# Regulation of Experimental Colitis by Enteric Neurons

> **NIH NIH R03** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $82,640

## Abstract

PROJECT SUMMARY
Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn disease, is a chronic and
progressive inflammatory disorder of the gastrointestinal (GI) tract most often diagnosed in
adolescence and young adulthood. While significant progress has been made, current treatments
for IBD are still often unsatisfactory, associated with long-term failure and side effects.
Investigation into the underlying pathogenesis and mechanisms of this condition are warranted to
identify new targets to develop novel treatment strategies. The autonomic nervous system
regulates key functions of the GI tract, including both intrinsic (enteric nervous system, ENS) and
extrinsic (sympathetic and parasympathetic) control of the intestine. Abnormalities of autonomic
nerve function have been described in patients with IBD and several studies suggest that the ENS
may play a role in the development and severity of intestinal inflammation. Acetylcholine (ACh)
from extrinsic parasympathetic nerves is known to have an anti-inflammatory effect on the gut via
the cholinergic anti-inflammatory pathway (CAIP). However, it is unknown whether ACh or other
neurotransmitters derived from the neurons of the ENS have a similar role. In preliminary
experiments, we find that the severity of experimentally induced colitis is worse in regions of focal
ENS ablation. Therefore, we hypothesize that the intrinsic neurons of the ENS can exert an anti-
inflammatory effect in the colon and that this can be leveraged for therapeutic applications. To
test this, we propose the following aims: (1) to determine the mechanisms by which intrinsic
enteric neurons attenuate inflammation in experimental colitis and to (2) examine whether ENS
cell transplantation can reduce inflammation in a mouse model of IBD. We will utilize a novel IBD
mouse with colonic aganglionosis that we recently developed by local injection of human
diphtheria toxin (DT) into transgenic mice that express DT receptor in the ENS. Focal ablation of
either all enteric neurons or the cholinergic enteric neurons will be followed by induction of colitis
to determine the anti-inflammatory roles of the ENS (Aim 1). We will then purify enteric neuronal
stem cells, enteric neurons, and enteric cholinergic neurons and transplant these into recipient
mice with focal colonic aganglionosis following induction of colitis. The impact of cell therapy on
the severity of inflammation will be examined (Aim 2). The results obtained will provide new
insights into the anti-inflammatory role of the ENS and identify new strategies for treating IBD.

## Key facts

- **NIH application ID:** 10195754
- **Project number:** 1R03HD104877-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Ryo Hotta
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $82,640
- **Award type:** 1
- **Project period:** 2021-04-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10195754

## Citation

> US National Institutes of Health, RePORTER application 10195754, Regulation of Experimental Colitis by Enteric Neurons (1R03HD104877-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10195754. Licensed CC0.

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