|Year : 2022 | Volume
| Issue : 3 | Page : 129-142
Skin microbiome in acne vulgaris, skin aging, and rosacea: An evidence-based review
Yu-Ching Weng1, Yi-Ju Chen2
1 Department of Dermatology, Taichung Veterans General Hospital, Taichung; Graduate Institute of Clinical Medicine, National Yang Ming Chiao Tung University, College of Medicine, Taipei, Taiwan
2 Department of Dermatology, Taichung Veterans General Hospital; College of Medicine, National Chung Hsing University, Taichung, Taiwan
|Date of Submission||19-Nov-2021|
|Date of Decision||03-May-2022|
|Date of Acceptance||17-May-2022|
|Date of Web Publication||14-Sep-2022|
Prof. Yi-Ju Chen
Department of Dermatology, Taichung Veterans General Hospital, No. 1650, Section 4, Taiwan Blvd., Taichung 407; College of Medicine, National Chung Hsing University, Taichung
Source of Support: None, Conflict of Interest: None
The goal of this systematic review was to explore emerging perspectives on the role of skin microbiota in acne vulgaris, skin aging, and rosacea. We searched the literature for published clinical trials, randomized controlled trials, cross-sectional studies, and cohort studies, both experimental and observational, whose primary main purpose was to ascertain the associations between the skin microbiome and chronic skin disease, acne vulgaris, rosacea, and skin aging, using the Embase and PubMed databases. Fifty-one relevant published articles were identified for systematic review (up to December 2021). The possible roles of the skin microbiome in these skin diseases were explored to shed light on its development and to identify potential therapeutic targets for treatment. However, the mechanisms of microbial interaction in these diseases are still under-studied. The results of this evidence-based review suggest that it may be possible to develop individualized therapies targeting the pathogenic strains within the skin microbiome involved in these diseases. This alternative therapeutic approach, involving modifications of the microbiome, may form the basis of the next generation of treatment, known collectively as “ecobiological” anti-inflammatory therapies.
Keywords: Acne vulgaris, rosacea, skin aging, skin microbiome
|How to cite this article:|
Weng YC, Chen YJ. Skin microbiome in acne vulgaris, skin aging, and rosacea: An evidence-based review. Dermatol Sin 2022;40:129-42
| Introduction|| |
Acne vulgaris is a chronic and relapsing inflammatory skin disease, mainly caused by Cutibacterium acnes. C. acnes overgrowth might increase lipid production and has long been proposed to be the only microorganism that leads to acne vulgaris inflammation. An increasingly body of evidence shows not only C. acnes but also Staphylococcus epidermidis, and a diverse skin microbiome play important roles in the development of acne.
Rosacea is a difficult-to-treat skin disease with uncertain mechanisms and can be categorized into essential-telangiectasia form, papular-pustular form, rhinophyma, or ocular rosacea in phenotype. In addition, the recent literature showed that Demodex spp. is a possible microorganism that can trigger either flare-up or remission of rosacea. Moreover, some other skin microorganisms, in addition to Demodex, play an important role in controlling the chronic inflammation of rosacea.
The aforementioned findings imply that certain prebiotics or probiotics could be applied to treat skin disease and provide a whole new approach to treatment, involving novel modalities, such as vaccine or phages, which have the potential to overtly tackle these challenging skin diseases and conditions.
It has also been proposed that the skin microbiota plays a role in the process of skin aging. Differences in the skin microbiome in different age groups have been demonstrated in many studies. However, further research is needed to clarify the relationship between aging and the skin microbiome.
In this evidence-based review, recent insights into various aspects of the skin microbiota and the interactions with the immune system would be discussed. Our goal was to undertake a comprehensive review of all relevant studies in the literature, which included studies on the relationships between the skin microbiome and acne vulgaris, rosacea, and skin aging, and to provide medical providers with an overview of current perspectives on treatment. A detailed understanding of these topics is important for further development of new therapeutic approaches involving targeting of the skin microbiome.
| Materials and Methods|| |
We searched the Embase and PubMed databases from 2012 to 2021 using the keywords “skin microbiome,” “acne vulgaris,” or “skin aging,” or “rosacea” and included all controlled studies on the skin microbiome and chronic skin inflammatory diseases. Article selection was conducted by two reviewers who examined each of the titles and abstracts independently to assess their suitability for inclusion. Regarding the inclusion and exclusion criteria, we searched the literature for published clinical trials, randomized controlled trials (RCTs), and cohort studies, both experimental and observational, whose primary main purpose was to ascertain the association of the skin microbiome and chronic skin diseases and conditions, such as acne vulgaris, skin aging, and rosacea. All of the reviewed articles were required to include explicit statements of search methods, inclusions, data synthesis, and exclusions. The primary outcomes of interest for inclusion in the review were associations between the skin microbiome and skin disease. Decisions regarding study quality and eligibility were done by two reviewers, and any disagreement between them was resolved by discussion of the authors' team. We used the following Oxford scales to evaluate the strength of evidence of searched published studies: 1a refers to a systematic review or meta-analysis of RCTs which with narrow confidence interval; 1b indicates an individual RCT with a narrow confidence interval; 2a is a systematic review of cohort studies; 2b denotes a low-quality RCT or individual cohort study; 3a refers to a systematic review of several case–control studies; 3b indicates the individual case–control study; 4 donates a case series or individual case–control study/low-quality cohort.
RCTs were considered to be high-level of evidence, whereas the levels of evidence of serial cross-sectional, ecological, and cross-sectional designs were considered to be lower.
| Results|| |
Fifty-one relevant published clinical trials, RCTs, and cohort studies, both observational and experimental, fulfilling the inclusion criteria were identified. With respect to the quality of studies included in the review, the published clinical trials, RCTs, and cohort studies, both observational and experimental, were published between 2012 and 2021; after excluding duplicate publications, we summarized 51 publications on the associations between skin microbiome and acne vulgaris, rosacea, or skin aging. All (100%) of the selected publications were prospective studies, 2% were RCTs, and the rest were cross-sectional studies, ex vivo studies, cohort studies, and before–after studies [Figure 1].
Publication bias was not addressed for any of the included articles. Some of the studies had some methodological limitations. Methods used to reduce bias in the data extraction were specified in most of the studies that were included. Because of the heterogeneity of the findings and the study design, data are listed as narrative summaries.
All 29 articles showed that the skin microbiota had associations with acne vulgaris, as depicted in [Table 1].,,,,,,,,,,,,,,,,,,,,,,,,,,,, All 13 articles shown in [Table 2] found that the skin microbiome was related to changes in skin aging.,,,,,,,,,,,, All nine articles on rosacea showed that the skin microbiome was related to the disease, as shown in [Table 3].,,,,,,,, Two RCTs showed that the skin microbiome was closely linked to acne vulgaris. Two RCTs showed that the skin microbiome had a close relationship with skin aging. The before–after studies on the skin microbiome showed that it plays a significant role in acne vulgaris, skin aging, and rosacea. Comprehensive comparisons of the three diseases and the skin microbiome are shown in [Table 4].
|Table 4: Comprehensive comparisons of acne vulgaris, skin aging, and rosacea in the relative abundance of skin microbiota|
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Data were primarily obtained from case series, before–after studies, and RCTs of the skin microbiome and acne vulgaris. Dreno et al. found an overabundance of Firmicutes and Proteobacteria and reduced colonization of Actinobacteria in acne patients. Staphylococcus spp. showed high abundance on the surfaces of comedones, pustules, and papules than on nonlesional skin, and its proportions increased with acne severity in a cohort study (n = 26, 26 acne patients, P = 0.004 and P = 0.003, respectively). On day 28 following the application of Effaclar® Duo+ or erythromycin 4%, the number of Actinobacteria decreased with erythromycin 4%, while Effaclar® Duo+ decreased both the number of Staphylococci spp. and Actinobacteria spp. Coughlin et al. showed that the main bacterium in the skin microbiome of adults with acne vulgaris was C. acnes, whereas there were more Streptococcus bacteria in pediatric populations, based on the results of a randomized control trial (n = 16, 8 healthy controls and 8 acne patients, P < 0.01). The number of bacterial phylogenetic diversity and bacterial species decreased after treatment with topical agent along with tretinoin and benzoyl peroxide (P < 0.01). Other studies revealed that the microbiome diversity was high in nonlesional skin and treated areas.,,,,,,,,,,,,,,,,,,,,,,,,,,,,
Recent data have shown that the interactions between C. acnes and S. epidermidis are vital for skin homeostasis. C. acnes growth and induced skin inflammation can be inhibited by S. epidermidis. S. epidermidis controls the proliferation of C. acnes by releasing succinic acid and fermentation of glycerol. The mechanism of the anti-inflammatory effects of S. epidermidis is to inhibit the production of Toll-like receptor (TLR)-2. TLR-2 can then suppress the tissue level of interleukin-6 (IL-6) and tumor necrosis factor (TNF)-alpha, which is induced by C. acne through the inflammation of keratinocyte., The most abundant fungus of skin microbiota in acne patients is Malassezia spp. The lipase, which can stimulate proinflammatory cytokine in Malassezia spp. is more active than that in C. acnes, as shown in [Figure 2].,
|Figure 2: New views on the pathophysiology of acne vulgaris, modified from O'Neill and Gallo. NF-kB: Nuclear factor kappa-light-chain-enhancer of activated B cells, TLR2: Toll-like receptor 2, LTA: Lipoteichoic acid, CAMP: Christie-Atkins-Munch-Peterson, FFAs: Free fatty acids, SCFAs: Short-chain fatty acids, ROS: Reactive oxygen species, MAPK: Mitogen-activated protein kinases, TRAF6: Tumor necrosis factor receptor-associated factor 6, TNF-α: Tumor necrosis factor α, MyD88: Myeloid differentiation primary response 88, IL-1α: Interleukin 1α, IL-1β: Interleukin 1β, IL-6: Interleukin 6.|
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Current acne treatment may affect skin microbiota. Isotretinoin and oral/topical antibiotics for acne treatment are capable of increasing bacterial diversity after treatment (P < 0.005). Probiotics and prebiotics supplementation has been reported to affect both skin and intestinal microbiome. Lactobacilli spp. and Bifidobacteria spp. have been used as probiotics to treat chronic inflammatory skin diseases. Short-chain fatty acids, a product of the glycerol fermentation by S. epidermidis, can suppress the growth of C. acnes. Sucrose, a fermentation initiator, is able to increase the fermentation activity of S. epidermidis and further leads to a significant decrease in the growth of C. acnes (P < 0.001). Further research is warranted to develop therapies that target pathogenic strains to teat acne. Probiotic, prebiotics, and phage therapy can be used to combat the bacteria. In addition, vaccines could be developed to reduce the infections caused by C. acnes and one such anti-inflammatory treatment approach is termed “ecobiological.”
Skin aging can be characterized by the appearance of wrinkles, pigmentary irregularities, and laxity. Both intrinsic and extrinsic factors can influence or deteriorate the process of skin aging., Physiological changes and skin structure changes in the elderly are caused, at least in part, by age-related factors, e.g., changes in immunosenescence, cellular metabolism, and altered hormone conditions. The changes in skin structure are also influenced by environmental and lifestyle factors, including pollution, cumulative UV exposure, and smoking. These physiological changes alter the composition of the skin microbiome, especially sebum production, which may decrease considerably. In several areas of skin, such as the cheek, forehead, and forearm, an age-associated decline in Cutibacterium spp. colonization was found, probably related to the decrease activity of sebaceous glands in old age, but Prevotella, Rothia, and Veillonella had become overrepresented. Aging significantly affects the proportion of archaea in the skin microbiome, which is more abundant in old age as a consequence of the reduced moisture and lower sebum levels. Further purification of metabolites of specific antiaging microorganisms is used in the development of cosmetic medical products. Regulators of skin microbiome homeostasis in different age groups could be developed as targets in new treatments of age-related skin diseases.
Several studies revealed that microbiome diversity was higher in areas without skin aging nonlesional than in areas with skin aging.,,,,, Jugé et al. revealed an increase of Proteobacteria and Corynebacterium and a lower colonization of Actinobacteria and Propionibacterium in old skin in a case–control study of European women (n = 68, 34 healthy controls, 17 younger and 17 older individuals, P < 0.05). In addition, similar findings across different age groups were found in Korean and Chinese women., Li et al. used nested polymerase chain reaction-denaturing gradient gel electrophoresis to prove that the skin microbiome undergoes both qualitative and quantitative changes related to aging in a case–control study (n = 80, 80 individuals of varying ages, P < 0.01). The resident skin microbiome include not only bacteria but also fungi and archaea, which the interaction between each other will produce different skin outcome., Further, Wu et al. found that not only bacteria but also fungi on the skin were significantly different in each age group in a cross-sectional study (n = 65, three age groups, P < 0.001). As skin aging, Cutibacterium spp. decreased colonization over skin. Even the presence of Cutibacterium spp. decreased with aging, it is well established that Cutibacterium spp. is still one of the most prevalent bacteria in aged skin. However, the current literature shows that the skin microbiome may partly explain the pathogenesis of skin aging, and thus, further study is needed to elucidate the relationship between the skin microbiome and skin aging.
It is generally accepted that Demodex-specific microorganisms play a major role in rosacea.
In the papulopustular rosacea, the proportions of Firmicutes and Proteobacteria are higher, whereas they were found to be lower in Actinobacteria. Nonetheless, bacterial diversity was not significantly altered by antibiotic treatments.,,,,,,, The role of cutaneous microbiota in rosacea has been elucidated in recent studies.,, In a cross-sectional study (n = 680 rosacea patients), Gutiérrez et al. noted that rosacea was more prevalent in subjects exposed to generally dust-rich environments and who worked indoors (25.0% confidence interval 16.1–33.91). Other environmental factors, such as environmental pollution, or sun exposure may also affect mites prevalence in skin. Forton et al. reported that the relative prevalence of Demodex spp. increased with age, especially in men (P = 0.001) but not in women (P = 0.004) in a large-scale case–control study (n = 1044, 200 healthy controls and 844 rosacea patients).
The skin microbiome is important for proper immune function within the skin. Several microorganisms including S. epidermidis, Demodex folliculorum, C. acnes, and Bacillus oleronius have been studied in the light of their potential roles in the pathogenesis of rosacea. These microorganisms induce activation of the immune system via TLR-2, causing significantly greater expression of cathelicidin. This can result in abnormal downstream effects, including vasodilation, angiogenesis, extracellular matrix deposition, and leukocyte chemotaxis. Research efforts are underway to understand the roles of timolol, a nonselective beta-adrenergic antagonist, and some human monoclonal antibodies which can reduce the effect of calcitonin gene-related peptide receptor. In addition, the gastrointestinal microbiome may also play roles in the propagation of rosacea. All of the abovementioned findings may be useful in discovering targets of treatment for chronic inflammatory skin disease, such as anti-inflammatory agents, vasoconstrictive agents, and antimicrobial agents. The whole new potential pathophysiology of skin microbiome in rosacea is shown in [Figure 3]., Innate immunity can be upregulated and activated by Demodex spp. in rosacea patients. In addition, skin commensal bacteria, such as B. oleronius, will induce the expressions of proinflammatory cytokines, leukocytes chemotaxis, and vasodilatation. Moreover, leukocytes aggregation will produce more severe skin inflammation.,
|Figure 3: New potential pathophysiology of skin microbiome in rosacea, modified from Kim and Holmes., TLR-2 and NLRP3 can be are upregulated and activated by Demodex spp. in rosacea patients. Bacillus oleronius can induce the expressions of MMP-9, TNF, and IL-8 by leukocytes chemotaxis. NLRP: Nucleotide-binding oligomerization domain, LRP: Leucine-rich repeat and pyrin domain containing, PAR: Protease-activated receptor, TLR: Toll-like receptor, AMP: Antimicrobial peptide, IL: Interleukin, KLK: Kallikrein, LL-37: Activated cathelicidin, MMP: Matrix metalloproteinase, TNF: Tumor necrosis factor.|
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| Conclusion|| |
The findings of this evidence review on the roles of the skin microbiota in acne vulgaris, skin aging, and rosacea suggest that the skin microbiota and its interactions with the skin could have potential in the development of targeting pathogenic strains for the treatment of chronic inflammatory skin diseases. Alternative modalities involving modifications of the skin and gut microbiota may form the next generation of treatment for skin diseases.
Financial support and sponsorship
Conflicts of interest
Prof. Yi-Ju Chen, an associate editor at Dermatologica Sinica, had no role in the peer review process of or decision to publish this article. The other author declared no conflicts of interest in writing this paper.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]