Stephen B. Hanauer, MD, on Human Models of Inflammatory Bowel Disease

From genetics to the environment, through individual disease scenarios and drug-induced colitis and enteritis, humans can be used to study the pathogenesis of inflammatory bowel disease (IBD) rather than relying on animal models that cannot replicate this heterogeneity of the diseases, Stephen B. Hanauer, MD, said at the Interdisciplinary Autoimmune Summit (IAS) virtual meeting.

Dr Hanauer is the is the Clifford Joseph Barborka Professor of Medicine at the Feinberg School of Medicine and medical director of the Digestive Health Center at Northwestern University in Chicago, Illinois.

“Animal models have a great deal of limitation,” he explained, emphasizing that the pathogenesis of IBD can be evaluated using “a number of potential human models. 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.”

He reviewed 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, while in adults and typical patients, IBD is more polygenic.

“Although we've identified over 200 gene mutations,” Dr Hanauer said, “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” to study individual genes and how they affect and actually can create these diseases.

Dr Hanauer also 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.”

The clinical scenarios that provide the opportunities to evaluate diseases in humans, he explained, include “the disease margin in ulcerative colitis where the colon is normal above the margin and diffusely inflamed below it.” This allows the study of the immune and mucosal processes both above and below the margin, Dr Hanauer stated. “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, gives us an opportunity to study that over a period of time.”

He further noted that in some cases in which patients have undergone ileal pouch surgery, “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.”

Dr Hanauer also spoke about a number of drug models for IBD, including checkpoint inhibitor colitis and enteritis that may evolve 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.”

—Rebecca Mashaw

Hanauer SB. Human models of IBD. Presented at: Interdisciplinary Autoimmune Summit 2023. Virtual.