Vijay Pandyarajan, MD, PhD

American Liver Foundation Liver Scholar Research Award
$225,000 over three years

Cedars Sinai Medical Center

Investigating the Role of CARD9 in Gut Barrier Function and MASLD Progression

Mentor:  Ekihiro Seki, MD, PhD

Metabolic dysfunction-associated steatotic liver disease (MASLD), affects an estimated 40% of the global population. It occurs when excess fat accumulates in the liver, leading to inflammation and damage. Over time, MASLD can progress to cirrhosis, liver failure, or even liver cancer. While poor diet, obesity, and inactivity are major contributors, recent studies highlight the role of the gut microbiome—the community of bacteria, fungi, and other microorganisms in the digestive system—in influencing MASLD progression. Our research focuses on the "gut-liver axis," the communication pathway between the gut and liver, and the role of a specific immune protein called CARD9 (Caspase recruitment domain family member 9). CARD9 helps the body recognize and respond to microbial threats, especially fungi. We aim to understand how disruptions in the gut microbiome might worsen MASLD by weakening the gut’s barrier and allowing harmful microbes to enter the bloodstream and reach the liver, further exacerbating inflammation and damage. CARD9's role in modulating the gut microbiome may be crucial in this process. We will use two models to explore this. First, mice genetically engineered to lack CARD9 will allow us to observe the effects of CARD9 deficiency on liver disease progression and microbial translocation. Second, we will use organoids—lab-grown mini-organs from human and animal tissues—to simulate the gut environment and study CARD9's influence on interactions between gut microbes and the intestinal barrier. By comparing organoids from healthy individuals and MASLD patients, we aim to identify the specific mechanisms through which CARD9 dysfunction contributes to disease. This research will enhance our understanding of how the gut-liver axis and immune responses affect MASLD. By identifying microbial triggers and immune pathways, we aim to develop new therapeutic strategies to prevent MASLD progression and improve outcomes for millions of people worldwide.