# Mechanisms of Experimental Crohn's Disease

> **NIH NIH R56** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $402,500

## Abstract

PROJECT SUMMARY
Crohn's disease (CD) affects more than 1.5 million individuals in the US alone and several million worldwide.
Despite significant advances in our understanding of the mechanism(s) of chronic intestinal inflammation, the
precise cause of disease is still unknown; therefore, available treatment modalities are not curative and possess
significant side effects. Increasing evidence suggest that the interactions between dietary components, including
food additives and artificial sweeteners (AS), the gut microbiome and the host mucosal immune system, may
play a critical role in either promoting or alleviating intestinal inflammation. However, little is known regarding the
specific role of AS that are used in large amounts by the general population, including IBD patients, to control
body weight and blood glucose, and their impact on the pathogenesis of small intestinal inflammation,
characteristic of CD. This renewal application will focus on the effects of different AS on the gut microbiome and
the intestinal mucosal immune system in the pathogenesis of SAMP CD-like ileitis. The central hypothesis is
that AS may have detrimental effects in regulating chronic intestinal inflammation by promoting proinflammatory
host-microbial interactions. The specific aims are: 1) Characterize the effects of different AS on the development
of ileitis in SAMP mice. We will test the hypothesis that AS have pro-inflammatory effects in the development of
CD-like ileitis. A series of in vivo experiments using 4 different commonly used AS (Equal, Sweet'N Low, Splenda
and Stevia) and their matched vehicle controls (Dextrose and Maltodextrin) or water and table sugar (sucrose),
will be tested in preclinical studies. 2) Determine the effects of AS on the composition and function of the gut
microbiome. The working hypothesis of this aim is that AS induce primary proinflammatory changes on gut
microbiome composition that are sufficient to promote intestinal inflammation in CD-like ileitis. We will first feed
AS to germ-free (GF) SAMP mice and control mice to determine the effects of AS on the severity of GF-SAMP
intestinal inflammation. We will then perform a series of in vitro experiments using stool samples from mice and
humans to characterize the effects of AS products and ingredients on gut microbiome composition. Finally, we
will conduct `humanized' FMT experiments into GF-SAMP mice (with feces from CD patients or healthy donors)
to determine if the AS-altered fecal microbiota increases the severity of intestinal inflammation in transplanted
GF-SAMP mice in vivo. 3) Determine the effects of artificial sweeteners on the gut mucosal immune system.
Using bone marrow chimera experiments and lymphocyte-depleted SAMP (i.e., SAMPxRag2-/-) mice, we will
first determine the role of T and B cells in response to AS. We will then study the role of Teff and Treg cells by
utilizing newly generated (SAMP×Foxp3gfp mice). Finally, using state-of-the-art scRNAseq techniques, w...

## Key facts

- **NIH application ID:** 10478316
- **Project number:** 2R56DK055812-19
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Fabio Cominelli
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $402,500
- **Award type:** 2
- **Project period:** 1999-07-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10478316

## Citation

> US National Institutes of Health, RePORTER application 10478316, Mechanisms of Experimental Crohn's Disease (2R56DK055812-19). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10478316. Licensed CC0.

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