GSBS Dissertations and Theses

ORCID ID

0000-0003-0341-7218

Publication Date

2018-07-18

Document Type

Doctoral Dissertation

Academic Program

MD/PhD

Department

Medicine

First Thesis Advisor

Dr. Gyongyi Szabo

Keywords

Alcohol, central nervous system, liver, intestine, microbiome, macrophage, microglia, immunology, innate immunity, chemokine, cytokine, CCR2

Abstract

Alcohol is a commonly consumed beverage, a drug of abuse and an important molecule affecting nearly every organ-system in the body. This project seeks to investigate the interplay between alcohol’s effects on critical organ-systems making up gut-liver-brain axis.

Alcohol initially interacts with the gastrointestinal tract. Our research describes the alterations seen in intestinal microbiota following alcohol consumption in an acute-on-chronic model of alcoholic hepatitis and indicates that reducing intestinal bacteria using antibiotics protects from alcohol-induced intestinal cytokine expression, alcoholic liver disease and from inflammation in the brain. Alcohol-induced liver injury can occur due to direct hepatocyte metabolic dysregulation and from leakage of bacterial products from the intestine that initiates an immune response. Here, we will highlight the importance of this immune response, focusing on the role of infiltrating immune cells in human patients with alcoholic hepatitis and alcoholic cirrhosis. Using a small molecule inhibitor of CCR2/CCR5 chemokine receptor signaling in mice, we can protect the liver from damage and alcohol-induced inflammation. In the brain, we observe that chronic alcohol leads to the infiltration of macrophages in a region-specific manner. CCR2/CCR5 inhibition reduced macrophage infiltration, alcohol-induced inflammation and microglial changes. We also report that chronic alcohol shifts excitatory/inhibitory synapses in the hippocampus, possibly through complement-mediated remodeling. Finally, we show that anti-inflammasome inhibitors altered behavior by reducing alcohol consumption in female mice.

Together, these data advance our understanding of the gut-liver-brain axis in alcoholism and suggest novel avenues of therapeutic intervention to inhibit organ pathology associated with alcohol consumption and reduce drinking.

DOI

10.13028/hxgs-mf56

Rights and Permissions

Copyright is held by the author, with all rights reserved.

Available for download on Sunday, August 23, 2020

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