The Role of the Microbiome in Acne

In medicine, we have long recognized that the microbial communities in our bodies and on our skin are intricately linked to health and disease. Acne vulgaris is a disease that exemplifies the importance of host-microbiome interactions in disease pathogenesis. It is one of the most common skin diseases worldwide, with rates of up to 85% among 12- to 24 year-olds.¹ Though the pathogenesis of acne is multifactorial, our understanding of acne is expanding with recent advances from studies on the microbiome. The skin microbiome is collectively composed of a complex community of bacteria, fungi, viruses, and microscopic arthropods that inhabit all skin surfaces and appear to have unique functions on the skin.² By culturing and sequencing of these microbial inhabitants, studies have confirmed topographical diversity of the bacterial communities on our skin.³ Sebaceous areas favor the growth of the lipophilic Cutibacterium species, formerly known as Propionibacterium.⁴ 

Cutibacterium acnes has long been implicated as a pathogenic factor in acne. Yet, it is also a major commensal of the normal skin microbiome. Contrary to popular belief, C acnes overgrowth does not correlate with acne development and severity; acne-affected skin does not harbor more C acnes than normal skin. Genomic analyses have confirmed that C acnes is dominant in the pilosebaceous units in both patients with acne and individuals with normal skin, with no significant difference in the relative abundance between these two cohorts.⁵ Thus, research is now focusing on the specific composition of C acnes strains within the acne microbiome and the host interactions, affecting both the innate and adaptive immune responses. 

DNA sequencing-based methods used for bacterial typing have now allowed for identification of distinct C acnes phylogenic groups, classifying strains with different genetic lineages into types I, II, and III. Various molecular typing methods use different nomenclature to further subdivide strains into clonal complexes, phylotypes, and ribotype denominations.^6,7 Typing of C acnes strains has taken on increased importance due to the emerging clinical relevance of differences between strains. Multiple research groups have investigated the association of different C acnes types with acne and revealed distinct patterns. It appears that while the majority of strains are found in both patients with acne and individuals with normal skin, there are indeed specific C acnes strains more highly associated with acne, while others are exclusively associated with healthy skin. Since the 1980s, it has been known that type I C acnes are more associated with acne than type II.⁸ Through sequence comparisons of the C acnes 16S rRNA gene in patients with acne vs normal controls, Fitz-Gibbon et al⁵ found that certain ribotypes (designated ribotypes 4, 5, 8, and 10) were statistically significantly enriched in acne patients, whereas ribotype 6 was strongly associated with healthy skin.⁵ Lomholt et al⁹ also found that the dominating C acnes clones in follicles from patients with acne were exclusively from the phylogenic clade I-1a and all belonged to corresponding ribotypes 4 and 5.⁹ Interestingly, phylotype III bacteria compose approximately 20% of isolates from healthy skin but have not been found in acne lesions.¹⁰ Thus, by correlating association data based on different typing systems, it is clear that IA-2 strains with a plasmid factor, IB-1, and I-C phylotypes of C acnes are associated with acne, while ribotype 6 strains within phylotype II, as well as phylotype III, are associated with healthy skin.⁶ 

These disease associations then beg the question of why? There is evidence to suggest that they may be related to specific phenotypic and functional differences among C acnes strains, which have implications in disease pathogenesis. Metagenomic analyses revealed that distinct virulence-associated genomic elements of tissue degradation and cell adhesion are enriched in acne-associated C acnes strains.¹¹ Proteomic studies using mass spectrometry also demonstrate differential protein expression of adhesion proteins, CAMP factors, proteases, and lipases.¹² Healthy skin-associated phylotype II strains possess a clustered regularly interspaced palindromic repeats (CRISPR)-Cas locus, which is protective against viruses and acquisition of foreign DNA that could promote virulence. This CRISPR-Cas locus is also partially present in healthy skin-associated phylotype III, but is absent in type I acne-associated strains.¹³ Furthermore, C acnes phylotypes exhibit differences in inflammatory potential. In vitro studies have shown that acne-associated phylotypes induce high T helper (T_H) 1 and T_H17 responses, while healthy skin-associated phylotypes induce relatively lower T_H1 and T_H17 responses but a higher IL-10 anti-inflammatory response.¹² Therefore, accumulating evidence suggests that certain phylotypes of C acnes and their host interactions play a central role in this chronic inflammatory condition. Further investigations are needed to gain better insight into strain-specific factors that may impact inflammatory response, acne severity, and distribution patterns in different acne lesions.

After recognizing the C acnes disease associations contributing to an acne microbiome, the logical next question asks how can we take advantage of this to target the skin microbiome for a beneficial therapeutic effect in acne. This is a new and exciting avenue of research that revolves around treatments with probiotics. Probiotics are defined as live microorganisms that when administered in adequate amounts may confer a health benefit on the host.¹⁴ The use of probiotics can be a targeted antimicrobial therapy. Specifically, certain C acnes could be reduced and others promoted. For example, healthy skin-associated C acnes phylotypes may be of use in a topical probiotic therapy or preventative regimen, designed to replace the acne-associated and other potentially opportunistic phylotypes.¹² To date, there are no probiotic studies that have implemented this strategy of utilizing nonpathogenic strains of the same species of bacteria that share an ecological niche with their pathogenic counterparts. Other than bacteria, topical probiotics may also include C acnes bacteriophages, which are viruses that can lyse host bacteria. Investigations have already shown that C acnes bacteriophage lyse acne-associated and uncorrelated phylotypes, but they are often ineffective against healthy skin-associated phylotypes.^15,16 Consequently, phages may also be utilized for highly specific strain replacement, and its formulation into a topical cream has already been demonstrated.¹⁷

Thus far, topical probiotic studies for the treatment of acne have been less selective in their choice of bacterial species. Several studies have shown that commensal bacteria like Staphylococcus epidermidis, Lactococcus, Lactobacillus, and Streptococcus species can directly inhibit C acnes growth via production of antimicrobial substances.^18-22 Actual clinical trials utilizing a topical probiotic for the treatment of acne are few in number. A randomized, double blinded, phase 2b/3 study has demonstrated that application of a soil bacteria, Nitrosomonas eutropha, for 12 weeks led to a two-point reduction in an Investigator’s Global Assessment of acne severity compared with the control and a trend in the reduction of the number of inflammatory lesions.²³ The results of a recent preprint show that twice-daily application of a cream containing a mixture of three different strains of Lactobacillus in patients with mild to moderate acne led to significant reduction in inflammatory lesions over an 8-week period.²⁴ However, since these few clinical studies utilized species that do not naturally occur on the skin, a continued protective effect after discontinuing the treatment is unlikely. Future studies should rationally select for topical probiotics containing normal “healthy” skin commensals such as S epidermidis and especially healthy skin-associated phylotypes, which would allow for more specific strain replacement, minimize off-target effects, and enhance effectiveness and longevity of treatment.

Interestingly, modulation of the gut microbiome via oral probiotics has also been studied in patients with acne. The gut microbiome indirectly affects the skin; gut microbes have the ability to influence systemic inflammation, oxidative stress, and tissue lipid content.²⁵ In fact, a recent clinical trial demonstrated the positive impact of an oral probiotic containing the gut commensal Lactobacillus paracasei on skin barrier function, supporting the link of this gut-skin axis.²⁶ The few published studies in patients with acne support oral probiotic supplementation. One study compared an oral probiotic mixture of Lactobacillus acidophilus, Lactobacillus delbrueckii bulgaricus, and Bifidobacterium bifidum to minocycline therapy over 12 weeks. Both treatments yielded 67% lesion reduction, but the probiotic treatment was associated with fewer side effects.²⁷ Another study revealed a 30% reduction in inflammatory lesions in patients with mild to moderate acne after daily consumption of fermented milk containing L bulgaricus and Streptococcus thermophilus for 12 weeks, though it should be noted that this study lacked a control.²⁸ Another study showed significant improvement in appearance of back acne in patients that received oral Lactobacillus rhamnosus SP1 for 12 weeks compared with a placebo.²⁹

In summary, the microbiome and host-microbiome interactions play an important role in acne. Thanks to recent genomic and metagenomic investigations, we now know that certain C acnes strains dominate in acne-affected skin. The emerging information on phenotypic and functional differences between members within the skin microflora offers new perspectives for the treatment of acne. Probiotics represent a microbiome-targeted therapeutic approach. However, more robust translational and clinical trials are needed to further characterize the skin microbiome in acne and the efficacy of probiotics in the treatment of the disease.

Dr Yu is a board-certified dermatologist and clinical instructor in the
division of dermatology, David Geffen School of Medicine, University of California, Los Angeles.

Disclosure: The author reports no relevant financial relationships.

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