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

> **NIH NIH R01** · EMORY UNIVERSITY · 2020 · $351,000

## Abstract

Between 100,000 and 250,000 patients with alcohol use disorder develop sepsis annually. Septic patients with
chronic alcohol abuse have increased mortality and severity of multiple organ dysfunction compared to septic
patients without a history of alcohol abuse. This proposal aims to understand why chronic alcohol abuse
worsens outcomes in sepsis, as this common -- and deadly -- scenario is responsible for thousands of deaths
per year and poses a huge financial burden on the U.S. healthcare system. In the previous cycle of finding, we
characterized murine models that replicate the increased mortality seen in alcoholic septic patients compared
to patients who develop sepsis without a history of alcohol abuse. Importantly, while the majority of organs
have similar function and histology between alcohol/septic and water/septic mice, both gut integrity and the
immune system are severely dysregulated in alcohol/septic mice. This is manifested in two complementary
ways. First, abnormalities in gut integrity and the immune response are exacerbated in alcohol/septic mice
compared to water/septic mice. Second, there are a number of differences identified only in alcohol/septic mice
that are not present with either alcohol in isolation or sepsis in isolation. Notably, intestinal permeability is
worsened in alcohol/sepsis, and this is associated with changes in the gut tight junction that are specific to the
combination of alcohol and sepsis. Blockade of the co-inhibitory receptor CTLA-4 is also significantly more
efficacious in alcohol/sepsis than water/sepsis, associated with differences in regulatory T cells and effector
CD4+ cells. Finally, CD43 (which is implicated in T cell homing and activation) expression is delayed in
alcohol/sepsis and survival is altered in septic CD43-/- mice. The proposal seeks to understand the
mechanisms underlying these specific differences in gut permeability and the adaptive immune response in
alcohol/septic mice. Since septic hosts with alcohol use disorders appear to respond differently to a septic
insult than those without a history of alcohol abuse, this may require a different therapeutic approach than
would be needed in a “typical” septic host. As such, this proposal will elucidate mechanisms underlying gut and
immune dysfunction during alcohol/sepsis with the ultimate goal of improving outcomes in this common and
very vulnerable population.

## Key facts

- **NIH application ID:** 9852944
- **Project number:** 5R01AA027396-06
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Craig M Coopersmith
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $351,000
- **Award type:** 5
- **Project period:** 2014-08-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852944

## Citation

> US National Institutes of Health, RePORTER application 9852944, The Impact of Chronic Alcohol Abuse on the Pathophysiology of Sepsis (5R01AA027396-06). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9852944. Licensed CC0.

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