Sex differences in the effect of dietary fiber on ozone induced airway hyperresponsiveness: role of the microbiome

Rationale: The air pollutant, ozone, causes asthma symptoms, loss of lung function, and airway hyperresponsiveness (AHR), a defining feature of asthma. We have reported that ozone exposure leads to greater increases AHR in male than female mice, and antibiotics attenuate ozone-induced AHR in males but increase AHR in females, thus ablating this sex difference and indicating a role for the microbiome. Prebiotics such as dietary fiber have the capacity to alter the gut microbiome. The purpose of this study was to examine sex differences in the effects of dietary fiber on ozone-induced AHR and to determine whether microbial production of short chain fatty acids (SCFAs) contributes to sex differences in the impact of the microbiome on ozone-induced AHR. Methods: Male and female wild type (WT) C57BL/6 mice were fed control, pectin-enriched, or cellulose-enriched diets for 4 days. Other male and female mice were fed control or fiberfree diets. Fecal pellets were collected for 16S rRNA sequencing to determine the taxonomic composition of the gut microbiome and the mice were then exposed to ozone (2 ppm for 3h) or room air. 24 h later, AHR was assessed. Bronchoalveolar lavage was performed and blood was collected for measurement of SCFAs and gut-derived hormones. Effects of ozone were also examined in WT mice and littermate mice deficient in GPR41, a receptor for SCFAs. Results: Compared to cellulose-fed male mice, pectin-fed and control diet-fed male mice had significantly greater increases AHR after ozone exposure (Figure, left). SCFAs in control and pectin-fed mice were higher than cellulose-fed mice. However, neither genetic deletion of GRP41 nor a fiber free diet had any effect on ozone-induced AHR in male mice. Instead, there were marked differences in the taxonomic composition of the gut microbiome in cellulose- versus pectin-fed male mice and corresponding differences in serum gut-derived hormone, GLP1. In females, there was no effect of diet on ozone-induced AHR (Figure, right), nor were there any marked differences of the gut microbiome or serum GLP1 in cellulose-fed versus pectin-fed female mice. However, both fiberfree diets and GPR41 deficiency augmented ozone-induced AHR in female mice.