Impacts of Early Weaning on Lamb Gut Health and Immune Function: Short-Term and Long-Term Effects

Despite the known impacts of weaning on animal health, the underlying molecular mechanisms remain unclear, particularly how psychological and nutritional stress differentially affect gut health and immune function over time. This study hypothesized that early weaning exerts distinct short- and long-term effects on lamb stress physiology, immunity, and gut health, mediated by specific molecular pathways. Twelve pairs of full-sibling male Hu sheep lambs were assigned to control (CON) or early-weaned (EW) groups. Plasma stress/immune markers were dynamically monitored, and intestinal morphology, antioxidant capacity, apoptosis, and transcriptomic profiles were analyzed at 5 and 28 days post-weaning. Early weaning triggered transient psychological stress, elevating hypothalamic–pituitary–adrenal (HPA) axis hormones (cortisol, catecholamines) and inflammatory cytokines (TNF-α) within 1 day (<i>p</i> < 0.05); however, stress responses were transient and recovered by 7 days post-weaning. Sustained intestinal remodeling was observed in EW lambs, featuring reduced ileal villus height, increased crypt depth (<i>p</i> < 0.05), and oxidative damage (MDA levels doubled vs. CON; <i>p</i> < 0.01). Compensatory epithelial adaptation included increased crypt depth but paradoxically reduced villus tip apoptosis. The transcriptome analysis revealed significant changes in gene expression related to immune function, fat digestion, and metabolism. Key DEGs included <i>APOA4</i>, linked to lipid transport adaptation; <i>NOS2</i>, associated with nitric oxide-mediated immune–metabolic crosstalk; and mitochondrial gene <i>COX1</i>, reflecting energy metabolism dysregulation. Protein–protein interaction analysis revealed <i>NOS2</i> as a hub gene interacting with <i>IDO1</i> and <i>CXCL11</i>, connecting oxidative stress to immune cell recruitment. Early weaning exerts minimal lasting psychological stress but drives persistent gut dysfunction through transcriptome-mediated changes in metabolic and immune pathways, highlighting key genes such as <i>APOA4</i>, <i>NOS2</i>, and <i>COX1</i> as potential regulators of these effects.