Cellular and molecular gastroenterology and hepatology · 2026
Single-Cell and Spatial Transcriptomics Across Populations With Perianal Fistulizing Crohn's Disease Shows Proinflammatory CD4+ Macrophage Involvement in Disease Progression.
СтатьяНазвание и аннотация: Перевод в очереди
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Maddipatla Sushma C, Munasinghe Sachith, Dodd Anne, Tastad Christopher, Moss Rachel, Yin Hong, Murthy Shanta, Dash Abhishek, Kolachala Vasantha L, Cutler David J, Cho Judy, Kugathasan Subra, Matthews Jason D
Аннотация
BACKGROUND & AIMS: Perianal fistulizing Crohn's disease is a severe morbidity with rectal involvement and a higher prevalence in African Americans compared with European Americans. In this study, we sought to define the distinguishing cellular and molecular features between inflamed rectal Crohn's disease with and without perianal fistula across populations that give new insight into disease severity or progression.
METHODS: Rectal mucosal biopsies were obtained for single-cell sequencing from 50 individuals (262k cells); 18 with Crohn's disease of the rectum with fistula, 25 with Crohn's disease of the rectum without fistula and any other perianal complications, and 7 from individuals with no past or present mucosal disease (controls). Spatial transcriptomics were conducted and analyzed by Sopa and Squidpy, whereas immunofluorescence was processed with QuPath. Patient-derived rectal organoids were used to test inflammatory signaling.
RESULTS: A major distinction between inflamed Crohn's disease of the rectum with and without fistula was the decreased phagocytic signature, antigen processing profile, and unique morphologic structures of proinflammatory CD4+CD68+ macrophages. In fistulizing Crohn's disease, these macrophages formed large aggregates in the lamina propria near epithelial crypts and appeared to disrupt cellular networks by engaging in signaling with other cell subtypes. At the population level, the most significant differences in cellular pathways were detected between African Americans and European Americans with inflamed Crohn's disease of the rectum and fistula, and between patients with and without fistulizing disease among African Americans.
CONCLUSIONS: During inflamed Crohn's disease of the rectum with fistula, CD4+ macrophages alter cellular networks in the lamina propria while forming large cell aggregates, likely mediating complex interactions with T cells and possibly microbial antigens that are involved in the more severe pathologic conditions associated with fistula tract formation and progression.
METHODS: Rectal mucosal biopsies were obtained for single-cell sequencing from 50 individuals (262k cells); 18 with Crohn's disease of the rectum with fistula, 25 with Crohn's disease of the rectum without fistula and any other perianal complications, and 7 from individuals with no past or present mucosal disease (controls). Spatial transcriptomics were conducted and analyzed by Sopa and Squidpy, whereas immunofluorescence was processed with QuPath. Patient-derived rectal organoids were used to test inflammatory signaling.
RESULTS: A major distinction between inflamed Crohn's disease of the rectum with and without fistula was the decreased phagocytic signature, antigen processing profile, and unique morphologic structures of proinflammatory CD4+CD68+ macrophages. In fistulizing Crohn's disease, these macrophages formed large aggregates in the lamina propria near epithelial crypts and appeared to disrupt cellular networks by engaging in signaling with other cell subtypes. At the population level, the most significant differences in cellular pathways were detected between African Americans and European Americans with inflamed Crohn's disease of the rectum and fistula, and between patients with and without fistulizing disease among African Americans.
CONCLUSIONS: During inflamed Crohn's disease of the rectum with fistula, CD4+ macrophages alter cellular networks in the lamina propria while forming large cell aggregates, likely mediating complex interactions with T cells and possibly microbial antigens that are involved in the more severe pathologic conditions associated with fistula tract formation and progression.