# Selective Depletion of Gut Gram-Negative Bacteria Attenuates Alcohol Binge-Induced Cardiovascular Dysfunction by Lowering Cardiac Anandamide Levels

## TL;DR

Reducing gut Gram-negative bacteria lessens heart problems caused by binge drinking by lowering heart levels of a compound called anandamide.

## Contribution

The study reveals that gut Gram-negative bacteria influence heart dysfunction after alcohol binge via cardiac anandamide levels.

## Key findings

- Selective depletion of gut Gram-negative bacteria reduced cardiac anandamide levels after alcohol binge.
- Antibiotic treatment improved gut barrier function and lowered circulating endotoxins.
- Alcohol-induced cardiac anandamide formation was not linked to toll-like receptor-4 signaling.

## Abstract

Binge drinking contributes to an increasing number of emergency department visits in the United States. Previous work demonstrated that an alcohol binge impairs cardiac performance and exerts complex hemodynamic effects through the activation of the endocannabinoid-mediated cannabinoid type 1 receptor (CB1R) signaling pathway. Anandamide (AEA), an endogenous CB1R agonist, is synthesized in response to various stressors and tissue injury. However, the role of binge drinking in increasing myocardial AEA levels, which leads to CB1R-dependent cardiodepression, remains unclear. This work studied how endotoxins from intestinal Gram-negative bacteria affect myocardial AEA levels, which further induce CB1R-dependent cardiac dysfunction following acute alcohol intoxication. Using a murine model of a single alcohol binge (5 g/kg orally), reduced mesenteric microcirculation concurrent with elevated circulating endotoxin levels was observed. Selective depletion of gut Gram-negative bacteria by antibiotics partially ameliorated alcohol-induced gut barrier dysfunction, significantly lowered circulating endotoxins, coinciding with reduced cardiac AEA levels at 3 hours after binge. These changes were paralleled with moderately improved cardiac performance and vascular tone. Cardiac RNA levels of genes involved in AEA synthesis increased after alcohol binge, but not in antibiotic-pretreated mice. However, acute alcohol-induced cardiac AEA formation was unrelated to toll-like receptor-4 signaling. These findings provide novel insights that highlight the pivotal role of intestinal Gram-negative bacteria in modulating cardiac AEA levels after an alcohol binge, leading to cardiovascular dysfunction.