Reviews and feature article
Influence of gastrointestinal commensal bacteria on the immune responses that mediate allergy and asthma

https://doi.org/10.1016/j.jaci.2011.02.012Get rights and content

The human intestine contains more than 100 trillion microorganisms that maintain a symbiotic relationship with the host. Under normal conditions, these bacteria are not pathogenic and in fact confer health benefits to the host. The microbiota interacts with the innate and adaptive arms of the host's intestinal mucosal immune system and through these mechanisms drives regulatory cell differentiation in the gut that is critically involved in maintaining immune tolerance. Specifically, the microbiota can activate distinct tolerogenic dendritic cells in the gut and through this interaction can drive regulatory T-cell differentiation. In addition, the microbiota is important in driving TH1 cell differentiation, which corrects the TH2 immune skewing that is thought to occur at birth. If appropriate immune tolerance is not established in early life and maintained throughout life, this represents a risk factor for the development of inflammatory, autoimmune, and allergic diseases. Early-life events are instrumental in establishing the microbiota, the composition of which throughout life is influenced by various environmental and lifestyle pressures. Significant efforts are now being made to establish interventional approaches that can create a healthy microbiota that confers maximum tolerogenic immunomodulatory effects in the gut and that will protect against systemic inflammatory disease pathologies.

Section snippets

Factors affecting development of the microbiota

A fetus is sterile in utero, but immediately after birth and throughout life, human subjects are colonized by microorganisms that inhabit most exposed mucosal surfaces, including nasal passages and the skin, mouth, vagina, and gut. The composition of the gut microbiota is heavily influenced by host and environmental factors experienced in the first year of life, with most subjects acquiring a stable gut microflora resembling that of an adult during this period.5

Because of the nature of the

Effect of the microbiota on the host

Nature has dictated that humans and microbes coexist in a multifaceted symbiotic relationship that confers benefits to both the host and the microbe. The host must gain maximum benefit from the commensal microbiota but must also protect itself against invasion by these commensal organisms that under some circumstances can become pathogenic. It has been suggested that a healthy microbiota exists when there is a balance between symbionts, commensal organisms, and pathobionts (Fig 1). Alterations

Immune privilege and immune tolerance in the gut

Immune tolerance in its simplest terms refers to the ability of the host to distinguish innocuous ingested or inhaled antigens and prevent activation of an immune response to these antigens. A breakdown of this tolerance is critically involved in the pathophysiology of various diseases. The adaptive immune system plays an important role in distinguishing between self-antigens and foreign antigens, but the intestinal microbiota represents a challenge to the adaptive immune system because it

Hygiene hypothesis

In 1989, Strachan15 proposed that a lack of exposure to microbes in early life caused by the “cleaner” environment of developed nations resulted in an impaired development of the immune system, leading to an increased risk of allergies in later life. This hygiene hypothesis was based on the observation that there was a lower risk of allergic diseases in children with larger numbers of older siblings or who were brought up on farms with exposure to livestock. However, this was an

Immune mechanisms in allergic diseases and asthma that might be influenced by gut microbial flora

Allergic diseases and asthma are traditionally associated with pronounced or dysregulated TH2 responses. However, our understanding of the mechanisms underlying the cause of this disease is continually evolving as we begin to appreciate the complexity of effector T-cell subsets. TH2 cells are characterized by their production of IL-4, IL-5, IL-9, and IL-13, and together, these cytokines contribute to the development and maintenance of allergic inflammation. Currently, the development of mAbs

Immunomodulatory effects of the microbiota on the mucosal immune system

Since the establishment of the hygiene hypothesis, immunologists have strived to understand the mechanisms by which the gut microbiota directly influences specific aspects of the host's immune response that protect against atopic disease. This protection is fundamentally dependent on the preservation of an immune-tolerant state. We will now discuss the intestinal microbiota as a master regulator of immune equilibrium that confers protection to the host against inflammatory, autoimmune, and

Intestinal epithelial cells and innate signaling in the gut

A single layer of intestinal epithelial cells (IECs) creates a barrier between the lumen of the intestine, which is an antigen-rich environment, and access to the rest of the body.31 This barrier is maintained by IECs through physical and biochemical mechanisms. Paracellular traffic is prevented by intracellular tight junctions. Microbial attachment and invasion is impeded by a brush border, which is created by actin-rich microvillar extensions on the surface of the cells.32 Finally, a viscous

Epithelial cell regulation of immune cell function

In addition to their role in providing the first line of innate defense against pathogens and commensal organisms, IECs also influence the function of APCs and lymphocytes in the intestinal microenvironment. IECs can regulate DC functions through the secretion of immunomodulatory molecules, such as thymic stromal lymphopoietin and TGF-β.42 Thymic stromal lymphopoietin is constitutively expressed by IECs and has been shown to limit the expression of IL-12 by DCs while promoting the production of

Treg cells

Studies in germ-free (GF) mice have identified an important interaction between the intestinal microbiota and the development of Treg cells both locally in the gut and systemically. GF mice express lower numbers of CD4+CD25+FoxP3+ cells both in the mesenteric lymph nodes and peripheral lymph nodes compared with conventional mice, and these Treg cells produce less IL-10.47 Oral tolerance could not be established in GF mice because of the impaired suppressive function of their CD4+CD25+ cells and

APCs

Mucosal DCs continually sample luminal content in the gut and are thus constantly exposed to the gut microbiota. These DCs are actively involved in bridging the gap between the innate and adaptive immune responses in the gut. The expression of pathogen recognition receptors on the surface of the DC allows them to respond to bacterial PAMPs, such as TLRs and NLRs, which are expressed by both commensal and invading pathogenic bacteria, while at the same time presenting antigen to naive T cells.

Effector T cells

Interaction with microbes in the gastrointestinal tract has been established as a principal environmental signal for postnatal maturation of T-cell function.10 It is believed that neonates are skewed toward a TH2-like response at birth64 and that exposure to gut microbial antigens stimulates the development of TH1 cells.65 The shift away from TH2 responses helps to establish immune tolerance and protects the host from the future development of atopic disease and asthma.64 Studies in GF mice

Can manipulation of the microbiota protect against allergic disease?

Herein we have highlighted the mechanisms by which the microbiota can directly influence effector and regulatory immune mechanisms. These effects are critical in establishing immune tolerance, which protects against allergic disease (Fig 2). The association between the intestinal microflora and allergy is now widely accepted. Epidemiologic evidence (reviewed in this issue by Ly et al8) strongly suggests that modulation of immune response mechanisms in the gut can directly affect the development

Probiotics

The World Health Organization has defined probiotics as “live microorganisms which when administered in adequate amounts confer a health benefit on the host.”70 Probiotics are typically of the Lactobacillus or Bifidobacterium species that, when ingested, increase the levels of these beneficial colonizers in the gut.71 Prebiotics are nondigestible food ingredients, in particular nondigestible carbohydrates and oligosaccharides, that selectively stimulate the growth of the host's own specific

Obesity

Clinical studies have established a link between obesity and atopic disease.77 The underlying immunologic mechanisms behind this link can in part be explained by a decrease in immune tolerance as a consequence of immunologic signals produced by the adipose tissue.78, 79 Notwithstanding the direct contributions made by the obese state to the disruption of immune tolerance, it is also plausible that obesity could alter tolerogenic responses as a result of indirect effects on the gut microbiota.

Vitamin D

There is increasing evidence that Vitamin D might play a role in protecting against asthma and allergic disease. As a consequence of lack of exposure to sunlight, vitamin D deficiency (VDD) is now common in populations worldwide.82 Studies have established a clear association between VDD and the increased incidence of asthma and other atopic diseases.83 Polymorphisms in the vitamin D receptor gene84 and other genes in the vitamin D signaling pathway are associated with increased susceptibility

Future perspectives

As we have discussed herein, the dialogue between the microbiota and the host is multifaceted and involves specific interactions between unique molecules expressed by the bacteria, with receptors on specific cells of the host's immune system. A critical goal for researchers is to identify what constitutes a healthy microbiota. The field has been significantly advanced in recent years through the introduction of culture-independent techniques, such as 16s RNA sequencing, for identifying

References (92)

  • S. Sierra et al.

    Intestinal and immunological effects of daily oral administration of Lactobacillus salivarius CECT5713 to healthy adults

    Anaerobe

    (2010)
  • K.L. Walton et al.

    Dendritic cells in germ-free and specific pathogen-free mice have similar phenotypes and in vitro antigen presenting function

    Immunol Lett

    (2006)
  • J.A. Hall et al.

    Commensal DNA limits regulatory T cell conversion and is a natural adjuvant of intestinal immune responses

    Immunity

    (2008)
  • P.G. Holt et al.

    Developmental factors associated with risk for atopic disease: implications for vaccine strategies in early childhood

    Vaccine

    (2003)
  • S.K. Mazmanian et al.

    An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system

    Cell

    (2005)
  • D. Ghadimi et al.

    Effects of probiotic bacteria and their genomic DNA on TH1/TH2-cytokine production by peripheral blood mononuclear cells (PBMCs) of healthy and allergic subjects

    Immunobiology

    (2008)
  • I.I. Ivanov et al.

    Induction of intestinal Th17 cells by segmented filamentous bacteria

    Cell

    (2009)
  • G.R. Gibson

    Dietary modulation of the human gut microflora using the prebiotics oligofructose and inulin

    J Nutr

    (1999)
  • H.H. Smits et al.

    Selective probiotic bacteria induce IL-10-producing regulatory T cells in vitro by modulating dendritic cell function through dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin

    J Allergy Clin Immunol

    (2005)
  • V. De Rosa et al.

    A key role of leptin in the control of regulatory T cell proliferation

    Immunity

    (2007)
  • D.A. Searing et al.

    Decreased serum vitamin D levels in children with asthma are associated with increased corticosteroid use

    J Allergy Clin Immunol

    (2010)
  • P.N. Black et al.

    Relationship between serum 25-hydroxyvitamin d and pulmonary function in the third national health and nutrition examination survey

    Chest

    (2005)
  • T.T. Wang et al.

    Direct and indirect induction by 1,25-dihydroxyvitamin D3 of the NOD2/CARD15-defensin beta2 innate immune pathway defective in Crohn disease

    J Biol Chem

    (2010)
  • S.R. Gill et al.

    Metagenomic analysis of the human distal gut microbiome

    Science

    (2006)
  • P.J. Turnbaugh et al.

    The human microbiome project

    Nature

    (2007)
  • P.B. Eckburg et al.

    Diversity of the human intestinal microbial flora

    Science

    (2005)
  • C. Palmer et al.

    Development of the human infant intestinal microbiota

    PLoS Biol

    (2007)
  • M. Rescigno

    The pathogenic role of intestinal flora in IBD and colon cancer

    Curr Drug Targets

    (2008)
  • L.V. Hooper et al.

    Commensal host-bacterial relationships in the gut

    Science

    (2001)
  • P.G. Falk et al.

    Creating and maintaining the gastrointestinal ecosystem: what we know and need to know from gnotobiology

    Microbiol Mol Biol Rev

    (1998)
  • S. Fagarasan et al.

    Intestinal IgA synthesis: regulation of front-line body defences

    Nat Rev Immunol

    (2003)
  • L.V. Hooper

    Do symbiotic bacteria subvert host immunity?

    Nat Rev Microbiol

    (2009)
  • Y.K. Lee et al.

    Has the microbiota played a critical role in the evolution of the adaptive immune system?

    Science

    (2010)
  • D.P. Strachan

    Hay fever, hygiene, and household size

    BMJ

    (1989)
  • C. Flohr et al.

    Atopic dermatitis and the “hygiene hypothesis”: too clean to be true?

    Br J Dermatol

    (2005)
  • R.M. Maizels

    Exploring the immunology of parasitism—from surface antigens to the hygiene hypothesis

    Parasitology

    (2009)
  • A.E. Wold

    The hygiene hypothesis revised: is the rising frequency of allergy due to changes in the intestinal flora?

    Allergy

    (1998)
  • J. Corren et al.

    A randomized, controlled, phase 2 study of AMG 317, an IL-4Ralpha antagonist, in patients with asthma

    Am J Respir Crit Care Med

    (2010)
  • M. Veldhoen et al.

    Transforming growth factor-beta “reprograms” the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset

    Nat Immunol

    (2008)
  • G. Cheng et al.

    Anti-interleukin-9 antibody treatment inhibits airway inflammation and hyperreactivity in mouse asthma model

    Am J Respir Crit Care Med

    (2002)
  • Y.H. Wang et al.

    A novel subset of CD4(+) T(H)2 memory/effector cells that produce inflammatory IL-17 cytokine and promote the exacerbation of chronic allergic asthma

    J Exp Med

    (2010)
  • M.R. Karlsson et al.

    Allergen-responsive CD4+CD25+ regulatory T cells in children who have outgrown cow's milk allergy

    J Exp Med

    (2004)
  • S. Provoost et al.

    Decreased FOXP3 protein expression in patients with asthma

    Allergy

    (2009)
  • M. John et al.

    Inhaled corticosteroids increase interleukin-10 but reduce macrophage inflammatory protein-1alpha, granulocyte-macrophage colony-stimulating factor, and interferon-gamma release from alveolar macrophages in asthma

    Am J Respir Crit Care Med

    (1998)
  • A. Joetham et al.

    Naturally occurring lung CD4(+)CD25(+) T cell regulation of airway allergic responses depends on IL-10 induction of TGF-beta

    J Immunol

    (2007)
  • W. Wei et al.

    Induction of CD4+CD25+Foxp3+IL-10+ T cells in HDM-allergic asthmatic children with or without SIT

    Int Arch Allergy Immunol

    (2010)
  • Cited by (175)

    • Unravelling the involvement of gut microbiota in type 2 diabetes mellitus

      2021, Life Sciences
      Citation Excerpt :

      No doubt the gut micro flora performs numerous important functions but any discrepancy in the microbiota can progress to various disorders such as colon-rectal cancer, inflammatory bowel disease, Crohn's disease [19–23]. Alteration in the gut micro flora is also related to metabolic disorders such as obesity, diabetes as well as food allergy [24–27]. Novel techniques such as 16S rRNA, gradient gel electrophoresis based on the denaturing of polymerase chain reaction, meta-genomics, meta-transcriptomics, microarrays have helped to explore the widespread species of microorganisms inhabiting the gut [28,29].

    • Evidence-Based Nutrition and Clinical Evidence of Bioactive Foods in Human Health and Disease

      2021, Evidence-Based Nutrition and Clinical Evidence of Bioactive Foods in Human Health and Disease
    • Reciprocal Translation Between Pathophysiology and Practice in Health and Disease

      2021, Reciprocal Translation Between Pathophysiology and Practice in Health and Disease
    • Microbiome-focused asthma management strategies

      2019, Current Opinion in Pharmacology
    View all citing articles on Scopus

    Series editors: Joshua A. Boyce, MD, Fred Finkelman, MD, William T. Shearer, MD, PhD, and Donata Vercelli, MD

    Terms in boldface and italics are defined in the glossary on page 1098.

    View full text