Single-cell integration reveals metaplasia in inflammatory gut diseases.

Oliver AJ., Huang N., Bartolome-Casado R., Li R., Koplev S., Nilsen HR., Moy M., Cakir B., Polanski K., Gudiño V., Melón-Ardanaz E., Sumanaweera D., Dimitrov D., Milchsack LM., FitzPatrick MEB., Provine NM., Boccacino JM., Dann E., Predeus AV., To K., Prete M., Chapman JA., Masi AC., Stephenson E., Engelbert J., Lobentanzer S., Perera S., Richardson L., Kapuge R., Wilbrey-Clark A., Semprich CI., Ellams S., Tudor C., Joseph P., Garrido-Trigo A., Corraliza AM., Oliver TRW., Hook CE., James KR., Mahbubani KT., Saeb-Parsy K., Zilbauer M., Saez-Rodriguez J., Høivik ML., Bækkevold ES., Stewart CJ., Berrington JE., Meyer KB., Klenerman P., Salas A., Haniffa M., Jahnsen FL., Elmentaite R., Teichmann SA.

The gastrointestinal tract is a multi-organ system crucial for efficient nutrient uptake and barrier immunity. Advances in genomics and a surge in gastrointestinal diseases1,2 has fuelled efforts to catalogue cells constituting gastrointestinal tissues in health and disease3. Here we present systematic integration of 25 single-cell RNA sequencing datasets spanning the entire healthy gastrointestinal tract in development and in adulthood. We uniformly processed 385 samples from 189 healthy controls using a newly developed automated quality control approach (scAutoQC), leading to a healthy reference atlas with approximately 1.1 million cells and 136 fine-grained cell states. We anchor 12 gastrointestinal disease datasets spanning gastrointestinal cancers, coeliac disease, ulcerative colitis and Crohn's disease to this reference. Utilizing this 1.6 million cell resource (gutcellatlas.org), we discover epithelial cell metaplasia originating from stem cells in intestinal inflammatory diseases with transcriptional similarity to cells found in pyloric and Brunner's glands. Although previously linked to mucosal healing4, we now implicate pyloric gland metaplastic cells in inflammation through recruitment of immune cells including T cells and neutrophils. Overall, we describe inflammation-induced changes in stem cells that alter mucosal tissue architecture and promote further inflammation, a concept applicable to other tissues and diseases.

DOI

10.1038/s41586-024-07571-1

Type

Journal article

Journal

Nature

Publication Date

11/2024

Volume

635

Pages

699 - 707

Keywords

Adult, Humans, Brunner Glands, Case-Control Studies, Celiac Disease, Colitis, Ulcerative, Crohn Disease, Datasets as Topic, Epithelial Cells, Gastric Mucosa, Gastrointestinal Diseases, Gastrointestinal Neoplasms, Gastrointestinal Tract, Health, Inflammation, Intestinal Mucosa, Metaplasia, Neutrophils, Pylorus, Quality Control, Single-Cell Analysis, Single-Cell Gene Expression Analysis, Stem Cells, T-Lymphocytes, Child

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