# The Impact and Regulation of IL-6 in Clostridioides difficile Infection

> **NIH NIH F31** · UNIVERSITY OF VIRGINIA · 2021 · $46,036

## Abstract

Project Summary
Clostridioides difficile is a Gram-positive bacterium responsible for more hospital-acquired
infections than any other pathogen. C. difficile infection (CDI) manifests in a range of severity
from diarrheal illness to death, especially in advanced aged patients. Current therapy for CDI
largely relies on antibiotics and, while effective short term, greatly increases the risk for
recurrent infection. To address this issue, we look to identify immunomodulatory approaches
that spare the protective gut microbial communities. In this proposal I will interrogate the role of
IL-6 in CDI disease progression. In preliminary experiments, we found that neutralizing IL-6
worsened disease symptoms in our CDI murine model, suggesting a protective role for IL-6 in
CDI. Further, we found that transcription of a neurotransmitter receptor and positive regulator of
IL-6, the alpha 2 adrenergic receptor(a2ar), is decreased in severe CDI as compared to mild
CDI. Norepinephrine and epinephrine can bind a2ar in immune cells to increase their production
of IL-6. Released IL-6 can act through two signaling pathways: trans-signaling and classical
signaling. IL-6 trans-signaling typically causes pro-inflammatory effects while classical signaling
tends to have anti-inflammatory, regenerative effects. We hypothesize that IL-6 acts through
classical signaling to induce epithelial regeneration and, in turn, decrease disease severity in
CDI. To test this hypothesis, I will use a murine model of CDI. In Aim 1 I will investigate the role
of IL-6 and determine if classical or trans-signaling pathways dictate the effect of IL-6 by
monitoring disease severity and inflammatory profile in models deficient in IL-6 activity or
stimulated or deficient in trans-signaling. In Aim 2, I will identify the primary cellular source of
IL-6 during CDI and determine whether IL-6 production is regulated by catecholamines
norepinephrine and epinephrine in this context. Together, these data will allow us to consider
the signaling axes and cellular determinants that are potentially targetable in CDI. This work not
only has implications for CDI therapy but more broadly, it will allow us to understand the
contributing factors to the pleiotropic role of IL-6 in the gut.

## Key facts

- **NIH application ID:** 10312855
- **Project number:** 1F31AI161787-01A1
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** David Tyus
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 1
- **Project period:** 2021-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10312855

## Citation

> US National Institutes of Health, RePORTER application 10312855, The Impact and Regulation of IL-6 in Clostridioides difficile Infection (1F31AI161787-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10312855. Licensed CC0.

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