New therapeutic strategy for combating the increasing burden of allergic disease: Probiotics—A Nutrition, Allergy, Mucosal Immunology and Intestinal Microbiota (NAMI) Research Group report
2005; Elsevier BV; Volume: 116; Issue: 1 Linguagem: Inglês
10.1016/j.jaci.2005.02.010
ISSN1097-6825
AutoresSamuli Rautava, Marko Kalliomäki, Erika Isolauri,
Tópico(s)Pediatric health and respiratory diseases
ResumoThe dietary approach to reducing the risk of atopic diseases in infancy is evolving from passive allergen avoidance to active stimulation of the immature immune system, the aim of which is to support the establishment of tolerance. The intestinal mucosa and the mucosa-associated immune system are the primary loci of allergen contact and induction of immune responsiveness. In this review we discuss cross-talk between the intestinal microbiota and the host as it pertains to healthy immunologic maturation. Understanding these complex phenomena provides the rationale for the use of probiotics in reducing the risk and nutritional management of atopic disease. The dietary approach to reducing the risk of atopic diseases in infancy is evolving from passive allergen avoidance to active stimulation of the immature immune system, the aim of which is to support the establishment of tolerance. The intestinal mucosa and the mucosa-associated immune system are the primary loci of allergen contact and induction of immune responsiveness. In this review we discuss cross-talk between the intestinal microbiota and the host as it pertains to healthy immunologic maturation. Understanding these complex phenomena provides the rationale for the use of probiotics in reducing the risk and nutritional management of atopic disease. The basic foundation of nutrition lies in a healthy balanced diet to meet the needs for growth and development in children. The first goal here is directed toward the prevention of diet-related deficiencies, and the second target is reduction of the risk of nutrition-related chronic diseases. Dietary attempts to reduce the risk of allergic disease have hitherto focused on elimination diets, even though the results of different elimination procedures with dietary restrictions alone or in combination with some other environmental control measures have been inconclusive regarding the long-term prevention of atopic diseases.1Zeiger R.S. Dietary manipulations in infants and their mothers and the natural course of atopic disease.Pediatr Allergy Immunol. 1994; 5: 33-43Crossref PubMed Scopus (35) Google Scholar Indeed, the association between antigen exposure and the development of atopic disease appears by no means direct or causal. In addition to elimination of potentially allergenic proteins, current research interest is directed toward intervention by novel immunomodulatory dietary compounds with specific effects in health promotion.The development of this new allergy prevention strategy calls for a better understanding of the processes that regulate the maturation of immune defense mechanisms at an early age and thereby promote the nonatopic mode of immune responsiveness. Many of the immunoregulatory aberrations favoring sensitization instead of tolerance induction prevail in early infancy. The intestine's antigen exclusion, elimination, and immune regulation mechanisms are incomplete, predisposing to aberrant antigen uptake and inflammatory responses. During pregnancy, the cytokine profile is polarized away from cell-mediated immunity (TH1 type) toward humoral immunity (TH2 type) to protect the developing fetus. Thus the TH2 responder phenotype is universal at an early age.2Piccinni M.P. Beloni L. Livi C. Maggi E. Scarselli G. Romagnani S. Defective production of both leukemia inhibitory factor and type 2 T-helper cytokines by decidual T cells in unexplained recurrent abortions.Nat Med. 1998; 4: 1020-1024Crossref PubMed Scopus (566) Google Scholar Allergic disease could thus be ascribed to a lack of immunologic counterregulatory processes and insufficient maturation signals endorsing the gut barrier function. The recent demonstration that the gut microbiota and, by the same token, probiotics have a strong effect on priming immunophysiologic regulation in the intestine's mucosal barrier has opened up new angles in the science of nutrition. In modulating specific target functions in the gut and the immune system, probiotics in the diet might exert clinical effects beyond the nutritional effect of food.Gut microbiota: The source of probioticsThe microbiota of a newborn develops rapidly after birth and is initially markedly dependent on genetic factors, maternal microbiota, mode of delivery, and birth environment.3Isolauri E. Rautava S. Kalliomäki M. Kirjavainen P. Salminen S. Role of probiotics in food hypersensitivity.Curr Opin Allergy Clin Immunol. 2002; 2: 263-271Crossref PubMed Scopus (87) Google Scholar The establishment of the gut microbiota is usually characterized by specific stages of development: early colonization by facultative anaerobes, such as enterobacteria, coliforms, and lactobacilli, succeeded by anaerobic genera, such as Bifidobacterium, Bacteroides, Clostridium, and Eubacterium.3Isolauri E. Rautava S. Kalliomäki M. Kirjavainen P. Salminen S. Role of probiotics in food hypersensitivity.Curr Opin Allergy Clin Immunol. 2002; 2: 263-271Crossref PubMed Scopus (87) Google Scholar The greatest difference in the microbiota of breast-fed and formula-fed infants lies in the numbers and species composition of bifidobacteria. Bifidobacterium breve, Bifidobacterium infantis, and Bifidobacterium longum are species frequently found in fecal samples from breast-fed infants, whereas later in life, Bifidobacterium adolescentis becomes more common. After weaning, the microbiota becomes more diverse, resembling that of adults. The gastrointestinal tract of the human adult harbors more than 500 identified species of culturable and a large number of unculturable bacteria.The relationship between intestinal bacteria and the host is referred to as host-microbe cross-talk, implying peaceful coexistence and mutual benefit. The importance of resident bacteria for the host's physiology has been clearly documented: major functions of the gut microbiota include metabolic activities, trophic effects on the intestinal epithelium, and protection of the host against the overgrowth of potential pathogens in the gastrointestinal tract. More recently, evidence from prospective studies in infancy demonstrate that specific aberrancies in the intestinal microbiota might predispose to disease later in life.A probiotic is currently defined as a live microbial food supplement with a proved beneficial effect on human health.3Isolauri E. Rautava S. Kalliomäki M. Kirjavainen P. Salminen S. Role of probiotics in food hypersensitivity.Curr Opin Allergy Clin Immunol. 2002; 2: 263-271Crossref PubMed Scopus (87) Google Scholar The aims of intervention are to avert deviant microbiota development, impaired gut barrier function, abnormal immune responsiveness, and immunoinflammatory disease. At an early age, probiotic supplementation aims to provide safe yet sufficient microbial stimulus for the immature immune system, contributing to the anti-inflammatory tone of the intestinal milieu.Probiotics are selected from members of the normal healthy intestinal microbiota, most of them belonging to Lactobacillus or Bifidobacterium species, but new probiotic microbes from other species and genera have recently been introduced. Improved understanding of the host-microbe interaction at different ages will lead to the development of a new generation of probiotics, the action of which could be selected for defined disease-associated aberrancies. Identification of new Bifidobacterium and Lactobacillus species and strains from the gastrointestinal tract of healthy subjects might then allow us to devise better target- and age-specific probiotics, which might be recognized with risk reduction of human disease in the future. It is well established that different probiotic strains induce distinct responses, and thus specific strains might have specific targets in reducing the risk and treatment of human disease. Probiotic strains selected for their beneficial effects in providing maturational signals for the infant's immune system and propagating oral tolerance induction might be of no use in treating adults. Further research might also substantiate the clinical efficacy of genetically modified probiotic bacteria, as indicated by the initial studies on Lactococcus lactis engineered to produce IL-10 locally.4Steidler L. Neirynck S. Huyghebaert N. Snoeck V. Vermeire A. Goddeeris B. et al.Biological containment of genetically modified Lactobacillus lactis for intestinal delivery of human interleukin 10.Nat Biotechnol. 2003; 21: 785-789Crossref PubMed Scopus (407) Google ScholarProbiotic research exemplifies that the dietary approach to reduce allergic diseases is evolving from passive elimination diets to supplementation with active immunomodulatory compounds. Still, because of interaction between nutrients, no single supplement can be expected to resolve the challenge of allergic disease, and better understanding of the interaction between nutrients is required.Host-microbe interaction in the gut epithelium: A key to intestinal homeostasisThe gastrointestinal epithelium is equipped with pattern recognition receptors, including Toll-like receptors (TLRs), which recognize specific conserved pathogen-associated molecular patterns, to sense the myriad of microorganisms found in the gastrointestinal lumen. Nonpathogenic microbes also possess these same structures, and therefore they might as well be called commensal-associated molecular patterns.5Akira S. Takeda K. Toll-like receptor signalling.Nat Rev Immunol. 2004; 4: 499-511Crossref PubMed Scopus (6586) Google Scholar, 6Cario E. Brown D. McKee M. Lynch-Devaney K. Gerken G. Podolsky D.K. Commensal associated molecular patterns induce selective toll-like receptor trafficking from apical membrane to cytoplasmic compartments in polarized intestinal epithelium.Am J Pathol. 2002; 160: 165-173Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar Thus TLRs cannot distinguish between pathogens and commensals. Human primary colonic epithelial cells have been demonstrated to express TLRs 1 through 6, 8, and 9, which can recognize several different microbial structures, including lipopeptides, lipoteichoic acid, LPS, single- and double-stranded RNA, flagellin, and unmethylated cytosine-guanine–rich DNA.5Akira S. Takeda K. Toll-like receptor signalling.Nat Rev Immunol. 2004; 4: 499-511Crossref PubMed Scopus (6586) Google Scholar, 7Otte J.-M. Cario E. Podolsky D.K. Mechanisms of cross hyporesponsiveness to toll-like receptor bacterial ligands in intestinal epithelial cells.Gastroenterology. 2004; 126: 1054-1070Abstract Full Text Full Text PDF PubMed Scopus (415) Google Scholar Most of the TLRs recognize more than one different pathogen-associated molecular pattern. Typically, an intracellular signaling domain known as the TIR domain initiates intracellular signaling pathways of TLRs that result in production of proinflammatory cytokines through activation of the transcription factors nuclear factor κB, activator protein 1, and interferon regulatory factor 3.5Akira S. Takeda K. Toll-like receptor signalling.Nat Rev Immunol. 2004; 4: 499-511Crossref PubMed Scopus (6586) Google Scholar In addition to TLRs, intestinal epithelial cells also express a second group of pattern recognition receptors (ie, 2 intracellular nucleotide oligomerization domains, NOD1 and NOD2, the ligands of which are diaminopimelic acid of peptidoglycan in gram-negative bacteria and muramyl dipeptide, a breakdown product of the peptidoglycan component of all bacterial cell walls, respectively).5Akira S. Takeda K. Toll-like receptor signalling.Nat Rev Immunol. 2004; 4: 499-511Crossref PubMed Scopus (6586) Google ScholarSeveral molecular characteristics of the gut epithelium have been thought to prevent inappropriate immune responses toward indigenous gut microbiota. These include a relatively sparse expression of both certain TLRs and their essential coreceptors on the intestinal epithelium, as well as intracellular location of a few TLRs. This topic is, however, a matter of some controversy.7Otte J.-M. Cario E. Podolsky D.K. Mechanisms of cross hyporesponsiveness to toll-like receptor bacterial ligands in intestinal epithelial cells.Gastroenterology. 2004; 126: 1054-1070Abstract Full Text Full Text PDF PubMed Scopus (415) Google Scholar A recent study suggests that a negative regulator of the TLR-signaling Toll-interacting protein (Tollip) might mediate some tolerogenic effects of commensal microbes.7Otte J.-M. Cario E. Podolsky D.K. Mechanisms of cross hyporesponsiveness to toll-like receptor bacterial ligands in intestinal epithelial cells.Gastroenterology. 2004; 126: 1054-1070Abstract Full Text Full Text PDF PubMed Scopus (415) Google Scholar In that study Otte et al7Otte J.-M. Cario E. Podolsky D.K. Mechanisms of cross hyporesponsiveness to toll-like receptor bacterial ligands in intestinal epithelial cells.Gastroenterology. 2004; 126: 1054-1070Abstract Full Text Full Text PDF PubMed Scopus (415) Google Scholar demonstrated that a continuous exposure of colonic epithelial cell lines to lipoteichoic acid and LPS resulted in a state of hyporesponsiveness (tolerance), whereas a short exposure elicited a proinflammatory response. In those hyporesponsive cells, Tollip expression was upregulated, although TLR expression was unaltered. Moreover, upregulation of Tollip in transfected colonic epithelial cells reduced significantly the proinflammatory response of those cells, implying that Tollip expression regulates innate immune responses of the intestinal epithelium toward molecular structures found in huge amounts in commensal microbes.Certain strains of commensal microbes and probiotics have been found to elicit anti-inflammatory responses in the intestinal epithelial cells in vitro, thus strengthening the intestinal homeostasis. Both some nonpathogenic salmonella strains and probiotic Lactobacillus reuteri were able to attenuate IL-8 secretion elicited by pathogenic salmonella or TNF-α in the polarized T84 model colonic epithelia.8Neish A.S. Gewirtz A.T. Zeng H. Young A.N. Hobert M.E. Karmali V. et al.Prokaryotic regulation of epithelial responses by inhibition of IκB-α ubiquitination.Science. 2000; 289: 1560-1563Crossref PubMed Scopus (745) Google Scholar, 9Ma D. Forsythe P. Bienenstock J. Live Lactobacillus reuteri is essential for the inhibitory effect on tumor necrosis factor alpha-induced interleukin-8 expression.Infect Immun. 2004; 72: 5308-5314Crossref PubMed Scopus (219) Google Scholar In either case this immunosuppressive effect was mediated by inhibition of the proinflammatory-antiapoptotic nuclear factor κB pathway. In contrast, Lactobacillus rhamnosus GG has been shown to prevent cytokine-induced apoptosis in mouse and human colon cells in vitro through activation of antiapoptotic Akt and protein kinase B and inactivation of proapoptotic p38 mitogen-activated protein kinase signaling cascade.10Yan F. Polk D.B. Probiotic bacterium prevents cytokine-induced apoptosis in intestinal epithelial cells.J Biol Chem. 2002; 277: 50959-50965Crossref PubMed Scopus (431) Google Scholar These examples imply that nonpathogenic microbes in the gut manipulate different intracellular signaling pathways of the intestinal epithelia to maintain equilibrium.Gut barrier: The target of probiotic effectsThe intestinal barrier consists of physiologic and immunologic factors that restrict mucosal colonization by pathogens, prevent foreign antigens and pathogens from penetrating the mucosa, and regulate the antigen-specific immune responses.11Sanderson I.R. Walker W.A. Uptake and transport of macromolecules by the intestine: possible role in clinical disorders (an update).Gastroenterology. 1993; 104: 622-639PubMed Google Scholar The intestinal microbiota constitute an important aspect of the mucosal barrier through their metabolic activity and trophic effects on the intestinal mucosa, complex immunomodulatory properties, and resistance to colonization by microbial invaders. All these aspects of the gut barrier function are potential targets for probiotic intervention. Probiotics have been shown to colonize the mouth12Meurman J.H. Antila H. Salminen S. Recovery of Lactobacillus strain GG (ATCC 53103) from saliva of healthy volunteers after consumption of yoghurt prepared with the bacterium.Microbiol Ecol Health Dis. 1994; 7: 295-298Crossref Scopus (55) Google Scholar and the intestine13Venturi A. Gionchetti P. Rizzello F. Johansson R. Zucconi E. Brigidi P. et al.Impact on the composition of the faecal flora by a new probiotic preparation: preliminary data on maintenance treatment of patients with ulcerative colitis.Aliment Pharmacol Ther. 1999; 13: 1103-1108Crossref PubMed Scopus (497) Google Scholar at least transiently and also alter the overall composition of the intestinal microbiota.14Spanhaak S. Havenaar R. Schaafsma G. The effect of consumption of milk fermented by Lactobacillus casei strain Shirota on the intestinal microflora and immune parameters in humans.Eur J Clin Nutr. 1998; 52: 899-907Crossref PubMed Scopus (327) Google Scholar, 15Tannock G.W. Munro K. Harmsen H.J. Welling G.W. Smart J. Gopal P.K. Analysis of the fecal microflora of human subjects consuming a probiotic product containing Lactobacillus rhamnosus DR20.Appl Environ Microbiol. 2000; 66: 2578-2588Crossref PubMed Scopus (529) Google Scholar, 16Agarwal R. Sharma N. Chaudhry R. Deorari A. Paul V.K. Gewolb I.H. et al.Effects of oral Lactobacillus GG on enteric microflora in low-birth-weight neonates.J Pediatr Gastroenterol Nutr. 2003; 36: 397-402Crossref PubMed Scopus (111) Google ScholarLactobacillus rhamnosus strain GG, ATCC 53103 (Lactobacillus GG), has been demonstrated to improve intestinal barrier function compromised by rotavirus infection17Isolauri E. Kaila M. Arvola T. Majamaa H. Rantala I. Virtanen E. et al.Diet during rotavirus enteritis affects jejunal permeability to macromolecules in suckling rats.Pediatr Res. 1993; 33: 548-553Crossref PubMed Scopus (72) Google Scholar or cow's milk antigens18Isolauri E. Majamaa H. Arvola T. Rantala I. Virtanen E. Arvilommi H. Lactobacillus casei strain GG reverses increased intestinal permeability induced by cow milk in suckling rats.Gastroenterology. 1993; 105: 1643-1650PubMed Google Scholar and the combination of Lactobacillus rhamnosus 19070-2 and Lactobacillus reuteri DSM 12246 stabilizes the impaired intestinal mucosal barrier in children with atopic dermatitis.19Rosenfeldt V. Benfeldt E. Valerius N.H. Paerregaard A. Michaelsen K.F. Effect of probiotics on gastrointestinal symptoms and small intestinal permeability in children with atopic dermatitis.J Pediatr. 2004; 145: 612-616Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar Of note, the same combination has earlier been shown to reduce the extent of atopic dermatitis.20Rosenfeldt V. Benfeldt E. Nielsen S.D. Michaelsen K.F. Jeppesen D.L. Valerius N.H. et al.Effect of probiotic Lactobacillus strains in children with atopic dermatitis.J Allergy Clin Immunol. 2003; 111: 389-395Abstract Full Text Full Text PDF PubMed Scopus (490) Google ScholarLactobacilli maintain gut barrier function by exerting a protective effect against brush border lesions caused by diarrhoegenic Escherichia coli.21Liévin-Le Moal V. Amsellem R. Servin A.L. Coconnier M.H. Lactobacillus acidophilus (strain LB) from the resident adult human gastrointestinal microflora exerts activity against brush border damage promoted by a diarrhoeagenic Escherichia coli in human enterocyte-like cells.Gut. 2002; 50: 803-811Crossref PubMed Scopus (124) Google Scholar Probiotics have also been demonstrated to improve colonization resistance by inhibiting adherence and invasion by potential pathogens.22Boudeau J. Glasser A.L. Julien S. Colombel J.F. Darfeuille-Michaud A. Inhibitory effect of probiotic Escherichia coli strain Nissle 1917 on adhesion to and invasion of intestinal epithelial cells by adherent-invasive E. coli strains isolated from patients with Crohn's disease.Aliment Pharmacol Ther. 2003; 18: 45-56Crossref PubMed Scopus (6) Google Scholar, 23Resta-Lenert S. Barrett K.E. Live probiotics protect intestinal epithelial cells from the effects of infection with enteroinvasive Escherichia coli (EIEC).Gut. 2003; 52: 988-997Crossref PubMed Scopus (491) Google Scholar Lactobacilli adhere to intestinal epithelial cells and induce mucin secretion in vitro, which inhibits adherence of enteropathogenic E coli.24Mack D.R. Michail S. Wei S. McDougall L. Hollingsworth M.A. Probiotics inhibit enteropathogenic E. coli adherence in vitro by inducing intestinal mucin gene expression.Am J Physiol Gastrointest Liver Physiol. 1999; 276: G941-G950Google Scholar, 25Mack D.R. Ahrne S. Hyde L. Wei S. Hollingsworth M.A. Extracellular MUC3 mucin secretion follows adherence of Lactobacillus strains to intestinal epithelial cells in vitro.Gut. 2003; 52: 827-833Crossref PubMed Scopus (455) Google Scholar In parallel, VSL#3, a probiotic compound containing 4 strains of lactobacilli, 3 strains of bifidobacteria, and Streptococcus thermophilus, has also been demonstrated to upregulate production of mucins in intestinal epithelial cells in vitro through the mitogen-activated protein kinase signaling pathway.26Otte J.-M. Podolsky D.K. Functional modulation of enterocytes by gram-positive and gram-negative microorganisms.Am J Physiol Gastrointest Liver Physiol. 2004; 286: G613-G626Crossref PubMed Scopus (335) Google Scholar E coli Nissle 1917 and a few lactobacilli, but none of the 40 enteropathogenic E coli strains studied, strongly induced the gene expression of the antimicrobial peptide human defensin-β2 in intestinal epithelial cells in a time- and dose-dependent manner.27Wehkamp J. Harder J. Wehkamp K. Wehkamp-von Meissner B. Schlee M. Enders C. et al.NF-κB- and AP-1-mediated induction of human beta defensin-2 in intestinal epithelial cells by Escherichia coli Nissle 1917: a novel effect of a probiotic bacterium.Infect Immun. 2004; 72: 5750-5758Crossref PubMed Scopus (408) Google Scholar A secreted proteinaceous soluble factor of VSL#3 increased gut epithelial barrier impermeability and resistance to salmonella invasion. The same probiotic was capable of reducing salmonella-induced alterations in the cellular cytoskeleton of the intestinal epithelium by modulating the distribution of the intercellular tight-junction protein zonula occluden 1.26Otte J.-M. Podolsky D.K. Functional modulation of enterocytes by gram-positive and gram-negative microorganisms.Am J Physiol Gastrointest Liver Physiol. 2004; 286: G613-G626Crossref PubMed Scopus (335) Google Scholar, 28Madsen K. Cornish A. Soper P. Mckaigney C. Jijon H. Yachimec C. et al.Probiotic bacteria enhance murine and human intestinal epithelial barrier function.Gastroenterology. 2001; 121: 580-591Abstract Full Text Full Text PDF PubMed Scopus (884) Google Scholar Still, administration of Lactobacillus plantarum failed to reduce the rate of bacterial translocation, gastric colonization, or infections in a randomized placebo-controlled study of patients undergoing abdominal surgery.29McNaught C.E. Woodcock N.P. MacFie J. Mitchell C.J. A prospective randomised study of the probiotic Lactobacillus plantarum 299V on indices of gut barrier function in elective surgical patients.Gut. 2002; 51: 827-831Crossref PubMed Scopus (131) Google Scholar The dilemma of whether colonization is mandatory for probiotic effects needs to be unraveled. However, oral consumption of a mixture of probiotics has been shown to result in a reduction in nasal colonization by the potentially pathogenic bacteria Staphylococcus aureus, Streptococcus pneumoniae, and β-hemolytic streptococci in human subjects without evidence of colonization by the probiotic strains.30Glück U. Gebbers J.O. Ingested probiotics reduce nasal colonization with pathogenic bacteria (Staphylococcus aureus, Streptococcus pneumoniae, and beta-hemolytic streptococci).Am J Clin Nutr. 2003; 77: 517-520PubMed Google Scholar Moreover, these apparently discrepant data demonstrate that probiotic effects might not only be strain specific but also that the effects might be different in health and on inflamed mucosa.Abundant IgA antibody production at mucosal surfaces contributes to the intestinal barrier function by binding to and excluding antigens. Maturation of dendritic cells carrying commensals and subsequent secretion of cytokines and chemokines then influence the polarization of TH cells and thereby the adaptive immune responses, ensuring a local IgA response.31Brandtzaeg P. Molecular and cellular aspects of the secretory immunoglobulin system.APMIS. 1995; 103: 1-19Crossref PubMed Scopus (172) Google Scholar This type of immune response has been suggested to prevent commensals from breaching the gut mucosal barrier, whereas pathogenic bacteria preferably destroy it.31Brandtzaeg P. Molecular and cellular aspects of the secretory immunoglobulin system.APMIS. 1995; 103: 1-19Crossref PubMed Scopus (172) Google Scholar, 32Macpherson A.J. Uhr T. Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria.Science. 2004; 303: 1662-1665Crossref PubMed Scopus (1149) Google Scholar, 33Isolauri E. Gotteland M. Heyman M. Pochart P. Desjeux J.F. Antigen absorption in rabbit bacterial diarrhea (RDEC-1). In vitro modifications in the ileum and Peyer's patches.Dig Dis Sci. 1990; 35: 360-367Crossref PubMed Scopus (32) Google Scholar A recent series of experimental studies in mice deficient in MyD88, an adaptor molecule essential for the TLR-mediated induction of inflammatory cytokines, demonstrated that TLR signaling pathways control the homeostasis of the epithelium and appear critical for protection of the host against gut injury in controlling cytoprotective factors and epithelial cell proliferation.34Rakoff-Nahoum S. Paglino J. Eslami-Varzaneh F. Edberg S. Medzhitov R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis.Cell. 2004; 118: 229-241Abstract Full Text Full Text PDF PubMed Scopus (3241) Google ScholarAnti-inflammatory effects of commensals and probiotics in the gut-associated lymphatic tissueIntestinal barrier function and immune regulation are closely linked and have common characteristics. The gut-associated immune system represents the largest mass of lymphoid tissue in the human body. Consequently, it comprises an important element of the total immunologic capacity of the host. Anti-inflammatory and regulatory mucosal immune responses are essential for withholding detrimental inflammatory reactions to dietary antigens and nonpathogenic microbes, a phenomenon referred to as mucosal tolerance. There are several active mechanisms through which mucosal tolerance is established and maintained, including clonal deletion, anergy, and antigen-specific suppression by T cells. Distinct regulatory mechanisms modulating both TH1 and TH2 responses have recently been discovered as novel T-cell subclasses with suppressive and regulatory functions have emerged. Gut-derived TH3 and TR1 cells exert their effects through the production of cytokines, mainly TGF-β and IL-10, respectively. The thymus-originated CD4+CD25+ regulatory T cells act through contact-dependent mechanisms probably involving membrane-bound TGF-β.35Nagler-Anderson C. Tolerance and immunity in the intestinal immune system.Crit Rev Immunol. 2000; 20: 103-120Crossref PubMed Google ScholarTGF-β–producing regulatory T cells have been implicated in the establishment and maintenance of oral tolerance,36Fukaura H. Kent S.C. Pietrusewicz M.J. Khoury S.J. Weiner H.L. Hafler D.A. Induction of circulating myelin basic protein and proteolipid protein-specific transforming growth factor-β1-secreting Th3 T cells by oral administration of myelin in multiple sclerosis patients.J Clin Invest. 1996; 98: 70-77Crossref PubMed Scopus (420) Google Scholar and indeed, infants with food allergy have been reported to display a defect in TGF-β–producing cells in the intestine.37Pérez-Machado M.A. Ashwood P. Thomson M.A. Latcham F. Sim R. Walker-Smith J.A. et al.Reduced transforming growth factor-beta1-producing T cells in the duodenal mucosa of children with food allergy.Eur J Immunol. 2003; 33: 2307-2315Crossref PubMed Scopus (124) Google Scholar TGF-β has direct suppressive effects on both TH1 and TH2 responses.38Lúdviksson B.R. Seegers D. Resnick A.S. Strober W. The effect of TGF-beta1 on immune responses of naive versus memory CD4+ Th1/Th2 T cells.Eur J Immunol. 2000; 30: 2101-2111Crossref PubMed Scopus (126) Google Scholar In addition, TGF-β is the initial trigger for the production of IgA antibodies39Stavnezer J. Regulation of antibody production and class switching by TGF-beta.J Immunol. 1995; 155: 1647-1651PubMed Google Scholar, 40Petitprez K. Khalife J. Cetre C. Fontaine J. Lafitte S. Capron A. et al.Cytokine mRNA expression in lymphoid organs associated with the expression of IgA response in the rat.Scand J Immunol. 1999; 49: 14-20Crossref PubMed Scopus (15) Google Scholar; IL-10, on the other hand, has been implicated in tolerance toward intestinal microbiota.The indigenous microbiota contribute to the anti-inflammatory tone of the mucosal immune system. The requirement of innate immune responses to enteric bacteria in the maintenance of tolerance has been demonstrated in an experimental animal model.41Newberry R.D. Stevenson W.F. Lorenz R.G. Cycloxynegase-2–dependent arachidonic acid metabolites are essential modulators of the immune response to dietary antigen.Nat Med. 1999; 5: 900-906Crossref PubMed Scopus (258) Google Scholar The importance of host-microbe interaction is most vital in the neonatal period when the establishment of a normal microbiota provides the host with the most substantial antigen challenge, with a strong stimulatory effect for the maturation of the gut-associated lymphoid tissue. Indeed, mice reared in germ-free conditions have been demonstrated to display defective oral tolerance formation and atopic-type immune responsiv
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