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Bacterial components plus vitamin D: The ultimate solution to the asthma (autoimmune disease) epidemic?

2011; Elsevier BV; Volume: 127; Issue: 5 Linguagem: Inglês

10.1016/j.jaci.2011.02.025

1097-6825

Scott T. Weiss,

Digestive system and related health

In this issue of the Journal, 2 review articles (1 immunologic and 1 epidemiologic) draw attention to the human gut microbiome and its potential importance in human health and the development of allergic and autoimmune disease.1McLoughlin R. Mills K.H.G. Influence of gastrointestinal commensal bacteria on the immune responses that mediate allergy and asthma.J Allergy Clin Immunol. 2011; 127: 1097-1107Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar, 2Ly N.P. Litonjua A.A. Gold D. Celedon J.C. Gut microbiota, probiotics, vitamin D, asthma, and obesity.J Allergy Clin Immunol. 2011; 127: 1087-1094Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar This editorial will try to synthesize the central messages of these reviews and outline the research directions in this emerging field. I will first review the data on the human microbiome, discuss factors that might influence gut bacterial colonization in human subjects, review the evidence that the microbiome is involved in allergic disease, and finally consider the role of vitamin D in this process. The gut microbiome is overwhelming in its size and its metabolic and antigenic complexity. There are 1014 bacteria in the gut, or 10 times more microbes in the human colon than there are cells in the human body. These bacteria belong to more than 1000 species and have 3.3 million genes, more than 150 times more genes than our own genome.3Zhu B. Wang X. Li L. Human gut microbiome: the second genome of human body.Protein Cell. 2010; 1: 718-725Crossref PubMed Scopus (224) Google Scholar Culture alone is inadequate to identify the mostly anaerobic organisms of the gut, and bacterial sequencing must be used, in conjunction with culture, to definitively speciate and hence identify all of these organisms. These bacteria interact with the host in a variety of ways. First, they interact with the gut-associated lymphoid tissue, the largest immune organ in the human body, and by their sheer size, they represent the major source of antigenic load to the human immune system. Second, these bacteria function as a metabolically active force to digest and modify the human diet. Third, our own genome interacts with and helps determine which bacteria are important to us,4Benson A. Kelly S. Legge R. Ma F. Low S.J. Kim J. et al.Individuality in gut microbiota composition is a complex polygenic trait shaped by multiple environmental and host genetic factors.Proc Natl Acad Sci U S A. 2010; 107: 18933-18938Crossref PubMed Scopus (870) Google Scholar thus providing a degree of complex gene-environment interaction effect. One of the most striking examples of this latter effect is that animal brain function and behavior can be influenced by the presence or absence of these commensal bacteria during development.5Diaz-Heijtz R, Wang S, Anuar F, et al. Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci U S A. In press 2011.Google Scholar The human gut flora is, quantitatively, the earliest, most diverse, and hence most important postnatal source of microbial stimulation of the immune system in most species, including the human, and hence the most likely determinant of normal tolerization.6Noverr M. Huffnagle G. Does the microbiota regulate immune responses outside the gut?.Trends Microbiol. 2004; 12: 562-568Abstract Full Text Full Text PDF PubMed Scopus (380) Google Scholar Experiments in rodents suggest that bacterial gut colonization is essential for the development of oral tolerance and normal postnatal maturation of immune responses,7Rask C. Evertsson S. Telemo E. Wold A.E. A full flora, but not monocolonization by Escherichia coli or lactobacilli, supports tolerogenic processing of a fed antigen.Scand J Immunol. 2005; 61: 529-535Crossref PubMed Scopus (33) Google Scholar including generation, expansion, or both of regulatory T (Treg) cells in peripheral tissues.8Strauch U.G. Obermeier F. Grunwald N. et al.Influence of intestinal bacteria on induction of regulatory T-cells: lessons from a transfer model of colitis.Gut. 2005; 54: 1546-1552Crossref PubMed Scopus (129) Google Scholar Most of these "good bacteria" are anaerobes that are among the earliest life forms on the planet, having an evolutionary age of almost 6 billion years relative to our much more recent 150,000 years. Dobzhansky9Dobzhansky T. Biology, molecular and organismic.Am Zool. 1964; 4: 443-452PubMed Google Scholar has said that "nothing in biology makes sense except in light of evolution," and our coevolution with these anaerobic bacteria is critical to our understanding of how our immune system functions. Ultimately, how tolerization occurs and how the gut microbiome relates to the skin and other microbiomes, such as the oral cavity, is currently unknown. However, Noverr and Huffnagle6Noverr M. Huffnagle G. Does the microbiota regulate immune responses outside the gut?.Trends Microbiol. 2004; 12: 562-568Abstract Full Text Full Text PDF PubMed Scopus (380) Google Scholar have postulated that the gut microbiome actually is the sensor for immune tolerance in the lung. What does seem clear is that tolerization as an immune phenomenon is dominated by the gut flora because of the size of the gut-associated lymphoid tissue and the sheer magnitude of the gut microbiome's antigenic mass. Initial colonizing bacteria can be a potent environmental stimulus to the host, inducing genes in the host's gut epithelium and hence influencing the host's immune response. Thus good bacteria can potentially control or prevent the growth of pathogenic bacteria in part through immune system development and metabolic processes and by mechanisms as yet not understood.10Guarner J. de Leon-Bojorge B. Lopez-Corella E. Ferebee-Harris T. Gooding L. Garnett C.T. et al.Intestinal intussusception associated with adenovirus infection in Mexican children.Am J Clin Pathol. 2003; 120: 845-850Crossref PubMed Scopus (55) Google Scholar The study of the natural history of microbial colonization of the human gut and its relevance to disease is in its infancy. Existing studies in this area are few because of the novelty of the technology, the high cost, and the technical difficulty of culturing anaerobes. Methodologic issues, such as small sample size, short duration of follow-up,11Harmsen H.J. Wildeboer-Veloo A.C. Raangs G.C. Wagendorp A.A. Klijn J. Bindels J.G. et al.Analysis of intestinal flora development in breast-fed and formula-fed infants by using molecular identification and detection methods.J Pediatr Gastroenterol Nutr. 2000; 30: 61-67Crossref PubMed Scopus (1060) Google Scholar missing data on potentially relevant variables, and, most importantly, reliance on cultures alone, might miss relevant organisms, thus limiting what we know.12Adlerberth I. Strachan D.P. Matricardi P.M. Ahrné S. Orfei L. Aberg N. et al.Gut microbiota and development of atopic eczema in 3 European birth cohorts.J Allergy Clin Immunol. 2007; 120: 343-350Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar Multiple clinical and molecular factors are likely to determine gut colonization in early fetal life: bacterial characteristics, such as the number and diversity of cell-surface antigens; the presence or absence of pili; host mucosal cell properties, such as cell-surface receptors; and epidemiologic factors, such as gestational age, mode of delivery, exposure to maternal fecal flora, maternal diet, fetal antibiotic use, and type of infant feeding, including probiotics.10Guarner J. de Leon-Bojorge B. Lopez-Corella E. Ferebee-Harris T. Gooding L. Garnett C.T. et al.Intestinal intussusception associated with adenovirus infection in Mexican children.Am J Clin Pathol. 2003; 120: 845-850Crossref PubMed Scopus (55) Google Scholar, 12Adlerberth I. Strachan D.P. Matricardi P.M. Ahrné S. Orfei L. Aberg N. et al.Gut microbiota and development of atopic eczema in 3 European birth cohorts.J Allergy Clin Immunol. 2007; 120: 343-350Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar, 13Edwards C.A. Parrett A.M. Intestinal flora during the first months of life: new perspectives.Br J Nutr. 2002; 88: S11-S18Crossref PubMed Google Scholar Of the multiple factors noted above, maternal and fetal diet, prebiotics, and probiotics deserve some greater attention. At a CIBA Foundation symposium in 1996, I was the first to suggest that dietary changes could be driving the allergy and autoimmune disease epidemic.14Weiss S.T. Diet as a risk factor for asthma. CIBA Foundations Symposium.in: Barnes P.J. Grunstein M.M. Leff A.R. Woolcock A.J. Asthma. Lippincott-Raven Publishers, Philadelphia1997: 244-247Google Scholar Food serves as an important substrate for bacteria digesting plant polysaccharides and hence producing short-chain fatty acids and other nutrients for the bacteria and hence amplifying their influence immunologically.15Maslowski K. Mackay C. Diet, gut microbiota and immune responses.Nat Immunol. 2011; 12: 5-9Crossref PubMed Scopus (859) Google Scholar This prebiotic function could potentially be exploited therapeutically if we knew which foods were promoting the good bacteria. Probiotics are cultures of normal gut flora organisms administered orally to influence immune function.16Borriello S.P. Hammes W.P. Holzapfel W. Marteau P. Schrezenmeir J. Vaara M. et al.Safety of probiotics that contain lactobacilli or bifidobacteria.Clin Infect Dis. 2003; 36: 775-780Crossref PubMed Scopus (413) Google Scholar Several studies, mostly with Lactobacillus species, have been performed,17Kalliomaki M. Salminen S. Poussa T. Arvilommi H. Isolauri E. Probiotics and prevention of atopic disease: 4-year follow-up of a randomised placebo-controlled trial.Lancet. 2003; 361: 1869-1871Abstract Full Text Full Text PDF PubMed Scopus (1044) Google Scholar including 2 small clinical trials.18Isolauri E. Arvola T. Sutas Y. Moilanen E. Salminen S. Probiotics in the management of atopic eczema.Clin Exp Allergy. 2000; 30: 1604-1610Crossref PubMed Scopus (809) Google Scholar, 19Weston S. Halbert A.R. Richmond P. Prescott S.L. Effects of probiotics on atopic dermatitis: a randomised controlled trial.Arch Dis Child. 2005; 90: 892-897Crossref PubMed Scopus (331) Google Scholar, 20Prescott S.L. Dunstan J.A. Hale J. Breckler L. Lehmann H. Weston S. et al.Clinical effects of probiotics are associated with increased interferon-gamma responses in very young children with atopic dermatitis.Clin Exp Allergy. 2005; 35: 1557-1564Crossref PubMed Scopus (115) Google Scholar The problem is that these studies are premature because they beg a critical question: What are the relevant bacteria and their specific antigens that drive the putative immunoprotective effects? The evidence that lactobacilli are sufficient to do this is weak at best. Bacteroides fragilis would seem to be a better bet, but unlike the mouse, a single bacterium is unlikely to be sufficient to achieve normal immune tolerization in a human subject. Existing clinical studies performed in the presequencing era suggest that the composition of the gut flora appears to differ between atopic and nonatopic infants, giving some credence to the hypothesis that the reduced number and diversity of gut bacteria early in life lead to faulty tolerization and the development of allergic and other autoimmune diseases.12Adlerberth I. Strachan D.P. Matricardi P.M. Ahrné S. Orfei L. Aberg N. et al.Gut microbiota and development of atopic eczema in 3 European birth cohorts.J Allergy Clin Immunol. 2007; 120: 343-350Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar, 21Sepp E. Julge K. Vasar M. Naaber P. Bjorksten B. Mikelsaar M. Intestinal microflora of Estonian and Swedish infants.Acta Paediatr. 1997; 86: 956-961Crossref PubMed Scopus (361) Google Scholar, 22Bjorksten B. Naaber P. Sepp E. Mikelsaar M. The intestinal microflora in allergic Estonian and Swedish 2-year-old children.Clin Exp Allergy. 1999; 29: 342-346Crossref PubMed Scopus (787) Google Scholar, 23Bottcher M.F. Nordin E.K. Sandin A. Midtvedt T. Bjorksten B. Microflora-associated characteristics in faeces from allergic and nonallergic infants.Clin Exp Allergy. 2000; 30: 1590-1596Crossref PubMed Scopus (205) Google Scholar, 24Kalliomaki M. Kirjavainen P. Eerola E. Kero P. Salminen S. Isolauri E. Distinct patterns of neonatal gut microflora in infants in whom atopy was and was not developing.J Allergy Clin Immunol. 2001; 107: 129-134Abstract Full Text PDF PubMed Scopus (1015) Google Scholar, 25Penders J. Thijs C. van den Brandt P.A. et al.Gut microbiota composition and development of atopic manifestations in infancy: the KOALA Birth Cohort Study.Gut. 2007; 56: 661-667Crossref PubMed Scopus (578) Google Scholar Ly et al2Ly N.P. Litonjua A.A. Gold D. Celedon J.C. Gut microbiota, probiotics, vitamin D, asthma, and obesity.J Allergy Clin Immunol. 2011; 127: 1087-1094Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar review much of this work in greater detail. In a small pilot study we found similar results to those of the studies cited above. We found that levels of IL-10, an anti-inflammatory Treg-controlling cytokine modulated in part by vitamin D, were increased in the cord blood of children whose mothers had a higher number of anaerobes in their guts. We went on to show that greater diversity of the infant's fecal flora was protective for atopic dermatitis occurrence at 6 months of age.26Forno E. Onderdonk A.B. McCracken J. et al.Diversity of the gut microbiota and eczema in early life.Clin Mol Allergy. 2008; 6: 11Crossref PubMed Scopus (93) Google Scholar A recent review found that 14 of 17 studies in this area supported the findings that gut bacteria influenced the development of allergic disease.27Penders J. Stobberingh E.E. Van den Brandt P.A. Thijs C. The role of the intestinal microbiota in the development of atopic disorders.Allergy. 2007; 62: 1223-1236Crossref PubMed Scopus (326) Google Scholar These cited studies, including ours, are mostly of small sample size and, most importantly, lack robust, state-of-the-art gut microbiome assessment with both anaerobic culture and sequencing to maximally speciate the organisms. Finally, most studies do not adequately account for the confounding variables noted above. Suffice it to say that as the review by Ly et al2Ly N.P. Litonjua A.A. Gold D. Celedon J.C. Gut microbiota, probiotics, vitamin D, asthma, and obesity.J Allergy Clin Immunol. 2011; 127: 1087-1094Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar notes, we have no clear epidemiologic evidence as to the importance of specific bacterial species and whether their number, diversity, or both is the determining factor with regard to allergic diseases generally or asthma specifically. This is in contrast to Crohn disease, in which specific bacteria have been identified.28Cadwell K. Patel K. Maloney N. Liu T.C. Ng A.C. Storer C.E. et al.Virus-plus-susceptibility gene interaction determines Crohn's disease gene Atg 16L1 phenotypes in intestine.Cell. 2010; 141: 1135-1145Abstract Full Text Full Text PDF PubMed Scopus (694) Google Scholar How is vitamin D related to this process? We have previously reviewed in these pages the potential role of vitamin D deficiency in the development of allergic and autoimmune diseases and specifically their dramatic increase in prevalence in the last 50 years.29Litonjua A. Weiss S. Is vitamin D deficiency to blame for the asthma epidemic?.J Allergy Clin Immunol. 2007; 120: 1031-1035Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar As we noted, vitamin D has clear structural effects on lung and airway development in utero.29Litonjua A. Weiss S. Is vitamin D deficiency to blame for the asthma epidemic?.J Allergy Clin Immunol. 2007; 120: 1031-1035Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar It is worth recapitulating the immune portion of the argument here. Vitamin D is essential in the development and function of both Treg cells30Taher Y.A. van Esch B.C.A.M. Hofman G.A. Henricks P.A.J. van Oosterhout A.J. 1 alpha, 25-dihydroxyvitamin D3 potentiates the beneficial effects of allergen immunotherapy in a mouse model of allergic asthma: role for IL-10 and TGF-B1.J Immunol. 2008; 180: 5211-5221PubMed Google Scholar, 31Xystrakis E. Kusumakar S. Boswell S. Peek E. Urry Z. Richards D.F. et al.Reversing the defective induction on IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients.J Clin Invest. 2006; 116: 146-155Crossref PubMed Scopus (486) Google Scholar and dendritic cells.32Adorini L. Giarratana N. Penna G. Pharmacological induction of tolerogenic dendritic cells and regulatory T cells.Semin Immunol. 2004; 16: 127-134Crossref PubMed Scopus (171) Google Scholar, 33Griffin M.D. Xing N. Kumar R. Gene expression profiles in dendritic cells conditioned by 1alpha,25-dihydroxyvitamin D3 analog.J Steroid Biochem Mol Biol. 2004; 89-90: 443-448Crossref PubMed Scopus (36) Google Scholar It seems quite likely that vitamin D is an important modulator of the signaling traffic between gut bacterial surface antigens through its effects on dendritic and Treg cells not just in human subjects but also in organisms as evolutionarily well preserved as the fly. Experimental evidence suggests that the biologically active form of vitamin D (1,25[OH]2 vitamin D3) influences the process by which immune cells acquire signaling molecules that enable them to migrate to normal extralymphoid tissue sites, as well as sites of inflammation. The gastrointestinal mucosa, as the main body surface exposed to environmental antigens (specifically gut bacteria), has well-described tissue-specific adhesion and chemoattractant homing receptors.34Moro J. Iwata M. von Andriano U. Vitamin effects on the immune system: vitamins A and D take centre stage.Nat Rev Immunol. 2008; 8: 685-698Crossref PubMed Scopus (1083) Google Scholar Vitamin D can block or downregulate gut homing of both normal immune and inflammatory cells. For example, vitamin D receptor gene expression is required for dendritic cells, T cells, and other immune cells to control inflammation in the il10 knockout mouse model.35Froicu M. Zhu Y. Cantorna M. Vitamin D receptor is required to control gastrointestinal immunity in IL-10 knockout mice.Immunology. 2006; 117: 310-318Crossref PubMed Scopus (107) Google Scholar By upregulating the normal immune function of Treg cells, specifically through IL10 and TGFB1, vitamin D can promote normal tolerization. Conversely, reduced vitamin D levels, a reduced number and diversity of gut bacteria, or both will promote inflammation that might disrupt the mucosal barrier and promote food and other allergen sensitization or abnormal tolerization. Thus pathogenic and commensal gut bacteria can play opposing roles in allergy development, and these roles might be modulated by the vitamin D receptor gene, other host genes, and vitamin D itself. It is also possible that independent of its immune effects, vitamin D has a direct effect on gut bacterial flora to increase or decrease the number of specific species of bacteria or species diversity. These complex effects are synthesized in Fig 1. Given the current Institute of Medicine report on vitamin D dosage (http://www.IOM.edu/reports/2010/dietary-reference-intakes-for-calcium-and-vitamin-D.aspx), it is worth considering what level of vitamin D would provide immunoprotection for the development of allergic and autoimmune disease. Although this is currently unknown, it would seem that higher doses than those currently recommended by the Institute of Medicine report for bone health will almost certainly be necessary. Further research is needed in this area. It is worth noting that the microbiome/vitamin D hypothesis to explain the origins of the autoimmune disease epidemic fits the facts far better than the hygiene hypothesis.29Litonjua A. Weiss S. Is vitamin D deficiency to blame for the asthma epidemic?.J Allergy Clin Immunol. 2007; 120: 1031-1035Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar The hygiene hypothesis never could explain the increase in TH1 autoimmune disease in addition to asthma and allergy and the high rates of asthma and allergy among the urban poor in the United States. Both phenomena are easily explained by vitamin D deficiency. The strong link between the microbiome and vitamin D closes the loop by providing a plausible immunologic substrate for vitamin D's effects on normal tolerization. We have clear evidence for dramatic changes in vitamin D levels over the 50-year period that has seen the dramatic increase in autoimmune disease; what we do not know is what has happened to the gut microbiome during that period. Current clinical trials in the United States and Denmark will test whether giving vitamin D to pregnant women will prevent asthma in their offspring (Vitamin D Antenatal Asthma Reduction Trial, VDAART, U01 HL091528, ClinicalTrials.gov: NCT00856947), although this is unlikely to be the whole story because this trial will not test the effect of postnatal sufficiency on asthma risk. A funded ancillary study will allow an exploration of the relative importance of vitamin D and the gut flora on disease risk. Identification of the good bacteria in the human gut microbiome is of primary scientific importance in understanding allergic diseases. This will not be a trivial exercise given the size and diversity of the gut microbiome. If this task can be accomplished, then it is conceivable that in the not-too-distant future we will prevent asthma, food allergies, atopic dermatitis, allergic rhinitis, and other autoimmune diseases, such as Crohn disease, type 1 diabetes mellitus, and multiple sclerosis, with a cocktail of anaerobic bacterial antigens, dietary constituents, or the bacteria themselves (prebiotics and probiotics) in combination with vitamin D administered orally to both pregnant women and their offspring. First we need to find the protective bacterial species, identify their antigens, understand more clearly how vitamin D modulates the signaling from gut bacteria to dendritic cells and Treg cells, and determine what dose of vitamin D is necessary. This is an exciting time for asthma research and for autoimmune disease research generally, and the gut microbiome will be an important extension of genomics to the environment. Elucidating its influence on the development of allergic disease is going to certainly contribute to this excitement.