# Neural sensing of gut bacteria

> **NIH NIH F30** · DUKE UNIVERSITY · 2020 · $46,224

## Abstract

ABSTRACT
The gut continuously senses resident bacteria, but how the brain recognizes these microbes remains
unclear. Microbe-associated molecular patterns such as flagellin are detected by the intestinal
epithelium by pattern recognition receptors such as Toll-like receptor 5. Recent reports have shown
that knocking out this receptor in the gut leads to metabolic syndrome. Pattern recognition receptors
are also known to be preferentially expressed on enteroendocrine cells, or electrically excitable
epithelial cells traditionally thought to signal hormonally. The sponsor’s laboratory has recently
discovered that some of these cells, now known as neuropod cells, are synaptically connected with
vagal and pelvic nerves. My preliminary data show that the neuropod cells preferentially express
Toll-like receptor 5, and that conditionally knocking out the receptor in neuropod cells leads to weight
gain in mice. These data suggest that neuropod cells are critical intermediaries in bacterial signaling
from gut to brain. Therefore, the central hypothesis of the research project is that neuropod cells
transduce flagellin in the lumen of the colon onto the sacral nerve through a synapse. To test this,
two aims are proposed: (1) to determine whether neuropod cells release glutamate in response to
flagellin in vitro, and (2) to test neuropod cell transduction of flagellin onto the sacral nerve in vivo. To
address these aims, state-of-the-art techniques from intestinal epithelial biology and neurobiology will
be combined by the trainee. In Aim 1, acutely dissociated neuropod cells and 3-dimensional organoid
cultures will be imaged for calcium activity and glutamate release in response to flagellin. In Aim 2,
optogenetic and pharmacological silencing of neuropod cells in sacral nerve recordings will be used
to test whether the circuit transduces bacterial signals. These studies are expected to uncover a
novel mechanism for microbes to communicate with the central nervous system that can be used to
develop therapeutics for patients with gastrointestinal disease. This proposal will ultimately support
the training of a dual-degree MD/PhD student, in preparation for his career as an independent
physician-scientist at the intersection of a clinical gastroenterology practice and a neuroscience
laboratory. The training plan will also include attending conferences and participating in organizing
an international society of gut-brain scientists started by his sponsor named Gastronauts. With the
support of this F30, the trainee will develop the requisite skill set to transition into post-doctoral clinical
and research training on the path to becoming an independent physician scientist.

## Key facts

- **NIH application ID:** 9991148
- **Project number:** 1F30DK122712-01A1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Winston W Liu
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $46,224
- **Award type:** 1
- **Project period:** 2020-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991148

## Citation

> US National Institutes of Health, RePORTER application 9991148, Neural sensing of gut bacteria (1F30DK122712-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9991148. Licensed CC0.

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