New model can help identify potential drug targets for ulcerative colitis

Scientists from the Lerner Research Institute at Cleveland Clinic have designed an innovative, patient-derived model of ulcerative colitis that will help scale up studies into new therapies for chronic inflammatory bowel disease. The study was published in the Nature Communications journal.

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The researchers used the novel model to detect a potential target that could be suppressed to delay the progression of the disease. Ulcerative colitis is generally characterized by atypical reactions of the immune system that result in ulcers and inflammation on the inner lining of the large intestines. This inflammation is very heterogeneous, both in terms of disease pathology and patients’ symptoms.

The present mainstay treatment for inflammatory bowel diseases is inhibiting the overactive immune response with anti-inflammatory medications, albeit these treatments have restricted long-term efficacy in patients with ulcerative colitis.

Research indicates that elements of the immune system, as well as the ulcerative colitis microenvironment (that is, the surrounding, less diseased components of cells), communicate to drive the development and progression of the disease.

Since immune-suppressing medications have shown only reduced success in treating ulcerative colitis, scientists are interested to know whether focusing on microenvironmental elements—such as stem cell-like cells known as stromal cells, and constituents of the intestinal lining (known as epithelium)—may be a complementary or better treatment method.

Gaining a more comprehensive understanding of the complex interplay between immune and other cell types will be critical to developing new and more effective ulcerative colitis therapies and tailored, patient-specific treatment approaches.”

Emina Huang, MD, Study Lead Author and Staff, Departments of Cancer Biology and Colorectal Surgery, Cleveland Clinic

Along with her team, Dr. Huang, who is also a practicing colorectal surgeon, designed the model using tissue samples collected from ulcerative colitis patients who went through surgery at Cleveland Clinic.

The team extracted a particular type of cell (known as fibroblasts) that can be “reprogrammed” to create all-purpose, undifferentiated cells, known as induced pluripotent stem cells, which have evolved as a growing research priority.

The team subsequently cultured the stem cells in laboratory settings and grew them into very small, 3D tissues that resemble real organs (called organoids). They observed that when compared to healthy colon organoids, the diseased organoids reflected functional and histological features typically seen in patients with ulcerative colitis, such as defective barrier integrity of the intestinal lining, decreased mucus secretions, and overexpression of select proteins (including one known as CXCL8).

Our in vitro model accurately mirrors what we observe in patients in the clinic and is much more dynamic than current models. For example, other organoid models only focus on the contributions of the epithelium, where ours reflects the contributions of other microenvironment components, too, like the stroma.”

Emina Huang, MD, Study Lead Author and Staff, Departments of Cancer Biology and Colorectal Surgery, Cleveland Clinic

Once the model was developed, the researchers were able to quickly detect new drug targets and candidates. They demonstrated that suppressing the expression of CXCL8 with a small molecule, known as repertaxin, helped to delay the progression of the disease.

We look forward to further exploring repertaxin's potential benefit in other preclinical and eventual clinical studies. We are hopeful that others will also find this model useful in identifying other potential anti-ulcerative colitis drugs.”

Emina Huang, MD, Study Lead Author and Staff, Departments of Cancer Biology and Colorectal Surgery, Cleveland Clinic

Huang also observed that the method used to design the novel ulcerative colitis model could also be used to model other similar complex diseases.