504 JOURNAL OF COSMETIC SCIENCE
in controlling S. aureus growth on skin.76 Barnard et al.77 found that there was a greater
relative abundance of C. acnes phages in healthy skin compared to lesional skin of acne
test subjects. Natarelli and coworkers noted that phage-based therapeutic strategies appear
promising for the treatment of a variety of dermatological conditions.75
MICROBIAL INTERACTIONS WITH THE SKIN
Many researchers have considered the dominant skin bacteria to be commensals.66,68,78
However, information gained over the past several years indicates that some members of
the skin microflora benefit from the nutrients and environment provided by the skin and
the skin benefits by having improved barrier function, an activated SIS, and protection
from colonization by transients and pathogens.79,80 Although “commensalism” describes
the biological interaction in which members of one species gain benefits while other
species neither benefit nor are harmed and “mutualism” describes the biological interaction
between two or more organisms in which each organism has a net benefit, this review
considers commensals to be microorganisms that are either neutral or beneficial to skin.
Orth observed that skin microflora may confer some of the same benefits to skin as
probiotics do in the GI tract.78,81 These benefits are achieved by “colonization resistance”
which helps maintain homeostasis of the skin/skin microbiome ecosystem. Colonization
resistance involves:
1. Growth of commensal microorganisms on skin and mucous membranes lowers the pH,
which makes it more difficult for competing microorganisms (transients and pathogens)
to grow.
2. Commensal skin microflora compete with transients and pathogens for nutrients, which
makes it more difficult for them to grow.
3. Commensal skin microflora compete with transients and pathogens for epidermal
receptor sites and may block their colonization on skin.
4. Association of commensal skin microflora with immunologically competent cells in the
skin, such as keratinocytes and Langerhans cells, may stimulate the SIS so that it is a state
of readiness when stimulated by transients and potentially harmful microorganisms.
5. Crosstalk between the commensal skin microflora and keratinocytes enhances
antimicrobial peptide (AMP) expression by keratinocytes including human β-defensin
2 (HBD2), cathelicidin LL-37, ribonuclease-7, psoriasin (S100A7), and dermicidin.80-83
Table VII
Top 10 Abundant Fungi on Various Skin Sites
Dry Moist Sebaceous Foot
Malassezia restricta Malassezia globosa Malassezia restricta Malassezia restricta
Malassezia globosa Malassezia restricta Malassezia globosa Tricophyton rubrum
Aspergillus tubingensis Tielleti walkeri Malassezia sympodialis Malassezia globosa
Candida parapsilosis Malassezia sympodialis Aureoumbra lagunensis Pyramimonas parkeae
Zymoseptoria tritici Pyramimonas parkeae Tielleti walkeri Trychophyton mentogrophytes
Malassezia sympodialis Parachlorella kessleri Pycnococcus provosolii Parachlorella kessleri
Epidermophyton floccosum Aspergillus tubingensis Gracilaria tenuistipitata Aspergillus tubingensis
Pyramimonas parkeae Zymoseptoria tritici Pyramimonas parkeae Zymoseptoria tritici
Nannizzia nana Nephroselmis olivacea Parachlorella kessleri Gracilaria tenuistipitata
Parachlorella kessleri Cyanophora paradoxa Leucocytozoon majoris Nephroselmis olivacea
*Table adapted from Byrd, Belkaid, and Segre.74

505 Evolution and Challenges of Sustainability
These AMPs help protect the skin from colonization and infection by transient
microorganisms and pathogens.
6. Commensal skin microflora may promote immunological quiescence by up-regulating
production of IL-10 (an anti-inflammatory cytokine) by dendritic cells.
Each microorganism in any environment—including the skin—is in a constant, life-
and-death struggle with other organisms in this environment as they compete for the
available nutrients needed for survival and growth. Microorganisms can make free fatty
acids, enzymes, and virulence factors including toxins, bacteriocins, AMPs, and antibiotics
that help them compete and survive, as illustrated by the following examples. C. acnes,
S. epidermidis, S. aureus, and Malassezia spp. secrete lipases that hydrolyze triglycerides in
sebum to produce free fatty acids that lower the pH of the skin surface and make it more
difficult for non-acid-tolerant microorganisms to grow, and stimulate epithelial cells and
neutrophils to express HBD2, which has antimicrobial activity against Gram-negative
bacteria and Candida spp.84-86 Many fatty acids upregulate AMPs and cytokines in sebaceous
glands, and sebaceous-gland-rich sites have higher levels of AMPs (e.g., psoriasin S100A7,
HBD2, and lipocalin than sebum-poor sites.87-90 Most Corynebacterium spp. contain mycolic
acid in the cell envelope. Mycolic acid can promote γδTcell accumulation with release of
IL-23, an inflammatory cytokine. Some strains of C. acnes produce cutimycin, a thiopeptide
antibiotic that limits S. aureus colonization.89,91 Staphylococcus lugdunensis produces lugdunin,
an antimicrobial peptide that induces keratinocytes to produce AMPs (cathelicidin LL-37
and CXCL8). CXCL8 is a neutrophil chemoattractant produced through the TLR-myeloid
differentiation response protein 88 (TLR-Myd88) pathway.92 S. epidermidis produces
bacteriocins, several types of AMPs, and stimulates keratinocytes and Langerhans cells
to produce AMPs to prevent the growth of other microorganisms. S. epidermidis produces
succinic acid (from fermentation of glycerol) which inhibits some strains of C. acnes.87,93-95
S. epidermidis also produces a serine protease, Esp, that is able to inhibit S. aureus biofilm
formation and colonization.96 Biofilm is involved in the pathogenicity and antimicrobial
susceptibility of C. acnes,97and it is likely that Esp produced by S. epidermidis, or proteases
produced by other microorganisms, may help control biofilm formation of C. acnes, which
in turn decreases C. acnes colonization to decrease the severity of acne.
Skin colonization with commensal microorganisms shapes immunity through activation
of cellular pattern recognition receptors, with distinct activation signatures defining skin
physiology.98 Commensal S. epidermidis, induces IL-17A+ CD8+ T cells that home to the
epidermis, enhance innate barrier immunity, and help prevent pathogen attachment and
colonization.99 Commensals also trigger activation of cellular Toll-like receptors (TLRs)
to enhance immunity and facilitate wound repair.100 Keratinocytes express TLRs and
other immunomodulatory proteins, such as nucleotide-binding oligomerization domain-
containing protein 2 (NOD2), that can recognize pathogenic substances, such as pathogen-
associated molecular patterns including bacterial cell wall peptidoglycans, and stimulate an
immune reaction to them.101,102 Immune response pathways are activated in a TLR-specific
process, which causes the release of cytokines, chemokines, and AMPs to attract circulating
immune cells (e.g., neutrophils and Langerhans cells). Keratinocytes constitutively express
certain AMPs, such as HBD1, while other AMPs are induced in response to injury or
infection.103-105 The Firmicutes and Actinobacteria produce lipoteichoic acid (LTA), which
is a major constituent of Gram-positive bacterial cell walls. LTA is a Toll-like receptor 2
(TLR2) ligand that down-regulates skin inflammation, which in turn, supports barrier
function.82,106