Acne, the Skin Microbiome, and Antibiotic Treatment

Haoxiang Xu; Huiying Li


Am J Clin Dermatol. 2019;20(3):335-344. 

In This Article

The Skin Microbiome and Acne

The skin is the largest organ in the body, with an average area in adults of 1.8–2 m2. If considering hair follicles, sweat gland ducts, and other skin appendages, the body surface area can reach up to 30 m2 according to Meisel et al..[13] Various heterogenous communities of microorganisms, including bacteria, viruses, fungi, and mites, occupy different skin environmental niches and appendages.[6,14]

Bacteria are the most dominant and best studied members of the skin microbiome. More than 40 bacterial genera have been identified on human skin, mainly belonging to four phyla: Actinobacteria, Firmicutes, Proteobacteria, and Bacteroidetes.[8–10] The proportions of these bacteria in each community vary depending on individuals, body sites, as well as skin micro-environments.[9,11,15] Propionibacteria, Staphylococcus and Corynebacteria, and Gram-negative bacteria are predominant in the sebaceous area, moist skin, and dry skin, respectively. Skin bacteria are not only diverse in taxonomy, but also vary in quantities. Culturebased methods suggest that the total colony-forming units per cm2 skin varies from 3.7 × 104 to 1.2 × 106.[16] It has been estimated that 106 aerobic bacteria are present per cm2 of moist skin, whereas less than 102 aerobic bacteria and up to 106 anaerobes are present per cm2 of dry skin.[17] The balance of the skin microbiome and its interaction with the host affect the states of skin health and disease.

Propionibacterium Acnes and Acne

P. acnes was first observed by Unna[18] in 1896 and later isolated by Sabouraud[19] from acne lesions in 1897, which led to speculation regarding its involvement in acne pathogenesis. P. acnes was initially named Bacillus acnes, which was then changed to Corynibacterium acnes as it is morphologically similar to Corynibacteria. The name was changed again in the 1940s to P. acnes due to its production of propionic acid.[20] With the identification of distinct phylogenetic groups based on multi-locus sequence typing (MLST) and whole-genome sequencing, it was proposed in 2015 to name the three major types as three subspecies known as P. acnes subsp. acnes, P. acnes subsp. defendens, and P. acnes subsp. elongatum.[21] In 2016, a new genus, Cutibacterium, was proposed for cutaneous propionibacteria[22] and, as such, P. acnes was renamed again to Cutibacterium acnes, although the name P. acnes continues to be used in the field in an effort to reduce the confusion between Cutibacterium and Corynibacterium.[23]

In the pilosebaceous unit, where acne arises, P. acnes is the most prevalent and abundant species, accounting for ~ 90% of the microbiome.[10,12] The scalp and facial skin harbor the highest density of P. acnes (~ 105–106/cm2), followed by the upper limbs and torso, and the lower limbs have the lowest density of P. acnes (~ 102/cm2).[24] The abundance of P. acnes also varies with age. It is low on the skin of children before puberty, but gradually increases with age, starting from adolescence to adulthood, and then decreases in older persons of age above 50 years.[24–26]

Several mechanisms of acne pathogenesis involving P. acnes have been proposed, including changes in sebaceous gland activity, comedone formation, and host inflammation.

  • Increasing sebum secretion: the colony-forming units of P. acnes in the pilosebaceous unit are correlated with the total amount and composition of the lipids on the skin. The secreted sebum is used by P. acnes as metabolic substrates to promote its growth.[24,27]P. acnes further enhances sebum secretion by increasing the activity of diacylglycerol acyltransferase, and exacerbates preexisting androgen-related seborrhea.[28]

  • Promoting comedone formation: P. acnes breaks down triglycerides secreted from sebaceous glands and releases free fatty acids. Porphyrins secreted by P. acnes are catalytic factors for the oxidation of squalene, a main component of sebum. Free fatty acids and oxidized squalene promote comedogenesis.[29] Comedones form due to retention of hyper-proliferating keratinocytes/corneocytes in the follicular duct. Studies have shown that P. acnes not only forms a biofilm to increase keratinocyte adhesion,[30,31] but also activates the insulin-like growth factor 1 (IGF-1)/IGF-1 receptor signaling pathway to up-regulate filaggrin expression. The up-regulation of filaggrin expression leads to increased levels of integrin-α3, -6 s, and -vβ6, and thereby affects keratinocyte proliferation and differentiation[32,33] and comedone formation.

  • Inducing/aggravating inflammation: upon binding to Toll-like receptor (TLR)-2 and -4 on the surface of keratinocytes, P. acnes induces monocytes and other cells to produce interleukin (IL)-1α, IL1-β, IL-6, IL-8, IL-12, tumor necrosis factor (TNF)-α, interferon, chemotactic factors, β-defensin, and other cytokines and polypeptides, thereby triggering and/or aggravating inflammatory responses.[34–37]P. acnes also activates the classical and alternative complement pathways to form C3a and C5a, which increase the vascular permeability and the involvement of chemotactic leukocytes in inflammatory responses.[38,39] Furthermore, P. acnes stimulates sebocytes and promotes the conversion of naïve T cells into T helper (Th) 17 cells by secreting transforming growth factor-β, IL-1β, and IL-6. P. acnes can also activate the NLRP3 inflammasome to induce the release of IL-1β, IL-8, and TNF-α from sebocytes.[40] P. acnes produces lipases, proteases, hyaluronidases, and phosphatases, and induces multiple cells to produce matrix metalloproteinases, thus directly impairing hair follicles, sebaceous glands, and dermal extracellular matrix, and ultimately aggravating inflammation.[41–43]

While a causal role of P. acnes in acne pathogenesis remains to be proven, P. acnes is also considered an important commensal for skin health. It releases free fatty acids through triglyceride hydrolysis to maintain low skin pH and inhibits the colonization of pathogenic bacteria, such as Staphylococcus aureus and Streptococcus.[44–46]P. acnes typing and genome sequencing efforts suggest that P. acnes can function as a commensal or an opportunistic pathogen depending on the strains and the disease.[10,47,48]P. acnes was previously classified into two types, I and II, based on serum lectin response, cell wall sugar content, and susceptibility to phages.[49] Later, an additional phylotype, type III, was defined.[50] Within type I, P. acnes can be further separated into clades IA1, IA2, IB, and IC based on the Belfast MLST scheme[51] or I-1a, I-1b, and I-2 based on the Aarhus MLST scheme.[52] With the whole-genome sequencing effort of a large number of P. acnes isolates,[48] higher resolution of the phylogeny became available. Based on the single nucleotide polymorphisms (SNPs) identified throughout the core genome regions, P. acnes can be classified into phylogenetic clades IA-1, IA-2, IB-1, IB-2, IB-3, IC, II, and III.[10,48]Table 1 summarizes the corresponding nomenclatures of the phylogenetic clades based on the whole-genome sequences and different MLST schemes.[48,51,52] Additionally, based on the 16S ribosomal RNA (rRNA) sequences, P. acnes can be classified into multiple ribotypes (RTs) with RTs 1–10 being the most common RTs found in the population.[10] These classifications are useful in understanding the associations between P. acnes strains and disease or healthy skin (Table 1). Strains from clades IA-2, (mainly RT4 and RT5), IB-1 (RT8), and IC (RT5) are strongly associated with acne. Type II strains, including RT2 and RT6, are associated with healthy non-acne skin. Strains from clades IA-1, IB-2, and IB-3 have been found in both healthy individuals and acne patients.[10,48,53] Type III strains are rarely found on the facial skin, but are abundant on the back and have been linked to the skin condition progressive macular hypomelanosis.[54,55]

Recent studies of P. acnes and the skin microbiome have shed new light on the strain-level differences in the roles of P. acnes in health and acne. Fitz-Gibbon et al.[10] revealed that certain P. acnes strains were enriched in acne patients, while some other strains were mostly found in healthy individuals. Tomida et al.[48] further compared the genomes of P. acnes strains isolated from healthy individuals and patients with acne, and identified that the non-core genomic regions of P. acnes strains associated with acne contain extra virulence-related genes when compared with other strains. Johnson et al.[56] showed that acne-associated strains produce more porphyrins, which are a group of proinflammatory molecules inducing inflammation in keratinocytes and aggravating tissue damage by producing reactive oxygen species. Kang et al.[57] further demonstrated that vitamin B12 supplementation alters the transcriptional activities and increases porphyrin production in acne-associated P. acnes strains, while health-associated P. acnes strains do not respond to vitamin B12 supplementation. Furthermore, several recent studies have shown that acne-associated P. acnes strains induce significant inflammatory responses in keratinocytes, sebocytes, and peripheral blood mononuclear cells, while health-associated strains do not.[58–61] These studies suggest that different strains of P. acnes may play different roles in skin health and acne pathogenesis.

Multiple other skin bacteria colonize the external surface of the skin, some of which may play a role in maintaining skin health or exacerbating diseases. Staphylococcus epidermidis, Staphylococcus hominis, and other coagulasenegative staphylococcal species can be found on the skin of healthy and acne individuals.[62] In acne skin, the relative abundance of S. epidermidis increases at the expense of P. acnes.[49] Several studies suggest that P. acnes can be inhibited by S. epidermidis. Wang et al.[63] showed that S. epidermidis strains could produce succinic acid, which has anti-P. acnes activity. The study by Christensen et al.[64] suggested that S. epidermidis possesses a functional ESAT-6 (early secreted antigenic target of 6 kDa) secretion system, which could inhibit P. acnes growth through polymorphic toxins that are antibacterial. Additionally, it was shown that S. epidermidis secretes staphylococcal lipoteichoic acid, which could reduce P. acnes-associated inflammation by inducing expression of miR-143 and inhibiting TLR-2 expression in keratinocytes.[65] These studies suggest that Staphylococci, especially S. epidermidis, may protect skin against acne. However, this hypothesis requires further examination.

Malassezia and Acne

Malassezia has been thought to induce acne.[66]Malassezia is the most abundant fungal organism on the skin, co-existing with P. acnes and other bacterial species. In a study by Hu et al.,[67] acne lesions were significantly reduced after administration of antifungal drugs. The authors suggested that Malassezia, not P. acnes, was potentially the cause of refractory acne.[67] The findings from several other studies are in support of this hypothesis. Song et al.[68] and Numata et al.[69] reported that Malassezia restricta and Malassezia globosa can be isolated from young acne patients. Akaza et al.[70] showed that the lipase activity of Malassezia is ~ 100 times higher than that of P. acnes. Malassezia can also hydrolyze triglycerides in the sebum to produce free fatty acids, which may affect the abnormal keratinization of hair follicular ducts, chemotize polymorphonuclear neutrophils,[71,72] and promote secretion of pro-inflammatory cytokines from keratinocytes and monocytes.[73,74] The role of Malassezia in acne pathogenesis remains to be further investigated.