# Control of intestinal innate immunity by the commensal microbiota in a model host

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2021 · $719,763

## Abstract

Abstract/Project Summary
Microbes interact with the intestinal epithelium in ways that modulate susceptibility to infection, malnutrition,
and predisposition to chronic metabolic diseases such as obesity and diabetes. However, the host signaling
pathways utilized by microbes to promote health and disease are poorly understood. The powerful genetic
tools provided by the model arthropod Drosophila melanogaster have enabled many discoveries that form the
basis of our modern understanding of innate immunity. Here we propose to exploit the Drosophila
melanogaster model to define the host signaling pathways that detect intestinal microbes and orchestrate the
innate immune response of the intestinal epithelium.
Drosophila intestinal stem cells, enterocytes and enteroendocrine cells (EECs) carry out functions similar to
those of the mammalian intestine. EECs, which constitute 5-10% of cells in the intestinal epithelium, secrete
enteroendocrine peptides (EEPs) that modulate host metabolic functions such as insulin signaling, satiety, and
intestinal contractions. We have identified a subset of EECs that responds uniquely to the microbial
fermentation product acetate by activating innate immune signaling through the TNF-like Immunodeficiency
(IMD) pathway. In these EECs, IMD signaling increases transcription of the genes encoding EEPs. These
EEPs, in turn, coordinate the response of the diverse cell types in the intestine to microbes. Here we
investigate the mechanism by which microbes activate the intestinal innate immune response and the ultimate
impact of this regulatory pathway on susceptibility to infection.
In this proposal, we will investigate the role of chromatin remodeling in acetate-mediated IMD signaling, the
contribution of peptidoglycan to intestinal IMD signaling, the role of EEPs as cytokines, and finally the cell-
specific roles of EEPs in modulating susceptibility to intestinal infection. The overarching objective of this
research is to uncover novel paradigms of the intestinal innate immune response to microbes with the goal of
informing therapies that modify nutrient utilization in malnutrition, chronic metabolic diseases and susceptibility
to intestinal infection.

## Key facts

- **NIH application ID:** 10360733
- **Project number:** 1R01AI158247-01A1
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** PAULA I WATNICK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $719,763
- **Award type:** 1
- **Project period:** 2021-09-24 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10360733

## Citation

> US National Institutes of Health, RePORTER application 10360733, Control of intestinal innate immunity by the commensal microbiota in a model host (1R01AI158247-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10360733. Licensed CC0.

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