Sex modulates the long-term effects of delivery mode on microbiota–gut barrier crosstalk and colitis susceptibility in mice

Sexual dimorphism and mode of delivery are key determinants of gut physiology and microbiota development and may differentially affect predisposition to gut-related diseases. Cesarean section delivery markedly shapes early-life microbiota, predisposing individuals to higher risk of immune and metabolic comorbidities later in life. Although both sex and delivery mode are known to influence gut barrier-microbiota crosstalk, whether delivery mode modulates or counter-regulates sex-specific features of this interaction remains, to our knowledge, largely unexplored. Here, we investigated how sex impacts gut barrier-microbiota crosstalk shaped by delivery mode across development until adulthood by reanalyzing existing data. Using a preclinical mouse model, we combined gut barrier analyses with differential abundance and co-occurrence network approaches (LinDA and NetMoss). We found that the impact of CSD on gut barrier-microbiota crosstalk is partially dependent on sex and life stage. During the first days of life, delivery mode dictates immune imprinting and microbial network topology, with only limited sex effects. However, trajectories diverged with age, with CSD males exhibiting colitis reoccurrence in adulthood. By applying integrative strategies to stratify data by sex and development, our study uncovers short- and long-term sex-dependent gut barrier and microbial signatures. These findings reveal that delivery mode might program sex-specific host-microbiota trajectories with consequences for gut health and disease susceptibility, highlighting the need to consider sex and early-life microbial imprinting in future microbiome-targeted interventions.