# Mechanisms of Altered Gastrointestinal Dysfunction

> **NIH NIH R01** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2020 · $342,000

## Abstract

ABSTRACT:
Diarrhea-predominant, irritable bowel syndrome (IBS-D) is one of the most frequent
gastrointestinal disorders seen and is characterized by abdominal pain, loose watery stools, and
urgency in the absence of an identifiable inflammatory, structural, or metabolic abnormality. One
of the most common and difficult to treat IBS-D groups are those who contract an enteric
infection from food poisoning and subsequently develop post-infectious, diarrhea-predominant,
irritable bowel syndrome (PI-IBS-D). The mechanism(s) of persistent diarrhea and visceral
nociception following resolution of the colitis are unclear and further work is needed to
understand its pathophysiology. It puts an enormous financial burden on health care resources
and decreases quality of life. Unfortunately, pharmacologic therapies for PI-IBS-D remain
limited and unsatisfactory. Therefore, we are focusing on this subpopulation of patients to study
the underling mechanism(s) of post-colitis gastrointestinal dysfunction.
 We now have preliminary data that provides a very strong rationale for the role of Catechol-O-
Methyl-Transferase (COMT) and miRNAs leading to GI dysfunction in PI-IBS-D patients.
Enteric infections alter gastrointestinal function and visceral nociception leading to PI-IBS-D.
We have identified miRNAs in PI-IBS-D patients, modulated by COMT signaling pathways, that
target downstream genes in the colonic enteric nervous system which control post-inflammatory
regulation of gastrointestinal function and visceral nociception. We hypothesize that miRNAs
dysregulate downstream targets following an enteric infection through altered COMT signaling
pathways. These new findings suggest that PI-IBS-D involves dysregulation of complex
regulatory pathways in which miRNAs interact through downstream targets. Our lab has
established techniques to determine inter- and intra-cellular roles of miRNAs in the epigenetic
regulation of the expression of their down-stream target genes. These methods include
interaction analysis of miRNAs; in vitro transfection of miRNAs; and in vivo injection of miRNAs
oligonucleotides. These findings may shed light on the mechanisms of dysregulation of
gastrointestinal function in PI-IBS-D patients. This will overcome a critical barrier to progress in
the management of patients following enteric infection and colitis–absence of effective treatment
interventions and may lead to preventive and/or therapeutic strategies in PI-IBS-D patients that
mimic or inhibit the effects of specific miRNAs on target gene expression.

## Key facts

- **NIH application ID:** 9900345
- **Project number:** 2R01DK099052-06A1
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** George Nicholas Verne
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $342,000
- **Award type:** 2
- **Project period:** 2013-09-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9900345

## Citation

> US National Institutes of Health, RePORTER application 9900345, Mechanisms of Altered Gastrointestinal Dysfunction (2R01DK099052-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9900345. Licensed CC0.

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