Abstract
Asthma is a phenotypically heterogeneous disease. In severe asthma, airway inflammation can be predominantly eosinophilic, neutrophilic, or mixed. Only a limited number of drug candidates are in development to address this unmet clinical need. Live biotherapeutics derived from the gut microbiota are a promising new therapeutic area. MRx0004 is a commensal Bifidobacterium breve strain isolated from the microbiota of a healthy human. The strain was tested prophylactically and therapeutically by oral gavage in a house dust mite mouse model of severe asthma. A strong reduction of neutrophil and eosinophil infiltration was observed in lung bronchoalveolar lavage fluid following MRx0004 treatment. Peribronchiolar and perivascular immunopathology was also reduced. MRx0004 increased lung CD4+CD44+ cells and CD4+FoxP3+ cells and decreased activated CD11b+ dendritic cells. Cytokine analysis of lung tissue revealed reductions of pro-inflammatory cytokines and chemokines involved in neutrophil migration. In comparison, anti-IL-17 antibody treatment effectively reduced neutrophilic infiltration and increased CD4+FoxP3+ cells, but it induced lung eosinophilia and did not decrease histopathology scores. We have demonstrated that MRx0004, a microbiota-derived bacterial strain, can reduce both neutrophilic and eosinophilic infiltration in a mouse model of severe asthma. This novel therapeutic is a promising next-generation drug for management of severe asthma.
Highlights
Asthma is an umbrella term for a highly heterogeneous disease with clinical presentations ranging from mild to severe
In this study we report that the candidate live biotherapeutic agent, Bifidobacterium breve MRx0004, significantly reduces disease pathology in a model of steroid-resistant severe asthma
C57BL/6 mice were sensitized to house dust mite (HDM) in Complete Freund’s Adjuvant (CFA) to generate a steroid-insensitive neutrophilic and eosinophilic response, with similar inflammatory mediators to severe asthma in humans
Summary
Asthma is an umbrella term for a highly heterogeneous disease with clinical presentations ranging from mild to severe. It is a chronic inflammatory lung disease characterised by recurrent, reversible airway obstruction and increased bronchial hyper-responsiveness. Endotypes of severe asthma are associated with distinct pathophysiological mechanisms characterised by molecular phenotypes, associated biomarkers and differential responses to therapy[7,8]. Similar approaches targeting TH1 or TH17 pathway effectors such as CXCR2 and IL-17 have shown some promise in the treatment of TH2-low, neutrophilic asthma[20,21,22]. The limitations of current treatment approaches highlight the need for new therapeutics that target underlying immune responses associated with severe asthma to provide greater disease control and increased efficacy. The gut microbiota provides a promising reservoir of novel therapeutic potential for asthma
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