Turnbull, J. L., Adams, H. N. & Gorard, D. A. Review article: the diagnosis and management of food allergy and food intolerances. Aliment. Pharmacol. Ther. 41, 3–25 (2015).
Rubio-Tapia, A. et al. Increased prevalence and mortality in undiagnosed celiac disease. Gastroenterology 137, 88–93 (2009).
Tang, M. L. & Mullins, R. J. Food allergy: is prevalence increasing? Internal Med. J. 47, 256–261 (2017).
Verdu, E. F., Galipeau, H. J. & Jabri, B. Novel players in coeliac disease pathogenesis: role of the gut microbiota. Nat. Rev. Gastroenterol. Hepatol. 12, 497–506 (2015).
Bouziat, R. et al. Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease. Science 356, 44–50 (2017). This study provides support for the concept that viruses can disrupt intestinal immune homeostasis and initiate loss of oral tolerance and T helper 1 cell immunity to dietary antigen.
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). This study shows that the intestinal microbiota has a dual effect in gluten metabolism in vivo, increasing or reducing gluten immunogenicity.
Smith, P. M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013).
McCarville, J. L., Caminero, A. & Verdu, E. F. Novel perspectives on therapeutic modulation of the gut microbiota. Ther. Adv. Gastroenterol. 9, 580–593 (2016).
Lomer, M. C., Parkes, G. C. & Sanderson, J. D. Review article: lactose intolerance in clinical practice — myths and realities. Aliment. Pharmacol. Ther. 27, 93–103 (2008).
Saito, Y. A., Locke, G. R. 3rd, Weaver, A. L., Zinsmeister, A. R. & Talley, N. J. Diet and functional gastrointestinal disorders: a population-based case-control study. Am. J. Gastroenterol. 100, 2743–2748 (2005).
Moayyedi, P. et al. The effect of dietary intervention on irritable bowel syndrome: a systematic review. Clin. Transl Gastroenterol. 6, e107 (2015).
Shepherd, S. J., Parker, F. C., Muir, J. G. & Gibson, P. R. Dietary triggers of abdominal symptoms in patients with irritable bowel syndrome: randomized placebo-controlled evidence. Clin. Gastroenterol. Hepatol. 6, 765–771 (2008).
Teufel, M. et al. Psychological burden of food allergy. World J. Gastroenterol. 13, 3456–3465 (2007).
Sicherer, S. H. Food allergy. Lancet 360, 701–710 (2002).
Morita, H., Nomura, I., Matsuda, A., Saito, H. & Matsumoto, K. Gastrointestinal food allergy in infants. Allergol Int. 62, 297–307 (2013).
Sicherer, S. H. & Sampson, H. A. Food allergy: recent advances in pathophysiology and treatment. Annu. Rev. Med. 60, 261–277 (2009).
Sampson, H. A. & Anderson, J. A. Summary and recommendations: classification of gastrointestinal manifestations due to immunologic reactions to foods in infants and young children. J. Pediatr. Gastroenterol. Nutr. 30, S87–S94 (2000).
Ludvigsson, J. F. et al. The Oslo definitions for coeliac disease and related terms. Gut 62, 43–52 (2013).
Schuppan, D., Pickert, G., Ashfaq-Khan, M. & Zevallos, V. Non-celiac wheat sensitivity: differential diagnosis, triggers and implications. Best Pract. Res. Clin. Gastroenterol. 29, 469–476 (2015).
DiGiacomo, D. V., Tennyson, C. A., Green, P. H. & Demmer, R. T. Prevalence of gluten-free diet adherence among individuals without celiac disease in the USA: results from the Continuous National Health and Nutrition Examination Survey 2009–2010. Scand. J. Gastroenterol. 48, 921–925 (2013).
Aziz, I. et al. A UK study assessing the population prevalence of self-reported gluten sensitivity and referral characteristics to secondary care. Eur. J. Gastroenterol. Hepatol. 26, 33–39 (2014).
Kaukinen, K. et al. Intolerance to cereals is not specific for coeliac disease. Scand. J. Gastroenterol. 35, 942–946 (2000).
Tanpowpong, P. et al. Coeliac disease and gluten avoidance in New Zealand children. Arch. Dis. Childhood 97, 12–16 (2012).
Lebwohl, B., Ludvigsson, J. F. & Green, P. H. Celiac disease and non-celiac gluten sensitivity. BMJ 351, h4347 (2015).
Verbeke, K. Nonceliac gluten sensitivity: what is the culprit? Gastroenterology 154, 471–473 (2018).
Skodje, G. I. et al. Fructan, rather than gluten, induces symptoms in patients with self-reported non-celiac gluten sensitivity. Gastroenterology 154, 529–539 (2018).
Junker, Y. et al. Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. J. Exp. Med. 209, 2395–2408 (2012).
Zevallos, V. F. et al. Nutritional wheat amylase-trypsin inhibitors promote intestinal inflammation via activation of myeloid cells. Gastroenterology 152, 1100–1113 (2017).
Prescott, S. L. et al. A global survey of changing patterns of food allergy burden in children. World Allergy Organiz. J. 6, 21 (2013).
Osborne, N. J. et al. Prevalence of challenge-proven IgE-mediated food allergy using population-based sampling and predetermined challenge criteria in infants. J. Allergy Clin. Immunol. 127, 668–676 (2011).
Wang, J. & Sampson, H. A. Food allergy. J. Clin. Invest. 121, 827–835 (2011).
Singh, P. et al. Global prevalence of celiac disease: systematic review and meta-analysis. Clin. Gastroenterol. Hepatol. 16, 823–836.e2 (2018).
Pozo-Rubio, T. et al. Influence of breastfeeding versus formula feeding on lymphocyte subsets in infants at risk of coeliac disease: the PROFICEL study. Eur. J. Nutr. 52, 637–646 (2013).
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 (2017).
Szajewska, H. et al. Gluten introduction and the risk of coeliac disease: a position paper by the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J. Pediatr. Gastroenterol. Nutr. 62, 507–513 (2016).
Decker, E. et al. Cesarean delivery is associated with celiac disease but not inflammatory bowel disease in children. Pediatrics 125, e1433–1440 (2010).
Marild, K. et al. Antibiotic exposure and the development of coeliac disease: a nationwide case-control study. BMC Gastroenterol. 13, 109 (2013).
Bashir, M. E., Louie, S., Shi, H. N. & Nagler-Anderson, C. Toll-like receptor 4 signaling by intestinal microbes influences susceptibility to food allergy. J. Immunol. 172, 6978–6987 (2004).
Crespo-Escobar, P. et al. The role of gluten consumption at an early age in celiac disease development: a further analysis of the prospective PreventCD cohort study. Am. J. Clin. Nutr. 105, 890–896 (2017).
Uusitalo, U. et al. Gluten consumption during late pregnancy and risk of celiac disease in the offspring: the TEDDY birth cohort. Am. J. Clin. Nutr. 102, 1216–1221 (2015).
Stene, L. C. et al. Rotavirus infection frequency and risk of celiac disease autoimmunity in early childhood: a longitudinal study. Am. J. Gastroenterol. 101, 2333–2340 (2006).
Marild, K., Kahrs, C. R., Tapia, G., Stene, L. C. & Stordal, K. Infections and risk of celiac disease in childhood: a prospective nationwide cohort study. Am. J. Gastroenterol. 110, 1475–1484 (2015).
Plot, L. & Amital, H. Infectious associations of Celiac disease. Autoimmun. Rev. 8, 316–319 (2009).
Cheung, D. S. & Grayson, M. H. Role of viruses in the development of atopic disease in pediatric patients. Curr. Allergy Asthma Rep. 12, 613–620 (2012).
Verdu, E. F., Mauro, M., Bourgeois, J. & Armstrong, D. Clinical onset of celiac disease after an episode of Campylobacter jejuni enteritis. Can. J. Gastroenterol. 21, 453–455 (2007).
Kagnoff, M. F., Austin, R. K., Hubert, J. J., Bernardin, J. E. & Kasarda, D. D. Possible role for a human adenovirus in the pathogenesis of celiac disease. J. Exp. Med. 160, 1544–1557 (1984).
Abadie, V., Sollid, L. M., Barreiro, L. B. & Jabri, B. Integration of genetic and immunological insights into a model of celiac disease pathogenesis. Annu. Rev. Immunol. 29, 493–525 (2011).
Shi, H. N., Liu, H. Y. & Nagler-Anderson, C. Enteric infection acts as an adjuvant for the response to a model food antigen. J. Immunol. 165, 6174–6182 (2000).
Honeyman, M. C. et al. Association between rotavirus infection and pancreatic islet autoimmunity in children at risk of developing type 1 diabetes. Diabetes 49, 1319–1324 (2000).
Silvester, J. A. & Leffler, D. A. Is autoimmunity infectious? The effect of gastrointestinal viral infections and vaccination on risk of celiac disease autoimmunity. Clin. Gastroenterol. Hepatol. 15, 703–705 (2017).
Vaarala, O., Jokinen, J., Lahdenkari, M. & Leino, T. Rotavirus vaccination and the risk of celiac disease or type 1 diabetes in Finnish children at early life. Pediatr. Infecti. Dis. J. 36, 674–675 (2017).
Karhus, L. L. et al. Influenza and risk of later celiac disease: a cohort study of 2.6 million people. Scand. J. Gastroenterol. 53, 15–23 (2018).
Garg, A., Reddy, C., Duseja, A., Chawla, Y. & Dhiman, R. K. Association between celiac disease and chronic hepatitis c virus infection. J. Clin. Exp. Hepatol. 1, 41–44 (2011).
Nadal, I., Donat, E., Ribes-Koninckx, C., Calabuig, M. & Sanz, Y. Imbalance in the composition of the duodenal microbiota of children with coeliac disease. J. Med. Microbiol. 56, 1669–1674 (2007).
Collado, M. C., Donat, E., Ribes-Koninckx, C., Calabuig, M. & Sanz, Y. Imbalances in faecal and duodenal Bifidobacterium species composition in active and non-active coeliac disease. BMC Microbiol. 8, 232 (2008).
Nistal, E. et al. Differences of small intestinal bacteria populations in adults and children with/without celiac disease: effect of age, gluten diet, and disease. Inflammatory Bowel Diseases 18, 649–656 (2012).
Nistal, E. et al. Differences in faecal bacteria populations and faecal bacteria metabolism in healthy adults and celiac disease patients. Biochimie 94, 1724–1729 (2012).
Wacklin, P. et al. Altered duodenal microbiota composition in celiac disease patients suffering from persistent symptoms on a long-term gluten-free diet. Am. J. Gastroenterol. 109, 1933–1941 (2014).
D’Argenio, V. et al. Metagenomics reveals dysbiosis and a potentially pathogenic N. flavescens strain in duodenum of adult celiac patients. Am. J. Gastroenterol. 111, 879–890 (2016).
Azad, M. B. et al. Infant gut microbiota and food sensitization: associations in the first year of life. Clin. Exp. Allergy 45, 632–643 (2015).
Abrahamsson, T. R. et al. Low diversity of the gut microbiota in infants with atopic eczema. J. Allergy Clin. Immunol. 129, 434–440 (2012).
Hua, X., Goedert, J. J., Pu, A., Yu, G. & Shi, J. Allergy associations with the adult fecal microbiota: analysis of the American Gut Project. EBioMedicine 3, 172–179 (2016).
Sanz, Y., De Pama, G. & Laparra, M. Unraveling the ties between celiac disease and intestinal microbiota. Int. Rev. Immunol. 30, 207–218 (2011).
Palma, G. D. et al. Influence of milk-feeding type and genetic risk of developing coeliac disease on intestinal microbiota of infants: the PROFICEL study. PLoS ONE 7, e30791 (2012).
Bunyavanich, S. et al. Early-life gut microbiome composition and milk allergy resolution. J. Allergy Clin. Immunol. 138, 1122–1130 (2016).
Ling, Z. et al. Altered fecal microbiota composition associated with food allergy in infants. Appl. Environ. Microbiol. 80, 2546–2554 (2014).
Collado, M. C., Donat, E., Ribes-Koninckx, C., Calabuig, M. & Sanz, Y. Specific duodenal and faecal bacterial groups associated with paediatric coeliac disease. J. Clin. Pathol. 62, 264–269 (2009).
Galipeau, H. J. et al. Intestinal microbiota modulates gluten-induced immunopathology in humanized mice. Am. J. Pathol. 185, 2969–2982 (2015). This study shows that the intestinal microbiota can both positively and negatively modulate gluten-induced immunopathology in mice.
Cahenzli, J., Koller, Y., Wyss, M., Geuking, M. B. & McCoy, K. D. Intestinal microbial diversity during early-life colonization shapes long-term IgE levels. Cell Host Microbe 14, 559–570 (2013).
Noval Rivas, M. et al. A microbiota signature associated with experimental food allergy promotes allergic sensitization and anaphylaxis. J. Allergy Clin. Immunol. 131, 201–212 (2013).
Atarashi, K. et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500, 232–236 (2013).
Stefka, A. T. et al. Commensal bacteria protect against food allergen sensitization. Proc. Natl Acad. Sci. USA 111, 13145–13150 (2014). In this study, selective colonization of gnotobiotic mice is used to demonstrate that the allergy-protective capacity is contained within the Clostridia class. Clostridia members induce IL-22 production, reducing uptake of orally administered dietary antigen into the systemic circulation and contributing to protection against food sensitization.
Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011).
Wu, G. D. et al. Linking long-term dietary patterns with gut microbial enterotypes. Science 334, 105–108 (2011).
David, L. A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2014).
Lee, D. et al. Diet in the pathogenesis and treatment of inflammatory bowel diseases. Gastroenterology 148, 1087–1106 (2015).
Sonnenburg, J. L. & Backhed, F. Diet-microbiota interactions as moderators of human metabolism. Nature 535, 56–64 (2016).
Gourbeyre, P. et al. Perinatal and postweaning exposure to galactooligosaccharides/inulin prebiotics induced biomarkers linked to tolerance mechanism in a mouse model of strong allergic sensitization. J. Agric. Food Chem. 61, 6311–6320 (2013).
Kunisawa, J. et al. Dietary omega3 fatty acid exerts anti-allergic effect through the conversion to 17,18-epoxyeicosatetraenoic acid in the gut. Sci. Rep. 5, 9750 (2015).
Hamer, H. M. et al. Review article: the role of butyrate on colonic function. Aliment. Pharmacol. Ther. 27, 104–119 (2008).
Koppel, N., Maini Rekdal, V. & Balskus, E. P. Chemical transformation of xenobiotics by the human gut microbiota. Science 356, eaag2770 (2017).
Shan, L. et al. Structural basis for gluten intolerance in celiac sprue. Science 297, 2275–2279 (2002).
Sollid, L. M. & Jabri, B. Triggers and drivers of autoimmunity: lessons from coeliac disease. Nat. Rev. Immunology 13, 294–302 (2013).
Caminero, A. et al. Diversity of the cultivable human gut microbiome involved in gluten metabolism: isolation of microorganisms with potential interest for coeliac disease. FEMS Microbiol. Ecol. 88, 309–319 (2014).
Caminero, A. et al. Differences in gluten metabolism among healthy volunteers, coeliac disease patients and first-degree relatives. Br. J. Nutr. 114, 1157–1167 (2015).
Herran, A. R. et al. Gluten-degrading bacteria are present in the human small intestine of healthy volunteers and celiac patients. Res. Microbiol. 168, 673–684 (2017).
Helmerhorst, E. J., Zamakhchari, M., Schuppan, D. & Oppenheim, F. G. Discovery of a novel and rich source of gluten-degrading microbial enzymes in the oral cavity. PLoS ONE 5, e13264 (2010).
Fernandez-Feo, M. et al. The cultivable human oral gluten-degrading microbiome and its potential implications in coeliac disease and gluten sensitivity. Clin. Microbiol. Infect. 19, E386–E394 (2013).
Nistal, E. et al. Study of duodenal bacterial communities by 16s rrna gene analysis in adults with active celiac disease versus non celiac disease controls. J. Appl. Microbiol. 120, 1691–1700 (2016).
Borton, M. A. et al. Chemical and pathogen-induced inflammation disrupt the murine intestinal microbiome. Microbiome 5, 47 (2017).
Dieterich, W. et al. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat. Med. 3, 797–801 (1997).
Zhou, L. et al. Abrogation of immunogenic properties of gliadin peptides through transamidation by microbial transglutaminase is acyl-acceptor dependent. J. Agric. Food Chem. 65, 7542–7552 (2017).
Toomer, O. T., Do, A., Pereira, M. & Williams, K. Effect of simulated gastric and intestinal digestion on temporal stability and immunoreactivity of peanut, almond, and pine nut protein allergens. J. Agric. Food Chem. 61, 5903–5913 (2013).
Tye-Din, J. A. et al. Comprehensive, quantitative mapping of T cell epitopes in gluten in celiac disease. Sci. Transl Med. 2, 41ra51 (2010).
Maynard, C. L., Elson, C. O., Hatton, R. D. & Weaver, C. T. Reciprocal interactions of the intestinal microbiota and immune system. Nature 489, 231–241 (2012).
Morrison, D. J. & Preston, T. Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. Gut Microbes 7, 189–200 (2016).
Lamas, B. et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat. Med. 22, 598–605 (2016).
Tjellstrom, B. et al. Gut microflora associated characteristics in children with celiac disease. Am. J. Gastroenterol. 100, 2784–2788 (2005).
Brestoff, J. R. & Artis, D. Commensal bacteria at the interface of host metabolism and the immune system. Nature Immunol. 14, 676–684 (2013).
Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T cell generation. Nature 504, 451–455 (2013). This study shows that bacterial metabolites such as short-chain fatty acids mediate communication between the commensal microbiota and the immune system, affecting the balance between pro-inflammatory and anti-inflammatory mechanisms.
Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013).
Hadis, U. et al. Intestinal tolerance requires gut homing and expansion of FoxP3+ regulatory T cells in the lamina propria. Immunity 34, 237–246 (2011).
Bilate, A. M. & Lafaille, J. J. Induced CD4+Foxp3+ regulatory T cells in immune tolerance. Annu. Rev. Immunol. 30, 733–758 (2012).
Tan, J. et al. Dietary fiber and bacterial SCFA enhance oral tolerance and protect against food allergy through diverse cellular pathways. Cell Rep. 15, 2809–2824 (2016). This study finds that dietary elements, including fibre and vitamin A, are essential for the tolerogenic function of CD103
+ dendritic cells and the maintenance of mucosal homeostasis, including proper IgA responses and epithelial barrier function. The practical outcome of this study is the promotion of oral tolerance and protection from food allergy.
Fukuda, S. et al. Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature 469, 543–547 (2011).
DePaolo, R. W. et al. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature 471, 220–224 (2011). This study finds that, in conjunction with IL-15, retinoic acid rapidly activates dendritic cells to release pro-inflammatory cytokines, and as a result, in a stressed intestinal environment, retinoic acid acts as an adjuvant that promotes rather than prevents inflammatory cellular and humoral responses to fed antigens.
Meisel, M. et al. Interleukin-15 promotes intestinal dysbiosis with butyrate deficiency associated with increased susceptibility to colitis. ISME J. 11, 15–30 (2017).
Berni Canani, R. et al. Lactobacillus rhamnosus GG-supplemented formula expands butyrate-producing bacterial strains in food allergic infants. ISME J. 10, 742–750 (2016).
Zelante, T. et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 39, 372–385 (2013).
Nguyen, N. T. et al. Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism. Proc. Natl Acad. Sci. USA 107, 19961–19966 (2010).
Schulz, V. J. et al. Aryl hydrocarbon receptor activation affects the dendritic cell phenotype and function during allergic sensitization. Immunobiology 218, 1055–1062 (2013).
Hammerschmidt-Kamper, C. et al. Indole-3-carbinol, a plant nutrient and AhR-Ligand precursor, supports oral tolerance against OVA and improves peanut allergy symptoms in mice. PLoS ONE 12, e0180321 (2017).
Schulz, V. J., Smit, J. J. & Pieters, R. H. The aryl hydrocarbon receptor and food allergy. Vet. Q. 33, 94–107 (2013).
Mazmanian, S. K., Round, J. L. & Kasper, D. L. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453, 620–625 (2008).
Atarashi, K. & Honda, K. Microbiota in autoimmunity and tolerance. Curr. Opin. Immunol. 23, 761–768 (2011).
Round, J. L. & Mazmanian, S. K. Inducible Foxp3+ regulatory T cell development by a commensal bacterium of the intestinal microbiota. Proc. Natl Acad. Sci. USA 107, 12204–12209 (2010). Here, the immunomodulatory molecule polysaccharide A of Bacteroides fragilis is shown to mediate the conversion of CD4
+ T cells into FOXP3
+ regulatory T cells that produce IL-10 during commensal colonization. B. fragilis co-opts the regulatory T cell lineage differentiation pathway in the gut to actively induce mucosal tolerance.
Cerf-Bensussan, N. & Gaboriau-Routhiau, V. The immune system and the gut microbiota: friends or foes? Nat. Rev. Immunology 10, 735–744 (2010).
Hrncir, T., Stepankova, R., Kozakova, H., Hudcovic, T. & Tlaskalova-Hogenova, H. Gut microbiota and lipopolysaccharide content of the diet influence development of regulatory T cells: studies in germ-free mice. BMC Immunol. 9, 65 (2008).
Schwarzer, M. et al. Diet matters: endotoxin in the diet impacts the level of allergic sensitization in germ-free mice. PLoS ONE 12, e0167786 (2017).
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).
Pinto-Sanchez, 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).
Enomoto, T. et al. Effects of bifidobacterial supplementation to pregnant women and infants in the prevention of allergy development in infants and on fecal microbiota. Allergol. Int. 63, 575–585 (2014).
Hill, D. A. et al. Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation. Nat. Med. 18, 538–546 (2012).
De Angelis, M. et al. VSL#3 probiotic preparation has the capacity to hydrolyze gliadin polypeptides responsible for celiac sprue. Biochim. Biophys. Acta 1762, 80–93 (2006).
Schiavi, E. et al. Oral therapeutic administration of a probiotic mixture suppresses established Th2 responses and systemic anaphylaxis in a murine model of food allergy. Allergy 66, 499–508 (2011).
Barletta, B. et al. Probiotic VSL#3-induced TGF-β ameliorates food allergy inflammation in a mouse model of peanut sensitization through the induction of regulatory T cells in the gut mucosa. Mol. Nutr. Food Res. 57, 2233–2244 (2013).
McCarville, J. L. et al. A commensal Bifidobacterium longum strain improves gluten-related immunopathology in mice through expression of a serine protease inhibitor. Appl. Environ. Microbiol. https://doi.org/10.1128/AEM.01323-17 (2017).
Galipeau, H. J. et al. Novel role of the serine protease inhibitor elafin in gluten-related disorders. Am. J. Gastroenterol. 109, 748–756 (2014).
Kim, J. H. et al. Extracellular vesicle-derived protein from Bifidobacterium longum alleviates food allergy through mast cell suppression. J. Allergy Clin. Immunol. 137, 507–516 (2016).
Tang, M. L. et al. Administration of a probiotic with peanut oral immunotherapy: a randomized trial. J. Allergy Clin. Immunol. 135, 737–744 (2015).
Wood, R. A. et al. A phase 1 study of heat/phenol-killed, E. coli-encapsulated, recombinant modified peanut proteins Ara h 1, Ara h 2, and Ara h 3 (EMP-123) for the treatment of peanut allergy. Allergy 68, 803–808 (2013).
Pabst, O. & Mowat, A. M. Oral tolerance to food protein. Mucosal Immunol. 5, 232–239 (2012).
Faria, A. M. & Weiner, H. L. Oral tolerance. Immunol. Rev. 206, 232–259 (2005).
Fasano, A. & Shea-Donohue, T. Mechanisms of disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases. Nat. Clin. Pract. Gastroenterol. Hepatol. 2, 416–422 (2005).
Menard, S., Cerf-Bensussan, N. & Heyman, M. Multiple facets of intestinal permeability and epithelial handling of dietary antigens. Mucosal Immunol. 3, 247–259 (2010).
Berin, M. C. & Sampson, H. A. Mucosal immunology of food allergy. Curr. Biol. 23, R389–R400 (2013).
Koning, F., Schuppan, D., Cerf-Bensussan, N. & Sollid, L. M. Pathomechanisms in celiac disease. Best Pract. Res. Clin. Gastroenterol. 19, 373–387 (2005).
Vogelsang, H., Schwarzenhofer, M. & Oberhuber, G. Changes in gastrointestinal permeability in celiac disease. Dig. Dis. 16, 333–336 (1998).
Perrier, C. & Corthesy, B. Gut permeability and food allergies. Clin. Exp. Allergy 41, 20–28 (2011).
Amieva, M. R. et al. Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA. Science 300, 1430–1434 (2003).
Wu, Z., Nybom, P. & Magnusson, K. E. Distinct effects of Vibrio cholerae haemagglutinin/protease on the structure and localization of the tight junction-associated proteins occludin and ZO-1. Cell. Microbiol. 2, 11–17 (2000).
Maharshak, N. et al. Enterococcus faecalis gelatinase mediates intestinal permeability via protease-activated receptor 2. Infection Immun. 83, 2762–2770 (2015).
Steck, N. et al. Enterococcus faecalis metalloprotease compromises epithelial barrier and contributes to intestinal inflammation. Gastroenterology 141, 959–971 (2011).
Ng, K. M. et al. Microbiota-liberated host sugars facilitate post-antibiotic expansion of enteric pathogens. Nature 502, 96–99 (2013).
Rescigno, M. & Di Sabatino, A. Dendritic cells in intestinal homeostasis and disease. J. Clin. Invest. 119, 2441–2450 (2009).
Esterhazy, D. et al. Classical dendritic cells are required for dietary antigen-mediated induction of peripheral Treg cells and tolerance. Nat. Immunol. 17, 545–555 (2016). This study finds that classic dendritic cells are critical for peripherally induced regulatory T cell induction and oral tolerance.
Wells, J. M., Rossi, O., Meijerink, M. & van Baarlen, P. Epithelial crosstalk at the microbiota-mucosal interface. Proc. Natl Acad. Sci. USA 108 (Suppl. 1), 4607–4614 (2011).
Coleman, O. I. & Haller, D. Bacterial signaling at the intestinal epithelial interface in inflammation and cancer. Frontiers Immunol. 8, 1927 (2017).
Araya, R. E. et al. Mechanisms of innate immune activation by gluten peptide p31-43 in mice. Am. J. Physiol. Gastrointest. Liver Physiol. 311, G40–49 (2016).
Biswas, A. et al. Negative regulation of Toll-like receptor signaling plays an essential role in homeostasis of the intestine. Eur. J. Immunol. 41, 182–194 (2011).
Medvedev, A. E. Toll-like receptor polymorphisms, inflammatory and infectious diseases, allergies, and cancer. J. Interferon Cytokine Res. 33, 467–484 (2013).
Miedema, K. G. et al. Polymorphisms in the TLR6 gene associated with the inverse association between childhood acute lymphoblastic leukemia and atopic disease. Leukemia 26, 1203–1210 (2012).
Cheng, J. et al. Duodenal microbiota composition and mucosal homeostasis in pediatric celiac disease. BMC Gastroenterol. 13, 113 (2013).
Marafini, I. et al. TNF-α producing innate lymphoid cells (ILCs) are increased in active celiac disease and contribute to promote intestinal atrophy in mice. PLoS ONE 10, e0126291 (2015).
Burton, O. T. et al. IgE promotes type 2 innate lymphoid cells in murine food allergy. Clin. Exp. Allergy 48, 288–296 (2017).
Di Liberto, D. et al. Predominance of type 1 innate lymphoid cells in the rectal mucosa of patients with non-celiac wheat sensitivity: reversal after a wheat-free diet. Clin. Transl Gastroenterol. 7, e178 (2016).
Chu, D. K. et al. T helper cell IL-4 drives intestinal Th2 priming to oral peanut antigen, under the control of OX40L and independent of innate-like lymphocytes. Mucosal Immunol. 7, 1395–1404 (2014).
Lee, J. B. et al. IL-25 and CD4+ TH2 cells enhance type 2 innate lymphoid cell-derived IL-13 production, which promotes IgE-mediated experimental food allergy. J. Allergy Clin. Immunol. 137, 1216–1225 (2016).
Artis, D. & Spits, H. The biology of innate lymphoid cells. Nature 517, 293–301 (2015).
Mortha, A. et al. Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science 343, 1249288 (2014).
Chua, H. H. et al. Intestinal dysbiosis featuring abundance of Ruminococcus gnavus associates with allergic diseases in infants. Gastroenterology 154, 154–167 (2018).
Gerbe, F. et al. Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites. Nature 529, 226–230 (2016).
Coombes, J. L. et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β and retinoic acid-dependent mechanism. J. Exp. Med. 204, 1757–1764 (2007).
Sun, C. M. et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J. Exp. Med. 204, 1775–1785 (2007).
Hall, J. A., Grainger, J. R., Spencer, S. P. & Belkaid, Y. The role of retinoic acid in tolerance and immunity. Immunity 35, 13–22 (2011).
Martinez-Lopez, M., Iborra, S., Conde-Garrosa, R. & Sancho, D. Batf3-dependent CD103+ dendritic cells are major producers of IL-12 that drive local Th1 immunity against Leishmania major infection in mice. Eur. J. Immunol. 45, 119–129 (2015).
Luda, K. M. et al. IRF8 transcription-factor-dependent classical dendritic cells are essential for intestinal T cell homeostasis. Immunity 44, 860–874 (2016).
Laffont, S., Siddiqui, K. R. & Powrie, F. Intestinal inflammation abrogates the tolerogenic properties of MLN CD103+ dendritic cells. Eur. J. Immunol. 40, 1877–1883 (2010).
Moretto, M. M., Harrow, D. I., Hawley, T. S. & Khan, I. A. Interleukin-12-producing CD103+CD11b–CD8+ dendritic cells are responsible for eliciting gut intraepithelial lymphocyte response against Encephalitozoon cuniculi. Infection Immun. 83, 4719–4730 (2015).
Di Sabatino, A. et al. Evidence for the role of interferon-α production by dendritic cells in the Th1 response in celiac disease. Gastroenterology 133, 1175–1187 (2007).
Jabri, B. & Sollid, L. M. Tissue-mediated control of immunopathology in coeliac disease. Nat. Rev. Immunol. 9, 858–870 (2009).
Verdu, E. F. & Caminero, A. How infection can incite sensitivity to food. Science 356, 29–30 (2017).
Abadie, V. & Jabri, B. IL-15: a central regulator of celiac disease immunopathology. Immunol. Rev. 260, 221–234 (2014).
Mattei, F., Schiavoni, G., Belardelli, F. & Tough, D. F. IL-15 is expressed by dendritic cells in response to type I IFN, double-stranded RNA, or lipopolysaccharide and promotes dendritic cell activation. J. Immunol. 167, 1179–1187 (2001).
Hunt, K. A. et al. Newly identified genetic risk variants for celiac disease related to the immune response. Nature Genet. 40, 395–402 (2008).
Guo, C. C. et al. Meta-analysis on associations of RGS1 and IL12A polymorphisms with celiac disease risk. Int. J. Mol. Sci. 17, 457 (2016).
Zhernakova, A. et al. Evolutionary and functional analysis of celiac risk loci reveals SH2B3 as a protective factor against bacterial infection. Am. J. Hum. Genet. 86, 970–977 (2010).
Green, P. H. & Jabri, B. Celiac disease and other precursors to small-bowel malignancy. Gastroenterol. Clin. North Amer. 31, 625–639 (2002).
Mention, J. J. et al. Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease. Gastroenterology 125, 730–745 (2003).
Setty, M. et al. Distinct and synergistic contributions of epithelial stress and adaptive immunity to functions of intraepithelial killer cells and active celiac disease. Gastroenterology 149, 681–691 (2015).
Licona-Limon, P., Kim, L. K., Palm, N. W. & Flavell, R. A. TH2, allergy and group 2 innate lymphoid cells. Nature Immunol. 14, 536–542 (2013).
Khodoun, M. V., Tomar, S., Tocker, J. E., Wang, Y. H. & Finkelman, F. D. Prevention of food allergy development and suppression of established food allergy by neutralization of thymic stromal lymphopoietin, IL-25, and IL-33. J. Allergy Clin. Immunol. 141, 171–179 e171 (2018).
Mayer, J. U. et al. Different populations of CD11b+ dendritic cells drive Th2 responses in the small intestine and colon. Nat. Commun. 8, 15820 (2017).
Bashir, M. E., Andersen, P., Fuss, I. J., Shi, H. N. & Nagler-Anderson, C. An enteric helminth infection protects against an allergic response to dietary antigen. J. Immunol. 169, 3284–3292 (2002).
Ben-Ami Shor, D., Harel, M., Eliakim, R. & Shoenfeld, Y. The hygiene theory harnessing helminths and their ova to treat autoimmunity. Clin. Rev. Allergy Immunol. 45, 211–216 (2013).
Hewitson, J. P., Grainger, J. R. & Maizels, R. M. Helminth immunoregulation: the role of parasite secreted proteins in modulating host immunity. Mol. Biochem. Parasitol. 167, 1–11 (2009).
Yamaguchi, N. et al. Gastrointestinal Candida colonisation promotes sensitisation against food antigens by affecting the mucosal barrier in mice. Gut 55, 954–960 (2006). This study finds that Candida spp. colonization promotes sensitization against food antigens, at least partly owing to mast cell-mediated hyperpermeability in the gastrointestinal mucosa of mice.