Microbiota Mediated Flavonoid Metabolites for Cognitive Health

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

Interventions

DIETARY_SUPPLEMENT

Polyphenol Supplement

Juice Plus Essentials, Berry Blend Capsules

DIETARY_SUPPLEMENT

Placebo Supplement

Micronutrient matched placebo

Sponsors & Collaborators

• University of Parma

  collaborator OTHER

• University College Cork

  collaborator OTHER

• National Institute on Aging (NIA)

  collaborator NIH

• University of California, Los Angeles

  collaborator OTHER

• University of Ulster

  lead OTHER

Principal Investigators

• Chris Gill, PhD · Ulster University, Human Intervention Studies Unit, Coleraine, Co. Londonderry, BT52 1SA, United Kingdom.

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Model

PARALLEL

Eligibility

Min Age

50 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2025-11-25

Primary Completion

2027-06-30

Completion

2028-01-31

Countries

• United Kingdom

Study Locations