# Mechanisms of the gut-brain axis that regulate innate immunity

> **NIH NIH R35** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $435,500

## Abstract

This project addresses the mechanisms of the gut-brain axis by which animals interact with bacterial
pathogens and their microbiota. The focus is on mechanisms by which the nervous system detects the
presence of distinct microbes, and communicates with the intestinal epithelium to elicit host defense
responses. Also of interest is how the intestinal epithelium communicates back with the nervous system to
modulate host physiology and behavior. Over the past ten years, our research program has used C. elegans
as a whole-animal, in vivo model. The advantages of C. elegans include its relative anatomical simplicity and
conserved signaling mechanisms, which enable sophisticated in vivo approaches to dissect inter-organ
communication during infection. In this period, we have made fundamental discoveries including the outsized
roles of TFEB-related transcription factors, acetylcholine-WNT brain-gut signaling, and pathogen-induced
neurodegeneration (PaIN), all of which are conserved in mammals. Thus, our prior research has contributed
to the fundamental understanding of host-microbe interactions and opened new avenues of research. The
present project builds on our prior success and on our new insights into the involvement of sensory neurons
and neurodegeneration in the host-microbe interaction. The goals for the next five years are to elucidate the
neuronal mechanisms of microbial sensing in complex environments, understand the mechanisms of PaIN,
and elucidate the mechanisms of regulation of intestinal host defense genes via TFEB-related transcription
factors by the nervous system, in vivo. Longer term, the overall vision is to produce a comprehensive
understanding of organismal, cellular, and molecular events that take place during initiation and resolution of
infection by pathogens and pathobionts in C. elegans, and to capitalize on the present and future success of
this project by continuing to translate our fundamental findings to murine and human model systems of
infection and inflammation. Because of its focus on the gut-brain axis and the evolutionary conservation of the
mechanisms that we have uncovered, the project is relevant to a broad range of human diseases and
conditions, including infections, immune-mediated diseases, neurodegenerative diseases, metabolic
syndrome, and cancer. We anticipate that the knowledge gained from the proposed work will advance the
field and be generally applicable to higher organisms, and thus inform the search for better therapeutics and
diagnostics for human infections and inflammation.

## Key facts

- **NIH application ID:** 10839430
- **Project number:** 5R35GM149284-02
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Javier Elbio Irazoqui
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $435,500
- **Award type:** 5
- **Project period:** 2023-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10839430

## Citation

> US National Institutes of Health, RePORTER application 10839430, Mechanisms of the gut-brain axis that regulate innate immunity (5R35GM149284-02). Retrieved via AI Analytics 2026-06-06 from https://api.ai-analytics.org/grant/nih/10839430. Licensed CC0.

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