# Role of epithelial cell intrinsic vitamin A metabolism in regulating immune function in the gut

> **NIH NIH R01** · BROWN UNIVERSITY · 2020 · $448,470

## Abstract

PROJECT SUMMARY
Vitamin A or retinol is amongst the most well characterized food-derived nutrients with diverse immune-
modulatory roles. Deficiency in dietary vitamin A has not only been associated with immune dysfunctions in the
gut, but also with several systemic immune disorders. To maintain sufficient levels of vitamin A, the body relies
on the uptake of retinol from the intestinal lumen by intestinal epithelial cells or IECs. After uptake by IECs,
retinol can either be processed for storage or be further metabolized into retinoic acid (RA). Even though IECs
are at the center of Vitamin A metabolism and play a dominant role in controlling the fate of dietary vitamin A,
our knowledge of how IEC intrinsic vitamin A metabolic machinery is regulated is extremely superficial. By
comparing germ-free (GF) and conventional (CV) mice we demonstrate that gut bacteria play a critical role in
modulating retinoic acid (RA) levels and expression of vitamin A metabolic machinery in the intestinal
epithelium. Specifically, we find bacteria differentially regulate expression of retinol dehydrogenase 7 (rdh7), a
key gene involved in conversion of retinol into RA in the intestinal epithelium. By employing genetic mouse
models harboring a deletion in rdh7 in IECs, we establish that IEC intrinsic RA production regulates the levels
of Interleukin IL-22, a key cytokine that controls barrier responses to gut bacteria. Our data demonstrates for
the first time that gut bacteria-dependent RA synthesis is critical for regulating local immune responses.
Current proposal seeks to understand the molecular mechanism by which gut bacteria regulate RA synthesis
and vitamin A metabolic gene rdh7 in IECs (Aim1), establish the role of rdh7 expression in IECs in regulating
RA-signaling in the gut (Aim 2) and determine the role of IEC-intrinsic vitamin A metabolism on host-microbe
homeostasis via modulation of IL-22 levels in the gut (Aim 3). To accomplish these goals, we have developed
innovative genetic approaches that enable us to conditionally delete or over-express rdh7 specifically in IECs.
Further we propose to utilize novel methodologies such as monoassociated and gnotobiotic mouse models to
delineate the bacterial cues that regulate RA generation in the intestinal epithelium. Our experimental
methodology incorporates robust analytical approaches such as tandem mass-spectrometry (LC-MS/MS) that
enables us to accurately determine the flux in vitamin A metabolic pathway in response to discrete bacterial
cues. This work will be significant because it will establish mechanistic links between gut bacteria and
intestinal epithelium intrinsic vitamin A metabolic pathway. Moreover, it will test the feasibility of manipulating
mucosal immunity by bacterial modulation of IEC intrinsic vitamin A metabolism for therapeutic purposes.

## Key facts

- **NIH application ID:** 9892004
- **Project number:** 5R01DK113265-03
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** Shipra Vaishnava
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $448,470
- **Award type:** 5
- **Project period:** 2018-06-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9892004

## Citation

> US National Institutes of Health, RePORTER application 9892004, Role of epithelial cell intrinsic vitamin A metabolism in regulating immune function in the gut (5R01DK113265-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9892004. Licensed CC0.

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