# IRE1beta links the gut microbiota and epithelial differentiation to protect against colitis

> **NIH NIH K01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $156,276

## Abstract

Project Summary
Ulcerative colitis (UC) is a common, chronic form of inflammatory bowel disease characterized by superficial
inflammation and damage to the epithelium of the colon and rectum. While causes of UC are unknown, genetic
studies point to inappropriate immune signaling, mishandling of the gut microbiota, and altered epithelial repair
mechanisms as contributing factors. A common feature of UC is an altered mucus layer in the colon
epithelium, which may be due to changes in mucin biosynthesis as well as to defects in differentiation of goblet
cells. As the mucus layer normally serves as a protective innate immune barrier, separating microbes from the
epithelial surface, defects in mucus assembly allow gut bacteria to interface with the colonic epithelium more
closely. This has been implicated in triggering immune responses or increasing susceptibility to infections that
contribute to UC pathophysiology. ER stress and the unfolded protein response is intimately linked to secretory
cell function and inflammation in the intestinal epithelium. The intestinal epithelium and other mucosal epithelia
are unique in that they express an additional ER stress sensor called IRE1β. IRE1β appears to protect against
colonic injury and inflammation by unknown mechanisms. We recently found that IRE1β functions in the
unfolded protein response in intestinal epithelial cells, and discovered that the colon of IRE1β-/- mice closely
resembles human UC. IRE1β-/- mice have fewer mature goblet cells in the colon compared to IRE1β+/+
littermates. This is associated with a nearly abolished inner mucus layer that places the gut microbiota
immediately adjacent to the colonic epithelium. Under steady state conditions IRE1β-/- colonic crypts do not
express elevated markers of a UPR, suggesting that unresolved ER stress cannot explain this phenotype.
Instead, it appears that IRE1β is required for expression of transcription factors that specify goblet cell
development. Notably, we find IRE1β expression and assembly of the colon mucus layer are stimulated by the
gut microbiota. These data place IRE1β's function at the interface of the microbiota and the epithelium,
regulating the innate barrier that protects the host from inflammatory signals and infection. The purpose of this
grant is to understand how IRE1β protects against colitis, where our central hypothesis is IRE1β protects
against colitis by controlling microbiota-induced goblet cell differentiation and assembly of the colon mucus
layer. We will use in vitro and in vivo models to understand how the microbiota regulates IRE1β function (Aim
1), define how IRE1β regulates goblet cell differentiation (Aim 2), and establish the relevance of IRE1β function
in protecting against colitis in experimental models and human UC (Aim 3).

## Key facts

- **NIH application ID:** 9849768
- **Project number:** 5K01DK119414-02
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Michael J Grey
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $156,276
- **Award type:** 5
- **Project period:** 2019-01-11 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9849768

## Citation

> US National Institutes of Health, RePORTER application 9849768, IRE1beta links the gut microbiota and epithelial differentiation to protect against colitis (5K01DK119414-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9849768. Licensed CC0.

---

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