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The role of gut-associated lymphoid tissues and mucosal defence

Published online by Cambridge University Press:  08 March 2007

Maria Luisa Forchielli
Affiliation:
Department of Pediatrics, University of Bologna, Bologna, Italy Department of Pediatrics, Harvard Medical School, Boston, MA, USA
W. Allan Walker*
Affiliation:
Department of Pediatrics, Harvard Medical School, Boston, MA, USA Harvard Medical School, Mucosal Immunology Laboratories, Massachusetts General Hospital, Boston, MA, USA
*
*Corresponding author: Professor W. Allan Walker, fax +1 617 432 2988, email allan_walker@hms.harvard.edu
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Abstract

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The newborn infant leaves a germ-free intrauterine environment to enter a contaminated extrauterine world and must have adequate intestinal defences to prevent the expression of clinical gastrointestinal disease states. Although the intestinal mucosal immune system is fully developed after a full-term birth, the actual protective function of the gut requires the microbial stimulation of initial bacterial colonization. Breast milk contains prebiotic oligosaccharides, like inulin-type fructans, which are not digested in the small intestine but enter the colon as intact large carbohydrates that are then fermented by the resident bacteria to produce SCFA. The nature of this fermentation and the consequent pH of the intestinal contents dictate proliferation of specific resident bacteria. For example, breast milk-fed infants with prebiotics present in breast milk produce an increased proliferation of bifidobacteria and lactobacilli (probiotics), whereas formula-fed infants produce more enterococci and enterobacteria. Probiotics, stimulated by prebiotic fermentation, are important to the development and sustainment of intestinal defences. For example, probiotics can stimulate the synthesis and secretion of polymeric IgA, the antibody that coats and protects mucosal surfaces against harmful bacterial invasion. In addition, appropriate colonization with probiotics helps to produce a balanced T helper cell response (Th1 = Th2 = Th3/Tr1) and prevent an imbalance (Th1 > Th2 or Th2 > Th1) contributing in part to clinical disease (Th2 imbalance contributes to atopic disease and Th1 imbalance contributes to Crohn's disease and Helicobacter pylori-induced gastritis). Furthermore, a series of pattern recognition receptors, toll-like receptors on gut lymphoid and epithelial cells that interact with bacterial molecular patterns (e.g. endotoxin (lipopolysaccharide), flagellin, etc.), help modulate intestinal innate immunity and an appropriate adaptive immune response. Animal and clinical studies have shown that inulin-type fructans will stimulate an increase in probiotics (commensal bacteria) and these bacteria have been shown to modulate the development and persistence of appropriate mucosal immune responses. However, additional studies are needed to show that prebiotics can directly or indirectly stimulate intestinal host defences. If this can be demonstrated, then prebiotics can be used as a dietary supplement to stimulate a balanced and an appropriately effective mucosal immune system in newborns and infants.

Type
Research Article
Copyright
Copyright © The Nutrition Society 2005

References

Akira, S, Takeda, K & Kaisho, T (2001) Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2, 675680.CrossRefGoogle ScholarPubMed
Borruel, N, Carol, M, Casellas, F, Antolin, M, de Lara, F, Espin, E, Naval, J, Guarner, F & Malagelada, JR (2002) Increased mucosal tumour necrosis factor α production in Crohn's disease can be downregulated ex vivo by probiotic bacteria. Gut 51, 659664.CrossRefGoogle ScholarPubMed
Bouhnik, Y, Flourie, B, D'Agay-Abensour, L, Pochart, P, Gramet, G, Durand, M & Rambaud, JC (1997) Administration of transgalacto-oligosaccharides increases fecal bifidobacteria and modifies colonic fermentation metabolism in healthy humans. J Nutr 127, 444448.CrossRefGoogle ScholarPubMed
Caramalho, I, Lopes-Carvalho, T, Ostler, D, Zelenay, S, Haury, M & Demengeot, J (2003) Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide. J Exp Med 197, 403411.CrossRefGoogle ScholarPubMed
Cario, E & Podolsky, DK (2000) Differential alteration in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infect Immun 68, 70107017.CrossRefGoogle ScholarPubMed
Cario, E, Brown, D, McKee, M, Lynch-Devaney, K, Gerken, G & Podolsky, DK (2002) Commensal-associated molecular patterns induce selective toll-like receptor-trafficking from apical membrane to cytoplasmic compartments in polarized intestinal epithelium. Am J Pathol 160, 165173.CrossRefGoogle ScholarPubMed
Catala, I, Butel, MJ, Bensaada, M, Popot, F, Tessedre, AC, Rimbault, A & Szylit, O (1999) Oligofructose contributes to the protective role of bifidobacteria in experimental necrotizing enterocolitis in quails. J Med Microbiol 48, 8994.CrossRefGoogle Scholar
Cebra, JJ (1999) Influences of microbiota on intestinal immune system development. Am J Clin Nutr 69, 1046s – 1051s.CrossRefGoogle ScholarPubMed
Clavano, NR (1982) Mode of feeding and its effect on infant mortality and morbidity. J Trop Pediatr 28, 287293.CrossRefGoogle ScholarPubMed
Dabbagh, K & Lewis, DB (2003) Toll-like receptors and T-helper-1/T-helper-2 responses. Curr Opin Infect Dis 16, 199204.CrossRefGoogle ScholarPubMed
Dai, D, Nanthkumar, N, Newberg, D & Walker, AW (2000) Role of oligosaccharides and glycoconjugates in intestinal host defence. J Pediatr Gastroenterol Nutr 30, S23S33.CrossRefGoogle Scholar
Edwards, AD, Diebold, SS, Slack, EM, Tomizawa, H, Hemmi, H, Kaisho, T, Akira, S & Reise, Sousa C (2003) Toll-like receptor expression in murine DC subsets: lack of TLR7 expression by CD8 alpha+ DC correlates with unresponsiveness to imidazoquinolines. Eur J Immunol 33, 827833.CrossRefGoogle ScholarPubMed
Falk, PG, Hooper, LV, Midtvedt, T & Gordon, JI (1999) Creating and maintaining the gastrointestinal ecosystem: what we know and need to know from gnotobiology. Microbiol Mol Biol Rev 62, 11571170.CrossRefGoogle Scholar
Fusunyan, RF, Nanthakumar, NN, Baldeon, ME & Walker, WA (2001) Evidence for an innate immune response in the immature human intestine: toll-like receptors on fetal enterocytes. Pediatr Res 49, 589593.CrossRefGoogle ScholarPubMed
Gewirtz, AT, Navas, TA, Lyons, S, Godowski, PJ & Madara, JL (2001) Cutting edge: bacterial flagellin activates basolaterally expressed tlr5 to induce epithelial proinflammatory gene expression. J Immunol 167, 18821885.CrossRefGoogle ScholarPubMed
Gibson, GR, Beatty, ER, Wang, X & Cummings, JH (1995) Selective stimulation of bifiodobacteria in the human colon by oligofructose and inulin. Gastroenterology 108, 975982.CrossRefGoogle ScholarPubMed
Hamada, H, Hiroi, T & Nishiyama, Y et al. (2002) Identification of multiple isolated lymphoid follicles on the antimesenteric wall of the mouse small intestine. J Immunol 168, 5764.CrossRefGoogle ScholarPubMed
Hershberg, RM & Mayer, LF (2000) Antigen processing and presentation by intestinal epithelial cells – polarity and complexity. Immunol Today 21, 2328.CrossRefGoogle ScholarPubMed
Higgins, SC, Lavelle, EC, McCann, C, Keogh, B, McNeela, E, Byrne, P, O'Gorman, B, Jarnicki, A, McGuirk, P & Mills, KH (2003) Toll-like receptor 4-mediated innate IL-10 activates antigen-specific regulatory T cells and confers resistance to Bordetella pertussis by inhibiting inflammatory pathology. J Immunol 171, 31193122.CrossRefGoogle ScholarPubMed
Hooper, LV, Wong, MH, Thelin, A, Hansson, L, Falk, PG & Gordon, JI (2002) Molecular analysis of comensal host–microbial relationships in the intestine. Science 291, 881884.CrossRefGoogle Scholar
Julia, V, McSorley, SS, Malherbe, L, Breittmayer, JP, Girard-Pipau, F, Beck, A & Glaichenhaus, N (2000) Priming by microbial antigens from the intestinal flora determines the ability of CD4+ T cells to rapidly secrete IL-4 in BALB/c mice infected with Leishmania major. J Immunol 165, 56375645.CrossRefGoogle ScholarPubMed
Khoo, UY, Proctor, IE & Macpherson, AJ (1997) CD4+ T cell down-regulation in human intestinal mucosa: evidence for intestinal tolerance to luminal bacterial antigens. J Immunol 158, 36263634.CrossRefGoogle ScholarPubMed
Lefrancois, L & Goodman, T (1989) In vivo modulation of cytolytic activity and Thy-1 expression in TCR-gamma delta+ intraepithelial lymphocytes. Science 243, 716718.CrossRefGoogle ScholarPubMed
Liu, T, Matsuguchi, T, Tsuboi, N, Yajima, T & Yoshikai, Y (2002) Differences in expression of toll-like receptors and their reactivities in dendritic cells in BALB/c and C57BL/6 mice. Infect Immun 70, 66386645.CrossRefGoogle ScholarPubMed
Liu, YJ, Kanzler, H, Soumelis, V & Gilliet, M (2003) Dendritic cell lineage, plasticity and cross-regulation. Nat Immunol 2, 585589.CrossRefGoogle Scholar
McCarthy, J, O'Mahony, L & O'Callaghan, L (2003) Double blind, placebo controlled trial of two probiotic strains in interleukin 10 knockout mice and mechanistic link with cytokine balance. Gut 52, 975980.CrossRefGoogle ScholarPubMed
Macpherson, AJ, Gatto, D, Sainsbury, E, Harriman, GR, Hengartner, H & Zinkernagel, RM (2001) A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. Science 288, 22222226.CrossRefGoogle Scholar
Madsen, KL, Doyle, JS, Jewell, LD, Tavernini, MM & Fedorak, RN (1999) Lactobacillus species prevents colitis in interleukin 10 gene-deficient mice. Gastroenterology 116, 11071114.CrossRefGoogle ScholarPubMed
Medzhitov, R, Preston-Hurlburt, P & Janeway, CA Jr (1997) A human homologue of the Drosophila toll protein signals activation of adaptive immunity. Nature 388, 394397.CrossRefGoogle ScholarPubMed
Melmed, G, Thomas, LS, Lee, N, Tesfay, SY, Lukasek, K, Michelsen, KS, Zhou, Y, Hu, B, Arditi, M & Abreu, MT (2003) Human intestinal epithelial cells are broadly unresponsive to toll-like receptor 2-dependent bacterial ligands: implications for host–microbial interactions in the gut. J Immunol 170, 14061415.CrossRefGoogle ScholarPubMed
Moreau, MC & Corthier, G (1988) Effect of the gastrointestinal microflora on induction and maintenance of oral tolerance to ovalbumin in C3H/HeJ mice. Infect Immun 56, 27662768.CrossRefGoogle ScholarPubMed
Moreau, MC & Gaboriau-Routhiau, V (1996) The absence of gut flora, the doses of antigen ingested and aging affect the long-term peripheral tolerance induced by ovalbumin feeding in mice. Res Immunol 147, 4959.CrossRefGoogle ScholarPubMed
Moreau, MC, Ducluzeau, R, Guy-Grand, D & Muller, MC (1988) Increase in the population of duodenal immunoglobulin A plasmocytes in mice associated with different living or dead bacterial strains of intestinal origin. Infect Immun 21, 532539.CrossRefGoogle Scholar
Moro, G, Minoli, I, Mosca, M, Fanaro, S, Jelinek, J, Stahl, B & Boehm, G (2002) Dosage-related bifidogenic effects of galacto- and fructooligosaccharides in formula-fed term infants. J Pediatr Gastroenterol Nutr 34, 291295.Google ScholarPubMed
Mottet, C, Uhlig, HH & Powrie, F (2003) Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. J Immunol 170, 39393943.CrossRefGoogle ScholarPubMed
Mushegian, A & Medzhitov, R (2001) Evolutionary perspective on innate immune recognition. J Cell Biol 155, 705710.CrossRefGoogle ScholarPubMed
Naik, S, Kelly, EJ, Meijer, L, Pettersson, S & Sanderson, IR (2001) Absence of toll-like receptor 4 explains endotoxin hyporesponsiveness in human intestinal epithelium. J Pediatr Gastroenterol Nutr 32, 449453.Google ScholarPubMed
Nanthakumar, NN, Dai, D, Newburg, DS & Walker, WA (2003) The role of indigenous microflora in the development of murine intestinal fucosyl- and sialyltransferases. FASEB J 17, 4446.CrossRefGoogle ScholarPubMed
Ortega-Cava, CF, Ishihara, S, Rumi, MA, Kawashima, K, Ishimura, N, Kazumori, H, Udagawa, J, Kadowaki, Y & Kinoshita, Y (2003) Strategic compartmentalization of toll-like receptor 4 in the mouse gut. J Immunol 170, 39773985.CrossRefGoogle ScholarPubMed
Qi, H, Denning, TL & Soong, L (2003) Differential induction of interleukin-10 and interleukin-12 in dendritic cells by microbial toll-like receptor activators and skewing of T-cell cytokine profiles. Infect Immun 71, 33373342.CrossRefGoogle ScholarPubMed
Re, F & Strominger, JL (2001) Toll-like receptor 2 (TLR2) and TLR4 differentially activate human dendritic cells. J Biol Chem 276, 3769237699.CrossRefGoogle ScholarPubMed
Read, S, Malmstrom, V & Powrie, F (2000) Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25+CD4+ regulatory cells that control intestinal inflammation. J Exp Med 192, 295302.CrossRefGoogle ScholarPubMed
Rescigno, M, Urbano, M, Valzasina, B, Francolini, M, Rotta, G, Bonasio, R, Granucci, F, Kraehenbuhl, JP & Ricciardi-Castagnoli, P (2001) Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat Immunol 2, 361367.CrossRefGoogle ScholarPubMed
Roller, M, Rechkemmer, & Watzl, B (2004) Prebiotic inulin enriched with oligofructose in combination with the probiotics Lactobacillus rhamnosus and Bifidobacterium lactis modulates intestinal immune functions in rats. J Nutr 134, 153156.CrossRefGoogle ScholarPubMed
Savidge, TC, Smith, MW, James, PS & Aldred, P (1991) Salmonella-induced M-cell formation in germ-free mouse Peyer's patch tissue. Am J Pathol 139, 177184.Google ScholarPubMed
Sghir, A, Chow, JM & Mackie, RI (1998) Continuous culture selection of bifidobacteria and lactobacilli from human faecal samples using fructooligosaccharide as selective substrate. J Appl Microbiol 85, 769777.CrossRefGoogle ScholarPubMed
Shevach, EM (2000) Suppressor T cells: rebirth, function and homeostasis. Curr Biol 10, R572R578.CrossRefGoogle ScholarPubMed
Steege, JC, Buurman, WA & Forget, PP (1997) The neonatal development of intraepithelial and lamina propria lymphocytes in the murine small intestine. Dev Immunol 5, 11211128.CrossRefGoogle ScholarPubMed
Sudo, N, Sawamura, S, Tanaka, K, Aiba, Y, Kubo, C & Koga, Y (1997) The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance induction. J Immunol 159, 17391745.CrossRefGoogle ScholarPubMed
Suri-Payer, E, Amar, AZ, Thornton, AM & Shevach, EM (1998) CD4+CD25+ T cells inhibit both the induction and effector function of autoreactive T cells and represent a unique lineage of immunoregulatory cells. J Immunol 160, 12121218.CrossRefGoogle ScholarPubMed
Talham, GL, Jiang, HQ, Bos, NA & Cebra, JJ (1999) Segmented filamentous bacteria are potent stimuli of a physiologically normal state of the murine gut mucosal immune system. Infect Immun 67, 19922000.CrossRefGoogle ScholarPubMed
Wannemuehler, MJ, Kiyono, H, Babb, JL, Michalek, SM & McGhee, JR (1992) Lipopolysaccharide (LPS) regulation of the immune response: LPS converts germfree mice to sensitivity to oral tolerance induction. J Immunol 129, 959965.CrossRefGoogle Scholar
Yamanaka, T, Helgeland, L, Farstad, IN, Fukushima, H, Midtvedt, T & Brandtzaeg, P (2005) Microbial colonization drives lymphocyte accumulation and differentiation in the follicle-associated epithelium of Peyer's patches. J Immunol 170, 816822.CrossRefGoogle Scholar
Yan, F & Polk, DB (2002) Probiotic bacterium prevents cytokine-induced apoptosis in intestinal epithelial cells. J Biol Chem 277, 5095950965.CrossRefGoogle ScholarPubMed
Yoshioka, H, Iseki, K & Fujita, K (1983) Development and differences of intestinal flora in the neonatal period in breast-fed and bottle-fed infants. Pediatrics 72, 317321.CrossRefGoogle ScholarPubMed
Zapolska-Downar, D, Siennicka, A, Kaczmarczyk, M, Kolodieg, B & Nruszewicz, M (2004) Butyrate inhibits cytokine-induced VCAM-1 and ICAM-1 expression in cultured endothelial cells: the role of NF-κB and PPARα. J Nutr Biochem 15, 220228.CrossRefGoogle ScholarPubMed