# Gut Intrinsic Inflammatory Responses

> **NIH NIH U01** · WASHINGTON UNIVERSITY · 2024 · $441,000

## Abstract

The gastrointestinal (GI) tract is a large surface lined by a single layer epithelium which is exposed
to trillions of microbes and innocuous substances from the diet. The largest collection of immune
cells in the body underlies this single layer epithelium and monitors the luminal contents to
maintain tolerance to dietary and commensal antigens in the steady-state while retaining the
ability to rapidly induce immunity to pathogens during infection. While great progress has been
made in elucidating the role(s) of specific immune cell subsets, cytokines, and other factors
promoting tolerance or immunity, the processes intrinsic to the gut that enable the immune system
to switch from an overwhelmingly tolerogenic tone in the steady-state to inflammatory responses
during infection remains a gap in our understanding. Recently, we have uncovered that inhibiting
goblet cell associated antigen passages (GAPs) in the small intestine (SI) rapidly shifts the
immunologic tone away from tolerance and promotes the rapid induction of inflammatory Th17
responses in the absence of infection or injury. We hypothesize that the inhibition of GAPs is a
physiologic response to enteric infection, which in and of itself, promotes the generation of Th17
cells and inflammatory cytokines and shifts the tone of the immune system away from tolerance
toward immunity. By studying this process in the absence of enteric infection or injury we can
disentangle contributions of the pathogen and injury to the inflammatory response from intrinsic
properties of the gut ecosystem promoting the switch from a tolerogenic to pro-inflammatory state.
Understanding intrinsic properties of the gut that allows the rapid generation of protective
responses could provide new approaches to treat enteric infections and provide insight into the
pathogenesis of chronic inflammatory diseases of the gut. We hypothesize that when SI GAPs
are inhibited, other pathways take over driving the development and/or expansion of Th17 cells
specific for dietary, microbial, and/or self antigens, which shifts the tone of the immune system to
provide enhanced protection during enteric infection and/or injury. To explore this hypothesis we
propose the following specific aims: In aim 1 we will identify the early events resulting in Th17
expansion following SI GAP inhibition, in aim 2 we will define the origins and specificities of the
Th17 cells that expand when SI GAPs are inhibited in aim 3 we will determine if the inhibition of
SI GAPs is protective in models of enteric infection and whether inappropriate inhibition of SI
GAPs potentiates intestinal inflammatory disease.

## Key facts

- **NIH application ID:** 10831384
- **Project number:** 5U01AI163073-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** CHYI S HSIEH
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $441,000
- **Award type:** 5
- **Project period:** 2021-07-26 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10831384

## Citation

> US National Institutes of Health, RePORTER application 10831384, Gut Intrinsic Inflammatory Responses (5U01AI163073-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10831384. Licensed CC0.

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