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Defining the mucosal ecosystem: epithelial–mesenchymal interdependence in gastrointestinal health and disease

Nature Reviews Gastroenterology & Hepatology (2025)Cite this article

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Abstract

The crypt–villus architecture of the intestinal mucosa is underpinned by dynamic interactions between distinct populations of epithelial, stromal and immune cells. Although the epithelial compartment has attracted substantial attention, there is a growing appreciation for the critical role of mesenchymal cells in shaping epithelial stem cell function and dictating lineage specification. In this Review, we outline how the epithelial and mesenchymal compartments of the developing gut evolve in a mutually dependent manner to establish dynamic reciprocal signalling gradients that maintain adult tissue homeostasis. We discuss how perturbations to this delicate ecosystem result in rapid adaptive cellular responses that act to restore tissue function. Furthermore, we explore how the intricate nature of cell fate interdependence also renders the mucosa susceptible to pathological disruption. Drawing on the latest studies, we highlight the crosstalk networks between the epithelial and stromal compartments that underlie these processes and consider how these insights are informing future research directions and therapeutic strategies. In doing so, we advocate for a shift away from the conventional epithelial-centric paradigm toward a more integrated framework that considers the full spectrum of intercellular interactions maintaining intestinal tissue integrity and shaping disease progression.

Key points

  • Epithelial–mesenchymal cell interactions orchestrate crypt–villus morphogenesis during development, establishing a cross-compartmental interdependence that persists through adult life.

  • In health, crypt–villus compartmentalization is maintained by opposing gradients of reciprocal morphogenic signals that collectively pattern epithelial and mesenchymal cell fate and function along the vertical axis.

  • This dynamic bidirectional interplay renders the intestinal mucosa remarkably sensitive to damage, enabling a rapid cascade of coordinated epithelial and mesenchymal remodelling events that drive tissue repair.

  • Mutant intestinal cells must either cooperate with their surrounding niche or subvert existing intercompartmental crosstalk networks to bypass homeostatic constraints in favour of tumorigenesis.

  • Metastatic outgrowth and colonization similarly rely on adaptive interactions with the evolving microenvironment, with resident cells in the host organ co-opted and reprogrammed into supportive pro-metastatic niches.

  • Adopting a systems-level approach that considers the intestinal mucosa as an integrated ecosystem will be needed to unravel the regulatory mechanisms underpinning these processes and guide innovative therapeutic strategies.

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Fig. 1: Localization of key cellular components constituting intestinal crypt–villus structures.
Fig. 2: Epithelial–stromal remodelling during intestinal regeneration.
Fig. 3: Mechanisms of mutant cell–niche crosstalk governing neoplastic transformation.

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Acknowledgements

F.J.E. was supported by a Foulkes Foundation Fellowship. M.S. was supported by the ERC (St Grant REVERT, 101040453) and the BMBF Consortium PACETHERAPY (01EJ2206A). S.J.L. was supported by a CRUK Program Grant (DRCNPG-Jun22\100002) and the CRUK Strategic Award CRC-STARS (SEBCRCS-2024/100001).

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Authors and Affiliations

  1. Intestinal Stem Cell Laboratory, Centre for Human Genetics, University of Oxford, Oxford, UK

    Frances J. England & Simon J. Leedham

  2. Medical Department, Division of Gastroenterology and Hepatology, Campus Virchow-Klinikum, Charité-Universitätsmedizin, Berlin, Germany

    Manqiang Lin & Michael Sigal

  3. Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, Berlin, Germany

    Manqiang Lin & Michael Sigal

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  1. Frances J. England
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The authors contributed equally to researching data for the article, discussion of the content and writing the article. M.S. and S.J.L. reviewed and/or edited the manuscript before submission.

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England, F.J., Lin, M., Sigal, M. et al. Defining the mucosal ecosystem: epithelial–mesenchymal interdependence in gastrointestinal health and disease. Nat Rev Gastroenterol Hepatol (2025). https://doi.org/10.1038/s41575-025-01113-4

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