University, Donders Centre for Cognitive Neuroimaging
    • Wageningen, Gelderland, Netherlands, 6708 WE
      • Wageningen University and Research, Division of Human Nutrition and Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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):

  1. Are there metal objects located in your upper body? Exception: tooth-fillings and/or dental crowns.
  2. Are there metal splinters in your body, in particular within the eyes? For example: through labour work in the metal industry.
  3. Are there jewellery items or piercings that you are unable to take off?
  4. Have you had a brain surgery in the past?
  5. Are there active implants present? For example: pacemaker, neurostimulator, insulin pump, hearing aid (that is unable to be removed).
  6. Are there any medical plasters or patches that you can't or may not take off? For example: nicotine patch.
  7. Do you suffer from epilepsy?
  8. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Colon-delivered multivitamin supplement; 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; 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.
Placebo Comparator: Placebo; 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; Placebo capsule containing microcrystalline cellulose and magnesium stearate up to 200 mg. Placebo capsules are coated with the Eudragit S 100 coating layer.

What is the study measuring?

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)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Body mass index	Measured in kg/m^2	Baseline (T0)
Waist circumference	Measured in cm	Baseline (T0)
Hip circumference	Measured in cm	Baseline (T0)
Blood pressure	Scores range from approximately (for diastolic) 60-120 and (for systolic) 100-180 mmHg, with higher scores indicating higher blood pressure.	Baseline (T0)
Abdominal fat distribution	VAT(visceral adipose tissue)/SAT(subcutaneous adipose tissue) ratio based on abdominal MRI scan	Baseline (T0)
Baseline Demographics and medical history (questionnaire)	Demographic information, medical history and medication use - qualitative assessment	Baseline (T0)
4DKL (questionnaire)	(Psychosocial) complaints in daily life. Separate scores for distress (>10 moderate, >20 severe), depression (>2 moderate, >5 severe), anxiety (>3 moderate, >9 severe) and somatisation (>10 moderate, >20 severe)	Baseline (T0)
EQ-5D-5L (questionnaire)	Quality of life. Scores range from 0-100, higher scores indicate better quality of life	Baseline (T0)
Five Facet Mindfulness Questionnaire (questionnaire)	Self-assessment of mindfulness. Total scale ranges from 24 - 120, higher scores indicate more mindfulness	Baseline (T0)
LIBRA (questionnaire)	Modifiable dementia risk using lifestyle for brain health. The score ranges from -5.9 (minimum score) to +12.7 (maximum score), with higher scores meaning a worse outcome (higher dementia risk)	Baseline (T0)
Lubben Social Network Scale (questionnaire)	Social contact and perceived social support. The score ranges from 0 (minimum score) to 30 (maximum score), with higher scores meaning a better outcome (higher level of perceived social support)	Baseline (T0)
SARC-F Sarcopenia questionnaire (questionnaire)	Sarcopenia. Scores range from 0 to 10 (i.e. 0-2 points for each component; 0 = best to 10 = worst).	Baseline (T0)
Sedentary Behaviour Questionnaire (questionnaire)	Average hours and minutes of sedentary behavior a day, range from 0 to 24 hours. Higher scores (more hours) means a more sedentary behavior.	Baseline (T0)
Change in Nutritional intake (questionnaire)	Nutritional intake measured with a Food Frequency Questionnaire, assessing food intake of the past month, qualitative assessment	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Change in Perceived Stress Scale (questionnaire)	Stress perception. Total score, scale 0 - 40, higher scores indicate more perceived stress	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Change in Pittsburgh Sleep Quality Index (PSQI) (questionnaire)	Sleep quality. Total score ranging from 0 to 21 with the higher total score (referred to as global score) indicating worse sleep quality	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Change in SQUASH (questionnaire)	Physical activity. METs derived from the Ainsworth's compendium of physical activity will be used to classify physical activity intensity (<1.5METs- sedentary, 1.6-2.9 METs- light, 3.0-5.9METs- moderate, >6.0- vigorous physical activity).	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Gastrointestinal symptoms questionnaire (questionnaire)	Gastrointestinal symptoms, qualitative assessment	Baseline (T0)
Gastrointestinal symptoms questionnaire (questionnaire)	Gastrointestinal symptoms, qualitative assessment	Follow-up after 6 weeks (T1)
Bristol stool chart (questionnaire)	Classification of faeces type, qualitative assessment	Baseline (T0)
Bristol stool chart (questionnaire)	Classification of faeces type, qualitative assessment	Follow-up after 6 weeks (T1)
Gut transit time	Gut transit time measured by blue muffin consumption and appearance in faeces	Baseline (T0)
Gut transit time	Gut transit time measured by blue muffin consumption and appearance in faeces	Follow up after 6 weeks (T1)
Change in Cognitive Failures Questionnaire (questionnaire)	Subjective cognitive functioning. Score ranges from 0-100. A higher total score indicates more subjective cognitive failure.	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Change in Cognitive Emotions Regulation Questionnaire (questionnaire)	Cognitive coping strategies. Answers are scored on a 7-point Likert-type scale ranging from 1 (strongly disagree) to 7 (strongly agree). The scoring takes the average of all the scores in each subscale of cognitive reappraisal and expressive suppression	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Change in Hospital Anxiety and Depression Scale (questionnaire)	Anxiety and depression. Separate scores for anxiety (max 21) and depression (max 21). For each domain, a score >8 indicates psychiatric condition of anxiety or depression.	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Change in Memory Self-Efficacy MIA (questionnaire)	Self-evaluation and confidence of memory. Sum of Part 1 + Part 2A and B. Part 1: Strategy (scores 10 - 50, higher scores indicate more use of strategies), Part 2A: Subjective memory functioning, scores ranges from 23 - 115, with higher scores indicate better memory self-efficacy and 2B: Locus, scores ranges from 7 - 35, higher scores indicate better perceived personal control over remembering abilities.	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Change in Starkstein Apathy Scale (questionnaire)	Screen and measure apathetic symptoms. A higher total score (range 0-42) indicates more severe apathy, with a score greater than 14 or greater is indicative of clinical apathy	Change between Baseline (T0), Follow-up after 6 weeks (T1)
User experiences (questionnaire)	User experiences of the supplement - qualitative assessment.	Follow up after 6 weeks (T1)
COVID status (questionnaire)	Vaccination status, COVID history - qualitative assessment.	Baseline (T0)
COVID status (questionnaire)	Vaccination status, COVID history - qualitative assessment.	Follow up after 6 weeks (T1)

Collaborators and Investigators

• Sponsor: Donders Centre for Cognitive Neuroimaging
• Collaborators: Wageningen University and Research
• Investigators: Principal Investigator: Esther Aarts, prof. dr., Radboud University, Donders Centre for Cognitive Neuroimaging

Study record dates

Study Major Dates

• Study Start (Actual): December 5, 2022
• Primary Completion (Actual): May 2, 2024
• Study Completion (Actual): May 2, 2024

Study Registration Dates

• First Submitted: October 24, 2022
• First Submitted That Met QC Criteria: December 21, 2022
• First Posted (Actual): January 9, 2023

Study Record Updates

• Last Update Posted (Actual): June 21, 2024
• Last Update Submitted That Met QC Criteria: June 19, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Gut-brain axis; Intestinal health
• Additional Relevant MeSH Terms: Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Cognitive Dysfunction
• Other Study ID Numbers: 3033003.02

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No