# Intestinal Microbiota Affect Stroke Outcome by Modulating the Dendritic Cell-regulatory T Cell Axis

> **NIH NIH F31** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $44,306

## Abstract

PROJECT SUMMARY
Stroke is a devastating disease and leading cause of death and disability in the United States. Ischemic stroke
results in massive activation of numerous immune cells that can infiltrate the brain following blood-brain-barrier
breakdown. The gut microbiota has previously been identified as a significant factor affecting outcome and
severity of ischemic stroke in clinical studies and animal models. However, mechanisms underlying the
modulatory role of microbiota on immune cells following stroke remain unclear. Dendritic cells (DCs) act as the
bridge between innate and adaptive immunity, with their ability to sample material from the intestinal lumen and
shape T-cell responses. Antibiotic-induced alteration of microbiota in mice results in stroke neuroprotection in
mice following middle cerebral artery occlusion model of ischemic stroke compared to control mice carrying
conventional microbiota, which are similarly treated but carry antibiotic-resistant microbiota resulting in
microbiota similar to that of naïve mice. This effect is attributed to the greater capacity of intestinal and mesenteric
lymph node dendritic cells of mice carrying “altered” microbiota to induce T-regulatory cells (Tregs) in the small
intestine which subsequently suppress destructive pro-inflammatory IL-17+ γδ T cells that traffic to the brain
following stroke. Using our in vitro model to simulate intestinal DC-T cell interactions, we show that priming naïve
DCs with isolated contents from the small intestine (SIC) of mice carrying “altered” or “conventional” microbiota
and subsequent co-culture with CD4 cells similarly induces greater proportions of Tregs following SIC from mice
carrying “altered” microbiota compared to SIC from mice with “conventional” microbiota. This proposal seeks to
elucidate the mechanism by which altering microbiota may result in changes in pattern-recognition receptors or
toll-like receptor ligands that are responsible for a DC-tolerizing phenotype and Treg induction observed with
microbiota alteration in mice. Using a variety of in vitro and in vivo approaches, I aim to identify the DC receptors
and signaling machinery responsible for sensing these luminal contents and producing a tolerogenic phenotype,
determine DC-produced signals/cytokines necessary for intestinal Treg induction, and establish the role of pro-
inflammatory IL-6 in stroke neuroprotection vs poor stroke outcome in mice carrying “altered” or “conventional”
microbiota. In summary, I seek to understand how intestinal DC receptor ligands that are microbiota-dependent
can act as regulators of intestinal immunity and stroke outcome, as well as identify potential therapeutic targets.

## Key facts

- **NIH application ID:** 10974018
- **Project number:** 5F31NS131007-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Emma O'Cinneide
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $44,306
- **Award type:** 5
- **Project period:** 2023-08-01 → 2025-06-17

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10974018

## Citation

> US National Institutes of Health, RePORTER application 10974018, Intestinal Microbiota Affect Stroke Outcome by Modulating the Dendritic Cell-regulatory T Cell Axis (5F31NS131007-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10974018. Licensed CC0.

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