Reviews and feature articleThe intersect of genetics, environment, and microbiota in asthma—perspectives and challenges
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
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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.