# The Impact of Chronic Alcohol Abuse on the Pathophysiology of Sepsis

> **NIH NIH R01** · EMORY UNIVERSITY · 2024 · $352,125

## Abstract

Over 100,000 patients with alcohol use disorder develop sepsis annually in the United States. Patients with
alcohol use disorder who develop sepsis are significantly more likely to die or have a complicated intensive
care unit stay than septic patients without a history of alcohol use disorder. This proposal aims to understand
why alcohol use disorder worsens outcomes in sepsis, as understanding this could lead to precision medicine
approaches in this patient population. Using a model of chronic alcohol ingestion that does not result in
detectable end organ damage followed by sepsis, we are able to identify possible mechanisms for why
mortality is worse in alcohol/sepsis. While the majority of organs have similar function and histology between
alcohol/septic and water/septic mice, both gut integrity and the adaptive immune system are severely
dysregulated in alcohol/septic mice. Intestinal permeability is mediated through three different pathways that
allow selective movement of gut luminal contents into the host. Each of these pathways is worsened in
alcohol/sepsis, leading to gut hyperpermeability. The pore and leak pathways are mediated via the apical tight
junction, allowing molecules of different sizes to pass through, although notably intact bacteria are too large to
pass through either pathway. Increased gut permeability leads to altered host inflammation. CD103 is a key
component in orchestrating immune responses in mucosal tissues, ensuring the body's defense against
infections while preventing unwarranted immune reactions that could harm host tissues. Additionally, under
normal conditions, Foxp3+ regulatory T cells are essential for maintaining immune homeostasis and preventing
excessive inflammation. However, during sepsis, the balance between pro-inflammatory and anti-inflammatory
responses becomes disrupted and impaired function of regulatory T cells allows for uncontrolled activation of
effector T cells and other immune cells, thus contributing to the sepsis-induced cytokine storm and organ
damage. Notably, CD103 is downregulated on CD4+ T cells and CD8+ T cells in alcohol/sepsis while regulatory
T cells are increased within the CD4+ T cell compartment in alcohol/sepsis. This proposal seeks to understand
the mechanisms underlying specific differences in alcohol/septic mice compared to water/septic mice with the
ultimate goal of improving outcomes in septic patients with alcohol use disorder prior to hospital admission.

## Key facts

- **NIH application ID:** 10981337
- **Project number:** 2R01AA027396-10
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Craig M Coopersmith
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $352,125
- **Award type:** 2
- **Project period:** 2014-08-01 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981337

## Citation

> US National Institutes of Health, RePORTER application 10981337, The Impact of Chronic Alcohol Abuse on the Pathophysiology of Sepsis (2R01AA027396-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10981337. Licensed CC0.

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