Does the microbiota regulate immune responses outside the gut?

doi:10.1016/j.tim.2004.10.008

Trends in Microbiology

Volume 12, Issue 12, December 2004, Pages 562-568

https://doi.org/10.1016/j.tim.2004.10.008 Get rights and content

Perturbations in the gastrointestinal (GI) microbiota composition that occur as a result of antibiotics and diet in ‘westernized’ countries are strongly associated with allergies and asthma (‘hygiene hypothesis’). The microbiota (‘microflora’) plays a crucial role in the development of mucosal tolerance, including the airways. Significant attention has been focused on the role of the microbiota in GI development, immune adaptation and initiation of GI inflammatory diseases. This review covers the post-developmental functions that the microbiota plays in regulating immunological tolerance to allergen exposure outside the GI tract and proposes the question: is the microbiota a major regulator of the immune system?

Section snippets

The normal microbiota: characterization and development

The process of colonization of the GI tract after birth leads to a series of ecological successions with the end result being the establishment of a stable microbiota (‘microflora’) that is unique to each individual. The stable adult microbiota is composed of autochthonous species (permanent members) and allochthonous species (transient colonizers that are briefly acquired from an external origin). The adult microbiota is composed of 400–1000 species, with as many as 60% that are not culturable

Altering the microbiota

Environmental pressures, such as antibiotics, diet and microbial inoculation, can cause alterations in an otherwise stable microbiota, both transient and permanent (Box 1). Those microbes that produce only beneficial effects for the host are termed ‘probiotic’ species and include Lactobacillus and Bifidobacterium spp. (Box 3). In addition, potentially pathogenic organisms (PPO) make up part of the microbiota and include the aerobic enteric bacteria, Clostridium spp. and Candida albicans (Box 2

The epidemiological connection between altered microbiota and allergies

Antibiotics, diet and infant-feeding regimens are all associated with the development of allergies and asthma [1]. All three of these also have profound effects on microbiota composition (Box 2). Until recently, the evidence to support a role for the microbiota in allergic disease was based on epidemiological studies as opposed to direct testing of this idea. Numerous studies indicate that the composition of the GI microbiota is different in atopic versus non-atopic individuals and in

The immunological consequences of altered microbiota

It has been known for several years that alterations in the GI microbiota can influence mucosal immunity [10]. Germ-free animals have smaller Peyer's patches, fewer intraepithelial lymphocytes, and lower levels of secretory IgA. In the context of allergic responses, germ-free animals are resistant to the induction of oral tolerance that can block IgE production 20, 21. Inoculation of germ-free mice with intestinal bacteria (conventionalization) can restore the ability to generate oral tolerance.

Role of altered microbiota in allergic airway disease

It has been proposed that the lung microenvironment is generally predisposed to Th2 responses [27]. However, repeated intranasal antigen exposure in the lungs leads to decreasing reactivity, a form of tolerance 28, 29. Oral tolerance is mediated by regulatory T-cell responses, which can down-modulate Th2 responses to the same antigens at sites throughout the body, including the lungs 30, 31, 32. Oral tolerance cannot be generated in germ-free mice, indicating that the GI microbiota plays an

Can the microbiota be manipulated to alter allergic responses?

Numerous studies have indicated that probiotic and prebiotic supplementation (Box 3) can produce positive results in both therapeutic and preventative ways [41]. Although the majority of human trials have focused on the benefits of probiotics in GI diseases (reviewed in Ref. [42]), there is some evidence to suggest that probiotic supplementation can alleviate and/or prevent development of allergic disease. Human trials have targeted neonatal or infant subjects who are at risk (one or more

Is the microbiota a major regulator of the immune system?

For a century, science has known that diet can dramatically alter the microbial composition of the microbiota. For decades, science has been able to demonstrate in animal models the importance of the microbiota for the development and maintenance of the immune system. However, the impact of these findings on human health has not become apparent until the past 20–40 years. During this period of time, powerful forces have been introduced into everyday society that can significantly alter the

Acknowledgements

This work was supported by a New Investigator Award in Molecular Pathogenic Mycology from the Burroughs-Wellcome Fund (Gary B. Huffnagle). Mairi C. Noverr was supported by NIH-NHLBI training grant 2T32HL007749–11. Additional support was provided by to Gary B. Huffnagle by the following grants from the National Institutes of Health: RO1-HL65912, RO1-AI59201.

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Trends in Microbiology

Does the microbiota regulate immune responses outside the gut?

Section snippets

The normal microbiota: characterization and development

Altering the microbiota

The epidemiological connection between altered microbiota and allergies

The immunological consequences of altered microbiota

Role of altered microbiota in allergic airway disease

Can the microbiota be manipulated to alter allergic responses?

Is the microbiota a major regulator of the immune system?

Acknowledgements

Lancet

J. Allergy Clin. Immunol.

FEMS Immunol. Med. Microbiol.

J. Allergy Clin. Immunol.

Trends Microbiol.

Trends Microbiol.

J. Allergy Clin. Immunol.

Trends Immunol.

Vaccine

Immunol. Lett.

Lancet

Lancet

J. Allergy Clin. Immunol.

J. Dairy Sci.

Lancet Infect. Dis.

Am. J. Clin. Nutr.

The germless theory of allergic disease: revisiting the hygiene hypothesis

Nat. Rev. Immunol.

Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC

Lancet

Antibiotic use in early childhood and the development of asthma

Clin. Exp. Allergy

The intestinal microflora in allergic Estonian and Swedish 2-year-old children

Clin. Exp. Allergy

Intestinal colonization with Enterobacteriaceae in Pakistani and Swedish hospital-delivered infants

Acta Paediatr. Scand.

Opinion: Interactions between commensal intestinal bacteria and the immune system

Nat. Rev. Immunol.

The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats

J. Exp. Med.

Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice

Infect. Immun.

Some factors associated with geographical variations in the intestinal microflora

Soc. Appl. Bacteriol. Symp. Ser.

The relation between diet and the gut microflora in man

Proc. Nutr. Soc.

An anthroposophic lifestyle and intestinal microflora in infancy

Pediatr. Allergy Immunol.

Early childhood infection and atopic disorder

Thorax

Effect of the gastrointestinal microflora on induction and maintenance of oral tolerance to ovalbumin in C3H/HeJ mice

Infect. Immun.

The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance induction

J. Immunol.

Microbial colonization drives lymphocyte accumulation and differentiation in the follicle-associated epithelium of Peyer's patches

J. Immunol.

Induction by a lactic acid bacterium of a population of CD4(+) T cells with low proliferative capacity that produce transforming growth factor beta and interleukin-10

Clin. Diagn. Lab. Immunol.

Lactobacilli differentially modulate expression of cytokines and maturation surface markers in murine dendritic cells

J. Immunol.

An oral introduction of intestinal bacteria prevents the development of a long-term Th2-skewed immunological memory induced by neonatal antibiotic treatment in mice

Clin. Exp. Allergy