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

Not Applicable

Completed

• Conditions: Cognitive Decline; Aging
• Interventions: Dietary Supplement: Colon-delivered multivitamin supplement; Dietary Supplement: Placebo capsule

• Registration Number: NCT05675007
• Lead Sponsor: Donders Centre for Cognitive Neuroimaging

Brief Summary

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

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 Timeline

• Study First Submitted: 2022-10-24
• Study Start: 2022-12-05
• Study First Submitted QC: 2022-12-21
• Study First Posted: 2023-01-09
• Status Verified: 2024-05
• Primary Completion: 2024-05-02
• Study Completion: 2024-05-02
• Last Update Submitted: 2024-06-19
• Last Update Posted: 2024-06-21

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 75

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Colon-delivered multivitamin supplement	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.
Placebo	Placebo capsule	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.

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (2)

Radboud University, Donders Centre for Cognitive Neuroimaging; 🇳🇱 Nijmegen, Gelderland, Netherlands

Wageningen University and Research, Division of Human Nutrition and Health; 🇳🇱 Wageningen, Gelderland, Netherlands