# Mechanisms associated with diet-induced colitis

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $588,884

## Abstract

SUMMARY
Many studies support a role for IL-23 in the pathogenesis of IBD, but it is unclear how IL-23 expression in vivo
promotes colitis. To better study the biology of IL-23 in immune-competent mice we have developed a mouse
model (R23FR mice) in which expression of IL-23 is promoted at low levels in CX3CR1+ cells in the intestine,
upon administration of tamoxifen (TAM). IL-23 induction via repeated cycles of TAM dissolved in a diet (diet
2019) different from the diet used in our facility (diet 5053) led to development of marked colitis that resembled
ulcerative colitis in humans. Cycles of relapse (flares) and remission, observed in humans, were also observed
in these animals upon diet switch. Mechanistic studies demonstrated that the diet switch promoted marked
changes in the microbiota of R23FR mice and their littermate controls (FR mice). Colitis induction and flares
required the presence of the microbiota and CD4+ T cells. CD4+ T cells from the mesenteric LN or colon of
R23FR mice at remission, but not those of controls, transferred disease to Rag-/- mice, but only when the
recipient mice received diet 2019, suggesting previous priming of the CD4+ T cells. Single cell transcriptomic
analysis of the disease-inducing CD4+ T cells demonstrated the existence of distinct populations expressing
the cytokines IL-17, IL-22, IFNγ, chemokines, and cytotoxic molecules. Gene-deficient mice and antibody
blockade showed that IL-22 and IL-17 were not critical for disease development, suggesting the existence of
alternative effector mechanisms. Indeed, in vitro experiments showed that CD4+ T cells from R23FR mice can
directly kill intestinal epithelial cells. Finally, MHC-II expression by epithelial cells was required for disease
development. Using this novel mouse model we will test the general hypothesis that changes in diet occurring
simultaneously with low level expression of IL-23 result in an immune response to the commensal microbiota
or their products. In Aim 1 we will define how diet changes and IL-23 expression promote immune
priming. In Aim 2 we will define how diet changes and IL-23 expression promote effector immune
responses.

## Key facts

- **NIH application ID:** 10093034
- **Project number:** 5R01DK121009-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** SERGIO A. LIRA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $588,884
- **Award type:** 5
- **Project period:** 2020-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10093034

## Citation

> US National Institutes of Health, RePORTER application 10093034, Mechanisms associated with diet-induced colitis (5R01DK121009-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10093034. Licensed CC0.

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