Vik Meadows, PhD, MS

Travel Award
$1,500

University of Pittsburgh

Follow the Cholangiocyte: How Bile Duct Integrity Affects the Gut-Liver Axis

Mentor: Satdarshan (Paul) Monga, MD

Cholangiopathies are rare diseases that target cholangiocytes, the cells that line the liver's bile ducts. These diseases are characterized by impaired bile flow, severe liver damage, and elevated bile acid levels. The mechanism behind cholangiopathies is complex and uncertain; however, understanding the physical and signaling connection between the liver and intestine, known as the gut-liver axis, may be crucial for therapeutic strategies.

The liver and intestine are both capable of regeneration, with the intestinal epithelium renewing itself weekly. In contrast, liver regeneration occurs more slowly, requiring weeks to months for cell replenishment and only taking place after liver injury. The Wnt/ß-catenin signaling pathway plays a crucial role in regulating regeneration in both organs. In the intestine, Wnt signaling governs cell differentiation and facilitates rapid cell turnover. Meanwhile, in the liver, Wnt signaling manages cell polarity, liver zonation, and bile acid signaling. We discovered that the loss of ß-catenin, and its related protein γ-catenin, in hepatocytes results in impaired bile flow and prompts hepatocyte reprogramming into cholangiocyte-like cells. Notably, when ß- and γ-catenin are lost in cholangiocytes, it leads to severe liver damage, hepatocyte reprogramming, and changes in microbiome composition. These results suggest that hepatocyte reprogramming and maintaining cholangiocyte health should be considered therapeutic targets for cholangiopathies treatment.

This project will focus on investigating two main questions: 1. Can we harness the mechanism behind hepatocyte reprogramming to improve cholangiopathies? 2. Does bile duct health influence intestinal function and gut microbiome composition? This work will clarify the gut-liver connection in cholestatic liver diseases and support future therapies and independent research on improving cholangiopathy patient outcomes.