Mount Sinai researchers have conducted a groundbreaking study using single-cell analysis to identify various pathophysiological mechanisms of perianal fistulae in patients with Crohn’s disease. Published in the journal Med on April 24, this research sheds light on the underlying causes of abnormal passageways in the digestive system that are often painful and debilitating for individuals with this chronic condition. Crohn’s disease is an inflammatory bowel disease that affects over half a million people in the United States, causing chronic inflammation in the gastrointestinal tract. Perianal fistulae, which are abnormal connections between the anal canal and perianal skin, are a common complication of Crohn’s disease.
This study is the first to apply single-cell transcriptomics to analyze perianal fistulous tracts, as well as the first to include Black patients with this condition in a diverse study cohort. Patients of African ancestry are typically underrepresented in genetic studies of Crohn’s disease, despite being twice as likely to develop perianal fistulae compared to individuals of European ancestry. By profiling more than 140,000 single cells from a diverse group of Crohn’s disease patients with perianal fistulae, the researchers identified several key pathways contributing to fistulizing Crohn’s disease. These pathways include cellular aging and loss of proliferation, reaction to microenvironmental stimuli, and a destructive gene signature in connective tissues that is unique to perianal fistulae.
The study also found subpopulations of fibroblasts with a destructive gene signature that may originate from mononuclear cells in the immune system, particularly in patients with African ancestry. By analyzing key transcription factor binding events in relevant gene promoter regions, the researchers uncovered potential epigenetic mechanisms underlying the differences in cell behavior between patients of African and European ancestry. These findings have significant implications for understanding the disparity in perianal fistula prevalence between Black and white patients with Crohn’s disease, providing valuable insights into potential therapeutic targets for this complication.
While a range of anti-inflammatory medications can help manage Crohn’s disease, they often have limited efficacy for closing perianal fistula tracts. In severe cases, surgical removal of the affected tissue may be necessary. However, the findings from this study offer new avenues for identifying novel therapeutic options for perianal fistulae. Future research should further explore epigenetic patterns in white blood cells of the immune system from diverse patient populations, as well as those with other immune-mediated inflammatory diseases, to better understand the role of transcription factors in race or ancestry-based disparities.
The study was supported by funding from the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health, as well as several charitable trusts. Lead author Rachel M. Levantovsky, a Mount Sinai Medical Scientist Training Program student, highlights the importance of understanding the mechanistic underpinnings of perianal fistula in order to optimize future treatments. By uncovering unique fibroblast populations, distinct monocyte differentiation in African-ancestry individuals, and key transcription factor binding events, this research paves the way for developing more effective therapies for this debilitating complication of Crohn’s disease.
