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

Tamoxifen administration induced substantial liver injury in mice affecting nearly 50% of patients in clinical settings.

• TAM exhibits significant hepatotoxicity in the clinic, affecting nearly 50% of patients, thereby limiting its clinical utility.
• TAM administration induced substantial liver injury in mouse models used in this study.
• The specific mechanisms underlying TAM-induced liver injury were previously poorly understood.

TAM administration caused gut microbiota dysbiosis characterized by increased abundance of Escherichia and reduced Lachnospiraceae NK4A136 group.

• TAM administration induced substantial gut microbiota dysbiosis in mice.
• The dysbiosis was specifically characterized by an increased abundance of Escherichia.
• A concurrent reduction in Lachnospiraceae NK4A136 group was observed following TAM administration.
• These microbial shifts were associated with downstream changes in bile acid metabolism.

TAM-induced gut microbiota dysbiosis resulted in decreased levels of total fecal bile acids, particularly hyodeoxycholic acid (HDCA), which was inversely correlated with liver injury.

• The microbial shifts from TAM resulted in decreased levels of total fecal bile acids.
• Hyodeoxycholic acid (HDCA) was specifically identified as a depleted bile acid species.
• HDCA levels were inversely correlated with TAM-induced liver injury.
• The depletion of HDCA was identified as a key mediator of TAM hepatotoxicity.

TAM disrupted bile acid homeostasis by enhancing intestinal FXR activity while concurrently stimulating hepatic bile acid synthesis through an alternative nonintestinal FXR mechanism.

• TAM disrupted BA homeostasis by enhancing intestinal Farnesoid X receptor (FXR) activity.
• Simultaneously, TAM stimulated hepatic BA synthesis through an alternative nonintestinal FXR mechanism.
• This dual disruption of the gut-liver FXR axis impaired enterohepatic BA circulation.
• The impairment of enterohepatic BA circulation contributed to the liver toxicity associated with TAM administration.

Gut microbiota depletion reversed TAM-induced effects on bile acid homeostasis and FXR signaling, demonstrating the critical role of the microbiota.

• Gut microbiota depletion reversed the effects of TAM on the gut-liver FXR axis.
• This reversal demonstrated the critical role of the microbiota in modulating the gut-liver FXR axis in TAM-induced liver injury.
• The experiment confirmed that the microbiota was mechanistically required for TAM's disruption of bile acid homeostasis.

Fecal microbiota transplantation confirmed that TAM directly stimulated hepatic bile acid synthesis through a microbiota-dependent mechanism.

• Fecal microbiota transplantation (FMT) was used to further confirm the role of gut microbiota.
• FMT confirmed that TAM directly stimulated hepatic BA synthesis through a microbiota-dependent mechanism.
• This finding established a causal relationship between TAM-induced gut microbiota changes and hepatic bile acid synthesis.

HDCA supplementation restored the gut-liver bile acid-FXR axis and alleviated TAM-induced liver injury.

• HDCA supplementation was tested as a therapeutic intervention in the context of TAM-induced liver injury.
• HDCA supplementation restored the gut-liver BA-FXR axis.
• HDCA supplementation alleviated TAM-induced liver injury in the study model.
• These findings suggest that targeting the gut-liver FXR axis with HDCA may serve as a promising therapeutic strategy for alleviating TAM-associated liver injury.