Exploring the influence of tuft cells on ionocyte regulation in the biliary system: implications for understanding bile System physiology and disease

• Applicant: Maryam Keshavarz, Ph.D.
• Subject Area: Gastroenterology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 561973651

Inflammations and functional disorders of the extrahepatic bile duct are common causes of human pathologies, including gallstones and cholangiocarcinomas. Despite their prevalence, the local regulation of biliary inflammation remains poorly understood. Gallstone disease is common, making cholecystectomy one of the most frequent surgical procedures worldwide. According to the European Association for the Study of the Liver (EASL), about 20% of Europeans are affected by gallstone disease. In Germany, over 175,000 cholecystectomies are performed annually due to cholelithiasis. Understanding the structural and functional characteristics of cell compartments in the biliary tract is vital, as it is crucial for the early diagnosis, effective management, and overall outcomes of gallstone-related health issues. The gallbladder plays an essential role in ion transport within the biliary tract, a network of ducts and organs that store and deliver bile produced by the liver, crucial for digesting and absorbing fats, nutrient assimilation, and maintaining metabolic balance, especially in mammals with cyclical fasting and feeding patterns. The gallbladder's lining consists of a simple mucosa with two cell types: (i) cholangiocytes, which are abundant columnar cells responsible for electrolyte transport, water reabsorption, and mucin secretion; and (ii) rare tuft (or brush/taste) cells distinguished by specialized microvilli. Tuft cells also found in the gastrointestinal and respiratory tracts and the urethra, perform unique functions specific to their location. In the gallbladder, tuft cells sense stimuli like bacterial products and activate signaling pathways that influence gallbladder activity. Beyond roles in chemoreception and inflammatory response, tuft cells contribute to absorption and secretion functions. Fluid and electrolyte transport across the gallbladder epithelium is a complex, regulated process that maintains ionic balance and can be affected by disease. We have identified an epithelial subgroup that specializes in ion transport. This project seeks to deepen understanding of tuft cell and ionocyte signaling, particularly concerning gallstone-related inflammation—an important yet underexamined factor in ion transport and bile regulation. Using in vivo mouse models and in vitro systems, we will explore tuft cell interactions with neighboring epithelial cells during inflammation. Additionally, we will gain translational insights by examining structural and cellular changes in gallbladder tissue from cholecystectomy patients. This research has the potential to uncover new mechanisms underlying gallbladder disease and open the door to targeted therapies and early diagnostic approaches.

• DFG Programme: Research Grants