Coeliac disease is a common enteropathy that occurs in genetically susceptible individuals in response to the ingestion of gluten proteins present in wheat, rye and barley. Currently, the only available treatment for the condition is a strict, life-long gluten-free diet that, despite being safe and often effective, is associated with several challenges. Due to the high cost, particularly restrictive nature and perception of decreased quality of life associated with the diet, some patients are continuously exposed to gluten, which prevents an adequate disease control. Moreover, a subgroup of patients does not respond to the diet adequately, and healing of the small-bowel mucosa can be incomplete. Thus, there is a need for alternative treatment forms. The increasingly understood pathogenetic process of coeliac disease has enabled the identification of various targets for future therapies. Multiple investigational therapies ranging from tolerogenic to immunological approaches are in the pipeline, and several drug candidates have entered phase II/III clinical trials. This Review gives a broad overview of the different investigative treatment modalities for coeliac disease and summarizes the latest advances in this field.
At present, a gluten-free diet is the only effective treatment for coeliac disease but is associated with several possible challenges, including a high economic and societal burden, inferior quality of life and sometimes inadequate response.
An increased understanding of the pathogenetic process in coeliac disease has revealed various therapeutic targets for future drugs that could complement or replace a gluten-free diet.
Novel therapeutic strategies include approaches to detoxify gluten already in the gastrointestinal tract by sequestrants or peptidases.
Other investigational approaches comprise blocking intestinal epithelial permeability or the enzymatic activity of transglutaminase 2.
Restoring immune tolerance to gluten or targeting the gluten-induced immune activation has also been investigated as possible therapeutic options.
The most advanced drug candidates have now entered phase III clinical trials.
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Singh, P. et al. Global prevalence of celiac disease: systematic review and meta-analysis. Clin. Gastroenterol. Hepatol. 16, 823–836.e2 (2018).
Ludvigsson, J. F. et al. The Oslo definitions for coeliac disease and related terms. Gut 62, 43–52 (2013).
Tye-Din, J. A., Galipeau, H. J. & Agardh, D. Celiac disease: a review of current concepts in pathogenesis, prevention, and novel therapies. Front. Pediatr. 6, 350 (2018).
Al-Toma, A. et al. European society for the study of coeliac disease (ESsCD) guideline for coeliac disease and other gluten-related disorders. United European Gastroenterol. J. 7, 583–613 (2019).
Husby, S., Murray, J. A. & Katzka, D. A. AGA clinical practice update on diagnosis and monitoring of celiac disease - changing utility of serology and histologic measures: expert review. Gastroenterology 156, 885–889 (2019).
Baggus, E. M. R. et al. How to manage adult coeliac disease: perspective from the NHS England rare diseases collaborative network for non-responsive and refractory coeliac disease. Frontline Gastroenterol. 11, 235–242 (2019).
Hall, N. J., Rubin, G. & Charnock, A. Systematic review: adherence to a gluten-free diet in adult patients with coeliac disease. Aliment. Pharmacol. Ther. 30, 315–330 (2009).
Weisbrod, V. M. et al. A quantitative assessment of gluten cross-contact in the school environment for children with celiac disease. J. Pediatr. Gastroenterol. Nutr. 70, 289–294 (2020).
Lee, A., Wolf, R., Lebwohl, B., Ciaccio, E. & Green, P. Persistent economic burden of the gluten free diet. Nutrients 11, 399 (2019).
Shah, S. et al. Patient perception of treatment burden is high in celiac disease compared with other common conditions. Am. J. Gastroenterol. 109, 1304–1311 (2014).
Daveson, A. J. M. et al. Baseline quantitative histology in therapeutics trials reveals villus atrophy in most patients with coeliac disease who appear well controlled on gluten-free diet. GastroHep 2, 22–30 (2020).
Lebwohl, B. et al. Mucosal healing and risk for lymphoproliferative malignancy in celiac disease: a population-based cohort study. Ann. Intern. Med. 159, 169–175 (2013).
Shan, L. et al. Structural basis for gluten intolerance in celiac sprue. Science 297, 2275–2279 (2002).
Dieterich, W. et al. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat. Med. 3, 797–801 (1997).
Cardoso-Silva, D. et al. Intestinal barrier function in gluten-related disorders. Nutrients 11, 2325 (2019).
Moreno, M. et al. Detection of gluten immunogenic peptides in the urine of patients with coeliac disease reveals transgressions in the gluten-free diet and incomplete mucosal healing. Gut 66, 250–257 (2017).
Iversen, R. et al. Evidence that pathogenic transglutaminase 2 in celiac disease derives from enterocytes. Gastroenterology https://doi.org/10.1053/j.gastro.2020.04.018 (2020).
Molberg, O. et al. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat. Med. 4, 713–717 (1998).
Kuja-Halkola, R. et al. Heritability of non-HLA genetics in coeliac disease: a population-based study in 107 000 twins. Gut 65, 1793–1798 (2016).
Sollid, L. M. et al. Update 2020: nomenclature and listing of celiac disease-relevant gluten epitopes recognized by CD4+ T cells. Immunogenetics 72, 85–88 (2020).
Hardy, M. Y. et al. Characterisation of clinical and immune reactivity to barley and rye ingestion in children with coeliac disease. Gut 69, 830–840 (2020).
Tye-Din, J. A. et al. Comprehensive, quantitative mapping of T cell epitopes in gluten in celiac disease. Sci. Transl Med. 2, 41ra51 (2010).
du Pré, M. F. et al. B cell tolerance and antibody production to the celiac disease autoantigen transglutaminase 2. J. Exp. Med. 217, e20190860 (2020).
Di Sabatino, A. et al. Epithelium derived interleukin 15 regulates intraepithelial lymphocyte Th1 cytokine production, cytotoxicity, and survival in coeliac disease. Gut 55, 469–477 (2006).
Abadie, V. et al. IL-15, gluten and HLA-DQ8 drive tissue destruction in coeliac disease. Nature 578, 600–604 (2020).
Bouziat, R. et al. Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease. Science 356, 44–50 (2017).
Caminero, A. et al. Duodenal bacterial proteolytic activity determines sensitivity to dietary antigen through protease-activated receptor-2. Nat. Commun. 10, 1198 (2019).
Kemppainen, K. M. et al. Factors that increase risk of celiac disease autoimmunity after a gastrointestinal infection in early life. Clin. Gastroenterol. Hepatol. 15, 694–702.e5 (2017).
Lindfors, K. et al. Metagenomics of the faecal virome indicate a cumulative effect of enterovirus and gluten amount on the risk of coeliac disease autoimmunity in genetically at risk children: the TEDDY study. Gut 69, 1416–1422 (2019).
Kahrs, C. R. et al. Enterovirus as trigger of coeliac disease: nested case-control study within prospective birth cohort. BMJ 364, l231 (2019).
Caminero, A., Meisel, M., Jabri, B. & Verdu, E. F. Mechanisms by which gut microorganisms influence food sensitivities. Nat. Rev. Gastroenterol. Hepatol. 16, 7–18 (2019).
Kasarda, D. D. Can an increase in celiac disease be attributed to an increase in the gluten content of wheat as a consequence of wheat breeding? J. Agric. Food Chem. 61, 1155–1159 (2013).
García-Molina, M., Giménez, M., Sánchez-León, S. & Barro, F. Gluten free wheat: are we there? Nutrients 11, 487 (2019).
Hujoel, I. A. & Murray, J. A. Refractory celiac disease. Curr. Gastroenterol. Rep. 22, 18 (2020).
Silvester, J. A. et al. Most patients with celiac disease on gluten-free diets consume measurable amounts of gluten. Gastroenterology 158, 1497–1499.e1 (2019).
Lerner, B. A. et al. Detection of gluten in gluten-free labeled restaurant food: analysis of crowd-sourced data. Am. J. Gastroenterol. 114, 792–797 (2019).
Viitasalo, L. et al. Microbial biomarkers in patients with nonresponsive celiac disease. Dig. Dis. Sci. 63, 3434–3441 (2018).
Garber, M. E. et al. A B-cell gene signature correlates with the extent of gluten-induced intestinal injury in celiac disease. Cell. Mol. Gastroenterol. Hepatol. 4, 1–17 (2017).
Catassi, C. et al. A prospective, double-blind, placebo-controlled trial to establish a safe gluten threshold for patients with celiac disease. Am. J. Clin. Nutr. 85, 160–166 (2007).
Lähdeaho, M.-L., Mäki, M., Laurila, K., Huhtala, H. & Kaukinen, K. Small-bowel mucosal changes and antibody responses after low- and moderate-dose gluten challenge in celiac disease. BMC Gastroenterol. 11, 129 (2011).
Thompson, T., Dennis, M., Higgins, L. A., Lee, A. R. & Sharrett, M. K. Gluten-free diet survey: are Americans with coeliac disease consuming recommended amounts of fibre, iron, calcium and grain foods? J. Hum. Nutr. Diet. 18, 163–169 (2005).
Di Nardo, G. et al. Nutritional deficiencies in children with celiac disease resulting from a gluten-free diet: a systematic review. Nutrients 11, 1588 (2019).
Raehsler, S. L., Choung, R. S., Marietta, E. V. & Murray, J. A. Accumulation of heavy metals in people on a gluten-free diet. Clin. Gastroenterol. Hepatol. 16, 244–251 (2018).
Kabbani, T. A. et al. Body mass index and the risk of obesity in coeliac disease treated with the gluten-free diet. Aliment. Pharmacol. Ther. 35, 723–729 (2012).
Singh, J. & Whelan, K. Limited availability and higher cost of gluten-free foods. J. Hum. Nutr. Diet. 24, 479–486 (2011).
Mårild, K. et al. Celiac disease and anorexia nervosa: a nationwide study. Pediatrics 139, e20164367 (2017).
Silvester, J. A., Weiten, D., Graff, L. A., Walker, J. R. & Duerksen, D. R. Living gluten-free: adherence, knowledge, lifestyle adaptations and feelings towards a gluten-free diet. J. Hum. Nutr. Diet. 29, 374–382 (2016).
Zingone, F. et al. Psychological morbidity of celiac disease: a review of the literature. U Eur. Gastroenterol. J. 3, 136–145 (2015).
König, J., Holster, S., Bruins, M. J. & Brummer, R. J. Randomized clinical trial: Effective gluten degradation by Aspergillus niger-derived enzyme in a complex meal setting. Sci. Rep. 7, 13100 (2017).
Daveson, A. J. et al. Effect of hookworm infection on wheat challenge in celiac disease–a randomised double-blinded placebo controlled trial. PLoS ONE 6, e17366 (2011).
Mansikkka, E. et al. Gluten challenge induces skin and small-bowel relapse in long-term gluten-free diet -treated dermatitis herpetiformis. J. Invest. Dermatol. 139, 2108–2114 (2019).
Daveson, A. J. M. et al. Masked bolus gluten challenge low in FODMAPs implicates nausea and vomiting as key symptoms associated with immune activation in treated coeliac disease. Aliment. Pharmacol. Ther. 51, 244–252 (2020).
Ludvigsson, J. F. et al. Outcome measures in coeliac disease trials: the Tampere recommendations. Gut 67, 1410–1424 (2018).
McCambridge, J., Witton, J. & Elbourne, D. R. Systematic review of the Hawthorne effect: New concepts are needed to study research participation effects. J. Clin. Epidemiol. 67, 267–277 (2014).
Gopalakrishnan, S. et al. Larazotide acetate regulates epithelial tight junctions in vitro and in vivo. Peptides 35, 86–94 (2012).
Paterson, B. M., Lammers, K. M., Arrieta, M. C., Fasano, A. & Meddings, J. B. 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. 26, 757–766 (2007).
Leffler, D. A. et al. A randomized, double-blind study of larazotide acetate to prevent the activation of celiac disease during gluten challenge. Am. J. Gastroenterol. 107, 1554–1562 (2012).
Kelly, C. P. et al. Larazotide acetate in patients with coeliac disease undergoing a gluten challenge: a randomised placebo-controlled study. Aliment. Pharmacol. Ther. 37, 252–262 (2013).
Leffler, D. A. et al. Larazotide acetate for persistent symptoms of celiac disease despite a gluten-free diet: a randomized controlled trial. Gastroenterology 148, 1311–9.e6 (2015).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03569007 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00620451 (2017).
Cavaletti, L. et al. E40, a novel microbial protease efficiently detoxifying gluten proteins, for the dietary management of gluten intolerance. Sci. Rep. 9, 13147 (2019).
Rey, M. et al. Addressing proteolytic efficiency in enzymatic degradation therapy for celiac disease. Sci. Rep. 6, 30980 (2016).
Tye-Din, J. A. et al. The effects of ALV003 pre-digestion of gluten on immune response and symptoms in celiac disease in vivo. Clin. Immunol. 134, 289–295 (2010).
Wolf, C. et al. Engineering of Kuma030: a gliadin peptidase that rapidly degrades immunogenic gliadin peptides in gastric conditions. J. Am. Chem. Soc. 137, 13106–13113 (2015).
Bethune, M. T. & Khosla, C. Oral enzyme therapy for celiac sprue. Methods Enzymol. 502, 241–271 (2012).
Mitea, C. et al. Efficient degradation of gluten by a prolyl endoprotease in a gastrointestinal model: implications for coeliac disease. Gut 57, 25–32 (2008).
Tack, G. J. et al. Consumption of gluten with gluten-degrading enzyme by celiac patients: a pilot-study. World J. Gastroenterol. 19, 5837–5847 (2013).
Salden, B. N. et al. Randomised clinical study: Aspergillus niger-derived enzyme digests gluten in the stomach of healthy volunteers. Aliment. Pharmacol. Ther. 42, 273–285 (2015).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00810654 (2011).
Ehren, J. et al. A food-grade enzyme preparation with modest gluten detoxification properties. PLoS ONE 4, e6313 (2009).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00962182 (2018).
Korponay-Szabó, I. R. et al. Food-grade gluten degrading enzymes to treat dietary transgressions in coeliac adolescents. J. Pediatr. Gastroenterol. Nutr. 50, E68 (2010).
Gass, J., Bethune, M. T., Siegel, M., Spencer, A. & Khosla, C. Combination enzyme therapy for gastric digestion of dietary gluten in patients with celiac sprue. Gastroenterology 133, 472–480 (2007).
Siegel, M. et al. Safety, tolerability, and activity of ALV003: results from two phase 1 single, escalating-dose clinical trials. Dig. Dis. Sci. 57, 440–450 (2012).
Lähdeaho, M.-L. et al. Glutenase ALV003 attenuates gluten-induced mucosal injury in patients with celiac disease. Gastroenterology 146, 1649–1658 (2014).
Murray, J. et al. No difference between latiglutenase and placebo in reducing villous atrophy or improving symptoms in patients with symptomatic celiac disease. Gastroenterology 152, 787–798.e2 (2017).
Syage, J. A., Murray, J. A., Green, P. H. R. & Khosla, C. Latiglutenase improves symptoms in seropositive celiac disease patients while on a gluten-free diet. Dig. Dis. Sci. 62, 2428–2432 (2017).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03585478 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04243551 (2020).
Lähdeaho, M.-L. et al. Safety and efficacy of AMG 714 in adults with coeliac disease exposed to gluten challenge: a phase 2a, randomised, double-blind, placebo-controlled study. Lancet Gastroenterol. Hepatol. 4, 948–959 (2019).
Cellier, C. et al. Safety and efficacy of AMG 714 in patients with type 2 refractory coeliac disease: a phase 2a, randomised, double-blind, placebo-controlled, parallel-group study. Lancet Gastroenterol. Hepatol. 4, 960–970 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04424927 (2020).
Waldmann, T. A. The biology of IL-15: implications for cancer therapy and the treatment of autoimmune disorders. J. Investig. Dermatol. Symp. Proc. 16, S28–S30 (2013).
Ciszewski, C. et al. Identification of a γc receptor antagonist that prevents reprogramming of human tissue-resident cytotoxic t cells by IL15 and IL21. Gastroenterology 158, 625–637.e13 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01893775 (2020).
Yokoyama, S., Perera, P.-Y., Waldmann, T. A., Hiroi, T. & Perera, L. P. Tofacitinib, a janus kinase inhibitor demonstrates efficacy in an IL-15 transgenic mouse model that recapitulates pathologic manifestations of celiac disease. J. Clin. Immunol. 33, 586–594 (2013).
EU Clinical Trials Register. ClinicalTrialsRegister.eu https://www.clinicaltrialsregister.eu/ctr-search/search?query=2018-001678-10 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00540657 (2008).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04524221 (2020).
Tato, M. et al. Cathepsin S inhibition combines control of systemic and peripheral pathomechanisms of autoimmune tissue injury. Sci. Rep. 7, 2775 (2017).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02679014 (2017).
Abraham, M. et al. In vitro induction of regulatory T cells by anti-CD3 antibody in humans. J. Autoimmun. 30, 21–28 (2008).
Høydahl, L. S., Frick, R., Sandlie, I. & Løset, G. Å. Targeting the MHC ligandome by use of TCR-like antibodies. Antibodies 8, 32 (2019).
Carballido, J. M. & Santamaria, P. Taming autoimmunity: Translating antigen-specific approaches to induce immune tolerance. J. Exp. Med. 216, 247–250 (2019).
Christophersen, A., Risnes, L. F., Dahal-Koirala, S. & Sollid, L. M. Therapeutic and diagnostic implications of t cell scarring in celiac disease and beyond. Trends Mol. Med. 25, 836–852 (2019).
Risnes, L. F. et al. Disease-driving CD4+ T cell clonotypes persist for decades in celiac disease. J. Clin. Invest. 128, 2642–2650 (2018).
Goel, G. et al. Epitope-specific immunotherapy targeting CD4-positive T cells in coeliac disease: two randomised, double-blind, placebo-controlled phase 1 studies. Lancet. Gastroenterol. Hepatol. 2, 479–493 (2017).
Daveson, A. J. M. et al. Epitope-specific immunotherapy targeting CD4-positive T cells in celiac disease: safety, pharmacokinetics, and effects on intestinal histology and plasma cytokines with escalating dose regimens of Nexvax2 in a Randomized, double-blind, placebo-controlled. EBioMedicine 26, 78–90 (2017).
Goel, G. et al. Cytokine release and gastrointestinal symptoms after gluten challenge in celiac disease. Sci. Adv. 5, eaaw7756 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03644069 (2019).
Truitt, K. E. & Anderson, R. P. Editorial: a non-dietary treatment for coeliac disease-two steps forward, one step back? Authors’ reply. Aliment. Pharmacol. Ther. 50, 956–957 (2019).
Freitag, T. L. et al. Gliadin nanoparticles induce immune tolerance to gliadin in mouse models of celiac disease. Gastroenterology 158, 1667–1681.e12 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03486990 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03738475 (2020).
Kelly, C. et al. CNP-101 prevents gluten challenge-induced immune activation in adults with celiac disease [abstract]. United Eur. Gastroenterol. J. 7, 1421 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04530123 (2020).
Clemente-Casares, X. et al. Expanding antigen-specific regulatory networks to treat autoimmunity. Nature 530, 434–440 (2016).
Grimm, A. J., Kontos, S., Diaceri, G., Quaglia-Thermes, X. & Hubbell, J. A. Memory of tolerance and induction of regulatory T cells by erythrocyte-targeted antigens. Sci. Rep. 5, 15907 (2015).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04248855 (2020).
Elliot, D. E. & Weinstock, J. V. Where are we on worms? Curr. Opin. Gastroenterol. 28, 551–556 (2012).
Croese, J. et al. Experimental hookworm infection and gluten microchallenge promote tolerance in celiac disease. J. Allergy Clin. Immunol. 135, 508–516 (2015).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02754609 (2020).
Sulic, A.-M., Kurppa, K., Rauhavirta, T., Kaukinen, K. & Lindfors, K. Transglutaminase as a therapeutic target for celiac disease. Expert Opin. Ther. Targets 19, 335–348 (2015).
Klöck, C. & Khosla, C. Regulation of the activities of the mammalian transglutaminase family of enzymes. Protein Sci. 21, 1781–1791 (2012).
Molberg, Ø. et al. T cells from celiac disease lesions recognize gliadin epitopes deamidated in situ by endogenous tissue transglutaminase. Eur. J. Immunol. 31, 1317–1323 (2001).
Maiuri, L. et al. Unexpected role of surface transglutaminase type II in celiac disease. Gastroenterology 129, 1400–1413 (2005).
Rauhavirta, T. et al. Epithelial transport and deamidation of gliadin peptides: a role for coeliac disease patient immunoglobulin A. Clin. Exp. Immunol. 164, 127–136 (2011).
Lebreton, C. et al. Interactions among secretory immunoglobulin A, CD71, and transglutaminase-2 affect permeability of intestinal epithelial cells to gliadin peptides. Gastroenterology 143, 698–707.e4 (2012).
Ventura, M. A. E. et al. Su1161 - The oral transglutaminase 2 (TG2) inhibitor Zed1227 blocks TG2 activity in a mouse model of intestinal inflammation [Abstract]. Gastroenterology 154, S-490 (2018).
EU Clinical Trials Register. ClinicalTrialsRegister.eu https://www.clinicaltrialsregister.eu/ctr-search/search?query=2017-002241-30 (2017).
Stamnaes, J., Pinkas, D. M., Fleckenstein, B., Khosla, C. & Sollid, L. M. Redox regulation of transglutaminase 2 activity. J. Biol. Chem. 285, 25402–25409 (2010).
Palanski, B. A. & Khosla, C. Cystamine and disulfiram inhibit human transglutaminase 2 via an oxidative mechanism. Biochemistry 57, 3359–3363 (2018).
Gujral, N., Löbenberg, R., Suresh, M. & Sunwoo, H. In-vitro and in-vivo binding activity of chicken egg yolk immunoglobulin Y (IgY) against gliadin in food matrix. J. Agric. Food Chem. 60, 3166–3172 (2012).
Sample, D. A. et al. AGY, a novel egg yolk-derived anti-gliadin antibody, is safe for patients with celiac disease. Dig. Dis. Sci. 62, 1277–1285 (2017).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03707730 (2019).
Stadlmann, V. et al. Novel avian single-chain fragment variable (scFv) targets dietary gluten and related natural grain prolamins, toxic entities of celiac disease. BMC Biotechnol. 15, 109 (2015).
Liang, L., Pinier, M., Leroux, J.-C. & Subirade, M. Interaction of alpha-gliadin with poly(HEMA-co-SS): structural characterization and biological implication. Biopolymers 91, 169–178 (2009).
McCarville, J. L. et al. BL-7010 demonstrates specific binding to gliadin and reduces gluten-associated pathology in a chronic mouse model of gliadin sensitivity. PLoS ONE 9, e109972 (2014).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01990885 (2017).
Caminero, A. et al. Duodenal bacteria from patients with celiac disease and healthy subjects distinctly affect gluten breakdown and immunogenicity. Gastroenterology 151, 670–683 (2016).
Hiippala, K. et al. The potential of gut commensals in reinforcing intestinal barrier function and alleviating inflammation. Nutrients 10, 988 (2018).
Abdel-Gadir, A. et al. Microbiota therapy acts via a regulatory T cell MyD88/RORγt pathway to suppress food allergy. Nat. Med. 25, 1164–1174 (2019).
McCarville, J. L. et al. A commensal Bifidobacterium longum strain prevents gluten-related immunopathology in mice through expression of a serine protease inhibitor. Appl. Environ. Microbiol. 83, e01323–17 (2017).
Papista, C. 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, 625–635 (2012).
Huibregtse, I. L. et al. Induction of antigen-specific tolerance by oral administration of Lactococcus lactis delivered immunodominant DQ8-restricted gliadin peptide in sensitized nonobese diabetic Abo Dq8 transgenic mice. J. Immunol. 183, 2390–2396 (2009).
Olivares, M., Castillejo, G., Varea, V. & Sanz, Y. Double-blind, randomised, placebo-controlled intervention trial to evaluate the effects of Bifidobacterium longum CECT 7347 in children with newly diagnosed coeliac disease. Br. J. Nutr. 112, 30–40 (2014).
Quagliariello, A. et al. Effect of Bifidobacterium breve on the intestinal microbiota of coeliac children on a gluten free diet: a pilot study. Nutrients 8, 660 (2016).
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. 60, 3386–3392 (2015).
Primec, M. 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. 38, 1373–1381 (2019).
Harnett, J., Myers, S. P. & Rolfe, M. Probiotics and the microbiome in celiac disease: a randomised controlled trial. Evid. Based Complement. Alternat. Med. 2016, 9048574 (2016).
Francavilla, R. 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. 53, e117–e125 (2019).
Smecuol, E. 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. 47, 139–147 (2013).
Pinto-Sánchez, M. I. 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. 51, 814–817 (2017).
Vriezinga, S. L. et al. Randomized feeding intervention in infants at high risk for celiac disease. N. Engl. J. Med. 371, 1304–1315 (2014).
Lionetti, E. et al. Introduction of gluten, HLA status, and the risk of celiac disease in children. N. Engl. J. Med. 371, 1295–1303 (2014).
Håkansson, Å. et al. Effects of Lactobacillus plantarum and Lactobacillus paracasei on the peripheral immune response in children with celiac disease autoimmunity: a randomized, double-blind, placebo-controlled clinical trial. Nutrients 11, 1925 (2019).
Uusitalo, U. et al. Early probiotic supplementation and the risk of celiac disease in children at genetic risk. Nutrients 11, 1790 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03562221 (2020).
The authors thank the Academy of Finland and the Sigrid Juselius Foundation (K.L.), Emil Aaltonen foundation and the Finnish-Norwegian Medical Foundation (L.K.), the National Health and Medical Research Council of Australia (NHMRC, Investigator Grant APP1176553), and the Mathison Centenary Fellowship, University of Melbourne (J.T.-D.). A.C. holds a Paul Douglas chair in intestinal research.
L.K. reports personal fees for lectures from the Finnish Coeliac Society outside the submitted work and participation in the AMG 714 trial. D.A.L. is the Medical Director for Takeda Pharmaceuticals. J.T.-D. is an inventor of patents pertaining to the use of gluten-derived T cell epitopes for use in coeliac disease therapeutics and was an investigator in the Nexvax2 phase II trial. The other authors declare no competing interests.
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Kivelä, L., Caminero, A., Leffler, D.A. et al. Current and emerging therapies for coeliac disease. Nat Rev Gastroenterol Hepatol (2020). https://doi.org/10.1038/s41575-020-00378-1