# A Novel Role for PTPN2 in Intestinal Epithelial Barrier Regulation

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA RIVERSIDE · 2023 · $596,461

## Abstract

SUMMARY/ABSTRACT
Compromised intestinal barrier function and alterations in intestinal microbes are critical factors contributing to
many autoinflammatory diseases such as Inflammatory Bowel Disease (IBD), celiac disease and Type 1
diabetes, and affect ~24 million Americans (www.niehs.nih.gov). Genetic contributions to these diseases
include the increased association with loss-of-function single-nucleotide polymorphisms (SNPs) in the protein
tyrosine phosphatase non-receptor type 2 (PTPN2) gene. Moreover, PTPN2 was identified as a major
influence on microbiome composition across multiple patient cohorts.In mice constitutively lacking Ptpn2, we
identified substantial changes in gut microbiota populations highlighted by increased abundance of a novel
mouse adherent-invasive E. coli (AIEC). This mouse AIEC was able to colonize mouse intestine, exacerbate
colitis onset, and delay recovery from colitis. Moreover, we now report that PTPN2 loss compromises Paneth
cells which have critical roles in preserving intestinal mucosal-microbial homeostasis. We also identify that
epithelial PTPN2 deletion reduces Paneth cell antimicrobial peptide expression, and increases susceptibility to
pathogen infection. Thus, we hypothesize that PTPN2 serves as a “microbial modulator” by regulating innate
defense mechanisms of epithelial cells to protect the intestine against bacterial ‘dysbiosis’, including expansion
of, and colonization with, the disease-relevant pathobiont, AIEC. The goals of this proposal are to determine
how loss of PTPN2 activity disrupts i) Paneth cell antimicrobial properties; and ii) how does PTPN2 regulate
other (non-Paneth cell) features of epithelial antimicrobial defense and intracellular bacterial handling.
Expected Outcomes & Impact: This proposal will increase our broader understanding of the molecular basis by
which host factors preserve the intestinal barrier and microbial homeostasis, and lead to development of new
approaches and targets to restore host-microbe relationships in diseases such as IBD.

## Key facts

- **NIH application ID:** 10752105
- **Project number:** 2R01DK091281-09
- **Recipient organization:** UNIVERSITY OF CALIFORNIA RIVERSIDE
- **Principal Investigator:** Declan McCole
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $596,461
- **Award type:** 2
- **Project period:** 2012-04-05 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10752105

## Citation

> US National Institutes of Health, RePORTER application 10752105, A Novel Role for PTPN2 in Intestinal Epithelial Barrier Regulation (2R01DK091281-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10752105. Licensed CC0.

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