Gonadal sex and chromosome complement influence the gut microbiome in a mouse model of allergic airway inflammation

Evidence abounds that gut microbiome components are associated with sex disparities in the immune system. However, it remains unclear whether the observed sex disparity in asthma incidence is associated with sex-dependent differences in immune-modulating gut microbiota, and/or its influence on allergic airway inflammatory processes. Using a mouse model of house dust mite (HDM)-induced allergic inflammation and the four core genotypes (FCG) model, we have previously reported sex differences in lung inflammatory phenotypes. Here, we investigated associations of gut microbiomes to these phenotypes by challenging FCG mice (XXM, XXF, XYM, XYF, n=7/group) withHDM (25 μg) or PBS intranasally for 5 weeks and collecting fecal samples. We extracted fecal DNA and analyzed the 16S microbiome via Targeted Metagenomic Sequencing. We compared alpha and beta diversity across genotypes and assessed the Firmicutes/Bacteroidetes ratio (F/B). When comparing baseline and after exposure for the FCG, we found that the gut F/B was only increased in the XXM genotype. We also found that alpha diversity was significantly increased in all FCG mice upon HDM challenge, with the highest increase in the XXF, and the lowest in the XXM genotypes. Similarly, beta diversity of the microbial community was also affected by challenge in a gonad- and chromosome-dependent manner. In summary, our results indicated that HDM treatment, gonads, and sex chromosomes significantly influence the gut microbial community composition. We concluded that allergic lung inflammation may be affected by the gut microbiome in a sex-dependent manner involving both hormonal and genetic influences.