Reviews and feature articleInfluence of gastrointestinal commensal bacteria on the immune responses that mediate allergy and asthma
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
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2022, Annals of Allergy, Asthma and ImmunologyUnravelling the involvement of gut microbiota in type 2 diabetes mellitus
2021, Life SciencesCitation 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 DiseaseReciprocal Translation Between Pathophysiology and Practice in Health and Disease
2021, Reciprocal Translation Between Pathophysiology and Practice in Health and DiseaseMicrobiome dysbiosis and alcoholic liver disease
2019, Liver ResearchMicrobiome-focused asthma management strategies
2019, Current Opinion in Pharmacology
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.