Systemic bile acids potentiate airway hyperresponsiveness and modulate Th17 cell function in obesity-associated asthma

Abstract

Abstract Obesity-associated asthma is phenotypically characterized by low grade inflammation and resistance to standard therapies. Like many other asthma endotypes, the molecular mechanisms contributing to obesity-associated asthma are diverse and ambiguous. A panoply of metabolites that act as signaling mediators are altered by obesity and may also promote lung dysfunction and a pro-asthma phenotype. Recent metabolomics studies indicate that bile acid profiles are altered in individuals with asthma, thus these metabolites were investigated in a murine model of obesity-associated asthma and clinically. In obese mice with allergic airway disease (AAD), the levels of β-muricholic acid (βMCA) and tauro-β-muricholic (tβMCA) were significantly increased in serum and positively correlated with impaired lung function. Two conjugated bile acids, glycocholic acid (GCA) and glycoursodeoxycholic acid (GUDCA), were elevated in the plasma of high body mass index (BMI) individuals and correlated with both BMI and airway hyperreactivity as measured by FEV1, forced expiratory volume in one second. In vitro differentiated T helper (Th) cells were treated with tβMCA and βMCA, which resulted in changes in T cell metabolism that were specific to Th17 cells. In addition, tβMCA treatment increased IL-17 production from Th17 cells upon stimulation. Finally, the anti-inflammatory and metabolic regulatory activities of nitro-oleic acid (NO2-OA) were evaluated in the murine model of obesity-associated asthma. NO2-OA reduced levels of βMCA and tβMCA, with a concomitant reduction in tissue resistance and elastance, providing a potential approach to improving the current standard of care for obese individuals with asthma. Supported by R01HL146445 (MLM), S10OD023402 (SGW), R61HL157069 (SGW, BAF, FH), R01HL132550 (BAF)