# The Impact of Circadian Misalignment on Colonic Barrier Homeostasis in Ulcerative Colitis

> **NIH NIH R01** · RUSH UNIVERSITY MEDICAL CENTER · 2022 · $588,018

## Abstract

ABSTRACT
Recently there has been compelling evidence that inflammatory bowel disease (IBD) subjects, both Crohn's
disease (CD) and Ulcerative Colitis (UC), commonly have disrupted sleep, and disrupted sleep correlates with
the risk of disease flare. Sleep/wake cycle, immune function, metabolism and multiple biological processes are
all orchestrated by circadian rhythms. Circadian misalignment between the central circadian clock in the brain
and environment has been found to contribute to a variety of metabolic and gastrointestinal tract (GIT)
diseases. Yet, the prevalence and impact of circadian misalignment on IBD disease activity and GIT mucosal
inflammation have not been established. The long-term objective of our research is to investigate the
hypothesis that circadian malalignment worsens GIT mucosal inflammation and disease course in IBD. To test
this hypothesis, we will conduct a prospective in lab study with human subjects on the impact of circadian
misalignment in left sided mild to moderate Ulcerative Colitis. We will perform two circadian measures phase
assessments under strictly controlled laboratory conditions at: 1) baseline, and after 2) circadian misalignment
after three days of simulated night shifts in both inactive UC patients and healthy control subjects. To test the
hypothesis that UC patients (compared to healthy subject controls) are less resilient to circadian misalignment
we will assess: time impact of our protocol on circadian rhythms (Aim 1) by the following: phase angle of
entrainment [time from dim light melatonin onset to sleep onset] (Aim1a); peripheral circadian rhythms by
clock gene expression in colonic tissue from a flexible sigmoidoscopy and in subjects peripheral blood
mononuclear cells (Aim1b); and colonic clock gene expression and Per2::Luc activity over 24 hours utilizing an
in-vitro model of colonic organoids (Aim1c). Next, we will test the hypothesis that circadian misalignment will
increase colonic permeability and mucosal inflammation in UC patients (vs. Controls) (Aim2) through the
following: endoscopy score, stool calprotectin, colonic barrier (permeability, AJC proteins), and markers of
systemic barrier function and inflammation (Aim 2a); adversely impacting microbial community
structure/function (Aim 2b); and use 2D colonic organoid monolayers to explore ex-vivo barrier function by co-
culturing with TNF-α/INF-γ (Aim 2c). The results of this innovative proposal will greatly increase our
understanding of the important role circadian misalignment may have in UC disease activity and colonic
inflammation, and identify new circadian regulated targets for treatment in UC.

## Key facts

- **NIH application ID:** 10330596
- **Project number:** 5R01DK124280-02
- **Recipient organization:** RUSH UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Garth R Swanson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $588,018
- **Award type:** 5
- **Project period:** 2021-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10330596

## Citation

> US National Institutes of Health, RePORTER application 10330596, The Impact of Circadian Misalignment on Colonic Barrier Homeostasis in Ulcerative Colitis (5R01DK124280-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10330596. Licensed CC0.

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