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Review
Impact of the environment on gut microbiome and allergy
  1. Christina E West
  1. Clinical Sciences, Umeå University, Umea, Sweden
  1. Correspondence to Professor Christina E West; christina.west{at}umu.se

Abstract

Rapid urbanisation and global biodiversity loss are changing human microbial ecology, which is accelerated by the progressive loss of protective factors for example, contact with natural environments and animals, and less consumption of traditional foods. Early life represents a critical window both for optimal colonisation and immune system development. The frequency of caesarean section (CS) delivery is high and increasing in many parts of the world, and there is strong evidence that CS delivery has a marked influence on early colonisation, with depletion of strains of commensal bacteria. Colonisation of human ecological niches, particularly the gastrointestinal tract, parallels normal local and systemic immune development. CS delivery has been associated with increased risk of allergic diseases and there is emerging evidence that this is mediated by alterations of the microbiome. Small proof-of-concept studies have demonstrated that transfer of maternal vaginal microbes directly after elective CS delivery partially restores the offspring microbiome but transfer of maternal faecal microbes is needed for restoration of the offspring gut microbiome. Randomised clinical trials (RCTs) using microbiome seeding after CS delivery are underway and are anticipated to unravel if this procedure will impact microbial, immunological and metabolic programming, and decrease allergy risk. RCTs using prebiotics and probiotics for primary prevention of allergic diseases (primarily eczema) have been conducted, but large heterogeneity between studies have hampered meta-analysis and the development of specific practice guidelines. In the first RCT to test the biodiversity hypothesis, exposure to playground sand with added microbially diverse soil, led to shifts in the skin and gut bacterial communities and increases in immunoregulatory biomarkers compared with exposure to microbially poor sand (placebo). Collectively, appropriate health-supporting microbial exposures by optimised nutrition and a microbially diverse environment in early life may curb the epidemic rise in allergic diseases, however, considerably more research is needed before this can be translated into specific practice guidelines.

  • preventive counselling
  • microbiome
  • food allergies

Data availability statement

No data are available.

https://creativecommons.org/licenses/by/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

https://doi.org/10.1136/bmjnph-2023-000680

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    Introduction

    The epidemic rise in eczema, food allergy, allergic rhinitis and asthma over the past century has occurred simultaneously with progressive urbanisation, less contact with our natural environments, increased hygiene, smaller family sizes, dietary change and excessive antibiotic use. As one of the leading candidates in the allergy epidemic, many theories have underscored the importance of microbials for normal immune development.1 Decades ago, David Strachan coined the hygiene hypothesis by demonstrating that the number of siblings and their birth order could predict the risk of hay fever2 and theorised that the number of older siblings served as a proxy for accumulating microbial exposures in childhood. This hypothesis was later followed by the old friends,3 gut microbial deprivation4 and biodiversity hypotheses5 proposing that the observed changes in early colonisation patterns over the last decades in affluent countries have resulted in failure to induce and maintain tolerance, with increased risk of developing inflammatory non-communicable diseases (NCDs) including allergic diseases and asthma.1 6 The biodiversity hypothesis proposes that contact with natural environments boosts the human microbiome, promotes efficient immune function and regulation and protects against the onset of inflammatory NCDs. It further emphasises that we are protected by two embedded layers of biodiversity, that is, the microbiota of the outer layer (including soil, natural waters, plants and animals) and the inner layer (including the mucosa of the gastrointestinal tract, lung, ears, nose, throat and skin).5 Interventions to improve the microbiota of the outer layers could thus favourably impact the inner layers as well.

    In this narrative review, the interactions between environmental exposures and the human microbiome, with a focus on the gut microbiome, are discussed in the context of development of allergic diseases in childhood (figure 1). Finally, allergy preventive interventions to restore the human microbiome are discussed.

    Figure 1
    Figure 1

    Early life represents a critical window for optimal colonisation, immune system development and allergy risk. This process is dependent on environmental exposures, for example, geography, delivery mode, family (siblings), upbringing in an urban or farm environment and antibiotics. Protective factors include breast feeding and optimised nutrition (complementary foods, fibre) which can modulate gut microbial ecology throughout infancy and into early toddlerhood. Biotics, that is, specific prebiotics, probiotics, synbiotics have been evaluated in clinical trials but more research using harmonised protocols is needed before specific practice guidelines can be given. Adding microbiological diversity (microbiome rewilding) to the everyday living environment may support immunoregulation and future studies could include interventions to impact the environments of day care and preschools. Finally, clinical trials investigating microbiome seeding, that is, vaginal and/or faecal microbiota transfer from the mother to her neonate after elective caesarean section delivery for primary prevention of allergy are underway.

    Environmental exposures influence microbiome establishment in early life

    In the first years of life, the infant gut microbiota and its corresponding genes (the microbiome) change from a low diverse microbiota at birth to a dynamic ecosystem.7 This process is shaped by genetics, epigenetics and environmental factors including country of origin, delivery mode, antibiotics, breast feeding and introduction of complementary foods.1 At birth and during infancy, the microbiome is more sensitive to environmental exposures. Despite alarmingly high rates of caesarean section (CS) delivery in many parts of the world, the majority of humans are delivered vaginally and will be exposed to maternal vaginal and perianal microbes.8 In contrast, CS delivered infants will acquire bacteria from the hospital environment including opportunistic bacteria such as Enterococcus and Klebsiella.9 CS-delivered infants also lack strains of commensal bacteria, that are commonly found in the gut of healthy individuals. The gut microbiota of vaginally delivered (VD) infants is enriched in Bifidobacterium, Escherichia coli and Bacteroides/Parabacteroides, and even though the gut microbiota of CS-delivered infants will gradually start to resemble that of VD infants over the first months of life, the immunomodulatory genus Bacteroides 9 10 remains less abundant. Observational studies have reported CS delivery to be associated with increased risk of allergic diseases and asthma,8 and the infant faecal microbiome has been associated with future asthma risk. In the Vitamin D Antenatal Asthma Reduction Trial, Lee-Sarwar et al investigated the role of environmental exposures (including delivery mode), the maternal microbiome and how the microbiome influences asthma phenotypes in childhood.11 They found that even though delivery mode was not directly associated with asthma, there was evidence for a pathway whereby CS delivery reduced faecal Bacteroides and microbial sphingolipids, increasing susceptibility to early-onset asthma.11

    As discussed below, colonisation of the gut is critical for the development of the immune system and disruptions in this process in early life have been associated with the development of allergic diseases.1 6 In recent longitudinal studies that have followed infants until preschool/school age, there have been both temporal and long-term variation in the differential abundance of specific bacterial taxa in the intestine of children with allergic diseases.10 12 13 In some of these studies, there was consistent under-representation of the immunomodulatory gut symbiont Bacteroides in allergic children,12 13 whereas genera such as Faecalibacterium were associated with reduced risk of atopy10 and a tolerogenic immune response12 suggesting an opportunity to expand such taxa for treatment and prevention of allergic diseases.

    A healthy commensal gut microbiota is critical for the protection of the host against infections, either by direct elimination or by indirect suppression, inside or outside the gut.14 The mucosal epithelium is the main entry route for many pathogens, and during infection in the mucosa, microorganisms may interact with the commensal microbiota. Depending on the host’s microbial profile, it may serve as an effective defence against infections, but may also create an environment which is beneficial for potential pathogens. Even though the respiratory and gastrointestinal tracts are separate, they share a mucosal immune system termed the ‘gut–lung axis’. Within the ‘gut–lung-axis’ there is ongoing cross-talk between the gut and lung in a reciprocal manner, including immune and microbial interactions due to systemic circulation of migrating immune cells and bacterial ligands and metabolites.15 There is also emerging evidence that a similar reciprocal relationship exists between the gut and skin.16 An exposure that has a marked effect on gut microbial composition and functions is antibiotic treatment. Antibiotics is the most prescribed drug to infants and children in the Western world.17 Antibiotic treatment influences gut microbial composition and even short courses may cause long-term dysbiosis.18 In infancy, antibiotics interfere with gut microbiota maturation with possible negative consequences for immune system ontogeny.12 19 In experimental mouse models, vancomycin treatment in the prenatal and postnatal period impacted gut microbiota composition, reduced regulatory T cell populations and increased immunoglobulin E (IgE) levels and asthma risk.20 Shared microbial strains have been reported in the gut of mothers and their infants due to vertical transmission, and maternal gut strains are ecologically better adapted to the infant gut than bacterial strains from other sources.21 Antibiotics given to the pregnant women may thus influence microbial transmission from mother to infant during delivery.

    The associations between both prenatal and postnatal antibiotic exposures and allergic diseases have been investigated in several studies. Systematic reviews have shown strong relationships between prenatal antibiotic exposure and asthma in the offspring.22 Birth cohort studies have reported postnatal antibiotic exposure to increase the risk of allergic diseases23–25 but the results are more ambiguous, and in some studies the increased risk was partially confounded by infections and familial factors.26 The mechanisms behind the associations between perinatal antibiotic exposure and allergic diseases have not yet been clearly demonstrated, but the effect might be mediated by a disturbed microbiota. Interestingly, in a recent study from the Canadian CHILD cohort study, the gut microbiota at 1 year of age was a significant mediator between antibiotic exposure in the first year of life and asthma diagnosis at 5 years of age.27 These results propose that cautious antibiotic prescriptions during infancy may preserve the gut microbiota and reduce the incidence of asthma and possibly other allergic manifestations.

    Interactions between the environment, the human microbiome and the immune system

    There is a critical role of the microbiome in normal immune ontogeny, with mutual benefit for the commensal symbiotic microbiota and their host.1 Early colonisation drives optimal development of both the innate and adaptive immune system and in experimental mouse models, the cellular immune networks of the gut-associated lymphoid tissues fail to mature if colonisation is held up beyond a critical window, resulting in persistent immune dysregulation and associated diseases.28 It is debated if such a critical window for microbial and immune programming also exists in humans. Nevertheless, microbial colonisation has been proposed as a major driving factor for the normal age-related development of both Th1, Th17 and T regulatory pathways in early childhood, that seem necessary to halter early predisposition for Th2 allergic responses.1

    Experimental mouse models have also been used to study how the environmental microbiome populate the host microbiome and influence immune responses using cohousing as a proxy for the environmental microbiome.6 One study found that the microbial composition and diversity of the caecum, lung and skin clustered strongly with factors, for example, shipment, laboratory of origin and the cage where the mice were housed.29 Notably, inflammatory cytokines were reported to correlate strongly with the lung microbiome. Collectively, experimental mouse models highlight that the environmental microbiome will impact both the host microbiome and baseline immunological state. As recently reviewed in more detail,6 there is also evidence from human studies that both cohousing and farm exposure (used as a proxy for the environmental microbiome) will lead to colonisation of the human microbiome by environmental microbes. Finnish children growing up in non-farm homes had reduced asthma risk if there was high similarity of their home bacterial microbiota composition compared with that of farm homes.30 In that study, a low abundance of Streptococcaceae in relation to outdoor-associated bacterial taxa was protective and associated with lower proinflammatory cytokine responses against bacterial cell wall components ex vivo. The findings were then reproduced in a cohort from rural Germany, as children living in German non-farm homes with an indoor microbiota more similar to that of Finnish farm homes had decreased asthma risk.30 There is also emerging evidence that the protective farm effect is mediated by gut microbiota maturation in early life. In a recent study from the PASTURE cohort, the estimated microbiome age (EMA) in 12-month-old infants was associated with previous farm exposure and reduced risk of asthma; EMA mediated the protective farm effect by 19%.31

    There is growing interest in the impact of air pollution on the lung and gut microbiome as a possible mechanism by which air pollutant exposure increases the risk for allergy and asthma. Ambient air pollution is reported to be associated with both the adult and infant gut microbiome. In infants, there were positive associations between proxy indicators of air pollution and bacterial taxa previously reported to be associated with systemic inflammation, for example, the genera Dialister and Dorea.32 Smoking also impacts the microbial ecologies in humans, and their built environments. Known as thirdhand smoke, pollutants from tobacco smoke are found on surfaces and in dust of indoor environments even after the cessation of smoking. Compared with infants from smoking households, preterm infants from non-smoking homes and/or with lower furniture surface nicotine at the neonatal intensive care unit had greater faecal microbial diversity.33 Also, lower relative abundance of Bifidobacterium was associated with greater furniture nicotine, urine cotinine and household smoking. Taken together, these data provide a foundation for further investigations of farm exposure, air pollution and tobacco-related exposures on healthy infant gut-microbiome development and the risk of developing allergies and asthma.

    Interventions to modulate the human microbiome for allergy prevention

    Human milk and complementary feeding

    Breast feeding is the gold standard in infant nutrition and human milk is abundant in a large variety of complex non-digestible human milk oligosaccharides (HMOs).34 Some of these HMOs function as decoy receptors to prevent the attachment of pathogens to the intestinal mucosa and since HMOs are non-digestible, they can pass through the small intestine and enter the colon where they promote colonisation with specific bifidobacterial strains and Bacteroides.1 34 In addition, a more direct immune effect seems to be mediated by the production of metabolites, for example, short-chain fatty acids (SCFAs) that have both nutritive and anti-inflammatory effects.1 35 When complementary feeding starts and dietary fibre and protein from various sources are introduced, the gut microbiota will undergo a shift from the milk-adapted profile to a more diverse bacterial community. This will result in increased capacity to digest complex carbohydrates (fibre) and proteins, as well as increased production of SCFAs and branched-chain fatty acids.7 Taken together, optimised nutrition in early life can modulate gut microbial ecology throughout infancy and into early toddlerhood.

    Prebiotics, probiotics, synbiotics and postbiotics

    A common strategy36 to modulate the microbiota of the gastrointestinal tract has been to use prebiotics (non-digestible, fermentable oligosaccharides),35 probiotics, predominantly combinations or single strains of lactobacilli and bifidobacteria37 and more recently synbiotics, that is, a combination of prebiotics and probiotics38 (table 1). Meta-analyses demonstrate a preventive effect of probiotics on eczema but not any other allergic diseases.36 Since most conducted probiotic prevention studies used eczema as a primary outcome, they were not adequately powered to look at less prevalent outcomes, for example, asthma and food allergy. Conducted prebiotic and synbiotic studies for allergy prevention are fewer.

    View this table:
    Table 1

    Definitions of biotics

    Postbiotics is a rather new term in the biotics field (table 1).39 Similarly to prebiotics, probiotics and synbiotics, all postbiotics are not the same and their mechanisms of action need to be investigated and characterised. Studies are still scarce but a recent meta-analysis of 11 randomised clinical trials (RCTs) of infant formulas containing postbiotics, found that they are safe and well tolerated and support adequate growth.40 To date, demonstrated clinical benefits remain limited and carefully designed studies should consider the type of disease and specific postbiotic, when choosing a postbiotic in the prevention or treatment of childhood diseases.41 This includes allergic diseases and asthma since studies are lacking.

    Collectively, despite the large body of literature, meta-analysis of probiotic prevention studies has been hampered by large heterogeneity in almost all aspects of the conducted studies (eg, probiotic strain, dose, vehicle, timing, duration), and lack of harmonisation across studies. Prebiotic and synbiotic allergy prevention studies are still few, and postbiotic allergy prevention studies are lacking. To date, many international expert organisations do not advocate using probiotics or prebiotics for allergy prevention.36 The Grading of Recommendations, Assessment, Development and Evaluations (GRADE)-based guidelines from the World Allergy Organization (WAO) guideline panel recommend probiotics for the primary prevention of eczema in pregnancy and during breast feeding when there is high risk of allergic disease (based on positive heredity) and in high-risk infants.42 WAO also recommends prebiotics for primary prevention of allergic disease in non-exclusively breastfed infants. In line with other expert bodies, the WAO guideline panel recognised that the recommendations on both probiotics and prebiotics are based on low-quality evidence and that they are conditional, which refers to the assumption that most patients may want to follow the proposed recommendation, whereas others may not.43 To date, specific practice guidelines on the most effective prebiotics or probiotics, dosages or optimal duration of treatment cannot be given. Still, if the families choose to use prebiotics or probiotics, they are not expected to cause harm; however, healthcare professionals need to inform families that the benefits are limited and do not include all allergic outcomes.36 Synbiotics appear to have more global effects on the composition and functions of gut microbiota than prebiotics alone, although comparative studies are few.44 At this point, conducted synbiotic allergy prevention studies are still scarce and carefully conducted RCTs are needed before firm conclusions can be drawn.36

    Microbiome seeding to restore the microbiome in CS-delivered infants

    It is theorised that absence of neonatal microbiota in CS-delivered infants after birth may result not only in immediate immunological, physiological and metabolic consequences but also possible negative health effects in the long term. The concept of microbiome seeding, that is, vaginal microbiota transfer and more recently faecal microbiota transfer from the mother to her neonate immediately after elective CS delivery, has already attracted a huge interest by the public and media. In the first proof of concept study Dominguez-Bello et al 45 reported that vaginal seeding partially restored the oral and skin microbiota of neonates delivered by elective CS, however the gut microbiota was not restored. To improve the restoration, it appears critical to transfer maternal faecal microbes as well, in an effort to mimic the vertical transmission of microbes during vaginal delivery. Importantly, studies have demonstrated that maternal faecal microbes are more persistent in the infant gut and better ecologically adapted than microbes from other sources.21 Also, two-thirds of the cellular component of the immune system is situated in the gut and the maturation of the immune system is dependent on stimulation by the gut microbiota.1 A logical step was thus to investigate if maternal faecal microbes could be transferred to the CS-delivered neonate. In contrast to vaginal seeding, Korpela et al 46 demonstrated that supplementation of breast milk with a maternal stool sample collected before birth was able to restore the gut microbiota of the neonate. Although these studies have provided evidence that both vaginal and faecal microbes can be successfully transferred to the neonate following elective CS delivery, they included very few mother–infant pairs and the follow-up was short.45 46 In a very recently published RCT, which included 120 neonates delivered by elective CS, vaginal seeding did not significantly influence offspring growth or IgE-sensitisation in the first 2 years of life.47 The secondary outcomes of this RCT included gut microbiota and symptoms and diagnoses of allergic diseases, with no differences between the active group and the control group, that received standard care. Large RCTs investigating the effects of transfer of vaginal or faecal microbes, and their combination, on the establishment of the microbiota, immune and metabolic programming and potential health benefits (growth, inflammatory diseases including allergic diseases) are underway. Although the conducted studies to date45–47 have not reported any harm, more safety data are also warranted. To date, the topic remains controversial due to the paucity of data supporting the efficacy, the lack of long-term and safety data and demonstrated health benefits in the offspring.

    Microbiome rewilding

    The Microbiome Rewilding Hypothesis proposes that restoring biodiverse habitats in urban green spaces can rewild the environmental microbiome to a state that helps prevent the onset of NCDs in the human.48 The role of the skin microbiome in allergic diseases is outside the scope of this review, and reviews on this topic are available elsewhere49; however, observational studies have shown that exposure to urban green spaces can increase the diversity of the skin microbiota50 as well as the gut microbiota.51 Despite this, the concept of ‘rewilding’ the microbiome has been heavily debated, and it was not until very recently that the first double-blinded RCT to test the biodiversity hypothesis was conducted. In that RCT,52 children aged 3–5 years were randomised to exposure to playground sand with added microbially diverse soil, or microbially poor sand (placebo). The children played twice daily in the sandbox for 2 weeks. Sand, gut and skin bacterial and blood samples were collected before the intervention started and after 2 weeks. Both bacterial richness and diversity were higher in the intervention than placebo sand and the skin bacterial community shifted only in the intervention group to resemble the bacterial community in the enriched sand. Immunoregulatory biomarkers were also increased in the treatment group. Gut microbial changes were less evident. The authors concluded that the environmental microbiome may contribute to child health, and that adding microbiological diversity to the everyday living environment may support immunoregulation. To boost appropriate health-supporting microbial exposures in early childhood, future studies may include interventions to impact the environments of day care and preschools.

    Summary and conclusions

    Inflammatory NCDs, including allergic diseases and asthma, are an emerging health threat in urbanised societies and there is an unmet need for improved prevention strategies. There is evidence from observational studies that global biodiversity loss and rapid urbanisation are changing human microbial ecology, but conclusive evidence from human intervention trials is still scarce. To address current knowledge gaps and advance this field, there is still need for collaborative interdisciplinary multicentre studies using harmonised protocols and outcomes.36 Eventually, this could lead to specific practice guidelines on biotics for allergy and asthma prevention and possibly other medical conditions. Despite huge media attention and interest from the public, it also remains to be determined if microbiome seeding to CS-delivered infants is safe, feasible and if it will translate into clinically relevant benefits for the child. At this stage, expert bodies do not endorse this practice53 and underscore the need for clinical research. Several RCTs on microbiome seeding are underway and are anticipated to address these questions. The concept of microbiome rewilding is still in its infancy, but interventions to restore both the environmental and human microbiome could be one way of curbing the epidemic rise of inflammatory NCDs. In the meantime, interim advice to healthcare practitioners and the public about the importance of the early colonisation including the role of optimised nutrition, breast feeding, introduction of complementary foods and exposure to green environments (figure 1) is required. There are also many reasons to advocate that vaginal delivery is usually the safest choice when there are no serious problems during pregnancy and labour,8 and that prudent use of antibiotics should remain a priority.

    Data availability statement

    No data are available.

    Ethics statements

    Patient consent for publication

    Ethics approval

    Not applicable.

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    Footnotes

    • Contributors CW performed the literature search, wrote and revised the manuscript.

    • Funding This study was funded by Vetenskapsrådet (2018-02642, 2019-00439).

    • Competing interests CEW has received research funding, which was paid directly to the institution, from Thermo Fisher Scientific/Phadia and Arla Foods. CEW has received speaker honorarium from Aimmune Therapeutics, a Nestlé Health Science company, receives royalties from UptoDate (prebiotics/probiotics), and serves as Consultant for Arla Foods Ingredients.

    • Provenance and peer review Not commissioned; externally peer reviewed.