Single-cell and spatial transcriptomics of stricturing Crohn's disease highlights a fibrosis-associated network

Lingjia Kong^{1

2

3}, Sathish Subramanian^{1

3

4

5}, Åsa Segerstolpe¹, Vy Tran², Angela R Shih⁶, Grace T Carter¹, Hiroko Kunitake⁷, Shaina W Twardus^{2

5}, Jasmine Li¹, Shivam Gandhi², Marco E Kaper², Christy Cauley⁷, Eric J Chen¹, Caroline B M Porter¹, Toni M Delorey¹, Liliana Bordeianou⁷, Rocco Ricciardi⁷, Ashwin N Ananthakrishnan⁴, Helena Lau^{1

2

5}, Daniel B Graham^{1

2

3

5}, Richard Hodin⁷, Jacques Deguine¹, Christopher S Smillie^{8

9

10}, Ramnik J Xavier^{11

12

13

14

15}

Affiliations

¹ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
³ Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁵ Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA, USA.
⁶ Department of Pathology and Laboratory Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁷ Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁸ Broad Institute of MIT and Harvard, Cambridge, MA, USA. csmillie@mgh.harvard.edu.
⁹ Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. csmillie@mgh.harvard.edu.
¹⁰ Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA, USA. csmillie@mgh.harvard.edu.
¹¹ Broad Institute of MIT and Harvard, Cambridge, MA, USA. xavier@molbio.mgh.harvard.edu.
¹² Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. xavier@molbio.mgh.harvard.edu.
¹³ Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. xavier@molbio.mgh.harvard.edu.
¹⁴ Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA, USA. xavier@molbio.mgh.harvard.edu.
¹⁵ Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. xavier@molbio.mgh.harvard.edu.

PMID: 40562913
DOI: 10.1038/s41588-025-02225-y

Single-cell and spatial transcriptomics of stricturing Crohn's disease highlights a fibrosis-associated network

Lingjia Kong et al. Nat Genet. 2025 Jul.

. 2025 Jul;57(7):1742-1753.

doi: 10.1038/s41588-025-02225-y. Epub 2025 Jun 25.

Authors

Affiliations

¹ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
³ Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁵ Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA, USA.
⁶ Department of Pathology and Laboratory Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁷ Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁸ Broad Institute of MIT and Harvard, Cambridge, MA, USA. csmillie@mgh.harvard.edu.
⁹ Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. csmillie@mgh.harvard.edu.
¹⁰ Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA, USA. csmillie@mgh.harvard.edu.
¹¹ Broad Institute of MIT and Harvard, Cambridge, MA, USA. xavier@molbio.mgh.harvard.edu.
¹² Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. xavier@molbio.mgh.harvard.edu.
¹³ Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. xavier@molbio.mgh.harvard.edu.
¹⁴ Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA, USA. xavier@molbio.mgh.harvard.edu.
¹⁵ Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. xavier@molbio.mgh.harvard.edu.

PMID: 40562913
DOI: 10.1038/s41588-025-02225-y

Abstract

Fibrosis is a major complication of Crohn's disease (CD) marked by excess deposition of extracellular matrix, leading to stricturing and functional impairment. As mechanistic characterization and therapeutic options are lacking, we paired single-cell and spatial transcriptomics in 61 samples from 21 patients with CD and 10 patients without inflammatory bowel disease (IBD). Intestinal strictures were characterized by increased immune cells, including IgG⁺ plasma cells, CCR7-hi CD4⁺ T cells and inflammatory fibroblasts. Spatial transcriptomics showed that key subsets colocalize within diseased tissues and identified additional populations such as interstitial cells of Cajal and enteric neurons. Furthermore, we mapped gene expression onto intestinal biogeography, finding that known genetic risk loci are enriched within discrete spatial modules, defined by the presence of inflammatory fibroblasts and lymphoid follicles. Altogether, our datasets chart the key transcriptomic and cellular networks in stricturing CD and highlight the spatial organization of multicellular genetic risk factors.

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Conflict of interest statement

Competing interests: R.J.X. is cofounder of Jnana Therapeutics, Scientific Advisory Board member at Nestlé, Magnet BioMedicine and Arena BioWorks, and Board Director at MoonLake Immunotherapeutics; these organizations had no roles in this study. S.S. is currently an employee of Vertex Pharmaceuticals, which also had no role in this study. The other authors declare no competing interests.

References

1. Lewis, J. D. et al. Incidence, prevalence, and racial and ethnic distribution of inflammatory bowel disease in the United States. Gastroenterology 165, 1197–1205 (2023). - PubMed
1. Graham, D. B. & Xavier, R. J. Pathway paradigms revealed from the genetics of inflammatory bowel disease. Nature 578, 527–539 (2020). - PubMed - PMC
1. Kugathasan, S. et al. Prediction of complicated disease course for children newly diagnosed with Crohn’s disease: a multicentre inception cohort study. Lancet 389, 1710–1718 (2017). - PubMed - PMC
1. D’Alessio, S. et al. Revisiting fibrosis in inflammatory bowel disease: the gut thickens. Nat. Rev. Gastroenterol. Hepatol. 19, 169–184 (2022). - PubMed
1. Smillie, C. S. et al. Intra- and inter-cellular rewiring of the human colon during ulcerative colitis. Cell 178, 714–730 (2019). - PubMed - PMC

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Single-cell and spatial transcriptomics of stricturing Crohn's disease highlights a fibrosis-associated network

Affiliations

Single-cell and spatial transcriptomics of stricturing Crohn's disease highlights a fibrosis-associated network

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials