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A Honey Trap for the Treatment of Acne: Manipulating the Follicular Microenvironment to Control Propionibacterium acnes

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Today, as 40 years ago, we still rely on a limited number of antibiotics and benzoyl peroxide to treat inflammatory acne. An alternative way of suppressing the growth of Propionibacterium acnes is to target the environment in which it thrives. We conjecture that P. acnes colonises a relatively "extreme" habitat especially in relation to the availability of water and possibly related factors such as ionic strength and osmolarity. We hypothesise that the limiting "nutrient" within pilosebaceous follicles is water since native sebum as secreted by the sebaceous gland contains none. An aqueous component must be available within colonised follicles, and water may be a major factor determining which follicles can sustain microbial populations. One way of preventing microbial growth is to reduce the water activity (a w ) of this component with a biocompatible solute of very high water solubility. For the method to work effectively, the solute must be small, easily diffusible, and minimally soluble in sebaceous lipids. Xylose and sucrose, which fulfil these criteria, are nonfermentable by P. acnes and have been used to reduce water activity and hence bacterial colonisation of wounds. A new follicularly targeted topical treatment for acne based on this approach should be well tolerated and highly effective.
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BioMed Research International
Volume , Article ID , pages
http://dx.doi.org/.//
Review Article
A Honey Trap for the Treatment of Acne:
Manipulating the Follicular Microenvironment to
Control Propionibacterium acnes
E. Anne Eady,1Alison M. Layton,1and Jonathan H. Cove2
1Department of Dermatology, Harrogate and District NHS Foundation Trust, Lancaster Park Road, Harrogate HG2 7SX, UK
2Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK
Correspondence should be addressed to E. Anne Eady; eaeady@gmail.com
Received  January ; Accepted  April 
Academic Editor: Peter A. Lambert
Copyright ©  E. Anne Eady et al. is is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Today, as  years ago, we still rely on a limited number of antibiotics and benzoyl peroxide to treat inammatory acne. An
alternative way of suppressing the growth of Propionibacterium acnes is to target the environment in which it thrives. We conjecture
that P. a c n e s colonises a relatively “extreme” habitat especially in relation to the availability of water and possiblyrelated factors such
as ionic strength and osmolarity. We hypothesise that the limiting “nutrient” within pilosebaceous follicles is water since native
sebum as secreted by the sebaceous gland contains none. An aqueous component must be available within colonised follicles, and
water may be a major factor determining which follicles can sustain microbial populations. One way of preventing microbial growth
is to reduce the water activity (𝑎𝑤) of this component with a biocompatible solute of very high water solubility. For the method to
work eectively, the solute must be small, easily diusible, and minimally soluble in sebaceous lipids. Xylose and sucrose, which
full these criteria, are nonfermentable by P. a c n e s and have been used to reduce water activity and hence bacterial colonisation of
wounds. A new follicularly targeted topical treatment for acne based on this approach should be well tolerated and highly eective.
1. Introduction
Propionibacterium acnes has long been implicated in the
pathogenesis of inammatory acne [,]. Although its role
in lesion formation is still heavily debated [,], there is
no doubt that treatment which reduce numbers of pro-
pionibacteria on skin are therapeutic [,]. Acne is a
disease of the infundibulum of the pilosebaceous follicle, and
antimicrobials directed against P. a c n e s must target this site
to be eective. Antibiotic therapy, now usually combined
with benzoyl peroxide to minimise the risk of resistance,
remains the only antimicrobial therapeutic option currently
available []. Novel antimicrobial treatments are required
that do not select for antibiotic resistance and which are
more friendly to skin and household linens than benzoyl
peroxide. Whilst good progress is being made with physical
therapies, especially those based on light [], development
of an acne vaccine is hampered by the fact that, with a
few notable exceptions, the major immunogens of P. ac n e s
associated with protective responses remain poorly dened.
A novel approach initially proposed by C. N. Burkhart
andC.G.Burkhart[] is to alter the microenvironment
within the pilosebaceous follicle beyond the permissible
boundaries for growth and survival of P. a c n e s . In prin-
ciple several environmental parameters could be altered,
for example, pH, oxygen tension, or ionic strength but
itisourcontentionthatoneofthemostpromisingand
amenable parameters to change has so far been overlooked.
We hypothesise that availability of water and possibly of
one or more water soluble micronutrients limit microbial
growth within follicles and that reduction of water activity
represents a novel and safe therapeutic approach in acne
management.
Whether the hypothesis put forward here turns out to
be right or wrong does not really matter. Our aim is to
stimulate more research on the follicular environment and on
the attributes of P. a c n e s that make it so well adapted to exploit
this rather unusual niche.
BioMed Research International
2. Water and Colonisation of
the Pilosebaceous Follicle
It is oen stated that the skin surface is a harsh environment
resistant to colonisation by transient contaminating bacte-
ria. Although recent evidence suggests that innate immune
mechanisms contribute much to skin defence against micro-
bial invaders [], arid conditions and the “acid mantle” have
long been invoked as determining factors that limit the diver-
sity of organisms colonising the skin surface []. It is well
documented that occlusion of the skin surface, which results
in signicant hydration of the skin and increase in surface
pH, gives rise to a corresponding increase in the number
of surface bacteria [] even when innate defences remain
intact. Similarly life for bacteria that colonise pilosebaceous
folliclesislikelytobestressful.Aswellasthelackofwater,
sebum is full of antimicrobial substances such as long and
short chain fatty acids derived from triglycerides through the
action of bacterial lipases as well as antimicrobial peptides
such as defensins, cathelicidin, and histone H []. ese
potent inhibitors of bacterial multiplication, which can act
synergistically,areproducedbysebocytesintheglandand/or
keratinocytes lining the duct [,]. Given that P. a c n e s is
susceptible to antimicrobial peptides and some sebaceous
type fatty acids in vitro, the concentration of these substances
in the sebum of colonised follicles must be subinhibitory,or
the organisms must be sequestered from their eects. e
pilosebaceous follicle is not a cosy environment for microbial
colonisation. Compared to mucosal surfaces which support
the growth of a dense and taxonomically complex resident
microora, P. a c n e s colonises a relatively “extreme” environ-
ment especially in relation to the availability of water and
possibly related factors such as ionic strength and osmolarity.
In adults, P. a c n e s is the predominant inhabitant of skin
regions rich in sebaceous glands including the face and upper
trunk [] and in healthy skin appears to be the exclusive
resident within pilosebaceous follicles []. In normal and
acne prone skin, population densities of viable P. a c n e s
within individual follicles typically exceed 5,althoughin
people with acne only a minority of follicles are colonised
[]. Presumably one or more dening characteristics of
the genus Propionibacterium together with species specic
traits make P. a c n e s particularly well adapted to the follicular
environment. It is interesting to note that Propionibacterium
freudenreichii, a dairy species that is used to manufacture
Swiss hard cheeses, is also adapted to a harsh low water envi-
ronment []. Perhaps members of this genus share an ability
to grow where water is scarce or biologically unavailable.
Within pilosebaceous follicles there are several possible
sources of water. Water may be released along with sebaceous
lipids upon rupture of mature sebocytes. Although sebum is
a rich source of potential macronutrients, sebum collected
from the skin surface apparently contains little or no water
[], and reported analyses of sebum do not mention the
presence of water [].Sebumwouldbeexpectedtohavea
higher water content if sebocytes sometimes rupture before
they are fully mature. Another possibility is that water
is derived exogenously, perhaps from eccrine sweat. is
seems unlikely given the barrier function of skin and that
exogenous water would have to permeate the follicular orice
against an outow of hydrophobic sebum. However, studies
with the asebia mouse have shown that sebaceous gland-
derived glycerol contributes to stratum corneum hydration
[]. Glycerol is released from sebaceous triglycerides by the
action of P. a c n e s lipases (glycerol esterases), and skin with
high numbers of P. a c n e s is depleted in glycerol []. As a
humectant, glycerol will allow sebum at the skin surface to
absorb water from the atmosphere. Wertz has shown that
synthetic sebum containing triglycerides but no free glycerol
will take up % of its weight in water when equilibrated
in an atmosphere saturated with water vapour []. Taken
together, these observations suggest that sebum can retain
water in the follicular lumen but do not explain where
it comes from. e most likely source of unbound water
is via diusion from the dermal vasculature through the
keratinocyte lining of the follicular wall. Anatomically this
becomes thinner below the infundibulum in the deeper
regions of the pilosebaceous follicle, and this could be a
possible location for the ingress of water []. Unlike the
exposed skin surface, evaporation is almost certainly not
a signicant driver of transepidermal water ux into the
infundibulum,sothatingressofwaterwouldsuggestabreach
intheintegrityofthefolliclewall.enalpossibilityisthatP.
acnes obtains water by growing on a substratum, for example,
from keratinocytes lining the infundibular wall. e wall
comprises a cornied epithelium that is continuous with the
stratum corneum. P. a c n e s producesahostoftissuedamaging
enzymes that may be able to destroy corneocyte membranes
[]. is assumption would appear to be conrmed by
scanning electron micrographs of acne comedones which
clearly show “holes” in shed corneocytes heavily colonised by
propionibacteria (Figure ,[]). Shed vellus hairs present an
alternative substrate, and P. a c n e s has been shown adhering
to hairs within comedones []. Hair contains signicant
amounts of water [].
3. Relationship between P. acnes Growth Rate
and Rate of Sebum Secretion
e classical picture of the follicular niche is that P. a c n e s
resides in a nutrient rich environment provided by a constant
supply of sebaceous lipids. However, sebum almost certainly
does not provide all that is necessary to support growth.
Water soluble vitamins, for example, are not present in sebum
andsomustbeprovidedfromanaqueouscompartment.
P. a c n e s has an absolute requirement for pantothenate and
nicotinamide and several trace elements including iron and
cobalt [,]. It is most unlikely that the growth limiting
nutrient, which is a major determinant of the population
density within a follicle, will be a sebaceous lipid. Despite
this, the sebum excretion rate will exert a profound inuence
on the rate of growth of P. a c n e s and may determine, along
with availability of water, whether a particular follicle is
capable of being colonised. e sebum excretion rate shows
circadian variation, and only a proportion of follicles is
actively secreting sebum at any one time [,]. P. a c n e s
growth has to respond to these changes in sebum availability
and sebum ow rate.
BioMed Research International
(a) (b)
F : Propionibacteria in a comedone from acneic skin: interaction with sebum and corneocytes. Scanning electron micrographs of
propionibacteria growing on the surface of corneocytes with an open comedone. e image on the right is a higher magnication (×,)
and shows sebum droplets adhering to the surface of the bacterial cells. Where is the aqueous component? B: bacteria; S: sebum; H: hole in
corneocyte. Arrows indicate dividing cells with visible septa. Images reproduced with permission from WH Wilborn, BM Hyde, Montes LF,
Scanning Electron Microscopy of Normal and Abnormal Human Skin, , VCH Publishers.
Allbacteriahaveamaximumspecicgrowthrate(𝜇max )
which they cannot exceed under any given set of environ-
mental conditions. e growth rate will be reduced under
adverse physicochemical conditions or nutrient starvation.
Consequently P. a c n e s will be washed out of follicles if the
rate of loss of bacterial cells due to the outward ow of
sebum and desquamation of keratinocytes from the follicle
wall (to which they may be attached) exceeds their ability to
be replaced by growth.
It is possible to make very approximate estimations of
the in vivo growth rate of P. a c n e s by applying chemostat
theory [] using follicular volume (𝑉, expressed in litres)
and the sebum ow rate (𝐹, expressed in litres per hour).
e rate at which the follicular content is diluted by the
outow of sebum is given by 𝐹/𝑉 = D, where Dh−1 is the
dilution rate. Assuming that the propionibacterial population
density within the follicle remains constant over time (i.e.
in a steady state), the specic growth rate 𝜇h−1 of P. a c n e s
growing exponentially must match the rate of loss of cells due
to dilution caused by the outow of sebum. us at steady
state, 𝜇=D, that is, the population density of P. a c n e s
doubles at the same rate, it is being diluted. Doubling time
(𝑇𝑑)is also a measure of bacterial growth and is given by the
expression 𝑇𝑑=ln 2/𝜇 or ./𝜇.SinceD =𝐹/𝑉and at
steady state D =𝜇, published values for the follicular volume
andsebumexcretionratecanbeusedtoapproximatethe
doubling time of P. a c n e s i n v iv o .evolumeofpilosebaceous
follicles has been reported to be .–. mm3cm−2 []
on the forehead, and typical values for the sebum excretion
rate have been given as .–. 𝜇gcm
−2 min−1 at this site
[] with higher rates in subjects with acne. e measured
rate is the average of the sebum output from hundreds of
follicles. It is generally held to be true that only half of the
follicles in a given area are actively secreting sebum at any
one time [], so that the range of values for D (equivalent
to specic growth rate 𝜇)iscalculatedtobefrom.h
−1
to . h−1 equivalent to doubling times between . and
. h. e maximum growth rate achieved by P. a c n e s under
optimum laboratory conditions with an abundant supply
of a fermentable carbohydrate such as glucose is . h−1
equivalent to a doubling time of . h. e growth rate will
be reduced markedly under suboptimal physical conditions
of pH, oxygen tension, and water activity and when utilising
energetically less favourable carbon sources such as glycerol.
For example, in the presence of oxygen (% air saturation),
𝜇max decreases to . h−1 corresponding to a doubling time
of . h []. Even growing at its maximum specic growth
rate, it would be very dicult for P. a c n e s to colonise de novo
those follicles with high sebum production rates, and this may
explain why most follicles in acne prone skin do not contain
propionibacteria.
One piece of experimental evidence gives an indirect
estimate of the actual in vivo growth rate of P. a c n e s .Benzoyl
peroxide reduces numbers of P. a c n e s on the skin surface
by an average of  logs (% of baseline value). In the
only study to investigate what happened aer treatment, the
P. a c n e s population density was observed to have partially
recovered by day three and fully by day seven []. e
doublingtimecalculatedfromthemeasuredrateofincrease
is approximately  h. is suggests that P. a c n e s may gain
entry into follicles when sebum output is low as a result of
diurnal rhythm or the follicle cycle and manages to maintain
a stable population by growing in contact with a substratum
to which it adheres strongly (see the following).
4. What Is Water Activity, and How Does It
Affect Microorganisms?
e term water activity is derived from fundamental prin-
ciples of thermodynamics and is a measure of the energy
status of water in a system. It is a measure of how eciently
the water can take part in a chemical reaction. e energy
status of water can be reduced by both osmotic and matric
eects. When substances such as salt (NaCl) or sugar are
dissolvedinwater,thewateractivityisreducedbythenumber
of particles in solution; hence water activity is dependent on
solute concentration. For a review on life at low water activity
see Grant,  [].
BioMed Research International
Essentially water activity (𝑎𝑤)=𝑝/𝑝
𝑜,where𝑝is the
vapour pressure of water in the substance and 𝑝𝑜is the vapour
pressure of pure water at the same temperature. e 𝑎𝑤of pure
wateris..Growthofmostmicrobesisnotpossiblebelow
an 𝑎𝑤of . although extremely xerophilic, and halotolerant
species can grow down to an 𝑎𝑤of .. Low water activity
not only aects bacterial growth but also bacterial exocellular
enzyme activity. Minimum 𝑎𝑤values for growth are solute
dependent. When the 𝑎𝑤of the suspending medium is
reduced by the dissolution of a solute such as sucrose, then
water is withdrawn from microbial cells, concentrating the
intracellular uid until the internal and external values are
similar. When the concentration of the intracellular uid goes
beyond a critical value, growth and metabolism cease. is
is because outwardly orientated cytoplasmic pressure is the
driving force for cell growth. e cells are not killed in a low
𝑎𝑤environment, but they cannot replicate.
Microbial cells have evolved ways of protecting them-
selves from low water activity, or so-called osmotic stress
[,]. Some synthesise and accumulate compatible solutes
(osmoprotectants) that reduce the intracellular 𝑎𝑤with rela-
tively minor eects on tness such as reduced growth rates.
Such solutes include proline, glutamine, betaines, glucosyl-
glycerol, ectoine, -dimethylsulphoniopropionate, and some
sugar alcohols such as trehalose. Accumulation of potassium
ions may also occur. Although there have been no reports on
this, it may be possible to turn some of these osmoprotectants
against themselves by increasing the concentration outside
thecelltoveryhighlevels.
5. Hypothesis
A new antimicrobial approach to the treatment of acne is
proposed based on the hypothesis that the growth of P.
acnes in pilosebaceous follicles is restricted by the availability
of water or water soluble nutrients. It may be possible to
inhibit the multiplication of propionibacteria within follicles
by reducing the water activity to a level below that which
permits microbial growth and colonisation of the follicle. is
could be achieved by introducing a highly water soluble, lipid
insoluble compound that would reach high concentrations in
the aqueous fraction of the follicular contents. Suitable com-
pounds for this purpose would be a nonmetabolisable such
as sucrose or xylose or one such as ribose or fructose which
is metabolisable at normal physiological concentrations. e
polyol, sorbitol, is an alternative, fermented by some but
not all P. a c n e s phylotypes. All except xylose have water
solubilities in excess of %. Mixtures may be preferable to
the use of a single solute. Formulation technology will need
to be developed to specically target these to follicular water
via the topical route.
6. Evaluation of the Hypothesis and Ways of
Evaluating It
6.1. Availability of Water in the Follicle. Although analyses
have shown that sebum collected from the skin surface
contains little or no water, the presence of microorganisms
within normal follicles indicates that water must be present
in at least those which are colonised. Similarly water can
gain access to abnormal follicles, and analyses of mature
noninamed comedones (blackheads) show that the water
contentofthesecanvaryfromlessthan%upto%
[], values a lot higher than for sebum collected at the
surface of healthy skin. It is reasonable to suppose that
the water content of individual follicles varies in either a
random or predetermined way depending upon the source.
e well-known premenstrual are that occurs in many
womenisassociatedwithwaterretentionthatdecreasesthe
size of the pore [] and may concomitantly and transiently
increase the water content of the follicular lumen. Moreover,
defective water barrier function in acne has been proposed
[].
Because of their depth below the skin surface, it would be
technically extremely dicult to measure the level of water
within follicular infundibula in situ. However, several experi-
mentalapproachescanbeusedtotesttheideathathealthy
follicles contain low levels of water. e simplest way is to
collect sebum from individual follicles and analyse its water
content. Sebum can be collected using a glass slide and very
short skin contact to avoid coalescence of sebum drops from
adjacent follicles. e skin must be precleaned rst to remove
skin surface lm. It is also relatively straightforward to
measure the water content of microcomedones extracted with
cyanoacrylate glue [] and of individual closed comedones
(blackheads). It may also be possible to determine the ux
of water through pilosebaceous follicles compared to stratum
corneum. In order to study the dynamics of transfollicular
drug delivery, a follicular closing method has been devised to
occlude the follicular orices using small drops of a varnish
wax mixture leaving the stratum corneum unoccluded [].
Transepidermal water loss (TEWL) can be measured using
specic sensors [],anditisfeasibletocompareTEWL
of untreated skin and skin in which the follicles had been
occluded. Aer determining the number of follicles cm2,it
would in principle be possible to determine the mean ux
of water through an individual follicle. It is anticipated that
these experiments would conrm low availability of water to
microorganisms within the follicle.
So far water activity has been considered as the limiting
factor for P. a c n e s growth within the follicle. In reality P. a c n e s
may face greater and more complex challenges in relation
to the availability of water. e lower limit of water activity
to support microbial growth is .. is, however, assumes
that water is available in the form of a homogeneous solution
which is unlikely to be the case in the hydrophobic and
heterogeneous environment of the pilosebaceous follicle. e
nonmiscibility of sebum and water is easily demonstrated on
a microscope slide held onto the forehead to collect droplets
of sebum. If a tiny drop of water is added to the slide, the
sebum droplets remain discrete. In fact water-sebum inter-
actions and the formation of droplets and hydrolipid lms
have been shown to depend on complex interactions between
natural surfactants within the lipids that favour wetting and
van der Waals forces that oppose it []. A discontinuous
aqueous milieu would give rise to signicant obstacles to
mass transfer of essential nutrients for P. a c n e s and may
BioMed Research International
T : Some osmoprotectant systems detected in P. a c n e s .
Osmoprotectant Comment
Aquaglyceroporin/glycerol uptake facilitator Adjacent glycerol kinase suggests role of glycerol as a carbon and energy
source, but glycerol--phosphate dehydrogenase is not in same operon.
Glycine betaine/L-proline three component ABC
transporter (uptake system) P. a c n e s can synthesise proline but not betaines or ectoine.
Trehalose synthesis Dierent pathways in dierent strains, for example, from maltose, possibly
from glycogen stores.
Osmosensitive potassium channel Six genes; products mediate signal transduction in response to changes in
turgor pressure.
Small conductance mechanosensitive ion channel
Large conductance mechanosensitive ion channel
Responsive to membrane stretch such as that induced by increased turgor
pressure inside the cell; small one close to glycerol uptake facilitator.
OsmC (peroxiredoxin) Close to glycerol uptake facilitator; typically induced in late exponential
phase. Strongly deregulated in P. a c n e s .
also generate unfavourable solute concentration gradients.
For example, hydrophilic salts and organic compounds could
be concentrated within the aqueous phase giving rise to
conditions of ionic and/or osmotic stress that must be
overcome for P. a c n e s tothrive.epresenceofmicrobial
cells may inuence interactions between the aqueous phase
and follicular lipids. For example, hydrophobic bacteria have
been shown to stabilise oil-water emulsions [].
Meticulous anatomical and microscopic investigations
are required to determine the precise location of P. a c n e s
within the follicular lumen and how it interacts with available
water. Processing of sections for histology typically removes
water, and conventional electron micrographs appear to
show follicular propionibacteria embedded in sebum [,].
Water may exist within discrete droplets, and P. a c n e s may
multiply only where these occur. Alternatively each bacterial
cell could be surrounded by a very thin lm of water and
eectively inhabit a highly restrictive aqueous environment.
e existence of water lipid interfaces is essential for the func-
tioning of bacterial lipases (triglyceride esterases) on which P.
acnes depends for acquisition of glycerol although invariably
also possesses a cutinase (lidless lipase) that functions in a
predominantly aqueous environment [].
6.2. Physiology and Genomics of P. acnes. e growth of P.
acnes within the pilosebaceous follicle may be challenged not
only by the availability of water required for cellular functions
but also by additional osmotic and ionic stresses. In these
respects it can be argued that P. a c n e s occupies a relatively
extreme environment. is idea is not as farfetched as it
may seem. As reported for Propionibacterium freudenreichii,
a related organism with GRAS status used in the manufacture
of Swiss cheese, P. a c n e s has within its genome capability for
synthesis and utilisation of polyphosphate and glycogen [],
characteristics of bacteria adapted to harsh environments
[]. Polyphosphates act as energy stores and enable the
organism to survive stationary phase and possibly extended
periods of extremely slow growth. P. a c n e s also possesses
sodium and potassium transport systems similar to those
found in halophiles that enable it to colonise environments
of high ionic strength together with at least three systems
facilitating the uptake, synthesis, and/or utilization of osmo-
protectants, namely, glycine betaine, proline, and trehalose.
Osmoprotectants counteract the eects of high osmotic stress
by maintaining turgor pressure without compromising cell
functions. An aquaglyceroporin (glycerol uptake facilitator)
is invariably present within the P. a c n e s genome enabling
the uptake of water, glycerol, and other small solutes. Tab l e 
summarises some of the systems encoded within the P. a c n e s
genome that may enable it to survive a low water follicular
environment. Of note is that the genes encoding a small
conductance mechanosensitive ion channel which responds
to membrane stretch, the glycerol uptake facilitator, and an
Osm-like protein induced by salt shock with a peroxiredoxin
type function, are located close together in the genome.
Of course the presence of these genes is not particularly
revealing in itself; much more important is uncovering how
they are regulated. By hydrolyzing sebum triglycerides, P.
acnes lipases may create a microniche in which the organism
can survive and multiply using glycerol as an energy source,
osmoprotectant, and water gatherer.
In recent years there has been much interest in the ability
of P. a c n e s to produce biolms [,]. Whilst it is beyond
dispute that some P. a c n e s strains produce biolms both in
vivo and in vitro, the role, if any, of biolms in the adaptation
of P. a c n e s toitsfollicularnicheandinacnepathogenesis
is not understood. e chemical composition of the biolm
has not been elucidated not has its relationship with cell
wall lipoglycans and possible capsular polysaccharides been
established. It is plausible that cell-associated polysaccharides
of P. a c n e s , whether organized into biolms or capsules, play
an important role in capturing and storing water and/or in
protecting the cells from dehydration.
Gene-knockout technology can now be applied to P.
acnes [], and knockout mutants could be created to test
theimportanceofdierentsystemsrequiredforgrowth
of P. ac n e s under conditions of low water availability. In
this way the relative importance of dierent osmoprotectant
systems, ion channels, aquaglyceroporins, and cell associated
polysaccharides could be revealed.
BioMed Research International
T : Water solubilities and approximate 𝐴𝑤values for selected solutes.
Solute (MW) Amount solute (g) Amount water (g) % solute Moles/ g 𝐴𝑤
Sucrose (.)   . . .
Fructose (.)   . . .
Mannose (.)   . . .
Ribose (.)   . . .
Sorbitol (.)   . . .
Maltitol (.)    . .
Proline (.)    . .
Rhamnose (.)    . .
Xylose (.)    . .
Glycerol (.)    . .
Urea (.)    . .
Glycine betaine (.)  . . .
Ectoine (.)   . . .
NaCl (.)    . .
Valu e s o f 𝐴𝑤in this table were calculated using the following formula: 𝑎𝑤= ./ + .  n, where n is moles of solute/ g water.
7. Candidate Compounds and
Formulation Technology
Compounds, mainly sugars and polyols, would be evaluated
for their ability to reduce water activity below the level
permissible for the growth of P. a c n e s using concentrations
that can be achieved in vivo using an ecient follicular
delivery system (Table ). Candidate compounds must be
well tolerated. ere is already a precedent for using high
concentrations of sugars or honey on broken skin, so the risk
of intolerance when used on essentially intact skin is low.
If necessary, skin tolerance tests can be performed on the
formulated product. Although we have suggested that non-
metabolisable solutes should be employed, it may be possible
toachievesucientlyhighconcentrationsofmetabolisable
compounds to be eective. Although there have been no
reports of bacterial inhibition using compatible solvents,
their use at high concentrations under conditions of low
water activity has not been tested. It may well be that under
these conditions even compatible solvents can be employed
to reduce the water activity below a level permissible for
growth.Ectoineandhydroxyectoineareverysafecompounds
alreadyusedonskinashumectants.eyhavegreateranity
for water than glycerol []. It is intriguing to consider
whether these compatible solvents could be harnessed to
sequester water from P. a c n e s . Development work will need
to be carried out in order to determine optimal mode of
deliveryoftheactivesolutealthoughitisanticipatedthat
this would involve follicular targeting, for example, using
encapsulation [,]. Dose response studies will be required
to determine the optimum concentration of solute in the
formulation and to ensure that maximum concentrations of
soluteareachievedinthesmallvolumeoffollicularwater
without distribution to other areas of skin. ese should take
into account the likely volume of the aqueous component
within the lumen of pilosebaceous follicles and the range of
variability from follicle to follicle and within a single follicle
at dierent times.
8. Concluding Remarks
e hypothesis proposed in this paper has been put forward
to highlight the paucity of information which is currently
available about the follicular niche in which P. a c n e s resides
both as a commensal and as a pathogen. Almost as little
is known about the bacterial attributes associated with the
abilityofpropionibacteriatothriveinthisunusualhabitat.
e availability of numerous P. a c n e s genome sequences
and the technology to exploit them is powerless to explain
theorganismsroleinskinhealthanddiseaseunlesswe
learn more about the environment in which it lives. More
and more studies with other bacterial species are revealing
that the distinction between housekeeping genes and viru-
lence determinants is an articial one. An example is N-
acetylmuramoyl-L-alanine amidase, a hydrolase involved in
septum cleavage during cell division and an autolysin, the
cell wall anchoring domain of which mediates adhesion to
epithelial cells in Listeria monocytogenes []. To date the
focusofeortstounderstandthebiologyofP. a c n e s has been
on candidate pathogenicity determinants of the traditional
kind [,] not one of which has been conclusively proven
toplayaroleinthegenesisofacnelesions.Itmayturnoutthat
apparently benign housekeeping genes are absolutely critical
to the ability of propionibacteria to survive within follicles
and these may represent better targets for the treatment of
acne than virulence determinants. e use of nonirritating
solutessuchassugarsandpolyolsoersasaferalternative
to the antimicrobials currently available without running the
risk of selecting for antibiotic resistance and without the
undesirable eects of benzoyl peroxide. ere may also be
medicinal product regulatory advantages to this approach.
Even if water is not the growth limiting factor in vivo,itmay
BioMed Research International
still be possible in future to treat acne via niche disruption
once we understand more about P. a c n e s adaptation to its ill-
dened follicular habitat.
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, Article ID e, .
... For the nourishment of the skin, a moisturiser is formulated (Burlando and Cornara, 2013). It is used to increase skin functioning by treating skin dryness (Eady et al., 2013). Mostly the moisturisers are used according to the kind of skin and its conditions. ...
... Mostly 'emollients', 'humectants' and some other constituents are used to prepare moisturisers. Honey's humectant properties are responsible for acting as a moisturiser (Eady et al., 2013;Hadi et al., 2016). However, the required process is undetermined. ...
... The presence of 20% oxygen causes a doubling time of 17.25 h. [34] Therefore it is supposed that much lower concentrations of bark extracts could suppress growth in the natural habitat of follicles on the human skin. ...
Article
Full-text available
Bark is a major by-product of woodworking industries. The contents of several wood species are known to harbor antimicrobial, antiviral, anti-inflammatory and wound-healing capacities. The aim of this work was to identify beneficial properties of Austrian larch, birch and beech bark extracts for their potential usage as additives or active ingredients in dermatological applications. Bacterial agar diffusion assay and resazurin-based broth microdilution assay were used to evaluate anti-bacterial activity. To gain more insight into the cellular response to bark extracts, viability-, scratch-assays and ELISAs were performed. Birch and beech extracts showed strong antimicrobial activities against Gram-positive bacteria, including Cutibacterium acnes, Staphylococcus epidermidis and MRSA. Wound closure was enhanced with birch and beech extracts as compared to controls in the scratch-assays. Whereas beneficial properties of birch bark components have previously been described, the similar effects of beech extracts are novel. The combined positive effect on wound-healing and antimicrobial activity has great potential for the treatment of various skin diseases, including acne in future dermal applications.
... Sebaceous Gland and Acne[41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56]. ...
... Additionally, childhood acne is strongly correlated with the development of persistent acne later in life. [40,[41][42][43][44][45][46][47][48][49][50][51][52][53][54][55]  The sebaceous gland (SG) is integral to the structure and function of the skin, providing 90% of its surface lipids. ...
Preprint
Acne, also known as acne vulgaris (AV), is a long-term skin disease that occurs when hair follicles are clogged with dead skin cells and oil from the skin. It is characterized by blackheads or whiteheads, pimples, oily skin, and possible scarring. An intact stratum corneum and barrier, normal natural moisturizing factor and hyaluronic acid levels, normal Aquaporin-3 (AQP3) expression (localized at the basal lateral membranes of collecting duct cells in the kidney), and balanced sebum secretion are qualities of the skin that fall in the middle of the oily-dry spectrum. Patients rarely, if ever, complain about reduced sebum production, but elevated sebum production, yielding oily skin that can be a precursor to acne, is a common complaint. Several factors are known to influence sebum production. AV is mostly triggered by Propionibacterium acnes in adolescence, under the influence of normal circulating dehydroepiandrosterone (DHEA). It is a very common skin disorder which can present with inflammatory and non-inflammatory lesions chiefly on the face but can also occur on the upper arms, trunk, and back. Age, in particular, has a significant and well-known impact, as sebum levels are usually low in childhood, rise in the middle-to-late teen years, and remain stable into the seventh and eighth decades until endogenous androgen synthesis dwindles. Sebum, the oily secretion of the sebaceous glands containing wax esters, sterol esters, cholesterol, di-and triglycerides, and squalene, imparts an oily quality to the skin and is well known to play an important role in acne development. Acne can't be prevented or cured, but it can be treated effectively. The pimples and bumps heal slowly, and when one begins to go away, others seem to crop up. Depending on its severity, acne can cause emotional distress and scar the skin. Acne may cause scarring of the skin, but generally causes no long-term health problems. In self-body image, some parts of the body including face play an important role. Existence of even a minor lesion in this part may be unpleasant for the patient and seems large. This image can cause mental disorders including depression and anxiety, low self-esteem, and decrease in social relationships. However, high levels of anxiety and depression in patients with facial acne are not related to oxidative stress, according to a study published online in the Journal of Cosmetic Dermatology.
... In addition, honey has been shown to have involvement in cellular pathways that increase expression of tissue repair mediators and keratinocyte proliferation [106]. Honey has also been shown to have protective benefits in the treatment of acne, by reducing aqueous availability of water in the skin and thus preventing microbial growth [107]. While common commercial recommendations for hair loss prevention have revolved around the use of honey, research surrounding the ability of honey to promote hair growth remains relatively limited. ...
Article
Full-text available
Background: The impact that hair loss has on an individual's psychological wellness, and subsequent quality of life, is widespread and long lasting. The current standard treatments for hair loss include surgery and medications, ranging from over-the-counter treatments to corticosteroid injections and immunosuppressants. Unfortunately, these current treatments are either expensive, invasive, or have extremely negative side effects. Recently, the role of vitamins, minerals, and functional foods with their associated bioactive compounds, have gained increasing recognition as a potential means to address this issue. Some of these compounds have been shown to decrease the risk of specific forms of hair loss, particularly alopecia, a form of balding that results due from an autoimmune disorder. These include experimental studies using black raspberry extract and egg yolks as well as epidemiological studies using Mediterranean diets and various micronutrients. Other compounds have been shown to promote hair growth on a more general scale, including in vivo studies using rice bran extract and mouse models using red ginseng oil and annurca apple polyphenols. This review identifies key hair growth promoting vitamins, minerals, and functional foods, as well as summarizes the relevant mechanisms of action of these compounds that have been elucidated. Knowledge regarding the effects of these nutriceuticals on reducing hair loss is rapidly expanding. However, it is imperative that further research be done in order to delineate mechanisms of actions for all compounds related to managing and treating hair loss and subsequently integrate these dietary modifications into clinical treatment recommendations for hair loss.Keywords: Hair loss, alopecia, berry extract, mediterranean diet, rice bran, ginseng, annurca apple, thuja orientalis, marine supplement, honey, egg yolk, functional foods, bioactive compounds
... However, in case of biofilm formation by P. acnes in acne, these methods are not particularly relevant. The human skin, the natural environment of this bacterium, is a lipid-rich environment in which free water and nutrients are limited [37]. These conditions are mimicked in the artificial sebum model, unlike most other biofilm models used in current acne-related P. acnes research [38e41]. ...
Article
Aim: The aim of the present study was to develop a new model system to study Propionibacterium acnes biofilms. This model should be representative for the conditions encountered in the pilosebaceous unit. Methods and results: The new model, consists of an artificial sebum pellet supported by a silicone disc. Sebum pellets were inoculated with various P. acnes strains isolated from both normal and acneic skin. Growth and biofilm formation was verified by conventional plating at different time points, as well as by resazurin assays and fluorescence microscopy after LIVE/DEAD staining. The artificial sebum pellets were also used in assays to measure the production of certain virulence factors implicated in the pathogenesis of acne, including lipase, protease and the presence of CAMP factors. Conclusion: The artificial sebum model can sustain biofilm growth of P. acnes, as was determined by increasing CFU counts for up to 1 week after inoculation. Metabolic activity and biofilm formation were confirmed using resazurin staining and fluorescence microscopy respectively. The production of virulence factors in this model was demonstrated as well.
Article
This study reports the bioactive compound of black cumin honey and investigates the antibacterial activity against Propionibacterium acnes and Pseudomonas aeruginosa. HPLC and GC-MS methods were used to analyze the bioactive compounds of the black cumin honey. The formulated cream of black cumin honey was prepared in an oil-in-water type cream with various concentrations of 1%, 5%, 10%, 15%, 20%, and 30% (w/w). Antibacterial effects against Propionibacterium acnes and Pseudomonas aeruginosa were examined by the disc diffusion method. Physical stability of formulated cream included organoleptic, homogeneity, and pH measurement test. The result of GC-MS analysis of black cumin honey showed 25 compounds: organic fatty acids, saccharides, and amino acid. HPLC analysis of flavonoid content showed quercetin as the bioactive compound at a concentration of 0.223 mg/g. Disc diffusion analysis showed great inhibitory potential against P. acnes and P. aeruginosa in 30% concentration with d = 11.2 mm and 10.8 mm, respectively. It can be concluded that the formulated cream of black cumin honey showed a great potential application as antibacterial agents of P. acnes and P. aeruginosa.
Article
Objectives Acne vulgaris is a common inflammatory disorder of the pilosebaceous unit and Propionibacterium acnes biofilm-forming ability is believed to be a contributing factor to the disease development. In vivo models mimicking hair follicle environment are lacking. The aim of this study was to develop an in vivo Propionibacterium spp. biofilm model in Drosophila melanogaster (fruit fly). Methods We created a sterile line of D. melanogaster able to sustain Propionibacterium spp. biofilms in the gut. In order to mimic the lipid-rich, anaerobic environment of the hair follicle, fruit flies were maintained on lipid-rich diet. Propionibacterium spp. biofilms were visualized by immunofluorescence and scanning electron microscopy. We further tested if the biofilm-dispersal activity of DNase I can be demonstrated in the developed model. Results We have demonstrated the feasibility of our in vivo model for development and study of P. acnes, P. granulosum and P. avidum biofilms. The model is suitable to evaluate dispersal as well as other agents against P. acnes biofilm. Conclusions We report a novel in vivo model for studying Propionibacterium spp. biofilms. The model can be suitable for both mechanistic as well as interventional studies.
Article
Acne, also known as acne vulgaris (AV), is a long-term skin disease that occurs when hair follicles are clogged with dead skin cells and oil from the skin. It is characterized by blackheads or whiteheads, pimples, oily skin, and possible scarring. An intact stratum corneum and barrier, normal natural moisturizing factor and hyaluronic acid levels, normal Aquaporin-3 (AQP3) expression (localized at the basal lateral membranes of collecting duct cells in the kidney), and balanced sebum secretion are qualities of the skin that fall in the middle of the oily–dry spectrum. Patients rarely, if ever, complain about reduced sebum production, but elevated sebum production, yielding oily skin that can be a precursor to acne, is a common complaint. Several factors are known to influence sebum production. AV is mostly triggered by Propionibacterium acnes in adolescence, under the influence of normal circulating dehydroepiandrosterone (DHEA). It is a very common skin disorder which can present with inflammatory and noninflammatory lesions chiefly on the face but can also occur on the upper arms, trunk, and back. Age, in particular, has a significant and well-known impact, as sebum levels are usually low in childhood, rise in the middle-to-late teen years, and remain stable into the seventh and eighth decades until endogenous androgen synthesis dwindles. Sebum, the oily secretion of the sebaceous glands containing wax esters, sterol esters, cholesterol, di- and triglycerides, and squalene, imparts an oily quality to the skin and is well known to play an important role in acne development. Acne can’t be prevented or cured, but it can be treated effectively. The pimples and bumps heal slowly, and when one begins to go away, others seem to crop up. Depending on its severity, acne can cause emotional distress and scar the skin. Acne may cause scarring of the skin, but generally causes no long-term health problems. In self-body image, some parts of the body including face play an important role. Existence of even a minor lesion in this part may be unpleasant for the patient and seems large. This image can cause mental disorders including depression and anxiety, low self-esteem, and decrease in social relationships. However, high levels of anxiety and depression in patients with facial acne are not related to oxidative stress, according to a study published online in the Journal of Cosmetic Dermatology
Article
Full-text available
During the past decade scientists have made great strides in understanding the microbiome’s role in human health. Today, the microbiome has become key in scientific research, therapeutic development, medical treatment, and as a news feature in the media. Most studies have focused on the microbiome of our gut, but recently researchers have turned their attention to other microbiomes, including that of the skin. These studies of gut and skin microbiomes are yielding very informative results, new treatment strategies, and the development of new prebiotic and probiotic products for the treatment of many skin conditions.
Book
Acne vulgaris is an extraordinarily common, worldwide dis­ ease. Some see the disorder as merely cosmetic. Nonetheless, few skin diseases cause as much physical and psychological misery as this scourge of adolescence. Dermatologists of course have more than a passing familiar­ ity with acne vulgaris. Recognition is easy but there is still an extraordinary amount of controversy concerning causa­ tive factors and the best modes of treatment. Recent studies have brought forth some important findings about which practicing physicians know too little. This volume" ACNE: MORPHOGENESIS AND TREAT­ MENT" is a surprising book. What features make it so unique? This is the first complete account of the great diver­ sity of clinical manifestations. Moreover, gross morphology is coordinated with a thorough microscopic analysis of evolu­ tion of the disease. The material is presented in a readable and stimulating way. References are limited because they have been carefully selected. The authors emphasize that this richly illustrated work is intended for physicians who care for acne patients. Accord­ ingly, this is above all a practical treatise to assist doctors to diagnose and treat acne, and not only acne vulgaris but all the species of acne. This work is an overview of the entire acne problem with contributions from bacteriology, endocrinology, physiology, anatomy, immunology, cellular kinetics, and experimental acne. Above all it concludes with an optimistic presentation of therapeutic strategies which make it possible for the in­ formed physician to control the abominable effects of this distressing disorder.
Article
Cited By (since 1996):24, Export Date: 23 March 2014, Source: Scopus, Art. No.: 230
Article
Free glycerol would be expected from biochemical considerations to be an end product of lipolysis of sebum triglycerides. Glycerol was measured in skin surface washings of acne vulgaris patients, in acne vulgaris patients treated for at least 3 mo with oral tetracycline and in control subjects. Surface glycerol in untreated acne subjects was significantly less than that expected theoretically, whereas the amounts of such glycerol in treated acne patients and in control subjects closely approached the theoretically expected values. It is suggested that glycerol may be an in vivo substrate for Propionibacterium acnes.
Article
of Propionibacterium acnes and analysis of two CAMP factor knock-out mutants, Journal of Microbiological Methods (2010), doi: 10.1016/j.mimet.2010.09.008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Article
Acne vulgaris is a skin disorder of the sebaceous follicles that commonly occurs in adolescence and in young adulthood. The major pathogenic factors involved are hyperkeratinization, obstruction of sebaceous follicles resulting from abnormal keratinization of the infundibular epithelium, stimulation of sebaceous gland secretion by androgens, and microbial colonization of pilosebaceous units by Propionibacterium acnes, which promotes perifollicular inflammation. The clinical presentation of acne can range from a mild comedonal form to severe inflammatory cystic acne of the face, chest, and back. At the ultrastruc-tural level, follicular keratinocytes in comedones can be seen to possess increased numbers of desmosomes and tonofilaments, which result in ductal hypercornification. The increased activity of sebaceous glands elicited by androgen causes proliferation of P. acnes, an anaerobe present within the retained sebum in the pilosebaceous ducts. The organism possesses a ribosome-rich cytoplasm and a relatively thick cell wall, and produces several biologically active mediators that may contribute to inflammation, for instance, by promoting leukocyte migration and follicular rupture. In inflamed lesions, numerous neutrophils and macrophages infiltrate around hair follicles and sometimes phagocytose P. acnes. To examine the participation of neurogenic factors in the pathogenesis of acne, we quantitatively assessed the effects of neuropeptides on the morphology of sebaceous glands in vitro using electron microscopy. Substance P, which can be elicited by stress, promoted the development of cytoplasmic organelles in sebaceous cells, stimulated sebaceous germinative cells, and induced significant increases in the area of sebaceous glands. It also increased the size of individual sebaceous cells and the number of sebum vacuoles for each differentiated sebaceous cell, all of which suggests that substance P promotes both the proliferation and the differentiation of sebaceous glands. In this review, we introduce the general concept of pathogenic factors involved in acne, including typical electron microscopic findings and recent evidence of stress-induced exacerbation of acne from a neurological point of view. An improved understanding of the pathogenesis of acne should lead to a rational therapy to successfully treat this skin disease.
Article
Acne vulgaris is a common disease that carries an enormous financial and psychosocial impact. Androgens, excessive sebum production, ductal hypercornification, changes in the microbial flora, as well as inflammation and immunological host reactions are considered the major contributors to acne pathogenesis. Despite extensive research on acne pathogenesis, the exact sequence of events and their possible mechanisms leading to the development of a microcomedone and its transformation into an inflamed lesion has remained unclear. There is a significant amount of in vitro evidence suggesting a possible pathogenetic role for Propionibacterium acnes in comedogenesis as well as inflammation in inflammatory acne. However, the microbiological data from non-inflamed as well as inflamed acne lesions, cultured individually, do not entirely support the hypothesis that these micro-organisms are actually responsible for their initiation. There appears to be comedones and inflamed lesions in which there is no clear evidence of Propionibacterium acnes involvement. Considering this microbiological data, alongside the in vitro evidence, we have tried to delineate the possible sequence of events and their mechanisms, leading to the development of a microcomedone and its transformation into an inflamed lesion. Based on the available literature we have analysed the evidence of both non-inflamed as well as inflamed acne lesions occurring in the absence of Propionibacterium acnes from the pilosebaceous follicles. We propose that the development of an inflamed acne lesion depends on an imbalance between the pro-inflammatory and anti-inflammatory pathways rather than the incitement of inflammation by Propionibacterium acnes.
Article
Acne vulgaris is a disorder of the sebaceous follicles. Propionibacterium acnes can be involved in inflammatory acne. This case-control study aimed at investigating the occurrence and localization of P. acnes in facial biopsies in acne and to characterize the P. acnes phylotype in skin compartments. Specific monoclonal and polyclonal antibodies were applied to skin biopsies of 38 patients with acne and matching controls to localize and characterize P. acnes and to determine expression of co-haemolysin CAMP factor, a putative virulence determinant. Follicular P. acnes was demonstrated in 18 (47%) samples from patients with acne and eight (21%) control samples [odds ratio (OR) 3·37, 95% confidence interval (CI) 1·23-9·23; P = 0·017]. In 14 (37%) samples from patients with acne, P. acnes was visualized in large macrocolonies/biofilms in sebaceous follicles compared with only five (13%) control samples (OR 3·85, 95% CI 1·22-12·14; P = 0·021). Macrocolonies/biofilms consisting of mixed P. acnes phylotypes expressing CAMP1 were detected in both case and control samples. Only four samples tested positive for the presence of Staphylococcus spp. and fungi were not observed. We have for the first time visualized different P. acnes phylotypes in macrocolonies/biofilms in sebaceous follicles of skin biopsies. Our results support the hypothesis that P. acnes can play a role in the pathogenesis of acne as acne samples showed a higher prevalence of follicular P. acnes colonization, both in terms of follicles containing P. acnes and the greater numbers of bacteria in macrocolonies/biofilms than in control samples.
Article
The innate immune system must recognize and rapidly respond to microbial pathogens, providing a first line of host defense. This is accomplished through an array of pattern recognition receptors (PRRs) that reside in specific subcellular compartments and can bind pathogen-associated molecular patterns. PRRs also recognize self-molecules that are released after cell damage or death, known as danger-associated molecular patterns, which can be actively transported across cell membranes. The activation of PRRs leads to host defense pathways in infectious diseases, but can also contribute to tissue injury in autoimmune diseases. The identification of these pathways has provided new insight into mechanisms of vaccination and holds promise for developing better vaccines. Finally, the identification of PRRs, their ligands, and signaling pathways provides an opportunity for developing new immunotherapeutic approaches to skin conditions in which activation of the innate immune response contributes to disease pathogenesis.