The epidermis and dermis together form a coordinated network of immune and non-immune cells that maintains barrier integrity, supports epithelial renewal, and protects against pathogen invasion. As an active barrier, the skin microbiota dynamically interacts with keratinocytes and multiple immune cell populations to maintain cutaneous homeostasis, establishing a regulated immune dialogue that limits unnecessary inflammation (Byrd et al., 2018; Belkaid and Segre, 2014). In healthy skin, keratinocytes and immune cells exhibit a highly organized, layer-specific distribution. The epidermis is primarily populated by Langerhans cells and tissue-resident memory T cells (T_RM), which serve as the first line of immunological surveillance (Hoeffel et al., 2012; Ginhoux et al., 2006). In contrast, the dermis has a more diverse immune landscape. It contains multiple dendritic cell (DC) subsets, including dermal DCs and plasmacytoid DCs (pDCs), as well as T-cell populations such as CD4⁺ helper T-cell subsets (Th1, Th2, and Th17), γδ T cells, and natural killer T (NKT) cells (Zareie et al., 2025). The dermis is further enriched with macrophages, mast cells, neutrophils, innate lymphoid cells (ILCs), mucosal-associated invariant T (MAIT) cells, and fibroblasts, all of which contribute to immune regulation and tissue homeostasis (Nestle et al., 2009; Tong et al., 2015). As shown in Figure 1, these immune cells engage in continuous crosstalk with resident commensal microbes.

Early microbial colonization contributes to the development of anti-infective immunity in infants, indicating that tolerance mechanisms between host and microbiota emerge early in life (Dwyer and Scharschmidt, 2022). For example, commensals such as S. epidermidis, C. acnes, and Corynebacterium species can activate DC–driven regulatory T-cell (Treg) responses, promoting immune tolerance. This is particularly evident during early follicular colonization, when commensal-induced CCL20 expression recruits (Weckel et al., 2023). The enrichment of Tregs in newborns is essential for establishing immune tolerance to skin commensal microbes later in life (Scharschmidt et al., 2015). In addition, tissue-resident MAIT cells develop under the influence of early commensal microbes and become a dominant IL-17–producing effector subset in the skin (Constantinides et al., 2019). γδ T and ILC2 cells also participate in barrier regulation through activation of the IAId–TSLP pathway (Cha et al., 2024).

In adulthood, healthy skin keratinocytes recognize commensals through TLR2, such as lipoteichoic acid(LTA) (Volz et al., 2018) from S. epidermidis. This activation induces AMP and IL-10, strengthening the immune barrier. S. lugdunensis can also induce LL-37 and CXCL8 expression through the TLR–MyD88 pathway, promoting monocyte and neutrophil recruitment to regulate inflammation and preserve homeostasis (Bitschar et al., 2019). The S. epidermidis can further activate keratinocytes through the LTA–TLR2 signaling pathway, thereby inducing the secretion of stem cell factor (SCF) and promoting mast cell recruitment and maturation (Di Nardo et al., 2023). Mature mast cells possess intrinsic antibacterial activity. In addition, under the regulatory influence of dermal fibroblasts, mast cells can develop tolerance toward commensal microbes, which contributes to the maintenance of cutaneous microbial homeostasis (Wang et al., 2017)

Commensal microbial antigens can be presented by DCs to activate CD4⁺T (Th17) and CD8⁺T (Tc17) cells (Naik et al., 2015). These effector cells secrete IL-17A, which stimulates the production of AMPs, enhances epithelial barrier integrity, strengthens antimicrobial defense, and contributes to cutaneous immune homeostasis. In particular, Tc17 cells can acquire CD8⁺ TRM17 which secrete IL-17A (Harrison et al., 2019) and play key crucial role in reinforcing local barrier defense and sustaining long-term immune surveillance in the skin. In parallel, through the presentation of N-formyl methionine–containing peptides(fMet) by non-classical MHC class I molecules(MHC-Ib), commensals such as S. epidermidis elicit a distinct population of tissue-resident CD8⁺ T cells endowed with integrated antimicrobial and immunoregulatory functions (Linehan et al., 2018). Unconventional T cells represent an important population of tissue-resident immune cells that continuously contribute to the maintenance of immune balance and barrier homeostasis in the skin. This group primarily includes γδ T cells, MAIT cells, and iNKT cells. Their antigen recognition is restricted by MHC-Ib, enabling them to sense highly conserved microbial metabolites or lipid antigens (Constantinides and Belkaid, 2021).

Notably, Corynebacterium can induce the expansion of γδ T cells (Ridaura et al., 2018). MAIT cells are activated via MR1-presented riboflavin metabolites from S. epidermidis and fungi, leading to IL-17A production and enhanced mucosal defense (Constantinides et al., 2019).

Although the traditional view held that B cells are largely absent from the skin (Bos et al., 1987), an increasing number of studies have demonstrated that B cells can indeed be detected in the healthy skin of humans and other mammals such as sheep and mice (Geherin et al., 2012; Geherin et al., 2016). Skin B cells include both conventional B-2 cells and innate-like B-1–like cells (Debes and McGettigan, 2019). Most skin B cells are B-2 cells derived from the peripheral blood, which transiently reside in the skin, although their residency duration is not well defined. Innate-like B-1–like cells are more abundant and can generate antibody responses independently of T-cell help, providing rapid humoral protection at the skin barrier. Overall, B cells play essential roles in antibody production, antigen presentation, T-cell activation, and the modulation of inflammatory responses (Debes and McGettigan, 2019).

Recent findings show that immunoglobulins secreted by B-1-like cells can be detected on the skin surface (Baumgarth, 2011; Kearney, JF, 2005). Electron microscopy has revealed that many skin microbes are coated with IgA, IgG, or IgM (Metze et al., 1991; Wilson et al., 2019; Dryla et al., 2005), and secretory IgA can be found in sebaceous glands and follicular ducts (Gebhart et al., 1986; Okada et al., 1988). These evidences indicate that antibodies produced by B cells contribute to the maintenance of skin microbial homeostasis by binding to commensal microbes and modulating their colonization and community stability. In children aged 2 months to 18 years, anti–S. aureus IgM appears earliest (Jiang et al., 2015), IgA peaks between ages 4 and 6, and IgG increases steadily with age (Jiang et al., 2015). These observations suggest that the skin, similar to the gut (Macpherson et al., 2018; Grasset et al., 2020; Kelly et al., 2005; Mann and Li, 2014; Kato et al., 2014; Magri et al., 2017), maintains a form of local humoral immune homeostasis in which antibodies cooperate with commensal microbes to provide early protection against pathogens. Early-life colonization by S. aureus is capable of eliciting high-titer, antigen-specific antibodies that can persist for years in healthy individuals, indicating potential for long-term immune memory and informing vaccine strategies (Dryla et al., 2005).

A recent study also identified tertiary lymphoid structures (TLOs) in healthy skin (Gribonika et al., 2025). Under stimulation by S. epidermidis, Langerhans cells present antigens to CD4⁺ T cells, suppress Foxp3 expression in Tregs, and promote the activation of follicular helper T cells (Tfh) (Gribonika et al., 2025). This process occurs locally in the skin and can extend to systemic immunity. In draining lymph nodes, Tfh cells drive B-cell activation and induce the production of systemic IgG1 and IgG3. In the skin, Tfh cells promote the formation of TLOs, where mucosa-associated antibodies such as IgG2b and IgG2c are generated (Gribonika et al., 2025). These antibodies eventually reach the skin surface to strengthen barrier immunity, while the resulting memory B cells and plasma cells can remain long-term within the tissue. Beyond antibody generation, regulatory B cells (Bregs), which secrete IL-10, constitute an important B-cell subset with immunomodulatory functions (Lykken et al., 2015). Bregs are increasingly recognized for their roles in limiting skin inflammation and maintaining immune balance (Candando et al., 2014). Even under non-inflammatory conditions, Bregs can suppress inappropriate immune activation against commensals, thereby contributing to local immune homeostasis (Geherin et al., 2016). Natural Bregs (nBregs) not only produce antibodies reactive to microbes but may also facilitate the establishment of early skin microbial communities (Gu et al., 2024). The influence of skin microbiota on Bregs requires further investigation and should be a promising area of research.

Given that the preceding sections primarily address microbiota-driven immune education, other protective mechanisms, such as physical barrier reinforcement, microbial antagonism, and chemical interactions, are summarized in Figure 2. Commensal skin bacteria maintain microbial balance through antimicrobial activity and quorum-sensing (QS)–mediated competition (Glatthardt et al., 2024)

S. epidermidis produces a variety of bioactive metabolites, including phenol-soluble modulins (PSMs), extracellular serine protease (ESP), lantibiotic (such as epidermin, Pep5, epilancin K7, epilancin 280, and epilancin A37), epifadin, and lactic acid. These compounds work synergistically to suppress the pathogenicity of S. aureus and other opportunistic pathogens (Peschel and Otto, 2013; Salgaonkar et al., 2022; Iwase et al., 2010; Sugimoto et al., 2013; Puls et al., 2024; Torres Salazar et al., 2024; Glatthardt et al., 2020), inhibit biofilm formation, and stimulate keratinocytes to secrete human β-defensins 2 and 3 (hBD-2 and hBD-3), thereby enhancing colonization resistance (Rademacher et al., 2019; Lai et al., 2010). Studies have also shown that PSMs can act in synergy with the host-derived antimicrobial peptide LL-37 to further enhance the inhibition of S. aureus (Liu et al., 2020).

Other coagulase-negative staphylococci (CoNS) exhibit similar capabilities. For instance, Staphylococcus lugdunensis produces lugdunin, Staphylococcus hominis produces hominicin, Staphylococcus chromogenes produces 6-thioguanine (6-TG), and Staphylococcus capitis secretes the broad-spectrum bacteriocin Nisin J. These antimicrobial molecules have demonstrated activity against both S. aureus and C. acnes (Bitschar et al., 2019; Nakatsuji et al., 2017; Chin et al., 2021; Nguyen et al., 2025; O’Sullivan et al., 2020).

In addition, C. acnes can produce short-chain fatty acids (SCFAs), such as succinic acid, butyric acid, and propionic acid, which possess anti-inflammatory and antimicrobial properties that contribute to maintaining skin microbial homeostasis. C. acnes also synthesizes cutimycin, a thiopeptide antibiotic that selectively inhibits methicillin-resistant S. aureus (MRSA) (Claesen et al., 2020; Shu et al., 2013). Moreover, Cutibacterium avidum has recently been shown to produce a novel bacteriocin, acidicin, which exhibits broad-spectrum antimicrobial activity against C. acnes, Lactobacillus, and Corynebacterium species (Koizumi et al., 2023), thereby supporting ecological stability and microbial balance on the skin. QS interference represents another major protective mechanism (Williams et al., 2019). S. epidermidis AIP-I and multiple AIPs from S. hominis inhibit the S. aureus agr system, thereby reducing toxin expression (Otto et al., 2001; Severn et al., 2022).

C.acnes contributes to skin homeostasis by secreting SCFAs that activate PPARα signaling, thereby promoting triglyceride and ceramide synthesis in keratinocytes. This process enhances the antimicrobial capacity of the skin barrier, improves water retention, and supports the regulation of skin permeability (Almoughrabie et al., 2023). In addition, the commensal skin microbiota reduces TEWL by modulating AHR signaling and strengthens the skin barrier by promoting tissue repair (Uberoi et al., 2021). S. epidermidis further reinforces the physical barrier of the skin through multiple mechanisms. Its secreted sphingomyelinase facilitates ceramide production, which is essential for maintaining the integrity of the stratum corneum (Zheng et al., 2022).

Following skin injury, loss of epidermal barrier integrity exposes the wound bed to resident and environmental microbial populations, reshaping the local microbial landscape. At the same time, the accumulation of wound fluids and the release of nutrients from damaged cells alter the local microenvironment, resulting in changes in temperature, hydration, oxygen availability, and pH compared with intact skin (Kruse et al., 2015). The ecological niche that sustains microbial homeostasis is therefore disrupted, creating conditions that favor the overgrowth of specific microorganisms and leading to microbial dysbiosis within the wound. These microecological alterations interfere with normal host cellular regulatory signaling, causing the dynamic equilibrium characteristic of healthy skin to rapidly collapse following injury.

Although the causal relationship between skin disorders and microbial dysbiosis remains incompletely defined (Byrd et al., 2018; Oh and Voigt, 2025), metagenomic and 16S rRNA sequencing studies consistently demonstrate that wound formation is accompanied by rapid and pronounced reorganization of the skin microbiota (Li et al., 2024; Malone et al., 2017). Relative to intact skin, dominant resident commensal populations decline in abundance, whereas opportunistic pathogens, including S. aureus, Pseudomonas aeruginosa, Enterococcus faecalis, and Proteus mirabilis, as well as certain environmental microorganisms, become enriched (Sachdeva et al., 2022). In parallel, the proportion of anaerobic bacteria increases (Coluccio et al., 2024), resulting in wound-associated microbial communities that differ from those observed under homeostatic conditions. In addition to changes in the composition of the community, the wound microbiota exhibit significant functional heterogeneity. Emerging evidence indicates that even classical pathogens such as S. aureus can be categorized into “generalist” and “specialist” strains (Kalan et al., 2019; MacLeod, 2019), reflecting distinct ecological adaptations across different microenvironments and host contexts.

Wounds are generally classified into two major types: acute wounds such as burns, blunt trauma and penetrating injuries, and chronic hard-to-heal wounds including diabetic foot ulcers (DFUs), pressure ulcers (PUs), venous leg ulcers (VLUs) and postoperative wounds (Bowler et al., 2001). In acute wounds, dysbiosis of the skin microbiota is often transient and tends to resolve as the epithelial barrier and tissue integrity are restored (Monaco and Lawrence, 2003). Rapid changes in microbial diversity have been associated with wound-healing outcomes, suggesting that dynamic microbial shifts may support resolution of inflammation and tissue regeneration (Loesche et al., 2017). In contrast, chronic or high-risk wounds are characterized by persistent microbial imbalance and prolonged inflammation. This sustained dysbiosis is influenced by host-related factors such as diabetes, neuropathy and vascular dysfunction, as well as microbial factors including excessive pathogen colonization, biofilm formation and interspecies microbial cooperation (Shumba et al., 2019; Ovington, 2003; Xu et al., 2021; Bejarano et al., 1989). When a small number of pathogenic species dominate the wound environment over time, the microbial imbalance can prevent progression through normal healing stages. Therefore, both the type of wound and the host’s capacity to restore microbial homeostasis play crucial roles in determining healing outcomes.

These early changes in the structure of the microbial community do not directly determine the outcome of the healing process but provide the ecological context for subsequent host–microbiota interactions. Within this restructured microbial environment, commensal microorganisms begin to play stage-specific roles that influence the resolution of inflammation, tissue regeneration and barrier restoration.

This section focuses on how skin microbiota dynamically regulate different stages of wound healing, including inflammation, proliferation, and remodeling, highlighting the gradual shift from instability to recovery which is shown in Figure 3. This process involves not only changes in microbial community structure but also bidirectional regulation by the host immune environment, forming a complex and dynamic host–microbe interaction network that ultimately determines wound healing outcomes. It is worth noting that the phases of wound healing often overlap, and commensal microbes may play a role across multiple stages. The discussion here is organized according to the stage at which they play a predominant role.