Systemic Consequences of Chronic Ethanol Intake: From Microbiome Shifts to Metabolic Impairment

Authors
Muni Swamy Ganjayi, Thomas A. Krauss, Gage E. Demster, Sehyung Park, Garrett B. Anspach, Sarah R. Anthony, Shaohua Wang, Michael Tranter, Robert N. Helsley, Cory W. Baumann


Lab

Journal
Comprehensive Physiology

Abstract
The chronic and excessive EtOH exposure used in this study likely impaired liver function through multiple mechanisms. EtOH metabolism in hepatocytes generates reactive oxygen species (ROS) and disrupts lipid homeostasis, leading to the accumulation of cholesterol, bile acids, and FFAs in the liver (Osna et al.2017; You and Arteel2019). Additionally, increased gut permeability elevates circulating LPS levels, which activate Kupffer cells and amplify cytokine production, thereby promoting inflammation (Osna et al.2017; Rao et al.2004). In our model, consumption of 20% EtOH resulted in significant liver injury, as evidenced by elevated serum ALT and AST levels and increased hepatic expression of the proinflammatory cytokines TNFα and IL-6, and the acute-phase protein serum amyloid A. Notably, the presence of hepatic amyloid deposition was unexpected, though not without precedent, at least in the case of amyloid-β. It was recently found that intragastric EtOH feeding increased hepatic amyloid-β content 61% in mice, accompanied by alterations in LRP1 and APP expression (Chandrashekar et al.2024; Garcia et al.2022), findings that largely align with those observed here. Despite downregulation of genes and proteins involved in cholesterol biosynthesis, we and others have reported hepatic accumulation of total cholesterol and primary bile acids following chronic EtOH exposure, including cholic acid, 7-keto-deoxycholic acid, and taurine-conjugated cholic acid (Donepudi et al.2018; Willis et al.2026). Furthermore, levels of secondary bile acids appear reduced in the livers of EtOH-fed mice (Willis et al.2026), implicating disrupted gut–liver signaling in the loss of bile acid homeostasis (Brandl et al.2018; Jew and Hsu2023). Taken together, these observations underscore the complexity of EtOH-induced liver injury and highlight impaired gut–liver signaling and hepatic homeostatic dysfunction as key contributors to disease progression.

Keywords/Topics
alcohol use disorder; dyslipidemia; gut-liver axis; tissue dysfunction

Source :

https://onlinelibrary.wiley.com/doi/abs/10.1002/cph4.70132

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