Eosinophils Orchestrate Intestinal Remodeling and Promote Innate Defense During Reproduction [scRNA-seq]

Mammalian reproduction requires profound maternal immune adaptations to safeguard reproductive success and ultimately shape the evolutionary trajectories of a species. While systemic and placental immunity is known to shift toward tolerance during pregnancy, how maternal immunity adapts in barrier tissues, sites of frequent infection and inflammation, from pregnancy through the postpartum lactation period remains poorly understood. Here, 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. Beginning in pregnancy and peaking during lactation, eosinophils originating from bone marrow accumulate in the small intestine in the absence of infection or inflammation. Using genetic and pharmacological perturbations, organoid cultures, and single-cell and spatial transcriptomics, we show that eosinophils promote goblet cell differentiation in a stem-cell-intrinsic manner, leading to increased mucus production. This adaptation culminates during lactation, limits pathogen entry and dissemination, conferring broad innate protection against enteric bacterial infections. Remarkably, both eosinophil accumulation and goblet cell induction persist after lactation, revealing durable remodeling of the intestinal immune and epithelial landscapes with sustained innate defense. Our findings demonstrate that, despite a general trend toward systemic immunosuppression during reproduction, the maternal intestine undergoes remodeling to strengthen innate defense against enteric pathogens, a mechanism that may have evolved to protect mothers and offspring in pathogen-rich environments. More broadly, our work establishes a framework for studying tissue immune adaptation across the reproductive cycle and highlights that tissue can retain memory of physiological states, with lasting implications for host defense and reproductive health.