# Maternal-Fetal AHR Signaling in the Pathogenesis and Treatment of Necrotizing Enterocolitis

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $367,398

## Abstract

The goals of the proposed research are to determine the mechanisms that lead to the development of
necrotizing enterocolitis (NEC), and to determine novel therapeutic strategies for this devastating
disease. To do so, we will explore novel roles of the Aryl Hydrocarbon Receptor (AHR) in the pathogenesis of
NEC through its previously unrecognized effects in reducing the inflammatory response to colonizing bacteria
in the premature intestine. We have discovered that toll like receptor 4 (TLR4) activation on the intestinal
epithelium plays a critical role in NEC development, as mice lacking TLR4 on the intestinal epithelium are
protected from NEC. We also determined that TLR4 expression on the intestinal epithelium is higher in the
premature human and mouse intestine, which in mice reflects a novel role played by TLR4 in the regulation of
intestinal differentiation. Importantly, the factors responsible for the elevated TLR4 signaling, and mechanisms
capable of restraining TLR4 in the premature intestine, remain largely unknown. We now show that AHR
expression is low in mouse and human NEC where TLR4 is high, and that activation of AHR within the
newborn intestinal mucosa by dietary ligands, including those present in breast milk, restrain TLR4 signaling
and attenuate NEC. Further, the administration of AHR ligands to the pregnant mother prevents NEC in the
offspring. Importantly, we have identified novel AHR ligands that can prevent NEC in mice through reduced
TLR4 signaling, and which reduce inflammation in human NEC tissue ex vivo. We thus hypothesize that
AHR in the newborn gut plays a previously unrecognized role in restraining the hyper-inflammatory response of
the newborn intestinal mucosa to colonizing microbes by limiting TLR4 signaling in the intestinal epithelium,
thus protecting against NEC, and further, that activation of AHR by dietary factors including those in breast
milk, can restrain TLR4 signaling and prevent NEC. Further, we hypothesize that the administration of an AHR
ligand to the pregnant mother can reduce NEC severity in the pup. Finally, we propose that a recently
discovered AHR ligand in our lab, termed “A18”, may represent a novel strategy for NEC prevention and
treatment. We will test this hypothesis in 3 aims: Aim 1: To understand the role of the Aryl Hydrocarbon
Receptor in the newborn intestinal epithelium in the pathogenesis and treatment of NEC; Aim 2 To
determine the effects and mechanisms by which the administration of a diet rich in AHR ligands to the
pregnant mother protects against NEC in the offspring. Aim 3. To evaluate the role of a recently
discovered AHR agonist, A18, in the prevention and treatment of experimental NEC in mice and piglets.
These studies will make a significant conceptual advance by defining how dietary ligands can activate AHR
and reduce inflammation in the premature intestinal epithelium, and provide a novel approach for NEC
prevention through intra-partum administration of novel AHR ligan...

## Key facts

- **NIH application ID:** 9882256
- **Project number:** 5R01DK117186-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** DAVID J HACKAM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $367,398
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9882256

## Citation

> US National Institutes of Health, RePORTER application 9882256, Maternal-Fetal AHR Signaling in the Pathogenesis and Treatment of Necrotizing Enterocolitis (5R01DK117186-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9882256. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*