# Actions of Resolvins on Intestinal Inflammation and Pain

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $466,549

## Abstract

PROJECT ABSTRACT
Visceral hypersensitivity is frequently observed in a subpopulation of irritable bowel syndrome (IBS)
patients. The responsible mechanism is unclear. Clinical studies show that many of these patients
display subclinical signs of mucosal inflammation accompanied by increased gut permeability. It is
therefore conceivable that impaired mucosal barrier function may facilitate increased antigen
presentation to the immune cells in the submucosa, resulting in inflammation. Mast cells been shown to
play important roles in the innate immune defense by producing proinflammatory agents and pain
mediators which may induce visceral hypersensitivity. Our preliminary data show that resolvins, a novel
class of endogenous anti-inflammatory lipid mediators derived from omega-3 polyunsaturated fatty
acids, are present in the colonic mucosa and play an important role in regulating submucosal mast cell
function and modulating the sensory threshold. Furthermore, our clinical studies show that in IBS-D
patients with gut dysbiosis, the level of colonic resolvin D1 (RvD1) is significantly reduced compared to
that observed in healthy controls. We also observed that resolvin-deficient mice exhibit evidence of
visceral hypersensitivity. The objectives of our studies are 1. to investigate the functional relationship
between the level of resolvins in the colonic tissue and visceral mechanical sensitivity; and 2. to
examine the mechanisms by which resolvins inhibit mucosal inflammation and reduce visceral
hypersensitivity. We hypothesize that the level of RvD1 in the colonic tissue modulates visceral
mechanical sensitivity. We further propose that RvD1 mechanistically controls mast cell activation and
synthesis of proinflammatory mediators, and decreases the excitability of sensory neurons, preventing
the development of visceral hypersensitivity. These beneficial actions of RvD1 are mediated through
the action of formyl peptide receptor 2 (FPR2)/ Gαi to reduce cAMP formation. To test this hypothesis,
we have 3 specific aims: Aim 1: Using 2 rodent models in which colonic RvD1 levels are modulated by
dietary factors and gut microbiota, respectively, we aim to demonstrate that the levels of RvD1 in the
colonic tissue play an important role in regulating visceral mechanical sensitivity; Aim 2: To show in vivo
and in vitro that RvD1 inhibits the degranulation of mast cells and prevents submucosal inflammation
and the development of visceral hypersensitivity. Aim 3: To demonstrate that RVD1 modulates the
excitability of gut-protecting DRG neurons by activating the FPR2 receptor, which in turn reduces
intracellular cAMP levels. Results from these studies will support the use of resolvins as a class of
novel therapeutic agents to reduce submucosal inflammation and decrease pain in IBS patients.

## Key facts

- **NIH application ID:** 10133646
- **Project number:** 5R01DK122350-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Gintautas Grabauskas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $466,549
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133646

## Citation

> US National Institutes of Health, RePORTER application 10133646, Actions of Resolvins on Intestinal Inflammation and Pain (5R01DK122350-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10133646. Licensed CC0.

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