Investigating Cathepsin B in the gut-liver axis in alcohol-associated liver disease

• Applicant: Dr. Maximilian Joseph Brol
• Subject Area: Gastroenterology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 567326083

One of the main causes of chronic liver disease is excessive alcohol consumption. Alcohol-associated liver disease (ALD) includes mild forms like fatty liver but also severe inflammatory conditions such as liver cirrhosis and hepatitis. In the latter, the intestine also becomes inflamed, and despite optimal treatment, the disease is often fatal. In advanced liver disease, infections are a common cause of death because a weakened intestinal barrier allows bacteria to spread to other parts of the body. It is known that alcohol damages the intestinal barrier and alters gut bacteria, but the exact mechanisms behind this process remain unclear. Previous studies have shown that patients with ALD have increased levels of certain proteins in their stool, which can break down other proteins—these are called proteases. Some of these proteases belong to a specific family known as cathepsins. Interestingly, only one protease in this family has been linked to a higher risk of death: Cathepsin B. We suspect that this protein plays a key role in ALD development, and in this project, we aim to study it further. We want to determine which cells release Cathepsin B. We suspect that macrophages, immune cells that help fight infections, are activated by alcohol and then release Cathepsin B. To investigate this, we will use a mouse model for ALD and isolate different immune cells for separate analysis. We will also examine how Cathepsin B damages the intestinal barrier. For this, we will grow human intestinal cells in the lab to form a gut-like cell layer (called an organoid). We will then apply stool samples from ALD patients and healthy individuals to these organoids and analyze the effects of Cathepsin B and alcohol using electrical resistance measurements and protein analysis. To better understand Cathepsin B’s function, we will create genetically modified mice in which Cathepsin B is removed from specific immune cells. This will help us determine whether these mice are more resistant to alcohol-induced damage. Finally, we want to test whether inhibiting Cathepsin B can improve liver function and gut health, potentially leading to the first therapy for ALD. In our experiments, we will induce ALD in mice and then administer a drug that specifically blocks Cathepsin B in the intestine. We will test whether giving this drug preventively or as a treatment for already sick mice can improve outcomes. Our ultimate goal is to gain a deeper understanding of Cathepsin B and, ideally, pave the way for the first effective therapy for alcohol-associated liver disease.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Bernd Schnabl