# The role of enterocyte apical structure in inflammatory bowel disease pathogenesis

> **NIH VA IK2** · VETERANS HEALTH ADMINISTRATION · 2022 · —

## Abstract

PROJECT SUMMARY
Inflammatory bowel disease (IBD), comprised of Crohn’s disease and Ulcerative colitis, is a chronic relapsing
disorder that affects 1.4 million Americans including an estimated 600 per 100,000 veterans causing
malabsorption, bloody diarrhea, strictures, fistulas, and infection. In addition, the chronic inflammatory state
increases the risk for colorectal cancer with poorer prognosis and reduced survival rates compared to non-IBD
patients. Immunotherapy is increasingly effective; however, refractory disease and relapse are not well
understood. My long-term goal is to apply my expertise in epithelial cell biology to understand how the
intestinal epithelium forms an effective barrier against microbes. The goal of this proposal is to understand how
the microscopic surface architecture of the gut is disrupted in and contributes to IBD pathogenesis and
bacterial infection. The epithelial cells lining the intestine are positioned at the interface of the intestinal
microbes and the gut-associated immune system. Enterocytes are the most abundant cell type and are coated
with ~2000 small hair-like protrusions, microvilli (MV) that facilitate nutrient absorption and serve as a
protective barrier from the millions of bacteria concentrated inside the gut. MV are the initial site of contact
between intestinal epithelial cells and luminal bacteria. Perturbations in MV structure and density result in
nutrient malabsorption and osmotic diarrhea as seen in IBD and infection with pathogenic bacteria. A recent
study showed that even in uninflamed tissue, patients with Crohn’s disease have lower levels of MV structural
proteins. These findings imply MV defects are not only present in IBD during active inflammation but persist
despite therapy and may contribute to relapse. Interestingly, our preliminary data show that mice lacking the
MV structural protein CDHR2 recapitulate several of the epithelial defects seen in Crohn’s patients, providing a
unique in vivo model system. In this proposal, we will test the hypothesis that defects in normal enterocyte
apical surface structure and function persist in the absence of active inflammation and provide a path for
microbial entry driving inflammation, infection, and disease relapse. In Aim 1, we will use Crohn’s patient
biopsy tissue and patient stem cell-derived intestinal enteroids to characterize the fundamental ultrastructural
defects present in Crohn’s disease. In Aim 2, we will challenge CDHR2 intestinal knockout mice and Crohn’s
patient stem cell-derived intestinal enteroids with Fusobacterium nucleatum and Enterococcus faecalis
infection to assess the functional consequences of defective MV structure on defense against bacterial
infection/colonization, susceptibility to colitis, and healing in response to inflammation. By the completion of
these studies, we will have identified defects in enterocyte structure in Crohn’s patients and characterized how
these defects contribute to persistent changes in t...

## Key facts

- **NIH application ID:** 10454103
- **Project number:** 5IK2BX004885-03
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Leslie M Meenderink
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10454103

## Citation

> US National Institutes of Health, RePORTER application 10454103, The role of enterocyte apical structure in inflammatory bowel disease pathogenesis (5IK2BX004885-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10454103. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*