Therapeutic effects of probiotics in topical treatment of infected wounds

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Abstract

Wound infections, exacerbated by antibiotic resistance and biofilm formation, necessitate alternative therapeutic options. One promising approach is topical bacteriotherapy with live probiotics. The work aimed to summarize existing research on the multifaceted effects of live probiotics in infected wound healing. The review examines how probiotics directly influence pathogenic wound microflora by competing for adhesion sites and nutrients, secreting antagonistic compounds, altering the wound environment, and promoting co-aggregation. Probiotics’ antibiofilm activity is highlighted, including inhibition of quorum sensing systems and disruption of the extracellular biofilm matrix. Moreover, the review discusses the findings of in vitro and in vivo studies on the effects of live probiotics on macroorganisms. Probiotics have been shown to activate signaling pathways that regulate macrophage shift from a pro-inflammatory (M1) phenotype to a pro-repair (M2) phenotype, cytokine synthesis, keratinocyte and fibroblast migration and proliferation, angiogenesis, and collagen matrix formation. Thus, the multifaceted effects of probiotics cannot be replicated by metabolites or inactivated cells alone, highlighting the need for effective delivery systems for live probiotic cultures in infected wound management.

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INTRODUCTION

Wound infections are a major challenge in healthcare due to prolonged treatment and increased disability and mortality rates [1]. Multiple drug resistance and refractory microbial biofilm formation decrease the efficacy of conventional antimicrobial therapy in the treatment of infected wounds [2]. The most common pathogens associated with wound infections are Pseudomonas aeruginosa, Staphylococcus aureus, and Candida albicans, which are known for their antibiotic resistance [1]. As a result, various alternative approaches to wound infection management are being investigated. These include antimicrobial peptides, physical therapy (phototherapy, ultrasound, electromagnetic therapy, negative pressure), silver dressings, and live bacterial therapeutics [2–4].

Bacteriotherapy uses bacterial interference (antagonism between bacterial species) as the primary mechanism of action in the treatment of wound infections [5]. There are several probiotic microorganisms that are non-pathogenic in humans and lack virulence factors. These beneficial bacteria have been extensively studied and utilized in various fields of medicine, including gastrointestinal diseases, immunomodulation, and, more recently, wound management [1]. According to numerous in vitro and in vivo studies, topical probiotics improve wound healing by inhibiting pathogens, modulating inflammation, and promoting tissue regeneration [2, 6]. Probiotic cultures are believed to have multifaceted therapeutic effects in wound management. As a result, they may be more effective than postbiotics containing nonviable cells or cellular components [7]. Real-world applications of probiotics in topical treatment are currently challenging due to the risk of uncontrolled spread or displacement from the infection site. This issue can be addressed by designing a carrier system that controls the release of probiotics into wounds [1].

Numerous studies have examined the effects of intestinal probiotics in gastrointestinal diseases [8] and skin injuries [9]. It is reasonable to assume that topical effects of probiotics can be equally diverse; therefore, they need to be examined and systematized, given the increasingly wide use of bacteriotherapy in topical wound care.

This review addresses the multifaceted topical effects of live probiotics in infected wound healing.

DIRECT ANTAGONISM

Probiotics’ direct mechanisms of action include competing for adhesion sites and essential nutrients, as well as secreting extracellular antagonistic substances such as surfactants, bacteriocins, extracellular polymeric substances, organic acids, fatty acids, enzymes (lipase, amylase), and hydrogen peroxide, which hinder the activity of pathogens [10]. Probiotics help maintain a balanced microbial ecosystem on the skin by outcompeting pathogens and fostering beneficial bacteria, which is crucial for healing all types of wounds [11].

Bacterial adhesion is the first stage of colonization; therefore, inhibiting adhesion is crucial to avoid pathogenic colonization [12]. Lactobacilli can inhibit pathogen invasion into keratinocytes by competitive exclusion [13]. An in vitro study in HaCaT cells (immortalized human keratinocytes) found that Lactobacillus rhamnosus and Propioniferax innocua effectively inhibited pathogen adhesion to keratinocytes when added simultaneously. Probiotic bacteria, particularly Lactobacillus and Lacticaseibacillus, had higher HaCaT invasion rates than pathogenic bacteria. Furthermore, probiotics and pathogens utilize different mechanisms of adhesion; specifically, probiotics use carbohydrates, whereas S. aureus uses adhesins [12].

Lactobacillus reuteri and L. rhamnosus GG can inhibit initial adhesion of S. aureus to keratinocytes and displace staphylococci that are already attached to human keratinocytes [14, 15]. Adhesion of probiotics to the epithelium has been suggested to occur via collagen-binding proteins, mucus-binding proteins, lipoteichoic acids, and S-layer proteins, and more than one adhesin may be in use. L. reuteri has been shown to inhibit staphylococcal adhesion to keratinocytes when cells were preexposed to a probiotic but not when applied after staphylococcal infection had begun, indicating that the pathogen cannot be displaced from binding sites. According to other research, competitive displacement may require longer to occur [15].

Many probiotics, such as Bifidobacterium longum, L. rhamnosus, and Lactobacillus delbrueckii, can form co-aggregates with other microorganisms, including the common wound pathogens S. aureus and C. albicans. In vitro studies have shown that aggregating probiotics can displace pathogens from epithelial cells; however, in vivo studies have yet to be conducted [15].

Another antimicrobial effect of probiotics is their ability to produce bacteriocins. Unlike antibiotics, which inhibit metabolism and synthesis in bacterial cells, bacteriocins cause structural damage and death of the target cell. They have lower toxicity and a reduced risk of microbial resistance [16].

Reuterin, a bacteriocin produced by L. reuteri, is well-studied in terms of topical wound care. In an in vitro hydrogel platform, reuterin achieved >95% eradication of E. coli and S. aureus, as well as effective biofilm disruption. In vivo rat tail amputation experiments showed that reuterin promoted mechanical reinforcement of the hydrogel matrix while also having a substantial antibacterial effect [17]. Jin et al. [18] have developed an L. reuteri-loaded microneedle patch containing glycerol for continuous reuterin production, achieving long-acting antimicrobial and anti-inflammatory effects in infected wounds. The produced reuterin caused considerable morphological changes in E. coli, S. aureus, and P. aeruginosa.

Reuterin can inhibit ribonucleic acid reductase activity, which in turn can interfere with bacterial DNA replication to inhibit bacterial proliferation [6]. Notably, reuterin also exerts an anti-inflammatory effect by downregulating the expression of toll-like receptor 4 (TLR4), blocking the activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, and activating antioxidant enzymes through the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling pathway [19].

Bacillus subtilis is known for its ability to produce bacteriocins with broad-spectrum antibiotic activities. Furthermore, it produces biosurfactant lipopeptides with antioxidant properties, which facilitates wound healing [20]. Surfactin secreted by B. subtilis inhibits the growth of E. coli and S. aureus by lysis of lipid membranes. Moreover, it reduces and inhibits S. aureus biofilm formation by disrupting surface adhesion [21, 22].

Lactobacilli, including Lactobacillus fermentum, Lactobacillus acidophilus, and Lactobacillus jensenii, produce hydrogen peroxide, which reduces the number of Gram-positive anaerobes such as Bacteroides, Prevotella, Gardnerella, and Mycoplasma spp. Diacetyl, another metabolic product of lactic acid bacteria, also has broad-spectrum antibiotic activities against both Gram-negative and Gram-positive pathogens [15].

ALTERATIONS IN WOUND ENVIRONMENT

Skin wound healing is a complex physiological process where the microenvironment plays an essential role [23]. The natural physiological pH of a healthy human epidermal layer is maintained in the range of 4.5–5.3, with a pH gradient over the horny layer increasing to 6.8. The microenvironment pH of wounds is more alkaline, reaching 7.4 [24]. More acidic or alkaline pH can considerably delay wound healing [25]. A mildly acidic environment inhibits bacterial growth and promotes oxygen supply [26]. Acidification of the wound improves metabolic activity and migration of keratinocytes and fibroblasts in the skin, likely through upregulation of the transforming growth factor-β (TGF-β) signaling pathway [24].

Lactic acid bacteria produce a wide range of organic acids by fermenting carbohydrates, including acetic, lactic, citric, succinic, and propionic acid. The key targets of these organic acids are cell walls of bacteria, cytoplasmic membranes, and specific metabolism of bacteria, leading to the destruction and death of pathogenic microorganisms [27].

Notably, different microorganisms have varying sensitivity to environmental pH. For example, P. aeruginosa has increased sensitivity to lactic acid produced by Lactobacillus plantarum, which decreases local pH, thus inhibiting bacterial growth. In contrast, S. aureus can grow at pH levels ranging from 4.2 to 9.3 [28].

Valdéz et al. [29] tested L. plantarum whole cultures, culture filtrates (acid filtrate and neutralized acid filtrate), and isolated, washed cells in vitro for their effects on the production of P. aeruginosa quorum-sensing signal molecules, acyl-homoserine-lactones, and two virulence factors controlled by these signal molecules (elastase and biofilm). All were inhibited by L. plantarum cultures and filtrates, but not by isolated, washed cells. The acid L. plantarum growth medium itself had some inhibitory activity, but the greatest activity was exerted by the whole culture.

ANTIBIOFILM ACTIVITY

Bacterial biofilms are formed by microbial communities embedded in a self-produced matrix of extracellular polymeric substances [30]. The compact three-dimensional structure of extracellular polymeric substances within biofilms considerably hinders the penetration of antimicrobial agents, resulting in persistent infections [31].

The first microorganisms reported to inhibit S. aureus biofilm formation were Staphylococcus epidermidis strains expressing glutamyl endopeptidase, a serine protease that degrades proteins essential for S. aureus biofilm formation and epithelial adhesion in macroorganisms [32].

The antibiofilm activity of bacteriocins has been demonstrated in numerous studies. Some bacteriocins eradicate biofilm by inducing pore formation on the bacterial cell surface, leading to adenosine triphosphate efflux, whereas others use proteolytic enzymes [10]. Bacteriocins may reduce the production of bacterial extracellular polysaccharides and bacterial motility by altering the expression of biofilm-related genes [33]. Levilactobacillus brevis DF01 bacteriocin inhibits biofilm formation; however, it does not eliminate existing E. coli and Salmonella typhimurium biofilms [34]. Biosurfactants produced by Pediococcus acidilactici and L. plantarum had good anti-adhesion and anti-biofilm activity against S. aureus by influencing the expression of biofilm-related genes (cidA, icaA, dltB, agrA, sortaseA, and sarA) and the release of autoinducer-2 (AI-2) signaling molecules [35]. Antibiofilm activity has been reported not only for individual bacterial metabolites, but also for live cells in an infected wound model. For example, an L. plantarum-containing hydrogel prevented P. aeruginosa and S. aureus biofilm formation in a human ex vivo skin model [35].

Several in vitro studies found that probiotics can influence the expression of genes that regulate cell adhesion and quorum sensing. Quorum sensing (QS) refers to an intercellular communication system that microorganisms utilize to alter gene expression based on cell population density in order to form biofilms and confer virulence. Most pathogens, including species commonly found in chronic wounds (e.g., P. aeruginosa and S. aureus), utilize QS for virulence, biofilm formation, and resistance to host defense. Nevertheless, probiotics can interfere with the pathogen’s QS [13]. L. plantarum inhibits P. aeruginosa QS signal molecules (acyl-homoserine-lactones) and reduces biofilm formation [29]. Subtilosin A, a cyclic bacteriocin produced by Bacillus subtilis, has been shown to inhibit QS in Gram-positive bacteria [36].

EFFECTS ON MACROORGANISMS

Maintaining Normal Microbiota

Extensive research is currently ongoing on host immune responses to normal microflora of the skin [37]. Commensal skin bacteria can induce T cell responses in a manner restricted to non-classical major histocompatibility complex I (MHC-I) molecules. These responses are uncoupled from inflammation and highly distinct from pathogen-induced responses. Commensal-specific T cells express defined immunoregulatory and tissue repair gene signatures. As such, commensal-specific immune responses not only protect from pathogens but also accelerate skin wound healing [38].

Skin microbiota can inhibit the expression of pro-inflammatory chemokines and promote the enrichment and localization of normal immune cells in the skin, whereas an imbalance in skin microbiota can inhibit the skin’s regenerative ability [39]. Thus, probiotics promote wound healing by maintaining normal microbiota.

Immunomodulation

Wound healing is a coordinated process that involves hemostasis, inflammation, proliferation, and remodeling. During normal wound healing, immune cells are recruited to the injury to clear tissue debris and prevent infection. Specifically, proinflammatory mediators such as immune cell chemoattractants, cytokines, reactive oxygen species, and prostaglandins are produced to promote wound healing. However, sustained inflammation may lead to lymphocyte death, reduced antigen presentation, and the inability of monocytes/macrophages to secrete inflammatory cytokines when stimulated [40].

Wound healing involves a macrophage shift from a pro-inflammatory (M1) phenotype to an anti-inflammatory (M2) phenotype. The accumulation of M1 macrophages promotes inflammation and prevents healing. Lactate produced by probiotics acts as a metabolic signaling molecule and can inhibit M1 macrophage activity while promoting M2 macrophage polarization [2]. Lactic acid-activated M2 macrophages can produce growth factors such as vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and TGF-β, resulting in a positive feedback that further promotes angiogenesis and tissue regeneration [41].

An analysis of gene expression by real-time reverse transcription polymerase chain reaction found that a Lactobacillus casei-containing hydrogel decreased the expression of M1 marker genes such as tumor necrosis factor-β (TNF-β) and inducible nitric-oxide synthase (iNOS) while increasing the expression of M2 marker genes such as signal transducer and activator of transcription 3 (STAT3) and mannose receptor C-type 1 (MRC1) [2].

Inflammatory cells, particularly macrophages and neutrophils, are essential for wound healing; however, their prolonged overactivation impairs healing. An L. plantarum-containing hydrogel decreased TNF-α and interleukin 6 (IL-6) levels in an in vivo experiment [23].

In an in vivo model of wound infection, L. acidophilus stimulated monocyte chemoattractant protein-1 (MCP-1) and IL-6 production in plasma after 24-hour wound infection. However, after 5 days, the postbiotic attenuated plasma MCP-1 and IL-6 levels. The authors postulate that the postbiotic modulates the host response by initially stimulating the immune response to clear infection, but over time, in the highly stimulated cells, its lowered concentration reduces the inflammatory response [40].

In an in vivo S. aureus–infected wound model, topical L. rhamnosus and Bifidobacterium animalis inhibited neutrophil infiltration and decreased the expression of pro-inflammatory cytokines TNF-α and IL-6. Notably, B. animalis markedly reduced IL-6 levels, while L. rhamnosus considerably lowered TNF-α, TGF-β, and VEGF levels. Additionally, both probiotics promoted macrophage polarization towards the anti-inflammatory M2 phenotype [39].

Effect on Keratinocytes, Fibroblasts, and Epidermal Blood Vessel Development

Microbiota regulates skin homeostasis by influencing a variety of cell signaling and homeostatic processes, including keratinocyte proliferation, epithelial differentiation, and epidermal blood vessel development. Each strain works differently and more effectively in different phases of healing [42].

The role of probiotics in gastrointestinal wound healing is reasonably well-studied; it is primarily mediated by the activation of epithelial cells and stimulation of fibroblast proliferation and/or migration [13]. Similar processes are likely to occur in the skin. In an in vitro study, B. longum, L. plantarum, L. reuteri, and L. rhamnosus GG lysates modified the tight-junction function of human primary keratinocytes [43]. Probiotics such as L. casei and L. rhamnosus GG improve the epithelial barrier by increasing the expression of tight junction proteins, which prevents pathogen entry and reduces the risk of infection [11].

In an in vitro experiment in a human dermal fibroblast culture, a probiotic mixture containing L. acidophilus, L. casei, and L. rhamnosus effectively stimulated fibroblast migration. It was associated with upregulation of genes involved in the phosphoinositide 3-kinase (PI3K) signaling pathways. Moreover, these probiotics downregulated the expression of NADPH oxidase 4, alpha-smooth muscle actin, and type I collagen in TGF-Smad signaling pathways, which are involved in the differentiation of fibroblasts to myofibroblasts and extracellular matrix type I collagen production [44]. One of the acting factors for such downregulation was the produced lactic acid.

Plantaricin A produced by L. plantarum promotes the expression of TGF-β1, FGF-7 (fibroblast growth factor), VEGF-A, and IL-8 genes in recipient cells [45]. Surfactin A produced by B. subtilis upregulated the expression of hypoxia-inducible factor-1α (HIF-1α) and VEGF, accelerated keratinocyte migration through MAPK and NF-κB signaling pathways, and regulated the secretion of pro-inflammatory cytokines and macrophage phenotypic switch. Moreover, surfactin A inhibited scar tissue formation by affecting the expression of α-smooth muscle actin and transforming growth factor [46].

Many wound healing effects (growth factor and cytokine modulation, proangiogenic effect, cell proliferation and migration, re-epithelization, etc.) are currently linked to exopolysaccharides produced by various bacteria. For example, an exopolysaccharide derived from the probiotic L. plantarum GD2 promoted fibroblast-mediated wound healing by facilitating fibroblast migration and collagen synthesis through the TGF-β1/Smad signaling pathway [47]. Furthermore, probiotics can induce re-epithelization through chemokine induction. For example, L. rhamnosus GG increased the expression of the chemokine CXCL2 (macrophage inflammatory protein 2-2β) and its receptor CXCR2 (interleukin 8 receptor, beta), which promote keratinocyte proliferation and migration during normal wound healing [48].

Neovascularization promotes fibroblast migration and proliferation, collagen deposition, and re-epithelization by delivering oxygen and nutrients to the injury site. In vivo experiments using live probiotics confirm the findings of in vitro studies. Jin et al. [18] reported that an L. reuteri-loaded microneedle patch was more effective in wound healing in vivo owing to increased collagen deposition, decreased IL-6 secretion, and improved angiogenesis. L. casei-containing cellular matrices (scaffolds) can induce macrophage polarization during the early stages of the wound process, thus reducing inflammation, and activate VEGF to promote angiogenesis. During the advanced stages, they can downregulate TGF-β1 expression, reducing tissue fibrosis and endoplasmic reticulum stress by inhibiting the expression of IRE1, XBP1, and CHOP markers [41].

Probiotic therapy with L. plantarum reduced type I collagen mRNA concentrations in an in vivo burn wound model in rabbits by approximately 50%, irrespective of wound infection [49]. Furthermore, L. plantarum-treated wounds showed considerably higher levels of immature type III collagen, indicating that probiotic therapy can modulate not only the quantity but also the type of collagen. The effect of probiotics on the ratio of different collagen types highlights their potential role in reducing fibrosis and scarring [49].

Thus, probiotics exert a variety of effects in macroorganisms through several signaling pathways. However, the health-promoting properties of probiotics are suggested to be strain-dependent. Therefore, the identity and characteristics of the strain are of paramount importance in the treatment of infected wounds in real-world practice [50].

CONCLUSION

According to numerous in vitro and in vivo studies, topical live probiotics accelerate the healing of infected wounds by targeting several factors of the wound process. First, probiotics directly outcompete pathogens and promote the growth of commensal microflora, preventing biofilm formation. Second, probiotics promote acidification of the wound, further influencing pathogens and macrophage activity. Third, probiotics and their metabolites activate a variety of signaling pathways associated with pro- and anti-inflammatory cytokine expression, keratinocyte and fibroblast proliferation and migration, angiogenesis, and collagen deposition, which promotes tissue regeneration.

As a result, the multifaceted effects of probiotics cannot be replicated by metabolites or inactivated cells alone. Thus, it is relevant to use live probiotics in dressings for infected wounds.

ADDITIONAL INFORMATION

Author contributions: R.V. Ishchenko, D.A. Filimonov, and A.G. Popandopulo contributed to the concept development; M.A. Belotserkovskaya, K.O. Golubitsky, I.A. Kisilenko, V.V. Turchin, and M.V. Solopov conducted the research and performed data work; M.A. Belotserkovskaya drafted the manuscript; A.G. Popandopulo, D.A. Filimonov, and V.A. Gasanov revised and edited the manuscript. Thereby, all authors provided approval of the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Funding sources: The study was carried out within the framework of a grant from the Russian Science Foundation (grant number 25-15-20602). The Russian Science Foundation did not participate in the organization, planning, or conduct of the study; in the collection, storage, analysis, or interpretation of the data; in the preparation of the manuscript or the decision to publish it; nor in the oversight of the study. The Russian Science Foundation imposed no restrictions on data use or dissemination of the study results.

Disclosure of interests: The authors declare no conflict of interests.

Statement of originality: All data presented in this work were obtained for the first time specifically for the purposes of this study. The manuscript text is original and does not contain borrowings from previous publications by the authors or other individuals without proper citation. Previously published or publicly available data (own or third-party) are not used in this article.

Data availability statement: All data obtained in the present study are available within the article.

Generative AI: Generative AI technologies were not used for this article creation.

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About the authors

Roman V. Ishchenko

V.K. Gusak Institute of Urgent and Recovery Surgery

Email: ishenkorv@rambler.ru
ORCID iD: 0000-0003-0260-6922
SPIN-code: 9021-7370

MD, PhD, Professor

Russian Federation, Donetsk

Kirill O. Golubitskiy

V.K. Gusak Institute of Urgent and Recovery Surgery

Email: kirill.golubitskiy@mail.ru
ORCID iD: 0000-0002-0174-5798
SPIN-code: 3953-2954

MD, PhD

Russian Federation, Donetsk

Maksim V. Solopov

V.K. Gusak Institute of Urgent and Recovery Surgery

Email: mxsolopov@yandex.ru
ORCID iD: 0000-0001-7053-4428
SPIN-code: 3147-0739
Russian Federation, Donetsk

Irina A. Kisilenko

V.K. Gusak Institute of Urgent and Recovery Surgery

Email: irinka.dn.15@gmail.com
ORCID iD: 0009-0006-6404-2930
SPIN-code: 1781-3235
Russian Federation, Donetsk

Margarita A. Belotserkovskaya

V.K. Gusak Institute of Urgent and Recovery Surgery

Author for correspondence.
Email: margarita-amb@mail.ru
ORCID iD: 0009-0004-3019-144X
SPIN-code: 7737-6730
Russian Federation, Donetsk

Viktor V. Turchyn

V.K. Gusak Institute of Urgent and Recovery Surgery

Email: turchin.dn@mail.ru
ORCID iD: 0000-0002-6461-4904
SPIN-code: 3675-2361
Russian Federation, Donetsk

Dmitry A. Filimonov

V.K. Gusak Institute of Urgent and Recovery Surgery

Email: neuro.dnmu@gmail.com
ORCID iD: 0000-0002-4542-6860
SPIN-code: 1491-8262

MD, PhD

Russian Federation, Donetsk

Andrey G. Popandopulo

V.K. Gusak Institute of Urgent and Recovery Surgery

Email: pag.lctc@mail.ru
ORCID iD: 0000-0001-9755-1869

MD, PhD, Professor

Russian Federation, Donetsk

Vagif A. Gasanov

Koltzov Institute of Developmental Biology Russian Academy of Science

Email: gasanovvagif@gmail.com
ORCID iD: 0000-0001-6311-0838
SPIN-code: 8212-9821

MD, PhD

Russian Federation, Moscow

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