Bile acid-sensitive tuft cells regulate biliary neutrophil influx

Area of Science:

• Gastroenterology and Hepatology
• Cell Biology
• Immunology

Background:

• Extrahepatic biliary tree inflammation and dysfunction are implicated in gallstones and cholangiocarcinoma.
• Local regulation of biliary inflammation remains poorly understood.
• Tuft cells are rare sensory epithelial cells found in the gallbladder and extrahepatic bile ducts.

Purpose of the Study:

• To investigate the role of biliary tuft cells in regulating inflammation within the extrahepatic biliary tree.
• To determine the relationship between bile acids, tuft cell abundance, and biliary inflammation.
• To explore the impact of tuft cell deficiency on biliary inflammation and the role of the microbiome.

Main Methods:

• Characterization of biliary tuft cell gene expression.
• Manipulation of enterohepatic bile acid recirculation.
• Analysis of tuft cell-deficient mouse models.
• Assessment of inflammatory gene signatures and neutrophil infiltration.
• Microbiome analysis in relation to biliary inflammation.

Main Results:

• Biliary tuft cells express a distinct genetic program and decrease postnatally with bile acid maturation.
• Bile acids negatively regulate tuft cell abundance, with loss of tuft cells observed in obstructive cholestasis.
• Tuft cell-deficient mice exhibit spontaneous gallbladder inflammation and neutrophil infiltration, modulated by the microbiome.

Conclusions:

• Biliary tuft cells function as bile acid-sensitive negative regulators of inflammation in the biliary tree.
• These cells may limit inflammation under homeostatic conditions.
• Findings suggest a novel mechanism for maintaining biliary tissue homeostasis involving tuft cells and bile acid signaling.