Skip to main content

Advertisement

SpringerLink
Log in

Resolution of ulcerative colitis

  • Review
  • Published:
Seminars in Immunopathology Aims and scope Submit manuscript

Abstract

Ulcerative colitis designates an idiopathic chronic inflammatory bowel disease leading to bloody diarrhea and inflammatory alterations mostly restricted to the large intestine. Many studies continue to unravel important aspects of its etiopathogenesis, and recent pharmaceutical developments broaden the arsenal of therapeutic opportunity. In this review, we delve into the cellular and molecular determinants of successful resolution of ulcerative colitis, describing novel insights in each of the phases of mucosal healing starting from damaging insults to the mucosa, epithelial restitution, and its adaption to inflammation as well as lymphocyte-driven maintenance and resolution of chronic inflammation. Additionally, molecular switches from inflammation to resolution are explored, paving the way for future avenues to resolve ulcerative colitis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Ungaro R, Mehandru S, Allen PB, Peyrin-Biroulet L, Colombel JF (2017) Ulcerative colitis. Lancet 389(10080):1756–1770

    Article  PubMed  Google Scholar 

  2. Greuter T, Vavricka SR (2019) Extraintestinal manifestations in inflammatory bowel disease - epidemiology, genetics, and pathogenesis. Expert Rev Gastroenterol Hepatol 13(4):307–317

    Article  CAS  PubMed  Google Scholar 

  3. Leppkes M, Ganslmayer M, Strauss R, Neurath MF (2015) Toxic megacolon. Med Klin Intensivmed Notfmed 110(7):500–505

    Article  CAS  PubMed  Google Scholar 

  4. Neufert C, Becker C, Türeci Ö, Waldner MJ, Backert I, Floh K, Atreya I, Leppkes M, Jefremow A, Vieth M, Schneider-Stock R, Klinger P, Greten FR, Threadgill DW, Sahin U, Neurath MF (2013) Tumor fibroblast-derived epiregulin promotes growth of colitis-associated neoplasms through ERK. J Clin Invest 123(4):1428–1443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hyams JS, Davis Thomas S, Gotman N, Haberman Y, Karns R, Schirmer M, Mo A, Mack DR, Boyle B, Griffiths AM, LeLeiko NS, Sauer CG, Keljo DJ, Markowitz J, Baker SS, Rosh J, Baldassano RN, Patel A, Pfefferkorn M, Otley A, Heyman M, Noe J, Oliva-Hemker M, Rufo PA, Strople J, Ziring D, Guthery SL, Sudel B, Benkov K, Wali P, Moulton D, Evans J, Kappelman MD, Marquis MA, Sylvester FA, Collins MH, Venkateswaran S, Dubinsky M, Tangpricha V, Spada KL, Saul B, Wang J, Serrano J, Hommel K, Marigorta UM, Gibson G, Xavier RJ, Kugathasan S, Walters T, Denson LA (2019) Clinical and biological predictors of response to standardised paediatric colitis therapy (PROTECT): a multicentre inception cohort study. Lancet 393(10182):1708–1720

    Article  PubMed  PubMed Central  Google Scholar 

  6. Fraser AG, Orchard TR, Jewell DP (2002) The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review. Gut 50(4):485–489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Tiede I, Fritz G, Strand S, Poppe D, Dvorsky R, Strand D, Lehr HA, Wirtz S, Becker C, Atreya R, Mudter J, Hildner K, Bartsch B, Holtmann M, Blumberg R, Walczak H, Iven H, Galle PR, Ahmadian MR, Neurath MF (2003) CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J Clin Invest 111(8):1133–1145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lichtiger S, Present DH, Kornbluth A, Gelernt I, Bauer J, Galler G, Michelassi F, Hanauer S (1994) Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 330(26):1841–1845

    Article  CAS  PubMed  Google Scholar 

  9. Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, Travers S, Rachmilewitz D, Hanauer SB, Lichtenstein GR, de Villiers WJS, Present D, Sands BE, Colombel JF (2005) Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 353(23):2462–2476

    Article  CAS  PubMed  Google Scholar 

  10. Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel JF, Sandborn WJ, van Assche G, Axler J, Kim HJ, Danese S, Fox I, Milch C, Sankoh S, Wyant T, Xu J, Parikh A (2013) Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 369(8):699–710

    Article  CAS  PubMed  Google Scholar 

  11. Sandborn WJ, Ghosh S, Panes J, Vranic I, Su C, Rousell S, Niezychowski W (2012) Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N Engl J Med 367(7):616–624

    Article  CAS  PubMed  Google Scholar 

  12. Neurath MF, Fuss I, Kelsall BL, Stuber E, Strober W (1995) Antibodies to interleukin 12 abrogate established experimental colitis in mice. J Exp Med 182(5):1281–1290

    Article  CAS  PubMed  Google Scholar 

  13. Ananthakrishnan AN et al (2018) Environmental triggers in IBD: a review of progress and evidence. Nat Rev Gastroenterol Hepatol 15(1):39–49

    Article  PubMed  Google Scholar 

  14. Liu TC, Stappenbeck TS (2016) Genetics and pathogenesis of inflammatory bowel disease. Annu Rev Pathol 11:127–148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Serhan CN, Chiang N, Van Dyke TE (2008) Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol 8(5):349–361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Serhan CN, Brain SD, Buckley CD, Gilroy DW, Haslett C, O’Neill LAJ, Perretti M, Rossi AG, Wallace JL (2007) Resolution of inflammation: state of the art, definitions and terms. FASEB J 21(2):325–332

    Article  CAS  PubMed  Google Scholar 

  17. Jostins L et al (2012) Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491(7422):119–124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Corfield AP, Myerscough N, Bradfield N, Do Amaral Corfield C, Gough M, Clamp JR, Durdey P, Warren BF, Bartolo DCC, King KR, Williams JM (1996) Colonic mucins in ulcerative colitis: evidence for loss of sulfation. Glycoconj J 13(5):809–822

    Article  CAS  PubMed  Google Scholar 

  19. Raouf AH, Tsai HH, Parker N, Hoffman J, Walker RJ, Rhodes JM (1992) Sulphation of colonic and rectal mucin in inflammatory bowel disease: reduced sulphation of rectal mucus in ulcerative colitis. Clin Sci (Lond) 83(5):623–626

    Article  CAS  Google Scholar 

  20. Rhodes JM, Black RR, Gallimore R, Savage A (1985) Histochemical demonstration of desialation and desulphation of normal and inflammatory bowel disease rectal mucus by faecal extracts. Gut 26(12):1312–1318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Pullan RD, Thomas GA, Rhodes M, Newcombe RG, Williams GT, Allen A, Rhodes J (1994) Thickness of adherent mucus gel on colonic mucosa in humans and its relevance to colitis. Gut 35(3):353–359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Dwarakanath AD, Campbell BJ, Tsai HH, Sunderland D, Hart CA, Rhodes JM (1995) Faecal mucinase activity assessed in inflammatory bowel disease using 14C threonine labelled mucin substrate. Gut 37(1):58–62

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Nuding S, Fellermann K, Wehkamp J, Stange EF (2007) Reduced mucosal antimicrobial activity in Crohn’s disease of the colon. Gut 56(9):1240–1247

    Article  PubMed  PubMed Central  Google Scholar 

  24. Van der Sluis M et al (2006) Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 131(1):117–129

    Article  PubMed  CAS  Google Scholar 

  25. Desai MS, Seekatz AM, Koropatkin NM, Kamada N, Hickey CA, Wolter M, Pudlo NA, Kitamoto S, Terrapon N, Muller A, Young VB, Henrissat B, Wilmes P, Stappenbeck TS, Núñez G, Martens EC (2016) A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility. Cell 167(5):1339–1353 e1321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Takeuchi K, Smale S, Premchand P, Maiden L, Sherwood R, Thjodleifsson B, Bjornsson E, Bjarnason I (2006) Prevalence and mechanism of nonsteroidal anti-inflammatory drug-induced clinical relapse in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 4(2):196–202

    Article  CAS  PubMed  Google Scholar 

  27. Okayasu I, Hatakeyama S, Yamada M, Ohkusa T, Inagaki Y, Nakaya R (1990) A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology 98(3):694–702

    Article  CAS  PubMed  Google Scholar 

  28. Fuss IJ, Heller F, Boirivant M, Leon F, Yoshida M, Fichtner-Feigl S, Yang Z, Exley M, Kitani A, Blumberg RS, Mannon P, Strober W (2004) Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J Clin Invest 113(10):1490–1497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Iyer SS, Gensollen T, Gandhi A, Oh SF, Neves JF, Collin F, Lavin R, Serra C, Glickman J, de Silva PSA, Sartor RB, Besra G, Hauser R, Maxwell A, Llebaria A, Blumberg RS (2018) Dietary and microbial oxazoles induce intestinal inflammation by modulating aryl hydrocarbon receptor responses. Cell 173(5):1123–1134 e1111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wirtz S, Popp V, Kindermann M, Gerlach K, Weigmann B, Fichtner-Feigl S, Neurath MF (2017) Chemically induced mouse models of acute and chronic intestinal inflammation. Nat Protoc 12(7):1295–1309

    Article  CAS  PubMed  Google Scholar 

  31. Mead PS, Slutsker L, Dietz V, McCaig LF, Bresee JS, Shapiro C, Griffin PM, Tauxe RV (1999) Food-related illness and death in the United States. Emerg Infect Dis 5(5):607–625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mattes FM, McLaughlin JE, Emery VC, Clark DA, Griffiths PD (2000) Histopathological detection of owl’s eye inclusions is still specific for cytomegalovirus in the era of human herpesviruses 6 and 7. J Clin Pathol 53(8):612–614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Engelmann B, Massberg S (2013) Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 13(1):34–45

    Article  CAS  PubMed  Google Scholar 

  34. Leppkes M, Maueröder C, Hirth S, Nowecki S, Günther C, Billmeier U, Paulus S, Biermann M, Munoz LE, Hoffmann M, Wildner D, Croxford AL, Waisman A, Mowen K, Jenne DE, Krenn V, Mayerle J, Lerch MM, Schett G, Wirtz S, Neurath MF, Herrmann M, Becker C (2016) Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis. Nat Commun 7:10973

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Brinkmann V et al (2004) Neutrophil extracellular traps kill bacteria. Science 303(5663):1532–1535

    Article  CAS  PubMed  Google Scholar 

  36. Kaiko GE, Chen F, Lai CW, Chiang IL, Perrigoue J, Stojmirović A, Li K, Muegge BD, Jain U, VanDussen KL, Goggins BJ, Keely S, Weaver J, Foster PS, Lawrence DA, Liu TC, Stappenbeck TS (2019) PAI-1 augments mucosal damage in colitis. Sci Transl Med 11(482):eaat0852

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Miyoshi H, Ajima R, Luo CT, Yamaguchi TP, Stappenbeck TS (2012) Wnt5a potentiates TGF-beta signaling to promote colonic crypt regeneration after tissue injury. Science 338(6103):108–113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Miyoshi H, VanDussen KL, Malvin NP, Ryu SH, Wang Y, Sonnek NM, Lai CW, Stappenbeck TS (2017) Prostaglandin E2 promotes intestinal repair through an adaptive cellular response of the epithelium. EMBO J 36(1):5–24

    Article  CAS  PubMed  Google Scholar 

  39. Chiriac MT, Buchen B, Wandersee A, Hundorfean G, Günther C, Bourjau Y, Doyle SE, Frey B, Ekici AB, Büttner C, Weigmann B, Atreya R, Wirtz S, Becker C, Siebler J, Neurath MF (2017) Activation of epithelial signal transducer and activator of transcription 1 by interleukin 28 controls mucosal healing in mice with colitis and is increased in mucosa of patients with inflammatory bowel disease. Gastroenterology 153(1):123–138 e128

    Article  CAS  PubMed  Google Scholar 

  40. Tschurtschenthaler M, Wang J, Fricke C, Fritz TMJ, Niederreiter L, Adolph TE, Sarcevic E, Künzel S, Offner FA, Kalinke U, Baines JF, Tilg H, Kaser A (2014) Type I interferon signalling in the intestinal epithelium affects Paneth cells, microbial ecology and epithelial regeneration. Gut 63(12):1921–1931

    Article  CAS  PubMed  Google Scholar 

  41. Pickert G, Neufert C, Leppkes M, Zheng Y, Wittkopf N, Warntjen M, Lehr HA, Hirth S, Weigmann B, Wirtz S, Ouyang W, Neurath MF, Becker C (2009) STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J Exp Med 206(7):1465–1472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Scheibe K, Backert I, Wirtz S, Hueber A, Schett G, Vieth M, Probst HC, Bopp T, Neurath MF, Neufert C (2017) IL-36R signalling activates intestinal epithelial cells and fibroblasts and promotes mucosal healing in vivo. Gut 66(5):823–838

    Article  CAS  PubMed  Google Scholar 

  43. Roediger WE (1980) The colonic epithelium in ulcerative colitis: an energy-deficiency disease? Lancet 2(8197):712–715

    Article  CAS  PubMed  Google Scholar 

  44. Roediger WE (1982) Utilization of nutrients by isolated epithelial cells of the rat colon. Gastroenterology 83(2):424–429

    Article  CAS  PubMed  Google Scholar 

  45. Halestrap AP, Dunlop JL (1986) Intramitochondrial regulation of fatty acid beta-oxidation occurs between flavoprotein and ubiquinone. A role for changes in the matrix volume. Biochem J 239(3):559–565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Haberman Y, Karns R, Dexheimer PJ, Schirmer M, Somekh J, Jurickova I, Braun T, Novak E, Bauman L, Collins MH, Mo A, Rosen MJ, Bonkowski E, Gotman N, Marquis A, Nistel M, Rufo PA, Baker SS, Sauer CG, Markowitz J, Pfefferkorn MD, Rosh JR, Boyle BM, Mack DR, Baldassano RN, Shah S, Leleiko NS, Heyman MB, Grifiths AM, Patel AS, Noe JD, Aronow BJ, Kugathasan S, Walters TD, Gibson G, Thomas SD, Mollen K, Shen-Orr S, Huttenhower C, Xavier RJ, Hyams JS, Denson LA (2019) Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response. Nat Commun 10(1):38

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Harig JM, Soergel KH, Komorowski RA, Wood CM (1989) Treatment of diversion colitis with short-chain-fatty acid irrigation. N Engl J Med 320(1):23–28

    Article  CAS  PubMed  Google Scholar 

  48. Zundler S, Dietz L, Matzel KE, Geppert CI, Becker E, Rath T, Neurath MF, Atreya R (2018) Successful long-term treatment of diversion colitis with topical coconut oil application. Am J Gastroenterol 113(12):1908–1910

    Article  PubMed  PubMed Central  Google Scholar 

  49. Delpre G, Avidor I, Steinherz R, Kadish U, Ben-Bassat M (1989) Ultrastructural abnormalities in endoscopically and histologically normal and involved colon in ulcerative colitis. Am J Gastroenterol 84(9):1038–1046

    CAS  PubMed  Google Scholar 

  50. Rath E, Moschetta A, Haller D (2018) Mitochondrial function - gatekeeper of intestinal epithelial cell homeostasis. Nat Rev Gastroenterol Hepatol 15(8):497–516

    Article  CAS  PubMed  Google Scholar 

  51. Alzahrani S et al (2014) Effect of Helicobacter pylori on gastric epithelial cells. World J Gastroenterol 20(36):12767–12780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Becker C, Neurath MF, Wirtz S (2015) The intestinal microbiota in inflammatory bowel disease. ILAR J 56(2):192–204

    Article  CAS  PubMed  Google Scholar 

  53. Gevers D, Kugathasan S, Denson LA, Vázquez-Baeza Y, van Treuren W, Ren B, Schwager E, Knights D, Song SJ, Yassour M, Morgan XC, Kostic AD, Luo C, González A, McDonald D, Haberman Y, Walters T, Baker S, Rosh J, Stephens M, Heyman M, Markowitz J, Baldassano R, Griffiths A, Sylvester F, Mack D, Kim S, Crandall W, Hyams J, Huttenhower C, Knight R, Xavier RJ (2014) The treatment-naive microbiome in new-onset Crohn’s disease. Cell Host Microbe 15(3):382–392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kostic AD, Xavier RJ, Gevers D (2014) The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology 146(6):1489–1499

    Article  CAS  PubMed  Google Scholar 

  55. Frank DN, St. Amand AL, Feldman RA, Boedeker EC, Harpaz N, Pace NR (2007) Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci U S A 104(34):13780–13785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Human Microbiome Project C (2012) Structure, function and diversity of the healthy human microbiome. Nature 486(7402):207–214

    Article  CAS  Google Scholar 

  57. Pickard JM, Zeng MY, Caruso R, Nunez G (2017) Gut microbiota: role in pathogen colonization, immune responses, and inflammatory disease. Immunol Rev 279(1):70–89

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ott SJ, Kühbacher T, Musfeldt M, Rosenstiel P, Hellmig S, Rehman A, Drews O, Weichert W, Timmis KN, Schreiber S (2008) Fungi and inflammatory bowel diseases: alterations of composition and diversity. Scand J Gastroenterol 43(7):831–841

    Article  CAS  PubMed  Google Scholar 

  59. Hochter W et al (1983) Fungus colonization in colitis. Dtsch Med Wochenschr 108(11):416–418

    Article  CAS  PubMed  Google Scholar 

  60. Iliev ID, Funari VA, Taylor KD, Nguyen Q, Reyes CN, Strom SP, Brown J, Becker CA, Fleshner PR, Dubinsky M, Rotter JI, Wang HL, McGovern DPB, Brown GD, Underhill DM (2012) Interactions between commensal fungi and the C-type lectin receptor Dectin-1 influence colitis. Science 336(6086):1314–1317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Leonardi I, Li X, Semon A, Li D, Doron I, Putzel G, Bar A, Prieto D, Rescigno M, McGovern DPB, Pla J, Iliev ID (2018) CX3CR1(+) mononuclear phagocytes control immunity to intestinal fungi. Science 359(6372):232–236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Wheeler ML, Limon JJ, Bar AS, Leal CA, Gargus M, Tang J, Brown J, Funari VA, Wang HL, Crother TR, Arditi M, Underhill DM, Iliev ID (2016) Immunological consequences of intestinal fungal dysbiosis. Cell Host Microbe 19(6):865–873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Monasterio C et al (2017) Fatal ulcerative enteritis of the small intestine in a patient with ulcerative colitis treated with vedolizumab. Z Gastroenterol 55(10):1014–1020

    Article  PubMed  Google Scholar 

  64. Leppkes M, Becker C, Ivanov II, Hirth S, Wirtz S, Neufert C, Pouly S, Murphy AJ, Valenzuela DM, Yancopoulos GD, Becher B, Littman DR, Neurath MF (2009) RORgamma-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F. Gastroenterology 136(1):257–267

    Article  CAS  PubMed  Google Scholar 

  65. Parks OB, Pociask DA, Hodzic Z, Kolls JK, Good M (2015) Interleukin-22 signaling in the regulation of intestinal health and disease. Front Cell Dev Biol 3:85

    PubMed  Google Scholar 

  66. Zindl CL, Lai JF, Lee YK, Maynard CL, Harbour SN, Ouyang W, Chaplin DD, Weaver CT (2013) IL-22-producing neutrophils contribute to antimicrobial defense and restitution of colonic epithelial integrity during colitis. Proc Natl Acad Sci U S A 110(31):12768–12773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Zheng Y, Valdez PA, Danilenko DM, Hu Y, Sa SM, Gong Q, Abbas AR, Modrusan Z, Ghilardi N, de Sauvage FJ, Ouyang W (2008) Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med 14(3):282–289

    Article  CAS  PubMed  Google Scholar 

  68. Pelczar P, Witkowski M, Perez LG, Kempski J, Hammel AG, Brockmann L, Kleinschmidt D, Wende S, Haueis C, Bedke T, Witkowski M, Krasemann S, Steurer S, Booth CJ, Busch P, König A, Rauch U, Benten D, Izbicki JR, Rösch T, Lohse AW, Strowig T, Gagliani N, Flavell RA, Huber S (2016) A pathogenic role for T cell-derived IL-22BP in inflammatory bowel disease. Science 354(6310):358–362

    Article  CAS  PubMed  Google Scholar 

  69. Gersemann M, Becker S, Kübler I, Koslowski M, Wang G, Herrlinger KR, Griger J, Fritz P, Fellermann K, Schwab M, Wehkamp J, Stange EF (2009) Differences in goblet cell differentiation between Crohn’s disease and ulcerative colitis. Differentiation 77(1):84–94

    Article  CAS  PubMed  Google Scholar 

  70. Magro F, Langner C, Driessen A, Ensari A, Geboes K, Mantzaris GJ, Villanacci V, Becheanu G, Nunes PB, Cathomas G, Fries W, Jouret-Mourin A, Mescoli C, de Petris G, Rubio CA, Shepherd NA, Vieth M, Eliakim R (2013) European consensus on the histopathology of inflammatory bowel disease. J Crohns Colitis 7(10):827–851

    Article  CAS  PubMed  Google Scholar 

  71. Ishikawa N, Wakelin D, Mahida YR (1997) Role of T helper 2 cells in intestinal goblet cell hyperplasia in mice infected with Trichinella spiralis. Gastroenterology 113(2):542–549

    Article  CAS  PubMed  Google Scholar 

  72. Khan WI, Blennerhasset P, Ma C, Matthaei KI, Collins SM (2001) Stat6 dependent goblet cell hyperplasia during intestinal nematode infection. Parasite Immunol 23(1):39–42

    Article  CAS  PubMed  Google Scholar 

  73. Mahapatro M, Foersch S, Hefele M, He GW, Giner-Ventura E, Mchedlidze T, Kindermann M, Vetrano S, Danese S, Günther C, Neurath MF, Wirtz S, Becker C (2016) Programming of intestinal epithelial differentiation by IL-33 derived from pericryptal fibroblasts in response to systemic infection. Cell Rep 15(8):1743–1756

    Article  CAS  PubMed  Google Scholar 

  74. Waddell A, Vallance JE, Hummel A, Alenghat T, Rosen MJ (2019) IL-33 induces murine intestinal goblet cell differentiation indirectly via innate lymphoid cell IL-13 secretion. J Immunol 202(2):598–607

    Article  CAS  PubMed  Google Scholar 

  75. Mavroudis G et al (2019) Mucosal and systemic immune profiles differ during early and late phase of the disease in patients with active ulcerative colitis. J Crohns Colitis. https://doi.org/10.1093/ecco-jcc/jjz072

    Article  PubMed  Google Scholar 

  76. Bianchi ME (2007) DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 81(1):1–5

    Article  CAS  PubMed  Google Scholar 

  77. Fiorucci S, Wallace JL, Mencarelli A, Distrutti E, Rizzo G, Farneti S, Morelli A, Tseng JL, Suramanyam B, Guilford WJ, Parkinson JF (2004) A beta-oxidation-resistant lipoxin A4 analog treats hapten-induced colitis by attenuating inflammation and immune dysfunction. Proc Natl Acad Sci U S A 101(44):15736–15741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Serhan CN, Hong S, Gronert K, Colgan SP, Devchand PR, Mirick G, Moussignac RL (2002) Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals. J Exp Med 196(8):1025–1037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Arita M, Yoshida M, Hong S, Tjonahen E, Glickman JN, Petasis NA, Blumberg RS, Serhan CN (2005) Resolvin E1, an endogenous lipid mediator derived from omega-3 eicosapentaenoic acid, protects against 2,4,6-trinitrobenzene sulfonic acid-induced colitis. Proc Natl Acad Sci U S A 102(21):7671–7676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Campbell EL, MacManus CF, Kominsky DJ, Keely S, Glover LE, Bowers BE, Scully M, Bruyninckx WJ, Colgan SP (2010) Resolvin E1-induced intestinal alkaline phosphatase promotes resolution of inflammation through LPS detoxification. Proc Natl Acad Sci U S A 107(32):14298–14303

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  81. Gobbetti T, Dalli J, Colas RA, Federici Canova D, Aursnes M, Bonnet D, Alric L, Vergnolle N, Deraison C, Hansen TV, Serhan CN, Perretti M (2017) Protectin D1n-3 DPA and resolvin D5n-3 DPA are effectors of intestinal protection. Proc Natl Acad Sci U S A 114(15):3963–3968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Marcon R, Bento AF, Dutra RC, Bicca MA, Leite DFP, Calixto JB (2013) Maresin 1, a proresolving lipid mediator derived from omega-3 polyunsaturated fatty acids, exerts protective actions in murine models of colitis. J Immunol 191(8):4288–4298

    Article  CAS  PubMed  Google Scholar 

  83. Mariathasan S, Weiss DS, Newton K, McBride J, O’Rourke K, Roose-Girma M, Lee WP, Weinrauch Y, Monack DM, Dixit VM (2006) Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440(7081):228–232

    Article  CAS  PubMed  Google Scholar 

  84. Atarashi K, Nishimura J, Shima T, Umesaki Y, Yamamoto M, Onoue M, Yagita H, Ishii N, Evans R, Honda K, Takeda K (2008) ATP drives lamina propria T(H)17 cell differentiation. Nature 455(7214):808–812

    Article  CAS  PubMed  Google Scholar 

  85. Bours MJ, Swennen EL, Di Virgilio F, Cronstein BN, Dagnelie PC (2006) Adenosine 5′-triphosphate and adenosine as endogenous signaling molecules in immunity and inflammation. Pharmacol Ther 112(2):358–404

    Article  CAS  PubMed  Google Scholar 

  86. Kumar V, Sharma A (2009) Adenosine: an endogenous modulator of innate immune system with therapeutic potential. Eur J Pharmacol 616(1–3):7–15

    Article  CAS  PubMed  Google Scholar 

  87. Wan P, Liu X, Xiong Y, Ren Y, Chen J, Lu N, Guo Y, Bai A (2016) Extracellular ATP mediates inflammatory responses in colitis via P2 x 7 receptor signaling. Sci Rep 6:19108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Coburn LA, Horst SN, Allaman MM, Brown CT, Williams CS, Hodges ME, Druce JP, Beaulieu DB, Schwartz DA, Wilson KT (2016) L-arginine availability and metabolism is altered in ulcerative colitis. Inflamm Bowel Dis 22(8):1847–1858

    Article  PubMed  Google Scholar 

  89. Gobert AP, Cheng Y, Akhtar M, Mersey BD, Blumberg DR, Cross RK, Chaturvedi R, Drachenberg CB, Boucher JL, Hacker A, Casero RA Jr, Wilson KT (2004) Protective role of arginase in a mouse model of colitis. J Immunol 173(3):2109–2117

    Article  CAS  PubMed  Google Scholar 

  90. Akazawa Y, Kubo M, Zhang R, Matsumoto K, Yan F, Setiawan H, Takahashi H, Fujikura Y, Ogino K (2013) Inhibition of arginase ameliorates experimental ulcerative colitis in mice. Free Radic Res 47(3):137–145

    Article  CAS  PubMed  Google Scholar 

  91. Kayama H, Kohyama M, Okuzaki D, Motooka D, Barman S, Okumura R, Muneta M, Hoshino K, Sasaki I, Ise W, Matsuno H, Nishimura J, Kurosaki T, Nakamura S, Arase H, Kaisho T, Takeda K (2018) Heme ameliorates dextran sodium sulfate-induced colitis through providing intestinal macrophages with noninflammatory profiles. Proc Natl Acad Sci U S A 115(33):8418–8423

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Hegazi RA et al (2005) Carbon monoxide ameliorates chronic murine colitis through a heme oxygenase 1-dependent pathway. J Exp Med 202(12):1703–1713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Hooper LV, Littman DR, Macpherson AJ (2012) Interactions between the microbiota and the immune system. Science 336(6086):1268–1273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Weiner HL, Friedman A, Miller A, Khoury SJ, al-Sabbagh A, Santos L, Sayegh M, Nussenblatt RB, Trentham DE, Hafler DA (1994) Oral tolerance: immunologic mechanisms and treatment of animal and human organ-specific autoimmune diseases by oral administration of autoantigens. Annu Rev Immunol 12:809–837

    Article  CAS  PubMed  Google Scholar 

  95. Saxon A, Shanahan F, Landers C, Ganz T, Targan S (1990) A distinct subset of antineutrophil cytoplasmic antibodies is associated with inflammatory bowel disease. J Allergy Clin Immunol 86(2):202–210

    Article  CAS  PubMed  Google Scholar 

  96. Neurath MF, Weigmann B, Finotto S, Glickman J, Nieuwenhuis E, Iijima H, Mizoguchi A, Mizoguchi E, Mudter J, Galle PR, Bhan A, Autschbach F, Sullivan BM, Szabo SJ, Glimcher LH, Blumberg RS (2002) The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn’s disease. J Exp Med 195(9):1129–1143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Gerlach K, Hwang YY, Nikolaev A, Atreya R, Dornhoff H, Steiner S, Lehr HA, Wirtz S, Vieth M, Waisman A, Rosenbauer F, McKenzie ANJ, Weigmann B, Neurath MF (2014) TH9 cells that express the transcription factor PU.1 drive T cell-mediated colitis via IL-9 receptor signaling in intestinal epithelial cells. Nat Immunol 15(7):676–686

    Article  CAS  PubMed  Google Scholar 

  98. Zundler S, Becker E, Spocinska M, Slawik M, Parga-Vidal L, Stark R, Wiendl M, Atreya R, Rath T, Leppkes M, Hildner K, López-Posadas R, Lukassen S, Ekici AB, Neufert C, Atreya I, van Gisbergen KPJM, Neurath MF (2019) Hobit- and Blimp-1-driven CD4(+) tissue-resident memory T cells control chronic intestinal inflammation. Nat Immunol 20(3):288–300

    Article  CAS  PubMed  Google Scholar 

  99. Fantini MC, Becker C, Monteleone G, Pallone F, Galle PR, Neurath MF (2004) Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25- T cells through Foxp3 induction and down-regulation of Smad7. J Immunol 172(9):5149–5153

    Article  CAS  PubMed  Google Scholar 

  100. Groux H, O’Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, Roncarolo MG (1997) A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389(6652):737–742

    Article  CAS  PubMed  Google Scholar 

  101. Himmel ME, Yao Y, Orban PC, Steiner TS, Levings MK (2012) Regulatory T-cell therapy for inflammatory bowel disease: more questions than answers. Immunology 136(2):115–122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Wiesinger M, Stoica D, Roessner S, Lorenz C, Fischer A, Atreya R, Neufert CF, Atreya I, Scheffold A, Schuler-Thurner B, Neurath MF, Schuler G, Voskens CJ (2017) Good manufacturing practice-compliant production and lot-release of ex vivo expanded regulatory T cells as basis for treatment of patients with autoimmune and inflammatory disorders. Front Immunol 8:1371

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Nostrant TT, Kumar NB, Appelman HD (1987) Histopathology differentiates acute self-limited colitis from ulcerative colitis. Gastroenterology 92(2):318–328

    Article  CAS  PubMed  Google Scholar 

  104. Goetz M, Atreya R, Ghalibafian M, Galle PR, Neurath MF (2007) Exacerbation of ulcerative colitis after rituximab salvage therapy. Inflamm Bowel Dis 13(11):1365–1368

    Article  PubMed  Google Scholar 

Download references

Funding

This work has been supported by the Deutsche Forschungsgemeinschaft (KFO 257, TRR241) and local funds of the ELAN fund and Interdisciplinary Center for Clinical Research (IZKF) of the University Erlangen-Nuremberg.

Author information

Authors and Affiliations

  1. Department of Medicine 1, Translational Research Center and Kussmaul Campus for Medical Research, Deutsches Zentrum Immuntherapie (DZI), University of Erlangen-Nürnberg, Erlangen, Germany

    Markus F. Neurath & Moritz Leppkes

Authors
  1. Markus F. Neurath
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Moritz Leppkes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Markus F. Neurath.

Ethics declarations

Conflict of interest

M.F.N. has served as an advisor for Pentax, Giuliani, MSD, AbbVie, Janssen, Takeda, and Boehringer. M.L. has no conflict of interest to report.

Additional information

This article is a contribution to the special issue on Resolution of Inflammation in Chronic Diseases - Guest Editor: Markus Neurath

Publisher’s note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Neurath, M.F., Leppkes, M. Resolution of ulcerative colitis. Semin Immunopathol 41, 747–756 (2019). https://doi.org/10.1007/s00281-019-00751-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-019-00751-6

Keywords

Search

Navigation