# Host integration of commensal and pathogenic bacterial-derived signals

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $357,750

## Abstract

PROJECT SUMMARY
Enteric bacterial infections remain one of the greatest public health challenges worldwide and deciphering the
mechanisms that protect against infection will enable development of new treatments. Intestinal tissues are in
constant direct contact with diverse beneficial and pathogenic microbes, highlighting the need for orchestrating
complex microbial signals to sustain protection against infection. Intestinal epithelial cells (IECs) reside at the
direct interface between intestinal pathogens, beneficial commensal bacteria, and intestinal immune
components. However, despite continuous exposure to diverse microbes, the mechanisms regulating how
IECs integrate microbial-derived signals to mount protective host responses to pathogens are not well
understood. Epigenetic changes represent a powerful interface that enable cells to respond to environmental
signals and modify gene expression. The goals of this proposal are to interrogate how specific commensal
bacterial-derived metabolites that regulate the epigenetic-modifying enzyme histone deacetylase 3 (HDAC3)
influence intestinal protection against infection and bacterial translocation. Employing Citrobacter rodentium, a
murine model of human enteropathogenic Escherichia coli infection, our studies identified that HDAC3 protects
against enteric bacterial infection. New preliminary data suggest commensal bacterial-derived metabolites can
directly modulate HDAC3 function in IECs and that distinct types of commensal bacteria establish unique
histone acetylation signatures in IECs. Collectively, these data suggest that HDAC3 senses distinct metabolite
signals derived from commensal bacteria to epigenetically prime host defense against pathogenic bacterial
infection. Employing an exciting array of transgenic animals, pathogenic and commensal bacterial strains, and
human intestinal organoids, three specific aims are proposed that will (i) investigate metabolite-dependent
regulation of enteric infection, (ii) decipher how the host calibrates intestinal barrier function by sensing distinct
commensal bacterial-derived metabolites, and (iii) interrogate whether distinct types of commensal bacteria
prime the epigenome to enhance host response to pathogenic bacteria. Defining pathways that integrate
commensal and pathogenic signals will provide a framework to test the therapeutic potential of manipulating
commensal bacterial-derived metabolites to promote antibacterial immunity.

## Key facts

- **NIH application ID:** 9938544
- **Project number:** 5R01DK116868-03
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Theresa Alenghat
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $357,750
- **Award type:** 5
- **Project period:** 2018-06-04 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9938544

## Citation

> US National Institutes of Health, RePORTER application 9938544, Host integration of commensal and pathogenic bacterial-derived signals (5R01DK116868-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9938544. Licensed CC0.

---

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