# Microbial flavonoid metabolites as modulators of AD markers in a 3D human neural tissue model

> **NIH NIH R01** · TEXAS A&M AGRILIFE RESEARCH · 2020 · $385,050

## Abstract

PROJECT SUMMARY
Several lines of evidence from animal and in vitro studies suggest that polyphenols, notably flavonoids, provide
protective benefits Alzheimer’s disease (AD). In rodent models of AD, oral administration of extracts containing
mixtures of flavonoids reduced inflammation, oxidative stress, and Amyloid beta (Ab) in the brain, while
attenuating the decline in cognitive functions. Similar benefits have been reported for individual flavonoid classes,
including flavanones, flavones, flavan-3-ols (catechins), and anthocyanins. Several mechanisms for how these
compounds confer their benefits have been proposed, including scavenging of reactive oxygen species (ROS),
modulation of the inflammatory cascade of the central nervous system (CNS) neurons, and slowing or halting
the formation of cytotoxic Ab oligomers. A key question that arises when investigating these mechanisms
is whether the effects are due to the original phytochemical or due to a metabolite that derives from the
flavonoid. Dietary flavonoids are typically present in their glycoside form, which have poor bioavailability. In
contrast, phenolic acids and other metabolic products are readily absorbed and accumulate in tissues, including
the brain. For example, phenyl-𝛾-valerolactones (PVL), metabolites derived from flava-3-ols by gut bacterial
metabolism, inhibit Ab oligomerization in vitro, and improved novel object recognition in mice injected with Ab
oligomers. This raises the intriguing hypothesis that the effects of flavonoids on the brain are mediated by
metabolic derivatives generated by gut bacteria. There is considerable evidence that gut bacteria are capable of
fully metabolizing polyphenol glycosides to bioactive phenolic compounds. In our ongoing R01 project, we have
identified naringenin chalcone as a significant metabolic product of naringenin, and determined that the chalcone
product more strongly activates the aryl hydrocarbon receptor (AhR), a key nuclear receptor regulating intestinal
xenobiotic metabolism immune homeostasis. The goal for this Administrative Supplement request is to
investigate the above hypothesis by extending our current studies on flavonoid-gut microbiota interactions to
AD-related pathways in the brain. To address the hypothesis, we propose to 1) identify flavonoid derived
compounds that unambiguously derive from gut bacterial metabolism and 2) evaluate the efficacy of the
metabolites to modulate AD markers using a novel 3D-tissue engineered brain model. We will combine
computational prediction and in vitro fecal culture experiments to determine bacterial metabolites of
representative flavonoids previously shown to protect against AD-related cognitive decline. Metabolic modeling
will be used to associate flavonoid metabolites with species that contribute to the metabolites’ synthesis. A
bioengineered 3D brain-like tissue model generated using human induced pluripotent stem cells (hiPSC) will
provide an ideal testbed to characterize the flavo...

## Key facts

- **NIH application ID:** 10123916
- **Project number:** 3R01AT010282-03S1
- **Recipient organization:** TEXAS A&M AGRILIFE RESEARCH
- **Principal Investigator:** ARUL JAYARAMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,050
- **Award type:** 3
- **Project period:** 2018-09-25 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123916

## Citation

> US National Institutes of Health, RePORTER application 10123916, Microbial flavonoid metabolites as modulators of AD markers in a 3D human neural tissue model (3R01AT010282-03S1). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/10123916. Licensed CC0.

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