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The role of gut microbiota in programming the immune phenotype

  • M. Weng (a1) and W. A. Walker (a1)

Abstract

The human fetus lives in a germ-free intrauterine environment and enters the outside world containing microorganisms from several sources, resulting in gut colonization. Full-term, vaginally born infants are completely colonized with a diverse array of bacterial families in clusters (Phyla) and species (>1000) by the first year of life. Colonizing bacteria communicating with the gut epithelium and underlying lymphoid tissues (‘bacterial–epithelial crosstalk’) result in a functional immune phenotype and no expression of disease (immune homeostasis). Appropriate colonization is influenced by the prebiotic effect of breast milk oligosaccharides. Adequate colonization results in an innate and adaptive mucosal immune phenotype via communication between molecular patterns on colonizing bacteria and pattern-recognition receptors (e.g., toll-like receptors) on epithelial and lymphoid cells. This ontogeny affects the immune system's capacity to develop oral tolerance to innocuous bacteria and benign antigens. Inadequate intestinal colonization with premature delivery, delivery by Cesarean section and excessive use of perinatal antibiotics results in the absence of adequate bacterial–epithelial crosstalk and an increased incidence of immune-mediated diseases [e.g., asthma, allergy in general and necrotizing enterocolitis (NEC)]. Fortunately, infants with inadequate intestinal colonization can be restored to a bacterial balance with the intake of probiotics. This has been shown to prevent debilitating diseases such as NEC. Thus, understanding the role of gut microbiota in programming of the immune phenotype may be important in preventing disease expression in later childhood and adulthood.

Copyright

Corresponding author

*Address for correspondence: Dr W. A. Walker, Mucosal Immunology Laboratory, Division of Gastroenterology, Department of Pediatrics, Massachusetts General Hospital for Children, Harvard Medical School, 114 16th Street (114-3503), Charlestown, MA 02129 4404, USA. (Email wwalker@partners.org)

References

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1.Walker, WA. Bacterial colonization, probiotics, and development of intestinal host defense. Funct Food Rev. 2009; 1, 1319.
2.Palmer, C, Bik, EM, Digiulio, DB, Relman, DA, Brown, P. Development of the human infant intestinal microbiota. Plos One. 2007; 5, e177.
3.Arumugam, M, Raes, J, Pelletier, E, et al. Enterotypes of the human gut microbiome. Nature. 2011; 473, 174180.
4.De Filippo, C, Cavalieri, D, Di Paola, M, et al. Impact of diet in shaping gut microbiota revealed by comparative study in children in Europe and rural Africa. Proc Natl Acad Sci U S A. 2010; 107, 1469114696.
5.Kim, JH, Ellwood, PE, Asher, MI. Diet and asthma: looking back, moving forward. Respir Res. 2009; 10, 49.
6.Fanaro, S, Chierici, R, Guerrini, P, Vigi, V. Intestinal microflora in early infancy: composition and development. Acta Paediatr Suppl. 2003; 91, 4855.
7.Sjögren, YM, Tomicic, S, Lundberg, A, et al. Influence of early gut microbiota on the maturation of childhood mucosal and systemic immune responses. Clin Exp Allergy. 2009; 39, 18421851.
8.Chichlowski, M, Guillaume, DL, German, JB, et al. Bifidobacteria isolated from infants and cultured in human milk oligosaccharides effect the intestinal epithelial function. J Pediatr Gastroenterol Nutr. 2012; 55, 321327.
9.Garrido, D, Kim, JH, German, JB, et al. Oligosaccharide binding proteins from Bifidobacterium longum subsp. Infantis reveal a preference for host glycans. PLoS One. 2011; 6, e17315.
10.Artis, D. Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut. Nat Rev Immunol. 2008; 8, 411420.
11.Hooper, LV, Littman, DR, Macpherson, AJ. Interactions between the microbiota and the immune system. Science. 2012; 336, 12681273.
12.Ubeda, C, Pamer, EG. Antibiotics, microbiota, and immune defense. Trends Immunol. 2012; 33, 459466.
13.Elson, CO, Cong, Y. Host-microbiota interactions in inflammatory bowel disease. Gut Microbes. 2012; 3, 332344.
14.Yu, LC, Wang, JT, Wei, SC, Ni, YH. Host-microbial interactions and regulation of intestinal epithelial barrier function: from physiology to pathology. World J Gastrointest Pathophysiol. 2012; 3, 2743.
15.Molloy, MJ, Bouladoux, N, Belkaid, Y. Intestinal microbiota: shaping local and systemic immune responses. Semin Immunol. 2012; 24, 5866.
16.Tanoue, T, Honda, K. Induction of Treg cells in the mouse colonic mucosa: a central mechanism to maintain host-microbiota homeostasis. Semin Immunol. 2012; 24, 5057.
17.Gordon, HA, Pestl, L. The gnotobiotic animal as a tool in the study of host microbial relationships. Bacteriol Rev. 1971; 35, 390429.
18.Smith, K, McCoy, KD, Macpherson, AJ. Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. Semin Immunol. 2007; 19, 5969.
19.Bauer, H, Horowitz, RE, Levenson, SM, Popper, H. The response of the lymphatic tissue to the microbial flora. Studies on germfree mice. Am J Pathol. 1963; 42, 471483.
20.Chung, H, Pamp, SJ, Hill, JA, et al. Gut immune maturation depends on colonization with a host-specific microbiota. Cell. 2012; 149, 15781593.
21.Jiang, HQ, Thurnheer, MC, Zuercher, AW, et al. Interactions of commensal gut microbes with subsets of B- and T- cells in the murine host. Vaccine. 2004; 22, 805811.
22.Hooper, LV, Wong, MH, Thelin, A, et al. Molecular analysis of commensal host-microbial relationships in the intestine. Science. 2001; 291, 881884.
23.Itoh, K, Mitsuoka, T. Characterization of clostridia isolated from faeces of limited flora mice and their effect on caecal size when associated with germ-free mice. Lab Anim. 1985; 19, 111118.
24.Kleerebezem, M, Vaughan, EE. Probiotic and gut lactobacilli and bifidobacteria: molecular approaches to study diversity and activity. Annu Rev Microbiol. 2009; 63, 269290.
25.Mazmanian, SK, Liu, CH, Tzianabos, AO, Kasper, DL. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell. 2005; 122, 107118.
26.McGuckin, MA, Lindén, SK, Sutton, P, Florin, TH. Mucin dynamics and enteric pathogens. Nat Rev Microbiol. 2011; 9, 265278.
27.Hattrup, CL, Gendler, SJ. Structure and function of the cell surface (tethered) mucins. Annu Rev Physiol. 2008; 70, 431457.
28.Thornton, DJ, Rousseau, K, McGuckin, MA. Structure and function of the polymeric mucins in airways mucus. Annu Rev Physiol. 2008; 70, 459486.
29.Moran, AP, Gupta, A, Joshi, L. Sweet-talk: role of host glycosylation in bacterial pathogenesis of the gastrointestinal tract. Gut. 2011; 60, 14121425.
30.Deplancke, B, Gaskins, HR. Microbial modulation of innate defense: goblet cells and the intestinal mucus layer. Am J Clin Nutr. 2001; 73, 1131S1141S.
31.Bevins, CL, Salzman, NH. Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis. Nat Rev Microbiol. 2011; 9, 356368.
32.Ganz, T, Selsted, ME, Szklarek, D, et al. Defensins. Natural peptide antibiotics of human neutrophils. J Clin Invest. 1985; 76, 142714142735.
33.Ouellette, AJ, Miller, SI, Henschen, AH, Selsted, ME. Purification and primary structure of murine cryptdin-1, a Paneth cell defensin. FEBS Lett. 1992; 304, 146148.
34.Lehrer, RI, Ganz, T. Defensins: endogenous antibiotic peptides from human leukocytes. Ciba Found Symp. 1992; 171, 276290.
35.Wilson, CL, Schmidt, AP, Pirilä, E, et al. Differential processing of {alpha}- and {beta}- defensin precursors by matrix metalloproteinase-7 (MMP-7). J Biol Chem. 2009; 284, 83018311.
36.Ayabe, T, Satchell, DP, Wilson, CL, et al. Secretion of microbicidal alpha-defensins by intestinal Paneth cells in response to bacteria. Nat Immunol. 2000; 1, 113118.
37.Vaishnava, S, Behrendt, CL, Ismail, AS, et al. Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. Proc Natl Acad Sci U S A. 2008; 105, 2085820863.
38.Salzman, NH, Hung, K, Haribhai, D, et al. Enteric defensins are essential regulators of intestinal microbial ecology. Nat Immunol. 2010; 11, 7683.
39.Mostov, KE. Transepithelial transport of immunoglobulins. Annu Rev Immunol. 1994; 12, 6384.
40.Cerutti, A, Rescigno, M. The biology of intestinal immunoglobulin A responses. Immunity. 2008; 28, 740750.
41.Macpherson, AJ, Gatto, D, Sainsbury, E, et al. A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. Science. 2000; 288, 22222226.
42.Lindner, C, Wahl, B, Föhse, L, et al. Age, microbiota, and T cells shape diverse individual IgA repertoires in the intestine. J Exp Med. 2012; 209, 365377.
43.Hapfelmeier, S, Lawson, MA, Slack, E, et al. Reversible microbial colonization of germ-free mice reveals the dynamics of IgA immune responses. Science. 2010; 328, 17051709.
44.Dominguez-Bello, MG, Blaser, MJ, Ley, RE, Knight, R. Development of the human gastrointestinal microbiota and insights from high-throughput sequencing. Gastroenterology. 2011; 140, 17131719.
45.Renz, H, Brandtzaeg, P, Hornef, M. The impact of perinatal immune development on mucosal homeostasis and chronic inflammation. Nat Rev Immunol. 2011; 12, 923.
46.Johansen, FE, Kaetzel, CS. Regulation of the polymeric immunoglobulin receptor and IgA transport: new advances in environmental factors that stimulate pIgR expression and its role in mucosal immunity. Mucosal Immunol. 2011; 4, 598602.
47.Hooper, LV, Wong, MH, Thelin, A, et al. Molecular analysis of commensal host-microbial relationships in the intestine. Science. 2001; 291, 881884.
48.Cebra, JJ, Gearhart, PJ, Kamat, R, et al. Origin and differentiation of lymphocytes involved in the secretory IgA responses. Cold Spring Harb Symp Quant Biol. 1977; 41(Pt 1), 201215.
49.Bouskra, D, Brézillon, C, Bérard, M, et al. Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature. 2008; 456, 507510.
50.Fagarasan, S. Intestinal IgA synthesis: a primitive form of adaptive immunity that regulates microbial communities in the gut. Curr Top Microbiol Immunol. 2006; 308, 137153.
51.Ivanov, II, Diehl, GE, Littman, DR. Lymphoid tissue inducer cells in intestinal immunity. Curr Top Microbiol Immunol. 2006; 308, 5982.
52.Girardin, SE, Boneca, IG, Carneiro, LA, et al. Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan. Science. 2003; 300, 15841587.
53.Round, JL, Lee, SM, Li, J, et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science. 2011; 332, 974977.
54.Rakoff-Nahoum, S, Paglino, J, Eslami-Varzaneh, F, et al. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell. 2004; 118, 229241.
55.Macpherson, AJ, Uhr, T. Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science. 2004; 303, 16621665.
56.Hapfelmeier, S, Müller, AJ, Stecher, B, et al. Microbe sampling by mucosal dendritic cells is a discrete, MyD88-independent step in Typhimurium colitis. J Exp Med. 2008; 205, 437450.
57.Rescigno, M, Urbano, M, Valzasina, B, et al. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat Immunol. 2001; 2, 361367.
58.Chieppa, M, Rescigno, M, Huang, AY, Germain, RN. Dynamic imaging of dendritic cell extension into the small bowel lumen in response to epithelial cell TLR engagement. J Exp Med. 2006; 203, 28412852.
59.Chabot, S, Wagner, JS, Farrant, S, Neutra, MR. TLRs regulate the gatekeeping functions of the intestinal follicle-associated epithelium. J Immunol. 2006; 176, 42754283.
60.Strober, W. Epithelial cells pay a Toll for protection. Nat Med. 2004; 10, 898900.
61.Zeuthen, LH, Fink, LN, Frokiaer, H. Epithelial cells prime the immune response to an array of gut-derived commensals towards a tolerogenic phenotype through distinct actions of thymic stromal lymphopoietin and transforming growth factor-beta. Immunology. 2008; 123, 197208.
62.Granucci, F, Zanoni, I. Role of Toll like receptor-activated dendritic cells in the development of autoimmunity. Front Biosci. 2008; 13, 48174826.
63.Rutella, S, Locatelli, F. Intestinal dendritic cells in the pathogenesis of inflammatory bowel disease. World J Gastroenterol. 2011; 17, 37613775.
64.Figdor, CG, van Kooyk, Y, Adema, GJ. C-type lectin receptors on dendritic cells and Langerhans cells. Nat Rev Immunol. 2002; 2, 7784.
65.Smits, HH, Engering, A, van der Kleij, D, et al. Selective probiotic bacteria induce IL-10-producing regulatory T cells in vitro by modulating dendritic cell function through dentritic cell-specific intercellular adhesion moledule-3-grabbing nonintegrin. J Allergy Clin Immunol. 2005; 115, 12601267.
66.Konieczna, P, Groeger, D, Ziegler, M, et al. Bifidobacterium infantis 35624 administration induces Foxp3 T regulatory cells in human peripheral blood: potential role for myeloid and plasmacytoid dendritic cells. Gut. 2012; 61, 354366.
67.Swiatczak, B, Rescigno, M. How the interplay between antigen presenting cells and microbiota tunes host immune responses in the gut. Semin Immunol. 2012; 24, 4349.
68.Sudo, N, Sawamura, S, Tanaka, K, et al. The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance induction. J Immunol. 1997; 159, 17391745.
69.Karlsson, MR, Kahu, H, Hanson, LA, et al. Neonatal colonization of rats induces immunological tolerance to bacterial antigens. Eur J Immunol. 1999; 29, 109118.
70.Belkaid, Y, Oldenhove, G. Tuning microenvironments: induction of regulatory T cells by dendritic cells. Immunity. 2008; 29, 362371.
71.Hauet-Broere, F, Unger, WW, Garssen, J, et al. Functional CD25- and CD25+ mucosal regulatory T cells are induced in gut-draining lymphoid tissue within 48 h after oral antigen application. Eur J Immunol. 2003; 33, 28012810.
72.Feuerer, M, Hill, JA, Kretschmer, K, et al. Genomic definition of multiple ex vivo regulatory T cell subphenotypes. Proc Natl Acad Sci U S A. 2010; 107, 59195924.
73.Chaudhry, A, Rudra, D, Treuting, P, et al. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science. 2009; 326, 986991.
74.Hadis, U, Wahl, B, Schulz, O, et al. Intestinal tolerance requires gut homing and expansion of FoxP3+ regulatory T cells in the lamina propria. Immunity. 2011; 34, 237246.
75.Rodriguez, B, Prioult, G, Hacini-Rachinel, F, et al. Infant gut microbiota is protective against cow's milk allergy in mice despite immature ileal T-cell response. FEMS Microbiol Ecol. 2012; 79, 192202.
76.Ohue, R, Hashimoto, K, Nakamoto, M, et al. Bacterial heat shock protein 60, GroEL, can induce the conversion of naïve T cells into a CD4 CD25(+) Foxp3-expressing phenotype. J Innate Immunol. 2011; 3, 605613.
77.Nagano, Y, Itoh, K, Honda, K. The induction of Treg cells by gut-indigenous Clostridium. Curr Opin Immunol. 2012; 24, 392397.
78.Atarashi, K, Tanoue, T, Shima, T, et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science. 2011; 331, 337341.
79.Finamore, A, Roselli, M, Britti, MS, et al. Lactobacillus rhamnosus GG and Bifidobacterium animalis MB5 induce intestinal but not systemic antigen-specific hyporesponsiveness in ovalbumin-immunized rats. J Nutr. 2012; 142, 375381.
80.Zhang, LL, Chen, X, Zheng, PY, et al. Oral Bifidobacterium modulates intestinal immune inflammation in mice with food allergy. J Gastroenterol Hepatol. 2010; 25, 928934.
81.O'Mahony, C, Scully, P, O'Mahony, D, et al. Commensal-induced regulatory T cells mediate protection against pathogen-stimulated NF-KappaB activation. PLoS Pathog. 2008; 4, 41000112.
82.Round, JL, Mazmanian, SK. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc Natl Acad Sci U S A. 2010; 107, 1220412209.
83.Mazmanian, SK, Round, JL, Kasper, DL. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature. 2008; 453, 620625.
84.Round, JL, Lee, SM, Li, J, et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science. 2011; 332, 974977.
85.Neish, AS, Gewirtz, AT, Zeng, H, et al. Prokaryotic regulation of epithelial responses by inhibition of I-kappaB-alpha ubiquitination. Science. 2000; 289, 15601563.
86.Collier-Hyams, LS, Sloane, V, Batten, BC, Neish, AS. Cutting edge: bacterial modulation of epithelial signaling via changes in neddylation of cullin-1. J Immunol. 2005; 175, 41944198.
87.Tien, MT, Girardin, SE, Regnault, B, et al. Anti-inflammatory effect of Lactobacillus casei on Shigella-infected human intestinal epithelial cells. J Immunol. 2006; 176, 12281237.
88.Kelly, D, Campbell, JI, King, TP, et al. Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-gamma and RelA. Nat Immunol. 2004; 5, 104112.
89.Risnes, KR, Belanger, K, Murk, W, et al. Antibiotic exposure by 6 months and asthma and allergy at 6 years: findings in cohort of 1,401 US children. Am J Epidemiol. 2011; 173, 310318.
90.Eggesbo, M, Botten, G, Stigum, H, et al. Is delivery by cesarean section a risk factor for food allergy? J Allergy Clin Immunol. 2003; 112, 420426.
91.Märild, K, Stephansson, O, Montgomery, S, et al. Pregnancy outcome and risk of celiac disease in offspring: a nationwide case-control study. Gastroenterology. 2012; 142, 39.e345.e3.
92.Sanderson, IR, Walker, WA. Establishment of a human fetal small intestinal epithelial cell line. Int Arch Allergy Immunol. 1995; 107, 396397.
93.Tanaka, M, Lee, K, Martinez-Augustin, O, et al. Exogenous nucleotides alter the proliferation, differentiation and apoptosis of human small intestinal epithelium. J Nutr. 1996; 126, 424433.
94.Savidge, TC, Lowe, DC, Walker, WA. Developmental regulation of intestinal epithelial hydrolase activity in human fetal jejunal xenografts maintained in severe-combined immunodeficient mice. Pediatr Res. 2001; 50, 196202.
95.Cotten, CM, Taylor, S, Stoll, B, et al. Prolonged duration of initial empirical antibiotic treatment is associated with increased rates of necrotizing enterocolitis and death for extremely low birth weight infants. Pediatrics. 2009; 123, 5866.
96.Calhoun, DA. Enteral administration of hematopoietic growth factors in the neonatal intensive care unit. Acta Paediatr Suppl. 2002; 91, 4353.
97.Claud, EC, Lu, L, Anton, PM, et al. Developmentally-regulated IκB expression in intestinal epithelium and susceptibility to flagellin-induced inflammation. Proc Natl Acad Sci USA. 2004; 101, 74047408.
98.Nanthakumar, NN, Fusunyan, RD, Sanderson, I, Walker, WA. Inflammation in the developing human intestine: A possible pathophysiologic contribution to necrotizing enterocolitis. Proc Natl Acad Sci USA. 2000; 97, 60436048.
99.Nanthakumar, N, Meng, D, Goldstein, AM, et al. The mechanism of excessive intestinal inflammation in necrotizing enterocolitis: an immature innate immune response. PLoS One. 2011; 6, e17776.
100.Deshpande, G, Rao, S, Patole, S. Probiotics for preventing necrotizing enterocolitis in preterm neonates: a meta-analysis perspective. Funct Food Rev. 2011; 3, 2230.
101.Lin, HC, Su, BH, Chen, AC, et al. Oral probiotics reduce the incidence and severity of necrotizing enterocolitis in very low birth weight infants. Pediatrics. 2005; 115, 14.
102.Lin, HC, Hsu, CH, Chen, HL, et al. Oral probiotics prevent necrotizing enterocolitis in very low birth weight preterm infants: a multicenter, randomized, controlled trial. Pediatrics. 2008; 122, 693700.
103.Ganguli, K, Meng, D, Rautava, S, et al. Probiotics prevent necrotizing enterocolitis by modulating enterocyte genes that regulate innate immune-mediated inflammation. Am J Phys: Gastrointestinal and Liver Physiology. 2012; Nov 8 [Epub ahead of print].
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