Chronic airway inflammation is associated with sex-dependent changes in behaviour, neuroinflammation and the gut microbiome.

Asthma is a chronic inflammatory lung disease linked to a higher prevalence of comorbid mood disorders, such as anxiety and depression, though the underlying pathophysiology and the influence of biological sex remain poorly understood. To investigate this complex relationship, we employed a chronic house dust mite (HDM) exposure model in male and female C57BL/6 mice, examining the sex-dependent effects of allergic airway inflammation across systemic, neuroimmune, behavioural, and gut microbiome axes. Chronic HDM exposure successfully induced hallmark features of allergic airway disease in both sexes. While females exhibited significantly higher levels of most measured airway and systemic inflammatory cytokines compared to males, the neuroinflammatory and behavioural changes were more pronounced in males. HDM-exposed males showed increased hippocampal microglial activation, enhanced mast cell presence, and widespread hypothalamic transcriptional alterations. Females, however, exhibited increased astrocytic activation and enrichment of the estrogen response pathway, suggesting a differential, potentially protective, glial responses. Behaviourally, males displayed reduced grooming and greater despair-like behaviour, consistent with depressive-like phenotypes, whereas females showed reduced grooming only. Parallel analyses revealed that males experienced more extensive gut microbial disruption, particularly in the small intestine, including reductions in taxa previously associated with depressive behaviours (Romboutsia, Turicibacter) and broader shifts in microbial metabolic pathways. The observation that males, despite lower systemic inflammation, exhibit greater neuroinflammatory signatures, more extensive hypothalamic changes, and distinct behavioural deficits underscores the necessity of a sex-informed approach to understanding and mitigating the neuropsychiatric sequelae of chronic allergic asthma.