Propionibacterium acnes plays a significant role in acne development, with different strains exhibiting varying biological activities and inflammatory profiles. The bacterium contributes to acne through mechanisms such as biofilm formation, stimulation of sebum production, and induction of inflammatory cytokines, which complicate therapeutic approaches. Understanding the molecular interactions of P. acnes can inform better acne treatment strategies, particularly targeting its biofilm and inflammatory responses.

1. Propionibacterium acnes has a major role in the development of acne lesions.
Antibiotic therapy directed against p. acnes has been a mainstay treatment for
over 30 years. Resistance was not seen though until the early 1980’s.
Molecular Basis for p.acnes Resistance
In general bacteria develop antibiotic resistance by acquiring genetic
elements such as plasmids, which can be transferred between strains of a
species and even between species in some instances. With tetracyclines and
erythromycin, mobile plasmids and transposons encode for pump proteins
that efflux antibiotics away from ribosomes.
Types of p.Acnes
Two main P. acnes classification systems are described in the literature:
The first is based on gene sequences and identifies two phenotypes
(Type I and II). The proportion of P. acnes Types I and II in different
situations suggest that different P. acnes clones may have different biological
activities with different clinical consequences. Of those, a certain number
were associated with moderate to severe acne whereas others were
considered related to other skin infections or simply to healthy skin conditions.
P. acnes type I was isolated from the majority of acne lesions in one study,
favouring the hypothesis that a specific P. acnes phenotype might be more
common in acne patients. They also found a subdivision of group I (I-1) to be
significantly associated with moderate to severe acne
A second classification system is based on biological characteristics. There is
a correlation between the severity of acne and lipase activity. Among the five
P. acnes biotypes identified, P. acnes B3, corresponding to Type I,
predominates in isolates from more severe acne. It produces higher quantities
of propionic and butyric acids than other P. acnes biotypes. This suggests that
different P. acnes strains may have different proinflammatory profiles and
hence the ability to modulate differently the innate immunity. Hence, profiles
of skin microbiomes and more specifically that of P. acnes strains may differ
between mild, moderate and severe acne and obviously for non-acneic skin.
Therefore, and according to the evolutionary lineages of P. acnes in the
follicle, a certain number of teenagers may develop mild acne, whereas other
may develop moderate, severe or even no acne. This confirms the hypothesis
that pathogenic vs. truly commensal lineages of P. acnes exist resulting in
important therapeutic and diagnostic considerations
p.Acnes and Comedones
P. acnes has been isolated from comedones. Interleukin 1 (IL-1) promotes
comedone formation and P. acnes produced IL-1 and stimulated IL-1
secretion by keratinocytes participating in the comedone formation.

2. So what are some of the mechanisms that p.Acnes can induce
comedone formation?
Biofilms and p.Acnes
Most microorganisms exist in nature not as plankton nor as free-floating
microorganisms in suspension, but as biofilms. The production of
extracellular polysaccharide is essential for development of the architecture of
any biofilm matrix.
While classic examples include dental plaques, and infections on implanted
prosthetic devices and urinary catheters, biofilms occur in dermatologic
conditions as well. By definition, biofilms are composed of populations (or
communities) of bacteria that adhere to environmental surfaces, such as the
pilosebaceous lining. These microorganisms encase themselves in an
extracellular polysaccharide, which they secrete after adherence to a surface.
The extracellular matrix usually comprises two-thirds of the biofilm mass, and
is composed of polysaccharides, water, extracellular DNA, and excreted
cellular products.
Propionibacterium acnes reside within the pilosebaceous unit in a biofilm. This
gylcocalyx polymer acts as a protective exoskeleton and serves as a physical
barrier, limiting effective antimicrobial concentrations within the biofilm
microenvironment. Bacteria in the protected microenvironment of a biofilm
are 50 to 500 times more resistant to antibacterial therapies.
Biofilm formation is a process during which microorganisms irreversibly attach
to and grow on a surface and produce extracellular polymers facilitating
adherence and matrix formation. This process results in an alteration of the
phenotype of the organisms with respect to their growth rate and gene
transcription. The biofilm created by P. acnes contributes to the forming of an
adhesive glue leading to the binding of corneocytes resulting in
microcomedones
The P. acnes’ biofilm model explains many aspects of acne pathogenesis and
therapy, including why prolonged antibiotic treatment is needed.
Biofilm infections tend to be persistent. The P. acnes biofilm can explain why
antibiotics are often used for numerous months in treating acne, whereas
much shorter courses are utilized for standard bacterial infections. In short, P.
acnes reveal great tolerance to even high concentrations of antibiotics as a
result of its existence in a biofilm matrix. Resistance within the biofilms may
relate to delayed penetration of antimicrobial agents into the biofilm
polysaccharide matrix, the slow growth rate of organisms within the biofilms,
and the phenotypes of bacteria expressed within the biofilms that are distinct
from planktonic cells.
Typically a wide range of enzymatic activities by bacteria can be found within
a biofilm. In the case of P. acnes , the organism secretes an array of

3. extracellular products, including hyaluronidase, proteases, lipases, and
chemotactic factors for neutrophils, lymphocytes, and macrophages. The
Furthermore, P.acnes is not pathogenic by normal standards because there is
no correlation between the number of bacteria and severity and type of acne.
Nevertheless, P. acnes is the target of oral and topical antibiotic usage
possibly because of its affect on the P. acnes biofilm.
In terms of antibiotics, minocycline is more fat-soluble than other
antimicrobials and achieves high therapeutic success, which might be
explained by means of this biofilm concept. Indeed, tetracycline-derivatives
proved to have the highest synergistic effect when used in combination
with another antibiotic when investigated in biofilms. Ideally, acne agents
would alter the physicochemical environment of the pilosebaceous unit in
which P. acnes live.
30 mM azelaic acid, 2.5% or 5% benzoyl peroxide does not result in a
significantly decreased biofilm. Benzoyl peroxide alone had no effect on P.
acnes biofilms.
p.Acnes stimulates the production of Sebum
P. acnes increases the production of sebum. P. acnes stimulates the
sebaceous glands and sebum synthesis via the corticotropin-releasing
hormone/CRH-receptor (CRH/CRH-R) system increasing the lipogenic activity
of human sebocytes. An increase in CRH/CRH-R1 expression was observed
in the sebaceous glands of acne patients and in that of healthy individuals. It
also stimulates in a similar manner the sebum production through the
IGF/IGF-R pathway present in sebocytes.
p.Acnes and IGF-1
IGF-1 stimulates the proliferation of keratinocytes via an activation of the IGF1 receptor (IGF-1R).
Recent studies describe a correlation between IGF-1 serum levels and the
severity of acne in women. IGF-1 serum levels also correlate directly with the
amount of facial sebum in both men and women. In the skin, IGF-1 induces
keratinocyte proliferation and it induces lipid production in human sebocytes.
In acne biopsies there is a strong expression of IGF-1 and IGF-1R in the
epidermis as compared with healthy skin. In addition, Ki-67 expression was
strongly increased in the basal layer of the epidermis of acne lesions as
compared with healthy skin.
In comparison with healthy skin, in which filaggrin expression is located only
in the stratum corneum, among the acne lesions, we observed expression
in the stratum corneum and the suprabasal layers of the epidermis.

4. P. acnes has been shown to stimulate IGF-1 and IGF-1R expression in
keratinocytes and increases IGF-1 secretion.
IGF-1 and IGF-1R are over expressed in both acne lesions and subsequently
have an Ki-67 and filaggrin expression in the epidermis, confirming that the
IGF-1/IGF-1R system is associated with the modulation of both proliferation
and differentiation of keratinocytes. It was previously noted that Ki-67
expression is higher in acne patients’ epidermis than in normal healthy skin.
So differentiation of keratinocytes is modulated by P. acnes through an
induction of filaggrin and integrin expression. P. acnes has a significant role in
the formation of comedones and that one of the mechanisms is the IGF1/IGF-1R pathway.
P. acnes acts not only in the inflammatory step of acne pathogenesis but also
in the retentional stage.
p.Acnes and Cytokines
P. acnes also induces the activation of Toll-like receptors-2 and -4 in
keratinocytes.
Inflammation resulted from the immune response targeting p. acnes plays a
significant role in the pathogenesis of acne vulgaris.
P. acnes induces IL-12 and IL-8 protein production by primary human
monocytes via a Tolllike receptor 2 (TLR2)-regulated pathway and that TLR2
is expressed on the cell surface of macrophages surrounding pilosebaceous
follicles of acne lesions. TLR2 is also expressed in human keratinocytes and
sebocytes. TLR2 and TLR4 expression was increased in the epidermis of
acne lesions, and P. acnes was found to induce TLR expression in human
keratinocytes.
The major difference is the ability of P. acnes and its products to induce
human B-defensin-2 (hBD2) expression in keratinocytes and sebocytes,
which may simulate immune cells by virtue of pathogen recognition and
abnormal sebum lipid production, followed by inflammatory cytokine
production.
p.Acnes and FFA
After colonization, P. acnes can potentiate comedogenesis by various
mechanisms. It is known that P. acnes produces lipases which hydrolyse
triglycerides, thereby releasing FFAs. These FFAs have been found to be
irritant and contribute significantly to inflammation. FFA have been found to
be comedogenic in the rabbit ear model. In addition, the lipase itself can act
as a neutrophil attractant. FFA increase the adhesion of P. acnes cells and
promote colonization of the sebaceous follicle.

5. Oxidized squalene is another substance that has been found to be
comedogenic in the rabbit ear model. P. acnes, through its production of
porphyrins, may act as a catalytic agent in the oxidation of squalene. This,
along with the fact that keratinocytes stimulated by P. acnes have been
shown to produce significantly more IL-1a compared with unstimulated
keratinocytes, might signify other potential pathways through which P. acnes
may be involved in comedogenesis.
p.Acnes and Aberrant Integrin Expression
Integrins play an important role in the modulation of both differentiation and
proliferation of keratinocytes in the epidermis.
Thus abnormal keratinocyte differentiation induces alterations of the
expression of b1, a3, a6 integrins. Interestingly, on biopsies of acne lesions,
it has been demonstrated that the alteration of keratinocytes differentiation is
associated with abnormal integrins expression.
Filaggrin is a cationic (basic) protein named for its ability to aggregate
filaments of keratin into fibers. Filaggrin is synthesized in the granular cells of
the epidermis as a large, highly phosphorylated precursor, profilaggrin, which
accumulates in the keratohyalin granules. A number of keratinization
disorders are associated with dysregulation in the formation of keratohyalin
granules and in the processing of profilaggrin. Seborrhoeic and acne skin
revealed considerable amounts of filaggrin in the intermediate layers of the
sebaceous duct and the infundibulum indicating a premature terminal
keratinization process in these areas. Furthermore it has been observed in
studies an increased number of keratohyaline granules in acne skin.
P. acnes extracts modulate the expression of b1 integrin and filaggrin. Thus
the induction of b1 integrin by P. acnes, by modulating the proliferation of
keratinocytes can play a role in the formation of micro-comedon. Concerning
a3 and a6 integrins, acne patients have shown an aberrant a2 and a3
integrins expression around comedones and uninvolved pilosebaceous
follicles from acne lesions.
Thus, these results suggest that P. acnes modulates the terminal phase of
differentiation of keratinocytes
P. acnes induce B1 integrin expression significantly on both proliferating
keratinocytes and differentiated keratinocytes. In addition, P. acnes induces
a3, a6 and aVB6 integrin expression and fillaggrin expression on
differentiated keratinocytes.
P. acnes extracts increase fillaggrin expression in the suprabasal layer of the
epidermis. P. acnes are directly able to modulate the differentiation of
keratinocytes suggesting that this bacteria plays a role not only in the
development of inflammatory acne lesions but also in the formation of the
microcomedo.

6. Follicular keratinocytes fail to differentiate by apoptosis and produce
hypergranulosis similar to the impermeable skin outer layer, resulting in the
formation of microcomedones. Further inflammatory responses lead to the
development of increasing degrees of severity in inflammatory forms of acne.
p.Acnes and ROS
P. acnes can lead to the formation of reactive oxygen species, especially
superoxide anions, by keratinocytes. These may be other potential
mechanisms explaining the involvement of P. acnes in inflammatory acne.
Last but not least, P. acnes can also exaggerate inflammation in acne by the
induction and activation of toll like receptors 2 and 4.
P. acnes secretes lipases, chemotactic factors, metalloproteases and
porphyrins. All interact with molecular oxygen generating toxic, reduced
oxygen species and free radicals causing keratinocyte damage. P. acnes
interacts with markers of the innate immunity, such as toll-like receptors
(TLR), antimicrobial peptides (AMP), protease- activated receptors,
inflammatory, protease-activated receptors (PAR) and the matrix
metalloproteinase (MMP).
TLRs are transmembrane receptors of the innate immunity system, detecting
the invasion by exogenous pathogens. In patients with acne, TLR-2 and TLR4 are overexpressed in the superficial layers of the epidermis. P. acnes
stimulate the expression of TLR-2 and TLR-4 by keratinocytes as well as of
TLR-2 by macrophages. Inhibition of the expression of TLR-2 is associated
with a reduced ability of the microorganism to stimulate keratinocyte synthesis
of IL-8 and human monocytes production of IL-8 and IL-12. TLR2 may
provide a novel target for the treatment of this common skin disease.
P. acnes upregulates the secretion of different proinflammatory cytokines (IL1a, IL-1b, IL-6, IL-8, IL-12, IL-17, TNF-a or granulocyte macrophage colony
stimulating factor) by human keratinocytes, sebocytes or macrophages and
strongly activates the inflammasome of human peripheral neutrophils.
p.Acnes and MMP’s
P. acnes induces MMP-9 expression in human keratinocytes. P. acnes
stimulates MMP-2 expression through tumour necrosis factor alpha in dermal
fibroblasts whereas doxycycline inhibits the expression of MMP-2 induced by
P. acnes. The proliferation of P. acnes in acne lesions induces an increase in
MMP secretion enhancing the rupture of the follicle and the spread of the
inflammation in the dermis.
p.Acnes and Inflammation

7. In particular, IL-8 along with other P. acnes -induced chemotactic factors may
play an important role in attracting neutrophils to the pilosebaceous unit. In
addition, P. acnes releases lipases, proteases and hyaluronidases which
contribute to tissue injury.
P. acnes triggers inflammatory cytokine responses in acne by activation of
TLR2. As such,
New Research in 2014 has shown
P. acnes contributes to the inflammatory response seen in acne by triggering
the activation of the NLRP3- inflammasome in antigen presenting cells
(APCs), subsequently leading to enhanced IL-1b secretion. The
inflammasome is a cytoplasmic molecular complex that can rapidly initiate
inflammation upon sensing pathogen- and danger-associated molecular
patterns (PAMPs/DAMPs) by regulating the secretion of caspase-1 activationdependent cytokines including IL-1b.
Inflammasome deficiency or IL-1b blockade prevents P. acnes-induced
inflammatory responses. Several human diseases are associated with the
activation of inflammasomes. Such findings suggest that molecules targeting
IL-1b and/or the NLRP3 inflammasome may constitute new treatment
possibilities for acne vulgaris.
References:
Propionibacterium acnes Activates the IGF-1/IGF-1R System in the
Epidermis and Induces Keratinocyte Proliferation
Isard, Knol, Arie`s, Nguyen, Khammari, Castex-Rizzi and Dre´
Journal of Investigative Dermatology (2011) 131, 59–66;
Investigation on mouse model for acne vulgaris-like lesions: The role of
inflammation induced by P. acnes
Lee, Kim, Lee, Sub Lee, Hyuk Choi, Son, Jung, Sohn, Jang, Lee, Kim
Department of Dermatology, Kyungpook National University School of
Medicine, Daegu, Republic of Korea
Propionibacterium acnes and Sebaceous Lipogenesis: A Love–Hate
Relationship?
Zouboulis. Journal of Investigative Dermatology (2009), Volume 129
pp2093-2095.
‘‘Acne biofilms,’’ temperature, and microenvironments” J AM ACAD
DERMATOLogy JANUARY 2005 pp 182.
Acne sans P. acnes B. Shaheen,* M. Gonzalez

8. Journal of the European Academy of Dermatology and Venereology
2013, 27, 1–10
Biofilm formation by Propionibacterium acnes is associated with
increased resistance to antimicrobial agents and increased production
of putative virulence factors.
Coenye, Peeters, and Nelis. Research in Microbiology 158 (2007) 386-392.
Microbiology’s principle of biofilms as a major factor in the
pathogenesis of acne vulgaris
Burkhart and Burkhart
International Journal of Dermatology 2003, 42, 925–927
An increased incidence of Propionibacterium acnes biofilms in acne
vulgaris: a case–control study.
Jahns, Lundskog, Ganceviciene, Palmer, Golovleva, Zouboulis,
McDowell, Patrick and Alexeyev
BJD _ 2012 British Association of Dermatologists 2012 167, pp50–58
Propionibacterium acnes: an update on its role in the pathogenesis of
acne
Beylot, Auffret, Poli, Claudel, Leccia, Del Giudice, Dreno.
July 2013 European Academy of Dermatology and Venereology
Review of the Innate Immune Response in Acne vulgaris: Activation of
Toll-Like Receptor 2 in Acne Triggers Infl ammatory Cytokine
Responses.
Kim. Dermatology 2005;211:193–198
Propionibacterium acnes Resistance: A Worldwide Problem
Eady, E A;Gloor, M;Leyden, J J
Dermatology; 2003; 206, 1;
New Insights into Acne Pathogenesis: Propionibacterium Acnes
Activates the Inflammasome.
Contassot and French. Journal of Investigative Dermatology (2014) 134,
310–313.
Natural compounds as inflammation inhibitors
Schumacher, Junckerm, Schnekenburger, Gaascht and Diederich.
Genes Nutr (2011) 6:89–92
Modulation of integrins and Fillaggrin expression by Propionibacterium
acnes extracts on keratinocytes.
Jarrousse, Castex-Rizzi, Khammari, Charveron and Dréno.
Arch Dermatol Res (2007) 299:441–447
Current Concepts of the Pathogenesis of Acne Implications for Drug
Treatment
Harald Gollnick

9. Drugs 2003; 63 (15): 1579-1596