Mount Sinai researchers have completed the initial study to utilize single-cell analysis in pinpointing various pathophysiological mechanisms of abnormal passageways in the digestive system known as perianal fistulae, a common complication of Crohn’s disease. The study has revealed that this complication is more prevalent and more severe in African American populations. This data was published in the journal Med on April 24. Crohn’s disease is an inflammatory bowel disease that causes chronic inflammation at any part of the gastrointestinal tract.The gastrointestinal (GI) tract affects over 500,000 people in the United States. Perianal fistulae, which are abnormal connections between the anal canal and perianal skin, are a common complication of Crohn’s disease. These fistulae often lead to painful abscesses and negatively impact the quality of life for patients.
For the first time, this study at Mount Sinai used single-cell transcriptomics to examine perianal fistulous tracts. The study also made a point to include Black patients with this chronic condition to create a diverse and comprehensive study cohort. Patients of African descent have been significantly underrepresented in genome-wide association studies of Crohn’s disease and inflammatory bowel disease.In general, the prevalence of Crohn’s disease is lower in African American populations compared to those with European ancestry. However, studies have shown that patients of African ancestry are approximately twice as likely to have perianal fistulae. The researchers examined over 140,000 single cells from a variety of Crohn’s disease patients with perianal fistulae. They discovered several important pathways associated with fistulizing Crohn’s disease, including cellular aging and reduced proliferation, response to microenvironmental stimuli, and a damaging gene signature in connective tissue.Perianal fistulae pose unique challenges. The study revealed that specific subgroups of fibroblasts, which are responsible for forming connective tissues, carry a gene signature linked to tissue destruction. These fibroblasts may be derived from mononuclear cells in the immune system, a trend that is more pronounced in individuals of African descent. Additionally, the researchers observed evidence of significant transcription factor binding events in gene promoter regions, indicating a potential epigenetic process that influences differences in cell behavior between individuals of African and European ancestry.
“Circulating blood monocytes can traffic to disease tissue””According to Judy H. Cho, MD, Dean and Ward-Coleman Chair in Translational Genetics at the Icahn School of Medicine at Mount Sinai, blood monocytes play a crucial role in fighting microbes in the body. Our study has identified specific differences in the response of blood monocytes in different populations, which may help explain the higher rates of perianal fistulous complications in African American patients with Crohn’s disease,” Cho stated. While there are various anti-inflammatory medications available for treating Crohn’s disease, they are not always effective in closing perianal fistula tracts. In severe cases, surgical removal of affected areas may be necessary for patients.The study focused on identifying new therapeutic options for immune-mediated inflammatory diseases by analyzing epigenetic patterns in white blood cells of diverse, healthy patients and those with a history of the complication. The researchers emphasized the need for future studies to delve into the role of the transcription factor underlying race or ancestry-based disparities in order to gain a deeper understanding of the issue. Leveraging various types of data, including transcriptomic, epigenetic, genetic, cellular, and tissue-based information, the team sought to uncover the reasons behind the prevalence differences in immune-mediated inflammatory diseases.”Our research has found distinct differences in fistula fibroblasts and monocyte differentiation between African-ancestry individuals and other patients,” said Rachel M. Levantovsky, PhD, a student in the Mount Sinai Medical Scientist Training Program. “Identifying these differences sheds light on the underlying mechanisms of perianal fistula, which is crucial for improving future treatments.” The study received financial support from the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health (U01DK062422, U24DK062429, R01DK123758, and F30DK127736).The research was supported by the Ona M. and Harry B. Helmsley Charitable Trust, Sanford J. Grossman Charitable Trust, and David and Margot Lowy Foundation Trust.
