Biomarkers linked to Microbiome and Asthma
An enormous variety of microbes colonize mucosal body surfaces and these microbes are organized within complex community structures, utilizing nutrients from other microbes, host secretions and the diet. Modern lifestyles, medications and social interactions have fundamentally altered and disrupted the human microbiome metacommunity and, as a consequence, risk of immune-mediated diseases such as allergy and asthma.49,50 The mechanisms that mediate host-microbe communication are highly sophisticated and are being intensely investigated by many research groups across the world. However, there is accumulating evidence that microbiome composition and metabolic activities within the gut and the airways can influence asthma pathogenesis.51-53 Here, we summarize some of the key recent findings that identify specific microbes or associated metabolites that may be useful as biomarkers to predict asthma risk, asthma severity or guide existing or novel therapies.
Alterations in the gut microbiota within the first year of life have been associated with asthma risk in multiple birth cohort studies.19 The lower relative abundance of genera including Lachnospira , Veillonella ,Faecalibacterium , Rothia , Bifidobacterium andAkkermansia in the gut during early life have been associated with the development of asthma.54,55 While fewer studies have examined pre-school children (2-4 years of age), a recent study in this age group demonstrated that certain bacterial genera within the gut were still associated with wheezing (Collinsellaand Dorea ) or subsequent development of asthma (Gemmigerand Escherichia ).56 In addition to the gut microbiota, studies are also showing changes in the microbial populations of the airways. Microbial diversity and the relative abundances of Veillonella and Prevotella in the airways at age one month were associated with asthma by age 6 years.57 Interestingly, higher relative abundance of these bacteria was associated with reduced TNF-α and IL-1β and increased CCL2 and CCL17 within the airways. A switch from aCorynebacterium  and Dolosigranulum cluster in the upper-airways to a Moraxella cluster was associated with a higher risk of severe asthma exacerbation in children with asthma.58 In adults, increased relative abundance of the phylum Proteobacteria (including Haemophilus ,Comamonadaceae , Sphingomonadaceae ,Nitrosomonadaceae , Oxalobacteraceae andPseudomonadaceae ) is often associated with asthma or with worse asthma control.59 Microbial changes within the gut, upper and lower airways of adult asthma patients are magnified in obese asthma patients and in those with severe disease.60Bronchoalveolar lavage levels of IL-5 and eosinophils correlated with a variety of microbes within the airways. Of note, severe asthma negatively correlated with fecal Akkermansia levels and oral administration of Akkermansia to murine models significantly reduced airway hyper-reactivity and airway inflammation (Figure 2).
In addition to microbiota composition, microbial metabolites may also be useful biomarkers in asthma. The fecal metabolome of children at increased risk of asthma contained increased levels of pro-inflammatory metabolites, among which 12, 13 DiHOME was able to induce IL-4 production in CD4+T cells and decreased the abundance of Tregs.55 High levels of short chain fatty acids (SCFAs), such as butyrate and propionate, at one year of age were associated with reduced risk of atopic sensitization and asthma by school age.61 Multiple immune modulatory effects have been described in murine models for SCFAs, which include the promotion of Treg development and the inhibition of pulmonary ILC2 functions and subsequent development of airway hyper-reactivity.62In adults, an increased abundance of histamine secreting bacteria were observed within the gut of patients with asthma, while disease severity correlated with high levels of the histamine secreting microbeMorganella morganii .63 Murine models have demonstrated that bacterial-derived histamine within the gut can influence inflammatory responses within the lungs.64
In the future, the application of recent advances in metagenomic sequencing technologies and bioinformatics will likely lead to the identification of novel functional traits and metabolites within the gut and airway microbiome of asthma patients.65 In addition, future asthma studies should include the microbiome as potential biomarkers that predict or associate with responses to biologics, as already observed for Faecalibacterium ,Bifidobacterium and Akkermansia that associate with immunotherapy responses in certain groups of cancer patients.66