Colonic epithelial cell diversity in health and inflammatory bowel disease

• Published in: Nature (London) Vol. 567; no. 7746; pp. 49 - 55
• Main Authors: Parikh, Kaushal, Antanaviciute, Agne, Fawkner-Corbett, David, Jagielowicz, Marta, Aulicino, Anna, Lagerholm, Christoffer, Davis, Simon, Kinchen, James, Chen, Hannah H., Alham, Nasullah Khalid, Ashley, Neil, Johnson, Errin, Hublitz, Philip, Bao, Leyuan, Lukomska, Joanna, Andev, Rajinder Singh, Björklund, Elisabet, Kessler, Benedikt M., Fischer, Roman, Goldin, Robert, Koohy, Hashem, Simmons, Alison
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2019; Nature Publishing Group
• Subjects: 13; 14; 14/28; 38; 38/91; 631/114/2404; 631/250/256; 692/699/1503/257; 82; 82/51; 82/58; Absorptivity; Animals; Antibacterial agents; Bacteria; Biomarkers - analysis; Breakdown; Cancer; Cells (biology); Colitis, Ulcerative - genetics; Colitis, Ulcerative - microbiology; Colitis, Ulcerative - pathology; Colon; Colon - cytology; Colon - microbiology; Colon - pathology; Disease control; Epithelial cells; Epithelial Cells - classification; Epithelial Cells - cytology; Epithelial Cells - microbiology; Epithelial Cells - pathology; Epithelium; Gastrointestinal diseases; Genetic Predisposition to Disease - genetics; Goblet cells; Goblet Cells - cytology; Goblet Cells - metabolism; Goblet Cells - pathology; Health; Humanities and Social Sciences; Humans; Hydrogen-Ion Concentration; Identification and classification; Immunity; Inflammation; Inflammatory bowel disease; Inflammatory bowel diseases; Inflammatory Bowel Diseases - genetics; Inflammatory Bowel Diseases - microbiology; Inflammatory Bowel Diseases - pathology; Intestinal Mucosa - metabolism; Intestinal Mucosa - microbiology; Intestinal Mucosa - pathology; Intestine; Ion Channels - metabolism; Male; Mice; Mucosal immunity; Mucous membrane; Mucus; multidisciplinary; Natriuretic Peptides - metabolism; Peptides; Physiological aspects; Progenitor cells; Proteins - metabolism; Protons; Satiety; Science; Science (multidisciplinary); Single-Cell Analysis; Stem cells; Stem Cells - cytology; Stem Cells - metabolism; Stem Cells - pathology; Tight junctions; Tight Junctions - metabolism; Transcription; Transcription, Genetic; Uroguanylin; WAP Four-Disulfide Core Domain Protein 2
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-019-0992-y

The colonic epithelium facilitates host–microorganism interactions to control mucosal immunity, coordinate nutrient recycling and form a mucus barrier. Breakdown of the epithelial barrier underpins inflammatory bowel disease (IBD). However, the specific contributions of each epithelial-cell subtype to this process are unknown. Here we profile single colonic epithelial cells from patients with IBD and unaffected controls. We identify previously unknown cellular subtypes, including gradients of progenitor cells, colonocytes and goblet cells within intestinal crypts. At the top of the crypts, we find a previously unknown absorptive cell, expressing the proton channel OTOP2 and the satiety peptide uroguanylin, that senses pH and is dysregulated in inflammation and cancer. In IBD, we observe a positional remodelling of goblet cells that coincides with downregulation of WFDC2—an antiprotease molecule that we find to be expressed by goblet cells and that inhibits bacterial growth. In vivo, WFDC2 preserves the integrity of tight junctions between epithelial cells and prevents invasion by commensal bacteria and mucosal inflammation. We delineate markers and transcriptional states, identify a colonic epithelial cell and uncover fundamental determinants of barrier breakdown in IBD. Profiling of single epithelial cells in healthy and inflamed colons identifies specialized cellular subpopulations, including a type of goblet cell that secretes the antibacterial protein WFDC2, which preserves the integrity of the epithelial barrier layer.