New! Sign up for our free email newsletter.
Science News
from research organizations

Apply single-cell analysis to reveal mechanisms of a common complication of Crohn's disease

Date:
April 24, 2024
Source:
The Mount Sinai Hospital / Mount Sinai School of Medicine
Summary:
Study identifies key pathways underlying perianal fistula, a disease complication that is more prevalent and severe in African American populations.
Share:
FULL STORY

Mount Sinai researchers have published the first study to use single-cell analysis in identifying several pathophysiological mechanisms of abnormal passageways in the digestive system known as perianal fistulae, a common complication of Crohn's disease. These findings were 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 (GI) tract and impacts more than half a million people in the United States. Perianal fistulae, abnormal connections between the anal canal and perianal skin, are a common complication of Crohn's disease that often result in painful abscesses and impact patients' quality of life.

This Mount Sinai study is the first to apply single-cell transcriptomics of perianal fistulous tracts, and to recruit Black patients with the chronic condition for a diverse and comprehensive study cohort. Patients with African ancestry have been substantially underrepresented in genome-wide association studies of Crohn's disease, and inflammatory bowel disease overall, reflecting in part the lower prevalence of Crohn's disease in African American populations compared to patients with European ancestry. However, patients of African ancestry are about twice as likely to have perianal fistulae, according to studies in adult and pediatric populations.

The researchers profiled more than 140,000 single cells from diverse Crohn's disease patients with perianal fistulae. The team identified several key pathways underlying fistulizing Crohn's disease, including 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 researchers also determined that subpopulations of fibroblasts -- cells forming the connective tissues -- with this destructive gene signature may originate from mononuclear cells in the immune system, a phenomenon observed in greater magnitude from patients with African ancestry. The experts found evidence for key transcription factor binding events in relevant gene promoter regions that suggests a potential epigenetic phenomenon underlying this apparent difference in cell behavior between patients of African and European ancestry.

"Circulating blood monocytes can traffic to disease tissues and form a critical first step in fighting microbes throughout the body," said corresponding author Judy H. Cho, MD, Dean and Ward-Coleman Chair in Translational Genetics at the Icahn School of Medicine at Mount Sinai. "In this study, we have defined population-specific differences in how blood monocytes respond, which contribute to the higher rates of perianal fistulous complications in African American patients with Crohn's disease."

A range of anti-inflammatory medications can treat Crohn's disease, but they show limited efficacy for closure of perianal fistula tracts. In severe cases, patients may require surgical removal of all or part of the rectum. But researchers said their findings provide avenues to identify new therapeutic options. The team said future studies should examine similar epigenetic patterns in white blood cells of the immune system from diverse, healthy patients and from patients with other immune-mediated inflammatory diseases to further explore the role of the transcription factor underlying race or ancestry-based disparities.

"We have leveraged transcriptomic, epigenetic, genetic, cellular, and tissue-based data from patients with a history of this devastating complication to better understand reasons for the discrepancy in prevalence between Black and white patients," said first author Rachel M. Levantovsky, PhD, who is working on her MD in the Mount Sinai Medical Scientist Training Program. "Our discovery of unique fistula fibroblasts, distinct monocyte differentiation in African-ancestry individuals, and key transcription factor binding events helps us illuminate mechanistic underpinnings of perianal fistula -- critical for the optimization of future treatment."

The study was supported by funding from the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health (U01DK062422, U24DK062429, R01DK123758, and F30DK127736), Leona M. and Harry B. Helmsley Charitable Trust, Sanford J. Grossman Charitable Trust, and David and Margot Lowy Foundation Trust.


Story Source:

Materials provided by The Mount Sinai Hospital / Mount Sinai School of Medicine. Note: Content may be edited for style and length.


Journal Reference:

  1. Rachel M. Levantovsky, Christopher Tastad, Jiayu Zhang, Kyle Gettler, Ksenija Sabic, Robert Werner, Colleen Chasteau, Ujunwa Korie, Diana Paguay, Michelle Bao, Huajun Han, Neha Maskey, Sayali Talware, Manishkumar Patel, Carmen Argmann, Mayte Suarez-Farinas, Noam Harpaz, Ling-shiang Chuang, Judy H. Cho. Multimodal single-cell analyses reveal mechanisms of perianal fistula in diverse patients with Crohn’s disease. Med, 2024; DOI: 10.1016/j.medj.2024.03.021

Cite This Page:

The Mount Sinai Hospital / Mount Sinai School of Medicine. "Apply single-cell analysis to reveal mechanisms of a common complication of Crohn's disease." ScienceDaily. ScienceDaily, 24 April 2024. <www.sciencedaily.com/releases/2024/04/240424111453.htm>.
The Mount Sinai Hospital / Mount Sinai School of Medicine. (2024, April 24). Apply single-cell analysis to reveal mechanisms of a common complication of Crohn's disease. ScienceDaily. Retrieved May 24, 2024 from www.sciencedaily.com/releases/2024/04/240424111453.htm
The Mount Sinai Hospital / Mount Sinai School of Medicine. "Apply single-cell analysis to reveal mechanisms of a common complication of Crohn's disease." ScienceDaily. www.sciencedaily.com/releases/2024/04/240424111453.htm (accessed May 24, 2024).

Explore More

from ScienceDaily

RELATED STORIES