Topical probiotics and postbiotics have emerged as promising alternatives to antibiotics by modulating the skin microbiota.4 In a double-blind, placebo-controlled trial conducted in 79 patients wild mild-to-moderate acne vulgaris, Lebeer et al. (2022) evaluated a topical cream containing Lactobacillus rhamnosus GG, Lactiplantibacillus plantarum WCFS1, and Lacticaseibacillus pentosus KCA1 applied twice daily for eight weeks. The treatment significantly reduced C. acnes and Staphylococcus spp. colonization, while increasing Lactobacillus spp. abundance, likely due to decreased lipase activity and lactic acid production. Clinically, inflammatory lesion counts decreased significantly compared with placebo at weeks 4, 8, and 12, with a 34.4% reduction at week 4 in the active group versus 1.7% in the placebo group (p < 0.001). Although the exact Mean Difference (MD) was not reported, the reduction was statistically significant. Furthermore, the topical probiotic cream was well tolerated and improved skin hydration.6

Sathikulpakdee et al. (2022) conducted a single-blind RCT including104 patients to compare a probiotic-derived lotion containing the cell-free supernatant of L. paracasei MSMC 39-1 with 2.5% benzoyl peroxide. After four weeks, both groups showed significant within-group reductions in inflammatory lesion counts (p < 0.001 for both), with no statistically significant difference between treatments (p = 0.23). The probiotic lotion also significantly reduced erythema index from baseline (from 22.9 ± 1.9 to 21.4 ± 2.1 at week 4, p < 0.001), and showed a favorable tolerability profile, with fewer adverse events (7.69%) compared with benzoyl peroxide (26.92%).7

In a smaller open-label pilot study, Casari et al. (2022) evaluated a serum containing Lactobacillus. paracasei LiveSkin88 combined with hyaluronic acid in 29 patients with mild-to-moderate acne, applied nightly for 28 days. The treatment led to a statistically significant reduction in the number of papules and/or pustules (p < 0.0001). By day 14, the mean number of papules and/or pustules decreased from 7.9 ± 4.0 (mean value ± SD) at baseline to 4.7 ± 3.0 (95% CI), with improvements maintained through day 28 (mean 4.5 ± 3.8). Erythema also showed a a modest but significant improvement (p < 0.0001), while skin hydration increased from 53.5 ± 22.0 to 64.7 ± 19.9 arbitrary units (p < 0.0001; 95% CI). The facial area affected by acne significantly improved after 28 days (p < 0.05). No adverse events were reported, and patient satisfaction was high.8

Taken together, these trials underscore the strain-specific benefits of topical probiotics in acne management, ranging from reductions in inflammatory lesions to improvements in erythema and hydration. However, current evidence remains preliminary. Limitations include small sample sizes, short follow-up periods, heterogeneous formulations, and the fact that only one trial to date has been double-blind and placebo-controlled. Replication in larger, high-quality RCTs with standardized clinical outcomes, including lesion counts, Investigator’s Global Assessment (IGA) scores, and relapse or recurrence rates, is essential to establish the efficacy, safety, and generalizability of topical probiotics in acne care.

Emerging literature also highlights the potential benefit of Live Biotherapeutic Products (LBPs), a novel class of therapeutics incorporating live bacteria into topical formulations designed to modulate the skin microbiota and address localized dysbiosis.37 Various LBP formulations using C. acnes strains have been investigated.

Karoglan et al. (2019) conducted an open-label pilot study in 14 patients with mild-to-moderate acne to assess whether non-pathogenic C. acnes strains could modulate the skin microbiome. Participants received one of two hydrogel formulations for five weeks. Non-inflammatory lesion counts decreased significantly in both groups: from 62 to 37 (mean reduction – 25 lesions; p = 0.029) and from 54 to 35 (mean reduction − 19 lesions; p = 0.036). Inflammatory lesion counts showed no significant changes (p > 0.26). Microbiome analysis revealed colonization by the applied strains, with no irritation or flare-ups reported, supporting the safety and feasibility of this microbiome-modulating approach.9

Knödlseder et al. (2024) developed an engineered C. acnes strain expressing Neutrophil Gelatinase-Associated Lipocalin (NGAL), a protein involved in lipid regulation. In sebocyte cultures, NGAL reduced sebum production by approximately twofold within 48 hours, an effect comparable to isotretinoin 10 μM (p < 0.0001). NGAL produced by recombinant E. coli reduced sebum 1.7-fold but was less effective than the engineered C. acnes. Importantly, no cytotoxicity or apoptosis was observed. In murine models, the engineered strain colonized the skin and maintained NGAL expression without increasing pro-inflammatory cytokines such as IL-1β, IL-6, or TNF-α, underscoring its potential as a safe approach for targeted sebum modulation.10

AOBiome’s Phase IIb trial (NCT02832063) investigated the topical application of Nitrosomonas eutropha B244, an ammonia-oxidizing bacterium, in 358 patients with mild-to-moderate acne. The randomized, double-blind, placebo-controlled design tested treatment for 12-weeks. Compared to placebo, B244 yielded a significantly higher proportion of participants reaching Investigator’s Global Assessment (IGA) success, defined as a post-baseline score of 0 or 1 (Odds Ratio = 2.45; 95% CI 1.08–5.56; p = 0.03). Inflammatory lesion counts showed a numerical, but not statistically significant, improvement versus placebo. The formulation was well tolerated, with no treatment-emergent adverse events reported.11

These findings underscore the potential of LBPs to introduce a paradigm shift in acne therapy, focusing on microbial composition and host-microbe interactions. However, current evidence remains preliminary. Karoglan et al. provided only pilot open-label data without a control group (n = 14). Knödlseder et al. demonstrated promising effects, but only in vitro and in murine models. AOBiome’s Phase IIb trial represents the most robust clinical evidence to date, though its primary outcome was not achieved in the intention-to-treat analysis. Larger, standardized, and controlled trials are warranted to confirm the clinical efficacy, durability, and safety of LBPs in acne management.

Postbiotics, defined as preparations of inanimate microorganisms and/or their components that provide health benefits to the host, have demonstrated multiple benefits for the skin microbiome, including enhancing skin barrier function and promoting the growth of beneficial endogenous bacteria.38 For acne management, various postbiotics have shown potential in restoring microbial balance and reducing acne severity through their anti-inflammatory and antimicrobial effects.39

Emerging evidence highlights the effectiveness of fermentation-derived products, such as Enterococcus faecalis CBT SL-5 extract, as a safe and well-tolerated topical option for reducing acne severity and addressing skin microbiome dysbiosis.12 Han et al. (2022) conducted a randomized, placebo-controlled, split-face comparative study in 20 patients with mild-to-moderate acne. Participants applied a lotion containing E. faecalis CBT SL-5 extract twice daily for four weeks. The treated side showed significantly greater IGA improvement scores compared with the control side at all time points: week 2 (1.65 ± 0.81 vs 1.05 ± 0.51; p = 0.009), week 4 (1.80 ± 0.83 vs 1.15 ± 0.49; p = 0.005), and week 6 (2.15 ± 0.88 vs 1.05 ± 0.51; p < 0.001). Additionally, C. acnes density decreased significantly on the treated side, whereas no significant changes occurred on the control side. No treatment-related adverse effects were reported. Confidence intervals were not reported in the original publication.12

Similarly, Ho et al. (2022) performed a randomized clinical trial evaluating a co-fermented postbiotic formulation containing probiotic strains TYCA06, AP-32, and CP-9 combined with collagen in 20 patients with acne vulgaris. The formulation was applied twice daily for four weeks. The formulation significantly improved skin hydration (+ 4.5% from baseline; p < 0.05), reduced erythema intensity by 7.1% (p < 0.01), and decreased the number of brown spots by 8.7% (p < 0.001). Sebum production showed a nonsignificant reduction of 6.2%. In vitro assays demonstrated downregulation of Thymic Stromal Lymphopoietin (TSLP) and Interleukin-33 (IL-33) expression in human keratinocyte cultures, supporting an anti-inflammatory effect. The treatment was well-tolerated with no adverse events. Confidence intervals were not reported.13

Although these early-phase trials suggest potential benefits, clinical evidence supporting topical postbiotics in acne remains exploratory. Both Han et al. and Ho et al. relied on small samples and short follow-up durations, lacked standardized acne endpoints, and assessed heterogeneous formulations. The split-face design used by Han introduces observer bias, while Ho et al. primarily evaluated surrogate and cosmetic outcomes. To establish the translational applicability of topical postbiotics, future studies should employ adequately powered randomized controlled trials with standardized clinical and microbiome-informed outcomes.

Recent studies have evaluated biotechnological phytocomplexes in acne treatment, highlighting their antibiofilm and microbiota-modulating properties. These formulations combine metabolomes derived from plant stem cell cultures of Camellia sinensis and Morinda citrifolia. C. sinensis exhibits anti-inflammatory effects by reducing IL-6, IL-8, TNF-α, and CXCL levels, along with antiseborrheic and antibiofilm properties. Meanwhile, M. citrifolia inhibits biofilm formation and blocks bacterial communication, contributing to microbiota rebalancing.14,15

A novel phytocomplex lotion containing Canonia allysis©, niacinamide 4.00% and succinic acid 2.00% was evaluated in two open-label trials in patients with mild-to-moderate facial and truncal acne.14,15 Guerra-Tapia et al. (2024) conducted a prospective open-label study in 43 subjects with mild-to-moderate truncal acne, treated for eight consecutive weeks (56 days). The application of this phytocomplex reduced inflammatory lesions by 52.1% (p = 0.006) and acne severity by 27.6% on the IGA scale, with 60.5% of patients achieving ≥ 1-point improvement (p < 0.001). Microbiome analysis showed a significant decrease in C. acnes relative abundance (66.4% to 58.1%, p = 0.009), indicating partial microbial rebalancing. Erythema decreased by 18.3% (p = 0.007) and desquamation by 63.8% (p = 0.02). No serious adverse events were reported, supporting favorable tolerability.14

Similarly, De Lucas et al. (2024) conducted an open-label study in 44 patients with mild-to-moderate facial acne, treated for eight weeks. Inflammatory lesions decreased by 47.3% (p < 0.001), while non-inflammatory lesions decreased by 31.1%, with borderline significance (p = 0.05). IGA scores also improved significantly at day 56 (p < 0.001). No serious adverse events occurred.15

Despite these encouraging findings, the clinical evidence supporting biotechnological phytocomplexes remains preliminary. Both studies were open-label, non-randomized, with modest sample sizes (n = 43 and n = 44), lacked control groups, and did not report 95% Confidence Intervals, limiting interpretation of effect sizes. Moreover, both evaluated the same proprietary formulation and were industry-sponsored, raising concerns regarding potential conflicts of interest and publication bias. Although reported outcomes include statistically significant reductions in acne severity and microbial imbalance, the lack of independent, adequately powered randomized controlled trials with standardized clinical and microbiome-informed endpoints limits external validity and underscores the need for further research to establish their therapeutic role in acne care.

Controlling the inflammatory response is a primary goal in acne treatment, particularly given the rise of antimicrobial resistance. Bacteriophage therapy has emerged as a potential alternative due to its ability to specifically target C. acnes while preserving beneficial microbes. This strategy may help restore microbial balance and maintain skin microbiota homeostasis.40,41

Preclinical studies provide the initial evidence for this approach. Kim et al. (2019) tested C. acnes-specific phages in a murine acne model, showing a reduction in inflammatory nodule size compared to controls. Histological analyses revealed decreased epidermal thickness and fewer microcomedone-like cysts, while immunohistochemical results suggested reduced CD8+ T-cell and neutrophil infiltration, as well as lower IL-1β and MMP-3 expression. However, most of these changes were not statistically significant, and no 95% Confidence Intervals were reported, limiting the interpretation of effect sizes.16 Similarly, Lam et al. (2021) evaluated the therapeutic phage TCUCAP1 in mice, observing significant reductions in nodule size and epidermal hyperplasia, together with decreased IL-1β (p < 0.05) and caspase-3 (p < 0.01). Only p-values were reported without confidence intervals.17

The only human evidence to date comes from Golembo et al. (2022), a randomized, double-blind, vehicle-controlled Phase 1 trial testing a topical gel containing the bacteriophage cocktail BX001 in patients with mild-to-moderate acne. The high-dose formulation significantly reduced C. acnes load compared with baseline and vehicle (p = 0.036), with effects observed from day 14 to day 35. The low-dose formulation did not show significant effects. Importantly, the study did not report lesion counts, Investigator’s Global Assessment (IGA) scores, or relapse outcomes, and no 95% Confidence Intervals were provided. BX001 was well tolerated, with no serious adverse events, and did not alter overall microbiome diversity.18

Bacteriophage therapy for acne remains early-phase, with encouraging but limited preclinical and Phase 1 findings. Current evidence is restricted to microbiological and histological outcomes, without robust clinical endpoints. To establish their therapeutic potential, durability of effect, and relevance for acne management, independently conducted randomized controlled trials with standardized clinical and microbiome-informed outcomes, including lesion counts, IGA scores, and relapse or recurrence rates, are required.

Vaccines represent another innovative strategy targeting acne pathogenesis. By focusing on virulence factors such as the CAMP factor and sialidase, these approaches aim to neutralize C. acnes pathogenicity and reduce the inflammatory response while preserving commensal microbiota and minimizing side effects.41–43 Sanofi is currently conducting a Phase I/II randomized, double-blind, placebo-controlled clinical trial (NCT06316297) evaluating the safety, immunogenicity, and efficacy of an mRNA acne vaccine targeting C. acnes virulence factors. This ongoing trial includes healthy participants aged 18–45 years with moderate-to-severe acne and is assessing different dose levels administered intramuscularly.44

Additionally, a completed Phase I trial (NCT05131373) investigated the safety, tolerability, and immunogenicity of ORI-A-ce001, an acne vaccine for treating moderate facial acne vulgaris in adults. This multicenter, randomized, double-blind, placebo-controlled trial evaluated various dose levels in adults aged 18-years and older. In addition to assessing safety and immune responses, the study collected preliminary data on the vaccine’s efficacy, including its impact on inflammatory and non-inflammatory lesions, acne severity, and skin microbiome composition.45 These findings provide valuable insights into the potential role of vaccines as a novel therapeutic approach for acne management.

Despite their conceptual appeal, acne vaccines remain in the early stages of clinical development. Both referenced trials are Phase I studies primarily focused on safety and immunogenicity, with no peer-reviewed efficacy results available to date. Larger, well-designed clinical trials are necessary to demonstrate meaningful improvements in acne severity, characterize immune durability, and assess real-world applicability.

The gut-skin axis highlights the bidirectional relationship between the gastrointestinal system and skin health, mediated by immune regulation, the microbiota, and neuroendocrine pathways. The gut microbiota plays a pivotal role in acne development and overall skin health by modulating immune responses and systemic inflammation. Disruptions such as dysbiosis or impaired intestinal barrier function can exacerbate skin conditions, including acne. Although the contribution of the gut microbiota to acne pathogenesis remains underexplored, targeting gut health through integrative approaches holds promising potential for improving skin outcomes.46

• a)

  Oral probiotics:

Eguren et al. (2024) conducted a 12-week randomized, double-blind, placebo-controlled clinical trial evaluating an oral probiotic supplement containing Lacticaseibacillus rhamnosus (CECT 30031) and the the cyanobacterium Arthrospira platensis (BEA_IDA_0074B) at 1 × 109 CFU per daily dose in 81 individuals with mild-to-moderate acne vulgaris. Non-inflammatory lesions decreased significantly versus placebo group, with a difference of −8.06 lesions (95% CI −15.37 to −0.74; p = 0.03). Improvements were also observed in acne severity, with 50% of probiotic-treated patients improving by at least one Acne Global Severity Scale (AGSS) category, and 42.5% achieving ≥ 30% reduction in Global Acne Grading System (GAGS) scores (both p < 0,05). Inflammatory and total lesion counts showed no significant differences between groups (p = 0.040). The treatment was well tolerated, with only mild digestive events reported.19

Rinaldi et al. (2022) conducted an 8-week randomized, double-blind, placebo-controlled trial evaluating a dietary supplement containing Bifidobacterium breve BR03 (DSM 16604), Lacticaseibacillus casei LC03, and Ligilactobacillus salivarius LS03 combined with botanical extracts (lupeol and Echinacea) in patients with mild-to-moderate acne. The intervention significantly reduced inflammatory lesions (-56.7% vs. -18.9% in placebo; p < 0.05), decreased sebum secretion and desquamation, and favorably modulated the skin microbiota by reducing C. acnes and S. aureus while increasing S. epidermidis. However, 95% Confidence Intervals were not reported, limiting the interpretation of the magnitude of these effects.20

Da Rocha et al. (2023) conducted a 180-day randomized, double-blind, placebo-controlled trial in 212 patients with mild-to-moderate acne, evaluating an oral probiotic supplement (Lactobacillus acidophilus and Bifidobacterium lactis) combined with a fixed-dose topical regimen of adapalene 0.1% and benzoyl peroxide 2.5%. The combined approach significantly improved outcomes, with a higher proportion of patients achieving an IGA score of 0 or 1 compared with topical therapy alone (p < 0.05). The probiotic regimen was well tolerated, but as with the Rinaldi trial, no 95% Confidence Intervals were provided.21

Although the clinical evaluation of oral probiotics in acne has progressed, substantial variability in strain composition, outcome measures, and treatment duration limits external validity and reproducibility. Mechanistic endpoints and microbiome-informed outcomes were inconsistently assessed across studies. Despite these limitations, the consistent safety profile and randomized, placebo-controlled designs underscore their potential. Standardized protocols incorporating both clinical and microbiome endpoints, with clear reporting of effect sizes and 95% Confidence Intervals, are necessary to define the therapeutic role of oral probiotics in acne care.

• b)

  Omega-3 fatty acids:

The fatty acids ω-3 and ω-6 are thought to have potential utility in acne through anti-inflammatory effects.47 Huang et al. (2024) conducted a 12-week randomized trial in 40 patients with moderate-to-severe acne treated with isotretinoin with or without ω-3 fatty acids (2400 mg/day). The combination group achieved greater reductions in Global Acne Grading System (GAGS) scores (mean 15.1 ± 4.5) compared with isotretinoin alone (18.7 ± 4.9), with a mean difference of -3.6 points (p = 0.02).22 These findings align with the results previously reported by Jung et al. (2014), who evaluated 45 patients randomized to ω-3 fatty acids (2000 mg/day EPA + DHA), γ-linoleic acid (GLA, 400 mg/day), or control for 10 weeks. The ω-3 group showed a 43% reduction in inflammatory lesions (10.1 ± 3.2 to 5.8 ± 3.4) and a 20% reduction in non-inflammatory lesions (23.5 ± 9.2 to 18.9 ± 8.3), both p < 0.05. Similar improvements were observed in the GLA group, while no significant changes occurred in controls. Acne severity (Cunliffe grade) improved from 2.4 to 1.7 in the ω-3 group and from 2.3 to 1.8 in the GLA group (p < 0.05).23

Collectively, these findings suggest that fatty acid supplementation may reduce acne lesion counts and severity; however, the lack of reported confidence intervals, small sample sizes, and short treatment durations limit interpretation of effect sizes and generalizability. In Huang et al., the concurrent use of isotretinoin precludes definitive attribution of effects to ω-3 fatty acids, and microbiome modulation was inferred rather than directly assessed. Similarly, Jung et al. lacked detailed reporting on blinding procedures and did not evaluate gut microbiota endpoints. Overall, although the anti-inflammatory role of fatty acids in acne pathophysiology remains biologically plausible, larger, independently replicated trials with standardized endpoints and reporting of 95% CIs are required to confirm their clinical efficacy and clarify underlying mechanisms.

Photodynamic Therapy (PDT) is a non-invasive, targeted modality for inflammatory acne. It involves the application of a topical photosensitizer, most commonly Aminolevulinic Acid (ALA), followed by irradiation with a specific light source.48 The most frequently used wavelength is red light (630 nm), which penetrates deeper into the skin and activates Protoporphyrin IX (PpIX), the metabolite of ALA. Upon activation, PpIX generates Reactive Oxygen Species (ROS), inducing selective cytotoxicity in sebaceous glands and reducing sebum production.49 Beyond sebosuppression, ALA-PDT has demonstrated anti-inflammatory and microbiome-modulating effects, including disruption of Cutibacterium acnes biofilms and restoration of microbial diversity.50,51 PDT has also been shown to downregulate Toll-Like Receptors (TLR-2 and TLR-4) and decrease pro-inflammatory cytokine production in sebaceous glands and the epidermis.52

• a)

  ALA-PDT and microbiome modulation:

Yang et al. (2021) conducted a prospective study evaluating microbiome changes in acne patients before and after ALA-PDT. Treatment reduced C. acnes abundance (p = 0.037), increased Bacillus (p = 0.012) and Lactococcus (p = 0.022), and enhanced overall microbial diversity (p = 0.003), suggesting a shift toward an eubiotic environment resembling healthy skin.24

Guo et al. (2023) investigated ALA-PDT utilizing a 630 ± 5 nm LED light source in patients with severe acne. This intervention caused a gradual increase in the relative abundance of genera such as Pseudomonas, Gordonia, Leptotrichia, and Mycobacterium, microbes that were found at lower levels in severe acne patients compared to healthy individuals. Notably, the study found no statistically significant difference in the relative abundance of C. acnes among the healthy control, pretreatment, and posttreatment groups. These findings suggest that PDT’s effects extend beyond bacterial suppression to include microbiome restoration.25 Neither study provided 95% Confidence Intervals, limiting the interpretation of effect sizes.

• b)

  Modified PDT protocols compared to standard therapy:

Zhang et al. (2023) performed a randomized multicenter trial comparing modified ALA-PDT (M-PDT) with low-dose isotretinoin in patients with moderate-to-severe acne. M-PDT achieved 50% clinical improvement after just 1 week, compared with 8-weeks for isotretinoin (p < 0.001). Adverse effects were limited to local skin irritation in the M-PDT group, while 70.67% of patients receiving isotretinoin experienced systemic side effects. Confidence intervals were not reported.26

• c)

  Novel Photosensitizers:

Recent studies have explored natural photosensitizers as alternatives to ALA for acne management. Kim et al. (2023) conducted a randomized split-face trial comparing St. John’s Wort (SJW)-PDT with Indole-3-Acetic Acid (IAA)-PDT. SJW-PDT reduced acne lesions by 56.5% at 1-week and 65.9% at 4-weeks (both p < 0.001), with sebum production decreasing by 27.9% (p = 0.012) and no adverse events reported; however, confidence intervals were not provided.27 Zheng et al. (2024) evaluated curcumin-based PDT in vitro against C. acnes biofilms. The treatment demonstrated dose-dependent suppression of bacterial viability and potent anti-biofilm activity, highlighting curcumin’s potential as a natural photosensitizer for acne vulgaris, particularly in cases involving antibiotic resistance.28

Although PDT shows promising antimicrobial, anti-inflammatory, and microbiome-modulating effects in acne, available studies are limited by small sample sizes, heterogeneity in photosensitizers, protocols, and endpoints, and the absence of reported confidence intervals. While early findings suggest efficacy and safety, robust multicenter randomized controlled trials with standardized clinical and microbiome-informed outcomes, including lesion counts, Investigator’s Global Assessment (IGA), and relapse rates, are required to establish PDT’s therapeutic role in acne care.