Seminars in Immunopathology

, Volume 41, Issue 6, pp 747–756 | Cite as

Resolution of ulcerative colitis

  • Markus F. NeurathEmail author
  • Moritz Leppkes


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.


Ulcerative colitis Resolution of inflammation Intestine Epithelium Lymphocytes 


Funding information

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.

Compliance with ethical standards

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.


  1. 1.
    Ungaro R, Mehandru S, Allen PB, Peyrin-Biroulet L, Colombel JF (2017) Ulcerative colitis. Lancet 389(10080):1756–1770PubMedGoogle Scholar
  2. 2.
    Greuter T, Vavricka SR (2019) Extraintestinal manifestations in inflammatory bowel disease - epidemiology, genetics, and pathogenesis. Expert Rev Gastroenterol Hepatol 13(4):307–317PubMedGoogle Scholar
  3. 3.
    Leppkes M, Ganslmayer M, Strauss R, Neurath MF (2015) Toxic megacolon. Med Klin Intensivmed Notfmed 110(7):500–505PubMedGoogle Scholar
  4. 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):1428–1443PubMedPubMedCentralGoogle Scholar
  5. 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):1708–1720PubMedGoogle Scholar
  6. 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):485–489PubMedPubMedCentralGoogle Scholar
  7. 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):1133–1145PubMedPubMedCentralGoogle Scholar
  8. 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):1841–1845PubMedGoogle Scholar
  9. 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):2462–2476PubMedGoogle Scholar
  10. 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):699–710Google Scholar
  11. 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):616–624PubMedGoogle Scholar
  12. 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):1281–1290Google Scholar
  13. 13.
    Ananthakrishnan AN et al (2018) Environmental triggers in IBD: a review of progress and evidence. Nat Rev Gastroenterol Hepatol 15(1):39–49PubMedGoogle Scholar
  14. 14.
    Liu TC, Stappenbeck TS (2016) Genetics and pathogenesis of inflammatory bowel disease. Annu Rev Pathol 11:127–148PubMedPubMedCentralGoogle Scholar
  15. 15.
    Serhan CN, Chiang N, Van Dyke TE (2008) Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol 8(5):349–361PubMedPubMedCentralGoogle Scholar
  16. 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):325–332PubMedPubMedCentralGoogle Scholar
  17. 17.
    Jostins L et al (2012) Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491(7422):119–124PubMedPubMedCentralGoogle Scholar
  18. 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):809–822PubMedGoogle Scholar
  19. 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):623–626Google Scholar
  20. 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):1312–1318PubMedPubMedCentralGoogle Scholar
  21. 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):353–359PubMedPubMedCentralGoogle Scholar
  22. 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):58–62PubMedPubMedCentralGoogle Scholar
  23. 23.
    Nuding S, Fellermann K, Wehkamp J, Stange EF (2007) Reduced mucosal antimicrobial activity in Crohn’s disease of the colon. Gut 56(9):1240–1247PubMedPubMedCentralGoogle Scholar
  24. 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):117–129PubMedGoogle Scholar
  25. 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 e1321PubMedPubMedCentralGoogle Scholar
  26. 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):196–202PubMedGoogle Scholar
  27. 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):694–702PubMedGoogle Scholar
  28. 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):1490–1497PubMedPubMedCentralGoogle Scholar
  29. 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 e1111PubMedPubMedCentralGoogle Scholar
  30. 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):1295–1309PubMedGoogle Scholar
  31. 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):607–625PubMedPubMedCentralGoogle Scholar
  32. 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):612–614PubMedPubMedCentralGoogle Scholar
  33. 33.
    Engelmann B, Massberg S (2013) Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 13(1):34–45PubMedGoogle Scholar
  34. 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 7:10973PubMedPubMedCentralGoogle Scholar
  35. 35.
    Brinkmann V et al (2004) Neutrophil extracellular traps kill bacteria. Science 303(5663):1532–1535Google Scholar
  36. 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):eaat0852PubMedCentralGoogle Scholar
  37. 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):108–113PubMedPubMedCentralGoogle Scholar
  38. 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):5–24PubMedGoogle Scholar
  39. 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 e128PubMedGoogle Scholar
  40. 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):1921–1931PubMedGoogle Scholar
  41. 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):1465–1472PubMedPubMedCentralGoogle Scholar
  42. 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):823–838PubMedGoogle Scholar
  43. 43.
    Roediger WE (1980) The colonic epithelium in ulcerative colitis: an energy-deficiency disease? Lancet 2(8197):712–715PubMedGoogle Scholar
  44. 44.
    Roediger WE (1982) Utilization of nutrients by isolated epithelial cells of the rat colon. Gastroenterology 83(2):424–429PubMedGoogle Scholar
  45. 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):559–565PubMedPubMedCentralGoogle Scholar
  46. 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):38PubMedPubMedCentralGoogle Scholar
  47. 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):23–28PubMedGoogle Scholar
  48. 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):1908–1910PubMedPubMedCentralGoogle Scholar
  49. 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):1038–1046PubMedGoogle Scholar
  50. 50.
    Rath E, Moschetta A, Haller D (2018) Mitochondrial function - gatekeeper of intestinal epithelial cell homeostasis. Nat Rev Gastroenterol Hepatol 15(8):497–516PubMedGoogle Scholar
  51. 51.
    Alzahrani S et al (2014) Effect of Helicobacter pylori on gastric epithelial cells. World J Gastroenterol 20(36):12767–12780PubMedPubMedCentralGoogle Scholar
  52. 52.
    Becker C, Neurath MF, Wirtz S (2015) The intestinal microbiota in inflammatory bowel disease. ILAR J 56(2):192–204PubMedGoogle Scholar
  53. 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):382–392PubMedPubMedCentralGoogle Scholar
  54. 54.
    Kostic AD, Xavier RJ, Gevers D (2014) The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology 146(6):1489–1499PubMedPubMedCentralGoogle Scholar
  55. 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):13780–13785PubMedPubMedCentralGoogle Scholar
  56. 56.
    Human Microbiome Project C (2012) Structure, function and diversity of the healthy human microbiome. Nature 486(7402):207–214Google Scholar
  57. 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):70–89PubMedPubMedCentralGoogle Scholar
  58. 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):831–841PubMedGoogle Scholar
  59. 59.
    Hochter W et al (1983) Fungus colonization in colitis. Dtsch Med Wochenschr 108(11):416–418PubMedGoogle Scholar
  60. 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):1314–1317PubMedPubMedCentralGoogle Scholar
  61. 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):232–236PubMedPubMedCentralGoogle Scholar
  62. 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):865–873PubMedPubMedCentralGoogle Scholar
  63. 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):1014–1020PubMedGoogle Scholar
  64. 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):257–267PubMedGoogle Scholar
  65. 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 3:85PubMedGoogle Scholar
  66. 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):12768–12773PubMedPubMedCentralGoogle Scholar
  67. 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):282–289PubMedGoogle Scholar
  68. 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):358–362PubMedGoogle Scholar
  69. 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):84–94PubMedGoogle Scholar
  70. 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):827–851PubMedGoogle Scholar
  71. 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):542–549PubMedGoogle Scholar
  72. 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):39–42PubMedGoogle Scholar
  73. 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):1743–1756PubMedGoogle Scholar
  74. 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):598–607PubMedGoogle Scholar
  75. 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. PubMedGoogle Scholar
  76. 76.
    Bianchi ME (2007) DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 81(1):1–5PubMedGoogle Scholar
  77. 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):15736–15741PubMedPubMedCentralGoogle Scholar
  78. 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):1025–1037PubMedPubMedCentralGoogle Scholar
  79. 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):7671–7676PubMedPubMedCentralGoogle Scholar
  80. 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):14298–14303PubMedCentralGoogle Scholar
  81. 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):3963–3968PubMedPubMedCentralGoogle Scholar
  82. 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):4288–4298PubMedGoogle Scholar
  83. 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):228–232PubMedPubMedCentralGoogle Scholar
  84. 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):808–812PubMedGoogle Scholar
  85. 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):358–404PubMedGoogle Scholar
  86. 86.
    Kumar V, Sharma A (2009) Adenosine: an endogenous modulator of innate immune system with therapeutic potential. Eur J Pharmacol 616(1–3):7–15PubMedGoogle Scholar
  87. 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 6:19108PubMedPubMedCentralGoogle Scholar
  88. 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):1847–1858PubMedPubMedCentralGoogle Scholar
  89. 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):2109–2117PubMedGoogle Scholar
  90. 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):137–145PubMedGoogle Scholar
  91. 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):8418–8423PubMedPubMedCentralGoogle Scholar
  92. 92.
    Hegazi RA et al (2005) Carbon monoxide ameliorates chronic murine colitis through a heme oxygenase 1-dependent pathway. J Exp Med 202(12):1703–1713PubMedPubMedCentralGoogle Scholar
  93. 93.
    Hooper LV, Littman DR, Macpherson AJ (2012) Interactions between the microbiota and the immune system. Science 336(6086):1268–1273PubMedPubMedCentralGoogle Scholar
  94. 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 12:809–837PubMedGoogle Scholar
  95. 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):202–210PubMedGoogle Scholar
  96. 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):1129–1143PubMedPubMedCentralGoogle Scholar
  97. 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):676–686PubMedGoogle Scholar
  98. 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):288–300PubMedGoogle Scholar
  99. 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):5149–5153Google Scholar
  100. 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):737–742PubMedGoogle Scholar
  101. 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):115–122PubMedPubMedCentralGoogle Scholar
  102. 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 8:1371PubMedPubMedCentralGoogle Scholar
  103. 103.
    Nostrant TT, Kumar NB, Appelman HD (1987) Histopathology differentiates acute self-limited colitis from ulcerative colitis. Gastroenterology 92(2):318–328PubMedGoogle Scholar
  104. 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):1365–1368PubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

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

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