Intestinal Remodeling Promotes Innate Defense During Reproduction 2259298

Abstract Introduction Mammalian reproduction requires profound maternal immune adaptations to ensure reproductive success and ultimately shape a species’ evolutionary trajectories. While systemic and placental immunity are known to shift toward tolerance during pregnancy, how maternal immunity adapts in barrier tissues, sites of frequent infection and inflammation, from pregnancy through lactation remains poorly understood. Defining these adaptations will provide fundamental knowledge to advance maternal and offspring health. Methods Using mouse models, organoid cultures and single-cell/spatial transcriptomics, we characterized intestinal immune adaptations during reproduction and studied their functional significance. Results We discovered a previously unrecognized role for eosinophils, a type of granulocyte typically associated with allergies and helminth infections, in remodeling the intestinal barrier during reproduction. From pregnancy through lactation, bone marrow-derived eosinophils accumulate in the small intestine and promote goblet cell differentiation in a stem-cell-intrinsic manner, leading to increased mucus production in the absence of infection or inflammation. This adaptation limits pathogen entry and enhances innate protection during lactation. Notably, both eosinophil accumulation and goblet cell induction persist after lactation, revealing durable remodeling of the intestinal immune and epithelial landscapes. Conclusion Our findings demonstrate that, despite a trend toward systemic immunosuppression during reproduction, the maternal intestine undergoes remodeling to enhance innate defense against enteric pathogens, a mechanism that likely benefits both mother and offspring in pathogen-rich environments. More broadly, our work establishes a framework for studying tissue immune adaptation during reproduction and highlights that tissue can retain memory of physiological states, with lasting implications for host defense and reproductive health. Funding Source Princeton University Topic Categories Mucosal and Regional Immunology (MUC)