The Role of the Skin Microbiota in Acne Pathophysiology

S. Ramasamy; E. Barnard; T.L. Dawson Jr; H. Li

Disclosures

The British Journal of Dermatology. 2019;181(4):691-699. 

In This Article

Acne and Skin Bacteria

Despite decades of research into the microbial pathogenesis of acne, specific molecular mechanisms of microbial involvement remain poorly understood. Initially, the divergent growth rates and robustness of Staphylococcus cultures resulted in a vast overestimation of their presence and role, and the initial difficulty in the cultivation of Cutibacterium hampered efforts to elucidate their role.[32] Despite these complications, C. acnes has long been considered the primary suspect as an acne pathogen.[9,33,34] To understand why C. acnes carries a heavy burden of responsibility, one must consider the significant evidence for its potential role. The skin microbiome in young children has been shown to be dominated by Streptococcal species, such as Streptococcus mitis and S. epidermidis.[35] However, during adolescence, hormonal changes lead to an increase in sebum production and hence the creation of a new follicular environment.[4,36] This lipid-rich environment provides a perfect niche for C. acnes and, as a result, the childhood Streptococcal-dominant microbiome is replaced with one dominated by Cutibacteria.[11,13,35] The alteration of skin-specific lipids has also been reported in patients with acne.[37]C. acnes is the dominant bacterial species found on postadolescent sebaceous skin. Other Cutibacteria such as Cutibacterium granulosum, Cutibacterium avidum and Cutibacterium propionicum have been repeatedly detected in follicles, although at much lower abundance.[11,13] In addition to the link between Cutibacterium colonization and acne onset during adolescence, early work on acne revealed that upon treatment with antibiotics such as tetracycline and erythromycin, the follicular bacterial load decreased and the condition improved.[3,38] Further support for a role for C. acnes is that acne prevalence decreases with increasing age, likely as a result of decreased sebum production with age, but the change in sebum secretion may be linked to changes in microbiome composition. Although there is promising evidence for the use of lytic formulations with bacteriophages for reducing C. acnes growth in vitro, substantial future work will be required to prove the utility of bacteriophage for treating human acne.[39,40]

While much evidence exists supporting the role of C. acnes in acne, the topic remains controversial. C. acnes is also considered a host-beneficial microbe. C. acnes contributes to skin health by keeping opportunistic pathogens, such as S. aureus, at bay via its ability to generate propionic acid and maintain an acidic skin pH.[41] One must also keep in mind that although C. acnes has been repeatedly isolated from follicles and inflammatory lesions of patients with acne, it is also the dominant species isolated from unaffected follicles in healthy individuals.[11,13] In support of C. acnes as beneficial, metagenomic shotgun sequencing of follicles in patients with acne and healthy individuals revealed that while C. acnes dominates the skin microbiome of both diseased and healthy skin, an increased prevalence of other bacterial species is observed in the disease state. This dual role of C. acnes is a feature that also extends to other skin microbes, for example Malassezia globosa. While generally accepted as the cause of seborrhoeic dermatitis, M. globosa has also been shown to secrete a potentially beneficial protease, which may prevent S. aureus biofilm formation (the role of fungal microbiota in acne is discussed later in this review).[42] Hence, many skin microbes may play dual roles in health and disease, and the differences in their function may lie at the strain or subspecies level.[16,43–46]

Multiple C. acnes studies have led to the classification of subspecies or types, each displaying a unique set of characteristics, activities and pathogenic potential.[34] Phylogenetic, biochemical and microscopic C. acnes analyses reveal distinct evolutionary lineages, known as types I, II and III[47,48] with recA analysis dividing type I into subclades IA and IB.[49] Multilocus sequence typing has allowed further resolution of C. acnes isolates, with strain clustering within clades.[50,51] Moreover, 16S rRNA analysis reveals that certain C. acnes strains are highly acne-associated while others are associated with healthy skin.[13] Genomic analysis of a large collection of clinical C. acnes isolates and recent skin metagenomic analysis comparing patients with acne with healthy individuals revealed specific genomic elements in disease-associated strains.[11,52,53] Also, potential mechanisms of microbe–host signalling and metabolic response using in vitro models with different C. acnes strains have been proposed (Figure 2).[54] More recently, a skin metatranscriptomic study revealed transcriptional differences in the skin microbiome in acne skin compared with the microbiome of healthy skin.[12] Among the differentially expressed microbial pathways, one significant feature of the disease state was the downregulation of vitamin B12 biosynthesis in C. acnes, which leads to the overproduction of the proinflammatory metabolites known as porphyrins.[12] A follow-up study comparing porphyrin production by individual C. acnes strains associated with either acne or healthy skin[55] revealed that strains associated with healthy skin produced significantly lower amounts of porphyrins compared with acne-associated strains, thus further supporting the different functions among C. acnes strains.[55] A separate study reported the effect of isotretinoin treatment that showed clinical improvement and lowered levels of porphyrins in patients with acne.[56] Analysis of the host immune responses against different C. acnes strains also corroborates the strain-level differences. Acne-associated C. acnes strains induced higher levels of the inflammatory cytokines interferon (IFN)-γ and interleukin (IL)-17 in peripheral blood mononuclear cells,[57] consistent with elevated levels of IFN-γ and IL-17 expression found in acne lesions.[58,59]C. acnes also increases expression of filaggrin and integrin that influence abnormal adhesion and differentiate keratinocytes.[60] On the other hand, health-associated C. acnes strains induced higher levels of anti-inflammatory IL-10.[57] Additionally, an adhesion protein, a cell surface hydrolase and several other proteins were expressed at a much higher level in acne-associated strains than in strains associated with healthy skin, suggesting differential functions of C. acnes strains in both host immune responses and acne pathogenesis.

Figure 2.

Skin microbiome commensal relationship. Multiple complex interactions occur between bacterial species, bacterial and fungal skin inhabitants, and the human host. Any of these interactions can lead to commensality or pathogenesis.

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