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  • Review Article
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Sphingosine 1-phosphate modulation and immune cell trafficking in inflammatory bowel disease

Nature Reviews Gastroenterology & Hepatology volume 19, pages 351–366 (2022)Cite this article

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An Author Correction to this article was published on 07 March 2022

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Abstract

Immune cell trafficking is a critical element of the intestinal immune response, both in homeostasis and in pathological conditions associated with inflammatory bowel disease (IBD). This process involves adhesion molecules, chemoattractants and receptors expressed on immune cell surfaces, blood vessels and stromal intestinal tissue as well as signalling pathways, including those modulated by sphingosine 1-phosphate (S1P). The complex biological processes of leukocyte recruitment, activation, adhesion and migration have been targeted by various monoclonal antibodies (vedolizumab, etrolizumab, ontamalimab). Promising preclinical and clinical data with several oral S1P modulators suggest that inhibition of lymphocyte egress from the lymph nodes to the bloodstream might be a safe and efficacious alternative mechanism for reducing inflammation in immune-mediated disorders, including Crohn’s disease and ulcerative colitis. Although various questions remain, including the potential positioning of S1P modulators in treatment algorithms and their long-term safety, this novel class of compounds holds great promise. This Review summarizes the critical mediators and mechanisms involved in immune cell trafficking in IBD and the available evidence for efficacy, safety and pharmacokinetics of S1P receptor modulators in IBD and other immune-mediated disorders. Further, it discusses potential future approaches to incorporate S1P modulators into the treatment of IBD.

Key points

  • Sphingosine 1-phosphate (S1P) is a pleiotropic and widely expressed bioactive molecule belonging to the sphingolipid family that binds to five receptors (found on numerous cell types) with varying affinities.

  • Oral S1P modulators have been tested in multiple immune-mediated disorders.

  • Cardiotoxicity of the non-selective S1P agonist fingolimod has led to the development of more selective compounds, including ozanimod and etrasimod.

  • Ozanimod and etrasimod have been shown to be safe and efficacious for the treatment of patients with inflammatory bowel disease.

  • Future treatment approaches including S1P modulators should be explored, such as combination therapy with approved biologic agents, as well as the identification of predictive biomarkers to facilitate personalized therapy.

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Fig. 1: Overview of mechanisms for targeting immune cell trafficking in inflammatory bowel disease.
Fig. 2: Overview of S1P metabolism.
Fig. 3: S1P receptors and downstream signalling pathways.

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Acknowledgements

The authors would like to thank L. Petti for granting permission to re-use her figure in our manuscript (Fig. 2 Overview of S1P metabolism), and L. M. Shackelton for critical technical review and editing.

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Authors and Affiliations

  1. University Hospitals Leuven Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium

    Bram Verstockt & Severine Vermeire

  2. KU Leuven Department of Chronic Diseases and Metabolism, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium

    Bram Verstockt & Severine Vermeire

  3. Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy

    Stefania Vetrano

  4. IBD Center, Laboratory of Immunology in Gastroenterology, IRCCS Humanitas Research Hospital — IRCCS, Rozzano, Milan, Italy

    Stefania Vetrano

  5. Inflammatory Bowel Disease Unit, Gastroenterology Department, Hospital Clinic of Barcelona, Barcelona, Spain

    Azucena Salas & Julian Panes

  6. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain

    Azucena Salas & Julian Panes

  7. Zane Cohen Centre for Digestive Diseases, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada

    Shadi Nayeri

  8. Inflammatory Bowel Disease Center, Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, Netherlands

    Marjolijn Duijvestein

  9. Amsterdam UMC, Amsterdam Medical Center, University of Amsterdam, Department of Gastroenterology and Hepatology, Amsterdam, Netherlands

    Marjolijn Duijvestein & Geert D’Haens

  10. Department of Medicine, University of California San Diego, La Jolla, CA, USA

    Niels Vande Casteele

  11. Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy

    Silvio Danese

  12. University Vita-Salute San Raffaele, Milan, Italy

    Silvio Danese

  13. Metabolism Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands

    Geert D’Haens

  14. Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA

    Lars Eckmann & William J. Sandborn

  15. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA

    William A. Faubion

  16. Departments of Medicine and Epidemiology and Biostatistics, Western University, London, Ontario, Canada

    Brian G. Feagan & Vipul Jairath

  17. Division of Gastroenterology and Hepatology, Departments of Medicine and Community Health Sciences, University of Calgary, Calgary, Alberta, Canada

    Christopher Ma

  18. F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Dermot McGovern

  19. Mount Sinai Hospital IBD Centre, University of Toronto, Toronto, Ontario, Canada

    Mark S. Silverberg

Authors
  1. Bram Verstockt
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  2. Stefania Vetrano
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  3. Azucena Salas
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  4. Shadi Nayeri
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  5. Marjolijn Duijvestein
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  6. Niels Vande Casteele
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Consortia

Alimentiv Translational Research Consortium (ATRC)

  • Silvio Danese
  • , Geert D’Haens
  • , Lars Eckmann
  • , William A. Faubion
  • , Brian G. Feagan
  • , Vipul Jairath
  • , Christopher Ma
  • , Dermot McGovern
  • , Julian Panes
  • , William J. Sandborn
  • , Mark S. Silverberg
  •  & Severine Vermeire

Contributions

The authors contributed equally to all aspects of the article. All authors approved the final version of the manuscript and agreed to submission.

Corresponding author

Correspondence to Niels Vande Casteele.

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Competing interests

B.V. reports financial support for research from Pfizer; lecture fees from Abbvie, Biogen, Chiesi, Falk, Ferring, Galapagos, Janssen, MSD, Pfizer, R-Biopharm, Takeda and Truvion; and consultancy fees from Janssen, Guidepont and Sandoz; these activities were all outside of the submitted work. A.S. reports research grants from Roche-Genentech, Abbvie, GSK, Scipher Medicine, Alimentiv (formerly Robarts Clinical Trials) and Boehringer Ingelheim and consulting fees from Genentech, GSK, Pfizer, HotSpot Therapeutics, Surrozen, and Morphic Therapeutic. M.D. reports advisory fees from Echo Pharma and Alimentiv (formerly Robarts Clinical Trials); speaker fees from Janssen, Merck & Co., Pfizer, Takeda and Tillotts Pharma; and non-financial support from Dr. Falk Pharm; these activities were all outside of the submitted work. N.V.C. reports research grants and personal fees from R-Biopharm, Takeda, and UCB and personal fees from Alimentiv (formerly Robarts Clinical Trials), Celltrion and Prometheus; these activities were all outside of the submitted work. N.V.C. holds a Research Scholar Award from the American Gastroenterological Association and this project was, in part, supported by the Digestive Diseases Research Center grant NIH DK120515. Alimentiv (formerly Robarts Clinical Trials) is an academic gastrointestinal contract research organization (CRO), operating under the Alimentiv Health Trust. Alimentiv provides centralized imaging management solutions in clinical trials, including endoscopy, histopathology and magnetic resonance imaging. Alimentiv provides full service CRO capabilities as well as precision medicine services. A.S., M.D. and N.V.C. as well as Alimentiv Translational Research Consortium Member Authors listed in Supplementary Box 1, including G.D’H., B.G.F., V.J., C.M. and W.J.S., are consultants, and have neither equity positions nor shares in the corporation. The other authors declare no competing interests.

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Verstockt, B., Vetrano, S., Salas, A. et al. Sphingosine 1-phosphate modulation and immune cell trafficking in inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 19, 351–366 (2022). https://doi.org/10.1038/s41575-021-00574-7

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