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:

Diet and host–microbial crosstalk in postnatal intestinal immune homeostasis

Key Points

  • Infant nutrition, including breast-milk, formula milk and solid weaning foods, is a key determinant of early microbial community structure that influences development of protective immunity and seems to affect health throughout life

  • Diet-induced dysbiosis changes the species composition of the gut microbiota and leads to immune-mediated inflammatory and metabolic diseases

  • Diet influences the postnatal development of innate and adaptive defences at the mucosal barrier surface and affects intestinal barrier function

  • A triad of diet, the microbiota and the immune system regulates postnatal intestinal homeostasis and host physiology, which has consequences through to adulthood

Abstract

Neonates face unique challenges in the period following birth. The postnatal immune system is in the early stages of development and has a range of functional capabilities that are distinct from the mature adult immune system. Bidirectional immune–microbial interactions regulate the development of mucosal immunity and alter the composition of the microbiota, which contributes to overall host well-being. In the past few years, nutrition has been highlighted as a third element in this interaction that governs host health by modulating microbial composition and the function of the immune system. Dietary changes and imbalances can disturb the immune–microbiota homeostasis, which might alter susceptibility to several autoimmune and metabolic diseases. Major changes in cultural traditions, socioeconomic status and agriculture are affecting the nutritional status of humans worldwide, which is altering core intestinal microbial communities. This phenomenon is especially relevant to the neonatal and paediatric populations, in which the microbiota and immune system are extremely sensitive to dietary influences. In this Review, we discuss the current state of knowledge regarding early-life nutrition, its effects on the microbiota and the consequences of diet-induced perturbation of the structure of the microbial community on mucosal immunity and disease susceptibility.

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

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

Figure 1: The 'diet hypothesis'.
Figure 2: Diet, gut microbiota and dysbiosis.
Figure 3: The intestinal barrier.
Figure 4: Development and maturation of the intestinal mucosal barrier and mucosal immune system.

Similar content being viewed by others

References

  1. Strachan, D. P. Hay fever, hygiene, and household size. BMJ 299, 1259–1260 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Bach, J. F. The effect of infections on susceptibility to autoimmune and allergic diseases. N. Engl. J. Med. 347, 911–920 (2002).

    PubMed  Google Scholar 

  3. von Mutius, E. & Vercelli, D. Farm living: effects on childhood asthma and allergy. Nat. Rev. Immunol. 10, 861–868 (2010).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  5. Turnbaugh, P. J. et al. The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci. Transl. Med. 1, 6ra14 (2009).

    PubMed  PubMed Central  Google Scholar 

  6. Maslowski, K. M. & Mackay, C. R. Diet, gut microbiota and immune responses. Nat. Immunol. 12, 5–9 (2011).

    CAS  PubMed  Google Scholar 

  7. Noverr, M. C. & Huffnagle, G. B. Does the microbiota regulate immune responses outside the gut? Trends Microbiol. 12, 562–568 (2004).

    CAS  PubMed  Google Scholar 

  8. Devereux, G. The increase in the prevalence of asthma and allergy: food for thought. Nat. Rev. Immunol. 6, 869–874 (2006).

    CAS  PubMed  Google Scholar 

  9. De Filippo, C. et al. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc. Natl Acad. Sci. USA 107, 14691–14696 (2010).

    PubMed  Google Scholar 

  10. Shoda, R., Matsueda, K., Yamato, S. & Umeda, N. Epidemiologic analysis of Crohn disease in Japan: increased dietary intake of n-6 polyunsaturated fatty acids and animal protein relates to the increased incidence of Crohn disease in Japan. Am. J. Clin. Nutr. 63, 741–745 (1996).

    CAS  PubMed  Google Scholar 

  11. Iso, H. Lifestyle and cardiovascular disease in Japan. J. Atheroscler. Thromb. 18, 83–88 (2011).

    PubMed  Google Scholar 

  12. Bang, H. O., Dyerberg, J. & Nielsen, A. B. Plasma lipid and lipoprotein pattern in Greenlandic West-coast Eskimos. Lancet 1, 1143–1145 (1971).

    CAS  PubMed  Google Scholar 

  13. Harris, W. S. et al. Omega-6 fatty acids and risk for cardiovascular disease: a science advisory from the American Heart Association Nutrition Subcommittee of the Council on Nutrition, Physical Activity, and Metabolism; Council on Cardiovascular Nursing; and Council on Epidemiology and Prevention. Circulation 119, 902–907 (2009).

    PubMed  Google Scholar 

  14. Jump, D. B., Depner, C. M. & Tripathy, S. Omega-3 fatty acid supplementation and cardiovascular disease. J. Lipid Res. 53, 2525–2545 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Myles, I. A., Pincus, N. B., Fontecilla, N. M. & Datta, S. K. Effects of parental omega-3 fatty acid intake on offspring microbiome and immunity. PLoS ONE 9, e87181 (2014).

    PubMed  PubMed Central  Google Scholar 

  16. Scholtens, P. A., Oozeer, R., Martin, R., Amor, K. B. & Knol, J. The early settlers: intestinal microbiology in early life. Annu. Rev. Food Sci. Technol. 3, 425–447 (2012).

    CAS  PubMed  Google Scholar 

  17. Bhutta, Z. A. & Black, R. E. Global maternal, newborn, and child health—so near and yet so far. N. Engl. J. Med. 369, 2226–2235 (2013).

    CAS  PubMed  Google Scholar 

  18. UN Inter-agency Group for Child Mortality Estimation (IGME). Levels and trends in child mortality [online], (2013).

  19. Barker, D. J. Adult consequences of fetal growth restriction. Clin. Obstet. Gynecol. 49, 270–283 (2006).

    PubMed  Google Scholar 

  20. Muegge, B. D. et al. Diet drives convergence in gut microbiome functions across mammalian phylogeny and within humans. Science 332, 970–974 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Kau, A. L., Ahern, P. P., Griffin, N. W., Goodman, A. L. & Gordon, J. I. Human nutrition, the gut microbiome and the immune system. Nature 474, 327–336 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Palmer, C., Bik, E. M., DiGiulio, D. B., Relman, D. A. & Brown, P. O. Development of the human infant intestinal microbiota. PLoS Biol. 5, e177 (2007).

    PubMed  PubMed Central  Google Scholar 

  23. Power, S. E., O'Toole, P. W., Stanton, C., Ross, R. P. & Fitzgerald, G. F. Intestinal microbiota, diet and health. Br. J. Nutr. 111, 387–402 (2014).

    CAS  PubMed  Google Scholar 

  24. Fanaro, S., Chierici, R., Guerrini, P. & Vigi, V. Intestinal microflora in early infancy: composition and development. Acta Paediatr. Suppl. 91, 48–55 (2003).

    CAS  PubMed  Google Scholar 

  25. Mackie, R. I., Sghir, A. & Gaskins, H. R. Developmental microbial ecology of the neonatal gastrointestinal tract. Am. J. Clin. Nutr. 69, 1035S–1045S (1999).

    CAS  PubMed  Google Scholar 

  26. Orrhage, K. & Nord, C. E. Factors controlling the bacterial colonization of the intestine in breastfed infants. Acta Paediatr. Suppl. 88, 47–57 (1999).

    CAS  PubMed  Google Scholar 

  27. Sela, D. A. & Mills, D. A. Nursing our microbiota: molecular linkages between bifidobacteria and milk oligosaccharides. Trends Microbiol. 18, 298–307 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Goldman, A. S. & Smith, C. W. Host resistance factors in human milk. J. Pediatr. 82, 1082–1090 (1973).

    CAS  PubMed  Google Scholar 

  29. Walker, A. Breast milk as the gold standard for protective nutrients. J. Pediatr. 156, S3–S7 (2010).

    CAS  PubMed  Google Scholar 

  30. Marcobal, A. et al. Bacteroides in the infant gut consume milk oligosaccharides via mucus-utilization pathways. Cell Host Microbe 10, 507–514 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Knol, J. et al. Colon microflora in infants fed formula with galacto- and fructo-oligosaccharides: more like breast-fed infants. J. Pediatr. Gastroenterol. Nutr. 40, 36–42 (2005).

    CAS  PubMed  Google Scholar 

  32. Parrett, A. M., Edwards, C. A. & Lokerse, E. Colonic fermentation capacity in vitro: development during weaning in breast-fed infants is slower for complex carbohydrates than for sugars. Am. J. Clin. Nutr. 65, 927–933 (1997).

    CAS  PubMed  Google Scholar 

  33. Klaassens, E. S. et al. Mixed-species genomic microarray analysis of fecal samples reveals differential transcriptional responses of bifidobacteria in breast- and formula-fed infants. Appl. Environ. Microbiol. 75, 2668–2676 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Collado, M. C., Delgado, S., Maldonado, A. & Rodriguez, J. M. Assessment of the bacterial diversity of breast milk of healthy women by quantitative real-time PCR. Lett. Appl. Microbiol. 48, 523–528 (2009).

    CAS  PubMed  Google Scholar 

  35. Martin, R. et al. Human milk is a source of lactic acid bacteria for the infant gut. J. Pediatr. 143, 754–758 (2003).

    CAS  PubMed  Google Scholar 

  36. Perez, P. F. et al. Bacterial imprinting of the neonatal immune system: lessons from maternal cells? Pediatrics 119, e724–e732 (2007).

    PubMed  Google Scholar 

  37. Stark, P. L. & Lee, A. The microbial ecology of the large bowel of breast-fed and formula-fed infants during the first year of life. J. Med. Microbiol. 15, 189–203 (1982).

    CAS  PubMed  Google Scholar 

  38. Amarri, S. et al. Changes of gut microbiota and immune markers during the complementary feeding period in healthy breast-fed infants. J. Pediatr. Gastroenterol. Nutr. 42, 488–495 (2006).

    CAS  PubMed  Google Scholar 

  39. Roger, L. C., Costabile, A., Holland, D. T., Hoyles, L. & McCartney, A. L. Examination of faecal Bifidobacterium populations in breast- and formula-fed infants during the first 18 months of life. Microbiology 156, 3329–3341 (2010).

    CAS  PubMed  Google Scholar 

  40. Koenig, J. E. et al. Succession of microbial consortia in the developing infant gut microbiome. Proc. Natl Acad. Sci. USA 108 (Suppl. 1), 4578–4585 (2011).

    CAS  PubMed  Google Scholar 

  41. Yatsunenko, T. et al. Human gut microbiome viewed across age and geography. Nature 486, 222–227 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Jost, T., Lacroix, C., Braegger, C. P. & Chassard, C. New insights in gut microbiota establishment in healthy breast fed neonates. PLoS ONE 7, e44595 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Arumugam, M. et al. Enterotypes of the human gut microbiome. Nature 473, 174–180 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Lin, A. et al. Distinct distal gut microbiome diversity and composition in healthy children from Bangladesh and the United States. PLoS ONE 8, e53838 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Bergstrom, A. et al. Establishment of intestinal microbiota during early life: a longitudinal, explorative study of a large cohort of Danish infants. Appl. Environ. Microbiol. 80, 2889–2900 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Yang, Y. et al. Focused specificity of intestinal TH17 cells towards commensal bacterial antigens. Nature 510, 152–156 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Pham, T. A. & Lawley, T. D. Emerging insights on intestinal dysbiosis during bacterial infections. Curr. Opin. Microbiol. 17, 67–74 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Lupp, C. et al. Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae. Cell Host Microbe 2, 204 (2007).

    CAS  PubMed  Google Scholar 

  50. Willing, B. P., Russell, S. L. & Finlay, B. B. Shifting the balance: antibiotic effects on host-microbiota mutualism. Nat. Rev. Microbiol. 9, 233–243 (2011).

    CAS  PubMed  Google Scholar 

  51. Cho, I. et al. Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature 488, 621–626 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Zeissig, S. & Blumberg, R. S. Life at the beginning: perturbation of the microbiota by antibiotics in early life and its role in health and disease. Nat. Immunol. 15, 307–310 (2014).

    CAS  PubMed  Google Scholar 

  53. Round, J. L. & Mazmanian, S. K. The gut microbiota shapes intestinal immune responses during health and disease. Nat. Rev. Immunol. 9, 313–323 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Hooper, L. V. & Macpherson, A. J. Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat. Rev. Immunol. 10, 159–169 (2010).

    CAS  PubMed  Google Scholar 

  55. Goodman, A. L. et al. Extensive personal human gut microbiota culture collections characterized and manipulated in gnotobiotic mice. Proc. Natl Acad. Sci. USA 108, 6252–6257 (2011).

    CAS  PubMed  Google Scholar 

  56. Oyama, N., Sudo, N., Sogawa, H. & Kubo, C. Antibiotic use during infancy promotes a shift in the T(H)1/T(H)2 balance toward T(H)2-dominant immunity in mice. J. Allergy Clin. Immunol. 107, 153–159 (2001).

    CAS  PubMed  Google Scholar 

  57. Russell, S. L. et al. Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma. EMBO Rep. 13, 440–447 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Noverr, M. C., Falkowski, N. R., McDonald, R. A., McKenzie, A. N. & Huffnagle, G. B. Development of allergic airway disease in mice following antibiotic therapy and fungal microbiota increase: role of host genetics, antigen, and interleukin-13. Infect. Immun. 73, 30–38 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  60. Olszak, T. et al. Microbial exposure during early life has persistent effects on natural killer T cell function. Science 336, 489–493 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. An, D. et al. Sphingolipids from a symbiotic microbe regulate homeostasis of host intestinal natural killer T cells. Cell 156, 123–133 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Food and Agriculture Organization of the United Nations. The multiple dimensions of food security [online], (2013).

  63. Lutter, C. K. et al. Undernutrition, poor feeding practices, and low coverage of key nutrition interventions. Pediatrics 128, e1418–e1427 (2011).

    PubMed  Google Scholar 

  64. Smith, M. I. et al. Gut microbiomes of Malawian twin pairs discordant for kwashiorkor. Science 339, 548–554 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Blaser, M. J. Who are we? Indigenous microbes and the ecology of human diseases. EMBO Rep. 7, 956–960 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Belkaid, Y. & Hand, T. W. Role of the microbiota in immunity and inflammation. Cell 157, 121–141 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006).

    PubMed  Google Scholar 

  68. Turnbaugh, P. J., Backhed, F., Fulton, L. & Gordon, J. I. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe 3, 213–223 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Turnbaugh, P. J. et al. A core gut microbiome in obese and lean twins. Nature 457, 480–484 (2009).

    CAS  PubMed  Google Scholar 

  70. Vijay-Kumar, M. et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328, 228–231 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Carvalho, F. A. et al. Transient inability to manage proteobacteria promotes chronic gut inflammation in TLR5-deficient mice. Cell Host Microbe 12, 139–152 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Ubeda, C. et al. Familial transmission rather than defective innate immunity shapes the distinct intestinal microbiota of TLR-deficient mice. J. Exp. Med. 209, 1445–1456 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Kostic, A. D., Howitt, M. R. & Garrett, W. S. Exploring host-microbiota interactions in animal models and humans. Genes Dev. 27, 701–718 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Karlsson, F. H. et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 498, 99–103 (2013).

    CAS  PubMed  Google Scholar 

  75. Qin, J. et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490, 55–60 (2012).

    CAS  PubMed  Google Scholar 

  76. Larsen, N. et al. Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults. PLoS ONE 5, e9085 (2010).

    PubMed  PubMed Central  Google Scholar 

  77. Lam, Y. Y. et al. Increased gut permeability and microbiota change associate with mesenteric fat inflammation and metabolic dysfunction in diet-induced obese mice. PLoS ONE 7, e34233 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Amar, J. et al. Involvement of tissue bacteria in the onset of diabetes in humans: evidence for a concept. Diabetologia 54, 3055–3061 (2011).

    CAS  PubMed  Google Scholar 

  79. Jayashree, B. et al. Increased circulatory levels of lipopolysaccharide (LPS) and zonulin signify novel biomarkers of proinflammation in patients with type 2 diabetes. Mol. Cell Biochem. 388, 203–210 (2014).

    CAS  PubMed  Google Scholar 

  80. Nielsen, D. S., Krych, L., Buschard, K., Hansen, C. H. & Hansen, A. K. Beyond genetics. Influence of dietary factors and gut microbiota on type 1 diabetes. FEBS Lett. http://dx.doi.org/10.1016/j.febslet.2014.04.010.

  81. de Goffau, M. C. et al. Fecal microbiota composition differs between children with β-cell autoimmunity and those without. Diabetes 62, 1238–1244 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Giongo, A. et al. Toward defining the autoimmune microbiome for type 1 diabetes. ISME J. 5, 82–91 (2011).

    CAS  PubMed  Google Scholar 

  83. Murri, M. et al. Gut microbiota in children with type 1 diabetes differs from that in healthy children: a case-control study. BMC Med. 11, 46 (2013).

    PubMed  PubMed Central  Google Scholar 

  84. Kriegel, M. A. et al. Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice. Proc. Natl Acad. Sci. USA 108, 11548–11553 (2011).

    CAS  PubMed  Google Scholar 

  85. Cardwell, C. R. et al. Breast-feeding and childhood-onset type 1 diabetes: a pooled analysis of individual participant data from 43 observational studies. Diabetes Care 35, 2215–2225 (2012).

    PubMed  PubMed Central  Google Scholar 

  86. Rosenbauer, J., Herzig, P. & Giani, G. Early infant feeding and risk of type 1 diabetes mellitus—a nationwide population-based case-control study in pre-school children. Diabetes Metab. Res. Rev. 24, 211–222 (2008).

    CAS  PubMed  Google Scholar 

  87. Norris, J. M. et al. Timing of initial cereal exposure in infancy and risk of islet autoimmunity. JAMA 290, 1713–1720 (2003).

    CAS  PubMed  Google Scholar 

  88. Ziegler, A. G., Schmid, S., Huber, D., Hummel, M. & Bonifacio, E. Early infant feeding and risk of developing type 1 diabetes-associated autoantibodies. JAMA 290, 1721–1728 (2003).

    CAS  PubMed  Google Scholar 

  89. Artis, D. Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut. Nat. Rev. Immunol. 8, 411–420 (2008).

    CAS  PubMed  Google Scholar 

  90. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Turner, J. R. Intestinal mucosal barrier function in health and disease. Nat. Rev. Immunol. 9, 799–809 (2009).

    CAS  PubMed  Google Scholar 

  92. Stockinger, S., Hornef, M. W. & Chassin, C. Establishment of intestinal homeostasis during the neonatal period. Cell. Mol. Life Sci. 68, 3699–3712 (2011).

    CAS  PubMed  Google Scholar 

  93. Levy, O. Innate immunity of the newborn: basic mechanisms and clinical correlates. Nat. Rev. Immunol. 7, 379–390 (2007).

    CAS  PubMed  Google Scholar 

  94. Schwartz, S. et al. A metagenomic study of diet-dependent interaction between gut microbiota and host in infants reveals differences in immune response. Genome Biol. 13, r32 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Wagner, C. L., Taylor, S. N. & Johnson, D. Host factors in amniotic fluid and breast milk that contribute to gut maturation. Clin. Rev. Allergy Immunol. 34, 191–204 (2008).

    PubMed  Google Scholar 

  96. Neu, J. & Walker, W. A. Necrotizing enterocolitis. N. Engl. J. Med. 364, 255–264 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Huffnagle, G. B. The microbiota and allergies/asthma. PLoS Pathog. 6, e1000549 (2010).

    PubMed  PubMed Central  Google Scholar 

  98. Peterson, L. W. & Artis, D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat. Rev. Immunol. 14, 141–153 (2014).

    CAS  PubMed  Google Scholar 

  99. Lorenz, R. G., Chaplin, D. D., McDonald, K. G., McDonough, J. S. & Newberry, R. D. Isolated lymphoid follicle formation is inducible and dependent upon lymphotoxin-sufficient B lymphocytes, lymphotoxin beta receptor, and TNF receptor I function. J. Immunol. 170, 5475–5482 (2003).

    CAS  PubMed  Google Scholar 

  100. Pabst, O. et al. Cryptopatches and isolated lymphoid follicles: dynamic lymphoid tissues dispensable for the generation of intraepithelial lymphocytes. Eur. J. Immunol. 35, 98–107 (2005).

    CAS  PubMed  Google Scholar 

  101. Cherrier, M. & Eberl, G. The development of LTi cells. Curr. Opin. Immunol. 24, 178–183 (2012).

    CAS  PubMed  Google Scholar 

  102. Bouskra, D. et al. Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature 456, 507–510 (2008).

    CAS  PubMed  Google Scholar 

  103. Tsuji, M. et al. Requirement for lymphoid tissue-inducer cells in isolated follicle formation and T cell-independent immunoglobulin A generation in the gut. Immunity 29, 261–271 (2008).

    CAS  PubMed  Google Scholar 

  104. Lotz, M. et al. Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells. J. Exp. Med. 203, 973–984 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Chassin, C. et al. miR-146a mediates protective innate immune tolerance in the neonate intestine. Cell Host Microbe 8, 358–368 (2010).

    CAS  PubMed  Google Scholar 

  106. Afrazi, A. et al. New insights into the pathogenesis and treatment of necrotizing enterocolitis: Toll-like receptors and beyond. Pediatr. Res. 69, 183–188 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Newburg, D. S. & Walker, W. A. Protection of the neonate by the innate immune system of developing gut and of human milk. Pediatr. Res. 61, 2–8 (2007).

    CAS  PubMed  Google Scholar 

  108. LeBouder, E. et al. Modulation of neonatal microbial recognition: TLR-mediated innate immune responses are specifically and differentially modulated by human milk. J. Immunol. 176, 3742–3752 (2006).

    CAS  PubMed  Google Scholar 

  109. Robinson, G., Volovitz, B. & Passwell, J. H. Identification of a secretory IgA receptor on breast-milk macrophages: evidence for specific activation via these receptors. Pediatr. Res. 29, 429–434 (1991).

    CAS  PubMed  Google Scholar 

  110. Cummins, A. G. & Thompson, F. M. Postnatal changes in mucosal immune response: a physiological perspective of breast feeding and weaning. Immunol. Cell Biol. 75, 419–429 (1997).

    CAS  PubMed  Google Scholar 

  111. Suzuki, T. Regulation of intestinal epithelial permeability by tight junctions. Cell. Mol. Life Sci. 70, 631–659 (2013).

    CAS  PubMed  Google Scholar 

  112. Capaldo, C. T. & Nusrat, A. Cytokine regulation of tight junctions. Biochim. Biophys. Acta 1788, 864–871 (2009).

    CAS  PubMed  Google Scholar 

  113. Mullin, J. M., Valenzano, M. C., Verrecchio, J. J. & Kothari, R. Age- and diet-related increase in transepithelial colon permeability of Fischer 344 rats. Dig. Dis. Sci. 47, 2262–2270 (2002).

    CAS  PubMed  Google Scholar 

  114. Ulluwishewa, D. et al. Regulation of tight junction permeability by intestinal bacteria and dietary components. J. Nutr. 141, 769–776 (2011).

    CAS  PubMed  Google Scholar 

  115. Resta-Lenert, S. & Barrett, K. E. Probiotics and commensals reverse TNF-α- and IFN-γ-induced dysfunction in human intestinal epithelial cells. Gastroenterology 130, 731–746 (2006).

    CAS  PubMed  Google Scholar 

  116. Fasano, A. et al. Vibrio cholerae produces a second enterotoxin, which affects intestinal tight junctions. Proc. Natl Acad. Sci. USA 88, 5242–5246 (1991).

    CAS  PubMed  Google Scholar 

  117. Muza-Moons, M. M., Schneeberger, E. E. & Hecht, G. A. Enteropathogenic Escherichia coli infection leads to appearance of aberrant tight junctions strands in the lateral membrane of intestinal epithelial cells. Cell. Microbiol. 6, 783–793 (2004).

    CAS  PubMed  Google Scholar 

  118. Visser, J., Rozing, J., Sapone, A., Lammers, K. & Fasano, A. Tight junctions, intestinal permeability, and autoimmunity: celiac disease and type 1 diabetes paradigms. Ann. NY Acad. Sci. 1165, 195–205 (2009).

    CAS  PubMed  Google Scholar 

  119. Chokshi, N. K. et al. The role of nitric oxide in intestinal epithelial injury and restitution in neonatal necrotizing enterocolitis. Semin. Perinatol. 32, 92–99 (2008).

    PubMed  PubMed Central  Google Scholar 

  120. Rhee, S. H., Pothoulakis, C. & Mayer, E. A. Principles and clinical implications of the brain–gut–enteric microbiota axis. Nat. Rev. Gastroenterol. Hepatol. 6, 306–314 (2009).

    CAS  PubMed  Google Scholar 

  121. El Aidy, S., Dinan, T. G. & Cryan, J. F. Immune modulation of the brain–gut–microbe axis. Front. Microbiol. 5, 146 (2014).

    PubMed  PubMed Central  Google Scholar 

  122. Veldhoen, M. & Brucklacher-Waldert, V. Dietary influences on intestinal immunity. Nat. Rev. Immunol. 12, 696–708 (2012).

    CAS  PubMed  Google Scholar 

  123. Renz, H., Brandtzaeg, P. & Hornef, M. The impact of perinatal immune development on mucosal homeostasis and chronic inflammation. Nat. Rev. Immunol. 12, 9–23 (2012).

    CAS  Google Scholar 

  124. van de Pavert, S. A. & Mebius, R. E. New insights into the development of lymphoid tissues. Nat. Rev. Immunol. 10, 664–674 (2010).

    CAS  PubMed  Google Scholar 

  125. Li, Y. et al. Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 147, 629–640 (2011).

    CAS  PubMed  Google Scholar 

  126. Kiss, E. A. et al. Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science 334, 1561–1565 (2011).

    CAS  PubMed  Google Scholar 

  127. Lee, J. S. et al. AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch. Nat. Immunol. 13, 144–151 (2012).

    CAS  Google Scholar 

  128. Qiu, J. et al. The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity 36, 92–104 (2012).

    CAS  PubMed  Google Scholar 

  129. Chieppa, M., Rescigno, M., Huang, A. Y. & Germain, R. N. Dynamic imaging of dendritic cell extension into the small bowel lumen in response to epithelial cell TLR engagement. J. Exp. Med. 203, 2841–2852 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 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).

    CAS  PubMed  Google Scholar 

  131. Satpathy, A. T. et al. Notch2-dependent classical dendritic cells orchestrate intestinal immunity to attaching-and-effacing bacterial pathogens. Nat. Immunol. 14, 937–948 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Zaghouani, H., Hoeman, C. M. & Adkins, B. Neonatal immunity: faulty T-helpers and the shortcomings of dendritic cells. Trends Immunol. 30, 585–591 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Jaensson, E. et al. Small intestinal CD103+ dendritic cells display unique functional properties that are conserved between mice and humans. J. Exp. Med. 205, 2139–2149 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Iwata, M. et al. Retinoic acid imprints gut-homing specificity on T cells. Immunity 21, 527–538 (2004).

    CAS  PubMed  Google Scholar 

  135. Mora, J. R. et al. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 314, 1157–1160 (2006).

    CAS  PubMed  Google Scholar 

  136. Sommer, A. Vitamin A deficiency and clinical disease: an historical overview. J. Nutr. 138, 1835–1839 (2008).

    CAS  PubMed  Google Scholar 

  137. Cheroutre, H., Lambolez, F. & Mucida, D. The light and dark sides of intestinal intraepithelial lymphocytes. Nat. Rev. Immunol. 11, 445–456 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Ooi, J. H., Chen, J. & Cantorna, M. T. Vitamin D regulation of immune function in the gut: why do T cells have vitamin D receptors? Mol. Aspects Med. 33, 77–82 (2012).

    CAS  PubMed  Google Scholar 

  139. Yu, S., Bruce, D., Froicu, M., Weaver, V. & Cantorna, M. T. Failure of T cell homing, reduced CD4/CD8αα intraepithelial lymphocytes, and inflammation in the gut of vitamin D receptor KO mice. Proc. Natl Acad. Sci. USA 105, 20834–20839 (2008).

    CAS  PubMed  Google Scholar 

  140. Gaboriau-Routhiau, V. et al. The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 31, 677–689 (2009).

    CAS  PubMed  Google Scholar 

  141. Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Huber, S., Gagliani, N. & Flavell, R. A. Life, death, and miracles: Th17 cells in the intestine. Eur. J. Immunol. 42, 2238–2245 (2012).

    CAS  PubMed  Google Scholar 

  143. Fujino, S. et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut 52, 65–70 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Seiderer, J. et al. Role of the novel Th17 cytokine IL-17F in inflammatory bowel disease (IBD): upregulated colonic IL-17F expression in active Crohn's disease and analysis of the IL17F p.His161Arg polymorphism in IBD. Inflamm. Bowel Dis. 14, 437–445 (2008).

    PubMed  Google Scholar 

  145. Duerr, R. H. et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Elson, C. O. et al. Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice. Gastroenterology 132, 2359–2370 (2007).

    CAS  PubMed  Google Scholar 

  147. Lee, Y. K. et al. Late developmental plasticity in the T helper 17 lineage. Immunity 30, 92–107 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Tanoue, T. & Honda, K. Induction of Treg cells in the mouse colonic mucosa: a central mechanism to maintain host-microbiota homeostasis. Semin. Immunol. 24, 50–57 (2012).

    CAS  PubMed  Google Scholar 

  149. Huber, S. et al. Th17 cells express interleukin-10 receptor and are controlled by Foxp3 and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner. Immunity 34, 554–565 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Rubtsov, Y. P. et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28, 546–558 (2008).

    CAS  PubMed  Google Scholar 

  151. Franke, A. et al. Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat. Genet. 40, 1319–1323 (2008).

    CAS  PubMed  Google Scholar 

  152. Glocker, E. O., Kotlarz, D., Klein, C., Shah, N. & Grimbacher, B. IL-10 and IL-10 receptor defects in humans. Ann. NY Acad. Sci. 1246, 102–107 (2011).

    CAS  PubMed  Google Scholar 

  153. Khor, B., Gardet, A. & Xavier, R. J. Genetics and pathogenesis of inflammatory bowel disease. Nature 474, 307–317 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Josefowicz, S. Z. et al. Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature 482, 395–399 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Mucida, D. et al. Oral tolerance in the absence of naturally occurring Tregs. J. Clin. Invest. 115, 1923–1933 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Cha, H. R. et al. Downregulation of Th17 cells in the small intestine by disruption of gut flora in the absence of retinoic acid. J. Immunol. 184, 6799–6806 (2010).

    CAS  PubMed  Google Scholar 

  157. Wang, C., Kang, S. G., Hogen Esch, H., Love, P. E. & Kim, C. H. Retinoic acid determines the precise tissue tropism of inflammatory Th17 cells in the intestine. J. Immunol. 184, 5519–5526 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  159. Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451–455 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  161. Geuking, M. B., McCoy, K. D. & Macpherson, A. J. Metabolites from intestinal microbes shape Treg. Cell Res. 23, 1339–1340 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Xu, W. & Di Santo, J. P. Taming the beast within: regulation of innate lymphoid cell homeostasis and function. J. Immunol. 191, 4489–4496 (2013).

    CAS  PubMed  Google Scholar 

  163. Spencer, S. P. et al. Adaptation of innate lymphoid cells to a micronutrient deficiency promotes type 2 barrier immunity. Science 343, 432–437 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. van de Pavert, S. A. et al. Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity. Nature 508, 123–127 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Aagaard, K. et al. The placenta harbors a unique microbiome. Sci. Transl. Med. 6, 237ra65 (2014).

    PubMed  PubMed Central  Google Scholar 

  166. Mold, J. E. & McCune, J. M. Immunological tolerance during fetal development: from mouse to man. Adv. Immunol. 115, 73–111 (2012).

    CAS  PubMed  Google Scholar 

  167. Gareau, M. G., Sherman, P. M. & Walker, W. A. Probiotics and the gut microbiota in intestinal health and disease. Nat. Rev. Gastroenterol. Hepatol. 7, 503–514 (2010).

    PubMed  PubMed Central  Google Scholar 

  168. Rautava, S., Luoto, R., Salminen, S. & Isolauri, E. Microbial contact during pregnancy, intestinal colonization and human disease. Nat. Rev. Gastroenterol. Hepatol. 9, 565–576 (2012).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

N.J. would like to acknowledge the support of the Charles King Trust/Charles Hood Foundation Postdoctoral Fellowship Award. W.A.W. would like to acknowledge the support of grants P30 DK040561, P01 DK33506, R01 HD012447 and R01 HD059126.

Author information

Authors and Affiliations

Authors

Contributions

N.J. and W.A.W. researched data for the article and N.J. wrote the article. N.J. and W.A.W. contributed equally to discussions of the content and to reviewing the manuscript before submission.

Corresponding author

Correspondence to Nitya Jain.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jain, N., Walker, W. Diet and host–microbial crosstalk in postnatal intestinal immune homeostasis. Nat Rev Gastroenterol Hepatol 12, 14–25 (2015). https://doi.org/10.1038/nrgastro.2014.153

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrgastro.2014.153

This article is cited by

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