The weaning period represents a critical developmental window during which the intestinal host–microbiota interaction network in piglets undergoes profound remodeling and becomes highly vulnerable to disruption. Abrupt dietary transition, reduced feed intake, environmental stressors, and pathogen exposure can collectively interfere with gut microbial succession, epithelial barrier maturation, mucosal immune homeostasis, and neuroendocrine regulation, thereby increasing the susceptibility of piglets to post-weaning diarrhea, intestinal inflammation, and growth retardation. Gut microorganisms contribute to intestinal homeostasis by regulating epithelial renewal, barrier function, immune tolerance, inflammatory thresholds, and host metabolic adaptation through diverse microbial-derived signals, including short-chain fatty acids, tryptophan metabolites, bile acid derivatives, and amino acid-derived metabolites. Conversely, the host actively shapes microbial composition, spatial organization, and functional activity through mucins, antimicrobial peptides, secretory immunoglobulin A, intestinal alkaline phosphatase, epithelial oxygen gradients, and genetic factors. Dysregulation of these bidirectional interactions under weaning stress may shift the intestinal ecosystem from a homeostatic state toward dysbiosis and inflammation. In this review, we summarize current knowledge regarding the establishment and succession of the piglet gut microbiota, the molecular mechanisms underlying host–microbiota crosstalk, the disruption of these interaction networks during weaning stress, and the application of multi-omics approaches to decipher causal mechanisms. We further discuss microbiota-targeted nutritional strategies, including probiotics, prebiotics, synbiotics, postbiotics, functional amino acids, trace elements, and bioactive compounds, for improving intestinal health in weaned piglets. This review aims to provide a mechanistic framework for precision nutritional regulation of piglet intestinal health and for the development of antibiotic-alternative strategies in swine production.

The gut microbiota and mucosal immune system undergo extensive remodeling after weaning and jointly influence intestinal homeostasis, resistance to enteric pathogens, and growth performance in piglets. This developmental transition is particularly vulnerable to dietary changes, the loss of maternally derived factors, environmental stressors, and pathogen exposure, all of which can disrupt microbial ecology and mucosal immune regulation. This review examines the reciprocal interactions between the gut microbiota and mucosal immunity in weaned piglets. It describes how microbial communities and their metabolites regulate epithelial barrier integrity, innate and adaptive immune responses, B-cell differentiation, and secretory immunoglobulin A (sIgA) production, with particular emphasis on short-chain fatty acids, tryptophan-derived metabolites, and bile acids. Conversely, host-derived factors, including mucins, antimicrobial peptides, sIgA, cytokines, and inflammation-associated changes in the intestinal microenvironment, are discussed in relation to microbial colonization, spatial distribution, and functional activity. Disruption of these interactions can impair epithelial barrier function, promote excessive inflammation, weaken colonization resistance, and increase susceptibility to enteric infection and post-weaning diarrhea. Finally, this review evaluates nutritional and microbiota-targeted strategies for modulating microbiota–immune interactions and improving intestinal health in weaned piglets.