The Human Gut Cell Atlas v1.0: A Unified, Community-Built Reference of Cellular Diversity Across the Gut

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Abstract
Single-cell RNA-sequencing (scRNA-seq) studies have transformed our understanding of cellular diversity in the human intestine, but differences in anatomical sampling, experimental processing and cell-type nomenclature limit comparison across datasets. Here, we present the Human Gut Cell Atlas (HGCA) V1, a community-curated reference of 944,390 healthy and disease-adjacent intestinal cells from 502 samples, 265 donors and 24 landmark studies, linked to detailed anatomical, clinical, and technical metadata. As this metadata is of critical importance to human biology, we developed MetaManager, an open source data management framework for standardized metadata collection and tracking. A five-level consensus taxonomy resolves 94 homeostatic cell identities and enables transferrable, high-resolution annotation of new gut datasets. By assembling cell identity, sampling metadata, and independent spatial validation, intestinal segment and radial tissue depth were revealed to systematically shape cellular composition and transcriptional state, enabling inference of the presence of sampling-dependent tissue niches, including lymphoid follicles. Reference mapping accurately and rapidly recovered cohort-level Crohn’s disease and treatment signatures without de novo annotation, while mapping human intestinal organoids quantified cell-type-specific identity, regional specification, maturation, and transcriptional fidelity to native tissue. The HGCA V1 provides a standardized cellular, anatomical coordinate, and metadata system for reproducible, high-quality analysis of intestinal biology across healthy tissue, disease-associated remodelling, and experimental models, providing a continuously evolving community reference for cumulative discovery in human intestinal biology.
Funding Information
  • European Commission (101080523)
  • Agencia Estatal de Investigación (PID2024-159113OB-I00)
  • Norwegian Cancer Society (294670)
  • National Institute for Health and Care Research
  • National Research, Development and Innovation Office (154125)
  • Wellcome Trust (220540/Z/20/A)
  • European Research Council (101118531)
  • Schmidt Futures
  • Research Foundation - Flanders (G045720N)
  • KU Leuven (C14/23/135)
  • Milner Therapeutics Institute
  • Helmholtz Association (VH NG 1716)
  • Generalitat de Catalunya (AGAUR_FI23-2023FI_1_00771)
  • Crohn’s & Colitis Foundation
  • Open Targets
  • Biotechnology and Biological Sciences Research Council (BB/X011054/1)
  • Biotechnology and Biological Sciences Research Council (BBS/E/F/000PR13631)
  • Medical Research Council
  • The Pew Charitable Trusts
  • Broad Institute
  • Kenneth Rainin Foundation
  • New York Stem Cell Foundation
  • The Manton Foundation
  • The Warren Alpert Foundation
  • Deutsche Forschungsgemeinschaft (KO 4891/6-1)
  • Deutsche Forschungsgemeinschaft (496078873)
  • Deutsche Forschungsgemeinschaft (KO 4891/5-1)
  • Deutsche Forschungsgemeinschaft (447562338)
  • Else Kröner-Fresenius-Stiftung (2019_A136)
  • Federal Ministry of Research, Technology and Space (01GL2406A)
  • Care-for-Rare Foundation
  • Silicon Valley Community Foundation (2021-235155)
  • National Institutes of Health (K01DK140610)
  • American Gastroenterological Association (AGA2024-13-01)

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