Maternal microbiota shapes brain and neuroendocrine development in piglets

The maternal microbiota plays a critical role in early‐life development, yet how maternal microbiota exposure shapes cellular and neuroendocrine programs during mammalian development remains poorly understood. Here, leveraging germ‐free (GF) and maternal microbiota transplantation (MMT) models, we generated an integrated multi‐organ porcine atlas by combining multi‐regional single‐nucleus RNA sequencing, spatial transcriptomics, bulk RNA sequencing of intestinal tissues, and metabolomics. Across five brain regions and the hypothalamic–pituitary–adrenal (HPA) axis, we profiled 673,623 high‐quality nuclei and revealed microbiota‐dependent remodeling of neuronal and glial states across early postnatal developmental stages. MMT reshaped neuronal maturation programs, altered the distribution of immature neuronal states, and elicited region‐specific transcriptional responses in glutamatergic and GABAergic neurons. MMT also reorganized neuron–glia interaction networks, accompanied by trends toward increased plasma glutamic acid and glutamine levels. Across the gut–brain–neuroendocrine axis, MMT was associated with coordinated remodeling of HPA‐axis cellular communication, stress‐response transcriptional programs, and immune signatures, together with reduced circulating cortisol levels. Integrated intestinal analyses revealed segment‐specific transcriptional and metabolic remodeling, including alterations in tryptophan/indole‐related metabolites and immune‐associated pathways. Cross‐species stratified linkage disequilibrium score regression further identified enrichment of human cognitive and neuropsychiatric trait‐associated genetic signals within cell‐type‐specific gene signatures derived from microbiota‐responsive porcine cell populations. Our study establishes a large‐animal cellular atlas linking maternal microbiota‐responsive remodeling across the brain, gut, and neuroendocrine axis, providing a translational framework for understanding how early‐life microbial signals shape mammalian developmental physiology.