# How Vitamin D Receptor Influences Intestinal Barrier Functions

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $413,719

## Abstract

Impaired intestinal barriers are associated with infection. Vitamin D and its receptor (VDR) levels are inversely
related to chronic inflammation in infectious diseases. Salmonella enterica serotypes are invasive enteric
pathogens spread through fecal contamination of food and water sources, and represent a constant public
health threat in US and around the world. The objective of this application is to study VDR regulation of
intestinal tight junctions (TJs) in response to Salmonella infection. Salmonella induces the disruption of TJs
during infection. This is associated with a decrease in trans-epithelial resistance, increase in tracer
permeability, and TJ protein alterations. Our publications and preliminary data have shown that: (1) lack of
VDR makes the host susceptible to Salmonella invasion; (2) Salmonella targets TJ proteins (e.g. ZO-1, Claudin)
and facilitates pathogenic enteric bacterial invasion. (3) We have identified the sequence of functional vitamin
D response element in Claudin 5, a potential novel target gene of VDR; (4) impaired VDR leads to reduced
expression of TJ proteins, abnormal TJ structure, and increased intestinal permeability in infection; and (5)
probiotics enhance VDR function and inhibit Salmonella infection. Thus, we hypothesize that: “intestinal
epithelial VDR regulation of barrier function is aberrant or lost in infectious states, and restoring VDR function
will attenuate infection and chronic inflammation.” We have now developed state-of-the-art transgenic models,
e.g. intestinal epithelial VDR conditional knockout (VDR∆IEC) mice, conditional transgenic VDR over-expressing
(Tg-VDR) mice, along with loss- and gain- function assays of VDR in organoids to investigate VDR actions that
critically affect barrier functions of the intestine.
 Aim 1. Determine the molecular mechanism by which intestinal VDR regulates barrier function that is
essential for mucosal homeostasis. We will elucidate the mechanism for abnormal epithelial TJs in the VDR-/-
organoids and VDR∆IEC mice.
 Aim 2. Determine the mechanisms by which impaired intestinal barrier is associated with severe infection
in VDR∆IEC mice. We will determine the physiological role and molecular mechanism of intestinal epithelial VDR,
as an upstream regulator, in linking TJs in the VDR∆IEC mice with Salmonella infection.
 Aim 3. Restore the intestinal epithelial VDR expression by force expression of VDR or probiotic treatment
to alleviate infection and associated inflammation. We will determine the roles and mechanisms of A) forced
intestinal epithelial VDR expression in restoring TJ integrity in Salmonella infected Tg-VDR mice; and B)
enhanced intestinal VDR expression by probiotic lactic acid bacteria in infected mice. This knowledge can then
be exploited to define strategies to prevent and treat pathogen infection, by restoring intestinal VDR.

## Key facts

- **NIH application ID:** 9893864
- **Project number:** 5R01DK114126-03
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Jun Sun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $413,719
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9893864

## Citation

> US National Institutes of Health, RePORTER application 9893864, How Vitamin D Receptor Influences Intestinal Barrier Functions (5R01DK114126-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9893864. Licensed CC0.

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