Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis

• Main Authors: Ordovas-Montanes, Jose Manuel (Author), Graham, Daniel B. (Author), Shalek, Alexander K (Author), Xavier, Ramnik Joseph (Author), Regev, Aviv (Author)
• Other Authors: Massachusetts Institute of Technology. Department of Chemistry (Contributor), Massachusetts Institute of Technology. Institute for Medical Engineering & Science (Contributor), Ragon Institute of MGH, MIT and Harvard (Contributor), Massachusetts Institute of Technology. Center for Microbiome Informatics and Therapeutics (Contributor), Massachusetts Institute of Technology. Department of Biology (Contributor), Koch Institute for Integrative Cancer Research at MIT (Contributor)
• Format: Article
• Language: English
• Published: Elsevier BV, 2020-08-26T17:28:41Z.
• Subjects: Article
• Online Access: Get fulltext

 Genome-wide association studies (GWAS) have revealed risk alleles for ulcerative colitis (UC). To understand their cell type specificities and pathways of action, we generate an atlas of 366,650 cells from the colon mucosa of 18 UC patients and 12 healthy individuals, revealing 51 epithelial, stromal, and immune cell subsets, including BEST4⁺ enterocytes, microfold-like cells, and IL13RA2⁺IL11⁺ inflammatory fibroblasts, which we associate with resistance to anti-TNF treatment. Inflammatory fibroblasts, inflammatory monocytes, microfold-like cells, and T cells that co-express CD8 and IL-17 expand with disease, forming intercellular interaction hubs. Many UC risk genes are cell type specific and co-regulated within relatively few gene modules, suggesting convergence onto limited sets of cell types and pathways. Using this observation, we nominate and infer functions for specific risk genes across GWAS loci. Our work provides a framework for interrogating complex human diseases and mapping risk variants to cell types and pathways.