Assessing Cellular and Transcriptional Diversity of Ileal Mucosa Among Treatment-Naive and Treated Crohn's Disease

• Authors: Sushma Chowdary Maddipatla, Emory University; Vasantha Kolachala, Emory University; Suresh Venkateswaran, Emory University; Anne F. Dodd, Emory University; Ranjit Singh Pelia, Emory University; Duke Geem, Emory University; Hong Yin, Emory University; Yutong Sun, Georgia Institute of Technology; Congmin Xu, Georgia Institute of Technology; Angela Mo, Georgia Institute of Technology; Astrid Kosters, Emory University; Junkai Yang, Emory University; Jason Matthews, Emory University; Eliver Ghosn, Emory University; Subramaniam Kugathasan, Emory University; Peng Qiu, Georgia Institute of Technology
• Journal Title: INFLAMMATORY BOWEL DISEASES
• Volume: Volume 29, Number 2
• Publisher: OXFORD UNIV PRESS INC | 2022-10-07, Pages 274-285
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1093/ibd/izac201
• Subjects: Biology, Genetics; Health Sciences, Medicine and Surgery
• Keywords: Science & Technology; Life Sciences & Biomedicine; Gastroenterology & Hepatology; single cell RNA-seq; Crohn's disease; inflammatory bowel disease; ileum; enterocytes; INFLAMMATORY-BOWEL-DISEASE; INTESTINAL EPITHELIAL-CELLS; ULCERATIVE-COLITIS; COLON

Abstract

BACKGROUND: Crohn's disease is a lifelong disease characterized by chronic inflammation of the gastrointestinal tract. Defining the cellular and transcriptional composition of the mucosa at different stages of disease progression is needed for personalized therapy in Crohn's. METHODS: Ileal biopsies were obtained from (1) control subjects (n = 6), (2) treatment-naïve patients (n = 7), and (3) established (n = 14) Crohn's patients along with remission (n = 3) and refractory (n = 11) treatment groups. The biopsies processed using 10x Genomics single cell 5' yielded 139 906 cells. Gene expression count matrices of all samples were analyzed by reciprocal principal component integration, followed by clustering analysis. Manual annotations of the clusters were performed using canonical gene markers. Cell type proportions, differential expression analysis, and gene ontology enrichment were carried out for each cell type. RESULTS: We identified 3 cellular compartments with 9 epithelial, 1 stromal, and 5 immune cell subtypes. We observed differences in the cellular composition between control, treatment-naïve, and established groups, with the significant changes in the epithelial subtypes of the treatment-naïve patients, including microfold, tuft, goblet, enterocyte,s and BEST4+ cells. Surprisingly, fewer changes in the composition of the immune compartment were observed; however, gene expression in the epithelial and immune compartment was different between Crohn's phenotypes, indicating changes in cellular activity. CONCLUSIONS: Our study identified cellular and transcriptional signatures associated with treatment-naïve Crohn's disease that collectively point to dysfunction of the intestinal barrier with an increase in inflammatory cellular activity. Our analysis also highlights the heterogeneity among patients within the same disease phenotype, shining a new light on personalized treatment responses and strategies.