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

INTRODUCTION

Asthma is a common chronic airway inflammatory disease characterized by airway hyperresponsiveness (AHR), reversible airflow limitation and airway remodeling. It is mediated by many inflammatory cells, such as eosinophils, mast cells and T lymphocytes,[1], [2] which cause recurrent symptoms involving paroxysmal and reversible attacks of wheezing, shortness of breath, chest tightness, coughing or shortness of breath.[3], [4] The World Health Organization and Global Initiative for Asthma estimated that approximately 300 million people worldwide suffer from asthma, and it is expected to reach 400 million by 2025.[5], [6], [7] Especially, an estimated population prevalence of severe asthma at age 10 years is 0.5% and 4.5% among current asthmatic children.[8] Although most asthmatic children achieve good symptom control by low dose inhaled corticosteroids (ICS) or self‐management, approximately 10% of asthmatic patients are refractory and show resistance to current corticosteroid‐based treatment.[9], [10] Nowadays, the global death rate in childhood asthma still ranges from 0 to 0.7 per 100,000 population.[11], [12] Consequently, further research is urgently needed to shed light on the pathogenesis of refractory asthma and promote the discovery of new treatment strategies for asthma. Recent studies have shown that the gut‐lung axis referring to the crosstalk between gut microbiota and the lung might play an important role in asthma.[13]

Gut microbiota, inherited from the mother to the child through breastfeeding, is a key regulator of gut‐lung axis function and considered to be an important contributor to regulate the homeostasis of the host through physiological, immune and metabolic functions.[14], [15], [16] In homeostatic conditions, the healthy gut microbiota can efficiently prevent pathogen infection, reducing the chance of developing inflammation.[17] On the contrary, early life gut dysbacteriosis may lead to altered immune response and chronic inflammatory respiratory disorders, especially childhood asthma.[18] Therefore, people are gradually paying attention to the role of gut microbiota and gut‐lung axis in asthma, as well as the mechanism of gut microbiota affecting homeostasis and susceptibility to asthma.[19] Further understanding of the pathogenesis of asthma, such as the crosstalk between immune factors and gut microbiota or the gut‐lung axis, is expected to provide a new opportunity for the diagnosis and treatment of asthma. This review mainly describes the current immune pathogenesis of asthma, and the role of gut microbiota and gut‐lung axis in asthma. In addition, we are also trying to explore the possibility of manipulating the microbiota, aiming to establish asthma prevention strategies and optimize asthma treatment.

THE IMMUNOPATHOGENESIS OF ASTHMA

Asthma is a heterogenous disease comprising different phenotypes and endotypes.[20], [21] Based on endotypes, T‐helper(Th)‐2‐high, Th2‐low and the mixed endotypes are described for severe asthma.[22], [23] Th2‐high asthma termed as eosinophilic asthma is associated with innate and adaptive immunity, while Th2‐low asthma associated with non‐eosinophilic asthma is characterized by neutrophilic inflammation or paucicellular inflammation.[24], [25] Studies have confirmed that innate immunity involving macrophages, neutrophils, mast cells and type II innate lymphoid cells (ILC2s) produce a variety of Th2 cytokines, such as interleukin (IL)‐4, IL‐5 and IL‐13, to control the persistence of allergic inflammation.[26] The ratio tilt of T lymphocyte subsets (Th1/Th2) is the most important pathogenesis of asthma.[27]

Upon allergen stimulation, epithelial‐derived cytokines and ILC2s initiate Th2‐high asthma by driving dendritic cell (DC) activation and phenotypic changes in the airways. On the one hand, airway epithelial cells activate dendritic cells to present antigens, which differentiate naive T cells into effector Th2 cells. Th2 cells amplify type II inflammation through secreting cytokines such as IL‐4, IL‐5 and IL‐13, while Th1 cells mainly mediate type I inflammation by secreting cytokines such as interferon‐γ (IFN‐γ), lymphotoxin (LT)‐α and tumor necrosis factor‐α (TNF‐α) and so on.[28], [29] Th2 cells secrete inflammatory cytokines driving B cells to produce more IgE, which would bind to mast cells to produce a series of inflammatory mediators such as leukotrienes, endothelin, prostaglandin and thromboxane A2, etc. The increased IgE eventually induces rapid onset allergies and chronic airway inflammation.[30], [31], [32] On the other hand, airway epithelial cells are involved in polarizing macrophages, DC cells and T cells by producing pro‐inflammatory cytokines such as alarmins IL‐25, IL‐33 and thymic stromal lymphopoietin (TSLP).[33], [34] Besides, alarmins also promote the occurrence of asthma by activating ILC2s. Studies have shown that ILC2 is related to allergic asthma. Under the environment of specific cytokines in patients with asthma, ILC2 facilitates the polarization of Th0 cells into Th2 cells and produces IL‐4.[35] Increased cytokines such as IL‐5 and IL‐13, rather than IFN‐γ, cause a deviated Th2 cell immune response.[34], [36]

Th2‐low asthma, simplistically referred to as non‐eosinophilic asthma, encompasses neutrophilic asthma characterized by the activation of Th1 and Th17 cells and paucigranulocytic asthma in which neither eosinophils nor neutrophils are increased.[37] Upon pollutant stimulation, the airway epithelium and alveolar macrophages produce pro‐inflammatory cytokines such as IL‐6, IL‐1β and so on, at the same time, Th17 cells produce IL17, which mediates neutrophil recruitment.[38] Activated neutrophils induce epithelial cell damage and contribute to increased mucus production through releasing factors such as neutrophil elastase, myeloperoxidase or reactive oxygen species (ROS) and so on, which result in asthma.[39] However, paucigranulocytic asthma, which occurs because of AHR caused by enhanced airway smooth muscle contraction, has a low correlation with airway inflammation.[37] Mechanistically, AHR promotes the expression of asthma susceptibility genes (GSDMB and ORMDL3)[40], [41] and inhibits the expression of critical signaling molecules (RGS5),[42] both of which together facilitate the development of asthma (Figure 1).

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.

In addition to the pathogenic mechanism of Th1/Th2 imbalance, regulatory T cells (Tregs)‐mediated regulatory mechanism is equally vital in asthma.[43] Studies have shown an imbalance in the Th17/Tregs ratio in the peripheral blood mononuclear cells of asthmatic patients, with an increase in Th17 and a decrease in Tregs. Treatment with a Th17 inhibitor results in an increase in Tregs and is effective in alleviating asthma.[44] What's more, oral administration of 14BME20, a Staphylococcus succinus strain isolated from soy foods, suppresses airway inflammation by enhancing Tregs responses.[45]

Some immune cells, including ILC2s, ILC3s and Th17 cells, can also produce inflammatory mediators to mediate asthma. For example, ILC2s can transfer from the gut to the lungs, which is involved in lung inflammation and asthma.[46] Moreover, gut DC senses the gut microbiota to make ILC3s migrate to the lungs, thus producing IL‐22 inflammatory factors that mediate protection against pneumonia.[47] Th17 cells directly migrate through the lungs and regulate the activities of the pulmonary immune response to mediate asthma.[48]

THE GUT‐LUNG AXIS AND ASTHMA

Lung microbiota in asthma

Microorganisms can inhabit all surfaces of the human body, including the respiratory tract and gut. The lung microbiota is mainly inhaled through the nasopharynx. Bacteria of phylum Firmicutes, Actinobacteria and Bacteroides are prevalent in healthy lungs. However, Haemophilus and Moraxella are enriched in asthmatics.[49] Nasal secretion samples from asthmatic children showed a microbiota dominated by Moraxella, a bacterium that induces epithelial damage and inflammatory cytokine expression.[50] Haemophilus, which is enriched in adult asthmatics, induces expression of Th17‐related genes and is associated with worsening asthma[51] (Table 1). Generally speaking, lung microbiota dysbiosis and subsequently dysregulated microbiota‐related immune response ultimately result in hypersensitivity and hyperreactivity of asthma.

TABLE 1. Bacteria related to asthma.

The gut microecology imbalance contributes to asthma

Human gut is the most densely colonized part of the body[61] and inhabits about 10¹⁴ bacteria that is approximately 10 times the total number of other cells in the human body.[62], [63] It is evident that the imbalance of gut microbiota may cause the host immune homeostasis disorder,[64] which in turn leads to respiratory diseases such as asthma. There is a link between the abundance of specific gut microbiota and asthma.[65] A recent study has suggested that breast‐fed infants can effectively prevent childhood asthma and allergic diseases, which may be related to the abundance of specific gut microbiota in breast‐fed infants rather than in formula infants.[66], [67] Moreover, the decrease in the abundance of bifidobacterium, akkermansia, faecalibacterium and increased abundance of fungi candida and rhodotorula all increase the risk of asthma in children.[68], [69], [70] Therefore, we speculate that the changes in the abundance of gut or airway microbiota and the dysbiosis of specific gut microbiota may be potential pathological markers of asthma. Changes in gut microbiota associated with asthma are described in Table 1.

Numerous studies have demonstrated that the bacterial structural components and metabolites of the gut microbiota, such as lipopolysaccharides (LPS) and peptidoglycan as well as multiple mediators, such as short‐chain fatty acids (SCFAs) and desaminotyrosine (DAT), etc., can disrupt the cascade reaction of pulmonary and intestinal immune homeostasis.[71] On the one hand, gut microbiota can not only provide energy for itself and the host by producing metabolites such as SCFA, but also exert immunomodulatory properties. In addition, SCFA enhances the epithelial barrier function and maintains mucosal immunity. On the other hand, gut microbiota can modify the bile acids synthesized by the liver into secondary bile acids, thus regulating multiple host metabolic processes and immune homeostasis.[72], [73] By contrast, bile acids can affect the growth of bacteria, resulting in changes in the structure of gut microbiota. Moreover, antibiotics and drug exposure can also destroy the stability of gut microbiota, leading to “malnutrition,” that is, dysbiosis of the gut microbiota.[74] Of course, gut microbiota is also affected by various factors including environment, genetics, diet, and lifestyle. Studies have shown that genetic and environmental factors greatly promote the occurrence of such malnutrition, which leads to the dysbiosis of immune homeostasis and results in disease.[75]

LPS plays a bidirectional regulatory role in asthma

The bacterial components of gut microbiota include LPS and peptidoglycan, which bind to toll‐like receptors (TLRs) or nod‐like receptors (NLRs) as pattern recognition receptors (PRRs) expressed in gut cells to regulate the immune response. Studies have found that LPS is the ligand of PRRs expressed by host antigen‐presenting cells by binding to PRRs (TLRs are the main representative) to trigger a variety of cellular processes that regulate lung immune response.[76], [77] The possible mechanism is that the binding of the LPS‐TLR4 ligand receptor participates in enhancing Th2 and Th1 asthma development.[78], [79] Studies have shown that LPS‐inactivated mice have reduced ability to respond to Th2 inflammation in house dust mite asthma models.[80] Interestingly, early life LPS exposure was negatively correlated with the incidence of asthma and patterned immune development,[81], [82] which may drive later Th2 asthma. More importantly, it has been observed in animal models that intratracheal perfusion of LPS can lead to changes in the host gut microbiota, suggesting that LPS plays a bidirectional regulatory role in the gut‐lung interaction.[80], [83], [84]

SCFAs alleviate asthma

SCFAs, the most abundant metabolites of gut microbiota, are considered to be the key mediator of the bidirectional gut‐lung interaction. SCFAs, including butyrate, propionate and acetate derived from the metabolism of dietary fiber by the gut microbiota, are directly proportional to the dietary fiber content.[85] After they are released into the gut lumen, some SCFAs (especially butyrate) form local immunity in the gut and provide energy for gut cells. SCFAs that are not used in the gastrointestinal tract enter the portal vein and are transported to the liver for metabolism. Access of unmetabolized SCFAs to the peripheral circulation and bone marrow affects immune cell development.[83] SCFAs may reduce the susceptibility to allergic airway diseases by activating G protein‐coupled receptors (GRP) such as GRP41.[76], [86] Studies have revealed that oral administration of SCFAs to mice can prevent the activation of Th2 cells and the production of cytokines by Th2 cells via weakening DCs, thus protecting mice from the development of asthma.[87], [88] This protection is mediated by changes in hematopoiesis and function of dendritic cells through the gut‐marrow‐lung axis.[89]

Furthermore, butyric acid extracted from dietary fiber has also been shown to enhance blood production of lung anti‐inflammatory macrophage precursors in bone marrow, thereby preventing asthma by controlling immunopathology caused by infiltrating neutrophils.[90] Recent studies have shown that SCFAs produced by lung microbiota can also mediate the host immune response and cause changes in gut microbiota. This immunomodulatory effect may be played by anti‐inflammatory and anti‐allergic Tregs.

Other metabolites of gut microbiota

DAT and biogenic amines also play an important role in gut‐lung communication. Among them, DAT can regulate the lung response by enhancing the type I interferon response. DAT can protect mice from allergic pneumonia, asthma and influenza virus infection.[91] In addition, gut microbiota produces metabolites with pro‐ and anti‐inflammatory potential, such as biogenic amines (including histamine)[92] which have profound effects on asthma through gut‐lung interactions. Both innate and adaptive immune systems can be regulated by histamine. The regulatory action of histamine depends on its binding to four receptors (named H1R‐H4R in the order of discovery).[93] H3R is mainly expressed in the nervous system and is mostly associated with neuro‐inflammation.[94] H1R and H4R are thought to be associated with asthma, and their activation can exacerbate asthma.[95] Histamine has a chemotactic effect on T cells, and H1R‐mediated migration of CD4 T cells into the lung is a key component of the inflammatory response.[96] Treatment with an H4R antagonist can suppress Th2‐driven asthma and also ameliorates airway dysfunction.[97] Only H2R agonists may alleviate asthma. H2R antagonist‐treated or H2R‐deficient animals show increased numbers of CD1d⁺ dendritic cells and iNKT cells, which increase inflammatory cells and Th2 cytokines.[95], [98] By contrast, selective H2R agonist treatment reverses these changes and exhibits a protective effect. In addition, histamine is found to promote IL‐10 and inhibit TGF‐α in OVA‐induced asthma in mice, thereby reducing the total number of cells in bronchoalveolar lavage fluid (BALF) and the number of inflammatory factors such as IL‐4, IL‐5, and IL‐13 in lung tissue.[99] This indicates that the metabolite histamine has a complex immunomodulatory effect on the bidirectional regulation of the gut‐lung interaction. Of course, other gut microbiota metabolites may also participate in immunomodulation.

As mentioned above, the dysbiosis of gut microbiota is closely associated with asthma (Figure 2). However, studies have also found that the inflammatory response to respiratory infections or allergic inflammatory diseases can lead to gut injury from the respiratory tract to the gut mucosa through the CCL25‐CCR9 axis.[100], [101]

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.

The bidirectional action of the gut‐lung axis on asthma

The bidirectional communication pathway between the gut and lung is called the gut‐lung axis.[102], [103] Gut microbiota actively interacts with the host immune system through bacterial structural components and secretion of metabolites, thus regulating the ability of local and systemic immune responses in the gastrointestinal tract, and affecting various distal parts of the host, including the lung, etc. and vice versa.[104] Pulmonary diseases also affect gut microbiota through lymphocyte migration and inflammatory mediators, leading to gut diseases.[105]

Type II inflammatory asthma involves T helper type 2 cells, ILC2, T follicular helper cells, eosinophils, mast cells, and type II mediators, such as cytokines IL‐4, IL‐5, IL‐13, and prostaglandin D2, etc.[9], [106], [107], [108] In fact, different types of gut microbiota affect asthma via the gut‐lung axis with different pathological changes. For example, the decreased abundances of gut microbiota such as lachnospira, veillonella, faecalibacterium and rothia increase the risk of asthma.[109], [110] Moraxella catarrhalis can cause lung neutrophil infiltration, IL‐6 and TNF‐α elevated and moderate levels of CD4T cell‐derived IFN‐γ and lung IL‐17.[69] By contrast, high doses of ICS treatment in patients with neutrophilic asthma can lead to the transformation of steroid‐sensitive diseases into steroid‐resistant diseases, manifested by relative enrichment of Haemophilus.[69], [111] Candida albicans aggravate Th2‐mediated asthma and reduce AHR through the IL‐13‐IL‐33 axis after infection.[69] On the other hand, clinical studies have found that the levels of inflammatory factors such as C‐reactive protein (CRP) in the peripheral blood of children with asthma are significantly higher than those of non‐asthmatic patients. CRP, the total gut bacterial load and gastrointestinal symptom score (GSRS) are positively related, which indicates that as the levels of peripheral blood inflammatory factors increase, the possibility of gut disorders and gastrointestinal inadaptability in children with asthma will increase.[112], [113] Therefore, this also indicates that bidirectional regulation of the gut‐lung axis and host immunity can mediate gut microbiota dysbiosis and the occurrence of asthma.

There is growing evidence of active and multiple forms of crosstalk between the bi‐directional gut‐lung axis and the host immune system.[114] This crosstalk is mainly mediated by the following immune cells.

Tregs are regulated by gut microbiota and metabolites

Tregs, a subpopulation of T cells, are important immune cells that mediate host immune responses. There are exact data indicating that gut microbiota in mice mediates the induction of Tregs in the gut and the role of allergen tolerance in the lung. In addition, Tregs also play an important role in host immune diseases such as allergic diseases, but the specific crosstalk between the two is not clear.[115] This interaction may be caused by blocking the induction of Tregs in the gut, thus leading to Th2‐type inflammation in the lung mucosa. However, more evidence is required to confirm this view. Studies in asthma models have shown that Tregs are regulated by gut microbiota and its metabolite SCFAs. For example, clostridium induces Tregs production. SCFAs participate in the differentiation of Tregs to protect asthma.[52], [87] SCFAs increase the expression of transcription factor FOXP3 by inhibiting histone deacetylation, supporting the expansion of Tregs and increasing the production of IL‐10, which in turn interacts with the host immune and participates in asthma.[116]

In addition to the above, there are significant changes in IgA patterns in children with high‐risk asthma. This may be related to the induction of IgA antibodies by Tregs in the gut mucosa and the disordered response of IgA to gut microbiota.[117]

The migration of Th17 cells causes asthma

Inflammatory response is a classic case of the interaction between the gut‐lung axis and the host immune system. That is to say, a local immune response originating from the gut tract will lead to different types of host immune cellular infiltrate into the local and distal organs of the lungs then causing pulmonary pathological changes. Nevertheless, asthma can be divided into Th1 or Th2 asthma according to the internal classification. Th2 asthma mainly refers to the asthma with eosinophil infiltration.[118], [119] Th1 asthma is more common in neutrophil infiltration‐based asthma and obesity‐related asthma, which is characterized by Th1 and Th17 cell infiltration and neutrophil infiltration. Studies have found that Th17 cells can directly migrate to the lungs through lymphatic circulation to activate Th2‐type inflammation,[84] leading to neutrophil inflammation, and thus causing asthma. Therefore, targeting Th17 cells may be a potential therapeutic target for asthma.[120] Moreover, Th1 asthma is also characterized by the presence of type I interferon, NLRP3 inflammasome activation and so on.[121], [122], [123] Conversely, Th17 cell responses induced by pulmonary infection may also lead to gut damage[124] (Figure 3).

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.

Apart from this, studies have also found that gut microbiota dysbiosis caused by antibiotic exposure in the early life of environmental factors can increase the risk of asthma in adulthood.[125] The possible pathogenesis of this process is as follows[126]: (1) By increasing the infiltration of inflammatory cells and the production of inflammatory cytokines (IL‐4 and IL‐13), the Th2 response is aggravated. For example, vancomycin treatment of neonates can aggravate the lung inflammation.[87], [127] (2) Reduce the abundance of Tregs in the lungs. Tests have shown that the use of antibiotics almost depletes the bacteria and promotes the overgrowth of lactobacillus.[128] (3) Amplifying the adaptive immune response of Th1/Th17 in the lung by streptomycin has been shown to exacerbate Th1/Th17 driven inflammatory lung disease and allergic pneumonia.[49], [129] Besides, in large epidemiological studies it has been found that the use of antibiotics and drugs plays an important role in shaping the composition of early gut microbiota.[130], [131] Children receiving a variety of courses of high‐dose and potent antibiotics early in life are predicted to affect the gut microbiota, thereby affecting the host's physiology and immune homeostasis, which may lead to the occurrence of asthma.[132] The use of antibiotics in the first year of infant life is associated with an increased risk of asthma in young children.[133], [134] Similarly, studies have confirmed that in British Columbia, reduced antibiotic use was significantly associated with reduced asthma risk during the first year of life.[77], [135] Therefore, there is sufficient evidence to support the hypothesis that the use of antibiotics can affect the composition of infant gut microbiota leading to an increase in the incidence of asthma in early childhood.[125]

MANIPULATE THE GUT MICROBIOTA TO FIGHT ASTHMA

Improving gut microbiota may stimulate its beneficial effects by helping to establish a healthy steady‐state immune balance. This review describes the manipulation of gut microbiota through probiotics, helminth therapy, and fecal microbiota transplantation (FMT) to combat asthma.

Probiotics

Probiotics are oral living microorganisms. Bacteria used for probiotics mainly belong to lactic acid bacteria, actinobacteria, and non‐pathogenic Escherichia coli.[136] Many studies currently report that probiotics can be used to prevent and treat asthma, especially bifidobacterium and lactobacillus. Studies have found that oral probiotics regulate asthma through many signaling pathways. For example, bifidobacterium can stimulate the balance of Th1/Th2 and up‐regulate the inflammatory factors such as IFN‐γ, IL‐4 and IL‐12 in the lungs to regulate asthma attacks. Oral probiotics can also induce Tregs to reduce the pathological changes of asthma in a mouse model of asthma.[137], [138] Moreover, studies have confirmed that oral probiotic lactobacillus rhamnosus GG (LGG) can reduce the expression of matrix metalloprotein 9 (MMP9) in alveolar lavage fluid and serum, inhibit the infiltration of inflammatory cells in lungs and protect asthma.[139]

Apart from the above, asthma children treated with probiotics in clinical studies not only improved their lung function but also reduced the number of asthma attacks. However, the exact mechanism of probiotics' effect on asthma and the regulation of immune response remain unknown.

Helminth therapy

Helminths balance the host immune system to reduce hypersensitivity to allergens by secreting proteins to create an inhibitory environment in the host.[140] Some studies have confirmed that helminth infection can reduce the morbidity of allergic asthma.[141] Accordingly, research on helminth therapy provides another clue to the benefits of gut microbiota balance on the respiratory system, and it is also expected to become another clue for the prevention and treatment of asthma. Researchers have discovered that helminths affect the composition of gut microbiota and indirectly affect the lung immune response and prevent asthma attacks.[142] Studies have shown that mice infected with Heligmosomoides polygyrus bakeri will change the composition of gut microbiota by increasing SCFAs and ultimately resulting in reduced inflammation in dust mites‐induced asthma models.[143]

Fecal microbiota transplantation

FMT is a procedure designed to restore the microbiome by transferring feces from a healthy donor into the gut of a recipient.[144], [145] FMT is another way to improve gut microbiota and has been successfully used to improve gut disease, but the potential role of FMT in asthma remains unexplored. FMT current clinical application in asthma is even more limited.[146] Consequently, further research is needed.

In addition to the methods mentioned above, human trials have shown that by increasing the proportion of fruits, vegetables, fish and probiotic food in the diet, purified metabolites have gradually become promising targets, which can be used as auxiliary intervention strategies for asthma. However, the specific mechanism is not yet clear.

CONCLUSIONS

Asthma is essentially a heterogeneous inflammatory disease. Different individuals will have different degrees of clinical symptoms, and the age of onset is relatively young, which also seriously endangers people's health. Furthermore, the complex pathogenesis of asthma and the resistance of some children to ICS treatment require people to seek alternative prevention and treatment.

Microbial dysbiosis in lung and gut can be influenced by multiple environmental factors, involving pollution, allergens, use of antibiotics and viruses. Currently, more and more studies have found that the inflammation in asthma seems to be related to the composition of microorganisms and the severity of airway obstruction.[147] The lung and gut microbiota are considered to be an important part of asthma management. There are significant differences in the abundance of lung microbiota in asthmatics compared with healthy people, which activates inflammatory pathways and contributes to bronchoconstriction and bronchial hyperreactivity.[49] Many studies have documented that gut microbiota has a regulatory effect on inflammatory diseases. Considering the important role of gut microbiota in inflammatory diseases, it has become a breakthrough for asthma research. By exploring the mechanism of gut microbiota dysbiosis in early life on asthma, researchers hope to intervene and prevent the asthmatic immune response.[56]

It is evident that gut microbiota also plays an important role in distal organs and lungs through immune regulation, which is achieved by bi‐directional gut‐lung axis and host immunity. Therefore, applying the crosstalk between gut microbiota, the gut‐lung axis and immune interaction, the establishment of a specific prevention and treatment model for asthma may be a good prospect for reducing the asthma pandemic.[3], [148] This crosstalk is biologically plausible and ultimately operational, as studies have shown that gut microbiota dysbiosis can be improved and gut microbiota balance is restored through probiotics, helminth therapy, FMT, or purified metabolites to achieve management of asthma prevention and treatment. However, probiotics and FMT have not yet entered clinical routines. Therefore, it is necessary to further explore how to popularize the operation of gut microbiota to benefit asthma patients clinically. Inspiringly, it has been observed through clinical and laboratory studies that asthmatic patients have attempted new therapeutic strategies targeting probiotics, which in most cases have shown encouraging results.

In conclusion, gut microbiota is closely related to asthma, and its dysbiosis increases the risk and severity of asthma. Consequently, the precise role and mechanism behind the changes in structural components and metabolites of gut microbiota and asthma are worthy of further exploration, especially the gut‐lung axis in mediating host immune response and asthma,[149] even the causal relationship between the gut microbiota and the gut‐lung axis and asthma is still being explored.

AUTHOR CONTRIBUTIONS

Xiu‐Ling Song: Investigation (supporting); visualization (lead); writing – original draft (lead). Juan Liang: Investigation (supporting); visualization (lead); writing – original draft (lead). Shao‐Zhu Lin: Conceptualization (supporting); formal analysis (supporting); investigation (lead). Yu‐Wei Xie: Investigation (supporting); writing – review & editing (supporting). Chuang‐Hong Ke: Supervision (supporting). Dang Ao: Supervision (supporting). Jun Lu: Supervision (supporting). Xue‐Mei Chen: Investigation (supporting). Ying‐Zhi He: Investigation (supporting). Xiao‐Hua Liu: Investigation (supporting). Wen Li: Conceptualization (lead); formal analysis (lead); funding acquisition (lead); supervision (lead); project administration (lead); writing – review & editing (lead).

CONFLICT OF INTEREST STATEMENT

All authors have no conflicts of interest to declare.

ACKNOWLEDGMENTS

We thank Prof. Yu‐Ge Huang for his suggestions on manuscript preparation. This work was supported by the National Natural Science Foundation of China (32100602), Guangdong Natural Science Foundation of China (2023A1515012755), and Scientific Research Start‐up Fund for High‐level Talents of Affiliated Hospital of Guangdong Medical University (GCC2021009).

Song X‐L, Liang J, Lin S‐Z, et al. Gut‐lung axis and asthma: a historical review on mechanism and future perspective. Clin Transl Allergy. 2024;e12356. 10.1002/clt2.12356

Xiu‐Ling Song, Juan Liang and Shao‐Zhu Lin contributed equally to the work.

REFERENCES

References

1. Luo H, Han H, Liu X, Liu Q. Efficacy and safety of montelukast sodium combined with fluticasone in the treatment of adult bronchial asthma: a protocol for systematic review and meta‐analysis. Medicine. 2020;99(52):e23453. 10.1097/md.0000000000023453
2. Przysucha N, Gorska K, Krenke R. Chitinases and chitinase‐like proteins in obstructive lung diseases ‐ current concepts and potential applications. Int J Chron Obstruct Pulmon Dis. 2020;15:885‐899. 10.2147/copd.s236640
3. Durack J, Lynch SV, Nariya S, et al. Features of the bronchial bacterial microbiome associated with atopy, asthma, and responsiveness to inhaled corticosteroid treatment. J Allergy Clin Immunol. 2017;140(1):63‐75. 10.1016/j.jaci.2016.08.055
4. Kim JH, Jang YJ. Role of natural killer cells in airway inflammation. Allergy, Asthma & Immunol Res. 2018;10(5):448‐456. 10.4168/aair.2018.10.5.448
5. Zairina E, Nugraheni G, Achmad GN, et al. Efficacy of an education session by pharmacists for patients with asthma: protocol and design of a randomized controlled trial. JMIR Res Protoc. 2018;7(12):e10210. 10.2196/10210
6. Zilaee M, Hosseini SA, Jafarirad S, et al. An evaluation of the effects of saffron supplementation on the asthma clinical symptoms and asthma severity in patients with mild and moderate persistent allergic asthma: a double‐blind, randomized placebo‐controlled trial. Respir Res. 2019;20(1):39. 10.1186/s12931-019-0998-x
7. Serebrisky D, Wiznia A. Pediatric asthma: a global epidemic. Ann Glob Health. 2019;85(1):6. 10.5334/aogh.2416
8. Dharmage SC, Perret JL, Custovic A. Epidemiology of asthma in children and adults. Front Pediatr. 2019;7:246. 10.3389/fped.2019.00246
9. Sharma A, Laxman B, Naureckas ET, et al. Associations between fungal and bacterial microbiota of airways and asthma endotypes. J Allergy Clin Immunol. 2019;144(5):1214‐1227.e7. 10.1016/j.jaci.2019.06.025
10. Qi C, Xu CJ, Koppelman GH. The role of epigenetics in the development of childhood asthma. Expet Rev Clin Immunol. 2019;15(12):1287‐1302. 10.1080/1744666x.2020.1686977
11. Russo D, Lizzi M, Di Filippo P, Di Pillo S, Chiarelli F, Attanasi M. Time‐specific factors influencing the development of asthma in children. Biomedicines. 2022;10(4):758. 10.3390/biomedicines10040758
12. Salih MRM, Abd AY, Fawzi HA. Awareness of asthma and its management in primary school teachers in Baghdad, Iraq. F1000Res. 2022;11:367.
13. Frei R, Heye K, Roduit C. Environmental influences on childhood allergies and asthma ‐ the farm effect. Pediatr Allergy Immunol. 2022;33(6):e13807. 10.1111/pai.13807
14. Shinde T, Hansbro PM, Sohal SS, Dingle P, Eri R, Stanley R. Microbiota modulating nutritional approaches to countering the effects of viral respiratory infections including SARS‐CoV‐2 through promoting metabolic and immune fitness with probiotics and plant bioactives. Microorganisms. 2020;8(6):921. 10.3390/microorganisms8060921
15. Ramírez‐Acosta S, Selma‐Royo M, Collado MC, Navarro‐Roldán F, Abril N, García‐Barrera T. Selenium supplementation influences mice testicular selenoproteins driven by gut microbiota. Sci Rep. 2022;12(1):4218. 10.1038/s41598-022-08121-3
16. Notarbartolo V, Giuffrè M, Montante C, Corsello G, Carta M. Composition of human breast milk microbiota and its role in children's health. Pediatr Gastroenterol Hepatol Nutr. 2022;25(3):194‐210. 10.5223/pghn.2022.25.3.194
17. Mukherjee S, Joardar N, Sengupta S, Sinha Babu SP. Gut microbes as future therapeutics in treating inflammatory and infectious diseases: lessons from recent findings. J Nutr Biochem. 2018;61:111‐128. 10.1016/j.jnutbio.2018.07.010
18. Frontela‐Saseta C, González‐Bermúdez CA, García‐Marcos L. Diet: a specific part of the western lifestyle pack in the asthma epidemic. J Clin Med. 2020;9(7):2063. 10.3390/jcm9072063
19. Taylor SL, Leong LEX, Choo JM, et al. Inflammatory phenotypes in patients with severe asthma are associated with distinct airway microbiology. J Allergy Clin Immunol. 2018;141(1):94‐103.e15. 10.1016/j.jaci.2017.03.044
20. Caruso C, Colantuono S, Arasi S, et al. Heterogeneous condition of asthmatic children patients: a narrative review. Children. 2022;9(3):332. 10.3390/children9030332
21. Licari A, Manti S, Castagnoli R, et al. Immunomodulation in pediatric asthma. Front Pediatr. 2019;7:289. 10.3389/fped.2019.00289
22. Agache I, Eguiluz‐Gracia I, Cojanu C, et al. Advances and highlights in asthma in 2021. Allergy. 2021;76(11):3390‐3407. 10.1111/all.15054
23. Liang J, Liu XH, Chen XM, Song XL, Li W, Huang Y. Emerging roles of non‐coding RNAs in childhood asthma. Front Pharmacol. 2022;13:856104. 10.3389/fphar.2022.856104
24. Fainardi V, Esposito S, Chetta A, Pisi G. Asthma phenotypes and endotypes in childhood. Minerva Med. 2022;113(1):94‐105. 10.23736/s0026-4806.21.07332-8
25. Ntontsi P, Loukides S, Bakakos P, et al. Clinical, functional and inflammatory characteristics in patients with paucigranulocytic stable asthma: comparison with different sputum phenotypes. Allergy. 2017;72(11):1761‐1767. 10.1111/all.13184
26. Castan L, Bøgh KL, Maryniak NZ, et al. Overview of in vivo and ex vivo endpoints in murine food allergy models: suitable for evaluation of the sensitizing capacity of novel proteins? Allergy. 2020;75(2):289‐301. 10.1111/all.13943
27. Tang Y, Huang W, Song Q, Zheng X, He R, Liu J. Paeonol ameliorates ovalbumin‐induced asthma through the inhibition of TLR4/NF‐κB and MAPK signaling. Evid base Compl Alternative Med: eCAM. 2018;2018:3063145. 10.1155/2018/3063145
28. Foster PS, Maltby S, Rosenberg HF, et al. Modeling T(H) 2 responses and airway inflammation to understand fundamental mechanisms regulating the pathogenesis of asthma. Immunol Rev. 2017;278(1):20‐40. 10.1111/imr.12549
29. Mukherjee M, Nair P. Autoimmune responses in severe asthma. Allergy Asthma Immunol Res. 2018;10(5):428‐447. 10.4168/aair.2018.10.5.428
30. Bégin P, Nadeau KC. Epigenetic regulation of asthma and allergic disease. Allergy Asthma Clin Immunol. 2014;10(1):27. 10.1186/1710-1492-10-27
31. Chogtu B, Bhattacharjee D, Magazine R. Epigenetics: the new frontier in the landscape of asthma. Sci Tech Rep. 2016;2016:4638949. 10.1155/2016/4638949
32. McCracken JL, Tripple JW, Calhoun WJ. Biologic therapy in the management of asthma. Curr Opin Allergy Clin Immunol. 2016;16(4):375‐382. 10.1097/aci.0000000000000284
33. Lejeune S, Deschildre A, Le Rouzic O, et al. Childhood asthma heterogeneity at the era of precision medicine: modulating the immune response or the microbiota for the management of asthma attack. Biochem Pharmacol. 2020;179:114046. 10.1016/j.bcp.2020.114046
34. Frati F, Salvatori C, Incorvaia C, et al. The role of the microbiome in asthma: the Gut⁻Lung Axis. Int J Mol Sci. 2018;20(1):123. 10.3390/ijms20010123
35. Smith SG, Chen R, Kjarsgaard M, et al. Increased numbers of activated group 2 innate lymphoid cells in the airways of patients with severe asthma and persistent airway eosinophilia. J Allergy Clin Immunol. 2016;137(1):75‐86.e8. 10.1016/j.jaci.2015.05.037
36. Qian LJ, Kang SM, Xie JL, et al. Early‐life gut microbial colonization shapes Th1/Th2 balance in asthma model in BALB/c mice. BMC Microbiol. 2017;17(1):135. 10.1186/s12866-017-1044-0
37. Tliba O, Panettieri RA, Jr . Paucigranulocytic asthma: uncoupling of airway obstruction from inflammation. J Allergy Clin Immunol. 2019;143(4):1287‐1294. 10.1016/j.jaci.2018.06.008
38. Hammad H, Lambrecht BN. The basic immunology of asthma. Cell. 2021;184(6):1469‐1485. 10.1016/j.cell.2021.02.016
39. Varricchi G, Modestino L, Poto R, et al. Neutrophil extracellular traps and neutrophil‐derived mediators as possible biomarkers in bronchial asthma. Clin Exp Med. 2022;22(2):285‐300. 10.1007/s10238-021-00750-8
40. Das S, Miller M, Beppu AK, et al. GSDMB induces an asthma phenotype characterized by increased airway responsiveness and remodeling without lung inflammation. Proc Natl Acad Sci USA. 2016;113(46):13132‐13137. 10.1073/pnas.1610433113
41. Chen J, Miller M, Unno H, Rosenthal P, Sanderson MJ, Broide DH. Orosomucoid‐like 3 (ORMDL3) upregulates airway smooth muscle proliferation, contraction, and Ca(2+) oscillations in asthma. J Allergy Clin Immunol. 2018;142(1):207‐218.e6. 10.1016/j.jaci.2017.08.015
42. Balenga NA, Jester W, Jiang M, Panettieri RA, Jr. , Druey KM. Loss of regulator of G protein signaling 5 promotes airway hyperresponsiveness in the absence of allergic inflammation. J Allergy Clin Immunol. 2014;134(2):451‐459. 10.1016/j.jaci.2014.01.019
43. Yu J, Liu X, Li Y, et al. Maternal exposure to farming environment protects offspring against allergic diseases by modulating the neonatal TLR‐Tregs‐Th axis. Clin Transl Allergy. 2018;8(1):34. 10.1186/s13601-018-0220-0
44. Hamzaoui A, Maalmi H, Berraïes A, Abid H, Ammar J, Hamzaoui K. Transcriptional characteristics of CD4 T cells in young asthmatic children: RORC and FOXP3 axis. J Inflamm Res. 2011;4:139‐146. 10.2147/jir.s25314
45. Song J, Lim HX, Lee A, Kim S, Lee JH, Kim TS. Staphylococcus succinus 14BME20 prevents allergic airway inflammation by induction of regulatory T cells via interleukin‐10. Front Immunol. 2019;10:1269. 10.3389/fimmu.2019.01269
46. Huang Y, Mao K, Chen X, et al. S1P‐dependent interorgan trafficking of group 2 innate lymphoid cells supports host defense. Science (New York, NY). 2018;359(6371):114‐119. 10.1126/science.aam5809
47. Gray J, Oehrle K, Worthen G, Alenghat T, Whitsett J, Deshmukh H. Intestinal commensal bacteria mediate lung mucosal immunity and promote resistance of newborn mice to infection. Sci Transl Med. 2017;9(376):eaaf9412. 10.1126/scitranslmed.aaf9412
48. Lee HS, Park HW, Song WJ, et al. TNF‐α enhance Th2 and Th17 immune responses regulating by IL23 during sensitization in asthma model. Cytokine. 2016;79:23‐30. 10.1016/j.cyto.2015.12.001
49. Hufnagl K, Pali‐Schöll I, Roth‐Walter F, Jensen‐Jarolim E. Dysbiosis of the gut and lung microbiome has a role in asthma. Semin Immunopathol. 2020;42(1):75‐93. 10.1007/s00281-019-00775-y
50. McCauley K, Durack J, Valladares R, et al. Distinct nasal airway bacterial microbiotas differentially relate to exacerbation in pediatric patients with asthma. J Allergy Clin Immunol. 2019;144(5):1187‐1197. 10.1016/j.jaci.2019.05.035
51. Huang YJ, Boushey HA. The microbiome in asthma. J Allergy Clin Immunol. 2015;135(1):25‐30. 10.1016/j.jaci.2014.11.011
52. van Nimwegen FA, Penders J, Stobberingh EE, et al. Mode and place of delivery, gastrointestinal microbiota, and their influence on asthma and atopy. J Allergy Clin Immunol. 2011;128(5):948‐955.e1‐3. 10.1016/j.jaci.2011.07.027
53. Huang YJ, Marsland BJ, Bunyavanich S, et al. The microbiome in allergic disease: current understanding and future opportunities‐2017 PRACTALL document of the American Academy of Allergy, Asthma & Immunology and the European Academy of Allergy and Clinical Immunology. J Allergy Clin Immunol. 2017;139(4):1099‐1110. 10.1016/j.jaci.2017.02.007
54. Stokholm J, Blaser MJ, Thorsen J, et al. Maturation of the gut microbiome and risk of asthma in childhood. Nat Commun. 2018;9(1):141. 10.1038/s41467-017-02573-2
55. Arrieta MC, Stiemsma LT, Dimitriu PA, et al. Early infancy microbial and metabolic alterations affect risk of childhood asthma. Sci Transl Med. 2015;7(307):307ra152. 10.1126/scitranslmed.aab2271
56. Durack J, Kimes NE, Lin DL, et al. Delayed gut microbiota development in high‐risk for asthma infants is temporarily modifiable by Lactobacillus supplementation. Nat Commun. 2018;9(1):707. 10.1038/s41467-018-03157-4
57. Bosch A, de Steenhuijsen Piters WAA, van Houten MA, et al. Maturation of the infant respiratory microbiota, environmental drivers, and health consequences. A prospective cohort study. Am J Respir Crit Care Med. 2017;196(12):1582‐1590. 10.1164/rccm.201703-0554oc
58. Teo SM, Tang HHF, Mok D, et al. Airway microbiota dynamics uncover a critical window for interplay of pathogenic bacteria and allergy in childhood respiratory disease. Cell Host Microbe. 2018;24(3):341‐352.e5. 10.1016/j.chom.2018.08.005
59. Durack J, Huang YJ, Nariya S, et al. Bacterial biogeography of adult airways in atopic asthma. Microbiome. 2018;6(1):104. 10.1186/s40168-018-0487-3
60. Chiu CY, Cheng ML, Chiang MH, et al. Gut microbial‐derived butyrate is inversely associated with IgE responses to allergens in childhood asthma. Pediatr Allergy Immunol. 2019;30(7):689‐697. 10.1111/pai.13096
61. Sender R, Fuchs S, Milo R. Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell. 2016;164(3):337‐340. 10.1016/j.cell.2016.01.013
62. Bäckhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI. Host‐bacterial mutualism in the human intestine. Science (New York, NY). 2005;307(5717):1915‐1920. 10.1126/science.1104816
63. Zeng H, Wang Y, Gu Y, et al. Polydatin attenuates reactive oxygen species‐induced airway remodeling by promoting Nrf2‐mediated antioxidant signaling in asthma mouse model. Life Sci. 2019;218:25‐30. 10.1016/j.lfs.2018.08.013
64. Chang CS, Kao CY. Current understanding of the gut microbiota shaping mechanisms. J Biomed Sci. 2019;26(1):59. 10.1186/s12929-019-0554-5
65. Zimmermann P, Messina N, Mohn WW, Finlay BB, Curtis N. Association between the intestinal microbiota and allergic sensitization, eczema, and asthma: a systematic review. J Allergy Clin Immunol. 2019;143(2):467‐485. 10.1016/j.jaci.2018.09.025
66. Oddy WH. Breastfeeding, childhood asthma, and allergic disease. Ann Nutr Metabol. 2017;70(Suppl 2):26‐36. 10.1159/000457920
67. Wang Q, Li F, Liang B, et al. A metagenome‐wide association study of gut microbiota in asthma in UK adults. BMC Microbiol. 2018;18(1):114. 10.1186/s12866-018-1257-x
68. Fujimura KE, Sitarik AR, Havstad S, et al. Neonatal gut microbiota associates with childhood multisensitized atopy and T cell differentiation. Nat Med. 2016;22(10):1187‐1191. 10.1038/nm.4176
69. Barcik W, Boutin RCT, Sokolowska M, Finlay BB. The role of lung and gut microbiota in the pathology of asthma. Immunity. 2020;52(2):241‐255. 10.1016/j.immuni.2020.01.007
70. van den Elsen LWJ, Garssen J, Burcelin R, Verhasselt V. Shaping the gut microbiota by breastfeeding: the gateway to allergy prevention? Front Pediatr. 2019;7:47. 10.3389/fped.2019.00047
71. Liu X, Cheng Y, Zang D, et al. The role of gut microbiota in lung cancer: from carcinogenesis to immunotherapy. Front Oncol. 2021;11:720842. 10.3389/fonc.2021.720842
72. Long SL, Gahan CGM, Joyce SA. Interactions between gut bacteria and bile in health and disease. Mol Aspect Med. 2017;56:54‐65. 10.1016/j.mam.2017.06.002
73. Parasar B, Zhou H, Xiao X, Shi Q, Brito IL, Chang PV. Chemoproteomic profiling of gut microbiota‐associated bile salt hydrolase activity. ACS Cent Sci. 2019;5(5):867‐873. 10.1021/acscentsci.9b00147
74. Milani C, Duranti S, Bottacini F, et al. The first microbial colonizers of the human gut: composition, activities, and health implications of the infant gut microbiota. Microbiol Mol Biol Rev: MMBR (Microbiol Mol Biol Rev). 2017;81(4):10‐1128. 10.1128/mmbr.00036-17
75. Cuevas‐Sierra A, Ramos‐Lopez O, Riezu‐Boj JI, Milagro FI, Martinez JA. Diet, gut microbiota, and obesity: links with host genetics and epigenetics and potential applications. Adv Nutr. 2019;10(Suppl l_1):S17‐S30. 10.1093/advances/nmy078
76. Loverdos K, Bellos G, Kokolatou L, et al. Lung microbiome in asthma: current perspectives. J Clin Med. 2019;8(11):1967. 10.3390/jcm8111967
77. Borbet TC, Zhang X, Müller A, Blaser MJ. The role of the changing human microbiome in the asthma pandemic. J Allergy Clin Immunol. 2019;144(6):1457‐1466. 10.1016/j.jaci.2019.10.022
78. Zakeri A, Russo M. Dual role of toll‐like receptors in human and experimental asthma models. Front Immunol. 2018;9:1027. 10.3389/fimmu.2018.01027
79. Del Moral MG, Martínez‐Naves E. The role of lipids in development of allergic responses. Immune Network. 2017;17(3):133‐143. 10.4110/in.2017.17.3.133
80. Qian G, Jiang W, Zou B, et al. LPS inactivation by a host lipase allows lung epithelial cell sensitization for allergic asthma. J Exp Med. 2018;215(9):2397‐2412. 10.1084/jem.20172225
81. Turturice BA, Gold DR, Litonjua AA, et al. Lower perinatal exposure to proteobacteria is an independent predictor of early childhood wheezing. J Allergy Clin Immunol. 2019;143(1):419‐421.e5. 10.1016/j.jaci.2018.06.051
82. Mizobuchi H, Soma GI. Low‐dose lipopolysaccharide as an immune regulator for homeostasis maintenance in the central nervous system through transformation to neuroprotective microglia. Neural Regen Res. 2021;16(10):1928‐1934. 10.4103/1673-5374.308067
83. Wypych TP, Wickramasinghe LC, Marsland BJ. The influence of the microbiome on respiratory health. Nat Immunol. 2019;20(10):1279‐1290. 10.1038/s41590-019-0451-9
84. Zhang D, Li S, Wang N, Tan HY, Zhang Z, Feng Y. The cross‐talk between gut microbiota and lungs in common lung diseases. Front Microbiol. 2020;11:301. 10.3389/fmicb.2020.00301
85. Silva C, Rojony R, Bermudez LE, Danelishvili L. Short‐chain fatty acids promote Mycobacterium avium subsp. hominissuis growth in nutrient‐limited environments and influence susceptibility to antibiotics. Pathogens. 2020;9(9):700. 10.3390/pathogens9090700
86. Abdel‐Aziz MI, Vijverberg SJH, Neerincx AH, Kraneveld AD, Maitland‐van der Zee AH. The crosstalk between microbiome and asthma: exploring associations and challenges. Clin Exp Allergy. 2019;49(8):1067‐1086. 10.1111/cea.13444
87. Cait A, Hughes MR, Antignano F, et al. Microbiome‐driven allergic lung inflammation is ameliorated by short‐chain fatty acids. Mucosal Immunol. 2018;11(3):785‐795. 10.1038/mi.2017.75
88. Thorburn AN, McKenzie CI, Shen S, et al. Evidence that asthma is a developmental origin disease influenced by maternal diet and bacterial metabolites. Nat Commun. 2015;6(1):7320. 10.1038/ncomms8320
89. Trompette A, Gollwitzer ES, Yadava K, et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med. 2014;20(2):159‐166. 10.1038/nm.3444
90. Trompette A, Gollwitzer ES, Pattaroni C, et al. Dietary fiber confers protection against flu by shaping Ly6c(‐) patrolling monocyte hematopoiesis and CD8(+) T cell metabolism. Immunity. 2018;48(5):992‐1005.e8. 10.1016/j.immuni.2018.04.022
91. Steed AL, Christophi GP, Kaiko GE, et al. The microbial metabolite desaminotyrosine protects from influenza through type I interferon. Science (New York, NY). 2017;357(6350):498‐502. 10.1126/science.aam5336
92. Pugin B, Barcik W, Westermann P, et al. A wide diversity of bacteria from the human gut produces and degrades biogenic amines. Microb Ecol Health Dis. 2017;28(1):1353881. 10.1080/16512235.2017.1353881
93. Smolinska S, Jutel M, Crameri R, O'Mahony L. Histamine and gut mucosal immune regulation. Allergy. 2014;69(3):273‐281. 10.1111/all.12330
94. Wang J, Liu B, Sun F, et al. Histamine H3R antagonist counteracts the impaired hippocampal neurogenesis in Lipopolysaccharide‐induced neuroinflammation. Int Immunopharm. 2022;110:109045. 10.1016/j.intimp.2022.109045
95. Yamauchi K, Ogasawara M. The role of histamine in the pathophysiology of asthma and the clinical efficacy of antihistamines in asthma therapy. Int J Mol Sci. 2019;20(7):1733. 10.3390/ijms20071733
96. Bryce PJ, Mathias CB, Harrison KL, Watanabe T, Geha RS, Oettgen HC. The H1 histamine receptor regulates allergic lung responses. J Clin Invest. 2006;116(6):1624‐1632. 10.1172/jci26150
97. Cowden JM, Riley JP, Ma JY, Thurmond RL, Dunford PJ. Histamine H4 receptor antagonism diminishes existing airway inflammation and dysfunction via modulation of Th2 cytokines. Respir Res. 2010;11(1):86. 10.1186/1465-9921-11-86
98. Ferstl R, Frei R, Barcik W, et al. Histamine receptor 2 modifies iNKT cell activity within the inflamed lung. Allergy. 2017;72(12):1925‐1935. 10.1111/all.13227
99. Barcik W, Pugin B, Brescó MS, et al. Bacterial secretion of histamine within the gut influences immune responses within the lung. Allergy. 2019;74(5):899‐909. 10.1111/all.13709
100. Minodier L, Charrel RN, Ceccaldi PE, et al. Prevalence of gastrointestinal symptoms in patients with influenza, clinical significance, and pathophysiology of human influenza viruses in faecal samples: what do we know? Virol J. 2015;12(1):215. 10.1186/s12985-015-0448-4
101. Schäfer A, Leist SR, Gralinski LE, et al. A multitrait locus regulates sarbecovirus pathogenesis. mBio. 2022;13(4):e0145422. 10.1128/mbio.01454-22
102. Anand S, Mande SS. Diet, microbiota and gut‐lung connection. Front Microbiol. 2018;9:2147. 10.3389/fmicb.2018.02147
103. Ahlawat S, Asha SKK. Immunological co‐ordination between gut and lungs in SARS‐CoV‐2 infection. Virus Res. 2020;286:198103. 10.1016/j.virusres.2020.198103
104. Marsland BJ, Trompette A, Gollwitzer ES. The gut‐lung axis in respiratory disease. Annals Am Thorac Soc. 2015;12(Suppl 2):S150‐S156. 10.1513/annalsats.201503-133aw
105. Budden KF, Gellatly SL, Wood DL, et al. Emerging pathogenic links between microbiota and the gut‐lung axis. Nat Rev Microbiol. 2017;15(1):55‐63. 10.1038/nrmicro.2016.142
106. Ray A, Kolls JK. Neutrophilic inflammation in asthma and association with disease severity. Trends Immunol. 2017;38(12):942‐954. 10.1016/j.it.2017.07.003
107. Kuo CS, Pavlidis S, Loza M, et al. T‐helper cell type 2 (Th2) and non‐Th2 molecular phenotypes of asthma using sputum transcriptomics in U‐BIOPRED. Eur Respir J. 2017;49(2):1602135. 10.1183/13993003.02135-2016
108. Cosío BG, Pérez de Llano L, Lopez Viña A, et al. Th‐2 signature in chronic airway diseases: towards the extinction of asthma‐COPD overlap syndrome? Eur Respir J. 2017;49(5):1602397. 10.1183/13993003.02397-2016
109. Jiang Y, Bao C, Zhao X, Chen Y, Song Y, Xiao Z. Intestinal bacteria flora changes in patients with Mycoplasma pneumoniae pneumonia with or without wheezing. Sci Rep. 2022;12(1):5683. 10.1038/s41598-022-09700-0
110. Lee J, Lee SH, Gu GJ, et al. Alterations of lung microbial communities in obese allergic asthma and metabolic potential. PLoS One. 2021;16(10):e0256848. 10.1371/journal.pone.0256848
111. Karaca S, Civelek E, Karaca M, et al. Allergy‐specific phenome‐wide association study for immunogenes in Turkish children. Sci Rep. 2016;6(1):33152. 10.1038/srep33152
112. Demirci M, Tokman HB, Uysal HK, et al. Reduced Akkermansia muciniphila and Faecalibacterium prausnitzii levels in the gut microbiota of children with allergic asthma. Allergol Immunopathol. 2019;47(4):365‐371. 10.1016/j.aller.2018.12.009
113. Zhang Y, Li T, Yuan H, Pan W, Dai Q. Correlations of inflammatory factors with intestinal flora and gastrointestinal incommensurate symptoms in children with asthma. Med Sci Mon Int Med J Exp Clin Res. 2018;24:7975‐7979. 10.12659/msm.910854
114. Budden KF, Shukla SD, Rehman SF, et al. Functional effects of the microbiota in chronic respiratory disease. Lancet Respir Med. 2019;7(10):907‐920. 10.1016/s2213-2600(18)30510-1
115. Ver Heul A, Planer J, Kau AL. The human microbiota and asthma. Clin Rev Allergy Immunol. 2019;57(3):350‐363. 10.1007/s12016-018-8719-7
116. Arpaia N, Campbell C, Fan X, et al. Metabolites produced by commensal bacteria promote peripheral regulatory T‐cell generation. Nature. 2013;504(7480):451‐455. 10.1038/nature12726
117. Dzidic M, Abrahamsson TR, Artacho A, et al. Aberrant IgA responses to the gut microbiota during infancy precede asthma and allergy development. J Allergy Clin Immunol. 2017;139(3):1017‐1025.e14. 10.1016/j.jaci.2016.06.047
118. Agache I, Akdis CA. Endotypes of allergic diseases and asthma: an important step in building blocks for the future of precision medicine. Allergol Int. 2016;65(3):243‐252. 10.1016/j.alit.2016.04.011
119. Kozik AJ, Huang YJ. The microbiome in asthma: role in pathogenesis, phenotype, and response to treatment. Ann Allergy Asthma Immunol. 2019;122(3):270‐275. 10.1016/j.anai.2018.12.005
120. Bradley CP, Teng F, Felix KM, et al. Segmented filamentous bacteria provoke lung autoimmunity by inducing gut‐lung Axis Th17 cells expressing dual TCRs. Cell Host Microbe. 2017;22(5):697‐704.e4. 10.1016/j.chom.2017.10.007
121. Rossios C, Pavlidis S, Hoda U, et al. Sputum transcriptomics reveal upregulation of IL‐1 receptor family members in patients with severe asthma. J Allergy Clin Immunol. 2018;141(2):560‐570. 10.1016/j.jaci.2017.02.045
122. Kim RY, Pinkerton JW, Essilfie AT, et al. Role for NLRP3 inflammasome‐mediated, IL‐1β‐dependent responses in severe, steroid‐resistant asthma. Am J Respir Crit Care Med. 2017;196(3):283‐297. 10.1164/rccm.201609-1830oc
123. Tan HT, Hagner S, Ruchti F, et al. Tight junction, mucin, and inflammasome‐related molecules are differentially expressed in eosinophilic, mixed, and neutrophilic experimental asthma in mice. Allergy. 2019;74(2):294‐307. 10.1111/all.13619
124. Tan TG, Sefik E, Geva‐Zatorsky N, et al. Identifying species of symbiont bacteria from the human gut that, alone, can induce intestinal Th17 cells in mice. Proc Natl Acad Sci USA. 2016;113(50):E8141‐E8150. 10.1073/pnas.1617460113
125. Ubags NDJ, Marsland BJ. Mechanistic insight into the function of the microbiome in lung diseases. Eur Respir J. 2017;50(3):1602467. 10.1183/13993003.02467-2016
126. Chunxi L, Haiyue L, Yanxia L, Jianbing P, Jin S. The gut microbiota and respiratory diseases: new evidence. J Immun Res. 2020;2020:2340670. 10.1155/2020/2340670
127. Yang X, Feng H, Zhan X, et al. Early‐life vancomycin treatment promotes airway inflammation and impairs microbiome homeostasis. Aging. 2019;11(7):2071‐2081. 10.18632/aging.101901
128. Adami AJ, Bracken SJ, Guernsey LA, et al. Early‐life antibiotics attenuate regulatory T cell generation and increase the severity of murine house dust mite‐induced asthma. Pediatr Res. 2018;84(3):426‐434. 10.1038/s41390-018-0031-y
129. Russell SL, Gold MJ, Reynolds LA, et al. Perinatal antibiotic‐induced shifts in gut microbiota have differential effects on inflammatory lung diseases. J Allergy Clin Immunol. 2015;135(1):100‐109. 10.1016/j.jaci.2014.06.027
130. Bokulich NA, Chung J, Battaglia T, et al. Antibiotics, birth mode, and diet shape microbiome maturation during early life. Sci Transl Med. 2016;8(343):343ra82. 10.1126/scitranslmed.aad7121
131. Hagan T, Cortese M, Rouphael N, et al. Antibiotics‐driven gut microbiome perturbation alters immunity to vaccines in humans. Cell. 2019;178(6):1313‐1328.e13. 10.1016/j.cell.2019.08.010
132. Blaser MJ. The past and future biology of the human microbiome in an age of extinctions. Cell. 2018;172(6):1173‐1177. 10.1016/j.cell.2018.02.040
133. Metsälä J, Lundqvist A, Virta LJ, Kaila M, Gissler M, Virtanen SM. Prenatal and post‐natal exposure to antibiotics and risk of asthma in childhood. Clin Exp Allergy. 2015;45(1):137‐145. 10.1111/cea.12356
134. Mitre E, Susi A, Kropp LE, Schwartz DJ, Gorman GH, Nylund CM. Association between use of acid‐suppressive medications and antibiotics during infancy and allergic diseases in early childhood. JAMA Pediatr. 2018;172(6):e180315. 10.1001/jamapediatrics.2018.0315
135. Yagi K, Huffnagle GB, Lukacs NW, Asai N. The lung microbiome during health and disease. Int J Mol Sci. 2021;22(19):10872. 10.3390/ijms221910872
136. Dargahi N, Johnson J, Donkor O, Vasiljevic T, Apostolopoulos V. Immunomodulatory effects of probiotics: can they be used to treat allergies and autoimmune diseases? Maturitas. 2019;119:25‐38. 10.1016/j.maturitas.2018.11.002
137. Mahooti M, Abdolalipour E, Salehzadeh A, Mohebbi SR, Gorji A, Ghaemi A. Immunomodulatory and prophylactic effects of Bifidobacterium bifidum probiotic strain on influenza infection in mice. World J Microbiol Biotechnol. 2019;35(6):91. 10.1007/s11274-019-2667-0
138. Huang CF, Chie WC, Wang IJ. Efficacy of lactobacillus administration in school‐age children with asthma: a randomized, placebo‐controlled trial. Nutrients. 2018;10(11):1678. 10.3390/nu10111678
139. Wu CT, Chen PJ, Lee YT, Ko JL, Lue KH. Effects of immunomodulatory supplementation with Lactobacillus rhamnosus on airway inflammation in a mouse asthma model. J Microbiol Immun Infection. 2016;49(5):625‐635. 10.1016/j.jmii.2014.08.001
140. Sun S, Li H, Yuan Y, et al. Preventive and therapeutic effects of Trichinella spiralis adult extracts on allergic inflammation in an experimental asthma mouse model. Parasites Vectors. 2019;12(1):326. 10.1186/s13071-019-3561-1
141. Shi W, Xu N, Wang X, Vallée I, Liu M, Liu X. Helminth therapy for immune‐mediated inflammatory diseases: current and future perspectives. J Inflamm Res. 2022;15:475‐491. 10.2147/jir.s348079
142. Melo‐González F, Sepúlveda‐Alfaro J, Schultz BM, et al. Distal consequences of mucosal infections in intestinal and lung inflammation. Front Immunol. 2022;13:877533. 10.3389/fimmu.2022.877533
143. Zaiss MM, Rapin A, Lebon L, et al. The intestinal microbiota contributes to the ability of helminths to modulate allergic inflammation. Immunity. 2015;43(5):998‐1010. 10.1016/j.immuni.2015.09.012
144. Ianiro G, Segal JP, Mullish BH, et al. Fecal microbiota transplantation in gastrointestinal and extraintestinal disorders. Future Microbiol. 2020;15(12):1173‐1183. 10.2217/fmb-2020-0061
145. Wei Z, Li F, Pi G. Association between gut microbiota and osteoarthritis: a review of evidence for potential mechanisms and therapeutics. Front Cell Infect Microbiol. 2022;12:812596. 10.3389/fcimb.2022.812596
146. Ooijevaar RE, Terveer EM, Verspaget HW, Kuijper EJ, Keller JJ. Clinical application and potential of fecal microbiota transplantation. Annu Rev Med. 2019;70(1):335‐351. 10.1146/annurev-med-111717-122956
147. Turturice BA, McGee HS, Oliver B, et al. Atopic asthmatic immune phenotypes associated with airway microbiota and airway obstruction. PLoS One. 2017;12(10):e0184566. 10.1371/journal.pone.0184566
148. Ozturk AB, Turturice BA, Perkins DL, Finn PW. The potential for emerging microbiome‐mediated therapeutics in asthma. Curr Allergy Asthma Rep. 2017;17(9):62. 10.1007/s11882-017-0730-1
149. Durack J, Lynch SV. The gut microbiome: relationships with disease and opportunities for therapy. J Exp Med. 2019;216(1):20‐40. 10.1084/jem.20180448

Where this page came from

This page was imported from Clinical and Translational Allergy (PubMed Central). “Gut‐lung axis and asthma: A historical review on mechanism and future perspective” by its authors, Clinical and Translational Allergy (2024), doi:10.1002/clt2.12356, published under CC BY 4.0. Changed here: set as a page from the journal’s XML, its supplementary files left out; figures the article marks as reproduced under other terms are left out.

Nobody has written it yet — it is the source material at a new address, which is why search engines are asked to skip it and why no one earns from it. It is up for grabs: take it on, and it is yours to rewrite and to earn from.