Dr Hanauer reviews his keynote address at the Advances in Inflammatory Bowel Diseases meeting on how variations in the presentation of IBD provide human models for the study of the disease that offer new insights over animal model studies.

Stephen B Hanauer, MD, is the is the Clifford Joseph Clifford Joseph Barborka professor of medicine at the Feinberg School of Medicine at Northwestern University in Chicago, Illinois.

TRANSCRIPT:

Dr. Steve Hanauer:

Hello. I'm Dr. Steve Hanauer from Northwestern University in Chicago. I want to welcome you to Advances in Inflammatory Bowel Disease 2022 here in Orlando, Florida, where earlier today, I gave a keynote talk on human models of inflammatory bowel disease. Instead of talking about animal models which have a great deal of limitation, I tried to emphasize a number of potential human models where IBD's pathogenesis can actually be evaluated using patients rather than mice. That's based on the fact that mice or other animals or cell cultures do not really give us the full picture of inflammatory bowel disease. They're bits of a puzzle, but they don't really give us a holistic approach or appraisal of the human diseases. So I looked at a number of examples, including genetics and in particular, early onset inflammatory bowel disease in very young children, which tends to be more of a monogenic process. Whereas in adults and typical patients, it's really more polygenic.

Although we've identified over 200 gene mutations, I emphasize that only about 20% of our patients with inflammatory bowel disease actually have one of those known mutations. In contrast, the monogenic, very early onset inflammatory bowel disease really represents a unique opportunity of individual genes and how they impact on and actually can create these diseases. Beyond that, we looked at epigenetic events, which really I think are mainly environmental. We know of a number of environmental exposures, such as cigarette smoking, that can redirect the inflammatory process not only in ulcerative colitis and Crohn's disease, but other immune-mediated inflammatory diseases. Of course, there are a number of other environmental factors that can impact on the disease, including ultraprocessed foods, antibiotics in our food chain, and other aspects.

Now, I also looked at a number of clinical scenarios that give us the opportunity to evaluate diseases in humans. That includes the disease margin in ulcerative colitis where the colon is normal above the margin and diffusely inflamed below it, and gave some examples of how we can actually study the immune and mucosal processes both above and below the margin. Likewise, postoperative Crohn's disease where the disease is eradicated temporarily, but begins to come back after reanastomosis and typically on the ileal side of the disease. That gives us an opportunity to study that over a period of time. Then finally, regarding these examples, I spoke about the ileal pouch, J-pouches, and how there's an evolution of the intestinal mucosa in a J-pouch from more of an ileal mucosa to one that becomes colon-ized as it becomes colonized with bacteria. That's when we see pouchitis evolving.

Then finally, I talked about a number of drug models for IBD, including the checkpoint inhibitor colitis and enteritis that evolves after immune therapy for melanoma and other malignancies, as well as the discrepancy in cytokines, where IL-17 inhibition in rheumatoid arthritis and the converse worsening of disease in inflammatory bowel disease gives us additional insights into really tissue specificity of cytokines and how they can be utilized. So from genetics to the environment to individual disease scenario and drug-induced colitis and enteritis really give us examples of how humans can be used to study the pathogenesis of IBD outside of animal models that don't replicate this heterogeneity of the diseases.