Over 100,000 patients with alcohol use disorders 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. We have created a murine model that replicates the increased mortality seen in alcoholic septic patients compared to patients who develop sepsis without a history of alcohol abuse. While the majority of organs are similar between alcohol-fed and water-fed septic mice, we found that both gut integrity and the immune system are severely dysregulated in alcohol-fed septic mice. Two key and complementary themes emerged in comparing alcohol-fed septic mice and water-fed septic mice: 1) abnormalities in gut integrity and the immune response are exacerbated in alcohol-fed septic mice and perhaps more importantly, 2) there are a number of mechanisms that appear to be specific to the combination of sepsis and chronic alcohol usage. Specifically, multiple abnormalities are present with the combination of chronic alcohol ingestion and sepsis that are not present with either chronic alcohol ingestion or sepsis in isolation. The proposal seeks to understand these mechanisms by examining both gut integrity (apoptosis, permeability, proliferation, and villus length) and the host immune response (primarily focusing on CD4+ T cells and NK cells). Finally, the proposal examines crosstalk between the gut and the immune system, seeking to understand how changing gut integrity alters the host response and reciprocally how altering the immune response changes gut integrity in alcohol-fed 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. Understanding the mechanisms underlying mortality in sepsis following chronic alcohol ingestion therefore has significant public health implications in a disease that is common, very costly, and highly lethal.

Public Health Relevance

Over 100,000 patients with alcohol use disorders develop sepsis annually, and 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. Both gut integrity and the immune system are severely dysregulated in alcohol-fed septic mice, and many of these abnormalities are specific to the combination of sepsis and chronic alcohol usage. Understanding mechanisms underlying why mortality is higher in alcoholic septic hosts may have significant implications in a disease that is common, very costly, and highly lethal.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01GM109779-01
Application #
8662516
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Dunsmore, Sarah
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Emory University
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Atlanta
State
GA
Country
United States
Zip Code
30322
McConnell, Kevin W; Coopersmith, Craig M (2016) Pathophysiology of septic shock: From bench to bedside. Presse Med 45:e93-8
Lyons, John D; Ford, Mandy L; Coopersmith, Craig M (2016) The Microbiome in Critical Illness: Firm Conclusions or Bact to Square One? Dig Dis Sci 61:1420-1
Klingensmith, Nathan J; Yoseph, Benyam P; Liang, Zhe et al. (2016) Epidermal Growth Factor Improves Intestinal Integrity and Survival in Murine Sepsis Following Chronic Alcohol Ingestion. Shock :
Liu, Danya; Burd, Eileen M; Coopersmith, Craig M et al. (2016) Retrogenic ICOS Expression Increases Differentiation of KLRG-1hiCD127loCD8+ T Cells during Listeria Infection and Diminishes Recall Responses. J Immunol 196:1000-12
Yoseph, Benyam P; Klingensmith, Nathan J; Liang, Zhe et al. (2016) Mechanisms of Intestinal Barrier Dysfunction in Sepsis. Shock 46:52-9
Klingensmith, Nathan J; Coopersmith, Craig M (2016) The Gut as the Motor of Multiple Organ Dysfunction in Critical Illness. Crit Care Clin 32:203-12
Margoles, Lindsay M; Mittal, Rohit; Klingensmith, Nathan J et al. (2016) Chronic Alcohol Ingestion Delays T Cell Activation and Effector Function in Sepsis. PLoS One 11:e0165886
Lyons, John D; Mittal, Rohit; Fay, Katherine T et al. (2016) Murine Lung Cancer Increases CD4+ T Cell Apoptosis and Decreases Gut Proliferative Capacity in Sepsis. PLoS One 11:e0149069
Krummey, Scott M; Ford, Mandy L (2015) New insights into T-cell cosignaling in allograft rejection and survival. Curr Opin Organ Transplant 20:43-8
Mittal, Rohit; Chen, Ching-Wen; Lyons, John D et al. (2015) Murine lung cancer induces generalized T-cell exhaustion. J Surg Res 195:541-9

Showing the most recent 10 out of 11 publications