Abstract
Results of recent genetic and immunologic studies have brought to the forefront several biologic pathways that allow for a better understanding of the mechanisms of tissue homeostasis, on the one hand, and inflammatory bowel disease (IBD) on the other. The explosion of research activity as a result of these newly identified targets is bringing the pathogenesis of these complex disorders into focus as well as creating new therapeutic opportunities. The greatest advances with perhaps the largest impact on our understanding of the etiology of Crohn’s disease are those related to bacterial sensing, such as through nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and its relationships to autophagy and the unfolded protein response as a consequence of endoplasmic reticulum stress. Interestingly, it appears as though these pathways, which are rooted in microbial sensing and regulation, are interrelated. Genetic studies have also renewed interest in previously studied pathways in IBD, such as the formation and function of the inflammasome and its relationship to interleukin (IL) 1-beta signaling. With the recent success of therapeutic agents designed to block tumor necrosis factor, the IL-12/23 pathways, and lymphocyte homing, insights have been gained into the biologic relevance and impact of these various inflammatory pathways in IBD. In this review, the exciting recent advances in these biologic pathways of IBD are discussed, particularly in light of their therapeutic relevance.
Similar content being viewed by others
References
Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature. 2011;474(7351):307–17.
Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol. 2009;9(5):313–23.
Kaser A, Zeissig S, Blumberg RS. Inflammatory bowel disease. Annu Rev Immunol. 2010;28:573–621.
Abbott DW, Wilkins A, Asara JM, Cantley LC. The Crohn’s disease protein, NOD2, requires RIP2 in order to induce ubiquitinylation of a novel site on NEMO. Curr Biol. 2004;14(24):2217–27.
Watanabe T, Kitani A, Strober W. NOD2 regulation of Toll-like receptor responses and the pathogenesis of Crohn’s disease. Gut. 2005;54(11):1515–8.
Watanabe T, Kitani A, Murray PJ, Strober W. NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses. Nat Immunol. 2004;5(8):800–8.
Hedl M, Li J, Cho JH, Abraham C. Chronic stimulation of Nod2 mediates tolerance to bacterial products. Proc Natl Acad Sci USA. 2007;104(49):19440–5.
Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, Nunez G, et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science. 2005;307(5710):731–4.
Wehkamp J, Salzman NH, Porter E, Nuding S, Weichenthal M, Petras RE, et al. Reduced Paneth cell alpha-defensins in ileal Crohn’s disease. Proc Natl Acad Sci USA. 2005;102(50):18129–34.
Hampe J, Franke A, Rosenstiel P, Till A, Teuber M, Huse K, et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet. 2007;39(2):207–11.
Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell. 2008;132(1):27–42.
Saitoh T, Fujita N, Jang MH, Uematsu S, Yang BG, Satoh T et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature. 2008;456(7219):264–8.
Kuballa P, Huett A, Rioux JD, Daly MJ, Xavier RJ. Impaired autophagy of an intracellular pathogen induced by a Crohn’s disease associated ATG16L1 variant. PLoS One. 2008;3(10):e3391.
Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Natl Rev Mol Cell Biol. 2007;8(7):519–29.
Kaser A, Lee AH, Franke A, Glickman JN, Zeissig S, Tilg H et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell. 2008;134(5):743–56.
Ivanov II, Frutos Rde L, Manel N, Yoshinaga K, Rifkin DB, Sartor RB et al. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe. 2008;4(4):337–49.
Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell. 2009;139(3):485–98.
Ogata M, Hino S, Saito A, Morikawa K, Kondo S, Kanemoto S, et al. Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol. 2006;26(24):9220–31.
Ding WX, Ni HM, Gao W, Yoshimori T, Stolz DB, Ron D, et al. Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability. Am J Pathol. 2007;171(2):513–24.
Yang L, Li P, Fu S, Calay ES, Hotamisligil GS. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab. 2010;11(6):467–78.
Bertolotti A, Wang X, Novoa I, Jungreis R, Schlessinger K, Cho JH et al. Increased sensitivity to dextran sodium sulfate colitis in IRE1beta-deficient mice. J Clin Invest. 2001;107(5):585–93.
Swidsinski A, Ladhoff A, Pernthaler A, Swidsinski S, Loening-Baucke V, Ortner M et al. Mucosal flora in inflammatory bowel disease. Gastroenterology. 2002;122(1):44–54.
Darfeuille-Michaud A, Boudeau J, Bulois P, Neut C, Glasser AL, Barnich N et al. High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn’s disease. Gastroenterology. 2004;127(2):412–21.
Darfeuille-Michaud A, Neut C, Barnich N, Lederman E, Di Martino P, Desreumaux P et al. Presence of adherent Escherichia coli strains in ileal mucosa of patients with Crohn’s disease. Gastroenterology. 1998;115(6):1405–13.
Lapaquette P, Glasser AL, Huett A, Xavier RJ, Darfeuille-Michaud A. Crohn’s disease-associated adherent-invasive E. coli are selectively favoured by impaired autophagy to replicate intracellularly. Cell Microbiol. 2010;12(1):99–113.
Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464(7285):59–65.
Frank DN, St Amand AL, Feldman RA, Boedeker EC, Harpaz N, Pace NR. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci USA. 2007;104(34):13780–5.
Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet. 2008;40(8):955–62.
Kaser A, Ludwiczek O, Holzmann S, Moschen AR, Weiss G, Enrich B et al. Increased expression of CCL20 in human inflammatory bowel disease. J Clin Immunol. 2004;24(1):74–85.
Varona R, Cadenas V, Flores J, Martinez AC, Marquez G. CCR6 has a non-redundant role in the development of inflammatory bowel disease. Eur J Immunol. 2003;33(10):2937–46.
Yamazaki T, Yang XO, Chung Y, Fukunaga A, Nurieva R, Pappu B et al. CCR6 regulates the migration of inflammatory and regulatory T cells. J Immunol. 2008;181(12):8391–401.
Katchar K, Kelly CP, Keates S, O’Brien MJ, Keates AC. MIP-3alpha neutralizing monoclonal antibody protects against TNBS-induced colonic injury and inflammation in mice. Am J Physiol Gastrointest Liver Physiol. 2007;292(5):G1263–71.
Sandborn WJ, Colombel JF, Enns R, Feagan BG, Hanauer SB, Lawrance IC et al. Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2005;353(18):1912–25.
Van Assche G, Van Ranst M, Sciot R, Dubois B, Vermeire S, Noman M, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. N Engl J Med. 2005;353(4):362–8.
Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol. 2008;8(5):349–61.
Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D, et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature. 2009;461(7268):1282–6.
Cox MA, Jackson J, Stanton M, Rojas-Triana A, Bober L, Laverty M, et al. Short-chain fatty acids act as antiinflammatory mediators by regulating prostaglandin E(2) and cytokines. World J Gastroenterol. 2009;15(44):5549–57.
Treem WR, Ahsan N, Shoup M, Hyams JS. Fecal short-chain fatty acids in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 1994;18(2):159–64.
Kanauchi O, Suga T, Tochihara M, Hibi T, Naganuma M, Homma T et al. Treatment of ulcerative colitis by feeding with germinated barley foodstuff: first report of a multicenter open control trial. J Gastroenterol. 2002;37(Suppl 14):67–72.
Davis BK, Wen H, Ting JP. The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu Rev Immunol. 2011;29:707-35.
Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol. 2009;27:519–50.
Villani AC, Lemire M, Fortin G, Louis E, Silverberg MS, Collette C et al. Common variants in the NLRP3 region contribute to Crohn’s disease susceptibility. Nat Genet. 2009;41(1):71–6.
Elinav E, Strowig T, Kau AL, Henao-Mejia J, Thaiss CA, Booth CJ et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell. 2011;145(5):745–57.
Casini-Raggi V, Kam L, Chong YJ, Fiocchi C, Pizarro TT, Cominelli F. Mucosal imbalance of IL-1 and IL-1 receptor antagonist in inflammatory bowel disease. A novel mechanism of chronic intestinal inflammation. J Immunol. 1995;154(5):2434–40.
Monteleone G, Trapasso F, Parrello T, Biancone L, Stella A, Iuliano R et al. Bioactive IL-18 expression is up-regulated in Crohn’s disease. J Immunol. 1999;163(1):143–7.
Pizarro TT, Michie MH, Bentz M, Woraratanadharm J, Smith MF Jr, Foley E, et al. IL-18, a novel immunoregulatory cytokine, is up-regulated in Crohn’s disease: expression and localization in intestinal mucosal cells. J Immunol. 1999;162(11):6829–35.
Cominelli F, Nast CC, Clark BD, Schindler R, Lierena R, Eysselein VE, et al. Interleukin 1 (IL-1) gene expression, synthesis, and effect of specific IL-1 receptor blockade in rabbit immune complex colitis. J Clin Invest. 1990;86(3):972–80.
Sivakumar PV, Westrich GM, Kanaly S, Garka K, Born TL, Derry JM, et al. Interleukin 18 is a primary mediator of the inflammation associated with dextran sulphate sodium induced colitis: blocking interleukin 18 attenuates intestinal damage. Gut. 2002;50(6):812–20.
Kontoyiannis D, Pasparakis M, Pizarro TT, Cominelli F, Kollias G. Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity. 1999;10(3):387–98.
Armaka M, Apostolaki M, Jacques P, Kontoyiannis DL, Elewaut D, Kollias G. Mesenchymal cell targeting by TNF as a common pathogenic principle in chronic inflammatory joint and intestinal diseases. J Exp Med. 2008;205(2):331–7.
Zeissig S, Bojarski C, Buergel N, Mankertz J, Zeitz M, Fromm M, et al. Downregulation of epithelial apoptosis and barrier repair in active Crohn’s disease by tumour necrosis factor alpha antibody treatment. Gut. 2004;53(9):1295–302.
Rutgeerts P, Vermeire S, Van Assche G. Mucosal healing in inflammatory bowel disease: impossible ideal or therapeutic target? Gut. 2007;56(4):453–5.
Yamazaki K, McGovern D, Ragoussis J, Paolucci M, Butler H, Jewell D, et al. Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn’s disease. Hum Mol Genet. 2005;14(22):3499–506.
Yang SK, Lim J, Chang HS, Lee I, Li Y, Liu J, et al. Association of TNFSF15 with Crohn’s disease in Koreans. Am J Gastroenterol. 2008;103(6):1437–42.
Strober W, Fuss IJ. Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases. Gastroenterology. 2011;140(6):1756–67.
Bamias G, Mishina M, Nyce M, Ross WG, Kollias G, Rivera-Nieves J et al. Role of TL1A and its receptor DR3 in two models of chronic murine ileitis. Proc Natl Acad Sci USA. 2006;103(22):8441–6.
Takedatsu H, Michelsen KS, Wei B, Landers CJ, Thomas LS, Dhall D, et al. TL1A (TNFSF15) regulates the development of chronic colitis by modulating both T-helper 1 and T-helper 17 activation. Gastroenterology. 2008;135(2):552–67.
Langrish CL, McKenzie BS, Wilson NJ, de Waal Malefyt R, Kastelein RA, Cua DJ. IL-12 and IL-23: master regulators of innate and adaptive immunity. Immunol Rev. 2004;202:96–105.
Neurath MF, Fuss I, Kelsall BL, Stuber E, Strober W. Antibodies to interleukin 12 abrogate established experimental colitis in mice. J Exp Med. 1995;182(5):1281–90.
Uhlig HH, McKenzie BS, Hue S, Thompson C, Joyce-Shaikh B, Stepankova R, et al. Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity. 2006;25(2):309–18.
Leonardi CL, Kimball AB, Papp KA, Yeilding N, Guzzo C, Wang Y, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008;371(9625):1665–74.
Papp KA, Langley RG, Lebwohl M, Krueger GG, Szapary P, Yeilding N, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet. 2008;371(9625):1675–84.
Sandborn WJ, Feagan BG, Fedorak RN, Scherl E, Fleisher MR, Katz S, et al. A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn’s disease. Gastroenterology. 2008;135(4):1130–41.
Heller F, Fuss IJ, Nieuwenhuis EE, Blumberg RS, Strober W. Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells. Immunity. 2002;17(5):629–38.
Fuss IJ, Heller F, Boirivant M, Leon F, Yoshida M, Fichtner-Feigl S, et al. Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J Clin Invest. 2004;113(10):1490–7.
Heller F, Florian P, Bojarski C, Richter J, Christ M, Hillenbrand B, et al. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology. 2005;129(2):550–64.
Mannon PJ, Hornung RL, Yang Z, Yi C, Groden C, Friend J, et al. Suppression of inflammation in ulcerative colitis by interferon-beta-1a is accompanied by inhibition of IL-13 production. Gut. 2011; 60(4):449–55.
Acknowledgments
The authors acknowledge support from the U.S. National Institutes of Health and Grants DK044319, DK051362, DK053056, and DK088199 and from the Harvard Digestive Diseases Center DK034854 (RSB and MJH) and the Crohn’s and Colitis Foundation of America (MJH).
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hamilton, M.J., Snapper, S.B. & Blumberg, R.S. Update on biologic pathways in inflammatory bowel disease and their therapeutic relevance. J Gastroenterol 47, 1–8 (2012). https://doi.org/10.1007/s00535-011-0521-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00535-011-0521-8