# Claudin-3, Gut Dysbiosis and Inflammatory Bowel Disease

> **NIH VA I01** · OMAHA VA  MEDICAL CENTER · 2021 · —

## Abstract

Inflammatory bowel disease (IBD), consisting primarily of the ulcerative colitis (UC) and Crohn’s disease (CD),
is a group of debilitating auto-immune disorders, which significantly affect one’s life-style and carry a high risk
of colon cancer. While significant advances have been made in the clinical management of these diseases, the
overall incidence rate and disease severity in active duty army personnel and veterans is constantly increasing
possibly due to the high level of stress involved. Moreover, IBD significantly increases the risk of colon cancer,
and therefore physical and economical burden of these diseases upon our veteran population is significantly
high. However, the etiology of IBD remains unclear. Taken together, there is an urgent and unmet need for
improved understanding of the molecular mechanisms that promote IBD susceptibility and/or disease severity,
as it can help identify novel therapeutic targets. In this regard, disruption of epithelial polarity and
compartmentalization, assisted by the tight junction (TJ) deregulation, plays key role in inducing and promoting
mucosal inflammation. Notably, an association between the leaky gut and IBD has long been suggested.
However, despite this knowledge, progress in this area for therapeutic gains has been limited due primarily to
the generic perspective that proteins constituting the TJ are static and redundant in their function. This proposal
disagrees with this generic view and proposes key role of claudin-3, a TJ-integral protein, in dynamic regulation
of the gut epithelial and inflammatory homeostasis. Our working hypothesis is that the loss of claudin-3, which
characterizes IBD patients, deregulates mucosal barrier integrity to induce gut dysbiosis and pro-inflammatory
environment. Accompanying deregulations of gp130/IL6/Stat3 and Hippo/Yap signaling cascades, due to the
polarity defects ensued by deregulated Par-3 expression, render chronicity to the initial inflammatory insult by
deregulating mucosal injury/repair leading ultimately to neoplastic growth.
 This proposal is built upon a strong scientific premise as a series of studies, including ours, have now
identified claudin-3 (hereon Cldn3) as a key TJ-protein in maintaining gut epithelial barrier maturity and integrity.
In this regard, we found Cldn3 to be the highest expressed cell-cell adhesion protein localized primarily amongst
differentiated colonocyte at the crypt top in normal colon. Furthermore, Cldn3KO mice, used to model decreased
Cldn3 levels in IBD patients, exhibited hyper-permeable gut and immune cell infiltration into the lamina propria.
In addition, gut dysbiosis along with specific and robust increase in gp130/IL6/Stat3 expression characterized
Cldn3KO mice. Cldn3 loss also compromised colonic epithelial cell (CEC) differentiation and polarity, and
promoted Hippo/Yap-signaling. Importantly, Stat-3 and Yap-signaling pathways promote hyper-proliferation,
chronic inflammation and malignant growth when dereg...

## Key facts

- **NIH application ID:** 10125812
- **Project number:** 5I01BX002761-06
- **Recipient organization:** OMAHA VA  MEDICAL CENTER
- **Principal Investigator:** Amar B Singh
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2016-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10125812

## Citation

> US National Institutes of Health, RePORTER application 10125812, Claudin-3, Gut Dysbiosis and Inflammatory Bowel Disease (5I01BX002761-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10125812. Licensed CC0.

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