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Mechanisms of mucosal healing: treating inflammatory bowel disease without immunosuppression?

Nature Reviews Gastroenterology & Hepatology volume 19, pages 493–507 (2022)Cite this article

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Abstract

Almost all currently available treatments for inflammatory bowel disease (IBD) act by inhibiting inflammation, often blocking specific inflammatory molecules. However, given the infectious and neoplastic disease burden associated with chronic immunosuppressive therapy, the goal of attaining mucosal healing without immunosuppression is attractive. The absence of treatments that directly promote mucosal healing and regeneration in IBD could be linked to the lack of understanding of the underlying pathways. The range of potential strategies to achieve mucosal healing is diverse. However, the targeting of regenerative mechanisms has not yet been achieved for IBD. Stem cells provide hope as a regenerative treatment and are used in limited clinical situations. Growth factors are available for the treatment of short bowel syndrome but have not yet been applied in IBD. The therapeutic application of organoid culture and stem cell therapy to generate new intestinal tissue could provide a novel mechanism to restore barrier function in IBD. Furthermore, blocking key effectors of barrier dysfunction (such as MLCK or damage-associated molecular pattern molecules) has shown promise in experimental IBD. Here, we review the diversity of molecular targets available to directly promote mucosal healing, experimental models to identify new potential pathways and some of the anticipated potential therapies for IBD.

Key points

  • Inflammatory bowel disease (IBD) has emerged as a global disease with no available cure.

  • Most drugs to treat IBD are immunosuppressive, leading to increased risk of infections and cancer.

  • Inter-individual variation in response to drugs means a wider range of therapeutic strategies is needed.

  • Promoting mucosal healing is a promising therapeutic strategy in IBD.

  • Experimental models have been instrumental to identify novel mechanisms promoting mucosal healing.

  • Drugs promoting regeneration have been identified, but the examination of tumorigenesis in this setting is urgently needed.

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Fig. 1: The stem cell niche in the small intestine and colon.
Fig. 2: The intestinal barrier.
Fig. 3: Experimental models to study mucosal healing.
Fig. 4: Novel and potential future therapies targeting mucosal healing.

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Acknowledgements

The authors thank members of the Villablanca lab for helpful comments. E.J.V. was supported by grants from the Swedish Research Council, VR grants K2015-68X-22765-01-6 and 2018-02533, Formas grant no. FR-2016/0005, Cancerfonden (19 0395 Pj), and the Wallenberg Academy Fellow program (2019.0315). K.S. has received support from The Swedish Medical Association (Svenska läkarsällskapet). C.R.H.H. gratefully acknowledges support from Julins Foundation, Bengt Ihre Fellowship, The Swedish Medical Association (Svenska Läkarsällskapet), the Calder Foundation, an ECCO project grant, Gastrofonden, MagTarm fund, Professor Nanna Svartz Fund and a clinical post-doc from Region Stockholm.

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Authors and Affiliations

  1. Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet and University Hospital, Stockholm, Sweden

    Eduardo J. Villablanca

  2. Gastroenterology unit, Department of Gastroenterology, Dermatovenereology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden

    Katja Selin & Charlotte R. H. Hedin

  3. Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden

    Katja Selin & Charlotte R. H. Hedin

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  1. Eduardo J. Villablanca
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  2. Katja Selin
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  3. Charlotte R. H. Hedin
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The authors contributed equally to all aspects of the article.

Corresponding authors

Correspondence to Eduardo J. Villablanca or Charlotte R. H. Hedin.

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Competing interests

E.J.V. has received research grants from F. Hoffmann-La Roche. C.R.H.H. has received speaker fees from Takeda, Ferring, AbbVie, and Janssen and consultancy fees from Pfizer. She has acted as local principal investigator for clinical trials for Janssen and GlaxoSmithKline. She has received project grants from Takeda and Tillotts. K.S. declares no competing interests.

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Nature Reviews Gastroenterology & Hepatology thanks Silvio Danese and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Villablanca, E.J., Selin, K. & Hedin, C.R.H. Mechanisms of mucosal healing: treating inflammatory bowel disease without immunosuppression?. Nat Rev Gastroenterol Hepatol 19, 493–507 (2022). https://doi.org/10.1038/s41575-022-00604-y

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