Microbial-derived metabolites potentiate airway hyperresponsiveness in obesity-associated asthma

PROJECT SUMMARY Asthma disproportionately affects obese patients with a body mass index (BMI) greater than 25 kg/m2. Obese individuals with asthma usually exhibit more severe symptoms, have a poorer prognosis, and respond poorly to conventional asthma medications. Obesity-associated asthma is a complex clinical phenotype as patients do not present solely with atopic T helper (Th)2 inflammatory profile, but often with mixed Th1/Th2/Th17 disease. As this subset of asthma is poorly defined, there is a need to understand the mechanistic basis for obese asthma to develop more targeted and effective therapies. It is well known that diet and obesity substantially contribute to changes in gut microbial profile and function and that these changes lead to decreased gut barrier integrity and systemic alterations in metabolite profiles. We believe that gut dysbiosis results in microbial-derived metabolites that promote lung dysfunction and airway hyperresponsiveness. We recently demonstrated that systemic increases in conjugated bile acids correlate with a clinical decline in lung function and increased airway closure in our murine model of obese asthma. It is known that conjugated bile acid formation and transport is regulated by trimethylamine-N-oxide (TMAO). TMAO selectively activates the unfolded protein response (UPR) in many inflammatory diseases, but the role of these metabolic mediators in asthma pathogenesis is unknown. In the gut, bile acids maintain barrier integrity and modulate CD4+ T cell homeostasis through the bile acid receptor, TGR5; however, little is known about the mechanistic role of bile acids in the lung. Based on our preliminary and published findings, we hypothesis that dysregulated bile acid metabolism and gut dysbiosis instigate obesity-associated asthma by altering the UPR and inhibiting beneficial TGR5 signaling in the lungs. In this proposal, we will (1) investigate whether dysregulated bile acid metabolism contributes to obesity-associated asthma through changes in TMAO levels and PERK signaling in the lungs (2) determine if altered gut microbial function increases disease severity in obesity-associated asthma and (3) examine if TGR5 signaling alters obesity-associated asthma by influencing CD4+ T cell function. These studies will pioneer novel investigations into the role of bile acids and gut microbiota as regulators of obesity-associated asthma and will uncover molecular mechanisms by which TGR5 regulates T cell responses to protect the lung from AAD-induced injury. This novel work in preclinical animal models and human samples will uncover innovative therapeutic targets to lessen asthma morbidity and prevent mortality.