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Constructing a ‘Eubiosis Reinstatement Therapy’ for Asthma

Periodic Reporting for period 3 - CURE (Constructing a ‘Eubiosis Reinstatement Therapy’ for Asthma)

Reporting period: 2020-04-01 to 2022-03-31

Asthma remains a major disease imposing a huge burden on patients and healthcare systems in Europe and worldwide. Although there are several therapeutic agents able to control, in most cases, the symptoms of the disease, asthma remains an uncurable condition. Furthermore, despite available treatments, symptom control is generally suboptimal and hospitalisations and deaths remain at unacceptably high levels. This calls for disruptive innovation towards a long-term treatment strategy. Asthma is an inflammatory condition associated with immune deviations, most often atopic allergy. However, a key characteristic of asthma that remains relatively unexplored is susceptibility to infection. Most acute asthma attacks follow upper respiratory tract infections; infections are also associated with asthma initiation and persistence. Recent studies reveal that the composition of the respiratory microbiome is characteristically imbalanced (dysbiotic) in asthma. Our own data indicate that a feature of dysbiosis in asthma in children is reduced abundance of bacteriophages (phages). These bacterial viruses infect and are able to naturally control bacterial populations, through a predator-prey balance. Phage therapy has been grossly neglected in the western world and is currently just appearing as a novel tool against infection. However, it has never been used for rebalancing dysbiosis in humans before. This has led us to propose the CURE hypothesis that suggests that reinstating eubiosis within the asthmatic airway through phage therapy is feasible and will be able to control the immune dysregulation and clinical presentation of the disease. The objectives of CURE were to describe the longitudinal dynamics of the respiratory microbiome in health and asthma, using metagenomics to include the complete range of viruses and bacteria, to evaluate and quantify interactions between respiratory metagenome composition, host responses and clinical activity, establishing a new basis for precision medicine in asthma, to generate mathematical models able to predict the impact of bacteriophage interventions on microbial ecology and clinical activity in health and asthma and finally to establish a well characterised bacteriophage collection with intervention potential in asthma.
A cohort of people with asthma – both children and adults – from two geographical areas with distinct climatic characteristics – Greece and Poland – was established and followed up closely. Healthy volunteers were also followed in parallel, as controls. Disease activity was documented at regular visits, as well as with a prospective electronic monitoring system, while upper respiratory and other samples were obtained at different time points, spanning from hours, up to a whole year. Next generation sequencing (NGS) and an in-house developed analytical pipeline were used to describe and understand the differences of respiratory metagenomes between the healthy and asthmatic individuals, as well as fluctuations in time. The metagenomes included the complete bacterial, viral, archeal and eukaryote microbiome; human sequences were removed. We have identified location, age and gender as major sources of respiratory microbiome compositional variability. Furthermore, it was confirmed that the respiratory microbiomes are ‘personal’ i.e. differences are larger between individuals than between different time points within an individual, similarly to what has been described in the gut and other body sites and expanding this concept for the complete metagenome. Highly interesting findings resulted from the study of metagenome variability in time. Microbiomes of people with asthma were more diverse, but also less stable in time, in comparison to healthy controls. Within different microbiome clusters, defined mostly by location and age, asthma microbiomes were always more different between themselves in contrast to healthy metagenomes that were more alike, following the “Anna Karenina” principle of dysbiotic microbiomes. To further support the biological relevance of this finding, within the asthmatic population, dysbiosis was associated with disease severity and activity. Phages were affected in only some subpopulations. In a theoretical model, we discovered that the balance between lytic and lysogenic phages may be able to affect the stability of the microbiome. In parallel to the NGS analyses, innate immune and epithelial responses to phages were studied both in-vitro and ex-vivo. It was thus established that phages have no direct effect on human epithelium, however they are capable of protecting from bacterially induced epithelial inflammation. In addition, they are capable of differentially activating subclasses of innate lymphoid cells.
Finally, the CURE centres in Georgia, in collaboration with the other partners, focused on isolating and characterising an expanded collection of phages against bacteria potentially relevant in asthma, establishing a biobank of more than 70 phages.
The findings of CURE are supportive of its hypothesis that phage interventions may be able to reinstate eubiosis and bring us a step closer to microbiome-based interventions in asthma and other chronic inflammatory conditions. CURE has taken forward our understanding of respiratory microbiomes and the potential for phage interventions, shifting the focus and redefining the concept of microbiome stability and the structural rather than the compositional characteristics of dysbiosis in asthma. The direct impact of these conceptual innovations will be towards the increasingly thriving community of researchers exploring the microbiome. In parallel, the new scientific community that has been developed, will join efforts with the wider phage community to advocate and support the optimization of regulations that will allow phage interventions in humans, bringing phage therapies closer to their full expected impact in reducing disease burden, both in regard to infection, but also chronic diseases characterized by dysbiosis.
Knowledge domains contributing to CURE and their interactions