Celiac Disease: Disease Models in Understanding Pathogenesis and Search for Therapy

Anton Chaykin; Elena Odintsova`; Andrey Nedorubov

doi:10.3889/oamjms.2022.11024

Authors

Anton Chaykin The Sechenov First Moscow State Medical University, Russian Federation, Moscow, Russia
Elena Odintsova` The Sechenov First Moscow State Medical University, Russian Federation, Moscow, Russia https://orcid.org/0000-0002-4098-5559
Andrey Nedorubov The Sechenov First Moscow State Medical University, Russian Federation, Moscow, Russia

DOI:

https://doi.org/10.3889/oamjms.2022.11024

Keywords:

Celiac disease, Gliadin, Gluten, in vitro; in vivo model

Abstract

Celiac disease is a complex polygenic systemic disorder caused by dietary gluten exposure that selectively occurs in genetically susceptible people. The potential celiac disease is defined by the presence of celiac disease-specific antibodies and compatible human leukocyte antigen but without histological abnormalities in duodenal biopsies. At present, the only treatment is lifelong adherence to a gluten-free diet. Despite its effectiveness, the diet is difficult to maintain due to its cost, availability of gluten-free foods, and hidden gluten. The need to develop non-dietary treatment methods is widely recognized, but this is prevented by the absence of a pathophysiologically relevant preclinical model. Nonetheless, in vitro and in vivo models have made it possible to investigate the mechanisms of the disease and develop new treatment approaches: The use of foods with neutralized gluten, microbiota correction, cocktails of specific endoproteinase, polymer gluten binders, specific inhibitors of transglutaminases and inflammatory cytokines, and a vaccine based on allergen-specific therapy.

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References

Barone MV, Troncone R, Auricchio S. Gliadin peptides as triggers of the proliferative and stress/innate immune response of the celiac small intestinal mucosa. Int J Mol Sci. 2014;15(11):20518-37. https://doi.org/10.3390/ijms151120518 PMid:25387079 DOI: https://doi.org/10.3390/ijms151120518

Re VD, Magris R, Cannizzaro R. New insights into the pathogenesis of celiac disease. Front Med (Lasusanne). 2017;4:137. https://doi.org/10.3389/fmed.2017.00137 PMid:28913337 DOI: https://doi.org/10.3389/fmed.2017.00137

Jericho H, Guandalini S. Extra-intestinal manifestation of celiac disease in children. Nutrients. 2018;10(6):755. https://doi.org/10.3390/nu10060755 PMid:29895731 DOI: https://doi.org/10.3390/nu10060755

Guandalini S, Assiri A. Celiac disease: A review. JAMA Pediatr. 2014;168(3):272-8. https://doi.org/10.1001/jamapediatrics.2013.3858 PMid:24395055 DOI: https://doi.org/10.1001/jamapediatrics.2013.3858

Alessio F, Carlo C. Celiac disease. N Engl J Med. 2012:367(25):2419-26. https://doi.org/10.1056/nejmcp1113994 PMid:23252527 DOI: https://doi.org/10.1056/NEJMcp1113994

Kårhus LL, Thuesen BH, Skaaby T, Rumessen JJ, Linneberg A. The distribution of HLA DQ2 and DQ8 haplotypes and their association with health indicators in a general Danish population. United European Gastroenterol J. 2018;6(6):866-78. https://doi.org/10.1177/2050640618765506 PMid:30023064 DOI: https://doi.org/10.1177/2050640618765506

Tye-Din JA, Cameron DJ, Daveson AJ, Day AS, Dellsperger P, Hogan C, et al. Appropriate clinical use of human leukocyte antigen typing for coeliac disease: An Australasian perspective. Intern Med J. 2015;45(4):441-50. https://doi.org/10.1111/imj.12716 PMid:25827511 DOI: https://doi.org/10.1111/imj.12716

Lionetti E, Gatti S, Pulvirenti A, Catassi C. Celiac disease from a global perspective. Best Pract Res Clin Gastroenterol.

;29(3):365-79. https://doi.org/10.1016/j.bpg.2015.05.004 PMid:26060103 DOI: https://doi.org/10.1016/j.bpg.2015.05.004

Murad H, Jazairi B, Khansaa I, Olabi D, Khouri L. HLA-DQ2 and-DQ8 genotype frequency in Syrian celiac disease children: HLA-DQ relative risks evaluation. BMC Gastroenterol. 2018;18:70. https://doi.org/10.1186/s12876-018-0802-2 DOI: https://doi.org/10.1186/s12876-018-0802-2

Bradauskiene V, Vaiciulyte-Funk L, Martinaitiene D, Andruskiene J, Verma AK, Lima JP, et al. Wheat consumption and prevalence of celiac disease: Correlation from a multilevel analysis. Crit Rev Food Sci Nutr. 2023;63(1):18-32. https://doi.org/10.1080/10408398.2021.1939650 PMid:34184959 DOI: https://doi.org/10.1080/10408398.2021.1939650

Poddighe D, Rebuffi C, De Silvestri A, Capittini C. Carrier frequency of HLA-DQB1*02 allele in patients affected with celiac disease: A systematic review assessing the potential rationale of a targeted allelic genotyping as a first-line screening. World J Gastroenterol. 2020;26(12):1365-81. https://doi.org/10.3748/wjg.v26.i12.1365 PMid:32256023 DOI: https://doi.org/10.3748/wjg.v26.i12.1365

Kupfer SS, Jabri B. Celiac disease pathophysiology. Gastrointest Endosc Clin N Am. 2012;22(4):639-60. https://doi.org/10.1016/j.giec.2012.07.003 PMid:23083984 DOI: https://doi.org/10.1016/j.giec.2012.07.003

Yagur VE, Kapralov NV, Dostanko NY, Polyanskaya AV. Celiac disease. Med J. 2016;3:48-56.

Shumilov PV, Yu GM, Netrebenko OK, et al. Modern ideas about the pathogenetic mechanisms of celiac disease: A decisive role in the clinical course. Pediatrics. 2016;95(6):110-9.

Schuppan D, Junker Y, Barisani D. Celiac disease: From pathogenesis to novel therapies. Gastroenterology. 2009;137(6):1912-33. https://doi.org/10.1053/j.gastro.2009.09.008 PMid:19766641 DOI: https://doi.org/10.1053/j.gastro.2009.09.008

Paolella G, Lepretti M, Martucciello S, Nanayakkara M, Auricchio S, Esposito C, et al. The toxic alpha-gliadin peptide 31-43 enters cells without a surface membrane receptor. Cell Biol Int. 2018;42(1):112-20. https://doi.org/10.1002/cbin.10874 PMid:28914468 DOI: https://doi.org/10.1002/cbin.10874

Sollid LM, Qiao SW, Anderson RP, Gianfrani C, Koning F. Nomenclature and listing of celiac disease relevant gluten T-cell epitopes restricted by HLA-DQ molecules. Immunogenetics. 2012;64(6):455-60. https://doi.org/10.1007/s00251-012-0599-z PMid:22322673 DOI: https://doi.org/10.1007/s00251-012-0599-z

Sollid LM, Jabri B. Triggers and drivers of autoimmunity: Lessons from coeliac disease. Nat Rev Immunol. 2013;13(4):294-302. https://doi.org/10.1002/cbin.10874 PMid:23493116 DOI: https://doi.org/10.1038/nri3407

Galipeau HJ, Verdu EF. Gut microbes and adverse food reactions: Focus on gluten related disorders. Gut Microbes. 2015;5(5):594-605. https://doi.org/10.4161/19490976.2014.969635 PMid:25483329 DOI: https://doi.org/10.4161/19490976.2014.969635

Lebwohl B, Sanders DS, Green PH. Coeliac disease. Lancet. 2018;391(10115):70-81. https://doi.org/10.1016/S0140-6736(17)31796-8 PMid:28760445 DOI: https://doi.org/10.1016/S0140-6736(17)31796-8

Zakharova IN, Dmitrieva YA, Dzebisova FS. Celiac disease and associated diseases. Russian Bull Perinatol Pediatr. 2014;3:44-9.

Khaleghi S, Ju JM, Lamba A, Murray JA. The potential utility of tight junction regulation in celiac disease: Focus on larazotide acetate. Ther Adv Gastroenterol. 2016;9(1):37-49. https://doi.org/10.1177/1756283X15616576 PMid:26770266 DOI: https://doi.org/10.1177/1756283X15616576

Sturgeon C, Fasano A. Zonulin, a regulator of epithelial and endothelial barrier functions, and its involvement in chronic inflammatory diseases. Tissue Barriers. 2016;4(4):e1251384. https://doi.org/10.1080/21688370.2016.1251384 PMid:28123927 DOI: https://doi.org/10.1080/21688370.2016.1251384

Lammers KM, Lu R, Brownley J, Lu B, Gerard C, Thomas K, et al. Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology. 2008;135(4):194-204. https://doi.org/10.1053/j.gastro.2008.03.023 PMid:18485912 DOI: https://doi.org/10.1053/j.gastro.2008.03.023

Sollid LM, Tye-Din JA, Qiao SW, Anderson RP, Gianfrani C, Koning F. Update 2020: Nomenclature and listing of celiac disease-relevant gluten epitopes recognized by CD4+T cells. Immunogenetics. 2019;72(1-2):85-8. https://doi.org/10.1007/s00251-019-01141-w PMid:31735991 DOI: https://doi.org/10.1007/s00251-019-01141-w

Tye-Din JA, Galipeau HJ, Agardh D. Celiac disease: A review of current concepts in pathogenesis, prevention, and novel therapies. Front Pediatr. 2018;6:350. https://doi.org/10.3389/fped.2018.00350 PMid:30519552 DOI: https://doi.org/10.3389/fped.2018.00350

Maiuri L, Ciacci C, Ricciardelli I, Vacca L, Raia V, Auricchio S, et al. Association between innate response to gliadin and activation of pathogenic T-cells in celiac disease. Lancet. 2003;362(9377):30-7. https://doi.org/10.1016/S0140-6736(03)13803-2 PMid:12853196 DOI: https://doi.org/10.1016/S0140-6736(03)13803-2

Thomas KE, Sapone A, Fasano A, Vogel SN. Gliadin stimulation of murine macrophage inflammatory gene expression and intestinal permeability are MyD88-dependent: Role of the innate immune response in Celiac disease. J Immunol. 2006;176(4):2512-21. https://doi.org/10.4049/jimmunol.176.4.2512 PMid:16456012 DOI: https://doi.org/10.4049/jimmunol.176.4.2512

McDonald BD, Jabri B, Bendelac A. Diverse developmental pathways of intestinal intraepithelial lymphocytes. Nat Rev Immunol. 2018;18(8):514-25. https://doi.org/10.1038/s41577-018-0013-7 PMid:29717233 DOI: https://doi.org/10.1038/s41577-018-0013-7

Cukrowska B, Sowińska A, Bierła JB, Czarnowska E, Rybak A, Grzybowska-Chlebowczyk U. Intestinal epithelium, intraepithelial lymphocytes and the gut microbiota-Key players in the pathogenesis of celiac disease. World J Gastroenterol. 2017;23(42):7505-18. https://doi.org/10.3748/wjg.v23.i42.7505 PMid:29204051 DOI: https://doi.org/10.3748/wjg.v23.i42.7505

Verdu EF, Galipeau HJ, Jabri B. Novel players in coeliac disease pathogenesis: Role of the gut microbiota. Nat Rev Gastroenterol Hepatol. 2015;12(9):497-506. https://doi.org/10.1038/nrgastro.2015.90 PMid:26055247 DOI: https://doi.org/10.1038/nrgastro.2015.90

Cenit MC, Codoñer-Franch P, Sanz Y. Gut microbiota and risk of developing celiac disease. J Clin Gastroenterol. 2016;50:148-52. https://doi.org/10.1097/MCG.0000000000000688 PMid:27741161 DOI: https://doi.org/10.1097/MCG.0000000000000688

Kumar V, Jarzabek-Chorzelska M, Sulej J, Karnewska K, Farrell T, Jablonska S. Celiac disease and immunoglobulin a deficiency: How effective are the serological methods of diagnosis? Clin Diagn Lab Immunol. 2002;9(6):1295-300. https://doi.org/10.1128/cdli.9.6.1295-1300.2002 PMid:12414763 DOI: https://doi.org/10.1128/CDLI.9.6.1295-1300.2002

Cénit MC, Olivares M, Codoner-Franch P, Sanz Y. Intestinal microbiota and celiac disease: Cause, consequence or coevolution? Nutrients. 2015;7(8):6900-23. https://doi.org/10.3390/nu7085314 PMid:26287240 DOI: https://doi.org/10.3390/nu7085314

Rossi S, Giordano D, Mazzeo MF, Maurano F, Luongo D, Facchiano A, et al. Transamidation down-regulates intestinal immunity of recombinant α-gliadin in HLA-DQ8 transgenic mice. Int J Mol Sci. 2021;22(13):7019. https://doi.org/10.3390/ijms22137019 PMid:34209932 DOI: https://doi.org/10.3390/ijms22137019

D’Argenio V, Casaburi G, Precone V, Pagliuca C, Colicchio R, Sarnataro D, et al. Metagenomics reveals dysbiosis and a potentially pathogenic, N. Flavescens strain in duodenum of adult celiac patients. Am J Gastroenterol. 2016;111(6):879-90. https://doi.org/10.1038/ajg.2016.95 DOI: https://doi.org/10.1038/ajg.2016.95

Quagliariello A, Aloisio I, Cionci NB, Luiselli D, D’Auria G, Martinez-Priego L, et al. Effect of Bifidobacterium breve on the intestinal microbiota of coeliac children on a gluten free diet: A pilot study. Nutrients. 2016;8(10):660. https://doi.org/10.3390/nu8100660 PMid:27782071

Tian N, Faller L, Leffler DA, Kelly CP, Hansen J, Bosch JA, et al. Salivary Gluten degradation and oral microbial profiles in healthy individuals and celiac disease patients. Appl Environ Microbiol. 2017;83(6):e03330-16. https://doi.org/10.1128/AEM.03330-16 PMid:28087531 DOI: https://doi.org/10.1128/AEM.03330-16

Abdukhakimova D, Dossybayeva K, Poddighe D. Fecal and duodenal microbiota in pediatric celiac disease. Front Pediatr. 2021;9:652208. https://doi.org/10.3389/fped.2021.652208 PMid:33968854 DOI: https://doi.org/10.3389/fped.2021.652208

Poddighe D, Kushugulova A. Salivary microbiome in pediatric and adult celiac disease. Front Cell Infect Microbiol. 2021;11:625162. https://doi.org/10.3389/fcimb.2021.625162 PMid:33680992 DOI: https://doi.org/10.3389/fcimb.2021.625162

CamineroA,GalipeauHJ,McCarvilleJL,JohnstonCW,BernierSP, Russell AK, et al. Duodenal bacteria from patients with celiac disease and healthy subjects distinctly affect gluten breakdown and immunogenicity. Gastroenterology. 2016;151(4):670-83. https://doi.org/10.1053/j.gastro.2016.06.041 PMid:27373514 DOI: https://doi.org/10.1053/j.gastro.2016.06.041

Caminero A, McCarville JL, Galipeau H, Deraison C, Bernier SP, Constante M, et al. Duodenal bacterial proteolytic activity determines sensitivity to dietary antigen through protease-activated receptor-2. Nat Commun. 2019;10(1):1198. https://doi.org/10.1038/s41467-019-09037-9 DOI: https://doi.org/10.1038/s41467-019-09037-9

Caminero A, Meisel M, Jabri B, Verdu EF. Mechanisms by which gut microorganisms influence food sensitivities. Nat Rev Gastroenterol Hepatol. 2018;16:7-18. https://doi.org/10.1038/s41575-018-0064-z DOI: https://doi.org/10.1038/s41575-018-0064-z

Turnbaugh PJ, Ridaura VK, Faith JJ, Rey FE, Knight R, Gordon JI. The effect of diet on the human gut microbiome: A metagenomic analysis in humanized gnotobiotic mice. Sci Transl Med. 2009;1(6):6ra14. https://doi.org/10.1126/scitranslmed.3000322 PMid:20368178 DOI: https://doi.org/10.1126/scitranslmed.3000322

Galipeau H, McCarville JL, Moeller S, Murray JA, Alaedini A, Jabri B, et al. Gluten-induced responses in NOD/DQ8 mice are influenced by bacterial colonization. Gastroenterology. 2014;146(5):S-833. https://doi.org/10.1016/ S0016-5085(14)63025-0 DOI: https://doi.org/10.1016/S0016-5085(14)63025-0

Papista C, Gerakopoulos V, Kourelis A, Sounidaki M, Kontana A, Berthelot L, et al. Gluten induces coeliac-like disease in sensitised mice involving IgA, CD71 and transglutaminase 2 interactions that are prevented by probiotics. Lab Invest.

;92(4):625-35. https://doi.org/10.1038/labinvest.2012.13 PMid:22330344 DOI: https://doi.org/10.1038/labinvest.2012.13

Laparra JM, Olivares M, Gallina O, Sanz Y. Bifidobacterium longum CECT 7347 modulates immune responses in a gliadin-induced enteropathy animal model. PLoS One. 2012;7(2):e30744. https://doi.org/10.1371/journal.pone.0030744 PMid:22348021 DOI: https://doi.org/10.1371/journal.pone.0030744

Hall N, Rubin G, Charnock A. Intentional and inadvertent non-adherence in adult coeliac disease. A cross-sectional survey. Appetite. 2013;68:56-62. https://doi.org/10.1016/j.appet.2013.04.016 PMid:23623778 DOI: https://doi.org/10.1016/j.appet.2013.04.016

Caputo I, Secondo A, Lepretti M, Paolella G, Auricchio S, Barone MV, et al. Gliadin peptides induce tissue transglutaminase activation and ER-stress through Ca2+ mobilization in caco-2 cells. PLoS One. 2012;7(9):e45209. https://doi.org/10.1371/journal.pone.0045209 PMid:23049776 DOI: https://doi.org/10.1371/journal.pone.0045209

Lindfors K, Blomqvist T, Juuti-Uusitalo K, Stenman S, Venäläinen J, Mäki M, et al. Live probiotic Bifidobacterium lactis bacteria inhibit the toxic effects induced by wheat gliadin in epithelial cell culture. Clin Exp Immunol. 2008;152(3):552-8. https://doi.org/10.1111/j.1365-2249.2008.03635.x PMid:18422736 DOI: https://doi.org/10.1111/j.1365-2249.2008.03635.x

De Palma G, Kamanova J, Cinova J, Olivares M, Drasarova H, Tuckova L, et al. Modulation of phenotypic and functional maturation of dendritic cells by intestinal bacteria and gliadin: Relevance for celiac disease. J Leukoc Biol. 2012;92(5):1043-54. https://doi.org/10.1189/jlb.1111581 PMid:22891290 DOI: https://doi.org/10.1189/jlb.1111581

Molberg O, Kett K, Scott H, Thorsby E, Sollid LM, Lundin KE. Gliadin specific, HLA DQ2-restricted T cells are commonly found in small intestinal biopsies from coeliac disease patients, but not from controls. Scand J Immunol. 1997;46(3):103-9. https://doi.org/10.1046/j.1365-3083.1997.d01-93.x PMid:9315123 DOI: https://doi.org/10.1046/j.1365-3083.1996.d01-17.x

Lundin KE, Scott H, Hansen T, Paulsen G, Halstensen TS, Fausa O, et al. Gliadin-specific, HLA-DQ(alpha 1*0501,beta 1*0201) restricted T cells isolated from the small intestinal mucosa of celiac disease patients. J Exp Med. 1993;178(1):187-96. https://doi.org/10.1084/jem.178.1.187 PMid:8315377 DOI: https://doi.org/10.1084/jem.178.1.187

Sato T, Stange DE, Ferrante M, Vries RG, Van Es JH, Brink SV, et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology. 2011;141(5):1762-72. https://doi.org/10.1053/j.gastro.2011.07.050 PMid:21889923 DOI: https://doi.org/10.1053/j.gastro.2011.07.050

Bhatia SN, Ingber DE. Microfluidic organs-on-chips. Nat Biotechnol. 2014;32(8):760-72. https://doi.org/10.1038/nbt.2989 PMid:25093883 DOI: https://doi.org/10.1038/nbt.2989

Moerkens R, Mooiweer J, Withoff S, Wijmenga C. Celiac disease-on-chip: Modeling a multifactorial disease in vitro. United European Gastroenterol J. 2019;7(4):467-76. https://doi.org/10.1177/2050640619836057 PMid:31065364 DOI: https://doi.org/10.1177/2050640619836057

Batt RM, McLean L, Carter MW. Sequential morphologic and biochemical studies of naturally occurring wheat-sensitive enteropathy in Irish setter dogs. Dig Dis Sci. 1987;32(2):184-94. https://doi.org/10.1007/BF01297107 PMid:3026759 DOI: https://doi.org/10.1007/BF01297107

Hall EJ, Batt RM. Abnormal permeability precedes the development of a gluten sensitive enteropathy in Irish setter dogs. Gut. 1991;32(7):749-53. https://doi.org/10.1136/gut.32.7.749 PMid:1906829 DOI: https://doi.org/10.1136/gut.32.7.749

Polvi A, Garden OA, Houlston RS, Maki M, Batt RM, Partanen J. Genetic susceptibility to gluten sensitive enteropathy in Irish setter dogs is not linked to the major histocompatibility complex. Tissue Antigens. 1998;52(6):543-9. https://doi.org/10.1111/j.1399-0039.1998.tb03085.x PMid:9894853 DOI: https://doi.org/10.1111/j.1399-0039.1998.tb03085.x

Bethune MT, Borda JT, Ribka E, Liu MX, Phillippi-Falkenstein K, Jandacek RJ, et al. A non-human primate model for gluten sensitivity. PLoS One 2008;3(2):e1614. https://doi.org/10.1371/journal.pone.0001614 PMid:18286171 DOI: https://doi.org/10.1371/journal.pone.0001614

Sardy M, Karpati S, Merkl B, Paulsson M, Smyth N. Epidermal transglutaminase (TGase 3) is the autoantigen of dermatitis herpetiformis. J Exp Med. 2002;195(6):747-57. https://doi.org/10.1084/jem.20011299 PMid:11901200 DOI: https://doi.org/10.1084/jem.20011299

Galipeau HJ, McCarville JL, Huebener S, LitwinO, Meisel M, Jabri B, et al. Intestinal microbiota modulates gluten-induced immunopathology in humanized mice. Am J Pathol. 2015;185(11):2969-82. https://doi.org/10.1016/j.ajpath.2015.07.018 PMid:26456581 DOI: https://doi.org/10.1016/j.ajpath.2015.07.018

Yokoyama S, Takada K, Hirasawa M, Perera LP, Hiroi T. Transgenic mice that overexpress human IL-15 in enterocytes recapitulate both B and T cell-mediated pathologic manifestations of celiac disease. J Clin Immunol. 2011;31(6):1038-44. https://doi.org/10.1007/s10875-011-9586-7 PMid:21938511 DOI: https://doi.org/10.1007/s10875-011-9586-7

Korneychuk N, Ramiro-Puig E, Ettersperger J, Schulthess J, Montcuquet N, Kiyono H, et al. Interleukin 15 and CD4+ T cells cooperate to promote small intestinal enteropathy in response to dietary antigen. Gastroenterology. 2014;146(4):1017-27. https://doi.org/10.1053/j.gastro.2013.12.023 PMid:24361466 DOI: https://doi.org/10.1053/j.gastro.2013.12.023

DePaolo RW, Abadie V, Tang F, Hall JA, Wang W, Jabri B, et al. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature. 2011;471(7337):220-4. https://doi.org/10.1038/nature09849 PMid:21307853 DOI: https://doi.org/10.1038/nature09849

Abadie V, Khosla C, Jabri B. A mouse model of celiac disease. Curr Protoc. 2022;2(8):e515. https://doi.org/10.1002/cpz1.515 DOI: https://doi.org/10.1002/cpz1.515

Cinova J, De Palma G, Stepankova R, Kofronova O, Kverka M, Sanz Y, et al. Role of intestinal bacteria in gliadin-induced changes in intestinal mucosa: Study in germ-free rats. PLoS One. 2011;6(1):e16169. https://doi.org/10.1371/journal.pone.0016169 PMid:21249146 DOI: https://doi.org/10.1371/journal.pone.0016169

Freitag TL, Rietdijk S, Junker Y, Popov Y, Bhan AK, Kelly CP, et al. Gliadin-primed CD4+CD45RBlowCD25-T-cells drive gluten-dependent small intestinal damage after adoptive transfer into lymphopenic mice. Gut. 2009;58(12):1597-605. https://doi.org/10.1136/gut.2009.186361 PMid:19671544 DOI: https://doi.org/10.1136/gut.2009.186361

Araya RE, Castro MF, Carasi P, McCarville JL, Jury J, Chirdo FG, et al. Mechanisms of innate immune activation by gluten peptide p31-43 in mice. Am J Physiol Gastrointest Liver Physiol. 2016;311(1):G40-9. https://doi.org/10.1152/ajpgi.00435.2015 PMid:27151946 DOI: https://doi.org/10.1152/ajpgi.00435.2015

Vijaykrishnaraj M, Kumar BV, Muthukumar SP, Kurrey NK, Prabhasankar P. Antigen-specific gut inflammation and systemic immune responses induced by pro-longing wheat gluten sensitization in BALB/c murine model. J Proteome Res. 2017;16(10):3514-28. https://doi.org/10.1021/acs.jproteome.7b00199 PMid:28809572 DOI: https://doi.org/10.1021/acs.jproteome.7b00199

Stepankova R, Tlaskalova-Hogenova H, Sinkora J, Jodl J, Fric P. Changes in jejunal mucosa after long-term feeding of germfree rats with gluten. Scand J Gastroenterol. 1996;31(6):551-7. https://doi.org/10.3109/00365529609009127 PMid:8789893 DOI: https://doi.org/10.3109/00365529609009127

Ciacci C, Maiuri L, Caporaso N, Bucci C, Del Giudice L, Massardo DR, et al. Celiac disease: In vitro and in vivo safety and palatability of wheat-free sorghum food products. Clin Nutr. 2007;26(6):799-805. https://doi.org/10.1016/j.clnu.2007.05.006 PMid:17719701 DOI: https://doi.org/10.1016/j.clnu.2007.05.006

Spaenij-Dekking L, Kooy-Winkelaar Y, van Veelen P, Drijfhout JW, Jonker H, van Soest L, et al. Natural variation in toxicity of wheat: Potential for selection of nontoxic varieties for celiac disease patients. Gastroenterology. 2005;129(3):797-806. https://doi.org/10.1053/j.gastro.2005.06.017 PMid:16143119 DOI: https://doi.org/10.1053/j.gastro.2005.06.017

CarroccioA, Di Prima L, Noto D, Fayer F,Ambrosiano G, Villanacci V, et al. Searching for wheat plants with low toxicity in celiac disease: Between direct toxicity and immunologic activation. Dig Liver Dis. 2011;43(1):34-9. https://doi.org/10.1016/j.dld.2010.05.005 PMid:20554485 DOI: https://doi.org/10.1016/j.dld.2010.05.005

Di Cagno R, De Angelis M, Auricchio S, Greco L, Clarke C, De Vincenzi M, et al. Sourdough bread made from wheat and nontoxic flours and started with selected lactobacilli is tolerated in celiac sprue patients. Appl Environ Microbiol. 2004;70(2):1088-96. https://doi.org/10.1128/AEM.70.2.1088-1096.2004 PMid:14766592 DOI: https://doi.org/10.1128/AEM.70.2.1088-1096.2004

Di Cagno R, Barbato M, Di Camillo C, Rizzello CG, De Angelis M, Giuliani G, et al. Gluten-free sourdough wheat baked goods appear safe for young celiac patients: A pilot study. J Pediatr Gastroenterol Nutr. 2010;51(6):777-83. https://doi.org/10.1097/MPG.0b013e3181f22ba4 PMid:20975578 DOI: https://doi.org/10.1097/MPG.0b013e3181f22ba4

Marino M, Casale R, Borghini R, Di Nardi S, Donato G, Angeloni A, et al. The effects of modified versus unmodified wheat gluten administration in patients with celiac disease. Int Immunopharmacol. 2017;47:1-8. https://doi.org/10.1016/j.intimp.2017.03.012 PMid:28343108 DOI: https://doi.org/10.1016/j.intimp.2017.03.012

Ribeiro M, Lopes S, Picascia S, Gianfrani C, Nunes FM. Reinventing the nutraceutical value of gluten: The case of l-theanine-gluten as a potential alternative to the gluten exclusion diet in celiac disease. Food Chem. 2020;324:126840. https://doi.org/10.1016/j.foodchem.2020.126840 PMid:32344339 DOI: https://doi.org/10.1016/j.foodchem.2020.126840

Sánchez-León S, Gil-Humanes J, Ozuna CV, Giménez MJ, Sousa C, Voytas DF, Barro F. Low-gluten, non-transgenic wheat engineered with CRISPR/Cas9. Plant Biotechnol. J. 2018;16(4):902-10. https://doi.org/10.1111/pbi.12837 PMid:28921815 DOI: https://doi.org/10.1111/pbi.12837

Gil-Humanes J, Pistón F, Tollefsen S, Sollid LM, Barro F. Effective shutdown in the expression of celiac disease-related wheat gliadin T-cell epitopes by RNA interference. Proc Natl Acad Sci USA. 2010;107(39):17023-8. https://doi.org/10.1073/pnas.1007773107 PMid:20829492 DOI: https://doi.org/10.1073/pnas.1007773107

Barro F, Iehisa JC, Giménez MJ, García-Molina MD, Ozuna CV, Comino I, et al. Targeting of prolamins by RNAi in bread wheat: Effectiveness of seven silencing-fragment combinations for obtaining lines devoid of coeliac disease epitopes from highly immunogenic gliadins. Plant Biotechnol. J. 2016;14(3):986-96. https://doi.org/10.1111/pbi.12455 PMid:26300126 DOI: https://doi.org/10.1111/pbi.12455

Siegel M, Garber ME, Spencer AG, Botwick W, Kumar P, Williams RN, et al. Safety, tolerability, and activity of ALV003: Results from two Phase 1 single, escalating-dose clinical trials. Dig Dis Sci. 2012;57(2):440-50. https://doi.org/10.1007/s10620-011-1906-5 PMid:21948339 DOI: https://doi.org/10.1007/s10620-011-1906-5

Lahdeaho M, Maki M, Kaukinen K, Laurila K, Adelman D. ALV003, a novel gluteanase, attneuates gluten-induced small intestinal mucosal injury in Celiac Disease patients: A randomized phase 2A clinical trial. In: Federation UEG. Vienna: United European Gastroenterology Week; 2011. p. 57.

Stepniak D, Spaenij-Dekking L, Mitea C, Moester M, de Ru A, Baak-Pablo R, et al. Highly efficient gluten degradation with a newly identified prolyl endoprotease: Implications for celiac disease. Am J Physiol Gastrointest Liver Physiol. 2006;291(4):621-9. https://doi.org/10.1152/ajpgi.00034.2006 PMid:16690904 DOI: https://doi.org/10.1152/ajpgi.00034.2006

Mitea C, Havenaar R, Drijfhout JW, Edens L, Dekking L, Koning F. Efficient degradation of gluten by a prolyl endoprotease in a gastrointestinal model: Implications for coeliac disease. Gut. 2008;57(1):25-32. https://doi.org/10.1136/gut.2006.111609 PMid:17494108 DOI: https://doi.org/10.1136/gut.2006.111609

Gordon SR, Stanley EJ, Wolf S, Toland A, Wu SJ, Hadidi D, et al. Computational design of an α-gliadin peptidase. J Am Chem Soc. 2012;134(50):20513-20. https://doi.org/10.1021/ja3094795 PMid:23153249 DOI: https://doi.org/10.1021/ja3094795

Wolf C, Siegel JB, Tinberg C, Camarca A, Gianfrani C, Paski S, et al. Engineering of Kuma030: A gliadin peptidase that rapidly degrades immunogenic gliadin peptides in gastric conditions. J Am Chem Soc. 2015;137(40):13106-13. https://doi.org/10.1021/jacs.5b08325 PMid:26374198 DOI: https://doi.org/10.1021/jacs.5b08325

Ehren J, Moron B, Martin E, Bethune MT, Gray GM, Khosla C. A food-grade enzyme preparation with modest gluten detoxification properties. PLoS One. 2009;4(7):6313. https://doi.org/10.1371/journal.pone.0006313 PMid:19621078 DOI: https://doi.org/10.1371/journal.pone.0006313

Korponay-Szabo IR, Tumpek J, Gyimesi J, Laurila K, Papp M, Maki M, et al. Food-grade gluten degradation enzymes to treat dietary transgressions in coeliac adolescents. J Pediatr Gastroenterol Nutr. 2010;50:68.

Pinier M, Verdu EF, Nasser-Eddine M, David CS, Vezina A, Rivard N, et al. Polymeric binders suppress gliadin-induced toxicity in the intestinal epithelium. Gastroenterology. 2009;136(1):288-98. https://doi.org/10.1053/j.gastro.2008.09.016 DOI: https://doi.org/10.1053/j.gastro.2008.09.016

Pinier M, Fuhrmann G, Galipeau HJ, Rivard N, Murray JA, David CS, et al. The copolymer P(HEMA-co-SS) binds gluten and reduces immune response in glu-ten-sensitized mice and human tissues. Gastroenterology. 2012;142(2):316-25. e1-12. https://doi.org/10.1053/j.gastro.2011.10.038 PMid:22079593 DOI: https://doi.org/10.1053/j.gastro.2011.10.038

Mccarville JL, Nisemblat Y, Galipeau HJ, Jury J, Tabakman R, Cohen A, et al. BL-7010 demonstrates specific binding to gliadin and reduces gluten-associated pathology in a chronic mouse model of gliadin sensitivity. PLoS One. 2014;9(11):e0109972. https://doi.org/10.1371/journal.pone.0109972 PMid:25365555 DOI: https://doi.org/10.1371/journal.pone.0109972

Ribeiro M, Picascia S, Rhazi L, Gianfrani C, Carrillo J, Rodriguez-Quijano M, et al. In situ gluten-chitosan interlocked self-assembled supramolecular architecture reduces T-cell- mediated immune response to gluten in celiac disease. Mol Nutr Food Res. 2018;62(23):e1800646. https://doi.org/10.1002/mnfr.201800646 PMid:30289620 DOI: https://doi.org/10.1002/mnfr.201800646

Olivares M, Laparra M, Sanz Y. Influence of Bifidobacterium longum CECT 7347 and gliadin peptides on intestinal epithelial cell proteome. J Agric Food Chem. 2011;59(14):7666-671. https://doi.org/10.1021/jf201212m DOI: https://doi.org/10.1021/jf201212m

McCarville A, Dong J, Caminero A, Bermudez-Brito M, Jury J, Murray JA, et al. Commensal Bifidobacterium longum strain prevents gluten-related immunopathology in mice through expression of a serine protease inhibitor. J Appl Environ Microbiol. 2017;83(19):e01323. https://doi.org/10.1128/AEM.01323-17 PMid:28778891 DOI: https://doi.org/10.1128/AEM.01323-17

D’Arienzo R, Maurano F, Lavermicocca P, Ricca E, Rossi M. Modulation of the immune response by probiotic strains in a mouse model of gluten sensitivity. Cytokine. 2009;48(3):254-9. https://doi.org/10.1016/j.cyto.2009.08.003 PMid:19736022 DOI: https://doi.org/10.1016/j.cyto.2009.08.003

Smecuol E, Hwang HJ, Sugai E, Corso L, Cherñavsky AC, Bellavite FP, et al. Exploratory, randomized, double-blind, placebo-controlled study on the effects of Bifidobacterium infantis Natren life start strain super strain in active celiac disease. J Clin Gastroenterol. 2013;47(2):139-47. https://doi.org/10.1097/MCG.0b013e31827759ac PMid:23314670 DOI: https://doi.org/10.1097/MCG.0b013e31827759ac

Olivares M, Castillejo G, Varea V, Sanz Y. Double-blind, randomized, placebo controlled intervention trial to evaluate the effects of Biofidobacterium longm CECT 7347 in children with newly diagnosed coeliac disease. Br J Nutr. 2014;112(1):30-40. https://doi.org/10.1017/S0007114514000609 PMid:24774670 DOI: https://doi.org/10.1017/S0007114514000609

Klemenak M, Dolinšek J, Langerholc T, Di Gioia D, Mičetić- Turk D. Administration of Bifidobacterium breve decreases the production of TNF-α in children with celiac disease. Dig Dis Sci. 2015;60(11):3386-92. https://doi.org/10.1007/s10620-015-3769-7 PMid:26134988 DOI: https://doi.org/10.1007/s10620-015-3769-7

Quagliariello A, Cionci NB, Luiselli D, D’Auria G, Martinez- Priego L, Pérez-Villarroya D, et al. Effect of Bifidobacterium breve on the intestinal microbiota of coeliac children on a gluten free diet: A pilot study. Nutrients. 2016;8(10):660. https://doi.org/10.3390/nu8100660 PMid:27782071 DOI: https://doi.org/10.3390/nu8100660

Harnett J, Myers SP, Rolfe M. Probiotics and the microbiome in celiac disease: A randomised controlled trial. Evid Based Complement Altern Med. 2016;2016:9048574. https://doi.org/10.1155/2016/9048574 PMid:27525027 DOI: https://doi.org/10.1155/2016/9048574

Pinto-Sánchez MI, Smecuol EC, Temprano MP, Sugai E, González A, Moreno ML, et al. Bifidobacterium infantis NLS Super strain reduces the expression of α-defensin-5, a marker of innate immunity, in the mucosa of active celiac disease patients. J Clin Gastroenterol. 2017;51(9):814-7. https://doi.org/10.1097/MCG.0000000000000687 PMid:27636409 DOI: https://doi.org/10.1097/MCG.0000000000000687

Primec M, Klemenak M, Di Gioia D, Aloisio I, Cionci NB, Quagliariello A, et al. Clinical intervention using Bifidobacterium strains in celiac disease children reveals novel microbial modulators of TNF-α and short-chain fatty acids. Clin Nutr. 2019;38(3):1373-81. https://doi.org/10.1016/j.clnu.2018.06.931 PMid:29960810 DOI: https://doi.org/10.1016/j.clnu.2018.06.931

Francavilla R, Piccola M, Francavilla A, Polimeno L, Semeraro F, Cristofori F, et al. Clinical and microbiological effect of a multispecies probiotic supplementation in celiac patients with persistent IBS-type symptoms: A randomized, double-blind, placebo-controlled, multicenter trial. J Clin Gastroenterol. 2019;53(3):e117-25. https://doi.org/10.1097/MCG.0000000000001023 PMid:29688915 DOI: https://doi.org/10.1097/MCG.0000000000001023

Martinello F, Roman CM, de Souza PA. Effects of probiotic intake on intestinal bifidobacteria of celiac patients. Arq Gastroenterol. 2017;54:85-90. https://doi.org/10.1590/s0004-2803.201700000-07 DOI: https://doi.org/10.1590/s0004-2803.201700000-07

Uusitalo U, Aronsson CA, Liu X, Kurppa K, Yang J, Liu E, et al. Early probiotic supplementation and the risk of celiac disease in children at genetic risk. Nutrients. 2019;11(8):1790. https://doi.org/10.3390/nu11081790 PMid:31382440 DOI: https://doi.org/10.3390/nu11081790

Hewitson JP, Grainger JR, Maizels RM. Helminth immunoregulation: The role of parasite secreted proteins in modulating host immunity. 2009;167(1):1-11. https://doi.org/10.1016/j.molbiopara.2009.04.008 PMid:19406170 DOI: https://doi.org/10.1016/j.molbiopara.2009.04.008

Marco G, La Rotta A, Rodriguez A, Baeza M. Effectiveness of helminths in two different mice strains in a murine model of anaphylaxis. J Allergy Clin Immunol. 2022;127(2):AB246. https://doi.org/10.1016/j.jaci.2010.12.979 DOI: https://doi.org/10.1016/j.jaci.2010.12.979

Daveson AJ, Jones DM, Gaze S, McSorley H, Clouston A, Pascoe A, et al. Effect of hookworm infection on wheat challenge in celiac disease--a randomised double-blinded placebo controlled trial. PLoS One. 2011;6(3):e17366. https://doi.org/10.1371/journal.pone.0017366 PMid:21408161 DOI: https://doi.org/10.1371/journal.pone.0017366

Bernardo D, Martinez-Abad B, Vallejo-Diez S, Montalvillo E, Benito V, Anta B, et al. Ascorbate-dependent decrease of the mucosal immune inflammatory response to gliadin in coeliac disease patients. Allergol Immunopathol (Madr). 2012;40(1):3-8. https://doi.org/10.1016/j.aller.2010.11.003 PMid:21420224 DOI: https://doi.org/10.1016/j.aller.2010.11.003

Yokoyama S, Watanabe N, Sato N, Perera PY, Filkoski L, Tanaka T, et al. Antibody-mediated blockade of IL-15 reverses the autoimmune intestinal damage in transgenic mice that overexpress IL-15 in enterocytes. Proc NatlAcad Sci USA. 2009;106(37):15849-54. https://doi.org/10.1073/pnas.0908834106 PMid:19805228 DOI: https://doi.org/10.1073/pnas.0908834106

Malamut G, El Machhour R, Montcuquet N, Martin-Lanneree S, Dusanter-Fourt I, Verkarre V, 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(6):2131-43. https://doi.org/10.1172/JCI41344 PMid:20440074 DOI: https://doi.org/10.1172/JCI41344

Rauhavirta T, Oittinen M, Kivisto R, Mannisto PT, Garcia- Horsman JA, Wang Z, et al. Are transglutaminase 2 inhibitors able to reduce gliadin-induced toxicity related to celiac disease? A proof-of-concept study. J Clin Immunol. 2012;33(1):134-42. https://doi.org/10.1007/s10875-012-9745-5 PMid:22878839 DOI: https://doi.org/10.1007/s10875-012-9745-5

Gopalakrishnan S, Durai M, Kitchens K, Tamiz AP, Somerville R, Ginski M, et al. Larazotide acetate regulates epithelial tight junctions in vitro and in vivo. Peptides. 2012;35(1):86-94. https://doi.org/10.1016/j.peptides.2012.02.015 PMid:22401908 DOI: https://doi.org/10.1016/j.peptides.2012.02.015

Schuppan D, Mäki M, Lundin KE, Isola J, Friesing-Sosnik T, Taavela J, et al. A randomized trial of a transglutaminase 2 inhibitor for celiac disease. N Engl J Med. 2021;385:35-45. DOI: https://doi.org/10.1056/NEJMoa2032441

Paterson BM, Lammers KM, Arrieta MC, Fasano A, Meddings JB. The safety, tolerance, pharmacokinetic and pharmacodynamic effects of single doses of AT-1001 in coeliac disease subjects: A proof of concept study. Aliment Pharmacol Ther. 2007;26(5):757-66. https://doi.org/10.1111/j.1365-2036.2007.03413.x PMid:17697209 DOI: https://doi.org/10.1111/j.1365-2036.2007.03413.x

A Double-blind Placebo-controlled Study to Evaluate Larazotide Acetate for the Treatment of Celiac Disease. Alba Therapeutics. Bethesda (MD): National Library of Medicine (US). Available from: https://www.clinicaltrials.gov/ct2/show/NCT01396213 [Last accessed on 2022 Jun 26].

Di Sabatino А, Lenti MV, Corazza GR, Gianfrani C. Vaccine immunotherapy for celiac disease. Front Med (Lausanne). 2018;5:187. https://doi.org/10.3389/fmed.2018.00187 PMid:29998106 DOI: https://doi.org/10.3389/fmed.2018.00187

Goel G, Mayassi T, Qiao SW, Ciszewski C, King T, Daveson AJ, et al. Sa1396 a single intradermal (ID) injection of nexvax2®, a peptide composition with dominant epitopes for gluten-reactive CD4+ T cells, activates T cells and triggers acute gastrointestinal symptoms in HLA-DQ2.5+people with celiac disease (CeD). Gastroenterology. 2016;150(4):S304. https://doi.org/10.1016/s0016-5085(16)31065-4 DOI: https://doi.org/10.1016/S0016-5085(16)31065-4

Murray JA, Kelly CP, Green PH, Marcantonio A, Wu TT, Mäki M, et al. No difference between latiglutenase and placebo in reducing villous atrophy or improving symptoms in patients with symptomatic celiac disease. Gastroenterology. 2017;152(4):787-98.e2. https://doi.org/10.1053/j.gastro.2016.11.004 PMid:27864127 DOI: https://doi.org/10.1053/j.gastro.2016.11.004

Popa SL, Chiarioni G. Anti-IL-15 monoclonal antibody for the treatment of coeliac disease: The light at the end of the gluten free diet tunnel? Dig Med Res. 2020;3:107-110. https://doi.org/10.21037/dmr-20-28 DOI: https://doi.org/10.21037/dmr-20-28

Anderson RP, Jabri B. Vaccine against autoimmune disease: Antigen-specific immunotherapy. Curr Opin Immunol. 2013;25(3):410-7. https://doi.org/10.1016/j.coi.2013.02.004 PMid:23478068 DOI: https://doi.org/10.1016/j.coi.2013.02.004