International Journal of Celiac Disease
ISSN (Print): 2334-3427 ISSN (Online): 2334-3486 Website: Editor-in-chief: Samasca Gabriel
Open Access
Journal Browser
International Journal of Celiac Disease. 2014, 2(4), 144-149
DOI: 10.12691/ijcd-2-4-6
Open AccessArticle

Celiac Disease: A Short Overview about Immunological Aspects and Role of Microbiota

Dmitry Stakheev1 and Luca Vannucci1,

1Institute of Microbiology, Academy of Sciences of the Czech Republic, Videnska 1083, Prague 4, CZ

Pub. Date: November 11, 2014

Cite this paper:
Dmitry Stakheev and Luca Vannucci. Celiac Disease: A Short Overview about Immunological Aspects and Role of Microbiota. International Journal of Celiac Disease. 2014; 2(4):144-149. doi: 10.12691/ijcd-2-4-6


Coeliac disease is an illness of the small bowel that accounts multiple pathological aspects: malabsorption, chronic inflammation, autoimmunity. The altered response of the immune system to gluten and derived peptides is the central event. In this short review, we intend propose some aspects of the immunological network that may address to possible role of the microbiota in this pathology.

coeliac disease gluten inflammation Toll-like receptor 4 transglutaminase-2 microbiota

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit


[1]  Barton SH, JA. Celiac disease and autoimmunity in the gut and elsewhere. Gastroenterol Clin North Am. 2008; 37: 411-428.
[2]  Lauret E, Rodrigo L. Celiac disease and autoimmune-associated conditions. Biomed Res Int. 2013; 2013: 127589.
[3]  Pooran N, Brar P, Singh P, Green PH. Trends in the presentation of celiac disease. Am J Med. 2006; 119: 355. e9-14.
[4]  Murray JA, Rubio-Tapia A. Diarrhoea due to small bowel diseases. Best Pract Res Clin Gastroenterol. 2012; 26: 581-600.
[5]  Kang JY, Kang AH, Green A, Gwee KA, Ho KY. Systematic review: worldwide variation in the frequency of coeliac disease and changes over time. Aliment Pharmacol Ther. 2013; 38: 226-245.
[6]  Leffler D, Saha S, Farrell RJ. Celiac disease. Am J Manag Care. 2003; 9: 825-831.
[7]  Husby S, Murray JA. Diagnosing coeliac disease and the potential for serological markers. Nat Rev Gastroenterol Hepatol. 2014; 11: 655-663.
[8]  Mårild K, Stephansson O, Grahnquist L, Cnattingius S, Söderman G, Ludvigsson JF. Down syndrome is associated with elevated risk of celiac disease: a nationwide case-control study. J Pediatr. 2013; 163: 237-242.
[9]  Bettendorf M, Doerr HG, Hauffa BP, Lindberg A, Mehls O, Partsch CJ, Schwarz HP, Stahnke N, Ranke MB. Prevalence of autoantibodies associated with thyroid and celiac disease in Ullrich-Turner syndrome in relation to adult height after growth hormone treatment. J Pediatr Endocrinol Metab. 2006; 19: 149-154.
[10]  Pallav K, Kabbani T, Tariq S, Vanga R, Kelly CP, Leffler DA. Clinical utility of celiac disease-associated HLA testing. Dig Dis Sci. 2014; 59: 2199-2206.
[11]  Mubarak A, Spierings E, Wolters V, van Hoogstraten I, Kneepkens CM, Houwen R. Human leukocyte antigen DQ2.2 and celiac disease. J Pediatr Gastroenterol Nutr. 2013; 56: 428-430.
[12]  Stepniak D, Koning F. Celiac disease--sandwiched between innate and adaptive immunity. Hum Immunol. 2006; 67: 460-468.
[13]  Lionetti E, Castellaneta S, Francavilla R, Pulvirenti A, Tonutti E, Amarri S, Barbato M, Barbera C, Barera G, Bellantoni A, Castellano E, Guariso G, Limongelli MG, Pellegrino S, Polloni C, Ughi C, Zuin G, Fasano A, Catassi C; SIGENP (Italian Society of Pediatric Gastroenterology, Hepatology, and Nutrition) Working Group on Weaning and CD Risk. Introduction of gluten, HLA status, and the risk of celiac disease in children. N Engl J Med. 2014; 371: 1295-1303.
[14]  Sollid LM. Molecular basis of celiac disease. Annu Rev Immunol. 2000; 18: 53-81.
[15]  Di Sabatino A, Vanoli A, Giuffrida P, Luinetti O, Solcia E, Corazza GR. The function of tissue transglutaminase in celiac disease. Autoimmun Rev. 2012; 11: 746-753.
[16]  Dørum S, Arntzen MØ, Qiao SW, Holm A, Koehler CJ, Thiede B, Sollid LM, Fleckenstein B. The preferred substrates for transglutaminase 2 in a complex wheat gluten digest are Peptide fragments harboring celiac disease T-cell epitopes. PLoS One. 2010; 5: e14056.
[17]  Lindfors K, Mäki M, Kaukinen K. Transglutaminase 2-targeted autoantibodies in celiac disease: Pathogenetic players in addition to diagnostic tools? Autoimmun Rev. 2010; 9: 744-749.
[18]  Iversen R, Di Niro R, Stamnaes J, Lundin KE, Wilson PC, Sollid LM. Transglutaminase 2-specific autoantibodies in celiac disease target clustered, N-terminal epitopes not displayed on the surface of cells. J Immunol. 2013; 190: 5981-5991.
[19]  Zanoni G, Navone R, Lunardi C, Tridente G, Bason C, Sivori S, Beri R, Dolcino M, Valletta E, Corrocher R, Puccetti A. In celiac disease, subset of autoantibodies against transglutaminase binds toll-like receptor 4 and induces activation of monocytes. PLoS Med. 2006; 3: e358.
[20]  Kagnoff MF , Paterson YJ, Kumar PJ, Kasarda DD, Carbone FR, Unsworth DJ, Austin RK. Evidence for the role of a human intestinal adenovirus in the pathogenesis of coeliac disease. Gut. 1987; 28: 995-1001.
[21]  Wagner H. Toll-like receptors in gastrointestinal diseases. Dig Dis. 2012; 30: 74-77.
[22]  Hoshino K, Takeuchi O, Kawai T, Sanjo H, Ogawa T, Takeda Y, Takeda K, Akira S. Cutting edge : Toll -like receptor 4 (TLR4) - deficient mice are hyporesponsive to lipopolysaccharide : evidence for TLR4 as the Lps gene product. J Immunol. 1999; 162: 3749-3752.
[23]  McClure R, Massari P. TLR-Dependent Human Mucosal Epithelial Cell Responses to Microbial Pathogens. Front Immunol. 2014; 5: 386.
[24]  Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell. 2004; 118: 229-241.
[25]  Mai CW, Kang YB, Pichika MR. Should a Toll-like receptor 4 (TLR-4) agonist or antagonist be designed to treat cancer? TLR-4: its expression and effects in the ten most common cancers. Onco Targets Ther. 2013; 6: 1573-1587.
[26]  Saito K, Katakura K, Suzuki R, Suzuki T, Ohira H. Modulating Toll-like receptor 4 signaling pathway protects mice from experimental colitis. Fukushima J Med Sci. 2013; 59: 81-88.
[27]  Hmida NB, Ben Ahmed M, Moussa A, Rejeb MB, Said Y, Kourda N, Meresse B, Abdeladhim M, Louzir H, Cerf-Bensussan N. Impaired control of effector T cells by regulatory T cells: a clue to loss of oral tolerance and autoimmunity in celiacdisease? Am J Gastroenterol. 2012; 107: 604-611.
[28]  Cseh Á1, Vásárhelyi B, Szalay B, Molnár K, Nagy-Szakál D, Treszl A, Vannay Á, Arató A, Tulassay T, Veres G. Immune phenotype of children with newly diagnosed and gluten-free diet-treated celiac disease. Dig Dis Sci. 2011; 56: 792-798.
[29]  Eiró N, González-Reyes S, González L, González LO, Altadill A, Andicoechea A, Fresno-Forcelledo MF, Rodrigo-Sáez L, Vizoso FJ.Duodenal expression of Toll-like receptors and interleukins are increased in both children and adult celiac patients. Dig Dis Sci. 2012; 57: 2278-2285.
[30]  Malamut G, El Machhour R, Montcuquet N, et al. IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis. J Clin Invest 2010; 120: 2131-2143.
[31]  Abadie V, Jabri B. IL-15: a central regulator of celiac disease immunopathology. Immunol Rev. 2014; 260: 221-234.
[32]  Castillo NE, Theethira TG, Leffler DA. The present and the future in the diagnosis and management of celiac disease. Gastroenterol Rep (Oxf). 2014 Oct 17. pii: gou065. [in press]
[33]  Foersch S, Neurath MF. Colitis-associated neoplasia: molecular basis and clinical translation. Cell Mol Life Sci. 2014; 71: 3523-3535.
[34]  Fukata M, Shang L, Santaolalla R, Sotolongo J, Pastorini C, España C, Ungaro R, Harpaz N, Cooper HS, Elson G, Kosco-Vilbois M, Zaias J, Perez MT, Mayer L, Vamadevan AS, Lira SA, Abreu MT. Constitutive activation of epithelial TLR4 augments inflammatory responses to mucosal injury and drives colitis-associated tumorigenesis. Inflamm Bowel Dis. 2011; 17: 1464-1473.
[35]  Palová-Jelínková L, Dáňová K, Drašarová H, Dvořák M, Funda DP, Fundová P, Kotrbová-Kozak A, Černá M, Kamanová J, Martin SF, Freudenberg M, Tučková L. Pepsin digest of wheat gliadin fraction increases production of IL-1β via TLR4/MyD88/TRIF/MAPK/NF-κB signaling pathway and an NLRP3 inflammasome activation. PLoS One. 2013; 8: e62426.
[36]  Abdul Sultan A, Crooks CJ, Card T, Tata LJ, Fleming KM, West J. Causes of death in people with coeliac disease in England compared with the general population: a competing risk analysis. Gut. 2014 Oct 24. pii: gutjnl-2014-308285.
[37]  Ilus T, Kaukinen K, Virta LJ, Pukkala E, Collin P. Incidence of malignancies in diagnosed celiac patients: a population-based estimate. Am J Gastroenterol. 2014; 109: 1471-1477.
[38]  Nagler-Anderson C. Man the barrier! Strategic defences in the intestinal mucosa. Nat Rev Immunol. 2001; 1: 59-67.
[39]  Tlaskalová-Hogenová H, Stěpánková R, Kozáková H, Hudcovic T, Vannucci L, Tučková L, Rossmann P, Hrnčíř T, Kverka M, Zákostelská Z, Klimešová K, Přibylová J, Bártová J, Sanchez D, Fundová P, Borovská D, Srůtková D, Zídek Z, Schwarzer M, Drastich P, Funda DP. The role of gut microbiota (commensal bacteria) and the mucosal barrier in the pathogenesis of inflammatory and autoimmune diseases and cancer: contribution of germ-free and gnotobiotic animal models of human diseases. Cell Mol Immunol. 2011; 8: 110-120.
[40]  Tlaskalová-Hogenová H, Farré-Castany MA, Stĕpánková R, Kozáková H, Tucková L, Funda DP, Barot R, Cukrowska B, Sinkora J, Mandel L, et al. The gut as a lymphoepithelial organ: the role of intestinal epithelial cells in mucosal immunity. Folia Microbiol (Praha). 1995; 40: 385-391.
[41]  Van Tyne D, Gilmore MS. A delicate balance: maintaining mutualism to prevent disease. Cell Host Microbe. 2014; 16(4): 425-427.
[42]  Perrigoue J, Das A, Mora JR. Interplay of nutrients and microbial metabolites in intestinal immune homeostasis: distinct and common mechanisms of immune regulation in the small bowel and colon. Nestle Nutr Inst Workshop Ser. 2014; 79: 57-71.
[43]  Vannucci L, Stepankova R, Grobarova V, Kozakova H, Rossmann P, Klimesova K, Benson V, Sima P, Fiserova A, Tlaskalova-Hogenova H. Colorectal carcinoma: Importance of colonic environment for anti-cancer response and systemic immunity. J Immunotoxicol. 2009; 6: 217-226.
[44]  Zeitz M, Ullrich R, Schneider T, Schieferdecker HL, Riecken EO.Cell differentiation and proliferation in the gastrointestinal tract with respect to the local immune system. Ann N Y Acad Sci. 1994; 733: 75-86.
[45]  Mowat AM, Agace WW. Regional specialization within the intestinal immune system. Nat Rev Immunol. 2014; 14: 667-685.
[46]  Xie G, Lo CC, Scholz M, Chain PS. Recruiting human microbiome shotgun data to site-specific reference genomes. PLoS One. 2014; 9: e84963.
[47]  Cassani B, Villablanca EJ, Quintana FJ, Love PE, Lacy-Hulbert A, Blaner WS, Sparwasser T, Snapper SB, Weiner HL, Mora JR. Gut-tropic T cells that express integrin α4β7 and CCR9 are required for induction of oral immune tolerance in mice. Gastroenterology. 2011; 141: 2109-2118.
[48]  Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, Liu H, Cross JR, Pfeffer K, Coffer PJ, Rudensky AY. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature. 2013; 504: 451-455.
[49]  Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, Nakanishi Y, Uetake C, Kato K, Kato T, Takahashi M, Fukuda NN, Murakami S, Miyauchi E, Hino S, Atarashi K, Onawa S, Fujimura Y, Lockett T, Clarke JM, Topping DL, Tomita M, Hori S, Ohara O, Morita T, Koseki H, Kikuchi J, Honda K, Hase K, Ohno H. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature. 2013; 504: 446-450.
[50]  Tedelind S, Westberg F, Kjerrulf M, Vidal A. Anti-inflammatory properties of the short-chain fatty acids acetate and propionate: a study with relevance to inflammatory bowel disease. World J Gastroenterol. 2007; 13: 2826-2832.
[51]  Kiss EA, Vonarbourg C, Kopfmann S, Hobeika E, Finke D, Esser C, Diefenbach A. Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science. 2011; 334: 1561-1565.
[52]  Sayin SI, Wahlström A, Felin J, Jäntti S, Marschall HU, Bamberg K, Angelin B, Hyötyläinen T, Orešič M, Bäckhed F. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 2013; 17: 225-235.
[53]  Bernstein H, Bernstein C, Payne CM, Dvorak K. Bile acids as endogenous etiologic agents in gastrointestinal cancer. World J Gastroenterol. 2009; 15: 3329-3340.
[54]  Májer F, Sharma R, Mullins C, Keogh L, Phipps S, Duggan S, Kelleher D, Keely S, Long A, Radics G, Wang J, Gilmer JF. New highly toxic bile acids derived from deoxycholic acid, chenodeoxycholic acid and lithocholic acid. Bioorg Med Chem. 2014; 22: 256-268.
[55]  Schulzke JD, Bojarski C, Zeissig S, Heller F, Gitter AH, Fromm M.Disrupted barrier function through epithelial cell apoptosis. Ann N Y Acad Sci. 2006; 1072: 288-299.
[56]  Goswami P, Das P, Verma AK, Prakash S, Das TK, Nag TC, Ahuja V, Gupta SD, Makharia GK. Are alterations of tight junctions at molecular and ultrastructural level different in duodenal biopsies of patients with celiac disease and Crohn's disease? Virchows Arch. 2014; 465: 521-530.
[57]  Cinova J, De Palma G, Stepankova R, Kofronova O, Kverka M, Sanz Y, Tuckova L. Role of intestinal bacteria in gliadin-induced changes in intestinal mucosa: study in germ-free rats. PLoS One. 2011; 6: e16169.
[58]  Goto Y, Ivanov II. Intestinal epithelial cells as mediators of the commensal-host immune crosstalk. Immunol Cell Biol. 2013; 91: 204-214.
[59]  Peterson LW, Artis D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol. 2014; 14: 141-153.
[60]  Mårild K, Ye W, Lebwohl B, Green PH, Blaser MJ, Card T, Ludvigsson JF. Antibiotic exposure and the development of coeliac disease: a nationwide case-control study. BMC Gastroenterol. 2013; 13: 109.
[61]  Swidsinski A, Sydora BC, Doerffel Y, Loening-Baucke V, Vaneechoutte M, Lupicki M, Scholze J, Lochs H, Dieleman LA. Viscosity gradient within the mucus layer determines the mucosal barrier function and the spatial organization of the intestinal microbiota. Inflamm Bowel Dis. 2007; 13: 963-970.
[62]  Hansson GC.Role of mucus layers in gut infection and inflammation. Curr Opin Microbiol. 2012; 15: 57-62.
[63]  Schulzke JD, Bojarski C, Zeissig S, Heller F, Gitter AH, Fromm M. Disrupted barrier function through epithelial cell apoptosis. Ann N Y Acad Sci. 2006; 1072: 288-299.
[64]  Goswami P, Das P, Verma AK, Prakash S, Das TK, Nag TC, Ahuja V, Gupta SD, Makharia GK. Are alterations of tight junctions at molecular and ultrastructural level different in duodenal biopsies of patients with celiac disease and Crohn's disease? Virchows Arch. 2014; 465: 521-530.
[65]  Cinova J, De Palma G, Stepankova R, Kofronova O, Kverka M, Sanz Y, Tuckova L. Role of intestinal bacteria in gliadin-induced changes in intestinal mucosa: study in germ-free rats. PLoS One. 2011; 6: e16169.
[66]  Montalto M, Cuoco L, Ricci R, Maggiano N, Vecchio FM, Gasbarrini GImmunohistochemical analysis of ZO-1 in the duodenal mucosa of patients with untreated and treated celiac disease. Digestion. 2002; 65: 227-233.
[67]  Pizzuti D, Bortolami M, Mazzon E, Buda A, Guariso G, D'Odorico A, Chiarelli S, D'Incà R, De Lazzari F, Martines D.Transcriptional downregulation of tight junction protein ZO-1 in active coeliac disease is reversed after a gluten-free diet. Dig Liver Dis. 2004; 36: 337-341.
[68]  Erdman SE, Rao VP, Olipitz W, Taylor CL, Jackson EA, Levkovich T, Lee CW, Horwitz BH, Fox JG, Ge Z, Poutahidis T. Unifying roles for regulatory T cells and inflammation in cancer. Int J Cancer. 2010; 126: 1651-165.
[69]  Whiteside TL. The tumor microenvironment and its role in promoting tumor growth. Oncogene. 2008; 27: 5904-5912.
[70]  Raghav K, Overman MJ. Small bowel adenocarcinomas--existing evidence and evolving paradigms. Nat Rev Clin Oncol. 2013; 10: 534-544.
[71]  Piscaglia AC1, Campanale M, Gasbarrini G. Small bowel nonendocrine neoplasms: current concepts and novel perspectives. Eur Rev Med Pharmacol Sci. 2010; 14: 320-326.
[72]  Rabeneck, L., Davila, J. A. & El‑Serag, H. B. Is there a true ‘shift’ to the right colon in the incidence of colorectal cancer? Am. J. Gastroenterol. 2003; 98: 1400-1409.
[73]  Triantafillidis JK, Nasioulas, G, Kosmidis, PA. Colorectal cancer and inflammatory bowel disease: epidemiology, risk factors, mechanisms of carcinogenesis and prevention strategies. Anticancer research 2009; 29: 2727-2737.
[74]  Hugh J. Freeman. Adult Celiac Disease and Its Malignant Complications. Gut and Liver 2009; 3: 237-246.
[75]  Zackular JP, Baxter NT, Iverson KD, Sadler WD, Petrosino JF, Chen GY, Schloss PD. The gut microbiome modulates colon tumorigenesis. MBio. 2013; 4: e00692-13.
[76]  de Sousa Moraes LF, Grzeskowiak LM, de Sales Teixeira TF, Gouveia Peluzio Mdo C.Intestinal microbiota and probiotics in celiac disease. Clin Microbiol Rev. 2014; 27: 482-489.
[77]  Duar RM, Clark K, Patil PB, Hernández C, Brüning S, Burkey TE, Madayiputhiya N, Taylor SL, Walter J. Identification and characterization of intestinal lactobacilli strains capable of degrading immunotoxic peptides present in gluten. J Appl Microbiol. 2014 Nov 6. [in press].