Single-nucleus transcriptome profiling of wild boar and domestic pig intestines reveals the spatiotemporal dynamics of immunity and nutrient absorption.

Pigs are important agricultural animals and valuable biomedical models. The intestinal tract is a crucial digestive organ and the largest immune organ. However, the function of pig intestines at single-cell resolution remains poorly understood. Here, we created single-nucleus transcriptomic maps of the ileum and cecum for wild boars, Bama Xiang pigs, and Large White pigs, aged 30, 42, 150, and 730 d. Our atlas revealed 19 major cell types and 58 cellular subtypes, including several previously uncharacterized cellular subtypes, such as EBF1⁺ fibroblasts, TMEM163⁺ macrophages, and neuron subtypes expressing FCAMR. We discovered and confirmed that ileum neurons, rather than cecum neurons, can regulate inflammatory responses, highlighting interactions of neurons with dendritic cells (DCs) and lymphatic endothelial cells (LECs) through the NAMPT-INSR ligand-receptor pair in the ileum. Microbial-derived short-chain fatty acids, such as propionic acid and acetic acid, enhanced plasma cell differentiation and humoral immune responses by upregulating XBP1 and SDC1 expression, thereby endowing wild boars with a stronger immune response than domestic pigs. We identified and validated the enterocyte-enriched transcription factors FOXO1 and NR1H4 in wild boars, which contributed to the superior nutrient absorption of wild boars relative to domestic pigs. Furthermore, we comprehensively characterized the postnatal development of wild boar intestinal cells and revealed that plasma cells presented the most pronounced developmental changes. We identified highly conserved cell types and features between pig and human intestines. Overall, our work provides a foundation for improving pig feed conversion and health while also providing a reference for research on human intestinal diseases.