Probiotics promote cellular wound healing responses by modulating the PI3K and TGF-β/Smad signaling pathways.

BACKGROUND: Skin wound healing represents a dynamic and intricate biological process involving the coordinated efforts of various cellular and molecular components to restore tissue integrity and functionality. Among the myriads of cellular events orchestrating wound closure, fibroblast migration and the regulation of fibrosis play pivotal roles in determining the outcome of wound healing. In recent years, probiotic therapy has emerged as a promising strategy for modulating wound healing and fibrosis. Here, we aim to investigate the effect of bacterial probiotics on cell migration and anti-fibrotic response of human dermal fibroblast (HDFs). METHODS: Probiotic mixture BioK was co-cultured with HDFs in vitro to assess its impact on fibroblast migration, gene expression, and protein production associated with important processes in wound healing. Gene expression was investigated by transcriptomic analysis and confirmed by RT-qPCR. Protein levels of the identified genes were evaluated by ELISA. The role of lactic acid, produced by BioK, in mediating pH-related effects on fibroblast activity was further examined. RESULTS: We observed that BioK effectively promoted HDFs migration in vitro, which was found to be related to the up-regulation of genes involved in the phosphoinositide 3-kinase (PI3K) signaling pathways such as Paxillin, PI3K, PKC and ITG-β1. Interestingly, we also found that BioK down-regulated the expression of Nox-4, α-SMA and Col-I in TGF-Smad signaling pathways, which are involved in the differentiation of fibroblasts to myofibroblasts, and extracellular matrix type I collagen production, demonstrating its potential in reducing formation of fibrosis and scars. One of the acting factors for such down-regulation was identified to be BioK-produced lactic acid, which is known to lower the surrounding pH and to play a major role in fibroblast activity and wound healing. CONCLUSIONS: This study demonstrates BioK's beneficial effects on fibroblast migration and its potential to mitigate fibrosis through pH modulation and pathway-specific gene regulation. These findings enhance our understanding of probiotic action on wound healing and offer promising therapeutic insights for the reduction of scar formation. CLINICAL TRIAL NUMBER: Not applicable.