Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Interrogating host immunity to predict treatment response in inflammatory bowel disease

Nature Reviews Gastroenterology & Hepatology volume 17, pages 9–20 (2020)Cite this article

Subjects

Abstract

IBD treatment is undergoing a transformation with an expanding repertoire of drugs targeting different aspects of the immune response. Three novel classes of drugs have emerged in the past decade that target leukocyte trafficking to the gut (vedolizumab), neutralize key cytokines with antibodies (ustekinumab) and inhibit cytokine signalling pathways (tofacitinib). In advanced development are other drugs for IBD, including therapies targeting other cytokines such as IL-23 and IL-6. However, all agents tested so far are hampered by primary and secondary loss of response, so it is desirable to develop personalized strategies to identify which patients should be treated with which drugs. Stratification of patients with IBD by clinical parameters alone lacks sensitivity, and alternative modalities are now needed to deliver precision medicine in IBD. High-resolution profiling of immune response networks in individual patients is a promising approach and different technical platforms, including in vivo real-time molecular endoscopy, tissue transcriptomics and germline genetics, are promising tools to help predict responses to specific therapies. However, important challenges remain regarding the clinical utility of these technologies, including their scalability and accessibility. This Review focuses on unravelling some of the complexity of mucosal immune responses in IBD pathogenesis and how current and emerging analytical platforms might be harnessed to effectively stratify and individualise IBD therapy.

Key points

  • IBD has a growing repertoire of treatments targeting different aspects of the immune response but all treatments are hampered by primary and secondary loss of response.

  • Tofacitinib, a JAK inhibitor, is licensed for the treatment of ulcerative colitis, and other selective JAK inhibitors and IL-23p19 inhibitors are in phase III trials and expected to change treatment paradigms in IBD.

  • Precision medicine is highly desirable to fast-track patients to the most appropriate therapy at the earliest opportunity, thereby reducing complications of chronic inflammation and limiting corticosteroid exposure.

  • Biological insights into disease pathogenesis have unveiled different targets that might serve to predict outcomes in IBD, and the identification of laboratory assays with clinical utility is now a pressing priority for biomarker development.

  • Promising platforms to deliver precision medicine approaches in IBD include in vivo molecular endoscopy, transcriptomics, germline genetics, gut microbiome analysis and profiling of the immune response.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Drug targets in IBD.
Fig. 2: Interactions between TNF and its receptors.
Fig. 3: Schematic of principles of molecular endoscopy in IBD.
Fig. 4: Proposed investigations for future personalized medicine in IBD.

Similar content being viewed by others

References

  1. Abraham, C. & Cho, J. H. Inflammatory bowel disease. N. Engl. J. Med. 361, 2066–2078 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Maloy, K. J. & Powrie, F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature 474, 298–306 (2011).

    CAS  PubMed  Google Scholar 

  3. Jostins, L. et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Liu, J. Z. et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat. Genet. 47, 979–986 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. de Lange, K. M. et al. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nat. Genet. 49, 256–261 (2017).

    PubMed  PubMed Central  Google Scholar 

  6. Molodecky, N. A. et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 142, 46–54.e42 (2012).

    PubMed  Google Scholar 

  7. Ng, S. C. et al. Environmental risk factors in inflammatory bowel disease: a population-based case-control study in Asia-Pacific. Gut 64, 1063–1071 (2015).

    PubMed  Google Scholar 

  8. Sokol, H. et al. Fungal microbiota dysbiosis in IBD. Gut 66, 1039–1048 (2017).

    CAS  PubMed  Google Scholar 

  9. Powell, N. et al. The transcription factor T-bet regulates intestinal inflammation mediated by interleukin-7 receptor+ innate lymphoid cells. Immunity 37, 674–684 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Chen, Y. et al. Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis. J. Clin. Invest. 116, 1317–1326 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Hyams, J. S. Standardized recording of parameters related to the natural history of inflammatory bowel disease: from Montreal to Paris. Dig. Dis. 32, 337–344 (2014).

    PubMed  Google Scholar 

  12. Glocker, E. O. et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N. Engl. J. Med. 361, 2033–2045 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Kotlarz, D. et al. Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy. Gastroenterology 143, 347–355 (2012).

    CAS  PubMed  Google Scholar 

  14. Friedrich, M., Pohin, M. & Powrie, F. Cytokine networks in the pathophysiology of inflammatory bowel disease. Immunity 50, 992–1006 (2019).

    CAS  PubMed  Google Scholar 

  15. Neurath, M. F. Current and emerging therapeutic targets for IBD. Nat. Rev. Gastroenterol. Hepatol. 14, 269–278 (2017).

    CAS  PubMed  Google Scholar 

  16. Ding, N. S., Hart, A. & De Cruz, P. Systematic review: predicting and optimising response to anti-TNF therapy in Crohn’s disease – algorithm for practical management. Aliment. Pharmacol. Ther. 43, 30–51 (2016).

    CAS  PubMed  Google Scholar 

  17. Kopylov, U. & Seidman, E. Predicting durable response or resistance to antitumor necrosis factor therapy in inflammatory bowel disease. Therap. Adv. Gastroenterol. 9, 513–526 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. MacDonald, T. T. et al. Tumour necrosis factor-alpha and interferon-gamma production measured at the single cell level in normal and inflamed human intestine. Clin. Exp. Immunol. 81, 301–305 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Breese, E. J. et al. Tumor necrosis factor alpha-producing cells in the intestinal mucosa of children with inflammatory bowel disease. Gastroenterology 106, 1455–1466 (1994).

    CAS  PubMed  Google Scholar 

  20. Scheurich, P. et al. Immunoregulatory activity of recombinant human tumor necrosis factor (TNF)-alpha: induction of TNF receptors on human T cells and TNF-alpha-mediated enhancement of T cell responses. J. Immunol. 138, 1786–1790 (1987).

    CAS  PubMed  Google Scholar 

  21. Hurme, M. Both interleukin 1 and tumor necrosis factor enhance thymocyte proliferation. Eur. J. Immunol. 18, 1303–1306 (1988).

    CAS  PubMed  Google Scholar 

  22. Ranges, G. E. et al. Tumor necrosis factor alpha/cachectin is a growth factor for thymocytes. Synergistic interactions with other cytokines. J. Exp. Med. 167, 1472–1478 (1988).

    CAS  PubMed  Google Scholar 

  23. Yokota, S., Geppert, T. D. & Lipsky, P. E. Enhancement of antigen- and mitogen-induced human T lymphocyte proliferation by tumor necrosis factor-alpha. J. Immunol. 140, 531–536 (1988).

    CAS  PubMed  Google Scholar 

  24. Israel, N. et al. Tumor necrosis factor stimulates transcription of HIV-1 in human T lymphocytes, independently and synergistically with mitogens. J. Immunol. 143, 3956–3960 (1989).

    CAS  PubMed  Google Scholar 

  25. Liu, Z. G. & Han, J. Cellular responses to tumor necrosis factor. Curr. Issues Mol. Biol. 3, 79–90 (2001).

    PubMed  Google Scholar 

  26. Ming, W. J., Bersani, L. & Mantovani, A. Tumor necrosis factor is chemotactic for monocytes and polymorphonuclear leukocytes. J. Immunol. 138, 1469–1474 (1987).

    CAS  PubMed  Google Scholar 

  27. Wedemeyer, J. et al. Enhanced production of monocyte chemotactic protein 3 in inflammatory bowel disease mucosa. Gut 44, 629–635 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Danese, S. et al. Angiogenesis as a novel component of inflammatory bowel disease pathogenesis. Gastroenterology 130, 2060–2073 (2006).

    CAS  PubMed  Google Scholar 

  29. Pender, S. L. F. et al. A p55 TNF receptor immunoadhesin prevents T cell-mediated intestinal injury by inhibiting matrix metalloproteinase production. J. Immunol. 160, 4098–4103 (1998).

    CAS  PubMed  Google Scholar 

  30. Okuno, T. et al. Interleukin-1β and tumor necrosis factor-α induce chemokine and matrix metalloproteinase gene expression in human colonic subepithelial myofibroblasts. Scand. J. Gastroenterol. 37, 317–324 (2002).

    CAS  PubMed  Google Scholar 

  31. Wajant, H., Pfizenmaier, K. & Scheurich, P. Tumor necrosis factor signaling. Cell Death Differ. 10, 45–65 (2003).

    CAS  PubMed  Google Scholar 

  32. Luettig, B., Decker, T. & Lohmann-Matthes, M. L. Evidence for the existence of two forms of membrane tumor necrosis factor: an integral protein and a molecule attached to its receptor. J. Immunol. 143, 4034–4038 (1989).

    CAS  PubMed  Google Scholar 

  33. Kriegler, M. et al. A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane protein: ramifications for the complex physiology of TNF. Cell 53, 45–53 (1988).

    CAS  PubMed  Google Scholar 

  34. Souza, H. S. et al. Expression of lymphocyte-endothelial receptor-ligand pairs, alpha4beta7/MAdCAM-1 and OX40/OX40 ligand in the colon and jejunum of patients with inflammatory bowel disease. Gut 45, 856–863 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Burgess, J. K. et al. Detection and characterization of OX40 ligand expression in human airway smooth muscle cells: a possible role in asthma? J. Allergy Clin. Immunol. 113, 683–689 (2004).

    CAS  PubMed  Google Scholar 

  36. Black, R. A. et al. A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature 385, 729–733 (1997).

    CAS  PubMed  Google Scholar 

  37. Slevin, S. M. & Egan, L. J. New insights into the mechanisms of action of anti-tumor necrosis factor-alpha monoclonal antibodies in inflammatory bowel disease. Inflamm. Bowel Dis. 21, 2909–2920 (2015).

    PubMed  Google Scholar 

  38. Eissner, G. et al. Reverse signaling through transmembrane TNF confers resistance to lipopolysaccharide in human monocytes and macrophages. J. Immunol. 164, 6193–6198 (2000).

    CAS  PubMed  Google Scholar 

  39. Corazza, N. et al. Transmembrane tumor necrosis factor is a potent inducer of colitis even in the absence of its secreted form. Gastroenterology 127, 816–825 (2004).

    CAS  PubMed  Google Scholar 

  40. Perrier, C. et al. Neutralization of membrane TNF, but not soluble TNF, is crucial for the treatment of experimental colitis. Inflamm. Bowel Dis. 19, 246–253 (2013).

    PubMed  Google Scholar 

  41. Atreya, R. et al. Antibodies against tumor necrosis factor (TNF) induce T-cell apoptosis in patients with inflammatory bowel diseases via TNF receptor 2 and intestinal CD14+ macrophages. Gastroenterology 141, 2026–2038 (2011).

    CAS  PubMed  Google Scholar 

  42. Holtmann, M. H. et al. Tumor necrosis factor-receptor 2 is up-regulated on lamina propria T cells in Crohn’s disease and promotes experimental colitis in vivo. Eur. J. Immunol. 32, 3142–3151 (2002).

    CAS  PubMed  Google Scholar 

  43. Blaydon, D. C. et al. Inflammatory skin and bowel disease linked to ADAM17 deletion. N. Engl. J. Med. 365, 1502–1508 (2011).

    CAS  PubMed  Google Scholar 

  44. Rutgeerts, P. et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 353, 2462–2476 (2005).

    CAS  PubMed  Google Scholar 

  45. Sandborn, W. J. et al. Colectomy rate comparison after treatment of ulcerative colitis with placebo or infliximab. Gastroenterology 137, 1250–1260 (2009).

    CAS  PubMed  Google Scholar 

  46. Reinisch, W. et al. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial. Gut 60, 780–787 (2011).

    CAS  PubMed  Google Scholar 

  47. Reinisch, W. et al. 52-week efficacy of adalimumab in patients with moderately to severely active ulcerative colitis who failed corticosteroids and/or immunosuppressants. Inflamm. Bowel Dis. 19, 1700–1709 (2013).

    PubMed  Google Scholar 

  48. Sandborn, W. J. et al. Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology 146, 85–95 (2014).

    CAS  PubMed  Google Scholar 

  49. Hanauer, S. B. et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 359, 1541–1549 (2002).

    CAS  PubMed  Google Scholar 

  50. Colombel, J. F. et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology 132, 52–65 (2007).

    CAS  PubMed  Google Scholar 

  51. Sandborn, W. J. et al. Certolizumab pegol for the treatment of Crohn’s disease. N. Engl. J. Med. 357, 228–238 (2007).

    CAS  PubMed  Google Scholar 

  52. Sandborn, W. J. et al. Etanercept for active Crohn’s disease: a randomized, double-blind, placebo-controlled trial. Gastroenterology 121, 1088–1094 (2001).

    CAS  PubMed  Google Scholar 

  53. Rutgeerts, P. et al. Onercept for moderate-to-severe Crohn’s disease: a randomized, double-blind, placebo-controlled trial. Clin. Gastroenterol. Hepatol. 4, 888–893 (2006).

    CAS  PubMed  Google Scholar 

  54. Billmeier, U. et al. Molecular mechanism of action of anti-tumor necrosis factor antibodies in inflammatory bowel diseases. World J. Gastroenterol 22, 9300–9313 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Van den Brande, J. M. H. et al. Prediction of antitumour necrosis factor clinical efficacy by real-time visualisation of apoptosis in patients with Crohn’s disease. Gut 56, 509–517 (2007).

    PubMed  Google Scholar 

  56. Van den Brande, J. M. et al. Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn’s disease. Gastroenterology 124, 1774–1785 (2003).

    PubMed  Google Scholar 

  57. Braegger, C. P. & MacDonald, T. T. Immune mechanisms in chronic inflammatory bowel disease. Ann. Allergy 72, 135–141 (1994).

    CAS  PubMed  Google Scholar 

  58. Imam, T. et al. Effector T helper cell subsets in inflammatory bowel diseases. Front. Immunol. 9, 1212 (2018).

    PubMed  PubMed Central  Google Scholar 

  59. Giuffrida, P., Corazza, G. R. & Di Sabatino, A. Old and new lymphocyte players in inflammatory bowel disease. Dig. Dis. Sci. 63, 277–288 (2018).

    CAS  PubMed  Google Scholar 

  60. Hamann, A. et al. Role of alpha 4-integrins in lymphocyte homing to mucosal tissues in vivo. J. Immunol. 152, 3282–3293 (1994).

    CAS  PubMed  Google Scholar 

  61. Postigo, A. A., Teixido, J. & Sanchez-Madrid, F. The alpha 4 beta 1/VCAM-1 adhesion pathway in physiology and disease. Res. Immunol. 144, 723–735; discussion 754–762 (1993).

    CAS  PubMed  Google Scholar 

  62. Berlin, C. et al. Alpha 4 integrins mediate lymphocyte attachment and rolling under physiologic flow. Cell 80, 413–422 (1995).

    CAS  PubMed  Google Scholar 

  63. Sandborn, W. J. et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N. Engl. J. Med. 369, 711–721 (2013).

    CAS  PubMed  Google Scholar 

  64. Feagan, B. G. et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 369, 699–710 (2013).

    CAS  PubMed  Google Scholar 

  65. Vermeire, S. et al. Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial. Lancet 384, 309–318 (2014).

    CAS  PubMed  Google Scholar 

  66. Vermeire, S. et al. The mucosal addressin cell adhesion molecule antibody PF-00547,659 in ulcerative colitis: a randomised study. Gut 60, 1068–1075 (2011).

    CAS  PubMed  Google Scholar 

  67. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02394028 (2019).

  68. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02136069 (2019).

  69. Sandborn, W. J. et al. Ozanimod induction and maintenance treatment for ulcerative colitis. N. Engl. J. Med. 374, 1754–1762 (2016).

    CAS  PubMed  Google Scholar 

  70. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03440372 (2019).

  71. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02435992 (2019).

  72. O’Shea, J. J. & Plenge, R. JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity 36, 542–550 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Coskun, M. et al. Involvement of JAK/STAT signaling in the pathogenesis of inflammatory bowel disease. Pharmacol. Res. 76, 1–8 (2013).

    CAS  PubMed  Google Scholar 

  74. Villarino, A. V. et al. Mechanisms of Jak/STAT signaling in immunity and disease. J. Immunol. 194, 21–27 (2015).

    CAS  PubMed  Google Scholar 

  75. Yamaoka, K. et al. The Janus kinases (Jaks). Genome Biol. 5, 253 (2004).

    PubMed  PubMed Central  Google Scholar 

  76. Panés, J. et al. Tofacitinib for induction and maintenance therapy of Crohn’s disease: results of two phase IIb randomised placebo-controlled trials. Gut 66, 1049–1059 (2017).

    PubMed  Google Scholar 

  77. Sandborn, W. J. et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 376, 1723–1736 (2017).

    CAS  PubMed  Google Scholar 

  78. Food and Drug Administration. Tofacitinib (CP-690,550) ulcerative colitis. Advisory committee meeting (FDA, 2018).

  79. European Medicines Agency. Xeljanz (tofacitinib): an overview of Xeljanz and why it is authorised in the EU (EMA, 2018).

  80. Goldstein, J. D. et al. Inhibition of the JAK/STAT signaling pathway in regulatory T cells reveals a very dynamic regulation of Foxp3 expression. PLOS ONE 11, e0153682 (2016).

    PubMed  PubMed Central  Google Scholar 

  81. Chinen, T. et al. An essential role for the IL-2 receptor in Treg cell function. Nat. Immunol. 17, 1322–1333 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Chaudhry, A. et al. Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Immunity 34, 566–578 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Vermeire, S. et al. Clinical remission in patients with moderate-to-severe Crohn’s disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial. Lancet 389, 266–275 (2017).

    CAS  PubMed  Google Scholar 

  84. Sandborn, W. J. et al. Safety and efficacy of ABT-494 (upadacitinib), an oral JAK1 inhibitor, as induction therapy in patients with Crohn’s disease: results from CELEST [abstract 874h]. Gastroenterology 152, S1308–S1309 (2017).

    Google Scholar 

  85. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03653026 (2019).

  86. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03345836 (2019).

  87. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02914561 (2019).

  88. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02914522 (2019).

  89. Parronchi, P. et al. Type 1 T-helper cell predominance and interleukin-12 expression in the gut of patients with Crohn’s disease. Am. J. Pathol. 150, 823–832 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Trinchieri, G. Interleukin-12: a cytokine produced by antigen-presenting cells with immunoregulatory functions in the generation of T-helper cells type 1 and cytotoxic lymphocytes. Blood 84, 4008–4027 (1994).

    CAS  PubMed  Google Scholar 

  91. Monteleone, G. et al. Enhancing lamina propria Th1 cell responses with interleukin 12 produces severe tissue injury. Gastroenterology 117, 1069–1077 (1999).

    CAS  PubMed  Google Scholar 

  92. Goldberg, R. et al. The unusual suspects–innate lymphoid cells as novel therapeutic targets in IBD. Nat. Rev. Gastroenterol. Hepatol 12, 271–283 (2015).

    CAS  PubMed  Google Scholar 

  93. Artis, D. & Spits, H. The biology of innate lymphoid cells. Nature 517, 293 (2015).

    CAS  PubMed  Google Scholar 

  94. Heller, F. et al. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology 129, 550–564 (2005).

    CAS  PubMed  Google Scholar 

  95. Biancheri, P. et al. Absence of a role for interleukin-13 in inflammatory bowel disease. Eur. J. Immunol 44, 370–385 (2014).

    CAS  PubMed  Google Scholar 

  96. Rovedatti, L. et al. Differential regulation of interleukin 17 and interferon gamma production in inflammatory bowel disease. Gut 58, 1629–1636 (2009).

    CAS  PubMed  Google Scholar 

  97. Kobayashi, T. et al. IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn’s disease. Gut 57, 1682–1689 (2008).

    CAS  PubMed  Google Scholar 

  98. Annunziato, F. et al. Phenotypic and functional features of human Th17 cells. J. Exp. Med. 204, 1849–1861 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Liang, S. C. et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J. Exp. Med. 203, 2271–2279 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Buonocore, S. et al. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464, 1371–1375 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Geremia, A. et al. IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease. J. Exp. Med. 208, 1127–1133 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Pantazi, E. & Powell, N. Group 3 ILCs: peacekeepers or troublemakers? What’s your gut telling you? Front. Immunol. 10, 676 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Powell, N. et al. Interleukin 6 increases production of cytokines by colonic innate lymphoid cells in mice and patients with chronic intestinal inflammation. Gastroenterology 149, 456–467 e15 (2015).

    CAS  PubMed  Google Scholar 

  104. Krausgruber, T. et al. T-bet is a key modulator of IL-23-driven pathogenic CD4+ T cell responses in the intestine. Nat. Commun. 7, 11627 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Geremia, A. et al. IL-23–responsive innate lymphoid cells are increased in inflammatory bowel disease. J. Exp. Med. 208, 1127–1133 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Duerr, R. H. et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Cho, J. H. & Brant, S. R. Recent insights into the genetics of inflammatory bowel disease. Gastroenterology 140, 1704–1712 (2011).

    CAS  PubMed  Google Scholar 

  108. Mannon, P. J. et al. Anti–interleukin-12 antibody for active Crohn’s disease. N. Engl. J. Med. 351, 2069–2079 (2004).

    CAS  PubMed  Google Scholar 

  109. Feagan, B. G. et al. Ustekinumab as induction and maintenance therapy for Crohn’s disease. N. Engl. J. Med. 375, 1946–1960 (2016).

    CAS  PubMed  Google Scholar 

  110. Harris, K. A. et al. Patients with refractory Crohn’s disease successfully treated with ustekinumab. Inflamm. Bowel Dis. 22, 397–401 (2016).

    PubMed  Google Scholar 

  111. Ma, C. et al. Clinical, endoscopic and radiographic outcomes with ustekinumab in medically-refractory Crohn’s disease: real world experience from a multicentre cohort. Aliment. Pharmacol. Ther. 45, 1232–1243 (2017).

    CAS  PubMed  Google Scholar 

  112. Sandborn, W. J. et al. Efficacy and safety of ustekinumab as maintenance therapy in ulcerative colitis: week 44 results from UNIFI [abstract OP37]. J. Crohns Colitis 13, S025–S026 (2019).

    Google Scholar 

  113. Uhlig, H. H. et al. Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity 25, 309–318 (2006).

    CAS  PubMed  Google Scholar 

  114. Hue, S. et al. Interleukin-23 drives innate and T cell–mediated intestinal inflammation. J. Exp. Med. 203, 2473–2483 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Sands, B. E. et al. Efficacy and safety of MEDI2070, an antibody against interleukin 23, in patients with moderate to severe Crohn’s disease: a phase 2a study. Gastroenterology 153, 77–86 e6 (2017).

    CAS  PubMed  Google Scholar 

  116. Feagan, B. G. et al. Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn’s disease: a randomised, double-blind, placebo-controlled phase 2 study. Lancet 389, 1699–1709 (2017).

    CAS  PubMed  Google Scholar 

  117. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03105128 (2019).

  118. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03398148 (2019).

  119. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03759288 (2019).

  120. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03616821 (2019).

  121. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03518086 (2019).

  122. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03926130 (2019).

  123. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03466411 (2019).

  124. Di Cesare, A., Di Meglio, P. & Nestle, F. O. The IL-23/Th17 axis in the immunopathogenesis of psoriasis. J. Invest. Dermatol. 129, 1339–1350 (2009).

    PubMed  Google Scholar 

  125. Lowes, M. A. et al. Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells. J. Invest. Dermatol. 128, 1207–1211 (2008).

    CAS  PubMed  Google Scholar 

  126. Villanova, F. et al. Characterization of innate lymphoid cells in human skin and blood demonstrates increase of NKp44+ ILC3 in psoriasis. J. Invest. Dermatol. 134, 984–991 (2014).

    CAS  PubMed  Google Scholar 

  127. Nair, R. P. et al. Genome-wide scan reveals association of psoriasis with IL-23 and NF-κB pathways. Nat. Genet. 41, 199–204 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Tsoi, L. C. et al. Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants. Nat. Commun. 8, 15382–15382 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Papp, K. A. et al. Risankizumab versus ustekinumab for moderate-to-severe plaque psoriasis. N. Engl. J. Med. 376, 1551–1560 (2017).

    CAS  PubMed  Google Scholar 

  130. Schmitt, H. et al. Expansion of IL-23 receptor bearing TNFR2+ T cells is associated with molecular resistance to anti-TNF therapy in Crohn’s disease. Gut 68, 814–828 (2019).

    CAS  PubMed  Google Scholar 

  131. Atreya, R. et al. In vivo imaging using fluorescent antibodies to tumor necrosis factor predicts therapeutic response in Crohn’s disease. Nat. Med. 20, 313–318 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Rath, T. et al. Molecular imaging of mucosal alpha4beta7 integrin expression with the fluorescent anti-adhesion antibody vedolizumab in Crohn’s disease. Gastrointest. Endosc. 86, 406–408 (2017).

    PubMed  Google Scholar 

  133. Ozsolak, F. & Milos, P. M. RNA sequencing: advances, challenges and opportunities. Nat. Rev. Genet. 12, 87–98 (2010).

    PubMed  PubMed Central  Google Scholar 

  134. Arijs, I. et al. Mucosal gene signatures to predict response to infliximab in patients with ulcerative colitis. Gut 58, 1612–1619 (2009).

    CAS  PubMed  Google Scholar 

  135. West, N. R. et al. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nat. Med. 23, 579–589 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Gaujoux, R. et al. Cell-centred meta-analysis reveals baseline predictors of anti-TNFalpha non-response in biopsy and blood of patients with IBD. Gut 68, 604–614 (2019).

    CAS  PubMed  Google Scholar 

  137. Verstockt, B. et al. Low TREM1 expression in whole blood predicts anti-TNF response in inflammatory bowel disease. EBioMedicine 40, 733–742 (2019).

    PubMed  PubMed Central  Google Scholar 

  138. Tew, G. W. et al. Association between response to etrolizumab and expression of integrin αe and granzyme A in colon biopsies of patients with ulcerative colitis. Gastroenterology 150, 477–487.e9 (2016).

    PubMed  Google Scholar 

  139. Cuthbert, A. P. et al. The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease. Gastroenterology 122, 867–874 (2002).

    CAS  PubMed  Google Scholar 

  140. Mascheretti, S. et al. Response to infliximab treatment in Crohn’s disease is not associated with mutations in the CARD15 (NOD2) gene: an analysis in 534 patients from two multicenter, prospective GCP-level trials. Pharmacogenetics 12, 509–515 (2002).

    CAS  PubMed  Google Scholar 

  141. Vermeire, S. et al. NOD2/CARD15 does not influence response to infliximab in Crohn’s disease. Gastroenterology 123, 106–111 (2002).

    CAS  PubMed  Google Scholar 

  142. Mascheretti, S. et al. Pharmacogenetic investigation of the TNF/TNF-receptor system in patients with chronic active Crohn’s disease treated with infliximab. Pharmacogenomics J. 2, 127–136 (2002).

    CAS  PubMed  Google Scholar 

  143. Pierik, M. et al. Tumour necrosis factor-alpha receptor 1 and 2 polymorphisms in inflammatory bowel disease and their association with response to infliximab. Aliment. Pharmacol. Ther. 20, 303–310 (2004).

    CAS  PubMed  Google Scholar 

  144. Jurgens, M. et al. Disease activity, ANCA, and IL23R genotype status determine early response to infliximab in patients with ulcerative colitis. Am. J. Gastroenterol 105, 1811–1819 (2010).

    PubMed  Google Scholar 

  145. Hlavaty, T. et al. Polymorphisms in apoptosis genes predict response to infliximab therapy in luminal and fistulizing Crohn’s disease. Aliment. Pharmacol. Ther. 22, 613–626 (2005).

    CAS  PubMed  Google Scholar 

  146. Urcelay, E. et al. IBD5 polymorphisms in inflammatory bowel disease: association with response to infliximab. World J. Gastroenterol 11, 1187–1192 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Louis, E. et al. Association between polymorphism in IgG Fc receptor IIIa coding gene and biological response to infliximab in Crohn’s disease. Aliment. Pharmacol. Ther. 19, 511–519 (2004).

    CAS  PubMed  Google Scholar 

  148. Louis, E. J. et al. Polymorphism in IgG Fc receptor gene FCGR3A and response to infliximab in Crohn’s disease: a subanalysis of the ACCENT I study. Pharmacogenet. Genomics 16, 911–914 (2006).

    CAS  PubMed  Google Scholar 

  149. Muise, A. M., Snapper, S. B. & Kugathasan, S. The age of gene discovery in very early onset inflammatory bowel disease. Gastroenterology 143, 285–288 (2012).

    PubMed  Google Scholar 

  150. Uhlig, H. H. et al. The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology 147, 990–1007.e3 (2014).

    PubMed  Google Scholar 

  151. Heyman, M. B. et al. Children with early-onset inflammatory bowel disease (IBD): analysis of a pediatric IBD consortium registry. J. Pediatrics 146, 35–40 (2005).

    Google Scholar 

  152. Uhlig, H. H. & Muise, A. M. Clinical genomics in inflammatory bowel disease. Trends Genet. 33, 629–641 (2017).

    CAS  PubMed  Google Scholar 

  153. Ashworth, I. et al. Reversal of intestinal failure in children with tufting enteropathy supported with parenteral nutrition at home. J. Pediatr. Gastroenterol. Nutr. 66, 967–971 (2018).

    PubMed  Google Scholar 

  154. Kammermeier, J. et al. Stem cell transplantation for tetratricopeptide repeat domain 7A deficiency: long-term follow-up. Blood 128, 1306–1308 (2016).

    CAS  PubMed  Google Scholar 

  155. Bigorgne, A. E. et al. TTC7A mutations disrupt intestinal epithelial apicobasal polarity. J. Clin. Invest. 124, 328–337 (2014).

    CAS  PubMed  Google Scholar 

  156. Chen, R. et al. Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias. J. Allergy Clin. Immunol. 132, 656–664.e17 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Canna, S. W. et al. Life-threatening NLRC4-associated hyperinflammation successfully treated with IL-18 inhibition. J. Allergy Clin. Immunol. 139, 1698–1701 (2017).

    CAS  PubMed  Google Scholar 

  158. Lo, B. et al. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science 349, 436–440 (2015).

    CAS  PubMed  Google Scholar 

  159. Chen, F. et al. mTOR mediates IL-23 induction of neutrophil IL-17 and IL-22 production. J. Immunol. 196, 4390–4399 (2016).

    CAS  PubMed  Google Scholar 

  160. Jones, J. et al. Relationships between disease activity and serum and fecal biomarkers in patients with Crohn’s disease. Clin. Gastroenterol. Hepatol. 6, 1218–1224 (2008).

    PubMed  Google Scholar 

  161. Regueiro, M. et al. Crohn’s disease activity index does not correlate with endoscopic recurrence one year after ileocolonic resection. Inflamm. Bowel Dis. 17, 118–126 (2011).

    PubMed  Google Scholar 

  162. Manichanh, C. et al. The gut microbiota in IBD. Nat. Rev. Gastroenterol. Hepatol. 9, 599–608 (2012).

    CAS  PubMed  Google Scholar 

  163. Round, J. L. & Mazmanian, S. K. The gut microbiota shapes intestinal immune responses during health and disease. Nat. Rev. Immunol. 9, 313–323 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Littman, D. R. & Pamer, E. G. Role of the commensal microbiota in normal and pathogenic host immune responses. Cell Host Microbe 10, 311–323 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Sokol, H. et al. Analysis of bacterial bowel communities of IBD patients: what has it revealed? Inflamm. Bowel Dis. 14, 858–867 (2008).

    PubMed  Google Scholar 

  166. Ott, S. J. et al. Reduction in diversity of the colonic mucosa associated bacterial microflora in patients with active inflammatory bowel disease. Gut 53, 685–693 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Kostic, A. D., Xavier, R. J. & Gevers, D. The microbiome in inflammatory bowel diseases: current status and the future ahead. Gastroenterology 146, 1489–1499 (2014).

    CAS  PubMed  Google Scholar 

  168. Paramsothy, S. et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet 389, 1218–1228 (2017).

    PubMed  Google Scholar 

  169. Moayyedi, P. et al. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology 149, 102–109.e6 (2015).

    PubMed  Google Scholar 

  170. Costello, S. P. et al. Effect of fecal microbiota transplantation on 8-week remission in patients with ulcerative colitis: a randomized clinical trial. JAMA 321, 156–164 (2019).

    PubMed  PubMed Central  Google Scholar 

  171. Rossen, N. G. et al. Findings from a randomized controlled trial of fecal transplantation for patients with ulcerative colitis. Gastroenterology 149, 110–118.e4 (2015).

    PubMed  Google Scholar 

  172. Paramsothy, S. et al. Faecal microbiota transplantation for inflammatory bowel disease: a systematic review and meta-analysis. J. Crohns Colitis 11, 1180–1199 (2017).

    PubMed  Google Scholar 

  173. Harvey, R. F. & Bradshaw, J. M. A simple index of Crohn’s-disease activity. Lancet 315, 514 (1980).

    Google Scholar 

  174. Ananthakrishnan, A. N. et al. Gut microbiome function predicts response to anti-integrin biologic therapy in inflammatory bowel diseases. Cell Host Microbe 21, 603–610.e3 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Barber, G. E. et al. Genetic markers predict primary non-response and durable response to anti-TNF biologic therapies in Crohn’s disease. Am. J. Gastroenterol. 111, 1816–1822 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. 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  PubMed Central  Google Scholar 

  177. Li-Pook-Than, J. & Snyder, M. iPOP goes the world: integrated personalized omics profiling and the road toward improved health care. Chem. Biol. 20, 660–666 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The Heisenberg Professorship of R.A. is funded by the German Research Council DFG. The research of R.A. is funded by DFG-CRC1811 project no. C02 and DFG-SFB/TRR241 project no. C02.

Author information

Authors and Affiliations

  1. School of Immunology and Microbial Sciences, King’s College London, London, UK

    Jonathan L. Digby-Bell & Nick Powell

  2. Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany

    Raja Atreya

  3. Department of Systems Medicine, Università Tor Vergata, Rome, Italy

    Giovanni Monteleone

  4. Department of Medicine, Imperial College London, London, UK

    Nick Powell

Authors
  1. Jonathan L. Digby-Bell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Raja Atreya
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Giovanni Monteleone
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nick Powell
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nick Powell.

Ethics declarations

Competing interests

R.A. discloses consultancy fees, grants or personal fees from AbbVie, Biogen, Boehringer Ingelheim, Dr Falk Pharma, Ferring, InDex Pharmaceuticals, Janssen-Cilag, MSD, Pfizer, Roche Pharma, Samsung Bioepsis, Stelic Institute, Takeda and Tillotts Pharma. J.L.D.-B. declares receiving speaker fees from Abbvie and Takeda and conference fees from MSD and Shield. N.P. declares advisory and/or speaker fees from Abbvie, Allergan, Celgene, Debiopharm, Ferring and Vitor Pharma, and lecture fees from Allergan, Dr Falk Pharma, Janssen, Takeda and Tillotts. G.M. declares no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Reviewer information

Nature Reviews Gastroenterology & Hepatology thanks C. Ha, H. Khalili and the other anonymous reviewer for their contribution to the peer review of this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Digby-Bell, J.L., Atreya, R., Monteleone, G. et al. Interrogating host immunity to predict treatment response in inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 17, 9–20 (2020). https://doi.org/10.1038/s41575-019-0228-5

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41575-019-0228-5

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing