Circadian disruption elicits sex-specific gut microbiota, endocannabinoidome, and lipid mediator responses

Circadian disruption is a pervasive environmental stressor associated with increased risk of metabolic and inflammatory disease, yet sex-specific physiological responses remain poorly defined. Here, we investigated how constant light (LL) exposure, used as a circadian stressor, is associated with changes in the fecal microbiome and short-chain fatty acids (SCFAs), tissue-specific bioactive lipid mediator and systemic cytokine levels in female and male mice. Mice were kept under standard light/dark (LD; 12 : 12) or LL (24 : 0) conditions for 10 days before feces collection and for 5 more days before tissue collection. Females exhibited broader microbiota restructuring along with decreases in oxylipins within the jejunum. In the brain pronounced increases of N-acylethanolamine levels in the cerebellum and hypothalamus were observed when male and female mice were analyzed together, though these changes were largely driven by increased levels in the hypothalamus of females. Changes in muscle lipids were associated with the predominant muscle fiber type, with the soleus showing increases in a broad variety of lipid classes in both females and males. Adipose tissues also showed divergent responses to LL, with subcutaneous white adipose tissue having significantly decreased oxylipin levels specifically in males. Within plasma, females generally showed a more inflammatory profile than males. Together, these findings suggest that sex strongly shapes microbial, lipidomic, and immune pathways changes under circadian stress, highlighting divergent physiological strategies in response to light-cycle perturbation, which may contribute to sex-specific vulnerability at the level of metabolic and inflammatory dysregulation.