# Urolithin A regulates gut: liver axis to ameliorate alcohol-associated liver disease

## TL;DR

Urolithin A may help treat alcohol-related liver disease by improving gut barrier function and reducing inflammation and fat buildup in the liver.

## Contribution

This study identifies Urolithin A as a potential therapeutic agent for alcohol-associated liver disease through gut-liver axis modulation.

## Key findings

- Urolithin A protects against ethanol-induced gut barrier dysfunction and inflammation in vitro and in vivo.
- Urolithin A reduces hepatic steatosis and inflammation in preclinical models of alcohol-associated liver disease.
- The protective effects of Urolithin A depend on the Aryl hydrocarbon receptor in intestinal epithelial cells.

## Abstract

Excessive alcohol consumption poses a significant global health concern, ranking as the world’s third-largest risk factor for diseases and disabilities, contributing to 5.9% of all deaths worldwide. Among various disorders linked to alcohol misuse, alcohol-associated liver disease (ALD) is the most prominent. ALD patients often exhibit increased intestinal permeability, systemic inflammation, gut dysbiosis, and hepatic steatosis. No FDA-approved therapies are available to treat ALD or to resolve the pathological domains of alcohol-induced gut barrier dysfunction, inflammation, and steatosis. The goal of this study is to investigate the potential therapeutic role of the microbial metabolite Urolithin A’ (UroA), in alleviating ALD.

Caco-2 (monolayer colon epithelial) cells and AML12 (hepatocytes) cells were used to test the protective activities of UroA against EtOH-induced gut barrier dysfunction and lipid accumulation in vitro. Preclinical ALD mouse models were used to test the therapeutic potential of UroA against EtOH exposure. Additionally, we generated cell-specific deletion mice with aryl hydrocarbon receptor (AHR) deletion to define the role of intestinal epithelial cell AHR in UroA-mediated protective activities against ALD.

The results presented here demonstrate the efficacy of UroA as a potential therapeutic agent to protect against EtOH-induced disruption of tight junction proteins, inflammation, and lipogenesis both in vitro and in vivo models.

Our findings suggest that the simultaneous targeting of gut barrier dysfunction, inflammation, and hepatic steatosis by treatment with UroA may offer new possibilities for combating ALD. Moreover, our results suggest that UroA-mediated protective activities against EtOH-induced gut barrier dysfunction and inflammation in ALD are dependent on intestinal epithelial cell-AHR.

EtOH, Ethanol; AHR, Aryl hydrocarbon receptor; IEC, Intestinal epithelial cells.Diagram illustrating the effects of ethanol and urolithin A on the body. On the left, ethanol leads to a leaky gut, inflammation, fatty liver, and hepatitis, depicted with alcohol bottles and liver images. On the right, urolithin A treatment enhances gut barrier function, decreases gut permeability, endotoxins, inflammatory cytokines, and lipid accumulation. Icons represent intestinal epithelial cells (IEC), macrophages, and hepatocytes.

EtOH, Ethanol; AHR, Aryl hydrocarbon receptor; IEC, Intestinal epithelial cells.