Probiotic therapy for chronic wound infections and wound healing promotion: from molecular mechanism to potential clinical application
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Date
2025
Publication Type
Doctoral Thesis
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Abstract
Chronic wound infections, particularly those driven by biofilm-forming Pseudomonas aeruginosa (PA), remain a significant clinical challenge due to their resistance to conven-tional therapies and their detrimental effects on tissue repair. Current treatments, including mechanical debridement and antibiotics, often fail to fully eradicate biofilms, leading to recurrent infections and delayed healing. This thesis investigates the potential of probiot-ics as dual-action therapeutic agents capable of both disrupting biofilm development and promoting regenerative processes in skin wounds.
Using an ex vivo human skin wound model, a probiotic formulation (BioK) comprising three lactic acid bacterial strains demonstrated complete eradication of mature PA biofilms, outperforming antibiotics and silver-based antimicrobials. BioK exhibited strong cyto-compatibility and significantly enhanced fibroblast migration, with its clinical potential further advanced by incorporation into a hydrogel dressing for sustained release and pro-longed antimicrobial activity.
To study the mechanisms by which probiotics interfere with pathogenic biofilms on a re-liable platform, a droplet-based cultivation method was established. This simple and ver-satile approach enables rapid, high-throughput assessment of anti-biofilm efficacy across diverse pathogenic biofilms grown on clinically relevant materials. In this method, bio-films are cultivated within a small inoculum droplet on a defined planar surface, which fa-cilitates oxygen diffusion and biomass production while improving reproducibility com-pared to conventional microtiter plate systems. The planar substrate geometry also allows direct surface analyses with advanced characterization techniques such as confocal laser scanning microscopy and scanning electron microscopy.
Mechanistic studies further uncovered how probiotics interfere with biofilm initiation. Lactobacillus. casei was shown to secrete long-chain fatty acid metabolites that directly influenced flagellar assembly and motility in PA. These metabolites downregulated fleR, a core transcriptional regulator in the flagellar biosynthesis pathway, impairing bacterial motility and surface adhesion. This disruption prevented effective colonization at the early, reversible stage of biofilm development, highlighting a novel probiotic strategy for halting biofilm formation before maturation.
At the tissue level, probiotic metabolites were found to actively regulate fibroblast behav-ior, linking infection control with wound repair. Lactic acid derived from BioK enhanced fibroblast migration by activating PI3K-related signaling pathways, including the upregulation of Paxillin, PKC, and integrin β1, which together support cytoskeletal remodeling and directional cell movement. At the same time, probiotics downregulated the TGF-β/Smad pathway, reducing the expression of Nox-4, α-SMA, and type I collagen, thereby suppressing fibroblast-to-myofibroblast differentiation. This dual action promoted efficient tissue regeneration while attenuating fibrosis, suggesting that probiotics not only accelerate wound closure but also reduce the risk of excessive scarring and impaired function.
Collectively, this work provides comprehensive insights into the interactions between probiotics, pathogenic bacteria, and host tissue. It demonstrates that probiotics can simul-taneously eradicate mature biofilms, prevent their early formation through long-chain fatty acid–mediated interference with bacterial motility, and fine-tuning of fibroblast responses to support regeneration and limit fibrosis. These findings establish a strong theoretical and experimental foundation for next-generation probiotic-based therapies in chronic wound management and other biofilm-associated conditions.
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Examiner : Maniura, Katharina
Examiner : Ren, Qun
Examiner : Schürle-Finke, Simone
Examiner : Glinel, Karine
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ETH Zurich
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Subject
Microbiology; Biofilm; Materials science; Molecular Biology; Bioinformatics
Organisational unit
02070 - Dep. Gesundheitswiss. und Technologie / Dep. of Health Sciences and Technology