# Tamoxifen induced hepatotoxicity via gut microbiota-mediated hyodeoxycholic acid depletion and Farnesoid X receptor signaling disruption

## TL;DR

This study shows that tamoxifen causes liver damage by disrupting gut bacteria and bile acid signaling, and suggests a treatment using hyodeoxycholic acid.

## Contribution

The study identifies a novel mechanism of tamoxifen-induced liver injury involving gut microbiota and bile acid-FXR signaling disruption.

## Key findings

- Tamoxifen causes liver injury by altering gut microbiota and reducing hyodeoxycholic acid levels.
- Farnesoid X receptor signaling disruption in the gut-liver axis contributes to tamoxifen hepatotoxicity.
- Hyodeoxycholic acid supplementation reverses tamoxifen-induced liver damage in mice.

## Abstract

Tamoxifen (TAM) is a widely used estrogen receptor modulator for breast cancer treatment. However, TAM exhibits significant hepatotoxicity in the clinic, affecting nearly 50% of patients and thereby limiting its clinical utility. The specific mechanisms underlying TAM-induced liver injury remain poorly understood. In this study, we elucidated the mechanistic role of the gut microbiota in the hepatotoxicity associated with TAM. TAM administration induced substantial liver injury and gut microbiota dysbiosis in mice, characterized by an increased abundance of Escherichia and a reduction in Lachnospiraceae NK4A136 group. These microbial shifts resulted in decreased levels of total fecal bile acids (BA), particularly hyodeoxycholic acid (HDCA), which was inversely correlated with TAM-induced liver injury. Additionally, TAM disrupted BA homeostasis by enhancing intestinal Farnesoid X receptor (FXR) activity and concurrently stimulating hepatic BA synthesis through an alternative nonintestinal FXR mechanism. Notably, gut microbiota depletion reversed these effects, demonstrating the critical role of the microbiota in modulating the gut‒liver FXR axis in TAM-induced liver injury. Fecal microbiota transplantation (FMT) further confirmed that TAM directly stimulated hepatic BA synthesis through a microbiota-dependent mechanism. The disruption of the gut‒liver BA‒FXR axis impaired enterohepatic BA circulation, contributing to the liver toxicity associated with TAM administration. Importantly, HDCA supplementation restored the gut‒liver BA‒FXR axis and alleviated TAM-induced liver injury. These findings highlight the intricate relationship between TAM, gut microbiota, and BA metabolism, suggesting that targeting the gut–liver FXR axis with HDCA may serve as a promising therapeutic strategy for alleviating TAM-associated liver injury.