# Modeling Host-Fungal Interactions in Hirschsprung-Associated Enterocolitis

> **NIH NIH R21** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2022 · $48,816

## Abstract

Hirschsprung-associated enterocolitis (HAEC) is a life-threatening complication of Hirschsprung Disease
(HSCR), a common cause of intestinal obstruction in the newborn. HAEC affects 30-60% of infants with HSCR
and carries a mortality of 5-10%, with the majority of deaths occurring in newborns prior to definitive operation.
A critical barrier in the field is that the etiology of HAEC is poorly defined and current treatment remains empiric
(bowel rest, rectal washouts, broad-spectrum antibiotics) and directed toward alleviating acute symptoms rather
than targeting underlying pathophysiology. The long-term goal of our research is to define the pathophysiology
of HAEC and develop novel therapeutic approaches that reduce morbidity and mortality in HSCR patients. Our
prior investigations and those of other groups, utilizing mouse models of HSCR/HAEC as well as human
HSCR/HAEC patient samples, have associated a dysbiotic microbiota with the development of HAEC but have
not directly tested causation or identified targetable molecular mechanisms to prevent or treat the disease. While
almost exclusive focus has been placed on gut bacteria (microbiome), other microbial kingdoms contribute to
the diverse intestinal community, including fungal yeast and molds (mycobiome), but these have largely been
overlooked. Here, we propose a focused investigation of the mucosal barrier responses, including IgA/IgG and
epithelial defense, to fungal pathogens in HSCR/HAEC patient and murine disease specific tissues. Our central
hypothesis that aberrant mucosal immune responses to fungal pathobionts trigger HAEC inflammatory
episodes. Our objectives are to 1) identify the disease-promoting members of the dysbiotic HAEC mycobiome
and 2) define the normal and HAEC mucosal immune response to fungal pathobionts to understand etiological
triggers and targets. We are approaching this problem through a synergistic and long-standing collaboration
between the MPIs laboratories. The proposed research is innovative because it will utilize novel, preclinical
models to establish a causative relationship between dysbiosis of the mycobiome and HAEC pathogenesis. Our
group is uniquely qualified to complete the aims because of our expertise in HSCR/HAEC, host-pathogen
interactions, gnotobiotic expertise, and mucosal immunology. The expected outcome of these studies will be a
deeper understanding of HAEC pathophysiology and identification of novel targets for prevention or treatment of
HAEC.

## Key facts

- **NIH application ID:** 10425448
- **Project number:** 5R21AI163503-02
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** Ankush Gosain
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $48,816
- **Award type:** 5
- **Project period:** 2021-06-09 → 2022-12-16

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10425448

## Citation

> US National Institutes of Health, RePORTER application 10425448, Modeling Host-Fungal Interactions in Hirschsprung-Associated Enterocolitis (5R21AI163503-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10425448. Licensed CC0.

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