The Role of the Microbiome in Sex and Obesity Effects on Ozone-Induced Airway Hyperresponsiveness

Abstract

Obesity is a risk factor for asthma, but standard asthma therapeutics have reduced efficacy in the obese. The obese asthmatic population is predominantly female, and often suffers from non-atopic asthma. Obesity alters the gastrointestinal microbial community structure. This change in structure contributes to some obesity-related conditions, including systemic inflammation, and could also be contributing to obesity-related asthma. Understanding the role of microbiota in obesity-related non-atopic asthma could lead to novel treatments for these patients. In this thesis, I first demonstrated that airway hyperresponsiveness induced by exposure to ozone, a common non-atopic asthma trigger, was attenuated in germ free mice, and in mice after antibiotic treatment. I identified two short chain fatty acid producing bacteria, Ruminococcus and Coprococcus, whose relative abundance decreased with antibiotic treatment in correlation with the attenuation of airway responsiveness. Exogenous short chain fatty acid administration, on the other hand, increased the ozone-induced airway hyperresponsiveness. The data suggest that the microbiome contributes to ozone-induced airway hyperresponsiveness, likely via its ability to produce short chain fatty acids. I next examined the impact of sex on responses to ozone. 16S sequencing of mouse fecal samples indicated differences in the gut microbial community structures of female and male lean mice. Compared to female mice, ozone-induced airway hyperresponsiveness was greater in male mice, and antibiotic treatment abolished this difference. In addition, compared to female weanlings housed in cages previously occupied by females, female weanlings housed in cages previously occupied by males developed greater ozone-induced airway hyperresponsiveness. Together, our data indicate that sex-related differences in the microbiome contribute to sex-related differences in ozone-induced airway hyperresponsiveness. Finally, I examined the role of the microbiome in obesity-related increases in ozone- induced airway hyperresponsiveness. There were obesity-related differences in the gut microbiome that differed by sex. Compared to lean mice, obese mice of both sexes had augmented ozone-induced airway hyperresponsiveness. In obese female mice, antibiotics attenuated ozone-induced airway hyperresponsiveness, whereas antibiotics caused no change in obese male mice. Our data indicate that the microbiome contributes to the obesity-related increases in ozone-induced airway hyperresponsiveness in females, possibly via obesity-related changes in IL-6 and serum short chain fatty acids. Together, our studies show that the microbiome contributes to the sex- and obesity-dependent effects on ozone-induced airway hyperresponsiveness. Understanding the role of the microbiome in obesity-related asthma may allow for the advancement of personalized therapeutics for obese asthmatic population.