Prebiotics: Mechanisms and Preventive Effects in Allergy

Abstract

Allergic diseases now affect over 30% of individuals in many communities, particularly young children, underscoring the need for effective prevention strategies in early life. These allergic conditions have been linked to environmental and lifestyle changes driving the dysfunction of three interdependent biological systems: microbiota, epithelial barrier and immune system. While this is multifactorial, dietary changes are of particular interest in the altered establishment and maturation of the microbiome, including the associated profile of metabolites that modulate immune development and barrier function. Prebiotics are non-digestible food ingredients that beneficially influence the health of the host by 1) acting as a fermentable substrate for some specific commensal host bacteria leading to the release of short-chain fatty acids in the gut intestinal tract influencing many molecular and cellular processes; 2) acting directly on several compartments and specifically on different patterns of cells (epithelial and immune cells). Nutrients with prebiotic properties are therefore of central interest in allergy prevention for their potential to promote a more tolerogenic environment through these multiple pathways. Both observational studies and experimental models lend further credence to this hypothesis. In this review, we describe both the mechanisms and the therapeutic evidence from preclinical and clinical studies exploring the role of prebiotics in allergy prevention.

Keywords: allergy; clinical studies; epithelial barrier; immune system; mechanisms; microbiota; prebiotics; preclinical studies.

Figure 1

Chemical structures of the first generation of prebiotics. FOS: Fructo-oligosaccharides, GlOS: Gluco-oligosaccharides, GOS: Galacto-oligosaccharides, HMO: Human milk oligosaccharides, IMO: Isomalto-oligosaccharids [22].

Figure 2

Human milk oligosaccharide composition blueprint.

Figure 3

Indirect effects of prebiotics. (A) The general mechanisms of SCFAs. The SCFAs are metabolites derived from the fermentation of prebiotics by the microbiota. They are consumed by the microbiota or released into the biological systems (blood, gut, lung, placenta). They can interact with the cells by three mechanisms. In the first mechanism, the GPRs which are receptors coupled to signaling pathways (AMP-activated protein kinase (AMP-K), mammalian target of rapamycin (mTOR), signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinases (MAPKs), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)) are involved. The second mechanisms correspond to the diffusion channels (solute carrier family 16 member 1 (Slc) 16a1 and 5a8) that allow the SCFAs transport directly to cytoplasm and their potential interactions with pathways. By these two mechanisms, the signaling cascade is activated and can influence the transcription of genes by acetylation and deacetylation respectively via the histone acetyltransferases (HAT) and the histone deacetylases (HDAC) enzymes (epigenetic mechanisms). In the last mechanisms, there is a passive diffusion of SCFAs able to modulate directly enzymes (HDAC, HAT) involved in epigenetic processes. The modulation of genes expression by acetylation and deacetylation will have different consequences such as a modification of metabolism, cell cycle or microbial activity described in Figure 3B,C. (B) The specific impact of SCFAs on epithelial cells. SCFAs (butyrate, propionate) can interact with the G-protein coupled receptor (GPR)43 receptor and activates the mTOR/STAT3 pathway allowing the modulation of genes to increase the expression of antimicrobial peptides such as regenerating islet-derived protein 3 gamma (RegIIIγ) and β-defensins. SCFAs can directly increase the epithelial barrier function by stimulating O2 metabolism in intestinal epithelial cell lines. This mechanism results in the stabilization of the transcription factor hypoxia-inducible factor (HIF-1). SCFAs interact also with the GPR 41 (acetate, propionate) and GPR43 receptors to activate the extracellular signal-regulated kinases (ERK) 1/2 and MAPK signaling pathway. In this way, epithelial cells produce inflammatory chemokines and cytokines during the immune response to protect the organism against aggressions or infections. The consumption of SCFA also increases the secretion of the antimicrobial peptide by epithelial cells. (C) The specific impact of SCFAs on IS. SCFAs can be found in the bloodstream. They can interact with different immune cell subtypes. In a first step they can modify the hematopoeisis of dendritic cells (DC) precursors in the bone marrow and induce CD11c+ CD11b+ DCs in lung-draining lymph nodes. The cells CD11c+ CD11b+ DC have a lower capacity to activate the Th2 cell which results in the reduction of allergic asthma. SCFAs are also able to modify in vitro the functionality of FMS-like tyrosine kinase 3 ligand (Flt3L)-elicited splenic DCs: a lower ability to activate T cell and to transport antigen to the lymph node and a lower expression of chemokine (C-C motif) ligand 19 (CCL19) on their surface decreasing their ability to move in different sites. In the lungs SCFAs are able to inhibit the enzyme HDAC9 resulting in an increase of the forkhead box P3 (FoxP3) transcription factor and then an increase of the number and the activity of Treg. In the intestine the increase of retinoic acid-synthesizing (RALDH) enzyme activity during the consumption of SCFA, allows the conversion of vitamin A to the retinoic acid in tolerogenic DC CD103 +. Then, the retinoic acid acts directly on T cells and induces their differentiation into Treg.

Figure 3

Indirect effects of prebiotics. (A) The general mechanisms of SCFAs. The SCFAs are metabolites derived from the fermentation of prebiotics by the microbiota. They are consumed by the microbiota or released into the biological systems (blood, gut, lung, placenta). They can interact with the cells by three mechanisms. In the first mechanism, the GPRs which are receptors coupled to signaling pathways (AMP-activated protein kinase (AMP-K), mammalian target of rapamycin (mTOR), signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinases (MAPKs), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)) are involved. The second mechanisms correspond to the diffusion channels (solute carrier family 16 member 1 (Slc) 16a1 and 5a8) that allow the SCFAs transport directly to cytoplasm and their potential interactions with pathways. By these two mechanisms, the signaling cascade is activated and can influence the transcription of genes by acetylation and deacetylation respectively via the histone acetyltransferases (HAT) and the histone deacetylases (HDAC) enzymes (epigenetic mechanisms). In the last mechanisms, there is a passive diffusion of SCFAs able to modulate directly enzymes (HDAC, HAT) involved in epigenetic processes. The modulation of genes expression by acetylation and deacetylation will have different consequences such as a modification of metabolism, cell cycle or microbial activity described in Figure 3B,C. (B) The specific impact of SCFAs on epithelial cells. SCFAs (butyrate, propionate) can interact with the G-protein coupled receptor (GPR)43 receptor and activates the mTOR/STAT3 pathway allowing the modulation of genes to increase the expression of antimicrobial peptides such as regenerating islet-derived protein 3 gamma (RegIIIγ) and β-defensins. SCFAs can directly increase the epithelial barrier function by stimulating O2 metabolism in intestinal epithelial cell lines. This mechanism results in the stabilization of the transcription factor hypoxia-inducible factor (HIF-1). SCFAs interact also with the GPR 41 (acetate, propionate) and GPR43 receptors to activate the extracellular signal-regulated kinases (ERK) 1/2 and MAPK signaling pathway. In this way, epithelial cells produce inflammatory chemokines and cytokines during the immune response to protect the organism against aggressions or infections. The consumption of SCFA also increases the secretion of the antimicrobial peptide by epithelial cells. (C) The specific impact of SCFAs on IS. SCFAs can be found in the bloodstream. They can interact with different immune cell subtypes. In a first step they can modify the hematopoeisis of dendritic cells (DC) precursors in the bone marrow and induce CD11c+ CD11b+ DCs in lung-draining lymph nodes. The cells CD11c+ CD11b+ DC have a lower capacity to activate the Th2 cell which results in the reduction of allergic asthma. SCFAs are also able to modify in vitro the functionality of FMS-like tyrosine kinase 3 ligand (Flt3L)-elicited splenic DCs: a lower ability to activate T cell and to transport antigen to the lymph node and a lower expression of chemokine (C-C motif) ligand 19 (CCL19) on their surface decreasing their ability to move in different sites. In the lungs SCFAs are able to inhibit the enzyme HDAC9 resulting in an increase of the forkhead box P3 (FoxP3) transcription factor and then an increase of the number and the activity of Treg. In the intestine the increase of retinoic acid-synthesizing (RALDH) enzyme activity during the consumption of SCFA, allows the conversion of vitamin A to the retinoic acid in tolerogenic DC CD103 +. Then, the retinoic acid acts directly on T cells and induces their differentiation into Treg.

Figure 4

Direct effects of prebiotics. (A) Direct effect of prebiotics on lung epithelial cells. Mannan prebiotic stimulates cell spreading and facilitates wound repair in damaged human bronchial epithelium, involving mannose receptors. Prebiotics also increases expression and activation of Krüppel-like factors (KLFs) inducing cell differentiation, survival, and proliferation. (B) Direct effect of prebiotics on skin epithelial cells. Prebiotics supplementation improved water retention and prevented erythema via the expression of CD44, metallopeptidase inhibitor 1 (TIMP)-1, and collagen type 1(Col1) improving the skin’s barrier properties. Prebiotics suppress overproductions of thymic stromal lymphopoietin (TSLP), substance P, IL-10, IL-4, and tumor necrosis factor (TNF)-a leading to reduced transepidermal water loss and skin dryness, prevention of keratin depletion, improvement of biophysical parameters of the epidermis, restoration of skin sebum levels, and limitation of bacterial infection. Prebiotics increase CD4+ Foxp3+ Treg in skin lymph nodes and prevent germline class-switching and IgE production. (C) Direct effect of prebiotics on gut epithelial cells. Prebiotics are Toll like receptor 4 (TLR4) ligands in IEC. Prebiotics induce a range of anti-inflammatory cytokines and reduce pro-inflammatory cytokines to inhibit gut inflammation. Prebiotics enhance galectin-9 expression correlated with reduced acute allergic skin reaction and mast cell degranulation and promoted Th1 and Treg responses. Prebiotics directly promoted barrier integrity to prevent pathogen-induced barrier disruptions involving the induction of protein kinase C (PKC). (D) Direct effect of prebiotics on immune cells. Prebiotics induce both the secretion of anti-inflammatory (IL-10) and pro-inflammatory (IL-1β and TNF-α) cytokines by blood monocytes due to the activation of the NF-ĸB pathway by the binding of TLR4. Prebiotics bind pathogen recognition receptor (PRRs) on the surface of DCs inducing IL-10 secretion and Treg cells. Prebiotics enhance the secretion of IL-10 and interferon-γ (IFN-γ) by CD4+ T cells and IgA.