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

## TL;DR

Long-term alcohol consumption disrupts body function by altering gut bacteria, reducing energy intake, and causing liver and metabolic issues.

## Contribution

A 60-week mouse model reveals systemic effects of chronic ethanol, including gut-liver axis disruption and microbiome changes.

## Key findings

- Chronic ethanol reduced caloric intake and body mass in mice after 52 weeks.
- Ethanol altered gut microbiota and reduced short-chain fatty acids, increasing gut permeability and liver inflammation.
- Ethanol induced dyslipidemia and glucose intolerance despite minimal changes in adipose tissue gene expression.

## Abstract

Chronic ethanol (EtOH) consumption is a major contributor to multi‐organ dysfunction, yet its systemic effects remain incompletely understood. To address this, we utilized a physiologically relevant long‐term mouse model, administering 20% EtOH in drinking water for 60 weeks, to investigate the integrated consequences of chronic exposure. EtOH‐consuming mice (0.4–0.5 mL/day) exhibited > 30% reductions in chow and fluid intake, resulting in a 12% decrease in total caloric intake compared to controls (p < 0.001). Body mass remained similar until Week 52, after which EtOH‐treated mice had lower body mass due to reductions in both lean and fat mass (p ≤ 0.004). Functional assessments revealed impaired treadmill endurance (−17%) and grip strength (−11%) (p ≤ 0.037), while motor coordination remained unaffected (p = 0.203). Chronic EtOH exposure significantly altered gut microbiota composition, reducing Lactobacillus and enriching Faecalibaculum, Clostridium, and Bifidobacterium at the genus level. These changes were accompanied by marked depletion of short‐chain fatty acids (p ≤ 0.05). Indirect markers of gut permeability (serum LPS & zonulin) and liver injury (serum ALT & AST, hepatic amyloid content) were elevated, alongside increased total cholesterol and > 62% upregulation of hepatic TNFα, IL‐6 & serum amyloid A (p ≤ 0.046). EtOH also induced dyslipidemia and glucose intolerance (p ≤ 0.041), although transcriptomic changes in white adipose tissue were minimal despite elevated free fatty acids. In conclusion, chronic EtOH consumption disrupts energy balance, compromises gut barrier integrity, and impairs hepatic metabolism, collectively driving systemic and metabolic dysfunction. These findings underscore the gut‐liver axis as a key mediator of EtOH‐induced pathology and highlight the gut microbiome as a promising therapeutic target.

Chronic ethanol intake disrupts whole‐body homeostasis by reducing energy intake and body mass, impairing physical function, and reshaping the gut microbiome. Microbiota shifts and depletion of short‐chain fatty acids increase gut permeability and drive hepatic inflammation, dyslipidemia, and glucose intolerance. Together, these effects identify the gut–liver axis as a central mediator of ethanol‐induced metabolic dysfunction.