miRNAs and Their Role in the Pathogenesis of Celiac Disease: A Review

  • Donatella BarisaniEmail author
Reference work entry


Celiac disease is an autoimmune disorder, mainly affecting the intestine, triggered by gluten exposure and the passage of its peptides through the gastrointestinal barrier in individuals with a specific genetic background.

Although numerous studies have unraveled a lot of the steps involved in the pathogenesis of celiac disease, there are still questions that remain only partially elucidated, in particular regarding the role of noncoding RNAs.

This chapter provides an overview of the pathogenetic processes and of the various cell types involved in celiac disease and focuses on the role of miRNAs as possible regulators of these events. Moreover, it analyzes the data obtained in the last few years, since some studies have demonstrated that miRNAs expression, either in the duodenal tissue or in the blood, differs in celiac disease patients compared to controls. Lastly, it discusses the possible role of plasmatic miRNAs as adjunct tools for diagnosis and follow-up of celiac patients.


Celiac disease Gene expression Innate immunity Adaptive immunity Tregs Tight junctions Paneth cells NOD2 FOXP3 Circulating miRNAs 

List of Abbreviations


Antigen-presenting cell


Autophagy-related 7


Beclin 1, autophagy related


Celiac disease


C-X-C Motif Chemokine Ligand 2


Dendritic cells


Forkhead box P3


Human leukocyte antigen


Intraepithelial lymphocytes


Interferon gamma




IL-1 receptor-associated kinase


Kruppel-like factor 4


Mitotic Arrest Deficient 2 Like 1


Major histocompatibility complex




Nuclear factor kappa-light-chain-enhancer of activated B cells


Natural killer


Nucleotide-binding oligomerization domain-containing protein


Pattern recognition receptor


Ras homolog


Src homology 2-containing inositol 5-phosphatase 1


Suppressor of cytokine signaling 1


Signal transducer and activator of transcription


Transglutaminase 2


Toll-Like Receptor


Tumor Necrosis Factor


TNF receptor-associated family


Regulatory T cells


Untranslated region


  1. Allantaz F, Cheng DT, Bergauer T et al (2012) Expression profiling of human immune cell subsets identifies miRNA-mRNA regulatory relationships correlated with cell type specific expression. PLoS One 7(1):e29979PubMedPubMedCentralCrossRefGoogle Scholar
  2. Archambaud C, Sismeiro O, Toedling J et al (2013) The intestinal microbiota interferes with the microRNA response upon oral Listeria infection. MBio 4(6):e00707–e00713PubMedPubMedCentralCrossRefGoogle Scholar
  3. Bandyopadhyay S, Long ME, Allen LA (2014) Differential expression of microRNAs in Francisella tularensis-infected human macrophages: miR-155-dependent downregulation of MyD88 inhibits the inflammatory response. PLoS One 9(10):e109525PubMedPubMedCentralCrossRefGoogle Scholar
  4. Banerjee S, Cui H, Xie N et al (2013) miR-125a-5p regulates differential activation of macrophages and inflammation. J Biol Chem 288(49):35428–35436PubMedPubMedCentralCrossRefGoogle Scholar
  5. Boldin MP, Taganov KD, Rao DS et al (2011) miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice. J Exp Med 208(6):1189–1201PubMedPubMedCentralCrossRefGoogle Scholar
  6. Buoli Comani G, Panceri R, Dinelli M et al (2015) miRNA-regulated gene expression differs in celiac disease patients according to the age of presentation. Genes Nutr 10(5):482PubMedCrossRefGoogle Scholar
  7. Cai X, Yin Y, Li N et al (2012) Re-polarization of tumor-associated macrophages to pro-inflammatory M1 macrophages by microRNA-155. J Mol Cell Biol 4(5):341–343PubMedCrossRefGoogle Scholar
  8. Capuano M, Iaffaldano L, Tinto N et al (2011) MicroRNA-449a overexpression, reduced NOTCH1 signals and scarce goblet cells characterize the small intestine of celiac patients. PLoS One 6(12):e29094PubMedPubMedCentralCrossRefGoogle Scholar
  9. Chassin C, Kocur M, Pott J et al (2010) miR-146a mediates protective innate immune tolerance in the neonate intestine. Cell Host Microbe 8(4):358–368PubMedCrossRefGoogle Scholar
  10. Chen Y, Wang C, Liu Y et al (2013) miR-122 targets NOD2 to decrease intestinal epithelial cell injury in Crohn’s disease. Biochem Biophys Res Commun 438(1):133–139PubMedCrossRefGoogle Scholar
  11. Chuang AY, Chuang JC, Zhai Z et al (2014) NOD2 expression is regulated by microRNAs in colonic epithelial HCT116 cells. Inflamm Bowel Dis 20(1):126–135PubMedPubMedCentralCrossRefGoogle Scholar
  12. Claes AK, Zhou JY, Philpott DJ (2015) NOD-Like receptors: guardians of intestinal mucosal barriers. Physiology (Bethesda) 30(3):241–250Google Scholar
  13. Comincini S, Manai F, Meazza C et al (2017) Identification of autophagy-related genes and their regulatory miRNAs associated with celiac disease in children. Int J Mol Sci 18(2):E391PubMedCrossRefGoogle Scholar
  14. Cook L, Munier CML, Seddiki N et al (2017) Circulating gluten-specific FOXP3(+)CD39(+) regulatory T cells have impaired suppressive function in patients with celiac disease. J Allergy Clin Immunol 140(6):1592–1603. pii:S0091-6749(17)30343-3PubMedCrossRefGoogle Scholar
  15. Dunand-Sauthier I, Irla M, Carnesecchi S et al (2014) Repression of arginase-2 expression in dendritic cells by microRNA-155 is critical for promoting T cell proliferation. J Immunol 193(4):1690–1700PubMedCrossRefGoogle Scholar
  16. Evavold CL, Kagan JC (2018) How inflammasomes inform adaptive immunity. J Mol Biol 430(2):217–237Google Scholar
  17. Fordham JB, Naqvi AR, Nares S (2015) Regulation of miR-24, miR-30b, and miR-142-3p during macrophage and dendritic cell differentiation potentiates innate immunity. J Leukoc Biol 98(2):195–207PubMedPubMedCentralCrossRefGoogle Scholar
  18. Galicia JC, Naqvi AR, Ko CC et al (2014) MiRNA-181a regulates Toll-like receptor agonist-induced inflammatory response in human fibroblasts. Genes Immun 15(5):333–337PubMedPubMedCentralCrossRefGoogle Scholar
  19. Guo Z, Wu R, Gong J et al (2015) Altered microRNA expression in inflamed and non-inflamed terminal ileal mucosa of adult patients with active Crohn’s disease. J Gastroenterol Hepatol 30(1):109–116PubMedCrossRefGoogle Scholar
  20. Han L, Yue X, Zhou X et al (2012) MicroRNA-21 expression is regulated by β-catenin/STAT3 pathway and promotes glioma cell invasion by direct targeting RECK. CNS Neurosci Ther 18(7):573–583PubMedCrossRefGoogle Scholar
  21. Hashimi ST, Fulcher JA, Chang MH et al (2009) MicroRNA profiling identifies miR-34a and miR-21 and their target genes JAG1 and WNT1 in the coordinate regulation of dendritic cell differentiation. Blood 114(2):404–414PubMedPubMedCentralCrossRefGoogle Scholar
  22. Husby S, Koletzko S, Korponay-Szabó IR et al (2012) European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr 54(1):136–160PubMedCrossRefGoogle Scholar
  23. Jensen MD, Andersen RF, Christensen H et al (2015) Circulating microRNAs as biomarkers of adult Crohn’s disease. Eur J Gastroenterol Hepatol 27(9):1038–1044PubMedCrossRefGoogle Scholar
  24. Junker Y, Zeissig S, Kim SJ et al (2012) Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. J Exp Med 209(13):2395–2408Google Scholar
  25. Kalla R, Ventham NT, Kennedy NA, Quintana JF, Nimmo ER, Buck AH, Satsangi J (2015) MicroRNAs: new players in IBD. Gut 64(3):504–17Google Scholar
  26. Karrich JJ, Jachimowski LC, Libouban M et al (2013) MicroRNA-146a regulates survival and maturation of human plasmacytoid dendritic cells. Blood 122(17):3001–3009PubMedPubMedCentralCrossRefGoogle Scholar
  27. Lind EF, Millar DG, Dissanayake D et al (2015) miR-155 upregulation in dendritic cells is sufficient to break tolerance in vivo by negatively regulating SHIP1. J Immunol 195(10):4632–4640PubMedCrossRefGoogle Scholar
  28. Lu LF, Boldin MP, Chaudhry A et al (2010) Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell 142(6):914–929PubMedPubMedCentralCrossRefGoogle Scholar
  29. Magni S, Buoli Comani G, Elli L et al (2014) miRNAs affect the expression of innate and adaptive immunity proteins in celiac disease. Am J Gastroenterol 109(10):1662–1674PubMedCrossRefGoogle Scholar
  30. Maiuri L, Ciacci C, Ricciardelli I et al (2003) Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease. Lancet 362(9377):30–37PubMedCrossRefGoogle Scholar
  31. McKenna LB, Schug J, Vourekas A et al (2010) MicroRNAs control intestinal epithelial differentiation, architecture, and barrier function. Gastroenterology 139(5):1654–1664PubMedPubMedCentralCrossRefGoogle Scholar
  32. Mohan M, Chow CT, Ryan CN et al (2016) Dietary gluten-induced gut dysbiosis is accompanied by selective upregulation of microRNAs with intestinal tight junction and bacteria-binding motifs in rhesus macaque model of celiac disease. Nutrients 8(11):E684PubMedCrossRefGoogle Scholar
  33. Nahid MA, Yao B, Dominguez-Gutierrez PR et al (2013) Regulation of TLR2-mediated tolerance and cross-tolerance through IRAK4 modulation by miR-132 and miR-212. J Immunol 190:1250–1263PubMedCrossRefGoogle Scholar
  34. Nakata K, Sugi Y, Narabayashi H et al (2017) Commensal microbiota-induced microRNA modulates intestinal epithelial permeability through a small GTPase ARF4. J Biol Chem 292(37):15426–15433. pii:jbc.M117.788596PubMedPubMedCentralCrossRefGoogle Scholar
  35. Naqvi AR, Fordham JB, Ganesh B et al (2016) miR-24, miR-30b and miR-142-3p interfere with antigen processing and presentation by primary macrophages and dendritic cells. Sci Rep 6:32925PubMedPubMedCentralCrossRefGoogle Scholar
  36. Nata T, Fujiya M, Ueno N et al (2013) MicroRNA-146b improves intestinal injury in mouse colitis by activating nuclear factor-κB and improving epithelial barrier function. J Gene Med 15(6–7):249–260PubMedCrossRefGoogle Scholar
  37. O’Connell RM, Taganov KD, Boldin MP et al (2007) MicroRNA-155 is induced during the macrophage inflammatory response. Proc Natl Acad Sci U S A 104:1604–1609PubMedPubMedCentralCrossRefGoogle Scholar
  38. Pan W, Zhu S, Dai D et al (2015) MiR-125a targets effector programs to stabilize Treg-mediated immune homeostasis. Nat Commun 6:7096PubMedCrossRefGoogle Scholar
  39. Park H, Huang X, Lu C et al (2015) MicroRNA-146a and microRNA-146b regulate human dendritic cell apoptosis and cytokine production by targeting TRAF6 and IRAK1 proteins. J Biol Chem 290(5):2831–2841PubMedCrossRefGoogle Scholar
  40. Peck BC, Mah AT, Pitman WA et al (2017) Functional transcriptomics in diverse intestinal epithelial cell types reveals robust microRNA sensitivity in intestinal stem cells to microbial status. J Biol Chem 292(7):2586–2600PubMedPubMedCentralCrossRefGoogle Scholar
  41. Picarelli A, Di Tola M, Sabbatella L et al (1999) 31-43 amino acid sequence of the alpha-gliadin induces anti-endomysial antibody production during in vitro challenge. Scand J Gastroenterol 34(11):1099–1102PubMedCrossRefGoogle Scholar
  42. Rodriguez A, Vigorito E, Clare S et al (2007) Requirement of bic/microRNA-155 for normal immune function. Science 316(5824):608–611PubMedPubMedCentralCrossRefGoogle Scholar
  43. Rouas R, Fayyad-Kazan H, El Zein N et al (2009) Human natural Treg microRNA signature: role of microRNA-31 and microRNA-21 in FOXP3 expression. Eur J Immunol 39(6):1608–1618PubMedCrossRefGoogle Scholar
  44. Schuppan D, Junker Y, Barisani D (2009) Celiac disease: from pathogenesis to novel therapies. Gastroenterology 137(6):1912–1933PubMedCrossRefGoogle Scholar
  45. Seddiki N, Brezar V, Ruffin N et al (2014) Role of miR-155 in the regulation of lymphocyte immune function and disease. Immunology 142(1):32–38PubMedPubMedCentralCrossRefGoogle Scholar
  46. Shan L, Molberg Ø, Parrot I et al (2002) Structural basis for gluten intolerance in celiac sprue. Science 297(5590):2275–2279PubMedCrossRefGoogle Scholar
  47. Sheedy FJ, Palsson-McDermott E, Hennessy EJ et al (2010) Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21. Nat Immunol 11(2):141–147PubMedCrossRefGoogle Scholar
  48. Singh N, Shirdel EA, Waldron L et al (2012) The murine caecal microRNA signature depends on the presence of the endogenous microbiota. Int J Biol Sci 8(2):171–186PubMedCrossRefGoogle Scholar
  49. Skinner JJ, Wood S, Shorter J et al (2008) The Mad2 partial unfolding model: regulating mitosis through Mad2 conformational switching. J Cell Biol 83(5):761–768CrossRefGoogle Scholar
  50. Taganov KD, Boldin MP, Chang KJ et al (2006) NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci U S A 103:12481–12486PubMedPubMedCentralCrossRefGoogle Scholar
  51. Tang Y, Luo X, Cui H et al (2009) MicroRNA-146A contributes to abnormal activation of the type I interferon pathway in human lupus by targeting the key signaling proteins. Arthritis Rheum 60(4):1065–1075PubMedCrossRefGoogle Scholar
  52. Tang B, Xiao B, Liu Z et al (2010) Identification of MyD88 as a novel target of miR-155, involved in negative regulation of Helicobacter pylori-induced inflammation. FEBS Lett 584(8):1481–1486PubMedCrossRefGoogle Scholar
  53. Tian R, Wang RL, Xie H et al (2013) Overexpressed miRNA-155 dysregulates intestinal epithelial apical junctional complex in severe acute pancreatitis. World J Gastroenterol 19(45):8282–8291PubMedPubMedCentralCrossRefGoogle Scholar
  54. Tili E, Michaille JJ, Cimino A et al (2007) Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock. J Immunol 179(8):5082–5089PubMedCrossRefGoogle Scholar
  55. Tserel L, Runnel T, Kisand K et al (2011) MicroRNA expression profiles of human blood monocyte-derived dendritic cells and macrophages reveal miR-511 as putative positive regulator of Toll-like receptor 4. J Biol Chem 286(30):26487–26495PubMedPubMedCentralCrossRefGoogle Scholar
  56. Vaira V, Roncoroni L, Barisani D et al (2014) microRNA profiles in coeliac patients distinguish different clinical phenotypes and are modulated by gliadin peptides in primary duodenal fibroblasts. Clin Sci (Lond) 126(6):417–423CrossRefGoogle Scholar
  57. Vorobjova T, Uibo O, Heilman K et al (2015) Increased density of tolerogenic dendritic cells in the small bowel mucosa of celiac patients. World J Gastroenterol 21(2):439–452PubMedPubMedCentralCrossRefGoogle Scholar
  58. Wang P, Hou J, Lin L et al (2010) Inducible microRNA-155 feedback promotes type I IFN signaling in antiviral innate immunity by targeting suppressor of cytokine signaling 1. J Immunol 185(10):6226–6233PubMedCrossRefGoogle Scholar
  59. Wang H, Chao K, Ng SC et al (2016) Pro-inflammatory miR-223 mediates the cross-talk between the IL23 pathway and the intestinal barrier in inflammatory bowel disease. Genome Biol 17:58PubMedPubMedCentralCrossRefGoogle Scholar
  60. Withoff S, Li Y, Jonkers I et al (2016) Understanding celiac disease by genomics. Trends Genet 32(5):295–308PubMedCrossRefGoogle Scholar
  61. Wu F, Zikusoka M, Trindade A et al (2008) MicroRNAs are differentially expressed in ulcerative colitis and alter expression of macrophage inflammatory peptide-2 alpha. Gastroenterology 135(5):1624–1635PubMedCrossRefGoogle Scholar
  62. Wu W, He C, Liu C et al (2015) miR-10a inhibits dendritic cell activation and Th1/Th17 cell immune responses in IBD. Gut 64(11):1755–1764PubMedCrossRefGoogle Scholar
  63. Yang Y, Ma Y, Shi C et al (2013) Overexpression of miR-21 in patients with ulcerative colitis impairs intestinal epithelial barrier function through targeting the Rho GTPase RhoB. Biochem Biophys Res Commun 434(4):746–752PubMedCrossRefGoogle Scholar
  64. Ye D, Guo S, Al-Sadi R et al (2011) MicroRNA regulation of intestinal epithelial tight junction permeability. Gastroenterology 141(4):1323–1333PubMedPubMedCentralCrossRefGoogle Scholar
  65. Yu T, Lu XJ, Li JY et al (2016) Overexpression of miR-429 impairs intestinal barrier function in diabetic mice by down-regulating occludin expression. Cell Tissue Res 366(2):341–352PubMedCrossRefGoogle Scholar
  66. Zanzi D, Stefanile R, Santagata S et al (2011) IL-15 interferes with suppressive activity of intestinal regulatory T cells expanded in Celiac disease. Am J Gastroenterol 106(7):1308–1317PubMedCrossRefGoogle Scholar
  67. Zhang GJ, Xiao HX, Tian HP et al (2013) Upregulation of microRNA-155 promotes the migration and invasion of colorectal cancer cells through the regulation of claudin-1 expression. Int J Mol Med 31(6):1375–1380PubMedCrossRefGoogle Scholar
  68. Zheng Y, Rudensky AY (2007) Foxp3 in control of the regulatory T cell lineage. Nat Immunol 8(5):457–462PubMedCrossRefGoogle Scholar
  69. Zheng J, Jiang HY, Li J et al (2012) MicroRNA-23b promotes tolerogenic properties of dendritic cells in vitro through inhibiting Notch1/NF-κB signalling pathways. Allergy 67(3):362–370PubMedCrossRefGoogle Scholar
  70. Zhi X, Tao J, Li Z et al (2014) MiR-874 promotes intestinal barrier dysfunction through targeting AQP3 following intestinal ischemic injury. FEBS Lett 588(5):757–763PubMedCrossRefGoogle Scholar
  71. Zhou H, Xiao J, Wu N et al (2015) MicroRNA-223 regulates the differentiation and function of intestinal dendritic cells and macrophages by targeting C/EBPβ. Cell Rep 13(6):1149–1160PubMedCrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.School of Medicine and SurgeryUniversity of Milano BicoccaMonzaItaly

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