Mark Sundrud, PhD: Bile Acid and T Cell Interplay in Cholestatic Diseases

Mark Sundrud, PhD, professor of medicine at the Geisel School of Medicine at Dartmouth College, sat down with HCPLive to discuss the interplay between bile acids and T cells, opportunities for applying this knowledge in clinical practice, and areas where further research may be warranted.

Sundrud was a speaker during the session “The Gut-Liver Axis as Therapeutic Target in Cholestatic Liver Disease” at The Liver Meeting 2023 from the American Association for the Study of Liver Diseases (AASLD) in Boston this weekend, where he presented on the liver-gut-axis and bile acid-induced polarization of intestinal T lymphocytes.

As knowledge on the role of bile acids both inside and outside of the liver continues to emerge, experts have shown a growing interest in understanding how T cells contribute to the pathogenesis of cholestatic liver disease and the broader connection between intestinal and liver functions.

“We're starting to really appreciate that the liver and the intestine are very intimately connected. If you have disease processes occurring in the liver, that absolutely affects what's happening in the intestine. And likewise, if you have pathophysiology in the intestine, that can then feed back and alter bile acids and how they return back to the liver,” Sundrud said.

In terms of understanding how bile acids influence T cells, Sundrud laid out 2 points he noted were important to consider: the influence of bile acid toxicity on T cells, and the bile acid receptors expressed by T cells.

“Generally speaking, if you have a high concentration of bile acids, like with many other cells, that's potentially dangerous to T cells. Lymphocytes, both in the liver and in the intestine, have figured out ways to sort of compensate for the presence of high potentially toxic bile acid concentrations,” Sundrud explained. “The second thing that's becoming clear is that of course, we now know that a lot of immune cells express pretty specific bile acid receptors, and there's at least a handful of different types of nuclear receptors that we and others have shown are expressed in T cells that can help them respond to the presence of not only bile acids in general, but different types of bile acids.”

To this point, research has focused primarily on understanding how bile acids interact with hepatocytes, with findings suggesting the most effective therapies in human clinical studies of liver disease affect both hepatocytes and intestinal cells. Now, efforts are being driven toward understanding which types of bile acids signal through which types of receptors in specific cells with the goal of reaping the beneficial effects of bile acid derivatives in both the liver and the intestine.

“I think the notion that immune cells, and T cells specifically, contribute to the pathogenesis of cholestatic liver disease is still emerging. We don't understand how it works, and I think it's probably too early to say which medicines or which prospective medicines could leverage immune modulation for therapeutic effect,” Sundrud said. “I just don't know that the field is there yet. Hopefully, that's why we keep having these meetings, and then in 10 or 15 years, we can figure that out.”

Sundrud also emphasized the importance of considering intestinal and liver diseases in terms of their broad physiology and how they’re connected and influence each other: “I think that is absolutely going to make a difference in how we end up and how successful we are treating these diseases.”