Reviews and feature article
The intersect of genetics, environment, and microbiota in asthma—perspectives and challenges

https://doi.org/10.1016/j.jaci.2020.08.026Get rights and content

In asthma, a significant portion of the interaction between genetics and environment occurs through microbiota. The proposed mechanisms behind this interaction are complex and at times contradictory. This review covers recent developments in our understanding of this interaction: the “microbial hypothesis” and the “farm effect”; the role of endotoxin and genetic variation in pattern recognition systems; the interaction with allergen exposure; the additional involvement of host gut and airway microbiota; the role of viral respiratory infections in interaction with the 17q21 and CDHR3 genetic loci; and the importance of in utero and early-life timing of exposures. We propose a unified framework for understanding how all these phenomena interact to drive asthma pathogenesis. Finally, we point out some future challenges for continued research in this field, in particular the need for multiomic integration, as well as the potential utility of asthma endotyping.

Section snippets

Genetics and environment in asthma

The genome is a strong contributor to asthma risk, with heritability estimates ranging from 35% to 70%.2 Genome-wide association studies (GWASs) have identified genetic loci associated with asthma and allergy: these typically include genes involved in immune function, but particularly implicate type 2 (T2) immune responses (eg, TSLP and IL13), antigen presentation (eg, HLA region), signaling molecules and their receptors for both innate and adaptive immunity (eg, IL2/IL21, IL1RL1/IL18R1, IL6R,

The role of environmental microbiota—The microbial hypothesis and the “farm effect”

The “microbial hypothesis,” an extension of the “hygiene hypothesis,” proposes that microbial exposures, particularly perinatal or early-life, influence physiological development, and that the historical rise in allergy may have been driven in part by changes to living environments and habits that drastically alter both environmental and host microbiota.7,20,21 Supporting this hypothesis is the observation of the “farm effect” in multiple populations.22, 23, 24, 25, 26 In many instances,

The specific effects of host microbiota

Dysbiosis of host microbiota typically comprises reduced microbial diversity and domination by microbial species or communities.91,92 However, there is debate as to whether the dysbiosis observed with asthma and allergic disease is primary or secondary to disease development.4,19 Therefore, interpretation of host microbial associations requires consideration of temporality and underlying biology. Ultimately, the host microbiota represents an (oftentimes transient and unstable) homeostasis

The role of viral respiratory infections in asthma

Although the genetic evidence linking bacterial microbiota with asthma remains scant, there is ample evidence for viral pathogens and asthma. Viral respiratory infections are common causes of asthma exacerbations, and have also been suspected to play a role in pathogenesis (Fig 1, C). The 2 most common viral respiratory pathogens in young children are rhinovirus (RV) and respiratory syncytial virus. Infection with these pathogens in early life has been associated with asthma outcomes later in

Synthesis

Fig 1 shows an overview of putative mechanisms for interactions between genetics, environment, and microbiota in asthma pathogenesis. Box 1 summarizes the key points. Exposure to environmental microbiota and endotoxin, through either maternal or early-life exposure, results in profound changes to the immune development of the young infant, including (1) altered expression of pattern recognition receptors (TLRs), (2) altered T-cell function, (3) altered antiviral responses, and (4) altered

Future directions and challenges

There remain many challenges in unraveling the genetic and environmental interactions that drive asthma. As other commentaries have indicated, there still remains much to understand about the key players in the process,19,21,70 and therefore it is problematic to make any substantial inferences about the physiology behind the microbial effect, let alone how we can best harness this knowledge to help patients.

Open questions include:

  • 1.

    the role of specific microbes and rare taxa (“the rare

Concluding statements

There are still many unknowns about the role of genetics and microbiota in asthma pathogenesis. Although we have made significant headway in understanding the key “players”—the environment and host microbiota, and how they interact with key asthma risk genes—there remains much to discover about the precise roles of each of these actors: the “lines” they read and the “stage directions” they follow as they interact with each other on the stage that is asthmatic disease. Many of our research

References (188)

  • S. Illi et al.

    Protection from childhood asthma and allergy in Alpine farm environments—the GABRIEL Advanced Studies

    J Allergy Clin Immunol

    (2012)
  • M. Holbreich et al.

    Amish children living in northern Indiana have a very low prevalence of allergic sensitization

    J Allergy Clin Immunol

    (2012)
  • S. Brix et al.

    Metagenomic heterogeneity explains dual immune effects of endotoxins

    J Allergy Clin Immunol

    (2015)
  • M.L. DeMarco et al.

    From agonist to antagonist: structure and dynamics of innate immune glycoprotein MD-2 upon recognition of variably acylated bacterial endotoxins

    Mol Immunol

    (2011)
  • N. Fyhrquist et al.

    Acinetobacter species in the skin microbiota protect against allergic sensitization and inflammation

    J Allergy Clin Immunol

    (2014)
  • J. Debarry et al.

    Acinetobacter lwoffii and Lactococcus lactis strains isolated from farm cowsheds possess strong allergy-protective properties

    J Allergy Clin Immunol

    (2007)
  • K.E. Fujimura et al.

    Microbiota in allergy and asthma and the emerging relationship with the gut microbiome

    Cell Host Microbe

    (2015)
  • R.T. van Strien et al.

    Microbial exposure of rural school children, as assessed by levels of N-acetyl-muramic acid in mattress dust, and its association with respiratory health

    J Allergy Clin Immunol

    (2004)
  • M.J. Ege et al.

    Not all farming environments protect against the development of asthma and wheeze in children

    J Allergy Clin Immunol

    (2007)
  • Z. Zhang et al.

    Beta-glucan exacerbates allergic asthma independent of fungal sensitization and promotes steroid-resistant TH2/TH17 responses

    J Allergy Clin Immunol

    (2017)
  • M.H. Grayson et al.

    Advances in asthma in 2017: mechanisms, biologics, and genetics

    J Allergy Clin Immunol

    (2018)
  • G. Loss et al.

    Prenatal and early-life exposures alter expression of innate immunity genes: the PASTURE cohort study

    J Allergy Clin Immunol

    (2012)
  • V.E. Rullo et al.

    Daycare centers and schools as sources of exposure to mites, cockroach, and endotoxin in the city of Sao Paulo, Brazil

    J Allergy Clin Immunol

    (2002)
  • W. Eder et al.

    Opposite effects of CD 14/-260 on serum IgE levels in children raised in different environments

    J Allergy Clin Immunol

    (2005)
  • A. Zambelli-Weiner et al.

    Evaluation of the CD14/-260 polymorphism and house dust endotoxin exposure in the Barbados Asthma Genetics Study

    J Allergy Clin Immunol

    (2005)
  • W. Eder et al.

    Toll-like receptor 2 as a major gene for asthma in children of European farmers

    J Allergy Clin Immunol

    (2004)
  • J. Krusche et al.

    TNF-alpha-induced protein 3 is a key player in childhood asthma development and environment-mediated protection

    J Allergy Clin Immunol

    (2019)
  • G. Loss et al.

    The protective effect of farm milk consumption on childhood asthma and atopy: the GABRIELA study

    J Allergy Clin Immunol

    (2011)
  • U. Kramer et al.

    Age of entry to day nursery and allergy in later childhood

    Lancet

    (1999)
  • E. von Mutius et al.

    Living on a farm: impact on asthma induction and clinical course

    Immunol Allergy Clin North Am

    (2008)
  • B. Schaub et al.

    Maternal farm exposure modulates neonatal immune mechanisms through regulatory T cells

    J Allergy Clin Immunol

    (2009)
  • P.I. Pfefferle et al.

    Cord blood allergen-specific IgE is associated with reduced IFN-gamma production by cord blood cells: the Protection against Allergy-Study in Rural Environments (PASTURE) study

    J Allergy Clin Immunol

    (2008)
  • M.G. Netea et al.

    Trained immunity: a memory for innate host defense

    Cell Host Microbe

    (2011)
  • G.T. O’Connor et al.

    Early-life home environment and risk of asthma among inner-city children

    J Allergy Clin Immunol

    (2018)
  • J.E. Gern et al.

    Patterns of immune development in urban preschoolers with recurrent wheeze and/or atopy

    J Allergy Clin Immunol

    (2017)
  • J. Neu et al.

    Cesarean versus vaginal delivery: long-term infant outcomes and the hygiene hypothesis

    Clin Perinatol

    (2011)
  • S.M. Teo et al.

    Airway microbiota dynamics uncover a critical window for interplay of pathogenic bacteria and allergy in childhood respiratory disease

    Cell Host Microbe

    (2018)
  • K.A. Capone et al.

    Diversity of the human skin microbiome early in life

    J Investig Dermatol

    (2011)
  • M. Depner et al.

    Bacterial microbiota of the upper respiratory tract and childhood asthma

    J Allergy Clin Immunol

    (2017)
  • J. Thorsen et al.

    Evaluating the effects of farm exposure on infant gut microbiome

    J Allergy Clin Immunol

    (2019)
  • A.J. Sandford et al.

    The genetics of asthma: the important questions

    Am J Respir Crit Care Med

    (2000)
  • C. Ober

    Asthma genetics in the post-GWAS era

    Ann Am Thoracic Soc

    (2016)
  • L.A. Smit et al.

    Endotoxin exposure, CD14 and wheeze among farmers: a gene--environment interaction

    Occup Environ Med

    (2011)
  • F. Demenais et al.

    Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks

    Nat Genet

    (2018)
  • K.W. Kim et al.

    Lessons learned from GWAS of asthma

    Allergy Asthma Immunol Res

    (2019)
  • K. Bonnelykke et al.

    Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization

    Nat Genet

    (2013)
  • K. Bonnelykke et al.

    A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations

    Nat Genet

    (2014)
  • S. Turner

    Gene-environment interactions—what can these tell us about the relationship between asthma and allergy?

    Front Pediatr

    (2017)
  • E. Morales et al.

    Genetics and gene-environment interactions in childhood and adult onset asthma

    Front Pediatr

    (2019)
  • S. Illi et al.

    Early childhood infectious diseases and the development of asthma up to school age: a birth cohort study

    BMJ

    (2001)
  • Cited by (0)

    H.H.F.T. wishes to acknowledge the Australian National Health and Medical Research Council (NHMRC) (ID: 1114753) for providing partial funding for research. M.I. is funded by the Munz Chair of Cardiovascular Prediction and Prevention.

    Terms in boldface and italics are detailed in the glossary on page 782.

    View full text