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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 (FCGs) model, we have previously reported sex differences in lung inflammatory phenotypes. Here, we investigated associations of gut microbiomes with these phenotypes by challenging FCG mice [mouse with female sex chromosome and male gonad (XXM), mouse with female sex chromosome and female gonad (XXF), mouse with male sex chromosome and male gonad (XYM), and mouse with male sex chromosome and female gonad (XYF); n = 7/group] with HDM (25 μg) or PBS intranasally for 5 wk and collecting fecal samples. We extracted fecal DNA and analyzed the 16S microbiome via Targeted Metagenomic Sequencing. We compared α and β diversity across genotypes and assessed the Firmicutes/Bacteroidetes (F/B) ratio. When comparing baseline and after exposure for the FCG, we found that the gut F/B ratio was only increased in the XXM genotype. We also found that α 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, β 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. NEW & NOTEWORTHY: Recently, the gut microbiome and its role in chronic respiratory disease have been the subject of extensive research and the establishment of its involvement in immune functions. Using the FCG mouse model, our findings revealed the influence of gonads and sex chromosomes on the microbial community structure before and after exposure to HDM. Our data provide a potential new avenue to better understand mediators of sex disparities associated with allergic airway inflammation. [ABSTRACT FROM AUTHOR]

Sex differences in allergic inflammation have been reported, but the mechanisms underlying these differences remain unknown. Contributions of both sex hormones and sex-related genes to these mechanisms have been previously suggested in clinical and animal studies. Here, Four-Core Genotypes (FCG) mouse model was used to study the inflammatory response to house dust mite (HDM) challenge and identify differentially expressed genes (DEGs) and regulatory pathways in lung tissue. Briefly, adult mice (8–10 wk old) of the FCG (XXM, XXF, XYM, XYF) were challenged intranasally with 25 μg of HDM or vehicle (PBS-control group) 5 days/wk for 5 wk (n ¼ 3/10 group). At 72 h after the last exposure, we analyzed the eosinophils and neutrophils in the bronchoalveolar lavage (BAL) of FCG mice. We extracted lung tissue and determined DEGs using Templated Oligo-Sequencing (TempO-Seq). DEG analysis was performed using the DESeq2 package and gene enrichment analysis was done using Ingenuity Pathway Analysis. A total of 2,863 DEGs were identified in the FCG. Results revealed increased eosinophilia and neutrophilia in the HDM-treated group with the most significantly expressed genes in XYF phenotype and a predominant effect of female hormones vs. chromosomes. Regardless of the sex hormones, mice with female chromosomes had more downregulated genes in the HDM group but this was reversed in the control group. Interestingly, genes associated with inflammatory responses were overrepresented in the XXM and XYF genotypes treated with HDM. Sex hormones and chromosomes contribute to inflammatory responses to HDM challenge, with female hormones exerting a predominant effect mediated by inflammatory DEGs. NEW & NOTEWORTHY Gene expression profiling helps to provide deep insight into the global view of disease-related mechanisms and responses to therapy. Using the Four-Core Genotype mouse model, our findings revealed the influence of sex hormones and sex chromosomes in the gene expression of lungs exposed to an aeroallergen (House Dust Mite) and identified sexspecific pathways to better understand sex disparities associated with allergic airway inflammation. [ABSTRACT FROM AUTHOR]

Introduction: Recent evidence has demonstrated that the microbiome is a driver of the underlying pathophysiological mechanisms of respiratory disease. Studies have indicated that bacterial metabolites produced in the gut and lung can impact lung inflammation and immune cell activity, affecting disease pathology. Despite asthma being a disease with marked sex differences, experimental work linking microbiomes and asthma has not considered the sex variable., Methods: To test the hypothesis that the lung and gut microbial composition impacts allergic lung inflammation in a sex-specific manner, we evaluated lung and gut microbiome alterations in a mouse model of allergic inflammation and assessed their association with lung function and inflammation phenotypes. For this, we exposed male and female adult C57BL/6J mice intranasally to 25 µg of a house dust mite extract mix (HDM) daily, or phosphate-buffered saline (PBS) as control, for 5 weeks ( n  = 4-6/group). DNA from fecal pellets collected before and after the 5-week treatment, and from lung tissue collected at endpoint, was extracted using the ZymoBIOMICS®-96 MagBead DNA Kit and analyzed to determine the 16S microbiome via Targeted Metagenomic Sequencing., Results: The HDM treatment induced a sex-specific allergic inflammation phenotype with significantly higher neutrophilia, lymphocytosis, inflammatory gene expression, and histopathological changes in females than males following exposure to HDM, but higher airway hyperresponsiveness (AHR) in males than females. In addition, sex-specific lung gene expression and associated pathways were identified HDM mix after challenge. These changes corresponded to sex-specific alterations in the gut microbiome, where the Firmicutes to Bacteroidetes ratio (F:B) was significantly reduced in fecal samples from only male mice after HDM challenge, and alpha diversity was increased in males, but decreased in females, after 5-weeks of HDM treatment., Discussion: Overall, our findings indicate that intranasal allergen challenge triggers sex-specific changes in both gut and lung microbiomes, and induces sex-specific lung inflammation, AHR, and lung inflammatory gene expression pathways, suggesting a contribution of the lung-gut axis in allergic airway disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Ekpruke, Alford, Rousselle, Babayev, Sharma, Parker, Davis, Hemmerich, Rusch and Silveyra.)