Microbial dysbiosis and childhood asthma development: Integrated role of the airway and gut microbiome, environmental exposures, and host metabolic and immune response

Abstract

Asthma is a chronic and heterogeneous respiratory disease with many risk factors that typically originate during early childhood. A complex interplay between environmental factors and genetic predisposition is considered to shape the lung and gut microbiome in early life. The growing literature has identified that changes in the relative abundance of microbes (microbial dysbiosis) and reduced microbial diversity, as triggers of the airway-gut axis crosstalk dysregulation, are associated with asthma development. There are several mechanisms underlying microbial dysbiosis to childhood asthma development pathways. For example, a bacterial infection in the airway of infants can lead to the activation and/or dysregulation of inflammatory pathways that contribute to bronchoconstriction and bronchial hyperresponsiveness. In addition, gut microbial dysbiosis in infancy can affect immune development and differentiation, resulting in a suboptimal balance between innate and adaptive immunity. This evolving dysregulation of secretion of pro-inflammatory mediators has been associated with persistent airway inflammation and subsequent asthma development. In this review, we examine current evidence around associations between the airway and gut microbial dysbiosis with childhood asthma development. More specifically, this review focuses on discussing the integrated roles of environmental exposures, host metabolic and immune responses, airway and gut microbial dysbiosis in driving childhood asthma development.

Keywords: airway microbiome; childhood asthma; gut microbiome; immune mechanism; metabolic mechanism; microbial dysbiosis.

Figure 1

Model of the host–microbiota interaction during dysbiosis as a pathogenetic mechanism underlying asthma development: the “gut-lung axis”. A variety of environmental exposures, either protective (green color) or non-protective (red color) can trigger microbial dysbiosis (i.e., the alteration of the function and composition of the microbiota). In this model, in response to the non-protective environmental exposures (air pollutants, antibiotics, allergens), there is lung tissue damage and release of molecules that interact with host immune and metabolic pathways. The lung and gut microbiota diversity is perturbed, and there is increase in pathobionts (i.e., potentially disease-causing organisms that under normal circumstances act as symbionts) in both lung and gut tissues. In response to microbial dysbiosis, there is also increased activation of leukocytes and other innate-mediated soluble factors, which circulate through blood and lymphatic vessels and trigger adaptive immune responses with T_H1, T_H2, T_H17, Treg differentiation. All host- and microbiota‐derived (e.g., SCFAs, cytokines and chemokines) products act at the local (lung) or distal (gut) levels via circulation through blood and lymphatic vessels. The “gut-lung axis” refers to bidirectional crosstalk between these two mucosal sites of the body as described above. SCFAs, short-chain fatty acids; T_H2, T helper 2; T_H17, T helper 17; Treg, regulatory T cell.

Figure 2

Metabolic and immune mechanisms for the link between airway or gut microbiota and asthma. (A) shows immune mechanisms for the airway epithelial cell signaling in response to bacterial pathogens. Various bacterial pathogens bind to innate sensors TLR2 and TLR4 and further activate MyD88- and TRIF-dependent pathways. MyD88 recruits TRAF6, which further activates the IKK complex, allows NF-кB to translocate into the nucleus, and leads to the overall production of inflammatory cytokines and chemokines, and activation of T cells. Additionally, recognition of various bacterial pathogens activates the TRIF-dependent signaling pathway, which involves the recruitment of TRIF, that leads to subsequent activation of TBK1 and IKKϵ along with induction of transcription factor IRF3. This signaling pathway results in interferon-related cytokines, and can potentiate NF-κB gene transcription. Enhanced neutrophil TLR2 and TLR4 signaling by bacterial pathogens promote neutrophils cytokine production and NETosis, a program for formation of NETs. Bacterial pathogens can also be recognized by TLR2 and TLR4 on macrophages, leading to activation of NF-κB and IRF3 signaling pathway and secretion of inflammatory mediators. Macrophages can also function as APC and regulate T cell activation. The T cell is presented an antigen with MHC II by APC. The recognition of the antigen-MHC II complex and the co-stimulatory molecules activates the T cell and leads downstream to differentiation into T_H2 and T_H17 cells, that can release various cytokines such as IL-4, IL-5 and IL-13, which lead to eosinophilic inflammation. APC, antigen-presenting cell; IKK, inhibitory kappa B kinases; IL, interleukin; IRF3, interferon regulatory factor 3; MHC, major histocompatibility complex; MyD88, myeloid differentiation primary response protein 88; NETosis, neutrophil extracellular trap formation; NETs, neutrophil extracellular traps; NF-кB, nuclear factor kappa B; TBK1, TANK-binding kinase 1; T_H2, T helper 2; T_H17, T helper 17; TLR, Toll-like receptor; TRAF6, tumor necrosis factor receptor associated factor 6; TRIF, TIR-domain-containing adapter-inducing interferon-β. (B) shows metabolic and immune mechanisms for the link between gut microbiota and asthma. PSA from Bacteroides fragilis induces and ligates TLR2 on pDC, which stimulate anti-inflammatory cytokine IL-10 secretion by CD4+ T cells. cDC and macrophage bound by gut microbiota show impaired ability to promote TH2- and TH17-type responses and tend to promote TH1-type responses and Treg proliferation, which lead to decreased eosinophilic inflammation. IL-10 dependent reprogramming of tissue macrophages is also essential for resolving inflammation by promoting M2 macrophage polarization. Bacteroides and Bifidobacterium can digest the fiber and produce SCFAs, such as butyrate. Faecalibacterium prausnitzii increases SCFAs level, such as butyrate and propionate, which leads to reduced levels of IL-4, IL-5 and IL-13, and elevated level of Tregs. cDC, classical dendritic cell; IFN, interferon; IL, interleukin; pDC, plasmacytoid dendritic cell; PSA, polysaccharide A; SCFAs, short-chain fatty acids; T_H2, T helper 2; T_H17, T helper 17; TLR, Toll-like receptor; Treg, regulatory T cell.