# Mechanisms underlying regulation of intestinal epithelial homeostasis in sepsis

> **NIH NIH R01** · LURIE CHILDREN'S HOSPITAL OF CHICAGO · 2022 · $600,032

## Abstract

Sepsis and severe surgical conditions cause profound decrease in epithelial cell proliferation in the intestinal
crypts. This pathophysiological response disrupts intestinal epithelial homeostasis, which is thought to contribute
to the pathogenesis of sepsis-induced immune dysfunction and multiple organ failure. Evidence shows that
sepsis is associated with increased levels of interferon γ (IFNγ), a proinflammatory cytokine known to inhibit
intestinal epithelial cell (IEC) proliferation in vitro. In preliminary studies, we found that IFNγ plays an important
role in disruption of crypt IEC proliferation in sepsis. The proliferative cells in the intestinal crypts are composed
of Lgr5-expressing crypt base columnar cells (Lgr5+-CBCs, a group of intestinal stem cells [ISCs]) and transit
amplifying cells (TACs). However, the mechanism by which sepsis-activated IFNγ signal affects proliferation of
these cells has not been rigorously studied. Furthermore, little is known about how to sustain proliferation of
Lgr5+-CBCs and TACs to maintain homeostasis in sepsis. Recently, we found that sepsis is associated with de
novo expression of a long noncoding RNA (lncRNA) molecule, H19, in Lgr5+-CBCs and TACs in the intestinal
crypts. Remarkably, we discovered that H19 lncRNA plays a critical role in attenuating sepsis-induced reduction
of crypt IEC proliferation and promoting intestinal epithelial regeneration. Mechanistically, H19 lncRNA binds to
molecules that inhibit cell proliferation and attenuates their activity. Collectively, these data suggest that IFNγ
signaling and H19 lncRNA play opposing roles in the regulation of Lgr5+-CBC and TAC proliferation in sepsis. In
this project, we will test the hypothesis that sepsis-induced inflammation activates de novo expression of H19
lncRNA, which in turn antagonizes the deleterious effect of the IFNγ signal axis, thereby releasing inhibition of
Lgr5+-CBC and TAC proliferation and rescuing homeostasis of the intestinal mucosa. To achieve this goal, we
will execute three complementary aims: (1) We will examine whether and how septic inflammation dysregulates
proliferation of Lgr5+-CBCs and TACs by focusing on the role of IFNγ signaling. We will precisely study the
harmful effect of sepsis on proliferation of Lgr5+-CBCs and TACs in vivo utilizing a clinically relevant mouse
model of polymicrobial sepsis, a novel method that combines 5-ethynyl-2'-deoxyuridine labeling with multi-probe
fluorescence in situ hybridization assay, and flow cytometry and cell sorting technology. Furthermore, we will
delineate how IFNγ signaling leads to inhibition of Lgr5+-CBC and TAC proliferation in sepsis. (2) We will
investigate the molecular mechanisms by which de novo expressed H19 lncRNA antagonizes the inhibitory
effect of sepsis on Lgr5+-CBC and TAC proliferation, taking a multidisciplinary in vivo and in vitro approach that
incorporates cell biology, organoid culture, molecular biology, and mouse genetic engineering techniques. (3)...

## Key facts

- **NIH application ID:** 10337285
- **Project number:** 5R01DK123826-03
- **Recipient organization:** LURIE CHILDREN'S HOSPITAL OF CHICAGO
- **Principal Investigator:** Xiao-Di Tan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $600,032
- **Award type:** 5
- **Project period:** 2020-02-15 → 2022-11-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10337285

## Citation

> US National Institutes of Health, RePORTER application 10337285, Mechanisms underlying regulation of intestinal epithelial homeostasis in sepsis (5R01DK123826-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10337285. Licensed CC0.

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