Department of Medicine, Division of Gastroenterology; Graduate School of Biomedical Sciences, Translational Science Program; Graduate School of Biomedical Sciences, MD/PhD Program
Biological Phenomena, Cell Phenomena, and Immunity | Cellular and Molecular Physiology | Digestive System | Digestive System Diseases | Gastroenterology | Nervous System | Pathological Conditions, Signs and Symptoms
BACKGROUND: The end-organ effects of alcohol span throughout the entire body, from the gastrointestinal tract to the central nervous system (CNS). In the intestine, alcohol use changes the microbiome composition and increases gut permeability allowing translocation of microbial components into the circulation. Gut-derived pathogen-associated signals initiate inflammatory responses in the liver and possibly elsewhere in the body. Because previous studies showed that the gut microbiome contributes to alcohol-induced liver disease, we hypothesized that antibiotic administration to reduce the gut microbiome would attenuate alcohol-induced inflammation in the brain and small intestine (SI).
METHODS: Six- to 8-week-old C57BL/6J female mice were fed alcohol in a liquid diet or a calorie-matched control diet for 10 days with an acute alcohol binge or sugar on the final day (acute-on-chronic alcohol administration). Some mice were treated with oral antibiotics daily to diminish the gut microbiome. We compared serum levels of TNFalpha, IL-6, and IL-1beta by ELISA; expression of cytokines Tnfalpha, Mcp1, Hmgb1, Il-17, Il-23, Il-6, and Cox2; and inflammasome components Il-1beta, Il-18, Casp1, Asc, and Nlrp3 in the CNS and SI by qRT-PCR. Microglial morphology was analyzed using immunohistochemical IBA1 staining in the cortex and hippocampus.
RESULTS: Antibiotics dramatically reduced the gut microbiome load in both alcohol- and pair-fed mice. Alcohol-induced neuroinflammation and increase in SI cytokine expression were attenuated in mice with antibiotic treatment. Acute-on-chronic alcohol did not induce serum TNFalpha, IL-6, and IL-1beta. Alcohol feeding significantly increased the expression of proinflammatory cytokines such as Tnfalpha, Mcp1, Hmgb1, Il-17, and Il-23 in the brain and intestine. Reduction in the gut bacterial load, as a result of antibiotic treatment, attenuated the expression of all of these alcohol-induced proinflammatory cytokines in both the brain and SI. Alcohol feeding resulted in microglia activation and morphologic changes in the cortex and hippocampus characterized by a reactive phenotype. These alcohol-induced changes were abrogated following an antibiotic-induced reduction in the gut microbiome. Unexpectedly, antibiotic treatment increased the mRNA expression of some inflammasome components in both the brain and intestine.
CONCLUSIONS: Our data show for the first time that the acute-on-chronic alcohol administration in mice induces both neuroinflammation and intestinal inflammation and that reduction in the intestinal bacterial load can attenuate alcohol-associated CNS and gut inflammation. Gut microbiome-derived signals contribute to neuroinflammation in acute-on-chronic alcohol exposure.
Alcohol, Cytokines, Inflammasome, Microbiome, Microglia, Neuroinflammation
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© The Author(s). 2018 Open Access: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
DOI of Published Version
J Neuroinflammation. 2018 Oct 27;15(1):298. doi: 10.1186/s12974-018-1328-9. Link to article on publisher's site
Journal of neuroinflammation
Lowe PP, Gyongyosi B, Satishchandran A, Iracheta-Vellve A, Cho Y, Ambade A, Szabo G. (2018). Reduced gut microbiome protects from alcohol-induced neuroinflammation and alters intestinal and brain inflammasome expression. Open Access Articles. https://doi.org/10.1186/s12974-018-1328-9. Retrieved from https://escholarship.umassmed.edu/oapubs/3638
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This work is licensed under a Creative Commons Attribution 4.0 License.
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