Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mechanisms by which gut microorganisms influence food sensitivities

Nature Reviews Gastroenterology & Hepatology volume 16, pages 7–18 (2019)Cite this article

Subjects

Abstract

Finely tuned mechanisms enable the gastrointestinal tract to break down dietary components into nutrients without mounting, in the majority of cases, a dysregulated immune or functional host response. However, adverse reactions to food have been steadily increasing, and evidence suggests that this process is environmental. Adverse food reactions can be divided according to their underlying pathophysiology into food intolerances, when, for instance, there is deficiency of a host enzyme required to digest the food component, and food sensitivities, when immune mechanisms are involved. In this Review, we discuss the clinical and experimental evidence for enteric infections and/or alterations in the gut microbiota in inciting food sensitivity. We focus on mechanisms by which microorganisms might provide direct pro-inflammatory signals to the host promoting breakdown of oral tolerance to food antigens or indirect pathways that involve the metabolism of protein antigens and other dietary components by gut microorganisms. Better understanding of these mechanisms will help in the development of preventive and therapeutic strategies for food sensitivities.

Key points

  • The mechanisms underlying the expression of food sensitivities remain unclear; however, several studies demonstrate that gut microorganisms, along with other host predisposing factors, dictate the development of these conditions.

  • Gut microorganisms can degrade or modify immunogenic food antigens or allergens, increasing or reducing their immunogenicity.

  • Dietary food components that are insufficiently digested by host enzymes become bacterial substrates, leading to the production of metabolites such as short-chain fatty acids, which are involved in gut homeostasis.

  • One key factor in the development of food sensitivities is intestinal barrier dysfunction, which can be influenced by gut microorganisms and pathogens through different pathways.

  • Mucosal dendritic cells present dietary antigens to naive T helper cells, promoting their differentiation into peripheral T regulatory cells; virus–host interactions abrogate this response, inducing a pathogenic response to antigens.

  • Enteric parasites induce T helper 2 cell immunity and protect against food allergy; this contradiction is explained by the observation that parasites induce IL-10, which blocks type 2 immunity.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Classification of adverse reaction to food according to underlying pathophysiology.
Fig. 2: Microbial metabolism in the pathogenesis of food sensitivities.
Fig. 3: Microorganisms can promote food sensitivities.

Similar content being viewed by others

References

  1. 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).

    Article  CAS  PubMed  Google Scholar 

  2. Rubio-Tapia, A. et al. Increased prevalence and mortality in undiagnosed celiac disease. Gastroenterology 137, 88–93 (2009).

    Article  PubMed  Google Scholar 

  3. Tang, M. L. & Mullins, R. J. Food allergy: is prevalence increasing? Internal Med. J. 47, 256–261 (2017).

    Article  Google Scholar 

  4. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 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.

    Article  CAS  PubMed  Google Scholar 

  7. Smith, P. M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013).

    Article  CAS  PubMed  Google Scholar 

  8. McCarville, J. L., Caminero, A. & Verdu, E. F. Novel perspectives on therapeutic modulation of the gut microbiota. Ther. Adv. Gastroenterol. 9, 580–593 (2016).

    Article  CAS  Google Scholar 

  9. 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).

    Article  CAS  PubMed  Google Scholar 

  10. 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).

    Article  PubMed  Google Scholar 

  11. Moayyedi, P. et al. The effect of dietary intervention on irritable bowel syndrome: a systematic review. Clin. Transl Gastroenterol. 6, e107 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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).

    Article  CAS  PubMed  Google Scholar 

  13. Teufel, M. et al. Psychological burden of food allergy. World J. Gastroenterol. 13, 3456–3465 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Sicherer, S. H. Food allergy. Lancet 360, 701–710 (2002).

    Article  PubMed  Google Scholar 

  15. Morita, H., Nomura, I., Matsuda, A., Saito, H. & Matsumoto, K. Gastrointestinal food allergy in infants. Allergol Int. 62, 297–307 (2013).

    Article  CAS  PubMed  Google Scholar 

  16. Sicherer, S. H. & Sampson, H. A. Food allergy: recent advances in pathophysiology and treatment. Annu. Rev. Med. 60, 261–277 (2009).

    Article  CAS  PubMed  Google Scholar 

  17. 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).

    Article  PubMed  Google Scholar 

  18. Ludvigsson, J. F. et al. The Oslo definitions for coeliac disease and related terms. Gut 62, 43–52 (2013).

    Article  PubMed  Google Scholar 

  19. 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).

    Article  CAS  PubMed  Google Scholar 

  20. 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).

    Article  PubMed  Google Scholar 

  21. 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).

    Article  PubMed  Google Scholar 

  22. Kaukinen, K. et al. Intolerance to cereals is not specific for coeliac disease. Scand. J. Gastroenterol. 35, 942–946 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Tanpowpong, P. et al. Coeliac disease and gluten avoidance in New Zealand children. Arch. Dis. Childhood 97, 12–16 (2012).

    Article  Google Scholar 

  24. Lebwohl, B., Ludvigsson, J. F. & Green, P. H. Celiac disease and non-celiac gluten sensitivity. BMJ 351, h4347 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Verbeke, K. Nonceliac gluten sensitivity: what is the culprit? Gastroenterology 154, 471–473 (2018).

    Article  PubMed  Google Scholar 

  26. 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).

    Article  CAS  PubMed  Google Scholar 

  27. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zevallos, V. F. et al. Nutritional wheat amylase-trypsin inhibitors promote intestinal inflammation via activation of myeloid cells. Gastroenterology 152, 1100–1113 (2017).

    Article  CAS  PubMed  Google Scholar 

  29. Prescott, S. L. et al. A global survey of changing patterns of food allergy burden in children. World Allergy Organiz. J. 6, 21 (2013).

    Article  Google Scholar 

  30. 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).

    Article  CAS  PubMed  Google Scholar 

  31. Wang, J. & Sampson, H. A. Food allergy. J. Clin. Invest. 121, 827–835 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Singh, P. et al. Global prevalence of celiac disease: systematic review and meta-analysis. Clin. Gastroenterol. Hepatol. 16, 823–836.e2 (2018).

    Article  PubMed  Google Scholar 

  33. 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).

    Article  CAS  PubMed  Google Scholar 

  34. 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).

    Article  PubMed  Google Scholar 

  35. 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).

    Article  CAS  PubMed  Google Scholar 

  36. Decker, E. et al. Cesarean delivery is associated with celiac disease but not inflammatory bowel disease in children. Pediatrics 125, e1433–1440 (2010).

    Article  PubMed  Google Scholar 

  37. Marild, K. et al. Antibiotic exposure and the development of coeliac disease: a nationwide case-control study. BMC Gastroenterol. 13, 109 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  38. 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).

    Article  CAS  PubMed  Google Scholar 

  39. 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).

    Article  CAS  PubMed  Google Scholar 

  40. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 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).

    Article  CAS  PubMed  Google Scholar 

  42. 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).

    Article  PubMed  Google Scholar 

  43. Plot, L. & Amital, H. Infectious associations of Celiac disease. Autoimmun. Rev. 8, 316–319 (2009).

    Article  CAS  PubMed  Google Scholar 

  44. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  45. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 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).

    Article  CAS  PubMed  Google Scholar 

  47. 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).

    Article  CAS  PubMed  Google Scholar 

  48. 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).

    Article  CAS  PubMed  Google Scholar 

  49. 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).

    Article  CAS  PubMed  Google Scholar 

  50. 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).

    Article  PubMed  Google Scholar 

  51. 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).

    Article  Google Scholar 

  52. 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).

    Article  PubMed  Google Scholar 

  53. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 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).

    Article  CAS  PubMed  Google Scholar 

  55. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  56. 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).

    Article  PubMed  Google Scholar 

  57. 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).

    Article  CAS  PubMed  Google Scholar 

  58. 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).

    Article  CAS  PubMed  Google Scholar 

  59. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  60. 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).

    Article  CAS  PubMed  Google Scholar 

  61. Abrahamsson, T. R. et al. Low diversity of the gut microbiota in infants with atopic eczema. J. Allergy Clin. Immunol. 129, 434–440 (2012).

    Article  PubMed  Google Scholar 

  62. 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).

    Article  PubMed  Google Scholar 

  63. Sanz, Y., De Pama, G. & Laparra, M. Unraveling the ties between celiac disease and intestinal microbiota. Int. Rev. Immunol. 30, 207–218 (2011).

    Article  PubMed  Google Scholar 

  64. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Bunyavanich, S. et al. Early-life gut microbiome composition and milk allergy resolution. J. Allergy Clin. Immunol. 138, 1122–1130 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ling, Z. et al. Altered fecal microbiota composition associated with food allergy in infants. Appl. Environ. Microbiol. 80, 2546–2554 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 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).

    Article  CAS  PubMed  Google Scholar 

  68. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. 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).

    Article  CAS  PubMed  Google Scholar 

  71. Atarashi, K. et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500, 232–236 (2013).

    Article  CAS  PubMed  Google Scholar 

  72. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011).

    Article  CAS  PubMed  Google Scholar 

  74. Wu, G. D. et al. Linking long-term dietary patterns with gut microbial enterotypes. Science 334, 105–108 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. David, L. A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2014).

    Article  CAS  PubMed  Google Scholar 

  76. Lee, D. et al. Diet in the pathogenesis and treatment of inflammatory bowel diseases. Gastroenterology 148, 1087–1106 (2015).

    Article  CAS  PubMed  Google Scholar 

  77. Sonnenburg, J. L. & Backhed, F. Diet-microbiota interactions as moderators of human metabolism. Nature 535, 56–64 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. 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).

    Article  CAS  PubMed  Google Scholar 

  79. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Hamer, H. M. et al. Review article: the role of butyrate on colonic function. Aliment. Pharmacol. Ther. 27, 104–119 (2008).

    Article  CAS  PubMed  Google Scholar 

  81. Koppel, N., Maini Rekdal, V. & Balskus, E. P. Chemical transformation of xenobiotics by the human gut microbiota. Science 356, eaag2770 (2017).

    Article  CAS  PubMed  Google Scholar 

  82. Shan, L. et al. Structural basis for gluten intolerance in celiac sprue. Science 297, 2275–2279 (2002).

    Article  CAS  PubMed  Google Scholar 

  83. Sollid, L. M. & Jabri, B. Triggers and drivers of autoimmunity: lessons from coeliac disease. Nat. Rev. Immunology 13, 294–302 (2013).

    Article  CAS  PubMed  Google Scholar 

  84. 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).

    Article  CAS  PubMed  Google Scholar 

  85. 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).

    Article  CAS  PubMed  Google Scholar 

  86. 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).

    Article  CAS  PubMed  Google Scholar 

  87. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. 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).

    Article  CAS  PubMed  Google Scholar 

  90. Borton, M. A. et al. Chemical and pathogen-induced inflammation disrupt the murine intestinal microbiome. Microbiome 5, 47 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Dieterich, W. et al. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat. Med. 3, 797–801 (1997).

    Article  CAS  PubMed  Google Scholar 

  92. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 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).

    Article  CAS  PubMed  Google Scholar 

  94. Tye-Din, J. A. et al. Comprehensive, quantitative mapping of T cell epitopes in gluten in celiac disease. Sci. Transl Med. 2, 41ra51 (2010).

    Article  CAS  PubMed  Google Scholar 

  95. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  97. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Tjellstrom, B. et al. Gut microflora associated characteristics in children with celiac disease. Am. J. Gastroenterol. 100, 2784–2788 (2005).

    Article  CAS  PubMed  Google Scholar 

  99. Brestoff, J. R. & Artis, D. Commensal bacteria at the interface of host metabolism and the immune system. Nature Immunol. 14, 676–684 (2013).

    Article  CAS  Google Scholar 

  100. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013).

    Article  CAS  PubMed  Google Scholar 

  102. 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).

    Article  CAS  PubMed  Google Scholar 

  103. Bilate, A. M. & Lafaille, J. J. Induced CD4+Foxp3+ regulatory T cells in immune tolerance. Annu. Rev. Immunol. 30, 733–758 (2012).

    Article  CAS  PubMed  Google Scholar 

  104. 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.

    Article  CAS  PubMed  Google Scholar 

  105. Fukuda, S. et al. Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature 469, 543–547 (2011).

    Article  CAS  PubMed  Google Scholar 

  106. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Meisel, M. et al. Interleukin-15 promotes intestinal dysbiosis with butyrate deficiency associated with increased susceptibility to colitis. ISME J. 11, 15–30 (2017).

    Article  CAS  PubMed  Google Scholar 

  108. 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).

    Article  CAS  PubMed  Google Scholar 

  109. Zelante, T. et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 39, 372–385 (2013).

    Article  CAS  PubMed  Google Scholar 

  110. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Schulz, V. J. et al. Aryl hydrocarbon receptor activation affects the dendritic cell phenotype and function during allergic sensitization. Immunobiology 218, 1055–1062 (2013).

    Article  CAS  PubMed  Google Scholar 

  112. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Schulz, V. J., Smit, J. J. & Pieters, R. H. The aryl hydrocarbon receptor and food allergy. Vet. Q. 33, 94–107 (2013).

    Article  CAS  PubMed  Google Scholar 

  114. Mazmanian, S. K., Round, J. L. & Kasper, D. L. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453, 620–625 (2008).

    Article  CAS  PubMed  Google Scholar 

  115. Atarashi, K. & Honda, K. Microbiota in autoimmunity and tolerance. Curr. Opin. Immunol. 23, 761–768 (2011).

    Article  CAS  PubMed  Google Scholar 

  116. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Cerf-Bensussan, N. & Gaboriau-Routhiau, V. The immune system and the gut microbiota: friends or foes? Nat. Rev. Immunology 10, 735–744 (2010).

    Article  CAS  PubMed  Google Scholar 

  118. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  120. 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).

    Article  CAS  PubMed  Google Scholar 

  121. 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).

    PubMed  Google Scholar 

  122. 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).

    Article  CAS  PubMed  Google Scholar 

  123. Hill, D. A. et al. Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation. Nat. Med. 18, 538–546 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. 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).

    Article  CAS  PubMed  Google Scholar 

  125. 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).

    Article  CAS  PubMed  Google Scholar 

  126. 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).

    Article  CAS  PubMed  Google Scholar 

  127. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Galipeau, H. J. et al. Novel role of the serine protease inhibitor elafin in gluten-related disorders. Am. J. Gastroenterol. 109, 748–756 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. 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).

    Article  CAS  PubMed  Google Scholar 

  130. Tang, M. L. et al. Administration of a probiotic with peanut oral immunotherapy: a randomized trial. J. Allergy Clin. Immunol. 135, 737–744 (2015).

    Article  CAS  PubMed  Google Scholar 

  131. 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).

    Article  CAS  PubMed  Google Scholar 

  132. Pabst, O. & Mowat, A. M. Oral tolerance to food protein. Mucosal Immunol. 5, 232–239 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Faria, A. M. & Weiner, H. L. Oral tolerance. Immunol. Rev. 206, 232–259 (2005).

    Article  CAS  PubMed  Google Scholar 

  134. 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).

    Article  CAS  PubMed  Google Scholar 

  135. Menard, S., Cerf-Bensussan, N. & Heyman, M. Multiple facets of intestinal permeability and epithelial handling of dietary antigens. Mucosal Immunol. 3, 247–259 (2010).

    Article  CAS  PubMed  Google Scholar 

  136. Berin, M. C. & Sampson, H. A. Mucosal immunology of food allergy. Curr. Biol. 23, R389–R400 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Koning, F., Schuppan, D., Cerf-Bensussan, N. & Sollid, L. M. Pathomechanisms in celiac disease. Best Pract. Res. Clin. Gastroenterol. 19, 373–387 (2005).

    Article  CAS  PubMed  Google Scholar 

  138. Vogelsang, H., Schwarzenhofer, M. & Oberhuber, G. Changes in gastrointestinal permeability in celiac disease. Dig. Dis. 16, 333–336 (1998).

    Article  CAS  PubMed  Google Scholar 

  139. Perrier, C. & Corthesy, B. Gut permeability and food allergies. Clin. Exp. Allergy 41, 20–28 (2011).

    Article  CAS  PubMed  Google Scholar 

  140. Amieva, M. R. et al. Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA. Science 300, 1430–1434 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. 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).

    Article  CAS  PubMed  Google Scholar 

  142. Maharshak, N. et al. Enterococcus faecalis gelatinase mediates intestinal permeability via protease-activated receptor 2. Infection Immun. 83, 2762–2770 (2015).

    Article  CAS  Google Scholar 

  143. Steck, N. et al. Enterococcus faecalis metalloprotease compromises epithelial barrier and contributes to intestinal inflammation. Gastroenterology 141, 959–971 (2011).

    Article  CAS  PubMed  Google Scholar 

  144. Ng, K. M. et al. Microbiota-liberated host sugars facilitate post-antibiotic expansion of enteric pathogens. Nature 502, 96–99 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Rescigno, M. & Di Sabatino, A. Dendritic cells in intestinal homeostasis and disease. J. Clin. Invest. 119, 2441–2450 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. 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).

    Article  CAS  PubMed  Google Scholar 

  148. Coleman, O. I. & Haller, D. Bacterial signaling at the intestinal epithelial interface in inflammation and cancer. Frontiers Immunol. 8, 1927 (2017).

    Article  CAS  Google Scholar 

  149. 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).

    Article  PubMed  Google Scholar 

  150. 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).

    Article  CAS  PubMed  Google Scholar 

  151. Medvedev, A. E. Toll-like receptor polymorphisms, inflammatory and infectious diseases, allergies, and cancer. J. Interferon Cytokine Res. 33, 467–484 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. 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).

    Article  CAS  PubMed  Google Scholar 

  153. Cheng, J. et al. Duodenal microbiota composition and mucosal homeostasis in pediatric celiac disease. BMC Gastroenterol. 13, 113 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Burton, O. T. et al. IgE promotes type 2 innate lymphoid cells in murine food allergy. Clin. Exp. Allergy 48, 288–296 (2017).

    Article  CAS  Google Scholar 

  156. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. 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).

    Article  CAS  PubMed  Google Scholar 

  158. 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).

    Article  CAS  PubMed  Google Scholar 

  159. Artis, D. & Spits, H. The biology of innate lymphoid cells. Nature 517, 293–301 (2015).

    Article  CAS  PubMed  Google Scholar 

  160. Mortha, A. et al. Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science 343, 1249288 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Chua, H. H. et al. Intestinal dysbiosis featuring abundance of Ruminococcus gnavus associates with allergic diseases in infants. Gastroenterology 154, 154–167 (2018).

    Article  PubMed  Google Scholar 

  162. Gerbe, F. et al. Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites. Nature 529, 226–230 (2016).

    Article  CAS  PubMed  Google Scholar 

  163. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. 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).

    Article  CAS  PubMed  Google Scholar 

  167. Luda, K. M. et al. IRF8 transcription-factor-dependent classical dendritic cells are essential for intestinal T cell homeostasis. Immunity 44, 860–874 (2016).

    Article  CAS  PubMed  Google Scholar 

  168. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. 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).

    Article  CAS  Google Scholar 

  170. 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).

    Article  CAS  PubMed  Google Scholar 

  171. Jabri, B. & Sollid, L. M. Tissue-mediated control of immunopathology in coeliac disease. Nat. Rev. Immunol. 9, 858–870 (2009).

    Article  CAS  PubMed  Google Scholar 

  172. Verdu, E. F. & Caminero, A. How infection can incite sensitivity to food. Science 356, 29–30 (2017).

    Article  CAS  PubMed  Google Scholar 

  173. Abadie, V. & Jabri, B. IL-15: a central regulator of celiac disease immunopathology. Immunol. Rev. 260, 221–234 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. 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).

    Article  CAS  PubMed  Google Scholar 

  175. Hunt, K. A. et al. Newly identified genetic risk variants for celiac disease related to the immune response. Nature Genet. 40, 395–402 (2008).

    Article  CAS  PubMed  Google Scholar 

  176. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Green, P. H. & Jabri, B. Celiac disease and other precursors to small-bowel malignancy. Gastroenterol. Clin. North Amer. 31, 625–639 (2002).

    Article  Google Scholar 

  179. Mention, J. J. et al. Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease. Gastroenterology 125, 730–745 (2003).

    Article  CAS  PubMed  Google Scholar 

  180. 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).

    Article  CAS  PubMed  Google Scholar 

  181. 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).

    Article  CAS  Google Scholar 

  182. 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).

    Article  CAS  PubMed  Google Scholar 

  183. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  184. 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).

    Article  CAS  PubMed  Google Scholar 

  185. 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).

    Article  CAS  PubMed  Google Scholar 

  186. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

E.F.V. is funded by Canadian Institute of Health Research grant MOP#142773 and holds a Canada Research Chair in Microbiota, Inflammation and Nutrition. A.C. holds a fellowship award from the Farncombe Family. M.M. was awarded a Crohn’s & Colitis Foundation of America Research fellowship award (ID: 480735). B.J. is funded by grants R01DK098435, R01DK100619 and R01DK067180 and by Digestive Diseases Research Core Center grant P30 DK42086. The authors thank R. Hinterleitner for critically editing the Review.

Reviewer information

Nature Reviews Gastroenterology & Hepatology thanks M. D. Kulis, H. Sampson and H. Tlaskalova-Hogenova for their contribution to the peer review of this work.

Author information

Author notes

  1. These authors contributed equally: Alberto Caminero, Marlies Meisel

Authors and Affiliations

  1. Farncombe Family Digestive Disease Research Institute, McMaster University, Hamilton, Ontario, Canada

    Alberto Caminero & Elena F. Verdu

  2. Department of Medicine and Committee on Immunology, University of Chicago, Chicago, IL, USA

    Marlies Meisel & Bana Jabri

Authors
  1. Alberto Caminero
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marlies Meisel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bana Jabri
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Elena F. Verdu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to all aspects of this manuscript.

Corresponding author

Correspondence to Elena F. Verdu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Caminero, A., Meisel, M., Jabri, B. et al. Mechanisms by which gut microorganisms influence food sensitivities. Nat Rev Gastroenterol Hepatol 16, 7–18 (2019). https://doi.org/10.1038/s41575-018-0064-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41575-018-0064-z

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing