Environmental influences on childhood asthma—The effect of diet and microbiome on asthma

Abstract

Early life dietary patterns and timely maturation of mucosa‐associated microbial communities are important factors influencing immune development and for establishing robust immune tolerance networks. Microbial fermentation of dietary components in vivo generates a vast array of molecules, some of which are integral components of the molecular circuitry that regulates immune and metabolic functions. These in turn protect against aberrant inflammatory processes and promote effector immune responses that quickly eliminate pathogens. Multiple studies suggest that changes in dietary habits, altered microbiome composition, and microbial metabolism are associated with asthma risk and disease severity. While it remains unclear whether these microbiome alterations are a cause or consequence of dysregulated immune responses, there is significant potential for using diet in targeted manipulations of the gut microbiome and its metabolic functions in promoting immune health. In this article, we will summarize our knowledge to date on the role of dietary patterns and microbiome activities on immune responses within the airways. Given the malleability of the human microbiome, its integration into the immune system, and its responsiveness to diet, this makes it a highly attractive target for therapeutic and nutritional intervention in children with asthma.

Key Message.

Diet–microbiome interactions in early life are emerging as key events that shape the infant's immune response to infectious and noninfectious encounters. Research on how specific dietary interventions impact the microbiota to generate immunoregulatory metabolites can be leveraged to develop more effective diets and molecules that improve human immune health.

1. INTRODUCTION

Recent decades have seen a rapid increase in chronic inflammatory disorders in children due to inappropriate or misdirected immune responses accompanied by insufficient development of immune regulatory networks. It is generally accepted that changes in environment, lifestyle, and dietary factors may play a role in the miseducation or deficient training of the immune system. ¹ , ² , ³ Epidemiological studies have suggested associations between the migration from traditional farming to urban environments, increase in processed food intake, lack of contact with animals, and increased exposure to epithelial barrier damaging agents with the increased incidence of asthma, atopic dermatitis and food allergy. ⁴ However, it is only relatively recently that the microbiota has been recognized as an important conduit for mediating environment and dietary effects on the regulation of immune tolerance networks.

Following birth, infants acquire microbes from their mother, other family members, animals, and their environmental exposures. ⁵ The complexity of the infant microbiome develops and matures during the first years of life and is supported by breastfeeding and the introduction of diverse complementary and solid foods. When microbiota acquisition and/or dietary supports are limited, this can lead to a delay in microbiota maturation. A shift away from traditional diets rich in plant‐based foods to highly processed foods is thought to be particularly important for negatively affecting microbiome diversity and composition, species‐specific characteristics, microbial metabolism, and immunological tolerance. ⁶ , ⁷ In fact, the American Gut Study showed that eating 30 plant‐based foods per week was associated with the highest levels of gut microbial diversity. ⁸ The consequences of altered microbiota composition or altered metabolic output include disrupted communication between the microbiota and the host immune system, which negatively influences immune homeostatic networks as the balance between immune tolerance and inflammation within tissues is regulated in part by the crosstalk between immune cells and the microbiota. ⁹ These mechanisms are important not only for protection against allergy and asthma but also for effective immune responses to pathogens such as SARS‐CoV‐2. ¹⁰ , ¹¹ , ¹² , ¹³ Microbial structural components (e.g., lipopolysaccharides, lipoteichoic acid, polysaccharide A, lipoproteins, peptidoglycans, and extracellular polysaccharides), genetic material (e.g., unmethylated CpG dinucleotides), microbe modified host factors (e.g., secondary bile acids), and metabolites derived from metabolism of dietary components (e.g., short‐chain fatty acids (SCFAs) and indoles) all impact immunological responses via a range of immune sensory systems including pattern recognition receptors (PRRs), G protein‐coupled receptors (GPCRs), aryl hydrocarbon receptor (AhR), nuclear hormone receptors such as the farnesoid X receptor (FXR) or can directly modulate gene expression through epigenetic mechanisms (Figure 1).

FIGURE 1.

Microbial factors impacting lung immune responses. Within the gut, bacterial metabolism of dietary components (e.g., fibers and amino acids) and host‐derived secretions (e.g., primary bile acids and mucins) generates metabolites including SCFAs, indoles and secondary bile acids that influence immune cells via GPCRs, aryl hydrocarbon receptor and nuclear receptors. Metabolites can be absorbed and have direct effects on distant organs such as the lungs. Cells exposed to bacterial factors in the gut can also migrate to the lung and exert their effects there. In addition to metabolites, bacterial structural components termed microbial‐associated molecular patterns can impact innate and adaptive processes via pattern recognition receptors (PRRs). Both microbes within the gut and the lungs signal via PRRs and can induce regulatory or effector cell lymphocytes.

Overall, changes in microbiota exposures and changes in dietary habits that occurred simultaneously may interact in unanticipated ways resulting in additive detrimental effects on the host immune system. Several studies have linked early life dietary and microbiota changes with an increased risk of asthma later in life, and these will be further discussed in this review.

2. INTERACTIONS BETWEEN INFANT DIET, MICROBIOME, AND ASTHMA

Overall dietary intake may influence allergic and asthma outcomes through intake of multiple nutrients with direct effects on the immune system (e.g., fish oils) and nutrients that have indirect effects on the immune system (e.g., fibers) via their utilization and metabolism by gut microbes. ¹⁴ , ¹⁵ However, nutrients do not exist in isolation, and it may be important to study nutrition (especially immunonutrition) using a whole diet approach to better understand the role of dietary intake on asthma outcomes. Whole diet approaches used in infancy and childhood in association with asthma outcomes include diet patterns that assess intake of advanced glycation end products (AGEs), diet indices such as the Mediterranean diet index and diet diversity. ¹⁴

A USA‐based study reported an association between increased AGEs intake in children 5–9 years of age and an increased odds of wheezing, wheeze‐disrupted sleep, and wheezing requiring prescription medication. ¹⁶ Despite the fact that this study was not conducted in children with allergic outcomes, it was postulated that increased intake of AGEs impacts immune inflammatory responses, disrupts the gut microbiome of children, and is associated with an increase in autoimmune diseases such as type I diabetes. ¹⁷ A number of studies have shown an increased prevalence of wheeze/asthma in children consuming a Western diet. ¹⁸ , ¹⁹ , ²⁰ In contrast to these studies, the Dutch Generation R cohort did not find an association between a healthy dietary pattern in early life and a lower risk of atopic diseases, including asthma, in childhood. ²¹ , ²² However, unfortunately, the majority of studies comparing dietary effects on allergic outcomes in infants and young children to date do not include measures of microbiota composition or metabolic activity.

Three systematic reviews examining the Mediterranean diet in children and asthma outcomes have shown an inverse relationship between this index and reported wheeze and asthma. ²³ , ²⁴ , ²⁵ While the Mediterranean diet studies in infants and children focused on asthma outcomes did not include microbiome measures, it is already known that increased fibers, fruit, and vegetable consumption during infancy is associated with an increase in gut microbial diversity. ¹⁵ Comparing Egyptian teenagers on a Mediterranean‐style diet to American teenagers consuming a Western diet, Egyptian children clustered to the Prevotella enterotype and American children clustered to the Bacteroides enterotype. In addition, higher levels of short‐chain fatty acids (SCFAs) were observed in Egyptian children, which was associated with increased abundance of microbial polysaccharide degradation‐encoding genes, and polysaccharide‐degrading genera. ²⁶ A study comparing the gut microbiota of Bangladeshi and American teenagers also showed lower levels of Bacteroides and higher levels of Prevotella, Butyrivibrio, and Oscillospira, in the Bangladeshi children, associated with their non‐Western diet that is low in meat and sugar with higher intake of rice, bread, and lentils. The American children consuming Western diets had a higher abundance of Bacteroides. ²⁷

Diet diversity in infancy and asthma/wheeze outcomes in childhood were reported by the PASTURE study and the Finnish Type I Diabetes Prediction and Prevention Study Prospective Cohort Study. ²⁸ , ²⁹ Roduit et al. showed in the PASTURE study that increased diet diversity in the first year of life was associated with reduced asthma by 6 years. For every additional food introduced, a 26% reduction in asthma risk was reported. Nwaru et al. also reported that reduced diet diversity at 12 months of life was associated with an increased risk of the development of asthma at age 5, as well as an increased risk of any wheeze. In the PASTURE cohort, a diet rich in fruit, vegetables, fish, and yogurt was associated with the highest levels of butyrate at 12 months, which correlated with a lower risk of asthma by 6 years of age. ³⁰ As a proxy for diet diversity, increased protein, carbohydrate and fiber intake, as well as increased intake of family foods during the weaning period, has also been associated with an increase in gut microbiome diversity in infants. ¹⁵

Of all the dietary ingredients studied to date, fibers may be one of the most important for microbiota and immune health. Certain fibers, also termed microbiota‐accessible carbohydrates, are an essential food source for the microbiota in that they provide resources for microbial growth. They are central to food webs in the gut microbiota established through cross‐feeding, and reduced fiber intake has been shown to be associated with the loss of ancestral microbes. ³¹ Overall, species diversity and richness have been shown to be reduced by about one‐third in North Americans than Malawians or Amerindians, which might be due in part to differences in dietary fiber consumption. ³² A high fat/low fiber diet and obesity have been associated with alterations in gut microbiota composition and metabolic activity. The degradation of dietary fibers requires specific CAZymes (carbohydrate active enzymes), which are encoded in the genomes of specific bacterial strains. ³³ , ³⁴ While the human genome encodes potentially up to 17 glycoside hydrolases, thousands of gut microbiota genes that encode glycoside hydrolases, polysaccharide lyases, glycosyltransferases, and carbohydrate esterases have been described, demonstrating the indispensable role of the gut microbiota in fiber metabolism. ³⁵ , ³⁶ Members of the Bacteroidetes phylum (in particular Prevotella copri) seem to possess a greater number of CAZymes than other phyla, suggesting an increased capability to ferment a wider range of substrates. ³⁷ , ³⁸ As specific CAZyme gene clusters target discrete structures within dietary fibers, consequently specific subsets of microbes are supported by different types of dietary fibers, which highlights the potential for using selected fiber structures to achieve targeted functional, metabolic, and perhaps immunological outcomes. ³⁹ , ⁴⁰ Future studies will hopefully better classify different dietary fiber types on the basis of their specific immune functional properties, such as promotion of the epithelial barrier, induction of T regulatory cells, prevention of TH2 polarization, and inhibition of mast cell degranulation. Overall, fiber diversity may be more important immunologically than any single individual fiber type.

In one cross‐sectional observational study, an association between low dietary fiber intake and increased odds of reported asthma was noted among respondents on the National Health and Nutrition Examination survey (NHANES) survey in the USA. ⁴¹ They noted increased odds of asthma with lower fiber intake (lowest vs. highest reported quartile, OR, 1.4; 95% CI 1.0–1.8; p = .027) with significant interactions between fiber and both sex and race/ethnicity, in particular among women and non‐Hispanic white adults. Lowest quartile fiber intake was associated with increased odds of reported wheeze (OR, 1.3; 95% CI, 1.0–1.6; p = .018) and cough (OR, 1.7; 95% CI, 1.2–2.3; p = 0.002).

Several guidelines and systematic reviews have previously examined the role of both fiber and prebiotic supplementation with respect to allergy outcomes. We recently published an updated review of the role of dietary fiber in influencing allergic diseases, including asthma. ⁴² In summary, fibers are essential components of a healthy diet with multiple health benefits, and fiber intake has decreased at the same time as allergy rates have increased. There are a wide variety of fiber types, and specific fibers may contribute to maintain a tolerogenic mucosal environment and may protect against allergic disorders. However, the optimal prevention or treatment strategies involving fibers in humans have yet to be defined. One mechanism by which fiber impacts the immune system is dependent on microbial fermentation and secretion of bioactive metabolites. Thus, fiber supplementation alone may not be sufficient and simultaneous replacement of missing microbes may be required for optimal benefits to be observed. Overall, there is some evidence that a higher intake of dietary fiber (soluble or insoluble) may have potential protective effects on respiratory symptoms. However, the majority of the studies reviewed were small observational studies that did not clearly label the type of fiber ingested, which limits their interpretation and extrapolation. Further prospective intervention studies are needed to better define the effects of fiber consumption on respiratory outcomes. Prebiotic supplementation to asthma patients seems to have a positive effect on exercise‐induced bronchoconstriction and accompanying inflammation markers; however, as this was only a single intervention study with this design, an overall recommendation cannot be made.

3. ROLE OF THE GUT MICROBIOTA

The largest reservoir of microbes within the body is contained in the gastrointestinal tract, which encodes a genetic repertoire that is at least two orders of magnitude greater than the number of genes in the human genome. ⁴³ The gut microbiome performs several essential functions including digestion of dietary components, synthesis of vitamins, education and regulation of the immune system, competitive exclusion of pathogens, removal of toxins and carcinogens, and support of intestinal barrier function. ⁴⁴ These activities do not occur in isolation but involve interconnected nodes of microbial and host metabolic pathways, resulting in the generation of metabolites with immunoregulatory properties. In addition, immune cells and metabolites from the gut can directly or indirectly impact other organs, such as the lungs, via the circulatory, lymphatic, endocrine, and nervous systems. The “common mucosal immune system” was originally proposed by McDermott and Bienenstock in 1979, which links the mucosal sites and balances the close relationship between the host and mucosal‐associated microbiota. ⁴⁵ , ⁴⁶ Both the gut and the lung share features such as inducible immune follicles (Gut‐Associated Lymphoid Tissue (GALT) and Bronchus‐Associated Lymphoid tissue (BALT)), which coordinate many tasks including the secretion of IgA at the mucosal epithelium and T‐cell responses to luminal microbes. ⁴⁷ Indeed, the importance of the gut microbiome in maintaining systemic homeostasis has now been recognized in other fields such as in metabolic diseases. ⁴⁸

While the pathogenesis of asthma is complex with many contributing factors from genetic to environmental exposures, the exploration of the role of the gut microbiota in asthma has yielded important insights. Several studies have noted that patterns of gut colonization in early childhood can be associated with altered risk of airway disease later in life. One recent study identified a pathway whereby birth by cesarean section results in reduced infant Bacteroides and microbial sphingolipid production, which associates with an increased risk of asthma by 3 years of age. ⁴⁹ Three gut microbiota composition states have been described for neonates, each of which was associated with a different relative risk of atopy and asthma later in life. ⁵⁰ The highest risk group had lower levels of Bifidobacterium, Akkermansia, and Faecalibacterium. Arrieta et al. observed lower abundance of key bacterial genera (Faecalibacterium, Rothia, Lachnospiria and Veillonella (FLVR)) and reduced levels of acetate (a SCFA) at 3 months of age in Canadian infants that became atopic and developed wheeze by 1 year of age, with a significantly elevated risk of asthma by 3 years of age. ⁵¹ Interestingly, a similar study in an Ecuadorian cohort also revealed a microbiome signature at 3 months of age and reduced acetate levels that associated with risk of atopic wheeze later in life. ⁵² However, other than Veillonella species, different taxa (Streptococcus, Bacteroides, Ruminococcus, and Bifidobacterium) were associated with disease risk in children from Ecuador. This finding suggests that compositional differences may be less important than functional and metabolic outputs such as SCFAs.

The gut microbiota has not just been associated with disease risk but has also been shown to be altered in asthma patients with severe disease. A significant reduction in the family Verrucomicrobiaceae was observed in the gut microbiota of severe asthmatics, than patients with mild/moderate asthma, which was primarily due to reduced levels of Akkermansia muciniphila. ³³ In experimental models, A. muciniphila protected mice from respiratory inflammatory responses to acute and chronic house dust mite extract exposure, associated with higher numbers of lung Tregs and reduced accumulation of the IL‐5‐dependent Siglec F^high eosinophils within lung tissue. This mechanism was MyD88 independent but did require viable bacterial cells, suggesting that heat sensitive factors or metabolites secreted in vivo were required for the A. muciniphila protective effects. In contrast to A. muciniphila, increased levels histamine secreting microbes, in particular Morganella morganii, were observed in the gut microbiota of severe asthma patients. ⁵³ M. morganii has been previously implicated as one of the causative microbes for histamine fish poisoning (HFP), or scombroid food poisoning, which is an illness associated with consumption of high levels of histamine in fish, following the metabolism of histidine in the fish by bacteria during inappropriate handling during storage or processing. ⁵⁴ , ⁵⁵ Murine models clearly show that histamine secreted by microbes within the gut can have immunological effects in the gut and the lungs; however, it is unknown whether increased levels of histamine secretion by gut microbes can contribute to disease severity in asthma patients. ⁵⁶ , ⁵⁷ , ⁵⁸ Indeed, given that specific microbes within the gut can also degrade histamine, perhaps it is the balance between microbial histamine generators and microbial histamine degraders that most significantly impacts the immune system and asthma symptoms. ⁵⁹

4. ROLE OF THE RESPIRATORY MICROBIOTA

The role of the respiratory microbiota in asthma has been the subject of intense focus in recent years. The lung microbiota is now recognized to play a role in the pathogenesis of asthma, may influence asthma phenotypes, and can potentiate asthma exacerbations. Previously, it was thought the lungs were sterile, but the lung has its own distinct microbiota, just like the gut, and it has been found to be significantly different in nonasthma controls compared with those with respiratory diseases such as asthma. ⁶⁰ , ⁶¹

The development of the lung microbiota begins early in life. Microbial dysbiosis, particularly at this early age, has been shown in multiple studies to increase a child's chances of later developing asthma, potentially by promoting Th2 inflammatory cascades. ⁶² , ⁶³ Bisgaard et al demonstrated that colonization with Streptococcus pneumonia, Moraxella catarrhalis, and/or Haemophilus influenza sampled from hypopharyngeal aspirates from 1‐month‐old babies born to asthmatic mothers was significantly associated with persistent wheeze, hospitalization for wheeze and asthma diagnosis at age 5 years. ⁶⁴ By contrast, increased abundance of nasopharyngeal Lactobacillus species during acute respiratory infection with respiratory syncytial virus (RSV) in infancy was associated with reduced risk of wheezing at 2 years of age. ⁶⁵ Microbiota composition in children is also correlated with changes in asthma control and asthma severity. One study suggested that 15 bacterial genera and seven fungal genera showed a significant difference in overall abundance between severe asthma and nonasthma bronchoalveolar lavage samples (BALs), while another study found that Moraxella was the most commonly associated genus in the nasal airways of children with severe persistent asthma (average age of 11 years old in both studies). ⁶⁶ , ⁶⁷ Conversely, early childhood exposure to a diverse range of microbes, allergens, and environmental exposures such as having pets, living on a farm, and drinking unpasteurised milk can be protective against asthma, perhaps via effects on immune education and immune regulatory networks. ⁶⁸ , ⁶⁹ , ⁷⁰ , ⁷¹ , ⁷² However, these exposures need to occur within a critical time window for this to occur successfully. There is also believed to be an interplay between the lung and the gut microbiome that can reduce the risk of allergic asthma later in life. ⁷³

The composition of the lung microbiome in adults has also been found to be different when healthy volunteers and asthmatic patients have been compared. ⁶¹ Not only bacteria but also fungi and viruses can impact immune responses in the lungs. ⁷⁴ , ⁷⁵ These differences may contribute to airway hyperreactivity, mucous production, and the increased release of proinflammatory cytokines, which all contribute to asthma development. An increased level of pathogenic proteobacteria particularly Haemophilus influenza but also Streptococcus pneumonia and Moraxella catarrhalis and reduced levels of Bacteroidetes were observed in asthmatics when compared to samples from control volunteers. ⁶¹ Within the airways, the phylum Proteobacteria is often associated with worse asthma control, whereas Actinobacteria can correlate with improvement, or no change in asthma control. Mycoplasma pneumoniae, Chlamydophila pneumoniae, Neisseria Haemophilus, Campylobacter, and Leptotrichia species are also more often found in the airways of severe asthmatics or in corticosteroid‐resistant patients. ⁷⁶ , ⁷⁷ However, the respiratory microbiome of those with mild‐to‐moderate asthma is usually more similar to that of a patient with severe asthma than control nonasthma patients. ⁷⁸

The mechanisms responsible for changes in the airway microbiota are not well‐understood, and in addition to medications, it is possible that the type of inflammatory response (i.e., eosinophil versus neutrophil), changes in host secretions (e.g., lipids), and cellular metabolism might influence microbial colonization and growth within the airways. Interestingly, neutrophilic exacerbations of asthma and chronic obstructive pulmonary disease (COPD) correlated with the presence of Proteobacteria in the sputum, whereas increased eosinophils in asthma patients, regardless of their BMI, was associated with an increased relative abundance of the genera Rothia, Dorea, Lautropia, and Haemophilus within BALs. ³³ One study compared the bronchial brushings of nonasthma patients to those with asthma and atopy and found that in those with type‐2 inflammation, there was a lower bacterial burden when compared to other phenotypes. ⁷⁹ Another study found that those with neutrophilic asthma were more likely to be colonized by Proteobacteria (Haemophilus and Moraxella), have an overall reduced microbial diversity and that this was usually related to a more severe asthma phenotype. ⁸⁰ There is a previously shown association between airway neutrophilia, severe airway obstruction, and interleukin 18 (IL‐18), which may be related to differences in the lung microbiota. ⁸¹ Importantly, obesity has been associated with changes in the nasal and lung microbiota, even in obese individuals that do not have an asthma diagnosis. ³³ It is unknown whether this difference in respiratory microbiota composition represents a pre‐asthma state, or whether obesity‐driven microbiota changes are independent of subsequent asthma risk.

Key to the role of the microbiota in the development of asthma is a cycle of inflammation, injury, repair, and remodeling that occurs in the airways. On the one hand, fungi, viruses, and bacteria within the airways can activate innate receptors such as Toll‐like receptor (TLR), RIG₁‐like helicase, and NOD‐like receptor, which in turn activate the nuclear factor κB (NFκB) family of transcription factors and as a result induce hundreds of proinflammatory and host response genes. ⁸² , ⁸³ The subsequent epithelial damage results in remodeling with airway thickening and a reduction in lung function, alterations in epithelial permeability and epithelial barrier with increased exposure to inflammatory molecules, allergens and an increased risk of infection that in turn can trigger an exacerbation. ²¹ , ⁸⁴ On the other hand, the microbial composition and high endotoxin load of dust from the homes of Amish children was associated with enhanced induction of innate immune pathways and protection from asthma development, compared with genetically similar Hutterite children. ⁸⁵ Several studies now support the concept that house dust samples from a traditional farming environment contain a diversity of microbes and microbial ligands that associate with increased nasal microbiome diversity of the same children who have lower risk of developing asthma. ⁶⁸ , ⁸⁶ , ⁸⁷ It is currently unknown whether the protective effect of the dust‐associated microbes might be due to inhalation of multiple bacteria species and further colonization of the airways, or whether inhaled bacterial components that stimulate innate immune responses or bacterial‐derived metabolites may also play a role.

5. IMMUNE MECHANISMS MEDIATING MICROBIAL PROTECTIVE EFFECTS WITHIN THE LUNG

Murine models have been extensively used to decipher the role of the microbiota in the pathogenesis of airway inflammation. Neonatal mice were more susceptible to develop house dust mite‐induced allergic airway inflammation and airway hyperactivity than mature mice, which was associated with a shift from Gammaproteobacteria and Firmicutes toward a Bacteroidetes dominated microbiota and the development of PDL‐1‐dependent Helios‐Treg cells. ⁸⁸ Germ‐free mice display significantly more pronounced type 2 inflammation when compared with conventionally colonized mice. Recolonization, especially early in life, can reverse many of these immunological defects. ⁸⁹ Similarly, antibiotic treatment of neonatal mice leads to impaired maturation of Tregs, enhanced TH2 responses, and promotes proinflammatory colonic iNKT cells. ⁹⁰ , ⁹¹ , ⁹² , ⁹³ , ⁹⁴ Conversely, specific bacterial strains, their components, or metabolites can successfully induce a variety of anti‐inflammatory responses in the gut and in the lung. For example, intranasal administration of an exopolysaccharide (EPS) from Bifidobacterium longum subsp. longum 35,624 was shown to protect against allergic airway disease in murine models, which was dependent on TLR2‐induced IL‐10 secretion. ⁹⁵ , ⁹⁶ Similarly, other microbial structural components such as lipopolysaccharides (LPS), polysaccharide A (PSA) and a Bifidobacterium‐derived cell wall extract can alter the allergic immune response and antiviral immune response in murine models. ⁹⁷ , ⁹⁸ , ⁹⁹ A recent study by Lai et al on a murine COPD model showed that a commensal gut bacterial‐associated LPS, derived from Parabacteroides goldsteinii, was anti‐inflammatory. ¹⁰⁰ The commensal‐derived LPS signaled via Toll‐like receptor 4 to reduce inflammatory signals, thereby enhancing epithelial barrier function and allowing for homeostatic metabolic processes to be restored.

In addition to bacterial structural components, multiple microbial metabolites influence respiratory inflammation. Products of amino acid metabolism, such as spermine, spermidine and tryptophan‐derived indoles, have been shown to reduce allergic inflammation in murine models. ¹⁰¹ , ¹⁰² Secondary bile acids (generated by microbial metabolism of primary bile acids) such as ursodeoxycholic acid have been shown to reduce eosinophilic airway inflammation via FXR signaling in dendritic cells. ¹⁰³ Similarly, chenodeoxycholic acid attenuates allergic airway inflammation by inhibiting TH2 cytokine secretion. ¹⁰⁴ One of the best‐studied immunoregulatory bacterial metabolites is the SCFAs butyrate, propionate, and acetate. ⁴² Fecal SCFA levels are low during the first 6 months of life, with acetate, propionate, and butyrate reaching stable levels in feces after 6, 8 or 10 months of age, respectively. ¹⁰⁵ Short‐chain fatty acids exert effects on the host immune system via binding to G protein‐coupled receptors (GPCRs) such as GPR41, GPR43, and GPR109A, via epigenetic modifications that inhibit histone deacetylase (HDAC) activity, and most recently butyrate has been described as an aryl hydrocarbon receptor (AhR) ligand. ¹⁰⁶ , ¹⁰⁷ Short‐chain fatty acids are potent immunomodulators that promote IL‐10 secretion by dendritic cells and lymphocytes, influence Treg numbers and effectiveness, influence bone marrow hematopoiesis, reduce effector T‐cell activity, improve epithelial barrier, support IgA secretion by B lymphocytes, inhibit mast cell degranulation and modulate ILC activation. ¹⁰⁸ , ¹⁰⁹ , ¹¹⁰ , ¹¹¹ , ¹¹² , ¹¹³ , ¹¹⁴ , ¹¹⁵ Fiber consumption or SCFA administration in experimental models protects against colitis, inflammatory arthritis, respiratory syncytial virus infection, allergic airway inflammation, and food allergy. ³⁰ , ¹¹⁶ , ¹¹⁷ Epigenetic mechanisms seem particularly important for the induction of T‐regulatory cells in the gut as butyrate enhances histone acetylation of the Foxp3 promoter, thereby driving Treg development. ¹¹⁸ , ¹¹⁹ Contrary to the beneficial effects of certain SCFAs, other bacterial‐derived metabolites such as 12,13‐ diHOME, an oxylipin, decrease the number of T regs via altering dendritic cell activation and reducing IL‐10 secretion. ¹²⁰

6. CONCLUSIONS AND FUTURE PERSPECTIVES

Microbial‐derived factors are integral components of the molecular circuitry that regulate immune and metabolic functions required for host fitness and survival. Recent advances in culture‐based methods and sequencing technologies have revealed previously unappreciated complex communities of bacteria, fungi, and viruses that inhabit all body surfaces, including the respiratory tract. Many studies have now shown differences in the composition of bacterial communities in children that go on to develop asthma, or in those who already have asthma. However, the functional consequences of changes in the abundances of specific microbial taxa and their relevance to asthma disease mechanisms remain largely unknown. Subtle structural, species‐ or strain‐specific differences, even for genetically closely related microbes, may lead to distinct immunological outcomes. This lack of fundamental knowledge on microbiome–host functional interactions severely limits our ability to understand how shifts in microbiome community structure and function may trigger the onset and progression of diseases such as asthma over a lifetime.

Notwithstanding these limitations, microbiota analysis and interventions may be of use in several areas:

1. Endotyping—currently, a range of host factors are measured to define asthma disease endotypes. However, a more detailed and accurate endotyping of patients with asthma may be assisted by including an analysis of the composition and metabolic activity of an individual's respiratory and gut microbiota.

2. Risk assessments—there is significant potential for analysis of the microbiota to assist in the early prediction of later life asthma risk, and to help to identify those children who may develop the most severe forms of asthma. However, these studies must carefully include demographic, clinical, exposure and lifestyle factors as possible confounders in their analysis to correctly interpret their findings.

3. Response to therapy—microbiota profiling should be included in future clinical studies examining novel asthma medications. Responsiveness to glucocorticosteroids may be microbiota‐dependent, while the optimal choice of biologic may be heavily influenced by microbial factors. In other fields, such as cancer immunotherapy using checkpoint inhibitors, the importance of the microbiota in therapy success is well‐established. ¹²¹

4. Microbial therapies—specific microbes, and their metabolites, are being examined for their preventive and therapeutic effects, but given the explosion in knowledge regarding disease endotypes, it is possible that specific microbes will need to be carefully selected to mechanistically fit with specific disease endotypes and it is likely that one intervention will not work equally well for everyone with different types of asthma. In addition, the efficacy of existing therapeutics may be significantly improved by microbiota‐targeted interventions.

5. Dietary interactions—the metabolism of certain dietary factors (e.g., fibers) by microbes is required for the full immunological benefits of that dietary component to be realized. Studies examining nutritional interventions should include an analysis of the direct and indirect effects of the microbiome on their study endpoints. While there are already many unique challenges and difficulties in performing nutrition studies to provide evidence‐based recommendations, the inclusion of microbiota assessments may help identify those who require the intervention and those most likely to respond. In addition, knowledge of how specific dietary interventions impact the microbiota to generate immunoregulatory metabolites can be leveraged to develop more effective diets and molecules that improve human immune health.

In conclusion, it remains unclear whether and, if so, to what extent patterns of microbial dysbiosis actually drives rather than merely reflects associated patterns of immune reactivity within the airways. It is likely that differences in functional or metabolic outputs are probably more important immunologically, than taxonomic diversity alone. Of particular importance to understand is the potential relationship between timing and dietary‐microbiome effects on the immune system, especially in early life where there is a critical window of opportunity to influence the development of immune regulatory networks. Future research on diet–microbe–host interactions should be strongly encouraged as these discoveries will provide fundamental knowledge on the molecular communication networks that underpin life as a multicellular metacommunity and will progress our appreciation for the principle of biological diversity as a driver of physiological resilience and immune tolerance.

7.

PEER REVIEW

The peer review history for this article is available at https://publons.com/publon/10.1111/pai.13892.

Lunjani N, Walsh L, Venter C, et al. Environmental influences on childhood asthma—The effect of diet and microbiome on asthma. Pediatr Allergy Immunol. 2022;33:e13892. doi: 10.1111/pai.13892