New Cronkhite-Canada Syndrome Findings from Human Micro Intestines

Baylor College of Medicine and collaborating institutions have shed new light on the potential causes of Cronkhite-Canada syndrome, a rare condition characterized by abundant non-cancerous growths or polyps in the intestine and other symptoms such as hair and nail loss and changes in skin pigmentation. The study, which was published in The Journal of Clinical Investigation, is the first to demonstrate a link between high polyp proliferation and elevated levels of serotonin produced by the intestinal epithelium.

The findings point to a potential new method to treating this disease with serotonin inhibitors currently licensed for other conditions, perhaps improving the outcome of a disease with a bad prognosis. The work further emphasizes the importance of human organoid technology in not just understanding disease but also identifying possible clinical uses.

“During my clinical rounds, I met a patient with Cronkhite-Canada syndrome and became very interested in better understanding this little known condition,” said first author Victoria Poplaski, a graduate student at Baylor in Dr. Sarah Blutt’s lab. “Cronkhite-Canada syndrome is characterized by diarrhea, weight loss, abdominal pain, anorexia, and nausea.” Because just about 500 people worldwide have been identified with this disease, there haven’t been many opportunities to examine it in order to find its causes and potential remedies.”

Poplaski and her colleagues used their experience in producing human intestinal organoids to investigate what was causing the patient’s bowel to proliferate so much. Human intestinal organoids, often known as tiny guts, are lab-grown human intestinal cells that closely resemble natural small intestine tissue and its activities.

Poplaski used a biopsy sample or tissue from the patient’s intestine to create micro intestines in the lab. “We discovered that the patient-derived mini guts were highly proliferative when compared to mini guts from people without Cronkhite-Canada syndrome.” They also possessed a greater number of enteroendocrine cells, a type of intestine cell that specialized in hormone production, and the enteroendocrine cells abundantly present in the patient’s tiny guts produced serotonin,” Poplaski explained. “We confirmed these features in patient tissue biopsies.”

The enteroendocrine cells in the digestive system create more than 90% of the serotonin in the body. Although serotonin is well known for its role as a neurotransmitter in the central nervous system, it also impacts a number of organ functions, including some of the activities of the intestinal epithelium.

Supporting the novel role of serotonin in intestinal epithelial proliferation, we found that treating non-Cronkhite-Canada syndrome organoids with serotonin increased their proliferation and inhibiting serotonin production in the Cronkhite-Canada syndrome organoids decreased proliferation, suggesting a link between local serotonin production and control of epithelial intestinal cell proliferation,” said Blutt, an associate professor of virology and microbiology at the University of Texas at Austin. “The findings suggest the potential benefit of serotonin inhibitors to treat this condition.”

This study exemplifies how organoid cultures can lead to fresh insights into the biology behind uncommon disorders.

“When we first started this research, some people said it wasn’t worth it because we only had one patient to study.” “I disagreed and hoped we might find something worthwhile,” said co-author Dr. Mary Estes, Distinguished Service Professor of Virology and Microbiology at Baylor and the Cullen Foundation Endowed Chair. She is also affiliated with Baylor’s Dan L Duncan Comprehensive Cancer Center. “The results from that single patient’s organoids yielded completely unexpected and exciting data that could lead to new therapies.” We were then able to corroborate these findings using organoids from a second patient. I’m hopeful that this study will lead to increased contacts with physicians who care for Cronkhite-Canada syndrome patients, as well as a clinical trial to evaluate the novel basis for a process that leads to this ailment that we discovered in this work.”

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