# Neuro-immune interactions at the intestinal surface

> **NIH NIH R01** · ROCKEFELLER UNIVERSITY · 2024 · $628,922

## Abstract

The gastrointestinal (GI) tract is the largest environmental interface of the mammalian body, which faces the
challenge of maintaining tolerance to dietary and microbial antigens while protecting against pathogen invasion.
In addition to hosting a large collection of immune cells, the GI tract contains diverse and numerous populations
of glial cells and neurons, both intrinsic and extrinsic. Enteric neurons are responsible for controlling various
physiological functions but can be targeted during enteric infections, resulting in functional gastrointestinal
disorders after pathogen clearance. While some mechanisms underlying neuronal damage have been
uncovered, the host and microbial factors that trigger enteric neuron loss and regeneration remain unclear. Over
the past three years, we have uncovered new mechanisms of enteric neuronal cell death following infection or
microbiota depletion and described the role of the gut microbiota and intestinal immune cells in regulating enteric
neuron maintenance and function. In new preliminary data presented in the application, we provide evidence
that enteric glial cells (EGC) experience a similar loss as enteric neurons following infection and antibiotic
treatment. Additionally, our new data strongly suggest that EGC de-differentiation may play a role in neuronal
recovery observed after microbiota transplantation. Finally, candidate metabolites involved in dysbiosis-
associated neuronal death and neuronal recovery were identified. Based on these observations, we hypothesize
that dysbiosis triggered by infection or antibiotic treatment generates ligands that trigger inflammasome-
associated neuronal loss. Upon injury, glia-to-neuron dedifferentiation mediates neuronal recovery in a
microbiota-dependent manner. The three complementary aims will delve deeper into these observations to
reveal novel cellular and molecular mechanisms of microbiota-dependent neuronal death and regeneration,
using novel imaging, state-of-the-art single-nuclei transcriptomics and chromatic accessibility, metabolomics,
murine genetic fate-mapping, gain- and loss-of-function, and gnotobiotic approaches. In Aim 1, we will define
the bacterial species and metabolites associated with specific glia and neuronal cell death after infection or
antibiotic treatment. In Aim 2, we will assess the cellular dynamics of EGC and neuronal recovery after microbiota
transplantation, followed by fate-mapping studies to define the possible role of glial cell de-differentiation in this
process. Finally, Aim 3 will use complementary gnotobiotic and metabolomic approaches to identify bacterial
signals and host pathways that induce gliogenesis and neurogenesis in different contexts. Overall, this proposal
seeks to uncover novel mechanisms of microbiota-dependent neuronal death and regeneration with implications
for the treatment of functional gastrointestinal disorders.

## Key facts

- **NIH application ID:** 10827169
- **Project number:** 2R01DK126407-05
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Daniel S Mucida
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $628,922
- **Award type:** 2
- **Project period:** 2024-04-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10827169

## Citation

> US National Institutes of Health, RePORTER application 10827169, Neuro-immune interactions at the intestinal surface (2R01DK126407-05). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10827169. Licensed CC0.

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