Application of Probiotics for Acne Vulgaris Topical Therapies

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This entry is adapted from the peer-reviewed paper 10.3390/cosmetics10030077

The skin microbiome is an essential barrier for preventing the invasion of pathogens and regulating the immune responses. When this barrier is disrupted, several dermatoses, including acne vulgaris, may arise. Probiotics have proven to be an alternative to the use of antibiotics, often associated with undesirable effects, in the treatment and prevention of dermatological disorders such as acne.

acne topical therapies Probiotics

1. Introduction

Human skin defends itself against microbes through secreted substances, such as sebum, proteases, antimicrobial peptides, and lisoenzymes, as well as with its pH, temperature and humidity levels. Despite this, commensal bacteria on the skin form complex ecosystems, and their competition with pathogens can prevent colonization by harmful bacteria ^[1]. As a result, most of the bacteria that colonize the skin are not harmful and some may even be beneficial to the host.

Over 1000 species of bacteria from 19 different phyla (of which the most representative are Actinobacteria, Proteobacteria, Firmicutes, and Bacteroidetes) inhabit human skin, alongside dermatophytes and viruses, as result of constant exposure to microbes found in the external environment ^[2]. Other important factors that influence the skin microbiota throughout an individual’s life include host factors, such as lifestyle, age, and gender, and environmental (socioeconomic and geographical) ones. At the onset of puberty, increased sebum production creates an environment favorable to the proliferation of lipophilic microbes, such as Cutibacterium acnes (formerly designated as Propionibacterium acnes), which compete with other commensal bacteria and dominate the areas of higher density in sebaceous glands, leading to a decrease in the overall diversity of skin microbiota during puberty ^[2]. While the sebaceous areas of the skin are less diverse, harboring mostly bacteria from the Actinobacteria and Firmicutes phyla, such as Propionibacterium and Staphylococcus species, moist zones (the navel, soles of feet, skin folds and creases) tend to be richer in Corynebacterium and Staphylococcus species, and drier regions such as the buttock, forearm, and parts of the hand tend to present the highest phylogenetic diversity ^[3].

Women and men also have differences in their skin microbiome, due to variations in pH, sweat, thickness, hormones, and sebum production. pH is generally lower and sebum secretion is higher in men when compared to women of the same age. These anatomical and physiological factors account for some of the differences observed; beyond those features, some variations may be caused by gendered behavioral tendencies regarding hygiene and cosmetics use ^[3].

Regarding the impact of a Westernized lifestyle versus non-Westernized living conditions, comparisons have shown that people subjected to the former possess less diverse skin microbiomes, with higher percentages of Actinobacteria, and, more specifically, Propionibacterium species ^[2]^[4].

Cosmetics also have the potential to change the skin microbiome, especially when the daily frequency with which most people use them is considered. Although sterility is not required in cosmetic products, the likelihood that they will introduce infectious microbes is very low, provided the products comply with current legislation. However, the presence of antimicrobial preservatives in formulations may have an impact in the skin microbiome, with hard-to-predict long-term consequences that could entail the selection of resistant bacteria, depending on the residual activity of the preservatives on skin ^[5].

Given the impact of acne on the lives of those who suffer from it, there is a rising number of recent reviews exploring acne vulgaris ^[6]^[7]^[8]^[9]^[10]. However, to date, there has been no comprehensive investigation into the use of topical products for acne-prone skin based on probiotics as an alternative or adjuvant therapy.

2. Acne Vulgaris

Acne vulgaris is a chronic inflammatory disease of the human pilosebaceous follicle. It has been reported that it affects 85% of Westernized adolescents, continuing into their twenties in 64% and into their thirties in 43% of individuals; as such, it is considered the most common skin disease ^[11]^[12]. The pathophysiology of acne is well-characterized, but despite its near universality in young individuals, the epidemiology of this disease remains uncertain; common risk factors have been difficult to confirm, and misconceptions about the causes of acne are still rather frequent ^[11].

2.1. Pathophysiology

Acne lesions, which can be divided into noninflammatory lesions (open or closed comedones) and inflammatory lesions (papules and pustules) are formed in two main stages. First, the keratinocytes lining the pilosebaceous unit undergo abnormal desquamation, resulting in the formation of a microcomedone. The follicle, which normally serves as an exit route for sebum secretions, becomes plugged due to the buildup of sebum and desquamated cells, and it eventually becomes swollen enough to become a visible comedone—a whitehead or a blackhead. If the microcomedone is colonized by bacteria, specifically C. acnes, an inflammatory process begins. C. acnes promotes pustule formation by releasing chemotactic factors that attract neutrophils, among other pro-inflammatory mediators ^[13].

2.2. Risk Factors

The physiological mechanisms underlying acne may be well-established, but the factors that may trigger it or lead to a higher propensity towards it are still hotly debated, and they are surrounded by many myths and misconceptions. Despite this, some correlations between certain characteristics or behaviors and an increased predisposition towards acne have been observed.

2.3. Symptoms and Treatment

Acne can be manifested on varying levels, ranging from mild to very severe, but even moderate cases can cause psychological and emotional suffering ^[13]. Beyond the physical discomfort caused by the lesions, acne patients of all ages and genders report feeling self-conscious and anxious due to the condition of their skin. Furthermore, regardless of the severity of the case, it can exacerbate depression, anxiety, anger and suicidal ideation ^[14]. Given the significant impact on the quality of life of sufferers, it is critical to provide an effective treatment course that can manage the development of new lesions while healing the pre-existing ones.

The clinical appearance of acne is polymorphic, with variable degrees of severity and both acute and chronic forms, as well as many subtypes. Acne vulgaris can be classified as inflammatory versus noninflammatory, comedonal, comedopapular, papular, papulopustular and cystic or nodular, though the definitions of what constitutes a papule versus a nodule, for instance, are not concordant ^[15]. Acne vulgaris proper usually refers to papulopustular acne, but more severe instances can fall under the designation of acne conglobata (nodular acne), infantile and juvenile acne, and acne tarda in patients older than the usual age range, that is, above 25 years of age ^[16]. Although acne is not often misdiagnosed, some conditions may have acneiform presentation and should be excluded, as is the case of grade 2 rosacea, Staphylococcus aureus folliculitis, milia, boils, acne agminata, syringomas, demodex folliculitis, pityrosporum folliculitis and perioral dermatitis ^[17].

Many scales for grading acne severity exist, but a review on their quality by Agnew et al. ^[18] indicated that most were poorly validated and their outcomes were inconsistent; lacking a gold-standard assessment scale, researchers and clinicians may resort to simplified methods, such as the classification of acne as mild, moderate, or severe in treatment guidelines. These methods present weak to moderate reliability ^[18].

3. Topical Probiotic Formulations for Acne-Prone Skin

Owing to recent discoveries regarding the cutaneous microbiome, cosmetic and pharmaceutical brands have begun to develop and advertise products that seek to enrich and protect the diversity of healthy skin bacteria, making use of probiotics (i.e., live microorganisms that, when administered in adequate amounts, confer a health benefit on the host) ^[19]. Microorganisms must meet certain criteria in order to be designated as probiotics. The criteria include all information about the microorganism, such as its genus and species, having a scientifically valid nomenclature, and having validated health benefits with at least one study carried out in humans ^[20].

Probiotics have been the subject of study in what is called the gut–brain–skin axis theory. These studies have shown that probiotics are effective in the treatment of some dermatological disorders, such as acne and atopic dermatitis ^[21]. Effectively, the intestinal microbiota is responsible for the body’s adequate immunity and defense against pathogenic microorganisms. Thus, variations considered harmful at the level of the intestinal microbiota could trigger inflammatory states and autoimmune diseases in various organs distant from the intestine, such as the skin ^[22]. Table 1 presents some of the main advantages and limitations associated with the topical administration of probiotics.

Table 1. Advantages and limitations of topical probiotic administration.

Advantages	Non-invasive Avoids gastrointestinal degradation Allows a controlled release High patient compliance Skin immunity regulation Skin pH reduction
Limitations	Low permeability of probiotics across stratum corneum Low probiotic stability in unfavorable skin environments Lack of scientifically validated clinical data about the efficacy and safety of topically applied probiotics

Topical probiotic treatments are considered safe and without adverse effects, when compared to topical and systemic standard therapies ^[23]. However, there are few human clinical trials based on probiotics in topical pharmaceutical formulas for the treatment of acne. Thus, there are insufficient clinical data to demonstrate effectiveness and a deep understanding of side effects of these products. Consequently, further clinical investigation is required, as well as better regulation of topical probiotic products, including those used in the treatment and prevention of acne. Patients seeking information about the use of topical probiotics should be informed not only about their clinical benefits, but also relevantly to the lack of knowledge regarding its potential adverse effects. In fact, despite the promising findings, the side effects of topical probiotics are not well-known ^[24].

Zmora et al. ^[25] concluded that probiotics could potentially cause damage if not implemented correctly, mainly in the case of immunocompromised patients (e.g., patients with AIDS—acquired immunodeficiency syndrome). Additionally, the administration of probiotic species that are not native to a particular ecosystem can potentially cause adverse effects. Thus, extensive research is needed to safely administer different strains, which may have different effects depending on the individual. In addition, the quantity of probiotics being introduced was not regulated ^[26]. However, several in vitro studies have demonstrated interesting properties of some probiotic strains ^[27].

The most well-known probiotics are Gram-positive anaerobic bacteria, such as Lactobacillus and Bifidobacterium. Their use in oral preparations is well-regulated; however, there is no legal regulation for topical probiotics ^[24]^[28]. Lopes et al. ^[29] observed that many strains of Lactobacillus and Bifidobacterium had a good ability to adhere to keratin and inhibit pathogenic bacteria biofilm formation; however, these bacteria had a limited ability to adhere to C. acnes, which could be relevant to their potential use as topical probiotics ^[27].

In cosmetic products, probiotics were initially used as ingredients in creams, intimate hygiene products, shampoos, and toothpastes. The most common probiotic strains included in cosmetics are Bacillus subtilis, Lactobacillus acidophilus, Lactobacillus casei, and Lactobacillus plantarum. These probiotics stimulate the production of lipids, having a moisturizing effect on the skin. Other benefits include the reduction in toxic metabolites, the increase in antibody production, the restoration of the immune system’s homeostasis, and the regulation of cytokine synthesis ^[30]^[31]^[32]. It is also worth noting that topically applied probiotics can also serve as a protective shield by functioning as a competitive inhibitor of binding sites, thereby preventing colonization by other potential pathogens ^[24].

Lactobacillus species are used in cosmetic products with anti-wrinkle, anti-aging, and moisturizing properties due to the production of lactic acid, which is one of the main components of skin’s natural moisturizing factor. Furthermore, the use of Streptococcus salivarium and Streptococcus thermophilus S244 in cosmetics also leads to the production of skin moisturizing enzymes, reducing skin dryness and aging ^[33]. The use of probiotics also has a beneficial effect on the regulation of skin pH ^[34].

Bifidobacterium species may also enhance the production of hyaluronic acid, a glycosaminoglycan that contribute to skin elasticity. Studies have shown that the ability of bifidobacteria-fermented soymilk extract to stimulate hyaluronic acid-improved skin appearance ^[35]^[36].

In addition to the use of probiotics in cosmetic products, their topical application in skin diseases (use of Lactobacillus bulgaricus), including acne, has been reported since 1912 ^[27].

Park et al. ^[37] verified that probiotics modify several factors involved in the pathophysiology of acne development. Thus, topical products containing probiotics or their lysates have shown potential in acne prevention. Individuals with acne treated with topical probiotics experienced a reduction in lesions, erythema, and pathogenic bacteria load with an improvement in the skin barrier. Because acne is associated with an overgrowth of pathogenic bacteria, and treatment often consists of antibiotics, topical probiotics can restore the skin’s microflora, shrinking acne lesions without causing systemic side effects ^[38].

Di Marzio et al. ^[39] showed that when applied to the skin for seven days, S. thermophilus can increase ceramide production and that some of the ceramide sphingolipids, mainly phytosphingosine, would provide both anti-inflammatory activity and antimicrobial effect against C. acnes.

Staphylococcus epidermis is also an example of a bacterium that has shown promise in the treatment of acne. A study showed that this bacterium is present in the microbiota of the skin and mediates the fermentation of glycerol, which is naturally produced by the skin, inhibiting the growth of C. acnes ^[40]. It was shown that succinic acid, a product of glycerol fermentation, was responsible for the inhibitory effects on C. acnes ^[40] and that increasing it with probiotics can result in better outcomes for patients with acne. In addition to S. epidermis, S. salivarius is also a bacterium obtained through the oropharyngeal system that inhibits the proliferation of C. acnes, in this case, by producing a bacteriocin-like inhibitory substance (BLIS) ^[41]^[42]. The S. salivarius K12 strain was able to inhibit the production of pro-inflammatory cytokines, such as interleukin-8 (IL-8) in epithelial cells and keratinocytes, most likely by inhibiting the nuclear factor kappa B (NK-kappa B) pathway ^[43].

Lactobacillus vulgaris produces lactic acid, which increases the production of substances with antimicrobial action against C. acnes and reduces significantly the amount of papules and pustules. Bifidobacterium longum and Lactobacillus paracasei are other examples of probiotics used to attenuate inflammation mediated by substance P, i.e., a primary stress-induced mediator that leads to inflammatory states and sebum production ^[44]. It is well-known that acne can be exacerbated due to stress, as result of the release of substance P, which stimulates sebocytes to produce higher levels of pro-inflammatory cytokines such as IL-1, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). Gueniche et al. ^[44] demonstrated that B. longum extract applied to the skin improved sensitive skin in various parameters associated with inflammation, such as decreased vasodilation, edema, mast cell degranulation, and TNF-alpha release. These findings suggested that B. longum extract application contributes to reinforcing skin homeostasis and improves skin resistance to external environmental effects.

Kang and colleagues ^[31] performed a double-blind, randomized, placebo-controlled clinical trial in 70 patients with acne. These authors concluded that the activity against C. acnes produced by Enterococcus faecalis SL-5, a species of Lactobacillus genus extracted from human feces, has a potential role in acne treatment and could serve as an alternative to topical antibiotics. A lotion containing this probiotic significantly decreased the inflammatory acne lesions such as pustules when compared to a placebo lotion ^[31]^[45]. Natural antibiotics (bacteriocins) are preferable to synthetic antibiotics due to their lack of multidrug resistance and the presence of fewer adverse effects ^[46]. In other study, Tagliolatto et al. ^[47] used Lactobacillus plantarum GMNL06, a tyndallized bacteria produced from heat-treated probiotics. This heat treatment allows the release of bacteriocins from cell membranes. According to the authors, using Lactobacillus plantarum GMNL06 cream topically to treat mild to moderate acne was shown to be both safe and effective in the treatment of mild and moderate acne, even as monotherapy. It did not cause skin irritations or discomfort; it was not photosensitizing, and 90% of the volunteers who were tested showed positive findings.

To compare the efficacy of a lotion based on L. paracasei MSMC 39-1 versus a 2.5% benzoyl peroxide lotion in 104 patients with mild to moderate acne, Sathikulpakdee et al. ^[48] conducted a randomized clinical trial. In both groups, acne lesions and erythema decreased; however, a greater percentage of patients treated with benzoyl peroxide experienced treatment-related side effects compared to patients treated with probiotic-based lotion (26.92% vs. 7.69%). Therefore, these authors concluded that the lotion based on L. paracasei MSMC 39-1 could be a safer alternative compared to the 2.5% benzoyl peroxide lotion ^[48]. In other clinical trial, involving 10 volunteers, Muizzuddin et al. ^[49] used L. plantarum-based aqueous lotion prepared in 1% and 5% concentrations of probiotics. While the formulation containing 5% of probiotics was effective at reducing acne lesion size, skin erythema and repairing the skin barrier, the lotion with a concentration of 1% did not present significant effects. This study suggested a dose-dependent effect of L. plantarum in mild acne treatment.

A study performed by Jung et al. ^[50] supported the conclusion that probiotics may also provide a synergistic anti-inflammatory effect with systemic antibiotics, such as minocycline, while also reducing potential adverse events associated with chronic antibiotic use.

It is described that nitrates participate in metabolic pathways, lead to nitrolipid formation, and regulate the inflammatory response. Nitrosomonas eutropha is a bacterium that converts ammonia to nitrite and nitric oxide. N. eutropha was an important bacterium usually found on human skin. However, due to the use of antibacterial soaps, and other hygienic practices, N. eutropha is no longer present on the skin in sufficient amounts to have a beneficial effect ^[51]. Thus, several researchers have hypothesized that the reintroduction of this bacterial strain to human skin may provide health benefits ^[52]. A randomized, double-blind, placebo-controlled, phase IIb/III study is currently underway to evaluate the safety, tolerability, and efficacy of B244 (topical N. eutropha D23) when used by subjects with mild to moderate acne over 12 weeks ^[52].

Several in vitro studies have shown the potential beneficial effects of probiotics in acne prevention; however, clinical trials with topical formulations containing probiotics are scarce, although they have shown positive results. Topical probiotics seem to produce their effects through the inhibition of growth of C. acnes in the pilosebaceous unit and decrease inflammatory responses.

Given the potential adverse effects caused by some standard acne treatments, probiotics have been investigated as an alternative or adjuvant therapy by employing less aggressive therapies and positive effects on the recovery of acne symptoms ^[27]. In fact, probiotics could complement the classical acne treatment by reducing the number of pathogens, lowering toxic metabolites, increasing antibody production, and regulating cytokine synthesis ^[50].

Prebiotics are specific fermented components that enhance changes in the composition and activity of the gut microflora in favor of the host ^[53]. Probiotics and prebiotics in association (i.e., synbiotics) have the capacity to maintain and restore the skin microbiota. In cosmetic formulations, prebiotics can selectively increase the activity and growth of beneficial skin probiotics. To study the symbiotic ability of probiotic bacteria (Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus plantarum, Lactobacillus gasseri, and Lactococcus lactis) in association with the prebiotic konjac glucomannan hydrolysates to inhibit C. acnes growth, an in vitro study was carried out by Al-Ghazzewi et al. ^[54]. These authors found that different probiotic bacteria strains were able to inhibit the growth of C. acnes, and the presence of the konjac glucomannan hydrolysates significantly enhanced the inhibition ^[54]^[55]. Bateni et al. ^[56] also proved that a formulation containing konjac glucomannan hydrolysate (5%, w/v) significantly improved the health of the skin of young women with acne.

It is also important to highlight that, especially in cosmetics, the application of live bacteria would require huge efforts to implement modified procedures for handling during the production, storage, and delivery of the products ^[57]. Given that formulation processes may inactivate probiotics and alter their functionality, it is critical to select suitable formulation techniques and manufacturing processes. Dehydration processes, such as spray-drying, freeze-drying, and fluidized bed-drying, are common practice used during the production of probiotics ^[58]. Unlike oral formulations, in which lyophilized probiotics can be packaged into capsules or tablets, topical probiotic formulations often require reconstitution to enable spreading onto the skin and/or incorporation into a pharmaceutical base (e.g., cream, emulsion, gel, and suspension) prior to use ^[59].

Another important issue is that these topical care products should be sterile and not contain antimicrobial preservatives that may affect probiotic strain viability and further alter the microbiota of the host ^[34].

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Ieva Dapkevicius

Vânia Romualdo

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Update Date: 30 May 2023

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