| Title: |
Concerted changes in the pediatric single-cell intestinal ecosystem before and after anti-TNF blockade |
| Authors: |
Zheng, Hengqi Betty; Doran, Benjamin A; Kimler, Kyle; Yu, Alison; Tkachev, Victor; Niederlova, Veronika; Cribbin, Kayla; Fleming, Ryan; Bratrude, Brandi; Betz, Kayla; Cagnin, Lorenzo; McGuckin, Connor; Keskula, Paula; Albanese, Alexandre; Sacta, Maria; de Sousa Casal, Joshua; van Esch, Ruben; Kwong, Andrew C; Kummerlowe, Conner; Taliaferro, Faith; Fiaschi, Nathalie; Kou, Baijun; Coetzee, Sandra; Jalal, Sumreen; Yabe, Yoko; Dobosz, Michael; Wipperman, Matthew F; Hamon, Sara; Kalliolias, George D; Hooper, Andrea; Lim, Wei Keat; Haxhinasto, Sokol; Wei, Yi; Ford, Madeline; Ambartsumyan, Lusine; Suskind, David L; Lee, Dale; Deutsch, Gail; Deng, Xuemei; Collen, Lauren V; Mitsialis, Vanessa; Snapper, Scott B; Wahbeh, Ghassan; Shalek, Alex K; Ordovas-Montanes, Jose; Kean, Leslie S |
| Publisher Information: |
eLife Sciences Publications, Ltd |
| Publication Year: |
2025 |
| Collection: |
eLife (E-Journal - via CrossRef) |
| Description: |
Crohn’s disease is an inflammatory bowel disease (IBD) commonly treated through anti-TNF blockade. However, most patients still relapse and inevitably progress. Comprehensive single-cell RNA-sequencing (scRNA-seq) atlases have largely sampled patients with established treatment-refractory IBD, limiting our understanding of which cell types, subsets, and states at diagnosis anticipate disease severity and response to treatment. Here, through combining clinical, flow cytometry, histology, and scRNA-seq methods, we profile diagnostic human biopsies from the terminal ileum of treatment-naïve pediatric patients with Crohn’s disease (pediCD; n=14), matched repeat biopsies (pediCD-treated; n=8) and from non-inflamed pediatric controls with functional gastrointestinal disorders (FGID; n=13). To resolve and annotate epithelial, stromal, and immune cell states among the 201,883 baseline single-cell transcriptomes, we develop a principled and unbiased tiered clustering approach, ARBOL. Through flow cytometry and scRNA-seq, we observe that treatment-naïve pediCD and FGID have similar broad cell type composition. However, through high-resolution scRNA-seq analysis and microscopy, we identify significant differences in cell subsets and states that arise during pediCD relative to FGID. By closely linking our scRNA-seq analysis with clinical meta-data, we resolve a vector of T cell, innate lymphocyte, myeloid, and epithelial cell states in treatment-naïve pediCD (pediCD-TIME) samples which can distinguish patients along the trajectory of disease severity and anti-TNF response. By using ARBOL with integration, we position repeat on-treatment biopsies from our patients between treatment-naïve pediCD and on-treatment adult CD. We identify that anti-TNF treatment pushes the pediatric cellular ecosystem towards an adult, more treatment-refractory state. Our study jointly leverages a treatment-naïve cohort, high-resolution principled scRNA-seq data analysis, and clinical outcomes to understand which baseline cell states may predict ... |
| Document Type: |
other/unknown material |
| Language: |
unknown |
| DOI: |
10.7554/elife.91792.2 |
| Availability: |
https://doi.org/10.7554/elife.91792.2; https://cdn.elifesciences.org/preprints/91792/elife-preprint-91792-v2.pdf; https://cdn.elifesciences.org/preprints/91792/elife-preprint-91792-v2.xml |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.593972BC |
| Database: |
BASE |