Allergy as a Disease of Dysbiosis: Is It Time to Shift the Treatment Paradigm?

OPINION published: 07 March 2019 doi: 10.3389/fcimb.2019.00050 Allergy as a Disease of Dysbiosis: Is It Time to Shift the Treatment Paradigm? Ian A. Myles* Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States Keywords: allergy, dysbiosis, microbiome, eczema, atopic dermatitis Edited by: D. Scott Merrell, Uniformed Services University, United States Reviewed by: Kari Christine Nadeau, Stanford University, United States *Correspondence: Ian A. Myles Specialty section: This article was submitted to Microbiome in Health and Disease, a section of the journal Frontiers in Cellular and Infection Microbiology Received: 23 December 2018 Accepted: 18 February 2019 Published: 07 March 2019 Citation: Myles IA (2019) Allergy as a Disease of Dysbiosis: Is It Time to Shift the Treatment Paradigm? Front. Cell. Infect. Microbiol. 9:50. doi: 10.3389/fcimb.2019.00050 Attempts to strike a truce in the “nature-vs. -nurture” debate often end up framing most human disease as “a complex interaction of genes and environment.” This truce fails to distinguish the driver of disease from the risk modifier. Health care providers universally identify tobacco smoke is the root cause (i.e., “driver”) of chronic obstructive pulmonary disease (COPD) despite the known presence of associated monogenetic disorders and risk alleles (“risk modifiers”) (Hardin and Silverman, 2014). However, manuscripts reviewing ailments with less overt environmental causes, such as those covering atopic disease, default to prioritizing this dynamic in the opposite orientation. Allergic disease is frequently referred to as a “complex genetic disease” with “interacting environmental factors” (Weidinger et al., 2018), rather than a complex environmental disease with interacting genetic modifiers. To some extent, a debate about defining disease by gene-environment vs. environment-gene interactions is one of semantics. However, just as language can shape how we define a problem, so too can it influence our perception of its solution. This manuscript will center its discussion on atopic dermatitis (AD), but the commentary is applicable to allergy writ large, as well as diseases ranging from oncology to psychiatry. Initial twin concordance studies overestimated heritability for AD to be around 75% (Weidinger et al., 2018), failing to recognize that identical twins share their environment more intensely than fraternal twins (Mayhew and Meyre, 2017). Early efforts using genome wide association studies (GWAS) to search for what these initial estimates of heritability suggested would be the causal gene were bolstered by the discovery of monogenic disorders marked by eczematous phenotypes (Lyons et al., 2015). However, many GWAS fail to find a single association; those that do, report allelic frequencies below 10% in their disease population (Bin and Leung, 2016). Of the variants implicated in AD by these individual GWAS trials, only association with FILAGGRIN could be confirmed by meta-analysis aggregation (Paternoster et al., 2011). While the resultant drop in sequence-specific heritability predictions to “<20%” (Weidinger et al., 2018) does not negate the importance of identified genetic pathways [particularly interleukin (IL-) 4 and IL-13], it does suggest that the majority of patients with AD manifest disease despite genomes that are indistinguishable from healthy controls. Often, the “missing heritability” is met with calls for better human-genomic assays, such as higher computational power combined with deeper sequencing or evaluation of epigenetic modifications. While greater technology may reveal currently undetectable interactions, it seems as if decades of advances in genomic assessment tools have only changed the working hypothesis from one stating improved genomics will uncover the causal gene, to one stating that improved genomics will uncover the causal gene(s). This hypothesis predominates despite the burden of atopy increasing at a rate more suggestive of being driven by environmental factors (Silverberg, 2017). In contrast with GWAS results, most microbiome publications have deployed tools of relatively low resolution to provide phyla-level differences in 16 S bacterial ribosomal RNA (Grice and Segre, 2012). For context, assays that could only provide phyla-level analysis Frontiers in Cellular and Infection Microbiology | www.frontiersin.org 1 March 2019 | Volume 9 | Article 50 Myles Is Allergy Truly Dysbiosis? coagulase negative Staphylococci demonstrated a reduction in the relative abundance of S. aureus (Nakatsuji et al., 2017). The increased depth of microbial identification offered by metagenomics combined with metabolic pathway analysis may reveal the critical functional pathways of the microbiome that have been suggested by investigations of gnotobiotic mice (Bhattarai and Kashyap, 2016). Elucidating immunologic functions that require microbes will be just as, if not more important, as learning which specific microbes can meet those needs. Of note, improved genetic tools might uncover human variants that lack the ability to support the growth of, or properly respond to, otherwise mutualistic organisms. Therefore, paradoxically, failure to sufficiently investigate the impact of microbes on human health may be causing researchers to overlook the functional consequences of some genetic variants. The major critique to the position of this manuscript is that current understanding of atopy deems it “obvious” that genetic contributions to allergic disease are low, while the environment is a major influencer. This sentiment is fair, and is supported by excellent recent reviews on the role of the environment in atopy (von Mutius, 2016; Gilles et al., 2018; Wikstén et al., 2018). However, the sentiment that the environment is the most important influencer of allergic disease does not appear to have been translated into the treatment guidelines. The only environmental modifications recommended by the consensus statements for AD treatment form the US (Schneider et al., 2013; Boguniewicz, 2014), Europe (Wollenberg et al., 2018), and Japan (Katayama et al., 2017) are to avoid known allergens such as animals in the home, clothing material, and foods triggers. Similarly, guidelines for rhinitis suggest avoiding those allergens known to be triggering (Dykewicz et al., 2017; Scadding et al., 2017), without any mentions of possible preventive strategies. Furthermore, a recent overview of the drugs in development for AD listed only Jak/Stat inhibitors and anti-cytokine biologics (Weidinger et al., 2018). Under a new environment-gene paradigm, we would not only expand research into therapeutics that target dysbiosis, we would devote far more resources into examining potential nutritional interventions, stress management, and environmental modifications for the purposes of primary prevention. Current chemical s (...truncated)