The updates and implications of cutaneous microbiota in acne

Abstract

Acne is a chronic inflammatory skin disorder that profoundly impacts the quality of life of patients worldwide. While it is predominantly observed in adolescents, it can affect individuals across all age groups. Acne pathogenesis is believed to be a result of various endogenous and exogenous factors, but the precise mechanisms remain elusive. Recent studies suggest that dysbiosis of the skin microbiota significantly contributes to acne development. Specifically, Cutibacterium acnes, the dominant resident bacterial species implicated in acne, plays a critical role in disease progression. Various treatments, including topical benzoyl peroxide, systemic antibiotics, and photodynamic therapy, have demonstrated beneficial effects on the skin microbiota composition in acne patients. Of particular interest is the therapeutic potential of probiotics in acne, given its direct influence on the skin microbiota. This review summarizes the alterations in skin microbiota associated with acne, provides insight into its pathogenic role in acne, and emphasizes the potential of therapeutic interventions aimed at restoring microbial homeostasis for acne management.

Introduction

Acne, a pervasive inflammatory skin disorder, is clinically characterised by seborrhea, noninflammatory and inflammatory lesions, along with potential scarring [1]. These acne lesions predominantly present on the face, neck, upper back, shoulders, and chest, correlating with the distribution and density of pilosebaceous units in acne patients [2, 3]. Recent studies provide growing evidence that dysbiosis—an imbalance of cutaneous microbiota—is implicated in the manifestation of inflammatory skin diseases, including acne [4,5,6]. Additionally, individuals with acne are more susceptible to be colonized by diverse microbiota, a phenomenon that has been associated with the clinical status of acne [4,5,6].

Alterations in skin microbiota correlate with acne severity

The skin microbiomes of individuals with acne show significant alterations when compared to healthy controls [7]. Intriguingly, acne patients, particularly those with severe symptoms, demonstrate increased alpha-diversity and a higher proportion of four gram-negative bacteria, namely Faecalibacterium, Klebsiella, Odoribacter, and Bacteroides. These differences are not observed in patients with milder acne grades [7], implying a potential correlation between the composition of the skin microbiota and the severity of acne.

The overgrowth of Cutibacterium acnes (C. acnes, previously known as Propionibacterium acnes) has a long-standing association with acne pathogenesis [8, 9]. Recent metagenomic analyses have revealed that the strain structure of C. acnes in acne patients differs from that of healthy individuals, despite their similar relative abundances. Specifically, type IV and V strains are particularly prevalent in acne-affected skins [10], which suggests a potential correlation between specific C. acnes strains and acne pathology. In terms of overall Cutibacterium population, there is no significant difference between acne patients and healthy individuals. However, acne patients harboring antibiotic-resistant strains exhibit a greater quantity of Cutibacterium than patients without these strains [11]. Coincidentally, Barnard et al. have noted that acne patients exhibit a more diverse microbiome composition at both species and C. acnes strain levels, with an increase in virulence-associated factors [12]. This finding hints at a potential link between the virulent characteristics of skin microbiota and acne. Moreover, recent research has identified potential genetic determinants of C. acnes strains associated with acne [10]. This provides new evidence for the pathogenic mechanisms involving cutaneous microbiota. By comparing multiple C. acnes isolates from patients with moderate to severe acne and healthy controls, it is further demonstrated that antibiotic-resistant C. acnes strains are implicated in acne development [13]. This finding suggests that the susceptibility of host affects the clinical outcome of colonization. Together, these studies emphasize the intricate association between skin microbiota composition and acne severity.

Endogenous risk factors contributing to skin microbiota dysbiosis in acne

Given the close association between acne severity and skin microbiota variations, it is crucial to consider the risk factors contributing to skin microbiota dysbiosis in acne. Generally, the unique microbiota colonization in acne-affected skin is influenced by multiple endogenous (primarily genetic factors, sex, skin site, etc.) and exogenous factors (including treatments like topical benzoyl peroxide, systemic antibiotics, and photodynamic therapy) [14,15,16,17].

Impact of sex on the skin microbiota in acne patients

The study on the cutaneous microbiota in healthy individuals revealed differences between male and female. More recent studies further demonstrated variations in skin microbiota of the two sexes in terms of community structure and composition [18]. Overall, both the alpha- and beta-diversity analyses depicted a contrasting microbiota composition between males and females, with a greater bacterial diversity observed in women. Although the relative abundance of Actinobacteria was similar in both sexes, the secondary dominant phylum varied, with Firmicutes primarily present in male skins and Proteobacteria predominantly present in female skins [18]. Given that sex hormones contribute to skin homeostasis and acne pathogenesis, their role in impacting the skin microbiota in acne cannot be overlooked [19]. Interestingly, adult acne in women is not associated with a specific subtype of C. acnes, as opposed to teenage acne [20]. Nonetheless, this study did not compare the microbiota compositions between male and female acne patients of similar ages, a comparison that could provide insightful information for sex-specific acne treatment strategies.

Microbial heterogeneity varies between skin sites in acne

The human skin is inhabited by distinct microbial communities that vary across different skin locations. Recent studies have revealed the heterogeneity in microbial distribution across skin sites in acne lesions and its association with disease severity [21,22,23]. For instance, alterations in skin microbiota are noted on the inflammatory skin of severe acne patients' backs, as well as on the faces of patients with mild to moderate acne [21]. These alterations, when compared to healthy individuals, suggest a correlation between the distinct microbial colonization across skin sites and acne severity. Particularly, changes in skin commensals, such as the Propionibacteriaceae, Staphylococcaceae, and Enterococcaceae families, have been observed [21]. These observations suggest their potential involvement in acne pathogenesis. C. acnes, a specific microbial species, is detected on the faces and backs of 71.4% of severe acne patients, contrasted to its presence in only 45.5% of healthy individuals [22]. Concurrently, acne patients exhibit a higher prevalence of phylotype IA1 (84.4%) in comparison to the healthy population. This phylotype is also predominantly found on the backs of acne patients [22]. However, a decrease in C. acnes phylotype diversity closely correlates with acne severity on the backs of acne patients [22]. These studies underscore the importance of considering site-specific variability when exploring the microbial heterogeneity in acne.

Additional endogenous factors that influence cutaneous microbiota in acne patients

In addition to the factors previously noted, additional endogenous elements influence the cutaneous microbiota in acne patients. The phase of pubertal development, for instance, impacts the composition of the skin microbiome, as evidenced by the shift in microbial diversity observed between early and late puberty stages [24]. Certain C. acnes strains, specifically those within single locus sequence typing (SLST) A [IA₁], D [IA₁], and F [IA₂] clusters, exhibit unique responses to pubertal stage and the presence of acne. Meanwhile, these strains exhibit a distinct acne-associated microbiome signature [24].

Furthermore, there is a documented correlation between the integrity of epidermal barrier and the skin microbiota in acne patients [25]. Individuals with acne typically display enhanced transepidermal water loss (TEWL) and reduced microbiome diversity in comparison to healthy subjects. The diversity of skin microbiota, as quantified by Shannon and Simpson diversity indices, shows negative correlation with both disease severity and TEWL, revealing the interplay between barrier function and cutaneous microbiota in acne patients [25].

Intriguingly, a greater prevalence of Malassezia is observed in noninflammatory lesions as opposed to inflammatory lesions in acne patients [26]. Concurrently, Malassezia restricta and C. acnes demonstrate similar proliferation patterns during the transition from noninflammatory to inflammatory lesions [26]. These observations suggest a potential role for shifts in fungal abundance during the transformation from non-inflammation to inflammation states.

Therapeutic interventions change skin microbiota in acne patients

The skin microbiota in acne patients is not only influenced by endogenous factors as discussed above but also by external factors, particularly various types of treatment. A growing body of researches have demonstrated that differential shifts in the skin microbiota contingent on the treatment employed [5, 27]. Table 1 summarizes the alterations in skin microbiota caused by different acne treatments.

Table 1 Summary of changed microorganisms during different treatments in acne

Effects of topical benzoyl peroxide on microbiota composition in acne patients

Benzoyl peroxide (BPO) has been a long-standing, first-line topical treatment for acne [3]. Meanwhile, an increasing number of studies have demonstrated that BPO treatment modulates the skin microbiota in acne patients [27]. To investigate alterations in the microbiome following topical BPO treatment, a pilot study involved participants aged 7–10 years (with or without acne) was conducted [28]. The baseline data demonstrated a higher diversity of cutaneous bacteria in teenagers with acne compared to those without. Notably, post-BPO treatment, both the number and diversity of bacterial species diminished, with the microbiome of treatment group closely resembling that of participants without acne [28]. In contrast, despite a reduction in acne counts among preadolescent acne patients post-BPO treatment, Ahluwalia's study found the bacterial diversity of the skin microbiome to be comparable between pre- and post-treatment preadolescents [29], suggesting the limited impact of BPO on microbial alterations during acne treatment. Recent findings by Zhou et al. reveal that BPO treatment improved the Global Acne Grading System (GAGS) score and diminished porphyrin and red areas, whereas compromised the epidermal barrier function [30]. Further, a significant reduction in microbial diversity is observed post-treatment, compared to baseline data [30]. Therefore, while BPO treatment decreases GAGS score and reduces microbial diversity, it also damages the epidermal barrier in acne, which can be considered as a side effect.

Impact of systemic antibiotics on cutaneous microbiota shift in acne

The application of antibiotics for acne treatment necessitates a comprehensive understanding of their effects on cutaneous microbial dysbiosis [5]. Chien et al. conducted a longitudinal cohort study to investigate the alterations in skin microbiota in response to antibiotic perturbation associated with acne treatment. Of all four acne patients prescribed oral minocycline, they observed an improvement in clinical outcomes, manifested by a reduction in C. acnes abundance post-treatment [31]. Concomitant with these findings, the study also reported distinct changes in other bacterial genera. Specifically, there was a transient increase in Pseudomonas species following antibiotic administration, a persistent increase in Streptococcus species, and a persistent decrease in Lactobacillus species, persisting up to eight weeks after minocycline withdrawal [31]. This study thereby demonstrates that systemic antibiotic treatment correlates with shifts in skin microbiota, characterized by variable changes in specific bacterial populations in acne. In a related study, Thompson et al. performed a case–control study to ascertain the impact of minocycline treatment on skin microbiota. Post-treatment, they observed an enrichment of probiotics Bifidobacterium longum and Leuconostoc mesenteroides within the skin microbiota, contrasted with a depletion of Staphylococcus epidermidis and Prevotella nigrescens [32]. At the phylum level, a decreased ratio of Firmicutes to Bacteroidetes in acne patients following treatment was detected [32]. This evidence suggests that minocycline treatment influences the composition of the acne skin microbiota, underscoring the potential benefits of developing more targeted antimicrobial strategies for acne.

To evaluate the alterations in skin microbiota structure and composition in acne patients following doxycycline treatment, a longitudinal cohort study was conducted on individuals with acne who were prescribed a six-week oral doxycycline [33]. Prior to the treatment, the dominant species was identified as C. acnes, which exhibited a positive correlation with the severity of acne [33]. Following doxycycline intervention, a decrease in clinical acne grades was observed, and this reduction was associated with a lower abundance of C. acnes. Furthermore, substantial variations were noted in other bacterial species such as Cutibacterium granulosum, which displayed increased abundance in the treated cohort [33]. Moreover, the administration of doxycycline resulted in an elevation of the bacterial alpha-diversity within the acne skin. In short, systemic antibiotics modify both the composition and diversity of acne microbiota, which in turn reflect the impact of antibiotic treatment.

Antimicrobial susceptibility of C. acnes varies among acne patients

Systemic antibiotics, commonly prescribed for the treatment of acne, confer substantial benefits to patients. Nonetheless, the pervasive use of these antibiotics has sparked concerns regarding bacterial resistance, particularly in the case of C. acnes [23, 34]. Grech conducted a study investigating the susceptibility of C. acnes to amoxicillin, minocycline, erythromycin, and clindamycin using isolates obtained from acne patients. Notably, 37.8% of these isolates were resistant to both erythromycin and clindamycin, while a mere 4.4% exhibited resistance to all four antimicrobials [35]. Complementing these findings, Zhang et al. reported that the highest prevalence of resistance among clinical C. acnes strains was observed for erythromycin and clindamycin, with resistance rates of 49.2% and 28.6%, respectively [36]. Additionally, they found that the high resistance rates to clindamycin and erythromycin were significantly influenced by a history of macrolide treatment [37]. This finding implies that patients with prior exposure to macrolides should refrain from using clindamycin and erythromycin. Zhang et al. proceeded to investigate the draft genome sequences of multidrug-resistant C. acnes strains, thereby shedding light on potential genetic clue for antibiotic-resistance in specific strains of C. acnes [38]. Collectively, these studies provide valuable insights that can guide antimicrobial prescription for treating acne. Nevertheless, further in-depth studies with larger sample sizes are warranted to validate these findings.

Impact of photodynamic therapy on cutaneous microbiota shift in severe acne

Photodynamic therapy (PDT) has been found to effectively improve clinical outcomes with favorable tolerability in the treatment of severe acne [39,40,41]. To investigate the impact of PDT on the diversity and composition of cutaneous microflora among severe acne patients, a study was conducted involving patients who were treated with 5-aminolevulinic acid-mediated PDT (ALA-PDT) once a week for three weeks. Healthy individuals were simultaneously recruited to serve as controls. The baseline data revealed marked differences in microbiota composition between healthy controls and acne patients, characterized by reduced alpha-diversity in the patient cohort [42]. Intriguingly, ALA-PDT treatment resulted in noticeable modifications to the patients’ microbiota composition, including 15 bacterial genera, such as Enhydrobacter, Cetobacterium, and Streptococcus [42]. In accordance with these findings, a recent prospective study demonstrated that ALA-PDT treatment served to enhance the diversity of the skin microbiome in acne patients [43]. Concurrently, ALA-PDT treatment suppressed the presence of C. acnes within the follicular microbiome, while increasing the abundance of resident follicular bacteria, predominantly Bacillus and Lactococcus [43]. This indicates that the therapeutic efficacy of ALA-PDT is partially attributed to its capacity to modulate the skin microbiome in acne cases. In support of this, Tao et al. reported a correlation between ALA-PDT administration and increased microbiota diversity in patients with severe facial acne [44]. Furthermore, their longitudinal cohort study provided evidence that ALA-PDT treatment contributed to clinical improvements, which were associated with a decrease in C. acnes colonization in severe acne patients [44]. Collectively, these findings suggest that the alterations observed in skin microbiota can serve as an indicator of the therapeutic efficacy of PDT in treating severe acne.

Other treatments that affect microbiota shifts in acne skin

Systemic interventions, such as oral retinoids and tetracyclines, play significant roles in acne management owing to their anti-inflammatory properties [45, 46]. Notably, these treatments diminish the severity of clinical acne symptoms and the prevalence of Cutibacterium, while simultaneously increase the presence of various other taxa, including Streptococcaceae, Pasteurellaceae, and Corynebacteriaceae, relative to controls [47]. Prior to the treatments, no significant difference in alpha-diversity between control and acne patients is observed; however, a significant increase is noted post-treatment [47]. These findings suggest the potential of systemic treatments, other than antibiotics, to modulate the skin microbiota in individuals with acne.

Peels incorporating 30% supramolecular salicylic acid (SSA), a modified form of salicylic acid, have recently been demonstrated to provide a safe and effective treatment for moderate to severe acne [48]. To explore this treatment further, patients with acne were subjected to biweekly 30% SSA peels over a two-month period. Post-treatment, significant improvements were observed in GAGS scores and skin barrier indicators, alongside decreased richness and evenness of the cutaneous microbiome, and a reduced Staphylococcus proportion [49]. These findings indicate that 30% SSA peels can therapeutically benefit acne patients by modulating the skin microbiota. Furthermore, an investigation into the effect of 2% SSA on acne revealed significant improvements in clinical outcomes, as evidenced by decreased lesion counts and GAGS scores [50]. Specifically, the 2% SSA treatment resulted in increased alpha- and beta-diversity indices, reduced relative abundance of Staphylococcus, Ralstonia, and Streptococcus, and an overall shift in bacteria genera distribution toward a healthier state in acne patients [50]. Consequently, 2% SSA appears to normalize the microbial dysbiosis associated with acne-afflicted skin.

The plant-derived extract, Myrtus communis (Myrtacine^®), is beneficial in acne treatment due to its anti-virulence and anti-inflammatory effects [51]. Notably, a cream formulated with Myrtacine^® significantly reduces the erythromycin-resistant (EryR) C. acnes population in acne patients [52]. Additionally, the Myrtacine^® cream improves acne lesions without altering the overall C. acnes load, suggesting its specific efficacy against EryR C. acnes [52].

The regulatory roles of skin microbiota, particularly Cutibacterium acnes, in acne pathogenesis

Increasing evidence has implicated skin microbiota dysbiosis as a significant contributor to acne pathogenesis. Meanwhile, comprehensive researches have elucidated the impacts and molecular mechanisms of cutaneous microbiota, focusing predominantly on C. acnes, in the onset and progression of acne (Fig. 1).

Fig. 1

The regulatory roles of C. acnes in the pathogenesis of acne. C. acnes participates in the regulation of acne pathogenesis through multiple different ways. It involves in the regulation of biofilm formation (A); participates in the abnormal regulation of epidermal keratinocytes (B); regulates the aberrant inflammation and lipogenesis of sebocytes (C); and dysregulates the immune response (D)

The influence of C. acnes on epidermal keratinocytes, biofilm formation, and immune regulation

Cutibacterium acnes, a gram-positive commensal bacterium, is a dominant species within the cutaneous microbiota and a crucial pathogenic factor in acne. This bacterium is involved in multiple pathways associated with acne pathogenesis. Its role in the regulation of keratinocytes' cell fate has been widely accepted, with several distinct mechanisms identified. Firstly, C. acnes has been found to stimulate epidermal keratinocyte proliferation via the IGF-1/IGF-1R axis, which correlates with increased expression of Ki67 and filaggrin [53]. Secondly, the bacterium influences keratinocyte differentiation by elevating levels of transglutaminase and keratin 17, while simultaneously reducing K1 and K10 levels in keratinocytes [54]. Thirdly, C. acnes has been reported to alter the barrier function of epidermal keratinocytes by modulating tight junction proteins and managing cell-to-cell contacts [55]. Fourthly, C. acnes has been implicated in the regulation of keratinocyte autophagy [56]. Further supporting this, propionic acid, a metabolite secreted by C. acnes, also contributes to autophagy in keratinocytes, underscoring the bacterium's profound influence on keratinocytes [56]. Lastly, C. acnes can trigger inflammatory responses in keratinocytes. Exposure to C. acnes results in a rapid production of superoxide anions in keratinocytes, associated with the release of pro-inflammatory molecules [57]. Moreover, keratinocytes coincubated with C. acnes instigate a pro-inflammatory response involving cytokines and chemokines, including IL-1β, granulocyte/macrophage colony-stimulating factor, and IL-8. This response implicates C. acnes in the recruitment of inflammatory cells to inflammation sites, thus facilitating acne lesion development [58]. Cumulatively, these studies demonstrate that C. acnes can shape acne pathogenesis through its substantial effects on keratinocyte proliferation, differentiation, barrier function, autophagy, and inflammation.

The role of bacterial biofilm formation in the pathogenesis of infections is crucial, and this has been particularly noted in the case of C. acnes both in vitro and in vivo [59,60,61]. A recent study examined the biofilm-forming characteristics of various C. acnes strains in acne patients and found that 23% of the acne specimens contained biofilm [62]. Biofilm was most frequently detected in comedones, present in 55.6% of specimens, whereas inflammatory papules and uninvolved skin had a lower frequency of detection at 22.2% each, among all the biofilm contained specimens [62]. This data suggests a potential correlation between biofilm formation by specific C. acnes strains and acne development. Interestingly, biofilm formation was also found to correlate with the phylotype of C. acnes, as different isolates showed variations in formed biofilm quantities [63]. Furthermore, different C. acnes phylotypes were observed to form structurally distinct biofilms and exhibit divergent adhesive properties [63]. Specifically, the phylotype IA1, which is more prevalent in acne-affected skin compared to healthy skin, displayed higher efficiency in early adhesion and biomass production than other phylotypes [64]. This implies a potential antibiotic tolerance, suggesting that novel antimicrobial agents targeting biofilm-forming C. acnes could serve as promising therapeutics for acne treatment. In acne lesions, the presence of biofilm-derived C. acnes activates miR-146a, TLR2 and its downstream pathways in keratinocytes [65]. Functionally, miR-146a inhibits the activation of TLR2 pathway mediated by C. acnes-derived biofilm [65]. This points toward the involvement of epigenetic regulation in the inflammation instigated by C. acnes biofilm and provides a novel clue for the C. acnes biofilm-mediated acne pathogenesis.

Cutibacterium acnes species derived from both acne lesions and healthy subjects did not show any distinct differences in cytokine production from peripheral blood mononuclear cells (PBMCs). However, the inflammatory cytokine production was markedly increased in PBMCs obtained from acne patients as opposed to those from healthy donors [66]. This finding suggests that the host response, rather than the bacterial species, serves as the crucial determinant of acne pathogenesis. Genomic studies have indeed unveiled the presence of both health-associated and acne-associated C. acnes strains in clinical contexts. This has considerably broadened our comprehension of the mechanisms involved in acne pathogenesis [10, 12, 67]. It was found that application of acne-associated C. acnes strains resulted in skin pathology in a murine model of acne, which was distinct from the effects observed with health-associated strains [68]. Moreover, acne-associated C. acnes strains elicited higher levels of inflammatory factors compared to their healthy counterparts [68]. Mechanistically, different C. acnes phylotypes induced distinctive immunological responses [69]. For example, acne-associated C. acnes phylotypes triggered higher levels of IFN-g and IL-17, while health-associated C. acnes phylotypes prompted a pronounced IL-10 response in PBMCs [69]. This provides evidence supporting a immunopathologic corroboration of health and disease association in C. acnes strains.

The host immune response toward C. acnes is also implicated in acne pathogenesis. Observations have been made of a substantial infiltration of CD4⁺ T cells in the perifollicular space of early acne lesions, further substantiating the role of T helper cells in the immune response prompted by C. acnes colonization [70]. In addition, IL-17-expressing cells were predominantly detected in lesional skins from acne patients. Furthermore, C. acnes robustly elicited a Th17 response in CD4⁺ T cells sourced from human PBMCs [70]. Importantly, supernatants from C. acnes-stimulated PBMCs effectively enhanced the differentiation of Th17 cells [70]. Consistently, PBMCs stimulated by acne-associated C. acnes strains manifested higher IL-17 levels as compared to those stimulated by C. acnes strains from healthy donors [71]. Interestingly, only health-specific Th17 clones secreted molecules with potent C. acnes-killing capabilities, with supernatants displaying strong antibacterial activity against C. acnes [71]. Hence, C. acnes strains from healthy or acne-ridden skin differentially modulate Th17 responses in acne. Supporting this, both Th17 and Th1 related cytokines and chemokines, along with their receptors, are notably upregulated in acne lesions [72]. Furthermore, C. acnes has been found to foster mixed Th17/Th1 responses by inducing the secretions of IL-17A and IFN-g from specific CD4⁺ T cells [72]. Intriguingly, C. acnes-specific Th17/Th1 cells are primarily found in the peripheral blood of acne patients [72], thus establishing these C. acnes-responding Th17/Th1 cells as a crucial CD4⁺ subpopulation implicated in acne pathogenesis.

In summary, C. acnes contributes to the pathogenesis of acne via several distinct mechanisms. These include the alteration of epidermal keratinocyte characteristics, the manipulation of biofilm formation, and the disruption of microbe-host immune interactions.

Cutibacterium acnes-associated pathways that contribute to acne pathogenesis

Cutibacterium acnes is widely recognized as an etiological agent that propagates acne inflammation through various pathways. First, C. acnes instigates a robust immune response that involves the NLRP3-inflammasome during acne development. This response is evident as C. acnes induces the activation of monocyte-macrophage NLRP3-inflammasome and boosts the secretion of IL-1β in acne, thereby demonstrating its role in skin inflammation [73]. Corroborating this, human monocytes respond to C. acnes and secrete IL-1β partially through NLRP3-mediated pathway [74]. Notably, mature caspase-1 and NLRP3 are identifiable around the pilosebaceous follicles and macrophages within acne lesions, thus affirming the potential for C. acnes-mediated NLRP3 activation in acne development [74]. C. acnes can also stimulate the NLRP3 inflammasome in sebaceous glands, as evidenced by the detection of activated caspase-1 and IL-1β in human sebocytes exposed to C. acnes [75]. Moreover, knockdown of NLRP3 abolishes C. acnes-induced IL-1β production in sebocytes [75]. In addition, the silencing of NLRP3 hinders the production of IL-1β induced by C. acnes in sebocytes, and NLRP3-deficient mice exhibit a diminished inflammatory response to C. acnes [75]. This suggests that sebocytes are key immunocompetent cells and that C. acnes-induced NLRP3 activation in sebaceous glands plays a significant role in acne pathogenesis.

Second, C. acnes engages TLR2, a signaling molecule highly activated in acne lesions, and elicits inflammation in keratinocytes, sebocytes, and monocytes, thereby facilitating acne development [76, 77]. C. acnes exposure escalates TLR2 expression in human keratinocytes [78] and significantly induces hBD2 and IL-8 expression in cultured keratinocytes [79]. This induction can be attenuated by anti-TLR2 antibodies [79], signifying that inflammation stimulated by C. acnes is TLR2 dependent in keratinocytes. In human sebocytes, C. acnes extracts stimulate the expression of IL-8 and TLR2. However, knockdown of TLR2 or anti-TLR2 antibodies obstruct C. acnes-induced IL-8 production [80], highlighting the vital role of TLR2 signaling in C. acnes-mediated inflammation in sebocytes. In a mouse model of acne, mutation of the Christie-Atkins-Munch-Petersen factor (CAMP, a secretory factor of C. acnes) or vaccination with CAMP factor antibodies reduces C. acnes colonization and C. acnes-mediated inflammation [81]. Contrarily, purified CAMP factor 1 triggers the production of IL-8, which can be mitigated by TLR2 antibodies [82]. CAMP1-TLR2 binding intensity is strong in C. acnes strains that produce copious amounts of IL-8 [81], indicating a direct interaction between CAMP1 and TLR2. Clinically, acne lesions exhibit higher levels of CAMP factor and TLR2 than nonlesional skins [82], further substantiating that the CAMP factor of C. acnes is a key contributor to TLR2-related inflammation in acne.

Third, an increasing body of evidence underscores the significance of C. acnes-mediated activation of the aryl hydrocarbon receptor (AhR) pathway in acne pathogenesis [83, 84]. The AhR or selective AhR ligands manage lipid synthesis and differentiation in human sebocytes [85, 86]. Additionally, the AhR is able to modulate TLR2-mediated expression of TNF-α and IL-8 in human sebocytes [87], thereby highlighting its role in acne inflammation. Interestingly, AhR downstream CYP genes are upregulated by C. acnes in human sebocytes [88]. Simultaneously, C. acnes induces the nuclear translocation of the AhR protein and activates the AhR pathway. Moreover, C. acnes inhibits lipogenesis and promotes the differentiation of sebocytes, effects that are negated by AhR gene silencing [88], suggesting a non-acnegenic role of C. acnes in promoting acne remission via the AhR pathway.

Factors that negatively regulate the C. acnes-induced inflammation in acne pathogenesis

Inflammation provoked by C. acnes is recognized as a pivotal factor in acne pathogenesis. Consequently, the identification of elements that deter this inflammation holds substantial potential for therapeutic intervention. Recent study reveal that Bmal1 and its downstream genes are suppressed in the skin of C. acnes-treated mice [89]. Furthermore, Bmal1 negatively regulates C. acnes-induced inflammation in vitro and in vivo [89], validating its repressive role in acne pathogenesis.

The TNFAIP3 interacting protein 1 (TNIP1), known to inhibit the NF-κB pathway, is rapidly induced in keratinocytes by C. acnes [90]. As such, TNIP1 acts to diminish NF-κB activation and the ensuing inflammatory response incited by C. acnes [90], establishing its role as a negative regulator of C. acnes-induced inflammation. Similarly, the tumor necrosis factor alpha-induced protein 3 (TNFAIP3), which inhibits TLR and NF-κB signaling, is induced by C. acnes in epidermal keratinocytes [91]. Concurrently, the TNFAIP3 expression is heightened in acne lesions relative to non-lesional skins. Notably, TNFAIP3 tempers the inflammation triggered by C. acnes in keratinocytes [91]. Recent evidence also implicates fibroblast growth factor 21 (FGF21) in exerting anti-inflammatory effects on the epidermal layer [92]. In keratinocytes, FGF21 acts to mitigate the activation of TLR2, NF-κB, and MAPK signaling prompted by C. acnes [92]. Moreover, FGF21 curbs the inflammation driven by C. acnes [92], suggesting its regulatory role in acne pathogenesis.

Staphylococcus epidermidis (S. epidermidis), an important constituent of the normal microflora and a beneficial skin commensal, has been found to cohabitate with C. acnes in acne lesions [93, 94]. Intriguingly, S. epidermidis represses C. acnes-induced inflammation [95]. Among the mechanisms involved, S. epidermidis facilitates glycerol fermentation, augmenting its inhibitory effects on C. acnes proliferation. Further, succinic acid, found in the fermented medium, efficaciously restricts C. acnes growth. In addition, the application of succinic acid significantly attenuates C. acnes-induced inflammation in mice [95]. Co-culture studies identified 30 out of 557 staphylococcal strains that displayed anti-C. acnes activities [94]. Remarkably, these strains selectively exclude acne-associated C. acnes phylotypes, favoring cohabitation with those healthy skin-associated phylotypes [94]. These strains also demonstrate selective antimicrobial activity against resilient C. acnes strains [96]. Furthermore, staphylococcal lipoteichoic acid mitigates inflammation induced by C. acnes [96], underlining its role in limiting inflammation and maintaining skin homeostasis.

Roles of C. acnes derivatives in acne pathogenesis

Cutibacterium acnes derivatives significantly contribute to acne pathogenesis. For instance, extracellular vesicles originating from C. acnes (CEVs) stimulate acne-like phenotype in human keratinocytes [97]. Mechanistically, these CEVs modify the cellular properties of epidermal keratinocytes, thus facilitating acne pathogenesis through the induction of keratinocyte differentiation, inflammation, and proliferation [97].

Moreover, C. acnes produces various proteases that are integral to acne pathogenesis. These proteases induce inflammation via PAR-2 signaling. It is notable that both the protease activity and PAR-2 expression are heightened in acne lesions [98]. In addition, inhibition of serine protease or blockade of PAR-2 diminishes inflammation induced by C. acnes [98]. Further, PAR-2 aids in the differentiation and lipogenesis of sebocytes, processes mediated by C. acnes [99,100,101]. Thus, C. acnes-derived proteases are instrumental in acne pathogenesis.

Porphyrins produced by C. acnes also have a crucial role in the disease development of acne. There is a significant decrease in porphyrin levels in acne patients post-treatment, which correlates with clinical improvement [102]. Additionally, porphyrin production fluctuates among various Cutibacterium species, with C. acnes being the highest producer [103]. Importantly, porphyrin levels in different C. acnes strains can elucidate disease status: acne-associated strains produce higher porphyrin levels, particularly when supplemented with vitamin B12, in contrast to health-associated strains that yield fewer porphyrins and remain unresponsive to vitamin B12 [104]. Functionally, these porphyrins and the acne-associated C. acnes strains trigger inflammation in keratinocytes [105, 106]. Furthermore, porphyrins or the acneic strains stimulate K⁺ leakage and activate NRLP3 inflammasome in keratinocytes. Notably, both porphyrin production and IL-1β release are higher in acne-associated strains [106]. A repressor gene of porphyrin biosynthesis, deoR, has been identified in health-associated C. acnes strains [103, 104], suggesting a novel mechanism in the pathogenesis of acne.

Additionally, propionic acid, a metabolite secreted by C. acnes, is known to exert deleterious effects when its local concentration surges due to excessive growth of C. acnes [107], providing insights into the dual role of C. acnes in maintaining healthy skin and facilitating pathogenic conditions.

In summary, extracellular vesicles, proteases, and metabolites derived from C. acnes collectively facilitate acne pathogenesis via numerous distinct mechanisms.

Therapeutic strategies targeting skin microbiota (especially C. acnes) in acne treatment

As discussed previously, C. acnes is implicated in acne pathogenesis by triggering hyperproliferation and inflammation in keratinocytes, mediating abnormal biofilm formation, and dysregulating sebocyte lipogenesis. Thus, interventions targeting pathogenic C. acnes introduce a novel frontier in anti-acne therapy.

Implications of natural products/molecules targeting C. acnes in acne treatment

Increasing evidence suggests that natural products and molecules possess substantial potential for acne treatment by targeting C. acnes-induced pathology (Table 2). For instance, Toona sinensis, traditionally used to manage enteritis and pruritus, exhibits antibacterial and anti-inflammatory effects on C. acnes-infected keratinocytes [108], indicating its potential use in acne treatment. Nicotinamide, a proven therapeutic agent for acne inflammation, attenuates inflammatory IL-8 production in C. acnes-stimulated keratinocytes [109]. Recently, piceatannol (3, 5, 3′, 4′-tetrahydroxy-trans-stilbene, PCT), a natural dietary component, has been noted for its role in mitigating acne by inhibiting C. acnes-mediated cell proliferation and inflammation [110]. Likewise, Orobol (3′,4′,5,7-tetrahydroxyisoflavone), a metabolite of genistein, suppresses NF-κB and MAPK signaling, and reduces expression of the proliferation marker Ki67 in C. acnes-induced keratinocytes [111]. Thus, both PCT and Orobol alleviate C. acnes-prompted inflammation and hyperkeratinization, presenting potential utility in acne treatment.

Table 2 Summary of natural products/molecules targeting C. acnes in acne treatment

The C. acnes-induced NLRP3 inflammasome activation is critical for triggering inflammation and aggravating acne progression. Therefore, natural products/molecules targeting this pathway represent innovative approaches to acne treatment. For instance, Yang et al. reported that licochalcone A, a chalconoid derived from Glycyrrhiza inflate, effectively inhibits the C. acnes-activated NLRP3 inflammasome [112]. Additionally, licochalcone A suppresses C. acnes-induced production of caspase-1 and IL-1β in macrophages and sebocytes, and topical application of this compound attenuates C. acnes-induced skin inflammation in mouse models [112], signifying clinical applicability for acne treatment. Schisandrin A, B, and C, representative lignans of Schisandra chinensis Baill., counteract C. acnes-induced pyroptosis and inflammation, notably by attenuating IL-1β secretion and pyroptosis mediated by NLRP3 activation [113]. This evidence underscores their potential as promising therapeutic agents for acne. Furthermore, baicalin, a lipophilic flavonoid glycoside from Radix Scutellariae, also reduces skin inflammation through inhibiting NLRP3 activation [114]. Finally, Polyphyllin I, a steroidal saponin derived from Paris polyphylla rhizomes, has been demonstrated to alleviate C. acnes-induced inflammation, in part by downregulating NLRP3 pathway [115, 116], thus implying its therapeutic potential for managing acne inflammation.

C. acnes stimulates an innate immune response through activation of TLR2 signaling, a pivotal process in comedogenesis, and a significant factor in acne pathogenesis [117]. The isoprenylcysteine molecule, SIG1273, has been shown to inhibit TLR2 pathway and kill C. acnes, offering dual benefits for acne-affected skin [118]. Results from a double-blind controlled trial further demonstrate that SIG1273 gel improves the clinical outcomes for acne patients and is well-tolerated, suggesting its potential application in the treatment of acne [118]. More recently, SIG1459, another anti-acne isoprenylcysteine molecule, demonstrated the ability to counteract C. acnes and inhibit TLR2 signaling [117]. Additionally, 1% SIG1459 exceeded the performance of 3% BPO in a comparative clinical study, revealing its potential as a promising and safe acne treatment [117]. Myricetin, an extract commonly found in traditional Asian medicine, mitigates C. acnes-stimulated inflammation in sebocytes by suppressing TLR2 and rapamycin pathways activated by C. acnes, suggesting its potential in acne treatment [119]. Quercetin, a widely recognized plant polyphenolic antioxidant, attenuates C. acnes-induced inflammation by inhibiting TLR2 and MAPK pathways in HaCaT and THP-1 cells [120]. Furthermore, quercetin significantly reduces cutaneous erythema and swelling triggered by C. acnes in mouse models [120], indicating its therapeutic value in treating acne.

C. acnes biofilm formation is implicated in acne pathogenesis, and blocking this process represents a novel therapeutic approach [59,60,61]. The methanolic extract of Helichrysum odoratissimum (L.) Sweet targets bacterial growth while concurrently inhibiting C. acnes biofilm formation, highlighting its potential as a comedolytic agent for acne treatment [121]. Arctostaphylos uva-ursi leaf extract, a natural product, has demonstrated a bacteriostatic action against C. acnes-induced inflammation [122]. Most importantly, this extract disrupts C. acnes biofilm formation without affecting keratinocyte growth [122]. Indoles are ubiquitous molecules in both prokaryotes and eukaryotes. Of the 20 indoles that have been tested, indole-3-carbinol and 3,3′-diindolylmethane (DIM) have been demonstrated to significantly inhibit C. acnes biofilm formation without altering cellular viability [123]. Also, DIM successfully inhibits the biofilm formation by multispecies, including C. acnes, S. aureus, and C. albicans. Transcriptional analyses further reveal that DIM suppresses the expression of biofilm-related genes in C. acnes, confirming its property in blocking the biofilm formation of C. acnes and suggesting its utility in acne treatment [123]. Recently, Attia-Vigneau et al. identified a G2 dendrigraft of lysine dendrimer (G2) capable of modifying membrane fluidity and biofilm formation in C. acnes [124]. Notably, G2 ameliorated inflammation and enhanced skin desquamation following C. acnes colonization [124]. Moreover, G2 treatment diversified C. acnes phylotypes, indicating that the incorporation of such compounds in cosmetic products could be a novel strategy for acne prevention.

Sebocyte dysfunction, mediated by C. acnes, contributes to acne pathogenesis. Notably, the main component of Kaempferia parviflora, a traditional health-promoting medicine, has been shown to inhibit sebocyte lipogenesis [125]. Additionally, Mangifera indica leave, a previously reported anti-acne agent, also decrease C. acnes lipase activity, hinting at their potential roles in acne treatment [126]. Bee venom (BV) and melittin, known for their antibacterial, antiviral, and anti-inflammatory activities in various cell types, have been found to mitigate the upregulation of genes involved in lipid biosynthesis and inflammation triggered by C. acnes. This indicates the potential of BV and melittin as natural anti-acne agents targeting C. acnes-induced abnormal lipogenesis [127].

Implications of next-generation antibiotics in acne treatment

The development of resistant C. acnes strains poses a significant challenge to the efficacy of current antibiotics in acne treatment, prompting urgent consideration in dermatology. Interestingly, isotretinoin, a non-antimicrobial retinoid, is shown to be effective in reducing the anaerobic bacteria C. acnes without antibiotic activity [128]. Orally administered isotretinoin displays satisfactory efficacy in moderate to severe acne, corresponding with the reduction in antibiotic-resistant C. acnes on the skin, hence suggesting its potential as an alternative to current antibiotic use [128].

VB-1953 is a next-generation antibiotic with bactericidal activity against resistant C. acnes strains. A recent study by Batra et al. showed that topical application of 2% VB-1953 gel resulted in substantial decrease in both inflammatory and noninflammatory lesion counts compared to the baseline [129]. In addition, VB-1953 treatment dramatically reduced resistant bacterial populations, specifically clindamycin-resistant C. acnes [129]. The study also reported minimal adverse events [129], affirming VB-1953 as a safe and effective therapy for acne involving resistant C. acnes strains.

Immunization with heat-inactivated C. acnes vaccines offers a novel therapeutic approach to acne. These vaccines have been shown to protect mice against C. acnes challenges and to suppress C. acnes-induced skin inflammation [130]. Furthermore, the vaccines effectively neutralize C. acnes cytotoxicity and attenuate inflammation in human sebocytes [130]. Thus, vaccination against cytotoxic skin bacteria represents a novel therapeutic for acne.

CBT-SL5, an antimicrobial peptide from Enterococcus faecalis SL5, exhibits antimicrobial activity against C. acnes [131]. Importantly, CBT-SL5 treatment diminishes C. acnes-induced inflammation by inhibiting NF-κB activation [132]. A randomized, placebo-controlled, split-face comparative study demonstrated that acne severity improved significantly on the side of the face treated with CBT-SL5 compared to the control side (treated with vehicle lotion) after 4 weeks [133]. Additionally, the phylogenetic diversity of the skin microbiota was reduced on the treated side [133], pointing CBT-SL5 as a promising antimicrobial option for acne treatment.

In short, next-generation antibiotics have the potential to provide an alternative choice, enhance the effectiveness of current antibiotics, and address the challenge of antibiotic resistance in acne treatment.

Implications of probiotics and postbiotics in acne treatment

Probiotics and postbiotics, which constitute a segment of viable microbial dietary supplements, have demonstrated beneficial effects in combating pathogens and preserving the balance of skin microbiota. They also serve as adjuvant therapies complementing traditional acne treatments [134,135,136].

In a comprehensive study leveraging functional screening, genetic analysis, and proteomics, O'Neill et al. identified a particular strain of Staphylococcus capitis (S. capitis E12) that selectively inhibited C. acnes growth [137]. Notably, the potency of S. capitis E12 surpassed that of commonly prescribed antibiotics without exhibiting any toxicity to human keratinocytes or impacting other commensal skin bacteria [137]. This suggests the potential for utilizing skin microbiome in a biotherapeutic approach toward acne treatment.

The non-acne-causing strains can regulate the skin microbiome, leading to a decline in acne severity, thereby suggesting their therapeutic potential in acne treatment [138]. In a pilot study, Karoglan et al. demonstrated that the application of these non-acne-causing strains led to an improvement in comedone counts [138]. Following treatment, the skin microbiome composition in acne patients shifted toward the study formulations, with no adverse effects or flare-ups, confirming the safety and efficacy of these non-acne-causing strains [138]. Specifically, select strains of actobacilli have been shown to decrease inflammatory lesions in patients with mild to moderate acne [139]. The application of these selected Lactobacilli strains led to a temporary modulation of the skin microbiome, including a decrease in the abundance of C. acnes and an increase in Lactobacilli [139]. Notably, the reduction in inflammatory lesions was sustained for over four weeks post-lactobacilli application. These findings suggest the use of a specific Lactobacilli strain as a feasible therapeutic strategy for acne.

As outlined in “Factors that negatively regulate the C. acnes-induced inflammation in acne pathogenesis” section, S. epidermidis has been proven to inhibit C. acnes growth and attenuate C. acnes-induced inflammation [95], indicating its potential for the development of probiotics for acne. Recent findings have demonstrated that polyethylene glycol (PEG)-8 Laurate, a carbon-rich compound, selectively enhances the fermentation of S. epidermidis, thereby amplifying its probiotic effect against acne [140]. The application of PEG-8 notably reduced C. acnes growth and associated inflammation, and potentiated the anti-C. acnes activity of clindamycin [140]. Thus, the fermentation of S. epidermidis can serve as a probiotic strategy against C. acnes, thereby minimizing the reliance on antibiotics. Furthermore, when S. epidermidis was incubated with 2% PEG-8 Laurate, electricity was generated, resulting in significant growth retardation and cell lysis of C. acnes [141]. Additionally, the electricity generated using the S. epidermidis and PEG-8 Laurate mixture substantially inhibited the overgrowth of C. acnes in mouse models [141]. Nonetheless, the direct application of live S. epidermidis as a probiotic carries the risk of bloodstream infections. To mitigate this risk, Yang et al. developed polysulfone microtube array membranes (PSF MTAM) to encapsulate the probiotic S. epidermidis [142]. The encapsulated S. epidermidis enhanced the glycerol fermentation of S. epidermidis without any leakage [142], thus positioning it as a secure probiotic patch for acne treatment.

A previous study demonstrated that the Weissella viridescens UCO-SMC3 strain hindered the growth of C. acnes [143]. Moreover, this UCO-SMC3 strain manifests both antimicrobial and immunomodulatory capabilities, decreasing the adhesion of C. acnes and modulating the immune response to this bacterial infection [144]. A pilot study further substantiated these findings, indicating that a facial cream incorporating the UCO-SMC3 strain significantly mitigate acne lesions, thereby corroborating its advantageous use as a probiotic in acne treatment [144].

To compare the effectiveness of a probiotic derived from Lactobacillus paracasei versus 2.5% BPO in treating mild to moderate acne, Sathikulpakdee et al. conducted a randomized controlled trial. Following a four weeks’ treatment, a significant decrease in both inflammatory acne lesions and erythema index was noted in relation to baseline metrics in both the probiotic and BPO groups, with no substantial difference discerned between the two cohorts [145]. This supports the proposition that a probiotic-derived lotion could effectively treat mild to moderate acne, yielding outcomes comparable to those achieved with 2.5% BPO.

The use of skincare cosmetics containing anti-acne postbiotics has also been identified as a potent modality for acne mitigation [146]. A notable improvement in acne lesions was observed following two weeks of postbiotic treatment when compared with baseline measurements. In addition, postbiotics were found to bolster skin barrier functions, as manifested by a reduction in TEWL and sebum production. These results suggest that postbiotics could offer a promising therapeutic avenue for acne reduction [146].

Prospects and perspectives

The dysbiosis of skin microbiota is increasingly being recognized as a crucial mechanism in the progression of acne. More specifically, a substantial correlation exists between the increased colonization of C. acnes and the severity of acne disease. Concurrently, treatments that target the skin microbiota, particularly C. acnes, are emerging as novel strategies for acne treatment. While numerous natural products, molecular compounds, and probiotics have demonstrated considerable potential in treating acne, the precise mechanisms underlying their efficacy remain to be elucidated, thereby presenting several obstacles to their improved clinical applications:

• 1. The majority of existing studies exploring the link between skin microbiota and acne have relied on cell-based or mouse models, with very few based on early-phase clinical trials. Therefore, significant further research is required to enable effective clinical implications.

• 2. The composition of skin microbiota is susceptible to both endogenous and external influences. Yet, existing research primarily investigates the impact of a single or a couple of factors on the dysbiosis of skin microbiota in acne pathogenesis. Consequently, it is imperative to establish a systematic model to examine skin microbiota alterations under various conditions. More importantly, we must comprehensively view the skin microbiome as a holistic entity involved in the pathogenesis and/or treatment of acne.

• 3. A multitude of natural products currently display potential for targeting C. acnes and mitigating acne. However, the complexity of some natural products' components can lead to severe side effects. Thus, it is important to carefully isolate the beneficial components and reevaluate their effects on acne treatment.

• 4. C. acnes is a widely known pathogenic factor in acne development. However, researchers have perhaps overly concentrated on its regulatory roles in acne pathogenesis over the past decades. Therefore, it is vital to expand our investigations to include other species associated with acne pathogenesis apart from C. acnes.