Lactate Alleviates Intestinal Barrier Injury in Weaned Piglets via Activation of the Wnt/β-Catenin Pathway and Promotion of Intestinal Epithelial Cell Proliferation1

Background: Inflammatory bowel disease causes intestinal structural damage, impairs gut function, hinders animal growth and development, and reduces farming efficiency. Previous studies demonstrated that lactate alleviates Dextran Sulfate Sodium (DSS)-induced inflammation and mitigates weight loss by enhancing intestinal barrier functions. However, the mechanisms underlying lactate-mediated protection of the intestinal epithelial barrier unclear . This study aimed to explore the protective effect of lactate on intestinal barrier damage in colitis piglets and the possible underlying mechanisms through in vivo and in vitro experiments. Methods: A colitis model was established using weaned piglets administered DSS, with three experimental groups: control, DSS-treated, and DSS-treated with lactate supplementation. Jejunal morphology was assessed via Hematoxylin·and Eosin staining, while Western blotting quantified the expression levels of proliferation markers, including Cluster of Differentiation·24 (CD24) and Cyclin D1, and Wingless / Integrated (Wnt)/β-catenin signaling components. In vitro, DSS and sodium lactate treated Intestinal Porcine Epithelial Cell line-J2 (IPEC-J2) intestinal epithelial cells were assessed for viability (Cell Counting Kit-8 assay), apoptosis (flow cytometry), and proliferation parameters, including cell cycle analysis and Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5+) stem cell quantification. Results: DSS administration induced significant jejunal villus shortening, downregulated CD24 and Cyclin D1 expression, and inhibited Wnt/β-catenin signaling in vivo. In vitro, DSS promoted apoptosis, inhibited proliferation, diminished the Lgr5+ cell populations, and reduced S-phase cell proportions. Conversely, lactate supplementation ameliorated DSS-induced villus atrophy, restored CD24 and Cyclin D1 levels, and activated Wnt/β-catenin signaling. Furthermore, in vitro, sodium lactate attenuated DSS-induced apoptosis, enhanced IPEC-J2 proliferation, expanded Lgr5+ cells, and increased S-phase progression. Conclusions: In summary, lactate ameliorated intestinal barrier damage in DSS-induced colitis by activating the Wnt/β-catenin pathway and restoring the balance between epithelial cell proliferation and apoptosis. This study provides novel mechanistic evidence supporting lactate’s therapeutic potential for IBD management.