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Keywords:

  • allergy;
  • hygiene hypothesis;
  • immunity;
  • microbial metabolites

Abstract

  1. Top of page
  2. Abstract
  3. Microbial effects on allergy and asthma
  4. Microbe–host immunoregulatory cellular mechanisms
  5. Dietary factors that influence microbial metabolism
  6. Immunoregulatory mechanisms associated with bacterial metabolites
  7. Concluding remarks
  8. Acknowledgments
  9. Conflicts of interest
  10. References

The dramatic increase in the incidence and severity of allergy and asthma has been proposed to be linked with an altered exposure to, and colonization by, micro-organisms, particularly early in life. However, other lifestyle factors such as diet and physical activity are also thought to be important, and it is likely that multiple environmental factors with currently unrecognized interactions contribute to the atopic state. This review will focus on the potential role of microbial metabolites in immunoregulatory functions and highlights the known molecular mechanisms, which may mediate the interactions between diet, microbiota, and protection from allergy and asthma.

Abbreviations
APC

antigen-presenting cell

BCG

Bacillus Calmette–Guerin

CLA

conjugated linoleic acid

CLR

C-type lectin receptor

DC

dendritic cell

DC-SIGN

DC-specific intercellular adhesion molecule-grabbing nonintegrin receptor

DHA

docosahexaenoic acid

GABA

γ-amino butyric acid

Gal

Galectin

GPCR

G protein-coupled receptor

IDO

indoleamine 2,3-dioxygenase

iNOS

inducible nitric oxide synthase

ITIM

immunoreceptor tyrosine–based inhibitory motif

JNK

c-Jun NH(2)-terminal kinase

LCFA

long-chain fatty acid

lcFOS

long-chain fructo-oligosaccharide

LPS

lipopolysaccharide

MCP

monocyte chemotactic protein

NGF

nerve growth factor

PBMC

peripheral blood mononuclear cell

PGE2

prostaglandin E2

PPAR

peroxisome proliferator–activated receptor

PRR

pattern-recognition receptor

RXR

retinoic X receptor

SCFA

short-chain fatty acid

scGOS

short-chain galacto-oligosaccharide

SHP

src homology region 2 domain–containing phosphatase

Sigelc

Sialic acid–binding immunoglobulin-like lectin

SOCS

suppressor of cytokine signaling

TH

T-helper cell

TIM

T-cell immunoglobulin mucin

TLR

toll-like receptor

Treg

T-regulatory cell

Atopic allergic sensitization is characterized by inappropriate immune activation resulting in high levels of specific IgE directed against a range of environmental antigens and animal proteins, leading to allergic disorders including asthma, rhinitis, and atopic dermatitis [1]. These disorders affect 15–25% of Western populations, and their prevalence has increased dramatically over the last few decades. While a number of hypotheses have been proposed to explain this phenomenon, it is clear that there is a strong environmental influence on the incidence and severity of these disorders. Originally, the hygiene hypothesis proposed that allergic diseases were prevented by early infectious exposure introduced by contact with older siblings [2]. In support of this hypothesis, a meta-analysis of published articles suggested that early-life Mycobacterium bovis Bacillus Calmette–Guerin (BCG) exposure has an inhibitory effect on the development of asthma [3]. However, other studies have shown no clear protective effect associated with early-life infections, while additional studies propose that certain infections can actually increase the risk of, and exacerbate, pre-existing asthma [4-10].

In light of these apparently conflicting findings, the hygiene hypothesis has expanded beyond the sole involvement of pathogenic microbes to include interactions of the host with a complex pattern of microbial stimuli. Consistently, a series of studies have shown that children who were in close contact with farm animals, early in life, exhibited significantly lower levels of allergy and asthma in later life [11-16]. In addition, the host microbiota (which includes commensal and symbiotic microbes) has been demonstrated to be essential for full immunological development and function in a range of experimental models, in particular germ-free and gnotobiotic animals.

The mechanisms underpinning the hygiene hypothesis were thought to include the polarizing effect of pathogenic microbes on the induction of type 1 T-helper (TH1) cell responses, thereby inhibiting the type 2 T-helper (TH2) cell–biased cytokine response associated with the induction of allergy. Understanding of the potential mechanisms has also evolved in the context of altered dendritic cell (DC) and T-regulatory (Treg) cell activity, which is now considered to be a critical feature of the immune dysregulation associated with allergy [17, 18]. The list of microbial factors that impact immune cell signaling is growing daily and includes pattern-recognition receptor (PRR) ligands and metabolic products. However, the microbiota is extremely versatile with regard to its ability to utilize a variety of dietary substrates, and the interaction between microbes, diet, and immunoregulation has been poorly described thus far. This review will focus on the influence of the microbiota on immunoregulatory mechanisms and, in particular, the immunoregulatory compounds that are generated by microbial metabolism of dietary factors (Table 1).

Table 1. Evidence for the interaction between microbial metabolites and the immune system
Dietary componentMicrobial metaboliteHost effectAssessedReferences
CarbohydratesPolysaccharides

IL-10

IL-12

Superoxide

Migration

Adhesion

Mast cell degranulation

Apoptosis

In vitro/Animal studies
Nondigestible carbohydratesShort-chain fatty acid (SCFA)

Prostaglandin E2 (PGE2)

Inflammation

dendritic cell differentiation

IL-10

iNOS

Mast cell degranulation

In vitro/Animal studies
Prebiotics, Sugar, Antioxidants, SCFALong-chain fatty acid

Inflammation

NO

PGE2, Leukotriene B4

IL-10

IgE

IgA

In vitro/Animal and human clinical studies
Aldehyde, Ketone, Fermentable carbohydrates, OxygenBiogenic amines

Maturation

Activation

Polarization

Effector function

Inflammation

Mucus production

In vitro/Animal and human clinical studies

Microbial effects on allergy and asthma

  1. Top of page
  2. Abstract
  3. Microbial effects on allergy and asthma
  4. Microbe–host immunoregulatory cellular mechanisms
  5. Dietary factors that influence microbial metabolism
  6. Immunoregulatory mechanisms associated with bacterial metabolites
  7. Concluding remarks
  8. Acknowledgments
  9. Conflicts of interest
  10. References

It is now widely accepted that the microbiota is important for optimal host development and for ongoing immune homeostasis [19-21]. The microbiota aids in the digestion of foods and nutrient absorption, protects against colonization by pathogens, degrades mucin, and promotes the differentiation of epithelial cells and mucosal-associated lymphoid tissue. In addition, the composition and metabolic activity of the microbiota have profound effects on the induction of immune tolerance. Accumulating evidence suggests that certain bacterial strains may provide protective signals, while other bacterial strains may stimulate aggressive and damaging immune responses. Thus, the activity of the mammalian immune system seems to be governed by the balance between symbiotic and pathogenic factors derived from our microbial inhabitants [22-24]. This raises the possibility that dysbiosis can lead to inappropriate inflammatory responses and may contribute to the dramatic increase in several immune-mediated disorders observed in recent decades, including allergy and asthma. However, it remains unclear whether dysbiosis is the cause or an epiphenomenon of the disease.

There is significant interest in the deliberate administration of microbes or microbial metabolites for the treatment of aberrant inflammatory activity [25-30]. The protective effects associated with these microbes are probably mediated by multiple mechanisms involving epithelial cells, DCs, and T cells. Despite encouraging animal model data, human clinical studies examining the effectiveness of therapeutic microbes for the prevention or treatment of allergic disease have not been conclusive thus far. A review of 13 randomized placebo-controlled trials concluded that certain, but not all, microbes could have utility particularly when administered early in life [31]. In particular, infants at high risk of atopy who received Lactobacillus rhamnosus GG developed atopic dermatitis significantly less frequently during the first 2 years of life. However, prenatal treatment alone failed to prevent atopic eczema during the first year of life [32]. A more recent study, which used a combination of three bacterial strains, demonstrated that prenatal and postnatal supplementation was effective in preventing the development of atopic eczema in infants at high risk of allergy during the first year of life [33]. The use of microbes for the treatment of allergic disease is less promising. A Cochrane meta-analysis concluded that the microbes tested to date are not effective for the treatment of eczema [34]. In addition, clinical data on the use of microbes in the treatment of asthma and allergic rhinitis are conflicting. One issue with the selection of immunoregulatory microbes is that the most suitable bacterial strain may not have been chosen, as not all probiotic strains exert the same effects in vivo compared with the results obtained in vitro. In addition, the metabolic activity of a bacterial strain is significantly influenced by the availability of suitable substrates, thereby leading to the secretion of varying quantities of different metabolites. Dietary factors are not usually considered in probiotic clinical studies, which may contribute to the inconsistent effects observed thus far.

Microbe–host immunoregulatory cellular mechanisms

  1. Top of page
  2. Abstract
  3. Microbial effects on allergy and asthma
  4. Microbe–host immunoregulatory cellular mechanisms
  5. Dietary factors that influence microbial metabolism
  6. Immunoregulatory mechanisms associated with bacterial metabolites
  7. Concluding remarks
  8. Acknowledgments
  9. Conflicts of interest
  10. References

In order to ensure the induction of tolerance and protective immunity, discriminative responses are required to commensals in comparison with pathogens, respectively. For example, segmented filamentous bacteria can promote the differentiation of T-helper 17 (TH17) cells, while certain Bifidobacterium, Lactobacillus, and Clostridium species can promote Treg development [24, 35-37]. At body surfaces that come into contact with bacteria, a number of cell types including DCs, lymphocytes, and epithelial cells are required to maintain immunological homeostasis and tolerance [38].

Dendritic cells are professional antigen-presenting cells (APCs), which are in close contact with microbes and are responsible for presenting microbial, environmental, and dietary antigens to the adaptive immune system, thereby influencing the polarization of the adaptive response via cytokine and metabolite production. Dendritic cells are proposed to be an important cellular component of the hygiene hypothesis, as suggested by murine studies. Dendritic cells isolated from mice, which were infected with Schistosoma japonicum, Chlamydia muridarum, or BCG, were able to inhibit allergic airway inflammation following adoptive transfer [39-41]. Depending on the specific infection, DCs secreted IL-10, IL-12, or both, suggesting that tolerogenic and TH1-polarizing DCs, induced by an infection, efficiently inhibit the induction of TH2 allergic polarization. Dendritic cells recognize different microbial structures and components via their expression of PRRs, which program DC gene expression and subsequent T-cell polarization [42]. For example, Toll-like receptor (TLR)-2 recognition of zymosan results in the secretion of retinoic acid and IL-10 leading to Foxp3 induction, while dectin-1 activation by zymosan leads to IL-23 secretion and TH17 induction [43]. Recent findings on the role of PRR signaling in mucosal homeostasis have emphasized the delicate balance between different PRR functions and revealed that defective PRR signaling can result in inflammation and atopic sensitization [44, 45]. Toll-like receptor-2 knock-out animals are more sensitive to dextran sodium sulfate–induced colitis, while TLR-2 gene variants are associated with disease phenotype in patients with inflammatory bowel disease. Indeed, TLR-2 has been demonstrated to promote Foxp3 expression in response to intestinal microbes in murine models [46, 47]. In addition, cross-talk between TLR-2/6, DC-specific intercellular adhesion molecule-grabbing nonintegrin receptor (DC-SIGN), and TLR-9 activation on human DCs, in response to a commensal microbe, is responsible for inducing high levels of IL-10 secretion and lymphocyte Foxp3 expression [48]. Toll-like receptor 3, but not TLR4, is responsible for IFN-λ secretion by intestinal DCs, which has been shown to play an important role in the maintenance of oral tolerance [49].

The primary function of epithelial cells is to provide a physical barrier between the external environment and the underlying body organs. In addition, epithelial cells provide immunoregulatory signals that can influence DC and lymphocyte activation. Epithelial cells express PRRs and therefore can respond to the presence of different microbial species. For example, lipoteichoic acid released by Staphylococcus epidermidis (a cutaneous commensal microbe) inhibits both inflammatory cytokine release from keratinocytes and inflammation triggered by injury through a TLR-2-dependent process [50]. Intestinal epithelial cells regulate DC, T- and B-cell functions through the secretion of immunomodulatory molecules, such as chemokines, retinoic acid, thymic stromal lymphopoietin, and TGF-β [51-53]. The presence of certain commensal microbes can influence the production of chemokines and regulatory factors by epithelial cells. Lactobacillus and Bifidobacterial strains have been shown to inhibit intestinal epithelial cell NF-κB activation and chemokine secretion to a range of proinflammatory and pathogenic stimuli, including flagellin, TNF-α, Salmonella enterica serovar Typhimurium, and Clostridium difficile[54-56]. Multiple mechanisms are thought to be involved in the direct inhibition of epithelial proinflammatory responses, which include the secretion of nerve growth factor (NGF), the prevention of the degradation of the NF-κB inhibitor IκB-α, or the nuclear export of the p65 subunit of NF-κB in a peroxisome proliferator–activated receptor (PPAR) γ-dependent manner [54, 57, 58].

A common feature of immunoregulatory microbes, which is being increasingly reported, is their ability to induce Treg cells. For example, encounters with a mixture of commensal microbes (VSL#3 probiotic cocktail) within the murine gut have been shown to drive the development of mucosal Treg cells, which is associated with the attenuation of inflammation in a murine model of colitis [59]. In addition, the consumption of a Bifidobacterium infantis strain promotes Treg-cell conversion and protects against lipopolysaccharide (LPS)-induced NF-κB activation in vivo, while Lactobacillus reuteri induces Treg cells that protect against an allergic airway response in mice [37, 60]. Treg cells are derived from the thymus but may also be induced in peripheral organs, including the gut mucosa [61, 62]. CD103+ DCs within the mucosa are largely responsible for the conversion of Treg cells via TGF-β and retinoic acid–dependent processes [63, 64]. The conversion is likely driven by gastrointestinal-specific environmental factors associated with the presence of large numbers of commensal organisms. Indeed, we have recently reported that retinoic acid–metabolizing enzymes can be upregulated in myeloid, but not in plasmacytoid, DCs following in vitro incubation with a Bifidobacterium infantis bacterial strain [48]. However, it is unlikely that all commensal microbes are equally effective at inducing Treg cells in vivo. A recent study comparing multiple commensal organisms (Bifidobacterium longumAH1206, Bifidobacterium breveAH1205, and Lactobacillus salivarius AH102) has shown that Bifidobacterium longumAH1206 induced Treg cells and was also able to protect against respiratory allergic inflammation [36]. The other bacterial strains did not effectively induce Treg cells and were not able to protect against allergic inflammation. Therefore, the induction of Treg cells may be a critical characteristic of a healthy microbiota, which is protective against the development of aberrant immunological reactivity to potential allergens. In addition to using live microbes for the treatment of allergy, another exciting approach is to identify the microbial factor(s) responsible for the beneficial effect and to use these isolated factor(s) alone. For example, polysaccharide A derived from Bacteroides fragilis promotes an appropriate TH1/TH2 balance in germ-free mice following presentation by mucosal DCs and protects against colitis in an animal model via IL-10-secreting CD4+ T cells [29, 65]. The continued identification of new microbial compounds, which induce tolerogenic DCs and Treg activity, will undoubtedly lead to novel therapeutic candidate molecules for assessment in clinical studies.

Dietary factors that influence microbial metabolism

  1. Top of page
  2. Abstract
  3. Microbial effects on allergy and asthma
  4. Microbe–host immunoregulatory cellular mechanisms
  5. Dietary factors that influence microbial metabolism
  6. Immunoregulatory mechanisms associated with bacterial metabolites
  7. Concluding remarks
  8. Acknowledgments
  9. Conflicts of interest
  10. References

A wide range of complex oligosaccharides, also called fiber, are not digested by the host, but enter the colon and provide fermentable substrates for the colonic microbiota [66]. Historically, diets high in fiber have been shown to diminish the severity of arthritis and inflammatory bowl diseases [67]. Certain dietary fibers that promote the growth of Bifidobacteria and Lactobacilli strains have been identified and these are called prebiotics. Typically, prebiotics are short-chain carbohydrates with a degree of polymerization between two and sixty, such as polydextrose, inulin, fructo-oligosaccharides, glacto-oligosaccharides, and soybean oligosaccharides [68-71]. Bacterial metabolic processing of these oligosaccharides leads to the generation of novel polysaccharide structures, in addition to the secretion of short-chain fatty acids (SCFAs). Bifidobacteria utilize the ‘bifid shunt’ catabolic pathway to produce SCFAs and ATP. Before entering the ‘bifid shunt’ pathway, oligosaccharides are processed into constituent carbohydrates by glycosyl hydrolases [72]. The catabolic pathway uses fructose-6-phosphate phosphoketolase to produce phosphoenolpyruvate that is degraded to pyruvate, the primary metabolite for SCFAs production. Pyruvate is further metabolized to acetyl-CoA leading to the formation of acetate and butyrate [73]. Depending on the specific polysaccharides, different SCFAs can be produced. Pectin and xylan fermentation primarily leads to acetate generation. Arabinogalactan breakdown results in acetate and propionate synthesis, while starch was shown to be metabolized into butyrate [66]. SCFAs are either secreted or incorporated in newly synthesized fatty acids within cellular structures.

In addition to SCFAs, long-chain fatty acids (LCFAs) are produced by bacterial metabolism within the gut. Long-chain fatty acids such as omega-3 fatty acids or conjugated linoleic acids (CLAs) have been reported to have beneficial effects on cancer, cardiovascular disease, diabetes, obesity, bone disorders, and inflammatory diseases as well as to have anti-oxidative and growth-promoting properties [67, 74]. Meat and milk products derived from ruminants are a traditional source of CLAs. In the rumen, CLAs are produced from free linoleic acid by bacterial isomerase activity [75]. Antioxidants, sugar, and certain prebiotic compounds as well as the sodium salt of SCFAs had a positive impact on the CLAs produced by Bifidobacteria in the intestine of mammalians [66, 74]. Certain probiotic bacteria are able to produce CLAs from linoleic acid, vaccenic acid, or hydroxyl fatty acids [75].

Biogenic amines are synthesized by decarboxylation of amino acids or by amination and transamination of aldehydes and ketones. Biogenic amines such as γ-amino butyric acid (GABA) or histamine can be synthesized by bacteria [76]. Enzymes that are able to generate biogenic amines are found in microbes, plants, and animal metabolic processes. In bacteria, the expression and activity of amino acid decarboxylases is enhanced in acidic environments, such as in the stomach. This leads to a local increase in pH around the bacteria and protects it from the acidic, chloride-rich environment [76, 77]. Furthermore, expression and activity of decarboxylases in bacteria is regulated by the presence of fermentable carbohydrates and oxygen, by the redox potential of the medium, by the temperature, and by the sodium chloride concentration [77].

Immunoregulatory mechanisms associated with bacterial metabolites

  1. Top of page
  2. Abstract
  3. Microbial effects on allergy and asthma
  4. Microbe–host immunoregulatory cellular mechanisms
  5. Dietary factors that influence microbial metabolism
  6. Immunoregulatory mechanisms associated with bacterial metabolites
  7. Concluding remarks
  8. Acknowledgments
  9. Conflicts of interest
  10. References

The dietary factors and their known effects on host immunoregulation are summarized in Fig. 1. Nondigestible carbohydrates may influence the immune response, independently of stimulating the growth of the microbial flora in the gut, potentially through two immunoregulatory mechanisms. The generation of carbohydrate structures, which bind PRRs, may influence immune regulatory activity, while SCFAs may also bind receptors on gut-associated cells.

image

Figure 1. Microbial metabolites such as lectin-binding carbohydrates, Short-chain fatty acids, and long-chain fatty acids influence immune responses such as inflammatory responses, immune regulation, cell migration and adhesion, and eicosanoid production in antigen-presenting cells, mast cells, T-helper cells, and B cells.

Download figure to PowerPoint

Polysaccharides

Carbohydrate binding proteins are increasingly being shown to regulate immune reactivity and immune tolerance mechanisms. Lectins are carbohydrate binding proteins and are expressed in virtually all animals and plants. The lectin family is categorized based on the structure and function [78, 79]. Many of the C-type lectins (CLRs) and sialic acid–binding immunoglobulin-like lectins (Siglec) are membrane bound, while the galectins are secreted. All lectins contain one or more carbohydrate-recognition domains [80]. They are involved in the activation or regulation of TLR-dependent or independent innate gene expression and antigen presentation. Lectins recognize various carbohydrate structures of pathogens, such as parasites, viruses, bacteria, and fungi. Additionally, lectins are further involved in translating glycan-encoded information of host cells into an effector immune function [81-84]. Binding of lectins to their ligands can positively or negatively influence the priming of the immune system and induction of tolerance [81].

C-type lectin receptors recognize monosaccharides, such as mannose, fucose, galactose, or N-acetylgalactosamine and more complex carbohydrate profiles of various pathogens or of host cells by their C-type carbohydrate-recognition domains leading to internalization into intracellular compartments of DCs resulting in the processing and presentation of the antigenic peptides on MHC class I and II molecules [82-84]. In general, targeting of CLRs on immature DCs in the absence of TLR stimulation does not lead to DC maturation but to peripheral tolerance and to induction of Treg cells, which is one mechanism exploited by tumor cells and some viruses to dampen an immune response [84-86]. So far, 15 CLRs have been identified in DCs and macrophages. One well-described CLR is DC-SIGN, a receptor for mannose-containing particles that binds HIV, Ebola, or mycobacteria [82, 83]. Targeting DC-SIGN on human DCs activates the serine and threonine kinase Raf-1 leading to the acetylation of the NF-κB subunit p65 and increased IL-10 transcription [87]. Interestingly, it has been shown that a sugar-modified antigen can induce oral tolerance in a mouse model of food allergy. This process seems to be dependent on IL-10, induced via the CLR SIGNR1 on DCs in the gastrointestinal lamina propria [88]. Another mannose receptor is langerin (CD207), selectively expressed on Langerhans cells [82]. Dectin-1 plays a crucial role in regulating immune responses against fungi via recognition of β-glucans [82]. The mannose receptor (CD206) has been described to recognize various airborne allergens leading to induction of a TH2 response by the inhibition of indoleamine 2,3-dioxygenase (IDO) activity [89].

S-type lectins comprise a group of 15 different galectins [82], which require a reduced thiol group for full function [78, 79]. Galectins are soluble lectins that bind to multiple glycosylated structures on host cells [90]. Galectins are involved in cell signaling, cell adhesion, chemotaxis, lipid raft stabilization, and cell apoptosis [91]. They act as receptors for N-acetyllactosamine and are expressed by activated T cells and B cells, eosinophils, basophils, thymic and intestinal epithelia cells and are upregulated in activated macrophages and Treg cells [80]. Variations in the activity of glycosyltransferases and glycosidases modulate the ligand density for galectins and thereby the activation of T cells, cytokine secretion, or apoptosis [82]. Interestingly, galectin-9 and TLR-9 have been shown to mediate the protective effect of a diet containing a probiotic bacterial strain combined with a mixture of short-chain galacto-oligosaccharides (scGOS) and long-chain fructo-oligosaccharides (lcFOS) in a food allergy model [91]. Galectin-3 induces neutrophil and macrophage migration and adhesion to endothelia and IL-8 secretion and activates NADPH oxidase leading to superoxide production [90]. Galectin-1 modulates phagocytosis and antigen presentation of macrophages by regulating Fcγ receptor 1 and MHC class II. Furthermore, IL-12 production is inhibited and IL-10 production increased in galectin-1-stimulated macrophages and DCs [90]. Mast cells from galectin-3-deficient mice secreted less histamine and IL-4 upon FcεRI cross-linking [92]. Extracellular galectin-3 induces apoptosis in mast cells, while galectin-1 and -9 reduce their ability to degranulate, possibly due to the inhibition of IgE–antigen complex formation [90]. Intestinal epithelial cells express galectin-2, -3, -4, -5, -6, -7, and -9 [91]. Galectin-1 has been shown to antagonize T-cell receptor signaling by inducing partial phosphorylation of the T-cell receptor ξ-chain and suppression of IL-2 production. Galectin-1 also blocks CD2 binding of T cells to APCs in the immunological synapse. Furthermore, galectin-1 enhances the secretion of IL-10 by Treg cells. Galectin-3 regulates T-cell receptor activation by binding the T-cell receptor. In addition, binding of galectin-9 to T-cell immunoglobulin mucin (TIM)-3 receptor on DCs induces IL-12 production in a p38-dependent manner and enhances TH1 response. Depending on the relative concentration of galectin-9, IFN-γ can be induced by TH1 cells, or galectin-9 can induce the development of Treg cells and suppress TH17 differentiation in mice [91].

Siglecs are I-type lectins, belong to the immunoglobulin superfamily, and recognize sialic acid attached to the terminal regions of cell-surface glycoconjugates [82, 93-96]. They are categorized into two groups [94]. Members of the more conserved group are sialoadhesin (Siglec-1/CD169), CD22 (Siglec-2), myelin-associated glycoprotein (Siglec-4), and Siglec-15. They have 25–30% sequence identity and have orthologues in all mammalian species. The group of CD33-related Siglecs share 50–99% sequence identity but their rapid evolution has resulted in differences between mammalian species. Nine human (CD33, Siglec-5 to 11, Siglec-14, and -16) and five murine CD33-related Siglecs (CD33, Siglec-E, -F, -G, and -H) have been identified. [93-96]. Many immune cell subsets, except T cells, express at least one Siglec [80, 96, 97]. Many Siglecs have intracellular immunoreceptor tyrosine–based inhibitory motifs (ITIM) indicating an inhibitory function that could suppress activation signals. After ligation, the ITIM is phosphorylated enabling the recruitment of the signaling molecules src homology region 2 domain–containing phosphatase (SHP)-1 and -2 tyrosine phosphatase and the suppressor of cytokine signaling (SOCS)-3 [97]. In fact, Siglecs dampen immune response activation or induce apoptosis also by enhancing the production of anti-inflammatory cytokines [95, 98, 99]. Each Siglec has a unique ligand-specificity profile. Targeting human Siglec-8 or Siglec-F, the mouse homolog, has been shown to regulate eosinophil viability by the induction of apoptosis [100, 101]. Furthermore, FcεRI-dependent histamine and prostaglandin D2 release was blocked by the engagement of Siglec-8 on mast cells [102].

SCFA

Short-chain fatty acids are ligands for G protein-coupled receptors (GPCRs), such as GPR43 and GPR41. Both fatty acid receptors are involved in metabolism and immunity. SCFAs, particularly butyrate, seem to exert anti-inflammatory activities by affecting immune cell migration, adhesion, cytokine expression as well as by affecting cellular processes such as proliferation, activation, and apoptosis [103]. GPR43 activation has been shown to be necessary for the optimal resolution of certain inflammatory responses, because GPR43-deficient mice showed exacerbated or un-resolving inflammation in the models of colitis, arthritis, and asthma. GPR43 deficiency is related to increased production of inflammatory mediators by immune cells and to increased immune cell recruitment [104]. GPR43 is expressed not only on immune cells such as monocytes and neutrophils but also on colonic epithelium, while GPR41 is more widely distributed over tissues but is particularly expressed on adipose tissues, immune and endothelial cells [105]. Both receptors couple through Gq and Gi/o families. The resulting intracellular pathways activated by these receptors include inositol 1,4,5-trisphosphate generation, intracellular Ca2+ release, ERK1/2 and p38 activation, and inhibition of cAMP accumulation [106, 107]. Depending on the concentration and type of SCFAs, GPR43 ligand binding can induce or reduce neutrophil migration and cell adhesion to endothelial cells [103, 108, 109]. Short-chain fatty acids induce the release of prostaglandin E2 (PGE2) in human monocytes and inhibit constitutive monocyte chemotactic protein-1 (MCP-1) production and LPS-induced IL-10 production in human monocytes. Similar activities were observed in human peripheral blood mononuclear cells (PBMCs) with regard to PGE2, MCP-1, and IL-10 secretion after SCFAs treatment. In addition, SCFAs inhibit LPS-induced IκB degradation and therefore the production of TNF-α, IFN-γ, IL-6, IL-1β, and the inducible nitric oxide synthase (iNOS) in human PBMCs [103, 110]. These effects seem to be strongest for butyrate, while propionate and acetate increased IFN-γ and IL-10 release. SCFAs inhibit DC differentiation from bone marrow stem cells by the regulation of gene transcription via inhibition of histone deacetylases [111, 112]. Butyrate has been shown to inhibit mast cell degranulation and TNF-α production by inhibiting c-Jun NH(2)-terminal kinase (JNK) and phospholipase D [113]. Furthermore, SCFAs inhibited antigen-induced contraction of guinea pig tracheal rings and colon and histamine release by rat peritoneal mast cells [114].

LCFA

Long-chain fatty acids such as omega-3 fatty acids or CLA possess immunoregulatory activity. The omega-3 fatty acid docosahexaenoic acid (DHA) inhibits p38 MAPK phosphorylation and the degradation of IκB kinase, following binding to GPR120 and PPARs. GPR120 is a physiological receptor for omega-3 fatty acids in macrophages and adipocytes. Ligand binding mediates anti-inflammatory and insulin-sensitizing effects [115]. Binding of GPR120 by omega-3 fatty acids results in the internalization of GPR120, which binds β-arrestin 2 and sequesters TAB 1, a molecule crucial for TLR- or TNF-α-mediated induction of inflammation [116]. PPARs form a heterodimer with retinoic X receptors (RXRs), subsequently regulating many target genes upon activation via transrepression [117]. PPAR ligands suppress the expression of various inflammatory components such as cytokines, chemokines, and costimulatory molecules in macrophages and DCs [118]. Omega-3 fatty acids diminished DC-induced T-helper cell activation by influencing antigen presentation and costimulatory molecule signaling [119, 120]. Ligand binding to PPARs within T cells reduces the secretion of IFN-γ and IL-17 [118].

There are two mechanisms described by which CLAs influence the immune response. CLAs diminish eicosanoid production leading to the downregulation of PGE2 and leukotriene B4. In addition, CLAs have been shown to bind PPARs. Humans, or guinea pigs, with diets supplemented with CLAs have higher IL-10, lower TNF-α, and lower IFN-γ serum levels. Furthermore, CLAs inhibit LPS-induced TNF-α and NO production [75, 121]. Dietary supplementation with CLAs in humans results in higher IgA and decreased IgE serum levels. Furthermore, CLAs increase the immune response toward hepatitis B vaccination and mice display enhanced CD8+ T-cell numbers after feeding with CLAs [121].

Biogenic amines

The biological consequences of biogenic amine secretion in vivo by the resident microbiota are largely unknown. Histamine production by bacteria present within decaying fish can result in scombroid food poisoning, which resembles symptoms associated with an allergic response. Histamine has been shown to exert potent immunoregulatory effects and may negatively or positively influence parasitic or bacterial infections [122]. A wide range of host immune cells can express histamine receptors, which can selectively recruit the major effector cells into tissue sites and affect their maturation, activation, polarization, and effector functions leading to tolerogenic or pro-inflammatory responses [123]. However, the influence of histidine-rich or depleted diets on histamine secretion by the enteric microbiota is currently unknown. Another biogenic amine, which has been shown to be produced by microbes present within certain foods, is GABA [124]. Two types of GABA receptors are known. The GABAA receptor subtype forms a part of a ligand-gated ion channel complex, and the GABAB receptor subtype is a GPCR. Interestingly, the GABA signaling pathway has been shown to be important for the stimulation of mucus production from airway epithelial cells, in both mouse models of respiratory allergy and allergen-challenged asthma patients [125]. The contribution of enteric microbes to the systemic GABA pool, via the metabolism of glutamate in vivo, is unknown and requires further investigation.

Concluding remarks

  1. Top of page
  2. Abstract
  3. Microbial effects on allergy and asthma
  4. Microbe–host immunoregulatory cellular mechanisms
  5. Dietary factors that influence microbial metabolism
  6. Immunoregulatory mechanisms associated with bacterial metabolites
  7. Concluding remarks
  8. Acknowledgments
  9. Conflicts of interest
  10. References

While it is clear that the microbiota significantly influences host immune maturation and immune activity, the molecular basis for these immunomodulatory mechanisms is only beginning to be elucidated. The presence of certain bacterial species or strains seems to be important, potentially because of direct interactions with the host (e.g., via PRR activation) or via their metabolic activity in vivo (e.g., SCFAs generation). Thus, care should be exercised in the selection of immunoregulatory microbes for administration in human studies as it is likely that not all microbes are equally effective and dietary factors may significantly influence the production of immunoregulatory metabolites. In addition, significant effort needs to be focused on the elucidation of the microbiota-associated molecular pathways that are impacted by dietary factors so that rationale prevention and treatment strategies can be formulated, which will include matching essential microbes and dietary components. Specific projects mining the microbiota for metabolites and ligands that modulate host immune function will likely lead to a new class of immunotherapeutic agents with relevance to a variety of inflammatory states, including allergy and asthma. Lastly, the hygiene hypothesis should now be updated to include dietary factors and the interaction of dietary factors with the microbiota.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Microbial effects on allergy and asthma
  4. Microbe–host immunoregulatory cellular mechanisms
  5. Dietary factors that influence microbial metabolism
  6. Immunoregulatory mechanisms associated with bacterial metabolites
  7. Concluding remarks
  8. Acknowledgments
  9. Conflicts of interest
  10. References

The authors are supported by Swiss National Foundation grants (project numbers 310030-127356 and 32003027618/1), Christine Kühne – Center for Allergy Research and Education (CK-CARE), European Union research grants, and EU Marie Curie grants.

References

  1. Top of page
  2. Abstract
  3. Microbial effects on allergy and asthma
  4. Microbe–host immunoregulatory cellular mechanisms
  5. Dietary factors that influence microbial metabolism
  6. Immunoregulatory mechanisms associated with bacterial metabolites
  7. Concluding remarks
  8. Acknowledgments
  9. Conflicts of interest
  10. References