Developing the microbiome-metabolome as a targeted therapy for obesity-associated asthma

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PROJECT SUMMARY/ABSTRACT Obesity worsens asthma severity, and nonatopic asthma that presents late-onset in obese individuals is a distinct asthma phenotype. Obesity-associated asthma poses a challenge to clinical management due to poor therapeutic response to asthma controller medications, resulting in increased frequency of asthma exacerbations and elevated risk of hospitalization. The microbiome-metabolome is a promising target for obesity-associated asthma. Numerous studies support that obesity-associated perturbations to the gut microbiome are mechanistically involved in enhanced airway responsiveness in asthma. Airway hyperresponsiveness is elevated in asthma patients with obesogenic microbiomes. Alterations to host-microbial metabolism in obesity include short-chain fatty acids and other small metabolites involved inflammatory signaling pathways along the gut-lung axis. We have established that nitro-oleic acid, a nitrated fatty acid, targets systemic inflammation in both the host and the gut microbiome. Nitro-oleic acid activates anti-inflammatory (Nrf2) and inhibits proinflammatory (NF- κB) cell signaling pathways in the host while reducing the abundance of unclassified Oscillospiraceae bacterial species associated with detrimental increased small airway resistance in obese asthma. This proposal aims to test the hypothesis that exogenous administration of nitro-oleic acid will modify gut microbiota composition and function to restore microbial-derived metabolites and produce endogenous anti- inflammatory mediators. In Aims 1-2, I will identify contributions from the microbiome, metabolome, and nitro- oleic acid treatment to pulmonary function in a murine model of obesity-associated asthma. Aim 1 will characterize changes to the microbiome, metabolome, and inflammatory gene expression in the lungs following nitro-oleic acid treatment in order to determine how nitro-oleic acid modifies host-microbial anti-inflammatory signaling and metabolism. I have recently adapted a new technique of profiling changes to the microbiome and microbial-derived metabolites with stable isotope probes. Aim 2 will apply this method to track nitro-oleic acid- driven changes to gut microbiota composition and to discern which disease-modifying metabolites are derived from the microbiome. The ultimate goal of this research is to develop targeted therapy options for obesity- associated asthma and reduce patient morbidity and mortality through improved control of airway hyperresponsiveness. The proposal findings will be translated into the clinical setting to leverage the gut microbiome and microbial-derived metabolites to manage symptoms and recover lung function in patients with obesity-associated asthma.