Evaluating the impact of the microbiome in preclinical studies

Although researchers have known for several decades that  about 75% of patients with Primary Sclerosing Cholangitis (PSC) also suffer from Inflammatory Bowel Disease (IBD), whether changes in the gut drive disease in the liver remains unclear. To shed new light on this “gut-liver axis”, Steven O’Hara, Ph.D., and his Mayo Clinic team are focusing on the role of the intestinal microbiome, or the microorganisms, including bacteria, viruses, fungi and protozoa, located in the human intestine. Although dysbiosis, or an imbalance in the composition of the intestinal microbial community, has been found to be associated with a range of diseases including autoimmune disorders and PSC, much remains unknown about which specific microbes may be helpful or harmful.

To address this gap in knowledge, Dr. O’Hara is investigating the role of “cholangiocytes,” or epithelial cells that line intrahepatic bile ducts, and how they recognize and respond to microbial pathogens. They have previously shown that microbial infection can damage the bile ducts in the liver, in a manner resembling PSC.  As such, the team hypothesized that PSC progression could be influenced by increased exposure of the bile ducts to the products of an abnormal gut microbiome that the body sees as a form of infection, which in turn triggers the body’s immune system, causing local inflammation and damage to the liver.

To test this hypothesis, Dr. O’Hara performed the first study to evaluate the impact of the microbiome in animal models of PSC. The team raised genetically-modified mice, which exhibit features similar to human PSC, in a “germ-free,” completely sterile environment. Having previously shown that microbial infection caused liver damage, the team anticipated that the absence of gut microbiota in these mice would lead to a decrease in liver damage.

“When we performed the experiment, we were surprised to find out that the disease got much worse,” Dr. O’Hara said. “So, then we started asking, why might this be?” They suspected that a healthy gut microbiome may actually provide a beneficial molecule to the liver, thus promoting health rather than disease.

“If we can define the output of a specific group of microbes as lacking in our rodent models, we can attempt to fix that by either changing the environment in which these microbes grow, or through microbial manipulations where we can add specific classes of microbes back into the animal to see if that changes disease progression.”

The ability to test interventional strategies at different time points in animal models represent a critical bridge between preclinical studies and clinical trials in humans. The end goal: developing new treatment strategies targeting the balance of microbes in PSC patients to restore hepatobiliary health.