Lactiplantibacillus plantarum promotes intestinal goblet cell differentiation via indole-3-lactic acid–AHR signaling in pigs

The swine intestinal microbiota dynamically remodels during development and supports gut homeostasis. However, whether stage-specific microbial shifts, are associated with epithelial development remains poorly understood. Here, longitudinal metagenomic profiling of the swine gut microbiome identified Lactiplantibacillus plantarum as a transiently enriched nursery-stage bacterium positively associated with goblet cell numbers. Dietary supplementation with L. plantarum validated this association, showing increased goblet cell numbers and MUC2 expression in the ileum of nursery piglets. Co-culture with porcine ileum organoids further demonstrated that L. plantarum cell-free supernatant promoted ileal organoid growth and goblet cell differentiation. Integrated untargeted metabolomic analyses of ileal samples and bacterial culture supernatants identified indole-3-lactic acid (ILA) as a potential key microbial metabolite from L. plantarum. Mechanistically, ILA promoted intestinal stem cell proliferation and MUC2 expression, accompanied by increased expression of aryl hydrocarbon receptor (AHR) and its downstream target CYP1A1 in ileal organoids. Consistently, activation of AHR using FICZ increased MUC2 expression, whereas inhibition with CH-223191 suppressed MUC2 expression in ileal organoids. Collectively, these findings uncover a L. plantarum-ILA-AHR signaling axis that promotes intestinal goblet cell differentiation, providing mechanistic insight into microbial metabolite-mediated regulation of epithelial homeostasis during post-weaning period in pigs.