# Mechanisms by Which Alcohol-Induced Dysbiosis Impairs Host Defense Against Klebsiella Pneumoniae

> **NIH NIH R00** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2021 · $246,208

## Abstract

Project Summary/Abstract: Alcohol use disorders (AUD) are a significant global health burden. AUDs are an
established risk factor for bacterial pneumonia, which accounts for ~3.1 million deaths annually. AUD patients
are more frequently infected with highly virulent respiratory pathogens and experience increased morbidity and
mortality from these infections, with Klebsiella pneumoniae being overrepresented in patients with AUDs.
Mortality from Klebsiella pneumonia in patients with AUDs is double that from other pathogens. Further,
preclinical and clinical studies show that alcohol consumption perturbs the normal intestinal microbial
communities (dysbiosis), yet no published data exist linking alcohol-mediated intestinal dysbiosis with respiratory
host defense dysfunction and no attempt has been made to isolate the direct effects of alcohol from those
resulting from intestinal dysbiosis. We have developed a mouse model system that enables us to investigate the
immune modulatory effects of alcohol-associated dysbiosis and isolate the host responses to K. pneumoniae
mediated directly or indirectly by ethanol-associated dysbiosis. Preliminary studies using fecal transfer show that
alcohol-naïve animals recolonized with microbiota isolated from alcohol-fed mice have increased susceptibility
to K. pneumoniae compared to mice recolonized with a control microbiota. The overall hypothesis to be tested
in the proposed study is that alcohol-mediated dysbiosis increases intestinal inflammation and permeability,
which leads to intestinal sequestration of T-cells, altered lung specific T-cell trafficking, and increased
susceptibility to Klebsiella pneumoniae. I will test my hypothesis using both a metabolomics and immunological
approach. Aim 1 will test the prediction that alcohol-dysbiosis promotes intestinal inflammation and permeability.
I will utilize fecal adoptive transfer and cell culture experiments to determine the microbial and metabolic
constituents that promote intestinal inflammation and permeability. Aim 2 will examine the impact of alcohol-dysbiosis
on intestinal T-cell programing and sequestration. I will use T-cell adoptive transfer experiments to
determine the effects of alcohol-dysbiosis on the location/sequestration of T-cells prior to respiratory infection.
Aim 3 will test the prediction that alcohol-dysbiosis impairs lung specific T-cell trafficking. I will assess T-cell
trafficking using microbial and metabolite primed T-cells adoptively transferred into alcohol-naïve animals
recolonized with an alcohol-dysbiotic or pair-fed microbiota.
The proposed studies will use a novel model system to clarify the role of the microbiota in host immune
responses, particularly with regard to AUDs and respiratory infection. The results from these studies will provide
data to support an R01 submission focused on the immunomodulatory effects of alcohol-induced dysbiosis on
the gut-lung axis. The scientific environment, and the research infrastructure prov...

## Key facts

- **NIH application ID:** 10247017
- **Project number:** 5R00AA026336-05
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Derrick R Samuelson
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $246,208
- **Award type:** 5
- **Project period:** 2019-09-20 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247017

## Citation

> US National Institutes of Health, RePORTER application 10247017, Mechanisms by Which Alcohol-Induced Dysbiosis Impairs Host Defense Against Klebsiella Pneumoniae (5R00AA026336-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10247017. Licensed CC0.

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