Spatial Microbiota-Metabolite-Mucosa Crosstalk During Piglet Weaning: A Niche-Aware Framework for the Design of Commensal Probiotic Consortia.

Weaning exposes piglets to abrupt dietary, social, and environmental changes that disrupt intestinal development and microbial ecosystem maturation. Post-weaning intestinal dysfunction is often accompanied by broad restructuring of intestinal microbial communities, but interpretations based primarily on fecal profiles can overlook the spatial organization of the gastrointestinal tract. Weaning also remodels local intestinal niches through changes in epithelial architecture, barrier integrity, nutrient flow, immune activity, and redox balance. These changes occur within distinct ecological habitats across the ileum, cecum, and colon, where digesta- and mucosa-associated microbial communities differ in substrate exposure and host interaction. Consequently, microbial communities and their functions may be reorganized in a site- and compartment-dependent manner. The physiological relevance of microbial metabolites similarly depends on their site of production, epithelial accessibility, microbial transformation, and host utilization. Amino acid metabolism, lactate-mediated cross-feeding, carbohydrate fermentation, tryptophan-derived signaling, and bile acid transformation illustrate this spatial dependence. Commensal lactobacilli are of particular interest because their abundance and metabolic activities change during weaning; however, adhesion, substrate utilization, metabolite production, and host interactions vary markedly among species and strains. Probiotic potential therefore cannot be inferred from taxonomic identity or fecal detection alone. This review proposes a niche-aware framework in which the target intestinal site and desired function are defined before strain selection. Candidate probiotics and defined consortia should be evaluated for niche fitness, functional complementarity, site-specific activity, and strain-level safety. Integrating region-resolved microbiota profiling with metabolomics and spatially matched host responses may enable more precise and reproducible microbial strategies to support intestinal adaptation during piglet weaning.