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Abstract
Emerging evidence demonstrates that the microbiota plays an essential role in shaping the development and function of host immune responses. A variety of environmental stimuli, including foods and commensals, are recognized by the host through the epithelium, acting as a physical barrier. Two allergic diseases, atopic dermatitis and food allergy, are closely linked to the microbiota, because inflammatory responses occur on the epidermal border. The microbiota generates metabolites such as short-chain fatty acids and poly-γ-glutamic acid (γ PGA), which can modulate host immune responses. Here, we review how microbial metabolites can regulate allergic immune responses. Furthermore, we focus on the effect of γ PGA on allergic T helper (Th) 2 responses and its therapeutic application.
References
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Figure 1.
Allergic immune responses in the skin and gut. (A) Basophils and LCs activated by lesional skin-derived TSLP induce the Th2 differentiation of allergen-specific CD4+ T cells. Th2 cells stimulate B cells to switch, and to thus produce IgE. Basophil-derived IL4 can induce IL5 production, promoting the accumulation of eosinophils in the skin. Besides, IL5 produced by IL33-activated ILC2s recruits eosinophils into the skin. Th9 cells induced by DCs accumulate under TSLP stimulation in the skin. TSLP also promotes iNKT cells to secrete IL4 and IL13. Furthermore, macrophage-derived ATP causes the release of TNFα by mast cells via P2X7 signaling, consequently resulting in skin inflammation. (B) TSLP triggers DCs to induce naive CD4+ T cell differentiation into Th2 cells. Th2 cells and IL25 stimulate ILC2s to secrete IL5 and IL13. IL4 produced by IL33-activated ILC2s and mast cells also induces GATA3+ Treg differentiation in the gut. IL4 secreted by IL33-triggered ILC2s increases IgE production by B cells in the intestine. Mast cells stimulated by Th2-derived IL4 produce IL9, which further induces the accumulation of mast cells in the intestine, in an autocrine fashion. IL9-producing mast cells increase gut permeability via the expression of VEGF. Note that blue arrows indicate induction or stimulation while red arrows represent migration or proliferation. ATP, adenosine triphosphate; TSLPR, TSLP receptor.
Figure 2.
Roles of the microbiota and its metabolites in AD and FA. (A) S. aureus is known to be the main pathogen that induces AD. SEB and δ-toxin, secreted by S. aureus, induce degranulation of mast cells in the skin. Survival of S. aureus in the skin is selectively inhibited by antimicrobial peptide (e.g., hogocidin) derived from commensal bacteria including S. epidermidis and S. hominis. S. epidermidis-derived γ PGA suppresses survival of S. aureus. S. epidermidis also produces SCFAs (butyrate and acetate), which suppress the colonization of S. aureus in the skin. In addition, H2-M3-restricted commensal-specific CD8+ T cells, induced by S. epidermidis-stimulated DCs, contribute to both anti-inflammatory and tissue repair functions. The skin Treg population can be increased by the resting LCs via TGFβ; these Tregs may be responsible for the suppression of mast cell degranulation. Skin-resident commensal S. epidermidis increases IFNγ production by dermal T cells. In addition, γ PGA from the skin commensal bacteria can activate DCs to induce differentiation of Th1 and activation of IFNγ-producing cells such as NK, iNKT, and γδ T cells. Consequently, IFNγ derived from S. epidermidis-activated Th1 cells, γ PGA-induced Th1, and IFNγ-producing cells may lead to the suppression of skin allergic effector cells (e.g., ILC2, basophils, eosinophil, Th2 cells, and Th9 cells). (B) Butyrate and acetate are produced from dietary fiber by commensal bacteria including Lactobacillus spp. and Bifidobacterium spp. Acetate suppresses TSLP and IL33 via epithelial GPR43 signaling, and butyrate triggers CD103+ DCs to produce retinoic acid via GPR109a signaling. Lactobacillus spp. stimulates macrophages to produce IL10 and IL6 in a TLR2/TLR6-dependent manner. Moreover, commensal bacteria including Lactobacillus spp. and Bifidobacterium spp. induce differentiation of naive CD4+ T cells into Foxp3+ Tregs via IDO, IL10, and TGFβ. γ PGA from gut commensal bacteria can directly induce the generation of adaptive Foxp3+ Tregs from naive CD4+ T cells. Gut extracellular γ PGA, derived from Bacillus spp., induces compositional change of microbiota, such as increase of Lactobacillus spp. Non-toxin-producing Clostridium spp., including Clostridium clusters XIVa, XIVb, and IV decrease intestinal permeability via increased IL22 production by ILC3s. Lactobacillus spp. (e.g., Lactobacillus casei) promotes RORγ t+ Treg differentiation in the gut. Thus, skin Tregs, induced by commensal microbiota and its metabolites (γ PGA and SCFAs), can participate in the inhibition of gut allergic effector cells (e.g., ILC2, mast cells, and Th2 cells). Note that blue arrows indicate induction or stimulation, red arrows represent secretion, and red flat lines indicate inhibition. Moreover, dotted arrows indicate decomposition or differentiation. SEB, S. aureus exotoxin B; TSLPR, TSLP receptor.
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