Gut-lung axis and asthma: A historical review on mechanism and future perspective

Abstract

Background: Gut microbiota are closely related to the development and regulation of the host immune system by regulating the maturation of immune cells and the resistance to pathogens, which affects the host immunity. Early use of antibiotics disrupts the homeostasis of gut microbiota and increases the risk of asthma. Gut microbiota actively interact with the host immune system via the gut-lung axis, a bidirectional communication pathway between the gut and lung. The manipulation of gut microbiota through probiotics, helminth therapy, and fecal microbiota transplantation (FMT) to combat asthma has become a hot research topic. BODY: This review mainly describes the current immune pathogenesis of asthma, gut microbiota and the role of the gut-lung axis in asthma. Moreover, the potential of manipulating the gut microbiota and its metabolites as a treatment strategy for asthma has been discussed.

Conclusion: The gut-lung axis has a bidirectional effect on asthma. Gut microecology imbalance contributes to asthma through bacterial structural components and metabolites. Asthma, in turn, can also cause intestinal damage through inflammation throughout the body. The manipulation of gut microbiota through probiotics, helminth therapy, and FMT can inform the treatment strategies for asthma by regulating the maturation of immune cells and the resistance to pathogens.

Keywords: asthma; gut microbiota; gut‐lung axis; host immune system; metabolites.

FIGURE 1

Immunopathogenesis of asthma. Th2‐high asthma: Infected airway epithelial cells release IL‐25, IL‐33 and TSLP, which promote asthma by activating ILC2 and Th2 cells. On the one hand, DC promotes the development of Th0 cells to Th2, resulting in Th1 (decreased secretion)/Th2 (increased secretion) cell dysfunction under IL‐4 induction. On the other hand, ILC2 also polarizes Th0 cells into Th2 cells, which release cytokines such as IL‐4, IL‐5 and IL‐13. IL‐4 acts on mast cells through IgE. IL‐5 acts on eosinophilia. IL‐13 causes goblet cell metaplasia and airway hyperreactivity in ASM. IL‐4, IL‐5, IL‐13 and other cytokines produce IFN‐γ and TNF‐α, causing a balanced skewed Th2 cellular immune response. IgE eventually induce rapid onset allergy and chronic airway inflammation, causing airway remodeling. They can cause vascular endothelial cell injury through intercellular adhesion molecules1 and vascular cell adhesion molecules1. Th2‐low asthma (neutrophilic asthma): Upon pollutants stimulation, the airway epithelium and alveolar macrophages produce pro‐inflammatory cytokines such as IL‐6 and IL‐1β; at the same time, Th17 cells produce IL17, which mediates neutrophil recruitment. Activated neutrophils induce epithelial cell damage and contribute to increased mucus production by releasing factors such as neutrophil elastase, myeloperoxidase or ROS and so on, which result in asthma. Pollutants also contribute to the recruitment of macrophages and Th1 cells to the airways. Th2‐low asthma (paucigranulocytic asthma): Enhanced ASM contraction causes AHR to promote the expression of asthma susceptibility proteins (GSDMB and ORMDL3) and inhibits asthma protective factors like RSG5, both of which together facilitate the development of asthma. AHR, airway hyperresponsiveness; ASM, airway smooth muscle; DC, dendritic cell; IFN‐γ, interferon‐γ; ILC2, type II innate lymphoid cells; ROS, reactive oxygen species; TNF‐α, tumor necrosis factor‐α; TSLP, thymic stromal lymphopoietin.

FIGURE 2

Bidirectional action of the gut‐lung axis. After exposure to antibiotics or drugs, the dysbiosis of gut microbiota leads to gut microecology imbalance. Bacterial structural components and metabolites of the gut microbiota, such as LPS and SCFAs, can regulate the development of asthma. Respiratory disease, in turn, can also cause intestinal damage, creating a vicious circle through inflammation throughout the body. LPS, lipopolysaccharides; SCFAs, short‐chain fatty acids.

FIGURE 3

The crosstalk between gut‐lung axis and host immunity. (A) LPS and gut microbiota are important components of gut epithelial cells. TLR4 of gut epithelial cells can recognize the pathogens and activate the immunity. In gut‐lung axis, the structural components and metabolites of gut microbiota such as LPS, SCFAs and DAT, etc. act directly or indirectly on the lung, which initiate immune responses. ILC2 and Th17 cells in the gut migrate to the lung and impact respiratory immunity. DAT produces IFN‐γ and acts on the lung. Neutrophil and DC cells restrain Th2 asthma. SCFAs form local immunity in the gut through resident immune cells, and access to the peripheral circulation and bone marrow, thereby affecting Tregs. (B) The interaction between the gut‐lung axis and host immunity mainly narrates pathological changes of asthma, involving Th2 cells, Th17 cells, other cells, inflammatory factors and mediators. Infected airway epithelial cells release IL‐25, IL‐33 and TSLP, which promote asthma by activating DC and Th2 cells. Th2 cells act on B cells through IL‐4, IL‐13 and IL‐9. Tregs restrain Th2 cells by IL‐10. Basophil and ILC2 cells can act on Th2 cells through IL‐4. ILC2 cells act on basophils through IL‐4 and IL‐13, and on eosinophils through IL‐5. Besides, Th17 cells produce IFN‐γ to mediate neutrophil recruitment. IFN‐γ, interferon‐γ; LPS, lipopolysaccharides; SCFAs, short‐chain fatty acids.