# Regulation of intestinal epithelial barrier and motility by the LPA1 receptor in the enteric nervous system

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2024 · —

## Abstract

Gastrointestinal (GI) problems are common during military conflict, and these exert significant adverse effects
on the health of service members involved in warfare. The onset of a GI disorder can be triggered by severe
stress and infections of the digestive tract. It is becoming more evident that high levels of anxiety that military
personnel face during war may contribute to the increased risk of developing GI disorders such as irritable bowel
syndrome (IBS) and inflammatory bowel disease (IBD). The GI tract is lined with a protective monolayer of
epithelial cells that separates the host from the hostile environment of the GI tract and increased intestinal
permeability has been linked to chronic GI symptoms in Gulf War veterans. The mucosal epithelial layer is
densely innervated by nerve fibers originating from the enteric nervous system (ENS), which is essential for GI
motility, ion secretion, fluid absorption, and epithelial barrier permeability. Unraveling the mechanisms of
epithelial and ENS interactions remains technically challenging, and much work remains to be done regarding
our understanding of how ENS influences intestinal epithelium. Lysophosphatidic acid (LPA) is a simple bioactive
phospholipid that exhibits numerous biological functions acting through six widely distributed G protein-coupled
receptors, LPA1-6. Our studies using mice with global loss of the LPA1 receptor have indicated a role for LPA1
signaling in intestinal epithelial barrier function and wound healing. Other have shown that the LPA1 receptor is
a critical mediator of neurological function so that the lack of LPA1 receptor leads to stress hypersensitivity,
anxious-depression phenotype, and dysregulation of pain perception. The proposed study is based on our
preliminary findings that mice lacking the LPA1 receptor in the ENS (Lpar1ΔENS) display dysregulated GI motility
and reduced numbers of enteric neurons and glial cells. Additionally, we observed that inhibition of the LPA1
receptor in enteric glial cells causes intestinal epithelial barrier defects. We hypothesize that LPA1 receptor
signaling in the ENS plays a role in the regulation of GI motility and intestinal barrier function and that the loss of
LPA1 function in the ENS leads to intestinal inflammation associated with increased levels of stress. We will use
established cell lines, primary cells, and novel mouse models to explore the role of LPA1 receptor in the
regulation of enteric neuron and EGC survival and intestinal motility (Aim 1). Aim 2 will examine the role of enteric
neuroglial LPA1 receptor in the regulation of epithelial barrier function. In Aim 3, we will study whether the loss
of LPA1 in the ENS increases the susceptibility of intestinal inflammation.

## Key facts

- **NIH application ID:** 10801611
- **Project number:** 1I01BX006369-01
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Changhyon Chris Yun
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2024-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10801611

## Citation

> US National Institutes of Health, RePORTER application 10801611, Regulation of intestinal epithelial barrier and motility by the LPA1 receptor in the enteric nervous system (1I01BX006369-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10801611. Licensed CC0.

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