Академический Документы
Профессиональный Документы
Культура Документы
Summary
Correspondence A microbial aetiology of acne has been suggested since the beginning of the last
Babar Shaheen. century. There is considerable evidence, circumstantial at best, which suggests
E-mail: babar524@hotmail.com that micro-organisms, particularly Propionibacterium acnes, are important in the path-
ogenesis of acne vulgaris. However, it is still unclear whether P. acnes is actually a
Accepted for publication
5 April 2011 causal agent in the development of noninflamed or inflamed acne lesions. Based
on a review of the microbiological data on normal and acne-affected skin, we
Funding sources propose that P. acnes neither initiates comedogenesis nor has a role in the initia-
None. tion of inflammation in inflamed acne lesions.
Conicts of interest
None declared.
DOI 10.1111/j.1365-2133.2011.10375.x
Abstinence
from Microbiology
Reference antibiotics Culture medium (percentage of
(first author Age range Type of Number of presampling incubation period for lesions
Comedones
Shehadeh Adolescent Comedones 71 (45 open; NM Extraction of lesion Brain-heart infusion C. acnes 96 Acne flora is a stable biad
(1963)19 boys and 26 closed) content by sharp blood agar fortified C. acnes and S. albus consisting of C. acnes and S. albus.
girls acne stylet or by 1% 92 These organisms are extension
pointed scalpel glucose 5 days S. albus 96 of those colonizing normal PSFs
after wiping under 90% N2 and Sterile 0
surface with 70% 10% CO2
isopropyl alcohol.
A sopping sponge
left on skin for
3 min
Ganor NM Open 101 (51 acne NM Comedo extraction Glucose blood Acne comedones: Comedonal microflora is
(1969)20 comedones comedones; by acne stylet after agar 7 days Corynebacteria 65 probably of a secondary nature
senile 50 senile wiping surface Staphylococci 51
comedones comedones) with 70% alcohol Yeasts 67
and an Senile comedones:
alcohol-soaked Corynebacteria 36
gauze left on skin Staphylococci 50
for 3 min Yeasts 60
A microbial aetiology of acne?, B. Shaheen and M. Gonzalez 475
Table 1 Continued
Abstinence
from Microbiology
Reference antibiotics Culture medium (percentage of
(first author Age range Type of Number of presampling incubation period for lesions
and year) (years) lesions sampled lesions sampled (weeks) Sampling technique P. acnes colonized sterile) Conclusion
Marples 1423 Comedones 150 (75 open; 3 Comedo extraction Marshall and Kelsey C. acnes 92 Incidence of cocci, Pityrosporum
(1973)21 75 closed) by Schamberg agar 7 days Aerobes (mainly and C. acnes is nearly 100% in
extractor after coagulase- comedones; the absence of a
wiping skin with negative group, in a given comedone, is
70% ethanol staphylococci) probably due to technical error
85
Yeasts 99
Puhvel 1630 Open 148 3 Comedo extraction Brain-heart infusion Anaerobic The comedonal microflora is an
(1979)22 comedones by a comedo agar supplemented diphtheroids 80 extension of the normal
extractor after with 1% Aerobic cocci 75 follicular flora and is unrelated
476 A microbial aetiology of acne?, B. Shaheen and M. Gonzalez
Abstinence
from Microbiology
Reference antibiotics Culture medium (percentage of
(first author Age range Type of Number of presampling incubation period for lesions
Abstinence
from Microbiology
Reference antibiotics Culture medium (percentage of
(first author Age range Type of Number of presampling incubation period for lesions
and year) (years) lesions sampled lesions sampled (weeks) Sampling technique P. acnes colonized sterile) Conclusion
Nishijima 1343 Pustules 24 NM, although The contents of Brucella HK agar Propionibacteria S. epidermidis and P. acnes may be
(2000)26 none of the pustules squeezed medium (predominantly the representative bacteria in
patients had out and collected supplemented with P. acnes) 79 any acne lesion. Other bacterial
any previous using a comedonal 5% defibrinated S epidermidis 83 species may be contaminants
oral and or extractor after horse blood NM P. acnes and
topical cleaning skin with S. epidermidis 58
antimicrobial 70% ethanol
treatment for
acne
Leeming 1339 Inflammatory 1 day papule 52 4 Punch biopsy with Reinforced clostridial 1 day papule: Micro-organisms found in
478 A microbial aetiology of acne?, B. Shaheen and M. Gonzalez
(1988)27 papules from 3 day papule 19 microdissection of medium Propionibacteria papules are an extension of
the back of PSFs from supplemented with 68 comedonal microflora and their
patients with unprepared skin 02% Staphylococci 19 presence is not essential for the
acne Tween-80 6 days Pityrosporum spp. initiation of inflammation in
52 acne
Sterile 10
3 day papule:
Propionibacteria
79
Staphylococci 32
Pityrosporum spp.
68
Sterile 0
Till Female 2651 Inflammatory 26 6 Punch biopsy with Brain-heart infusion Propionibacteria The presence of micro-organisms
(2000)18 (10)a papules microdissection of agar with 60 is not a prerequisite for the
Male 2550 (duration PSFs furazolidone 7 days Staphylococci 24 initiation of inflammation in
(10)a unknown) Malassezia 32 acne. However,
Female 2654 Sterile 10 micro-organisms may be
(6)a involved in the inflammatory
process at some stage
P. acnes (synonymous with C. acnes), Propionibacterium acnes; S. albus, Staphylococcus albus; S. epidermidis, Staphylococcus epidermidis; NM, not mentioned. aNumber of patients in each group in parentheses.
no information about the microbial ecology of an individual more information about the role of micro-organisms in acne
PSF. By using this technique, it has been shown that propioni- vulgaris. Leeming et al.16 used punch biopsies to separate the
bacterial colonization of normal skin shows significant age- epidermis with intact follicles from the dermis after CaCl2
related and body site-related differences.2,6,10 Propionibacterium treatment, in order to study the microbiology of normal folli-
acnes density, as well as prevalence, is highest in the oily cles from the upper back of patients with acne. This technique
regions of the body such as the face and upper trunk. Body enables quantification of bacteria from a single PSF but has the
sites with few sebaceous glands show a lower prevalence and drawback that it is dependent on obtaining biopsies of skin
much lower mean densities.10 Propionibacterium acnes counts on for sampling. Of 140 normal follicles isolated from 54
scalp and face can be as high as 105 organisms per cm2.6 Pro- patients, only 12% of the follicles were colonized by propioni-
pionibacterium granulosum is also found in the oily regions but at a bacteria, with a mean population density of 26 105 per fol-
lower density and prevalence, while P. avidum is normally iso- licle.16 Similarly, the incidence of Staphylococcus and Pityrosporum
lated from wet areas of the body such as the axilla, groin and was 4% and 13%, respectively. The geometric mean density of
rectum.6 It is well recognized that P. acnes uses triglycerides in staphylococci was found to be 55 103, with S. epidermidis
sebum as a carbon and energy source with the resultant libera- being the major colonizing species (approximately 50% of all
tion of FFA. The evidence in favour of this process includes staphylococci). Colonized follicles, in this study, were
the following observations: (i) Marples et al.4 established that described as those containing high densities of bacteria, and
P. acnes lipase is responsible for the cleavage of sebaceous tri- PSFs with low numbers were considered to have contami-
glycerides into glycerol and FFA; (ii) Rebillo and Hawk11 nants.16 Intriguingly, approximately 34% of the normal folli-
demonstrated an inverse correlation between skin surface glyc- cles were found to be sterile even if the micro-organisms
erol levels and the P. acnes population, suggesting that glycerol thought to be contaminants were included as colonists.17 Like-
may be a substrate for P. acnes; and (iii) results of two studies wise, Till et al.,18 by using the same technique, found propioni-
in which drugs were used either to increase or to decrease bacteria and Staphylococcus to colonize only 17% and 10% of 48
sebum production, resulting in a concomitant increase or normal follicles from the back of patients with persistent and
decrease in the numbers of propionibacteria, helped to late-onset acne, respectively. They were, however, unable to
strengthen this hypothesis further.12,13 Thus a high density detect any viable Malassezia in these follicles. Moreover, like
and prevalence of P. acnes at skin sites with large numbers of Leeming et al.,16 they also found 90% of these normal PSFs to
sebaceous glands is not unexpected. be sterile.
Likewise, age-related differences have been found in P. acnes Despite the scarcity of data on the microbiology of normal
colonization, with infants and young children up to the age of PSFs, based on the findings of Leeming et al.16 and Till et al.18
5 years carrying significantly higher numbers than older chil- it can be concluded that only a proportion of normal PSFs is
dren up to age 10 years.2 Sebum production by the sebaceous colonized by bacteria. Furthermore, Leeming et al.16 observed
glands is androgen dependent so that at puberty there is an the proportion of follicles colonized by micro-organisms to
increase in the sebum excretion rate14,15 which is accompa- vary widely among patients, which can probably explain indi-
nied by a rise in the population density of cutaneous propioni- vidual differences in microbial densities found at the skin sur-
bacteria.2 The population density keeps increasing until the face. The slightly higher prevalence of propionibacteria and
age of 25 years, remaining constant thereafter through adult- staphylococci in the study of Till et al.18 may be explained by
hood and middle age.2 A declining trend is seen after age the fact that no attempt was made to differentiate colonized
70 years,2 which is consistent with decreasing sebaceous follicles from those having contaminants only.
secretion at that time.14,15 After age 20 years, men carry sig-
nificantly higher numbers of P. acnes as compared with
Microbiology of acne lesions
women.2 This is in accordance with the observation that nor-
mal men over the age of 20 years produce greater quantities In the hope of establishing a microbial aetiology for acne, var-
of sebum than women.14,15 No significant racial difference in ious investigators have extensively studied the microbiology of
the population density of P. acnes has been found in healthy acne lesions.1727 The sampling technique varied with the type
black and white individuals.2 Moreover, the pattern for aero- of lesion being studied.
bic bacterial population, particularly cocci, in relation to age,
sex and race has been found to be the same as for P. acnes.2
Microbiology of comedones
The surface scrub technique is useful for removing micro- Shehadeh and Kligman19 examined (Gram-stained smears) and
organisms that are located on or near the skin surface, but it cultured a total of 71 comedones (45 open; 26 closed), from
is likely that most of the follicular inhabitants are not over 100 adolescent boys and girls, and found Corynebacterium
removed. As acne is a disease of the PSFs, the microbial eco- acnes (synonymous with P. acnes) and C. acnes along with S. albus
logy of individual follicles is more relevant when dealing with in 96% and 92% of the lesions, respectively. Likewise, S. albus
acne-affected skin and gaining this knowledge could yield was isolated from 96% of the lesions while none of the come-
dones was found to be sterile. Similarly, Ganor and Sacks20 material from patients with acne, which suggests that these
compared the microbial flora of senile and acne comedones casts represent potential comedones. The authors concluded
and found corynebacteria (synonymous with propionibacteria) that as these abnormalities occurred in the complete absence
and staphylococci in 65% and 51% of the acne comedones, of bacteria, therefore bacteria are not essential for the forma-
respectively. Moreover, yeasts were seen in 67% of these le- tion of follicular casts or comedones.23 Complete absence of
sions. The investigators failed to culture all the corynebacteria P. acnes in the follicular casts was validated by various tech-
identified microscopically and, therefore, corynebacteria from niques and yielded compelling evidence against the role of
only 20% of the acne comedones were identified as C. acnes. P. acnes in the initiation of comedogenesis. However, whether
Similarly, staphylococci from only 41% of the comedones these prepubertal children did develop acne at puberty is
were identified as S. albus.20 No significant difference was unknown. A long-term study investigating the occur-
found in the incidence of staphylococci or Pityrosporum spp. rence prevalence of acne in this group would have been
between the acne and senile comedones. However, corynebac- more informative in drawing conclusions as to the role of
teria were found less frequently in the senile compared with P. acnes in comedogenesis.
acne comedones.20 Both these studies showed that < 100% of
comedones are colonized by propionibacteria or staphylococci
Microbial ecology of comedones isolated by
but the researchers failed to mention the avoidance of antibi-
microdissection from skin biopsies
otics (presampling) in their cohort of patients. Therefore, it is
difficult to rule out completely the role of antibiotics affecting In order to resolve the ongoing controversy of the role of
the bacterial colonization in these studies. P. acnes in the initiation of comedogenesis, Leeming et al.17
Subsequently, Marples et al.,21 in their attempt to quantify studied the bacteriology of 59 comedones (29 open; 30
the microbial population of individual comedones, studied the closed), isolated by microdissection from skin biopsies, from
microflora of open and closed comedones in 15 patients with the upper back of 49 patients with acne. Approximately 55%
acne and isolated C. acnes in 92% of the lesions at a geometric and 22% of the comedones were found to be colonized by
mean density of 82 104 per comedone. Furthermore, aer- propionibacteria and staphylococci, respectively. Likewise, Pity-
obes (mainly coagulase-negative staphylococci) were recov- rosporum spp. colonized 74% of these lesions.17 Comparing
ered from 85% of all lesions while yeasts were seen in all but these results with the findings of their study on the microbial
one preparation.21 Similarly, Puhvel and Amirian22 studied the ecology of normal PSFs, no significant difference was observed
bacterial ecology of 148 open comedones from the face and in the population density of propionibacteria among normal
back of 38 patients with acne and cultured anaerobic diphthe- follicles and comedones. However, micro-organisms were
roids (synonymous with propionibacteria) and aerobic cocci found to colonize significantly more comedones. Moreover,
from 80% and 75% of the lesions, respectively. Seven per cent compared with 34% of the normal follicles, approximately
of the comedones were found to harbour neither of the two 11% of closed and 7% of open comedones were found to be
micro-organisms. The results of this study were in agreement sterile.16,17
with the findings of Shehadeh and Kligman, Ganor and Sacks Because of the different sampling and culturing techniques
and Marples et al.1921 who also showed that comedones are used by various investigators it is difficult to compare all the
not universally colonized by P. acnes, supporting the argument microbiological data on comedones. However, one consistent
that the presence of P. acnes is not a prerequisite for comedo- observation that can be made is the fact that there was not
genesis. universal colonization of these lesions by a single microbial
agent. Secondly, some of the lesions have been found to be
sterile,17,22 again arguing against the role of micro-organisms
Microbial ecology of follicular casts comedones isolated
in the initiation of comedogenesis.
by the cyanoacrylate sampling technique
sterile and were observed to contain very few organisms on rates among the comedones and the two types of papules.
Gram-stained smears.19 Likewise, Marples and Izumi24 investi- Although a rising trend was seen in the bacterial population
gated the bacteriology of pustular acne in 109 pustules from densities among the normal PSFs, comedones and inflamed le-
27 patients with acne and found C. acnes in 73%, Gram-posi- sions, with the highest being in the 3 day papules, this was
tive cocci in 60% (predominantly S. epidermidis), and Gram- not found to be statistically significant.16,17,27 The authors
negative rods in 10% of these lesions. Furthermore, 12% of concluded that micro-organisms found in inflamed lesions are
the pustules were found to be sterile, with microscopic exami- just an extension of those colonizing comedones and that their
nation of the Gram-stained smears substantiating the negative presence is not necessary for the initiation of inflammation in
culture results.24 Brook et al.,25 who also studied the bacteriol- acne.
ogy of 32 pustular acne lesions, isolated only aerobes (pre- Similarly Till et al.,18 by using the sampling technique
dominantly S. epidermidis) and anaerobes (predominantly adopted by Leeming et al.,16 also studied the microbiology of
Peptostreptococcus followed by Propionibacterium spp.) from 47% and acne papules and found propionibacteria and staphylococci in
34% of the lesions, respectively. The results from the study of 60% and 24% of the inflamed lesions, respectively. Malassezia
Nishijima et al.26 also yielded propionibacteria (predominantly spp. were found in 32% while 10% of the inflamed follicles
P. acnes) and S. epidermidis as the most common (but never had no detectable viable micro-organisms. Comparing these
100%) micro-organisms colonizing acne pustules. All these findings with the results obtained from the normal PSFs, biop-
studies were limited by the fact that the duration of individual sied from the same cohort of patients, the inflamed lesions
lesions was not given and it is possible that the antimicrobial were found to have significantly higher density and prevalence
effect of the host immune response could have been responsi- of propionibacteria.18 These results also supported the work of
ble for the sterility of a number of these lesions. Furthermore, Leeming et al.27 who suggested that the inflammatory response
provision of some essential information, such as avoidance of in the follicles is not always initiated by the micro-organisms.
antibiotics, presampling, in a number of these studies, would
have been more informative in drawing conclusions about the
Discussion
bacterial ecology of these lesions.
From the above discussion, one consistent observation that
can be made is that only a proportion of normal as well as
Inamed lesions (papules)
acne-affected PSFs, whether inflamed or noninflamed, is colo-
A key shortcoming of the above studies, i.e. not mentioning nized by any specific microbial agent. Further, the microflora
the duration of individual inflamed lesions, was finally reme- of normal or acne-affected PSFs (inflamed and noninflamed)
died by Leeming et al.27 They studied the microbiology of in- generally consists of three major genera of micro-organisms
flammatory papules which had been inflamed for only short (Propionibacterium, Staphylococcus and Malassezia). We propose that
periods, and used microdissection from skin biopsies to isolate bacteria, particularly P. acnes, are not a requirement for
52 1 day and 19 3 day papules from the upper back of comedogenesis. The evidence for this is provided by a number
patients with acne.27 They found propionibacteria and staphy- of studies which failed to yield P. acnes from a proportion of
lococci to have a colonizing population (i.e. 200 organisms noninflamed acne lesions.17,1923 However, after colonization
per papule) in only 71% and 23% of the papules, respec- of the PSFs by P. acnes, the organism can potentially aggravate
tively.27 Moreover, 3 day papules were observed to be colo- or intensify abnormal desquamation by various mechanisms
nized more frequently than 1 day papules, although this (Fig. 1). The fact that P. acnes produces lipases which release
difference was not statistically significant. Interestingly, bacte- FFA from triglycerides4 and that FFA have been found to be
rial cultures from 20% and 54% of the papules (including le- comedogenic in the rabbit ear model5 suggests a possible
sions with both high and low microbial densities) were mechanism by which P. acnes can influence comedogenesis.
negative for propionibacteria and staphylococci (along with Propionibacterium acnes through its production of porphyrins
other aerobes), respectively. Furthermore, 10% of 1 day pap- may act as a catalytic agent in squalene oxidation.28 Oxidized
ules were found not to be colonized by any micro-organism squalene has been found to be comedogenic in the rabbit ear
(Pityrosporum, Propionibacterium or Staphylococcus spp.) while all the model29 and this may be another possible mechanism by
3 day lesions were found to be colonized. The population which the organism can be involved in comedogenesis. It has
density of propionibacteria and staphylococci in 3 day pap- also been proposed that P. acnes biofilm may act as a biological
ules was almost 2 and 26 times greater than in 1 day le- glue causing adhesiveness of keratinocytes, thus aggravating
sions, respectively. No bacteria were observed on microscopic comedogenesis.30
examination of the papules without associated bacterial Both viable and formalin-killed P. acnes have been shown to
growth, further validating the negative culture results. Com- augment sebum production and accumulation by increasing
paring these results with the findings of their studies on the diacylglycerol acyltransferase activity in hamster sebocytes,
microbial ecology of normal PSFs and comedones, propioni- in vivo and in vitro.31 Patients with acne are known to have a
bacteria, staphylococci and Pityrosporum spp. were found to col- high rate of sebum excretion14 with low linoleic acid levels.32
onize significantly more lesions. However, no significant The linoleate concentration returns to normal, with a concom-
difference was noted in the bacterial and yeast colonization itant decrease in sebum excretion rate, after treatment with
Comedogenesis
Inflammation
Alternative pathway
Free fatty acid Cell mediated
production secondary immunity
to P.acnes lipase From
keratinocytes
Humoral
P.acnes biofilm acting Immunity (IL-1, TNF-,
as biological glue Propionibacterium acnes GM-CSF)
Cytokines
Abnormal proliferation
and differentiation of From
keratinocytes Induction and mononuclear
activation of cells
toll-like
Increased receptors 2 (IL-1, TNF-,
diacylglycerol and 4 IL-8)
acyltransferase
activity, leading to
increased sebum Extracellular
production which may enzymes
contribute to linoleic
acid deficiency seen in
Chemotactic For monocytes
acne patients.
substances
For neutrophils
Increased production
of IL-1 by the
keratinocytes
Fig 1. Possible ways of involvement of Propionibacterium acnes in comedogenesis and inflammation in acne. IL, interleukin; GM CSF,
granulocyte macrophage colony-stimulating factor; TNF, tumour necrosis factor.
antiandrogens.33 These results indicate that the proportion of these lesions to be sterile.18,19,2427 However, P. acnes, in colo-
linoleic acid in sebum is influenced by sebum excretion rate. nized lesions, may play a role in the intensification of the
A low concentration of linoleate in sebum has been proposed inflammatory process by its enzymatic,41,42 antigenic,3,43,44
to cause follicular hyperkeratosis and decreased barrier func- chemoattractant45,46 and complement activation47,48 activities
tion.34 It is, thus, understandable that P. acnes, by increasing (Fig. 1). Furthermore, various investigators have demonstrated
lipogenesis, can further aggravate linoleic acid deficiency and the production of proinflammatory cytokines by keratino-
as a result may aggravate comedogenesis. cytes38 (IL-1a, tumour necrosis factor-a and granulocyte
Aberrant a6 integrin expression has been demonstrated macrophage colony-stimulating factor) and peripheral blood
around clinically normal follicles and early inflamed lesions of mononuclear cells49 (IL-1b, tumour necrosis factor-a and IL-8)
patients with acne when compared with normal controls.35 after P. acnes stimulation. These proinflammatory cytokines
Integrins are thought to be important in the proliferation and may also intensify inflammation in patients with acne. Induc-
differentiation of keratinocytes36 and an in vitro study has dem- tion50 and stimulation51 of toll-like receptors 2 and 4 can be
onstrated that P. acnes can induce the expression of b1, a3, a6 another mechanism by which P. acnes can intensify inflamma-
and aVb6 integrins and filaggrin on epidermal cells.37 These tion in acne. This still does not rule out the role of other
data provide other potential pathways through which P. acnes micro-organisms (Staphylococcus and Malassezia) in acne pathogen-
may potentiate comedogenesis. Moreover, P. acnes-stimulated esis, as not enough research has been done on their specific
keratinocytes have been shown to cause significantly higher role in acne.
production of interleukin (IL)-1a compared with unstimulated It has been postulated that the microenvironment of indi-
keratinocytes.38 IL-1a has been demonstrated to cause hyper- vidual follicles, whether normal or acne affected, is important
cornification of the follicular infundibulum, which can be for colonization as well as the production of extracellular
blocked by IL-1 receptor antagonist (IL-1Ra).39 Ingham enzymes by the micro-organisms.52,53 Oxygen and carbon
et al.,40 however, failed to demonstrate that cutaneous micro- dioxide tension, water availability and follicular pH are some
organisms or their products directly upregulated IL-1a release, of the possible factors that might differ from one PSF to
in vitro, by the keratinocytes. Hence it is difficult to interpret another and may determine colonization and enzyme produc-
these findings as supporting a comedogenic role for P. acnes. tion by the micro-organisms.52 Comparing the available data
Likewise, P. acnes is probably not necessary for the initiation on the microbiology of normal follicles with the microbio-
of inflammation, as it is never isolated from 100% of inflamed logical information obtained from comedones and inflamed
lesions and various investigators also found a proportion of lesions by Leeming et al., it seems that the microenvironment
A proportion of normal
Pilosebaceous follicles pilosebaceous follicles
are colonised by P.acnes
A favourable
microenvironment
leads to increased
Microcomedones colonisation of
microcomedones by
P.acnes which may
further aggravate
comedogenesis
An inflamed lesion
may further provide an
Inflammation enriched environment
for the colonisation as
well as proliferation of
P.acnes. P.acnes can
intensify the
inflammatory process
but is not a
prerequisite for its
initiation.
Fig 2. Possible sequence of events for the involvement of Propionibacterium acnes in acne.
of a proportion of microcomedones (earliest subclinical acne This still leaves us with the as yet unanswered question of
lesion) is more suitable for microbial growth. This leads to a what initiates comedogenesis and inflammation in acne. How-
significantly greater colonization of these lesions compared ever, these findings can explain why acne resolves in a pro-
with the unaffected follicles (Fig. 2).16,17 The microenviron- portion of patients, without a significant reduction in the
ment in microcomedones may also be more suitable for the population density of P. acnes. It has been postulated that like
production of extracellular enzymes by micro-organisms, the hair follicles, PSFs and comedones undergo cyclical
particularly P. acnes, and can aggravate comedogenesis. The fact growth.54,55 It might be possible that an individual PSF under-
that Leeming et al.27 found 10% of the 1 day papules not to goes only a certain number of cycles during its lifetime and,
be colonized by any micro-organism while all the 3 day therefore, depending on how many active PSFs are left in
lesions were found colonized suggests that these early lesions acne-prone areas, acne might decrease in severity and eventu-
might be free from any microbial colonization at the start of ally subside. Another possible explanation may be the resis-
inflammation. This may partly explain the sterility of a signifi- tance of PSFs to the factor factors triggering comedogenesis,
cant proportion of inflamed lesions within patients with therefore, leading to the clinical resolution of the disease.
acne as reported by various investigators. As 3 day papules Upregulation of IL-1Ra and or IL-1 receptor type II (IL-1R2)
were also found to have the highest microbial density (albeit may be one of the mechanisms of such resistance.56 IL-1Ra
a nonsignificant difference), it is plausible that an inflamed le- binds tightly to IL-1 receptor while IL-1R2 acts as a decoy
sion may provide an enriched environment not only for the receptor blocking the action of IL-1 on various cells. These
colonization but also for the proliferation of cutaneous micro- two physiological mechanisms help to regulate the activity of
organisms. Once inflammation has started in an acne lesion, IL-1 in various tissues.
P. acnes can cause intensification of the inflammatory process In summary, there is at present no incontrovertible evidence
by a number of different mechanisms mentioned above; how- that micro-organisms, particularly P. acnes, initiate either
ever, P. acnes presence is not a prerequisite for its initiation. comedogenesis or inflammation in acne vulgaris. Antibiotics
The results from other studies on the microbial ecology of such as tetracycline have been shown to have anti-inflamma-
comedones and inflamed lesions could not be compared tory effects in addition to their antibacterial activity, which
because of differences in the sampling techniques used by the may in part explain the improvement delivered by these
researchers. agents.57 Similarly, although patients with severe acne produce
more antibodies to P. acnes than do normal controls,3,43 the 3 Puhvel SM, Barfatani M, Warnick M, Sternberg TH. Study of anti-
antibody titres of patients with mild to moderate acne have body levels to Corynebacterium acnes in the serum of patients with acne
not been found to differ significantly compared with normal vulgaris, using bacterial agglutination, agar gel immunodiffusion,
and immunofluorescence techniques. Arch Dermatol 1964; 90:4217.
controls.43 Furthermore, patients with severe acne do not har-
4 Marples R, Downing D, Kligman AM. Control of free fatty acids in
bour significantly larger numbers of P. acnes.5860 Thus, it is human surface lipids by Corynebacterium acnes. J Invest Dermatol 1971;
possible that the increased level of antibodies to P. acnes in 56:12731.
patients with severe acne is due to an increased exposure of 5 Kligman AM, Wheatley V, Mills OH. Comedogenicity of human
these individuals to the immunogen as a result of their sebum. Arch Dermatol 1970; 102:26775.
pathological condition. Likewise, cell-mediated immunity 6 McGinley KJ, Webster GF, Leyden JJ. Regional variations of cutane-
(CMI) to P. acnes may be a contributing factor in the inflam- ous propionibacteria. Appl Environ Microbiol 1978; 35:626.
7 Gueho E, Boekhout T, Ashbee H et al. The role of Malassezia species
matory response in acne but this has been found to occur late
in the ecology of human skin and as pathogens. Med Mycol 1998;
in the chain of events and does not necessarily initiate inflam- 36 (Suppl. 1):2209.
mation in all patients with acne.61 Moreover, Gowland et al.61 8 Leyden JJ, McGinley KJ, Vowels B. Propionibacterium acnes colonization
found only four of 22 patients with moderate acne and 12 of in acne and nonacne. Dermatology 1998; 196:558.
22 patients with severe acne to have CMI to P. acnes. Addition- 9 Williamson P, Kligman AM. A new method for the quantitative
ally, they did not find any evidence of CMI to P. acnes in 13- investigation of cutaneous bacteria. J Invest Dermatol 1965; 45:498
to 14-year-old children with severe acne. This suggests that an 503.
10 McGinley KJ, Webster GF, Ruggieri M, Leyden JJ. Regional varia-
exaggerated immune response (humoral or cell-mediated) to
tions in density of cutaneous propionibacteria: correlation of Propi-
P. acnes cannot solely be held responsible either for the initia- onibacterium acnes populations with sebaceous secretion. J Clin Microbiol
tion of inflammation in inflamed acne lesions or for the varia- 1980; 12:6725.
tion in its severity. 11 Rebillo T, Hawk JL. Skin surface glycerol levels in acne vulgaris.
J Invest Dermatol 1978; 70:3524.
12 Kiraly C, Alen M, Korvola J, Horsmanheimo M. The effect of tes-
Conclusions tosterone and anabolic steroids on the skin surface lipids and the
population of Propionibacteria acnes in young postpubertal men. Acta
We conclude that P. acnes is likely to be a bystander and not
Derm Venereol (Stockh) 1988; 68:216.
an active participant in the development of noninflamed and 13 Miller J, Wojnarowska F, Dowd P et al. Anti-androgen treatment in
inflamed acne lesions and factors other than micro-organisms, women with acne: a controlled trial. Br J Dermatol 1986; 114:70516.
i.e. androgens, abnormalities of the sebaceous lipids or key 14 Cunliffe WJ, Shuster S. Pathogenesis of acne. Lancet 1969; i:6857.
cytokines such as IL-1a may play an important role in the 15 Pochi P, Strauss J. Endocrinologic control of the development and
initiation of acne vulgaris. activity of the human sebaceous gland. J Invest Dermatol 1974;
62:191201.
16 Leeming J, Holland K, Cunliffe WJ. The microbial ecology of pilo-
Whats already known about this topic? sebaceous units isolated from human skin. J Gen Microbiol 1984;
130:8037.
Propionibacterium acnes is regarded as one of the pathoge- 17 Leeming J, Holland K, Cunliffe WJ. The pathological and ecological
netic factors in acne vulgaris. significance of microorganisms colonizing acne vulgaris comedo-
It is still not clear whether it is actually a causal agent in nes. J Med Microbiol 1985; 20:1116.
the development of noninflamed and inflamed acne le- 18 Till A, Goulden V, Cunliffe WJ, Holland K. The cutaneous micro-
sions. flora of adolescent, persistent and late-onset acne patients does not
differ. Br J Dermatol 2000; 142:88592.
19 Shehadeh N, Kligman AM. The bacteriology of acne. Arch Dermatol
1963; 88:82931.
What does this study add? 20 Ganor S, Sacks T. A comparison of the flora of the comedones of
acne vulgaris and comedones in elderly people. Dermatologica 1969;
Our review summarizes the microbiological data on nor-
138:19.
mal and acne-affected skin. 21 Marples R, McGinley KJ, Mills OH. Microbiology of comedones in
We suggest that P. acnes is likely to be a bystander and acne vulgaris. J Invest Dermatol 1973; 60:803.
not an active participant in the development of nonin- 22 Puhvel S, Amirian D. Bacterial flora of comedones. Br J Dermatol
flamed and inflamed acne lesions. 1979; 101:5438.
23 Lavker RM, Leyden JJ, McGinley KJ. The relationship between bac-
teria and the abnormal follicular keratinization in acne vulgaris.
J Invest Dermatol 1981; 77:32530.
24 Marples R, Izumi A. Bacteriology of pustular acne. J Invest Dermatol
References 1970; 54:2525.
1 Evans C, Smith W, Johnston E, Giblett E. Bacterial flora of the nor- 25 Brook I, Frazier EH, Cox ME, Yeager JK. The aerobic and anaerobic
mal human skin. J Invest Dermatol 1950; 15:30524. microbiology of pustular acne lesions. Anaerobe 1995; 1:3057.
2 Leyden JJ, McGinley KJ, Mills OH, Kligman AM. Age-related 26 Nishijima S, Kurokawa I, Katoh N, Watanabe K. The bacteriology
changes in the resident bacterial flora of the human face. J Invest of acne vulgaris and antimicrobial susceptibility of Propionibacterium
Dermatol 1975; 65:37981.
acnes and Staphylococcus epidermidis isolated from acne lesions. J Dermatol response in acne patients but not in normal individuals. Exp Dermatol
2000; 27:31823. 1993; 2:1216.
27 Leeming J, Holland K, Cunliffe WJ. The microbial colonization of 45 Russell R, McInroy R, Wilkinson P, White R. A lipid chemotactic
inflamed acne vulgaris lesions. Br J Dermatol 1988; 118:2038. factor from anaerobic coryneform bacteria including Corynebacterium
28 Saint-Leger D, Bague A, Cohen E, Chivot M. A possible role for parvum with activity for macrophages and monocytes. Immunology
squalene in the pathogenesis of acne I. In vitro study of squalene 1976; 30:93549.
oxidation. Br J Dermatol 1986; 114:53542. 46 Webster GF, Leyden JJ. Characterization of serum-independent
29 Motoyoshi K. Enhanced comedo formation in rabbit ear skin polymorphonuclear leukocyte chemotactic factors produced by
by squalene and oleic acid peroxides. Br J Dermatol 1983; Propionibacterium acnes. Inflammation 1980; 4:2619.
109:1918. 47 Webster GF, Leyden JJ, Nilsson UR. Complement activation in acne
30 Burkhart CG, Burkhart CN. Expanding the microcomedone theory vulgaris: consumption of complement by comedones. Infect Immun
and acne therapeutics: Propionibacterium acnes biofilm produces biolog- 1979; 26:1836.
ical glue that holds corneocytes together to form plug. J Am Acad 48 Webster GF, Leyden JJ, Norman ME, Nilsson UR. Complement
Dermatol 2007; 57:7224. activation in acne vulgaris: in vitro studies with Propionibacterium acnes
31 Iinuma K, Sato T, Akimoto N et al. Involvement of Propionibacterium and Propionibacterium granulosum. Infect Immun 1978; 22:5239.
acnes in the augmentation of lipogenesis in hamster sebaceous 49 Vowels B, Yang S, Leyden JJ. Induction of proinflammatory cyto-
glands in vivo and in vitro. J Invest Dermatol 2009; 129:211319. kines by a soluble factor of Propionibacterium acnes: implications for
32 Morello A, Downing D, Strauss J. Octadecadienoic acids in the skin chronic inflammatory acne. Infect Immun 1995; 63:315865.
surface lipids of acne patients and normal subjects. J Invest Dermatol 50 Jugeau S, Tenaud I, Knol A et al. Induction of toll-like receptors by
1976; 66:31923. Propionibacterium acnes. Br J Dermatol 2005; 153:110513.
33 Stewart M, Greenwood R, Cunliffe WJ et al. Effect of cyproterone 51 Nagy I, Pivarcsi A, Koreck A et al. Distinct strains of Propionibacterium
acetate-ethinyl estradiol treatment on the proportions of linoleic acnes induce selective human beta-defensin-2 and interleukin-8
and sebaleic acids in various skin surface lipid classes. Arch Dermatol expression in human keratinocytes through toll-like receptors.
Res 1986; 278:4815. J Invest Dermatol 2005; 124:9318.
34 Downing D, Stewart M, Wertz P, Strauss J. Essential fatty acids and 52 Holland K, Cunliffe WJ, Roberts C. The role of bacteria in acne
acne. J Am Acad Dermatol 1986; 14:2215. vulgaris: a new approach. Clin Exp Dermatol 1978; 3:2537.
35 Jeremy A, Holland DB, Roberts S et al. Inflammatory events are 53 Greenman J, Holland K, Cunliffe WJ. Effects of pH on biomass,
involved in acne lesion initiation. J Invest Dermatol 2003; 121:207. maximum specific growth rate and extracellular enzyme produc-
36 Watt F. Role of integrins in regulating epidermal adhesion, growth tion by three species of cutaneous propionibacteria grown in con-
and differentiation. EMBO J 2002; 21:391926. tinuous culture. J Gen Microbiol 1983; 129:13017.
37 Jarrousse V, Castex-Rizzi N, Khammari A et al. Modulation of inte- 54 Aldana OL, Holland DB, Cunliffe WJ. Variation in pilosebaceous
grins and filaggrin expression by Propionibacterium acnes extracts on duct keratinocyte proliferation in acne patients. Dermatology 1998;
keratinocytes. Arch Dermatol Res 2007; 299:4417. 196:989.
38 Graham G, Farrar M, Cruse-Sawyer J et al. Proinflammatory cyto- 55 Cunliffe WJ, Holland DB, Clark S, Stables G. Comedogenesis: some
kine production by human keratinocytes stimulated with Propionibac- new aetiological, clinical and therapeutic strategies. Br J Dermatol
terium acnes and P. acnes GroEL. Br J Dermatol 2004; 150:4218. 2000; 142:108491.
39 Guy R, Green M, Kealey T. Modeling acne in vitro. J Invest Dermatol 56 Sims J, Smith D. The IL-1 family: regulators of immunity. Nat Rev
1996; 106:17682. Immunol 2010; 10:89102.
40 Ingham E, Walters C, Eady E et al. Inflammation in acne vulgaris: 57 Webster GF, Graber E. Antibiotic treatment for acne vulgaris. Semin
failure of skin micro-organisms to modulate keratinocyte interleu- Cutan Med Surg 2008; 27:1837.
kin 1 alpha production in vitro. Dermatology 1998; 196:868. 58 Leyden JJ, McGinley KJ, Mills OH, Kligman AM. Propionibacterium
41 Puhvel S, Reisner R. The production of hyaluronidase (hyaluronate levels in patients with and without acne vulgaris. J Invest Dermatol
lyase) by Corynebacterium acnes. J Invest Dermatol 1972; 58:6670. 1975; 65:3824.
42 Hoffler U, Kohler HC, Adam R, Mauff G. Neuraminidase produc- 59 Cove J, Cunliffe WJ, Holland K. Acne vulgaris: is the bacterial
tion of Propionibacterium acnes and related bacteria. FEMS Microbiol Lett population size significant? Br J Dermatol 1980; 102:27780.
1978; 4:1779. 60 Holland K, Cunliffe WJ, Roberts C. Acne vulgaris: an investigation
43 Ingham E, Gowland G, Ward R et al. Antibodies to P. acnes and into the number of anaerobic diphtheroids and members of the
P. acnes exocellular enzymes in the normal population at various Micrococcaceae in normal and acne skin. Br J Dermatol 1977;
ages and in patients with acne vulgaris. Br J Dermatol 1987; 96:6236.
116:80512. 61 Gowland G, Ward R, Holland K, Cunliffe WJ. Cellular immunity
44 Holland K, Holland DB, Cunliffe WJ, Cutcliffe A. Detection of Pro- to P. acnes in the normal population and patients with acne vulgaris.
pionibacterium acnes polypeptides which have stimulated an immune Br J Dermatol 1978; 99:437.