# Vitamin A metabolism at the host-microbiome interface

> **NIH NIH R01** · BROWN UNIVERSITY · 2024 · $599,127

## Abstract

PROJECT SUMMARY:
In the context of the gut barrier, Vitamin A metabolite retinoic acid (RA) is central to immune homeostasis in the
gut, coordinating both innate and adaptive immunity. Vitamin A directly regulates proliferation and differentiation
in the intestinal epithelium, which is crucial for maintaining optimal gut barrier. Our work in the last funding cycle
revealed that gut bacteria are crucial in regulating how dietary vitamin A is processed in the intestinal mucosa.
Specifically, we showed for the first time that commensal bacteria suppress RA synthesis in the gut by modulating
the intestinal epithelium’s vitamin A metabolic gene rdh7. Our findings delineated the previously unknown impact
of commensal bacteria on the vitamin A homeostasis, thus opening up questions regarding the role of microbially
regulated RA synthesis on mucosal immunity and epithelial regeneration. Using a mouse model that
constitutively expresses rdh7 gene in IECs we now show that dysregulated epithelium intrinsic RA synthesis is
detrimental to host and results in increased number of IFNγ producing T-cells and enhanced susceptibility to
experimental colitis. We find that overexpressing Rdh7 gene in IECs results in decreased proliferation and repair
upon damage compared to control mice. Additionally, our work establishes that commensal bacteria in the gut
possess vitamin A metabolic activity and significantly increase RA concentration in the gut lumen. Precise role
of bacteria derived RA on epithelial barrier and intestinal immune homeostasis remains to be discovered. We
hypothesize that the host and bacteria collaborate to generate an RA gradient that supports optimal
intestinal epithelium renewal and immune homeostasis. In this grant proposal we will:1) determine the
mechanism by which IEC intrinsic RA regulates T-cell effector responses and whether impact of IEC intrinsic RA
is restricted to T-cells residing in close proximity to IECs. Additionally, we will evaluate the role of IEC intrinsic
rdh7 expression in regulating IFNγ dependent immunity against intestinal pathogens and infection burden
(Aim1), 2) delineate the mechanism by which RA regulates stem cells and assess the role of rdh7 expression in
remodeling stem cell niche during infection via interactions with underlying immune cells (Aim2), and 3)
metabolic difference in ability of gut bacteria to produce RA from pro-form vs pre-form vitamin A to probe the
exclusive role of gut-bacteria sourced RA on host physiology(Aim3). Our work will deliver an unprecedented and
comprehensive understanding of the role of bacterially regulated vitamin A homeostasis in the host. Our Aims
will generate new paradigms for investigating and understanding vitamin A-mediated ISC remodeling. Our work
will provide microbial and dietary interventions that could be therapeutic for diseases with an underlying defect
in ISC regeneration and mucosal immunity.

## Key facts

- **NIH application ID:** 10999776
- **Project number:** 2R01DK113265-06A1
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** Shipra Vaishnava
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $599,127
- **Award type:** 2
- **Project period:** 2018-06-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10999776

## Citation

> US National Institutes of Health, RePORTER application 10999776, Vitamin A metabolism at the host-microbiome interface (2R01DK113265-06A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10999776. Licensed CC0.

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