# Brain-gut interactions regulating stress-related gut inflammation and barrier permeability

> **NIH NIH K99** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $90,000

## Abstract

Project Summary
Chronic psychosocial stress is a major risk factor for functional gastrointestinal disorders, such as irritable
bowel syndrome (IBS). Notably, there is high co-morbidity between IBS and stress-related psychiatric
disorders such as major depressive disorder (MDD), with IBS and MDD representing two of the most prevalent
and debilitating illnesses worldwide. Potentially underlying this co-morbidity is the recent finding that chronic
stress elicits low-grade inflammation, which has been associated with both IBS and MDD. Moreover,
increasing evidence suggests that the gut-brain axis, or connections between the central and enteric nervous
systems, contributes to the etiology of IBS. However, the mechanisms through which an emotional state such
as chronic stress influences gut pathophysiology, including inflammation, remain poorly understood. In
preliminary experiments using the chronic social defeat stress (CSDS) model in mice, we find that intestinal
inflammation and barrier permeability become elevated following CSDS in both male and female mice, and
these phenomena correlate with depression-like behaviors such as social avoidance. In this project, I will
investigate how psychosocial stress causes this gut pathophysiology. Using retrograde viral tracing strategies
from the gut to the brain, and whole-brain imaging, I have generated a list of candidate stress-activated brain
regions that directly innervate the gut. In the first aim of this proposal, I will use integrated neuroscience and
immunology techniques, such as chemogenetics and flow cytometry, to determine if activation of these brain
regions can trigger gut inflammation and barrier permeability. Moreover, I aim to identify subsets of enteric
neurons in the intestine that receive signals from the brain during stress to propagate IBS-like symptoms. In
the second aim, I will then assess how inflammatory signals in the gut are conveyed to the brain to influence
stress-relevant behaviors. As the brain can detect the inflammatory state of peripheral tissues through sensory
afferent nerves, I will first identify which stress-responsive brain regions receive input from gut. I will then use
fiber photometry to evaluate how gut inflammation modulates neuronal activity in these brain regions and its
consequences on behavior. In parallel, I will investigate if a compromised intestinal barrier allows bacterial
toxin translocation from the gut lumen into circulation to promote systemic inflammation and depression-like
behaviors. Collectively, this project aims to define bi-directional stress-activated gut-brain circuits that
contribute to IBS- and MDD-related symptoms.

## Key facts

- **NIH application ID:** 10876365
- **Project number:** 5K99DK137037-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Kenny Chan
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $90,000
- **Award type:** 5
- **Project period:** 2023-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10876365

## Citation

> US National Institutes of Health, RePORTER application 10876365, Brain-gut interactions regulating stress-related gut inflammation and barrier permeability (5K99DK137037-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10876365. Licensed CC0.

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