# Optogenetic activation of enteric cholinergic neurons to treat colitis

> **NIH NIH R03** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $81,096

## Abstract

Project Summary
The overarching objective of this proposal is to establish a new and innovative strategy for Inflammatory
bowel disease (IBD) treatment that leverages the important role of cholinergic innervation in mediating
intestinal inflammation. Current treatments of IBD have limited efficacy and fail to promote sustained disease
remission, necessitating surgical intervention in the majority of patients. The development of an effective,
durable, and well-tolerated therapy is a major unmet need. Developing a neuroimmune therapy for IBD will
add a valuable and complementary new approach to treating this disease and hopefully reducing its long-
term consequences. It has been shown that intestinal inflammation can lead to enteric neuronal injury and
subsequent intestinal dysfunction, including disorders of gut motility. Damage to the enteric nervous system
(ENS) may also contribute to the development and severity of intestinal inflammation. Therefore, the ENS
emerges as a critical participant in immunomodulation within the gut. Previous studies have demonstrated
that cholinergic neurons directly interact with muscularis macrophages, and their numbers are reduced in
inflammation. Our preliminary data show for the first time that selective optogenetic stimulation of cholinergic
neurons attenuates colitis, while ablation of enteric cholinergic neurons worsens inflammation in DSS-
induced acute colitis. We hypothesize that enteric cholinergic signalling can be harnessed as a novel
therapeutic strategy for the treatment of IBD. In the proposed study, we will first determine the mechanism
by which cholinergic signaling attenuates inflammation by investigating the impact of cholinergic neuronal
activation on muscularis macrophage polarization and cytokine production. Second, we will use optogenetics
to selectively stimulate enteric cholinergic neurons in Winnie mice, a well-established model of chronic colitis
that closely resembles human IBD to determine the effect of cholinergic signaling on disease onset and the
severity of inflammation. As parameters of anti-inflammatory activity, we will investigate changes in
morphology and inflammatory indices, as well as changes in smooth muscle contractility and motility as
measured by organ bath experiments and electromyography. These studies will provide important insights
into the mechanisms by which cholinergic neurons can improve colitis and offer a potential novel treatment
strategy for IBD.

## Key facts

- **NIH application ID:** 10949136
- **Project number:** 1R03AI185293-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** ALLAN M GOLDSTEIN
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $81,096
- **Award type:** 1
- **Project period:** 2024-06-21 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10949136

## Citation

> US National Institutes of Health, RePORTER application 10949136, Optogenetic activation of enteric cholinergic neurons to treat colitis (1R03AI185293-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10949136. Licensed CC0.

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