Microbiota Mediated Flavonoid Metabolites for Cognitive Health

NCT07226674 | Recruiting

• 3 other identifiers: REC/25/00461R01AG081768-015R01AG081768-02
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

Globally, populations are ageing increasing the prevalence of Alzheimer's disease (AD), due to lack of effective treatments. The traditional Mediterranean diet, rich in fibre and polyphenols (PPs) can help prevent or delay cognitive dysfunction and preserve healthy brain structure and function. Cognitive decline is inversely associated with higher PP intakes (\>421mg/day) i.e., total flavonoids, flavan-3-ols and flavonoid oligomers. The positive brain effects of flavonoid intake are likely mediated in part by gut microbial PP metabolites, consistent with the emerging role of the brain-gut microbiome (BGM) system in neurodegeneration. Our preliminary data indicate that circulating phenyl-γ-valerolactones (PVL), neuroprotective compounds exclusively produced by gut microbiota from flavan-3-ol rich foods18 are associated with delaying cognitive dysfunction. Intake of PPs change gut microbial composition and function, altering the physiology of the host's secondary bile acid (BA) pool through modulation of bacterial 7α-dehydroxylation of de-conjugated primary BAs into secondary BAs. This is noteworthy as 7α-dehydroxylation of BAs does not happen in the brain and because gut microbial BA metabolites have regulatory and signalling functions in the brain. The ratio between certain primary and secondary BAs is also dysregulated in AD with significantly lower serum concentrations of cholic acid (a primary BA) and increased levels of deoxycholic acid (a bacterially produced secondary BA). The increased ratio of cholic acid to deoxycholic acid is correlated with cognitive decline. Increased levels of tyrosine, tryptophan, purine, and tocopherol have also been identified in postmortem AD brains. However, specific pathways and mechanisms underlying these associations are unclear. In this multi-PI application by leaders in the field of BGM interactions, we leverage the collectively (NIH, HSC, SFI) funded Tripartite US-Ireland R\&D Partnership Program to determine the mechanisms involved in PP intake on maintaining healthier cognitive and brain function, as mediated by gut microbiota metabolites of PP and BAs in 50+ year old elderly with enhanced AD risk.

Conditions

Cognitive Decline; Cognitive Dysfunction

Keywords

Polyphenols; Mediterranean Diet; Gut Microbiome; Alzheimer Disease

Outcome Measures

Primary Outcomes (10)

• Differences in Polyphenol-derived metabolite concentrations pre, mid, & post intervention - stool

  Measurement of metabolomics via stool specimen.

  Collected three times by the participant at home, once at baseline (week 0), once at mid-study (month 6), and once at the final 12month appointment (month 12)

• Differences in Polyphenol-derived metabolite concentrations pre, mid, & post intervention - blood

  Measurement of metabolomics via blood specimen.

  Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12).

• Differences in microbiome levels pre, mid, & post intervention - Stool

  16S RNA sequencing to measure microbiome levels via stool specimen.

  Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12).

• Differences in microbiome levels pre & post intervention - Blood

  16S RNA sequencing to measure microbiome levels via blood specimen.

  Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12).

• Differences in microbiome levels pre, mid, & post intervention - Stool

  Shotgun metagenomics, sequencing to measure microbiome levels via stool specimen.

  Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12).

• Differences in microbiome levels pre, mid, & post intervention - Blood

  Shotgun metagenomics, sequencing to measure microbiome levels via stool specimen.

  Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12).

• Differences in Cognitive Measures pre, mid, & post intervention - Executive Function

  Administration of a standardized Stroop Neuro-psychological test; participants ability to correctly identify colours when words are printed in conflicting ink colours.

  Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12).

• Differences in Cognitive Measures pre, mid, & post intervention - Executive Function

  Administration of a standardized Trails A \& B; participants ability to connect dots, in order, as quickly as possible.

  Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12).

• Differences in Cognitive Measures pre, mid, & post intervention

  The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)

  Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12).

• Differences in Cognitive Measures pre, mid, & post intervention

  Administration of a standardized arithmetic task; participants ability to complete quick mental math.

  Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12).

Secondary Outcomes (9)

• Differences in tryptophan-associated metabolite profiles pre, mid, and post intervention - Stool

  Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12).

• Differences in Bile Acid's (BA's) pre, mid, & post intervention - Stool

  Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12).

• Differences in Inflammatory markers pre, mid, & post intervention - Blood

  Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12).

• Differences in Alzheimer's Disease (AD) markers pre, mid, & post intervention - Blood [Time

  Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12).

• Anthropometrics - BMI

  Measured three times, once at each in-clinic appointment (week 0, month 6, month 12)

Other Outcomes (1)

• Differences in Multimodal Brain Signatures pre, mid, & post intervention

  Measured thrice, once at baseline (week 0), mid-study (month 6), and final 12month appointment (month 12) visit.

Study Arms (2)

Polyphenol Supplement

EXPERIMENTAL

Juice Plus Essentials, Berry Blend Capsules

Dietary Supplement: Polyphenol Supplement

Placebo Supplement

PLACEBO COMPARATOR

Dietary Supplement: Placebo Supplement

Interventions

Polyphenol Supplement DIETARY_SUPPLEMENT

Juice Plus Essentials, Berry Blend Capsules

Polyphenol Supplement

Placebo Supplement DIETARY_SUPPLEMENT

Micronutrient matched placebo

Placebo Supplement

Eligibility Criteria

• Age: 50 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• + years
• BMI ≥ 25 kg/m2
• Enhanced risk of AD - defined as family history of AD, 1st degree family member
• Habitually consume suboptimal diets such as typical Western diet (i.e., high in animal products, refined carbohydrates and processed food).
• Subjects capable of and willing to comply with the protocol and to give their written informed consent.

You may not qualify if:

• Cognitive impairment at time of recruitment into the study, as measured by the Mini Mental Status Exam (MMSE, score 25-30), and Clinical Dementia Rating (CDR, score=0) or Everyday Cognition Scale-12 (ECog-12, score\<1.36 included).
• Pre-existing psychosis or psychiatric conditions.
• Currently receiving treatment for dementia.
• History of substance abuse or cerebrovascular events.
• Heavy use of tobacco (\>1/2 pack per day)
• Any intolerance or allergy documented or suspected to one of the components of the study products.
• Have taken probiotics or antibiotic therapy within the last 1 month
• Change in medication use in the last 3 months.
• Frailty, malnutrition, or food allergy/intolerance requiring special diets will also be excluded.
• Following any specific diet (vegetarian, vegan, etc.)
• Body weight at enrolment greater than 400lbs due to weight restrictions on the MRI table.
• Pregnant, breastfeeding, postpartum for less than 6 months, or unwilling to practice birth control during participation in the study.
• Unable to safely participate in the MRI (claustrophobia, presence of devices affected by MRI such as pacemakers, neurostimulators, or metallic foreign body, etc.)
• Chronic pain.
• Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data.

Sponsors & Collaborators

• University of Ulster: lead
• University of Parma: collaborator
• University College Cork: collaborator
• National Institute on Aging (NIA): collaborator
• University of California, Los Angeles: collaborator

Study Sites (1)

Ulster University, Human Intervention Studies Unit

Coleraine, BT52 1SA, United Kingdom

RECRUITING

MeSH Terms

Conditions

Cognitive Dysfunction; Alzheimer Disease

Condition Hierarchy (Ancestors)

Cognition Disorders; Neurocognitive Disorders; Mental Disorders; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases

Study Officials

• Chris Gill, PhD

  Ulster University, Human Intervention Studies Unit, Coleraine, Co. Londonderry, BT52 1SA, United Kingdom.

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Chris Gill, PhD

CONTACT

+44 28 7012 3181; c.gill@ulster.ac.uk

Aoife Caffrey, PhD

CONTACT

+44 (0) 28 701 23401; a.caffrey@ulster.ac.uk

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Interventional Model

Study Record Dates

• First Submitted: November 7, 2025
• First Posted: November 10, 2025
• Study Start: November 25, 2025
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): January 1, 2028
• Last Updated: November 24, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)