Changing Our Microbiome: Probiotics in Dermatology

Y. Yu; S. Dunaway; J. Champer; J. Kim; A. Alikhan

Disclosures

The British Journal of Dermatology. 2020;182(1):39-46. 

In This Article

Methods

A literature search was conducted using the PubMed and ClinicalTrials.gov databases for relevant studies with the keywords 'microbiome', 'microbiota', 'commensal', 'bacteria', 'probiotic', 'topical', 'skin' and 'dermatology'. All search terms were used in various combinations and studies were screened for relevance based on their abstracts. Basic science, in vitro research, animal model studies and clinical trials were included for both oral and topical probiotic interventions. Studies written in a language other than English were not considered. We focused on diseases for which studies existed that had investigated the differences in the cutaneous microbiome and the impact of probiotics in their relevant patient populations. Among the search results, such studies existed for the following: atopic dermatitis (AD), acne vulgaris, psoriasis, seborrhoeic dermatitis, chronic wounds and wound healing, and skin carcinogenesis.

The Skin Microbiome and Topical Probiotics

Humans harbour over 1000 species of bacteria on the skin, each adapted to a particular microenvironment.[7] Most skin bacteria are commensals that generally do not harm their hosts[7] and contribute to a diverse microbiome, which can prevent or aid in the resolution of disease (Figure 1).[8–10] Commensal bacteria can accomplish this by passively occupying a similar ecological niche to that of a pathogenic microbe, thus impeding its colonization of the skin. Additionally, a commensal may actively compete against pathogenic bacteria by secreting antimicrobial factors. Commensals may also modulate the immune system, directing it to attack disease-causing organisms or promoting immune tolerance, which can reduce the severity of inflammatory diseases.[11,12]

Figure 1.

Mechanisms of disease inhibition by commensal bacteria. Commensal bacteria may occupy a similar ecological niche to that of pathogenic microbes, directly impeding their colonization. Commensals may also either directly secrete antimicrobial factors such as bacteriocins, phenol-soluble modulins, propionic acid and antimicrobial peptides (AMPs) or indirectly prime the immune system to attack disease-causing microbes. Commensal bacteria can also promote immune tolerance, reducing inflammation and severity of disease. Th, T helper cell; Treg, regulatory T cell.

Topical probiotics represent a direct method to alter the skin microbiome and immune response in various diseases.[8,9] Although currently few in number, several clinical trials have already demonstrated favourable results with topical probiotic use (Table S1; see Supporting Information).

The Gut Microbiome and Oral Probiotics for Skin Disease

The mechanisms by which the gut microbiome induces and prevents disease states have many applications to the skin. Disturbances in the normal gut microbiome promote chronic inflammation, which can lead to neoplasia.[13,14] Commensals in the gut independently regulate and reduce gastrointestinal inflammation.[13] Thus, by restoring a healthy gut microbiome, commensal microbes can protect against malignancy by acting as antioxidants, inducing tumour suppressor genes,[15] priming the immune system against cancer cells, or reducing inflammation via regulatory T cells.[16–18]

Gut microbes also have the ability to influence systemic inflammation, oxidative stress, glycaemic control and tissue lipid content.[2] A disturbed gut microbiome has been described in patients with inflammatory skin diseases such as the bowel-associated dermatosis–arthritis syndrome[2,19] and rosacea,[20] for which restoration of the normal gut microflora has resulted in complete disease remission. Thus, modulation of the intestinal microflora via oral probiotics can indirectly influence skin diseases (Table S1; see Supporting Information). Such therapy is most well studied in AD.

Atopic Dermatitis

The combination of epidermal barrier dysfunction and immune dysregulation in AD favours pathogenic bacterial colonization. AD skin harbours increased Staphylococcus aureus abundance with overall decreased microbial diversity.[21–24] A recent investigation confirmed lower diversity in both lesional and nonlesional skin of patients with AD, suggesting a globally affected skin microbiome in AD.[25] Microbial diversity is also inversely correlated with disease severity. Dramatic reductions in the skin microbial diversity are observed in more severe disease and during AD flares, whereas treatment of AD lesional skin leads to rediversification.[21,24,25] Specifically, staphylococcal species increase during AD flares, including Staphylococcus epidermis, which may serve as a compensatory mechanism to control S. aureus.[21,22,24] Indeed, an investigation of AD flares showed that S. aureus dominated in patients with more severe disease, while S. epidermidis was more abundant in patients with less severe disease.[26] Furthermore, the intestinal environment may also impact the pathogenesis of AD. Infants with IgE-associated eczema have a reduced proportion of bifidobacterial species and low microflora diversity early in life.[19] Early intestinal colonization with Escherichia coli at 2 months of age may even confer long-term health benefits, as it was associated with decreased incidence of AD by the age of 6 years.[27] Hence, modulation of the microbiome may be a promising new preventative and therapeutic strategy in AD.

The utility of oral probiotics for the treatment and prevention of AD has been explored through several large cohort and randomized controlled studies. In a recent meta-analysis including 1070 children, significant reductions were observed in Scoring Atopic Dermatitis (SCORAD) values for patients receiving oral probiotics with Lactobacillus fermentum, Lactobacillus salivarius and a mixture of different strains.[28] Results from older meta-analyses support the use of oral probiotics for the treatment of AD[29] and even for prevention, suggesting that Lactobacillus alone and Lactobacillus with Bifidobacterium bifidum are protective against development of AD, with odds ratios of 0·7 and 0·62, respectively.[30] Additionally, daily oral supplementation with a mixture of Bifidobacterium and Lactobacillus casei strains for 12 weeks in patients with moderate AD led to a 19·2-point greater mean reduction in SCORAD compared with control patients.[31] However, some effects may be strain or species specific, as probiotics with Lactobacillus rhamnosus and Lactobacillus paracasei have yielded mixed results.[32–36]

Thus far, few studies have utilized live bacteria in topical probiotics for treatment of AD. Nakatusji et al. recently demonstrated that topical application of commensal skin bacteria protects against pathogens.[37] When coagulase-negative staphylococci were applied to the skin of patients with AD, S. aureus colonization decreased due to selective killing by highly potent antimicrobial peptides secreted by the commensal, coagulase-negative staphylococci.[37] Early data show that this type of intervention not only suppresses S. aureus, but is also associated with clinical improvement and decreased local inflammation.[38] Other skin commensal species have been investigated, including the Gram-negative species Roseomonas mucosa, application of which was associated with significant decreases in pruritus, SCORAD and steroid usage in adults and paediatric patients, without adverse events or complications.[39]

Several topical probiotic studies have also explored the utility of gut commensals, with favourable results. Application of Lactobacillus johnsonii to AD lesions twice daily for 3 weeks led to reduction in S. aureus load, which correlated with decrease in SCORAD.[40] Another study revealed that a 2-week topical administration of Streptococcus thermophilus cream in patients with AD led to a significant improvement in erythema, scaling and pruritus.[41] Furthermore, a topical cream containing lysate of Vitreoscilla filiformis, a Gram-negative bacterium found in thermal spring water, also led to clinical improvement in patients with AD.[42] Although research on probiotics for AD remains in its early stages, many trials thus far have shown benefits.

Acne Vulgaris

Acne vulgaris is associated with Cutibacterium acnes, recently renamed from Propionibacterium acnes. Disruption of the gut microbiome has also been implicated in acne pathogenesis via the gut–skin axis,[2] suggesting the potential utility of oral probiotics. One study showed that consumption of Lactobacillus acidophilus, Lactobacillus delbrueckii bulgaricus and B. bifidum was as effective as minocycline in the treatment of acne, with 67% lesion reduction after 12 weeks and fewer side-effects.[43] A combination of this oral probiotic and minocycline had even greater effectiveness.[43] Another study showed a 30% reduction in inflammatory lesions after daily consumption of L. bulgaricus and S. thermophilus for 12 weeks.[44] Sebum content and free fatty acid concentration also decreased by 50% or more in the skin of patients taking this oral probiotic.[44] A recent study revealed that patients receiving oral L. rhamnosus SP1 for 12 weeks exhibited significant improvement of their back acne compared with placebo, which was accompanied by normalized skin expression of insulin signalling genes.[45]

Recently, several studies found that certain phylotypes (IA-2 with plasmid factor, IB-1, I-C) of C. acnes were more commonly associated with acne, while others (II-ribotype 6, III) were exclusively associated with healthy skin.[46–50] Therefore, these phylotypes may be a factor in the pathogenesis of acne. An in vitro study revealed that acne-associated phylotypes induce high T helper cell (Th)1 and Th17 responses, while healthy skin-associated phylotypes induce relatively low Th1 and Th17 responses, but a high interleukin (IL)-10 anti-inflammatory response.[51] This suggests that the healthy skin-associated C. acnes phylotypes may be of use in a topical probiotic treatment or preventative regimen, designed to replace acne-associated and other potentially opportunistic phylotypes.[46,51,52] Such a targeted strategy utilizing the same species of bacteria that share an ecological niche may be a more effective approach than using other skin or especially gut commensals, by allowing faster and longer-lasting improvements to the skin microbiota.

Unfortunately, the limited number of topical probiotic studies for acne have utilized gut or other nonskin bacteria. A lyophilized powder containing enterocins from Enterococcus faecalis SL-5 has already been studied in patients with acne, decreasing inflammatory lesions by 60% compared with the control after 8 weeks.[53] A new phase IIb/III study has demonstrated that application of Nitrosomonas eutropha, twice daily for 12 weeks, led to a 2-point reduction in Investigator's Global Assessment of acne severity compared with control and a trend in the reduction of the number of inflammatory lesions.[54] However, as these species do not naturally occur on the skin, a continued protective effect after discontinuing the treatment is unlikely compared with utilization of a skin microbe. In contrast, twice-weekly application of a topical gel containing S. epidermidis changes the host skin microbiome and leads to robust colonization.[55] Thus, utilization of a skin commensal like S. epidermidis may be more suitable than N. eutropha, particularly as S. epidermidis has been shown to inhibit C. acnes growth in vitro.[56]

Topical probiotics may also include C. acnes bacteriophages, which are viruses that can lyse host bacteria. Two studies showed that some C. acnes bacteriophages lyse only acne-associated and uncorrelated (potentially pathogenic) phylotypes, but are often ineffective against phylotypes associated with healthy skin.[57–60] This potential combination of healthy-skin-associated C. acnes together with bacteriophages that target other C. acnes could potentially allow for highly specific strain replacement (Figure 2).

Figure 2.

Topical probiotic combination therapy for strain-specific replacement. A novel topical probiotic formulation containing health-promoting, commensal bacterial combined with bacteriophages that target only the pathogenic microbes could potentially allow for highly specific strain replacement.

Psoriasis

It has been proposed that alteration of the skin microbiome may trigger activation of the Th17 pathway in psoriasis.[61,62] Several studies have demonstrated differences between the cutaneous microbial communities of psoriatic skin compared with unaffected skin, such as a trend towards decreased microbial diversity.[63–65] Actinobacteria is significantly underrepresented in psoriatic lesions compared with healthy skin.[64,65] Staphylococcus aureus and Streptococcus pyogenes are also minimally present to absent in psoriatic lesions.[64,65] However, much is still unknown given the limited number of studies with different sampling techniques.

To date, studies investigating the role of probiotics in psoriasis are lacking, although there is some evidence that probiotics may exert beneficial immunoregulatory effects by reducing inflammation.[66,67] In patients with psoriasis, oral administration of Bifidobacterium infantis for 8 weeks led to significantly decreased levels of inflammatory C-reactive protein and tumour necrosis factor-α, although it is unclear whether this was accompanied by clinical improvements.[67] However, in a mouse model of psoriasis, oral administration of Lactobacillus pentosus GMNL-77 reduced tumour necrosis factor-α and IL-23–IL-17 axis cytokines, which was associated with decreased erythematous scaling lesions.[66] More research exploring the role of the microbiome and its modulation as a therapy in psoriasis would be complementary to the many ongoing immunological treatment studies.

Seborrhoeic Dermatitis

Seborrhoeic dermatitis is thought to be an inflammatory response to free fatty acids produced by the fungus Malassezia furfur, a normal resident of the skin.[68,69] While improvement of disease has been associated with a decrease in yeast burden, absolute levels of Malassezia do not correlate with disease severity.[70,71] Decreased bacterial diversity is a better predictor of disease severity.[72–74] For this reason, several investigators have evaluated the use of probiotics for treatment of seborrhoeic dermatitis. Topical application of V. filiformis decreased erythema, scaling and pruritus in a double-blinded study of 60 patients.[75]Vitreoscilla filiformis lysate increased IL-10 production by dendritic cells and increased regulatory T-cell activity.[76] Patients receiving oral L. paracasei experienced significant symptomatic relief, accompanied by improvements in scalp dandruff, erythema and seborrhoea.[77] Similarly to Vitreoscilla, L. paracasei induced a switch to a normal immune state by producing IL-10 and transforming growth factor-β,[78] lending support to the utility of both topical and oral probiotics in seborrhoeic dermatitis.

Wound Healing

Disruption of the cutaneous microbiome and prolonged inflammation after injury result in delayed wound healing.[79] Probiotics may promote the healing process by modulating the inflammatory response and limiting pathogen colonization. A recent meta-analysis of animal studies concluded that topical probiotics with Lactobacillus brevis, Lactobacillus plantarum and L. fermentum led to reduced inflammation and acceleration of wound contraction.[80] Several human studies also demonstrated the benefits of these bacteria in chronic ulcers. Topical probiotics containing L. plantarum reduced bacterial load and induced healing of diabetic ulcers through the regulation of IL-8 and recruitment of phagocytic cells and fibroblasts.[81] Similarly, application of L. plantarum for 30 days led to > 90% area reduction of chronic leg ulcers in nondiabetic patients.[81] Oral probiotics containing Lactobacillus species were also effective in treating chronic diabetic ulcers, resulting in decreased ulcer size and decreased levels of inflammatory markers.[82]

Probiotic studies have also shown enhancement of wound healing in burn patients[83,84] and in the prevention and treatment of skin infections. A topical probiotic containing L. plantarum reduced Pseudomonas aeruginosa skin infections in a mouse model of burn wounds.[85] In humans, L. plantarum, when applied to second- and third-degree burns, was as effective as silver sulfadiazine in reducing the risk of infection and bacterial load, while promoting granulation tissue and wound healing.[84] Skin commensals are also excellent candidates in a topical probiotic, with likely superior resilience given their inherent adaptation to the skin environment. For example, Propioniferax innocua, a skin commensal, has been found to degrade established biofilms.[86]Staphylococcus caprae is able to exert antimicrobial activity against methicillin-resistant S. aureus and inhibit S. aureus colonization in a mouse model.[87]Staphylococcus epidermidis produces antimicrobial compounds that selectively target S. aureus and S. pyogenes, while also suppressing skin inflammation via lipoteichoic acid.[10,12,88] Two studies have also shown that C. acnes inhibited the growth of S. aureus in an open wound mouse model[89] via production of propionic acid.[90]

Skin Cancer

Disturbances in the skin microbiome exist in several cutaneous neoplasms and have been implicated in the promotion of carcinogenesis. One example is the link between S. aureus infection and cutaneous T-cell lymphoma disease severity, through the potential role of a staphylococcal superantigen in carcinogenesis.[91–94]

In contrast, a healthy microbiome may suppress carcinogenesis through its regulation of the immune system and control of inflammation by activating antineoplastic or immunosurveillance pathways.[3,95] For example, oral intake of lipoteichoic acid from lactobacilli was associated with less ultraviolet damage and a reduced risk of skin cancer.[96] Recently, strains of S. epidermidis were found to produce a nucleobase molecule that selectively inhibited tumour proliferation, and application of these strains reduced the incidence of ultraviolet-induced tumours in mice.[97] A healthy microbiome can also potentially impact cancer response to therapy by modulating the tumour microenvironment. In one study, oligonucleotide immunotherapy or platinum chemotherapy regimens for tumours had superior effectiveness in mice with healthy gut microbiomes compared with germ-free or antibiotic-treated mice.[98] It is therefore conceivable that the use of probiotics may be beneficial for reducing the risk of or even during the treatment of cutaneous neoplasms.

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