Acne vulgaris, probiotics and the gut-brain-skin axis - Back to the future?

Abstract

Over 70 years have passed since dermatologists John H. Stokes and Donald M. Pillsbury first proposed a gastrointestinal mechanism for the overlap between depression, anxiety and skin conditions such as acne. Stokes and Pillsbury hypothesized that emotional states might alter the normal intestinal microflora, increase intestinal permeability and contribute to systemic inflammation. Among the remedies advocated by Stokes and Pillsbury were Lactobacillus acidophilus cultures. Many aspects of this gut-brain-skin unifying theory have recently been validated. The ability of the gut microbiota and oral probiotics to influence systemic inflammation, oxidative stress, glycemic control, tissue lipid content and even mood itself, may have important implications in acne. The intestinal microflora may also provide a twist to the developing diet and acne research. Here we provide a historical perspective to the contemporary investigations and clinical implications of the gut-brain-skin connection in acne.

Full text

REVIE W Open Access
Acne vulgaris, probiotics and the gut-brain-skin
axis - back to the future?
Whitney P Bowe
1*
, Alan C Logan
2*
Abstract
Over 70 years have passed since dermatologists John H. Stokes and Donald M. Pillsbury first proposed a
gastrointestinal mechanism for the overlap between depression, anxiety and skin conditions such as acne. Stokes
and Pillsbury hypothesized that emotional states might alter the normal intestinal microflora, increase intestinal
permeability and contribute to systemic inflammation. Among the remedies advocated by Stokes and Pillsbury
were Lactobacillus acidophilus cultures. Many asp ects of this gut-brain-skin unifying theory have recently been
validated. The ability of the gut microbiota and oral probiotics to influence systemic inflammation, oxidative stress,
glycemic control, tissue lipid content and even mood itself, may have important implications in acne. The intestinal
microflora may also provide a twist to the developing diet and acne research. Here we provide a historical
perspective to the contemporary investigations and clinic al implications of the gut-brain-skin connection in acne.
Introduction
The co-morbidi ty of chronic skin conditions and mental
health disorders has long been recognized, and in recent
years specialty psychodermatology and neurodermatol-
ogygroupshaveemerged.Acnevulgarisisacommon
dermatological disor der frequently associated with
depression, anxiety and other psychological sequelae.
The menta l health impai rment scores among acne
patients are higher vs. a number of other chronic, non-
psychiatric medical conditions, including e pilepsy and
diabetes [1-7]. Along with the psychological fallout,
there have also been in dications that acne pa tients are
at a higher risk for gastrointestinal distress. For example,
one study involving over 13,000 adolescents showed that
those with acne were more likely to experience gastroin-
testinal symptoms such as constipation, halitosis, and
gastric reflux. In particular, abdominal bloating was 37%
more likely t o be associated with acne and other sebor-
rheic diseases [8].
The growing awareness that the functional integrity
and microbial residents of the intestinal tract may play a
mediating role in both skin inflammation and emotional
behavior has shed further light on yet another dimension
to the relationship between dermatology and mental
health. The notion that intestinal microflora, inflamma-
tory skin conditions such as acne, and psychological
symptoms such as depression, are all physiologically
intertwined is not a new one. Nor is the notion that
so-called beneficial bacteria can mediate both skin
inflammation and mental health a novel one - what has
changed is an acc umulation of evidence which provide
some early hints at physiological pathways and potential
the rapeutic avenues in acne vulgaris. Here we review the
70-year-old gut-brain-skin unifying theory, first postu-
lated by dermatologists John H. Stokes and Donald
M. Pillsbury in 1930 [9], and provide a historical perspec-
tive to the contemporary investigatio ns and clinical
implications of the gut-brain-skin connection in acne.
The Brain-Gut-Skin Theory
Drawing on several lines of experimental evidence and
clinical anecdotes, Stokes and Pillsbury provided a ‘theo-
retical and practical consideration of a gastrointestinal
mechanism’ for ways in which the skin is influenced by
emotional and nervous states. These authors connected
emotional states - depression, worry and anxiety - to
altered gastrointestinal tract function, changes that
cause alterations to the microbial flora, which they theo-
rized, in turn promotes local and systemic inflammation.
They provided, as they wrote, ‘ an important linkage of
* Correspondence: wpbowe@gmail.com; aclnd@cfs-fm.org
1
Department of Dermatology, State University of New York Downstate
Medical Center, Brooklyn, New York, 11203, USA
2
Integrative Care Centre of Toronto, 3600 Ellesmere Road, Unit 4, Toronto,
ON M1C 4Y8, Canada
Full list of author information is available at the end of the article
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© 2011 Bowe and Logan; licensee BioMed Central L td. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrest ricted use, distri bution, and
reproduction in any medium, provided the original work is properly cited.

emotion with cutaneous outbreaks of erythema, urticaria
and dermatitis by way of the physiology a nd bacteriol-
ogy of the gastrointestinal tract’ .Citingresearchshow-
ingthatasmanyas40%ofthosewithacnehave
hypochlorhydria, Stokes and Pillsbury hypothesized that
less than adequate stomach acid would set the stage for
migration of bacteria from the colon towards the distal
portions of the small intestine, as well as an alteration
of normal intestinal microflora. Furthermore, Stokes and
Pillsbury suggested that stress-induced alterations to
microbial flora could increase the likelihood of intestinal
permeability, which in turn sets the stage for systemic
and local skin inflammation. The remedies these authors
dis cussed as a means to cut off the stress- induced cycle
included the ‘direct introduction of acidophil organisms
in cultures such as those of Bacillus acidophilus’.They
also advocated for an acidophilus milk preparation and
cod liver oil, long before they would be referred to as
probiotics and a rich source of omega-3 fatty acids
respectively. Stokes and Pillsbury may well have been
aware that some physicians had previously reported
mental health benefits with the oral administration of
lactic acid bacilli tablets and Lactobacillus-fermented
drinks [10,11]. Several months before Stokes and Pills-
bury completed their theory on the ‘emotional linkage’
between the brain, gut and skin, another study had
reported low stool levels of L. acidophilus in 53 patients
with a variety of mental health disorders [12]. As w e
will discuss below, the theory constructed by these
authors was well before its time, and indeed much of it,
including the potential of probiotics, has subsequently
been proven correct in preliminary studies.
Contemporary Evidence
In recent years it has been confirmed that hypochlorhy-
dria is a significant risk factor for small intestinal bacter-
ial over growth (SIBO). Indeed SIBO is detected v ia
hydrogen breath testing in half of patients on long-term
proton pump inhib itor t reatment [13]. SIBO pres ents
itself on a wide continuum b etween being asymptomatic
and, at its extreme, a severe malabsorption syn drome.
For many, there may be very mild gastrointestinal symp-
toms, including bloating, diarrhea, abdo minal pain, and
constipation [14]. It is also reported to be prevalent in
functional syndromes such as fibromyalgia and chronic
fatigue syndrome [15]. S IBO can compromise proper
absorption of proteins, fats, carbohydrates, B vitamins,
and other micronutrients due to bacterial interference.
Excess bacteria can successfully compete for nutrients,
produce to xic metabol ites, and cause direct injury to
enterocytes in the small intestine [16]. Just as Stokes
and Pillsbury had supposed, SIBO has recently been
shown to be associated with increased intestinal pe rme-
ability, whereas antimicrobial treatment of S IBO helps
to restor e the normal intestinal barrier [17]. Experimen-
tal studies show that psychological stress stagnates nor-
mal small intestinal trans it time, encourages overgrowth
of bacteria, and compromises the intestinal barrier [18].
SIBO is strongly associated with depression and anxiety,
while eradication of SIBO improves emotional symp-
toms [19,20]. Althou gh the frequency o f SIBO in acne
vulgaris has not yet been investi gated, a recent report
indicates that SIBO is 10 times more prevalent in those
with acne rosacea vs. healthy controls. Correc tion of
SIBO leads to marked clinical improvement in patient s
with rosacea [21]. The oral administration of probiotics
has also proven beneficial in the reduction of SIBO [22].
Interestingly, the omega-3 fatty acid-rich cod liver o il
advocated by Stokes and Pillsbury may have been ahead
of its scientific time. Not only does an omega-3 deficient
diet increase SIBO [23], it has also been linked multiple
times to an increased risk of depressive symptoms [24].
A small series of case reports indicates value of omega-3
fatty acids in both the clinical grade of acne and global
aspects of well-being [25].
As for intestinal p ermeability in acne vulgaris, there
have been hints that the intestinal lining may be com-
promised. One older study used a blood serum comple-
ment fixation test and reported that acne patients were
more likely to show enhanced reactivity to bacterial
strains isolate d from stool. Approximately 66% of the 57
patients with acne showed positive reactivity to stool-
isola ted coliforms, this compared to no ne of the control
patients without active skin disease [26]. Furthermore, a
study involving 40 acne patients showed both the pre-
sence of, and high reactivity to, lipopolysaccharide (LPS)
endotoxins in the blood as measured by the stellate
fibrin crystal test. None of the ma tched healthy controls
reacted to the E. co li lipopolysaccharide endotoxin
(E. coli LPS), while 65% of the acne patients did have a
positive reaction [27]. The inference of these results i s
that circulating endotoxins derived from gut microbes i s
not an uncommon feature of acne vulgaris, and one
indicating that intestinal permeability is a potent ial issue
for a sizable group of acne patients. Since systemic
E. coli LPS itself can produce depression-like behavior
in animal s [28], and enhanced reactivity to E.coli LPS is
noted in irritable bowel patients with higher anxiety
levels [29], an updated investigation in acne seems
warranted.
At this point it is unknown if, as confidently suspected
by Sto kes and many of his contemporaries, constipatio n
is more prevalent in those with acne. They considered it
to be an ‘important factor’ [30] and even ‘the rule’ rather
than the exception [31]. O ne older study using a bis-
muth test bev erage and objective fluoroscopy did report
intestinal stagnation in 47% of a small group of acne
(n = 30) acne patients. They also reported constipation
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as a clinical complaint in 40% of acne patients [32].
Even if constipation we re more frequent, as the recent
population study involving 1 3,000 adolescents indicates
[8], it would be tempting to dismiss it as having no rele-
vance whatsoever to the pathogenesis of acne and/or
depression. Yet, an important study in 2005 should pro-
vide cause for further consideration; among 57 patients
with functional constipation, fecal concentrations of
Lactobacillus and Bifidobacterium were significantly
lower and intestinal permeability was significantly higher
compared to healthy adults without constipation. In
addition, there was an enhanced systemic immune
response, almost certainly due to larger molecules gain-
ing access across the intestinal barrier [33]. Separate
research has r ecently shown that chronic constipation
(in otherwise healthy adults without irritable bowel sy n-
drome) is associated with marked alterations to the
intestinal microflora [34]. Combined with new findings
indicating increased gut permeability in those with
depression [35], we must surely reframe the obvious
overlap between depre ssion and constipation [36], and
the more specific finding of longer whole gut transit
time positively correlated with depression [37].
Intestinal Microflora
The Stokes-Pillsbury theory was also predicated upon
changes not only to the residential location of microbes
within the intestinal tract, they suspected that a quanti-
tative alteration to the microrobial flora was also at play.
This suggestion has also been suppo rted by contempor-
ary investigations. Experimental and human studies have
shown that a variety of psychological and physiological
stressors - confinement, e xtremes of temperature,
crowding, acoustic, academic examination - can impair
normal intestinal microflora [38-40]. Most notable are
stress- induce d re ducti ons in Lactobacillus and Bifido-
bacteria species.
The potential of stress-induced ch anges to the gastro-
intestinal microflora among acne patients has sadly
received little attention. The first attempt to determine
if there were differences in the intestinal bacterial
microflora was a 1955 investigation that focused on the
presence or absence of potentially pathogenic bacteria in
10 acne patients vs. controls. Obviously there can be few
generalizations drawn from a study invo lving o nly
10 subjects with acne, and the author s simply concluded
that there appeared to be no major differences (vs. con-
trols) in a small selection of enteric bacteria genera
under culture technique [41] . However, we find it note-
worthy that Bacteroides sppweremorecommonlyiso-
lated from the acne patients, particularly since
elevations of Bacteroides have been noted in humans
under psychological stress [42]. Unfortunately this pilot
investigati on was restricted t o a small group of bacterial
genera and did not culture for potentially beneficial bac-
teria such as Lactobacilli and Bifidobacterium.Theonly
other investigations examining the intestinal microflora
in acne, to our knowledge, are within non-English lan-
guage journals. A R ussian investigation reported that
54% of acne patients have marked alterations to the
intestinal microflora [43], while a Chinese study invol-
ving patients with seborrheic dermatitis also noted dis-
ruptions of the normal gastrointestinal microflora [44].
With recent advances in molecular identification of
intestinal microbial inhabitants, we are hopeful that
investigators will take a ren ewed interest in potential
changes to the enteric microbial profile among acne
patients.
Probiotic Administration
As mentioned, Stokes and Pillsbury made numerous
references to the use of L. acidophilus and L. acidophi -
lus-fermented milk products as a t reatment modality in
the context of the brain-gut-skin inflammatory process.
Indeed, other physicians writing in the 1930s made
reference to the popularity of L. acidophilus cul tures
among the general public as an internal means to treat
acne [45]. However, despite the apparent appe al of wh at
would later be described as probiotics, t here was little
research to determine efficacy.Thefirstformalclinical
case report series on the pot ential value of Lactobacillus
probiotics was published in 1961. A physician from
Union Memorial Hospital in Baltimore, Robert H. Siver,
followed 300 patients who were administered a com-
mercially available probiotic (Laxtinex t ablets providing
amixtureofL. ac idophilus and L. bulgaricus). He used
a protocol of pr obiotic supplementation for 8 days fol-
lowed by two-week w ash out then re-introduction for
an additional eight days. The rationale for such a dosing
regimen is unclear. In any case, he reported that 80 per-
cent of those with acne had some degree of clinical
improvement, and that the intervention was most valu-
able in case s of in flammatory acne. Without a placebo
control, Dr Siver concluded merely that ‘interactions of
skin manife stations of acne vulgaris and of metabolic
processes of the intestinal tract are suggestive’ [46].
More recent investigations i nvolving the internal
application of probiotic supplements in acne are
restricted to non-English language journals. The first, an
Italian study involving 40 patients, added an oral supple-
ment of 250 mg freeze-dried L. acidophilus and B. bifi-
dum as an adjuvant to standard care in half the group.
In addition to better clinical outcomes among the
patients supplemented with probiotics, the researchers
reported better to lerance and compliance wit h antibio-
tics [47]. Additional research from Russia supports the
benefit of probiotics added to standard care, with a
reported acceleration in time to significant clinical
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improvement in those who had been administered pro-
biotics [43]. It is difficult to critically evalua te thes e for-
eign investigations, for now they should serve as simply
as a further indi cation that oral probiotics warrant thor-
ough investigati on in acne vulgaris. In the meantime, a
recent study involving 56 patients with acne showed
that the consumption of a La ctobacillus-fermented dairy
beverage improved clinical aspects of acne over
12 w eeks. Specifically, the probiotic drink consumption
led to significant reductions in total lesion count in
association with a marked reduction in sebum produc-
tion. Although the addition of lactoferrin (an anti-
inflammatory milk protein) to the probiotic drink did
provide greater efficacy in the reduction of inflammatory
lesions, the benefits of the probiotic drink alone lend
further support to the notion that probiotics have an
adjuvant role to play in acne therapy [48].
The theoretical value of oral probiotics as adjuvant
care in acne vulgaris seems sound. Recent studies have
shown that orally consumed pre and probiotics can
reduce systemic markers of inflammation and oxidative
stress [49-51]. Since the loc al burden of lipid peroxida-
tion in acne is high, such that it appears to place a great
demand up on blood-derived antioxid ants [52], the abil-
ity of oral probiotics to limit systemic oxidative stress
[53] may be an important therapeutic pathway. Oral
probiotics can regulate the release of inflammatory cyto-
kines within the skin [54], and a specific reduction in
interleukin-1 alpha (IL -1-a), noted under certain ex peri-
mental conditions [55], would c ertainly be of potential
benefit in acne. In line with observations of internal
antibiotic use, it is also true that oral encapsulated pro-
biotics have the potential to change the microbial com-
munity at sites f ar removed from the gastrointestinal
tract [56]. We will address the potential of pr obiotics to
mediate acne through the gut-brain connection shortly.
Topical Probiotics
While the intent of this r eview is to focus on the brain-
gut-skin connection , the ability of ingested probiotics to
alter distant microbial residents suggests t hat topical
probiotics are worthy of brief discussion. Once again,
the notion that topically applied probiotics may be help-
ful in acne vulgaris is not a new one. The first report
that ‘topical bacteriotherapy’ (via local Lactobacillus bul-
garicus application) may b e helpful in acne and sebor-
rhea was published in 1912 [57]. However, it was not
until 1999 that proper scientific t echnique was used to
evaluate some of the potential skin-specific benefits of
lactic acid bacterial application. Specifically, researchers
showed that the lactic acid bacteria Streptococcus ther-
mophilus, a species found in most yogurts, can increase
ceramide production when applied to the skin for
7 days as a cream [58] . This work, which has since been
replicated [59,60], is of relevance to acne, particularly
when considering t hat some of the ceramide sphingoli-
pids, most notably phytosphingosine (PS), provide both
antimicrobial activity a gainst Propionibacterium a cnes
(P. acnes) and direct anti-inf lammatory activity [61].
Sphingolipids have been noted to be low in acne [62],
and the seasonal loss of ceramides may be a driving
force behind much higher dermatological office visits
for acne during winter months [63]. Indeed, topical
application of 0.2% PS r educed papules and pustules by
89% in a recent 2-month pilot study [61]. Additional
studies hinting at the value of topical pro biot ics in acne
include recent reports that strains of Bifidobacterium
longum and Lactobacil lus paracasei can attenuate skin
inflammation mediated by substance P [64,65]. This is
ofrelevancebecausesubstancePmaybeaprimary
mediator of stress-induced amplification of inflamma-
tion and s ebum production in acne [66]. Two separate
reports have also indicated that various p robiotic lactic
acid bacteria can provide in vitro antimicrobial activity
against P. acnes [67,68]. The latter study also used a
clinical arm, the results sho wing that topical application
of an Enterococcus faecalis probiotic lotion for 8 weeks
reduced inflam matory lesions by over 50% vs. plac ebo
[68]. Certain substances secreted by bacterial strains,
such as antimicrobial peptides, have been shown to inhi-
bit growth of P. acnes. Streptococcus salivarius, a promi-
nent member of the oral microbiota of healthy humans,
has been shown to secrete a bacteriocin-like inhibitory
substance(BLIS-likesubstance) capable of inhibiting
P. acnes [69]. In addition to the antimicrobial activity,
S. sa livarius bacterial cells themselves inhibit a number
of inflammatory pathways, thus acting as immune mod-
ulators [70]. Final ly, the app lication of select bacteria to
theskinmayprovideaprotectiveshield,similartoa
physical barrier. This so-called bacterial interference,
through competitive inhibition of binding sites, i s
thought to prevent colonization by other, potentially
pathogenic, bacterial strains [71].
Internal Bacteriotherapy and The Gut-Brain-Skin Triangle
As mentioned, there had been older commentaries and
clinical anecdotes suggesting that orall y consumed lactic
acid bacteria might be of benefit in alleviating depressive
symptoms. It was also report ed that patients with men-
tal health disorders appeared to have very low levels of
L. acidophilus. In a series of case reports in 1924, one
Illinois physician reported value of oral L. acidophilus
for the treatment of both acne and mental health disor-
ders; in addition to L. acidophilus improving the com-
plexion, it was stated that ‘in certain patients it even
seemingly contributes to mental improvement’ [72]. It
wasalsoreportedthattheyeastSaccharomyces cerevi-
siae could improve both acne vulgaris a nd constipation
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when orally consumed [73], an interesting anecdote
when considering new research on the ability of this
organism to improve the integrity of a disturbed gut
barrier [74]. However, these early observations were
mostly explained as simply the ability of administered
lactic acid bacteria to improve bowel function and
reduce constipation. Too often clinicians in the early
part of the 20
th
century associated constipa tion with the
root of all acne and depression. These clinical ca se
reports were never advanced to proper scientific
investigations.
In the last decade, following t he publication of two
influential hypotheses papers [38,39], the potential phy-
siol ogical mech anisms by which mental health might be
influenced by intentional manipulation of the intestinal
flora have finally been explored. The oral administration
of probiotics via laboratory chow has been shown to
increase peripheral tryptophan levels as well as alter ser-
otoni n and dopam ine turnover in the frontal cortex and
limbic system [75]. Indeed, oral probiotics appear to
increase resiliency of nerve cells and reduce apoptosis
during conditions of experimental physiological stress
[76]. The addition of probiotic to laboratory chow
increases the tissue levels of omega-3 fatty acids neces-
sary for normal mood s tates [77], while in humans the
plasma levels of anti-inflammatory fatty acids increases
when co-administered with probiotics [78]. The pre-
sence in the gastrointestinal tract of non-pathogenic
bacteria such as Bifidobacteria appear to attenuate an
exaggerated stress response, and maintain levels of brain
derived neurotrophic factor (BDNF), a neuropeptide
known to be low in depressi on [79]. On the other hand,
even mild degrees of chronic gastrointestinal tract
inflammation can provoke anxiety and diminish BDNF
production in animals [80]. Recently it was reported
that in ad dition to systemic protection against lipid per-
oxidation, oral Bifidobacterium decreased brain monoa-
mine oxidase activity, thereby p otentially increasing
neurotransmitter levels between synapses [81]. In
experimental models of psychological stress, oral Bifido-
bacteria reduces systemic inflammatory cytokines and
normalizes brain levels of stress hormones in rats, while
intentionally manipulating the diet of animals such as to
double the fecal Lactobacillus counts, results in
decreased anxiety-like behavior [82,83].
The influence of probiotics as a means to attenuate
substance P relea se, both in the intestinal tract and the
skin [64,84] , cannot be overlooked as a relevant pathwa y
connecting the nervous system to the gut a nd the s kin.
Experimental alterations to the normal gut microbio ta
can increase substance P release in the nervous system
and promote behaviors reflective of anxiety [85]. Indeed,
even minute elevations in circulating substance P
can lead to anxiety, depression and aggression [86].
Conversely, those who respond to antidepressant phar-
macotherapy are known to have declines in serum sub-
stance P in conjunction with improved mood states
[87]. Thirty years have passed since it was discovered
that biologically active pepti des such as substanc e P not
only communicate within the gut, brain a nd skin, they
are also of commo n embryo nic or igin [ 88] . With e mer-
ging research showing that substance P increases sebum
production, surely this pathway warrants serious
investigation.
An additional mechanism whereby probiotics might
influence both mood and acne is via regulation of glyce-
mic control. In recent years it has become evident that
there may indeed be a connection between dietary com-
ponents, most notably low-fiber carbohydrates, and the
risk of acne [89]. For example, regional diets low in pro-
cessed foods and sugars (with an overall low glycemic
load) a re assoc iated with de creased acne risk. I nterven-
tion studies using similar low glycemic load meals have
reported improvements [90,91]. On the other hand,
even in healthy adults, epidemiological studies have
made associations between blood chemistry indicative of
insulin resistance and an elevated risk of dep ressive
symptoms [92,93]. This is of relevance because emerging
research shows that the gut microbiota contributes to
glucose to lerance [94], and that orally administered Bifi-
dobacterium lactis can improve fasting insulin levels and
glucose turnover rates, even in the presence of a high-
fat diet [95]. While much more research is necessary,
the m echanisms appear to involve the ability of bifido-
bacteria to prevent the efflux of lipopolysaccharide
(LPS) endotoxins into systemic circulation. Specifically,
the loss of bi fido bacteria by poor diet ary choices - high
fat, sugar - leads to incre ased intestinal permeability,
encroachment of LPS endot oxins through the intestinal
barrier, which i n turn leads to low-grade inflammation,
oxidative stress, insulin resist ance and sickness behavior
[96,97]. In humans, probiotic administration may dimin-
ish systemic a ccess of g ut-derived L PS endotoxins and
reduce reactivity to such endotoxins[98].Thisentire
picture takes on gre ater meaning when considering
recent international studies showing that acne is asso-
ciated with increased consumption of highly palatable,
sweet, fried, calorie-rich foods with low nutrient density
[99-101] - and that it is well documented that a period
of insulin resistance occurs during puberty [102], one
coinciding with the development of acne, depression
and/or anxiety. Therefore, it se ems reason able to ask, to
what degree might the gut microbiota influence these
processes and disease risk during pub erty? A summar y
of potential pathways of interaction between the brain-
gut-skin axis in acne is provided in figure 1.
We also find it noteworthy that of thr ee large popula-
tion studies linking dairy consumption (most notably
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milk) and acne, none made a positive correlation between
fermented dairy (e.g. yogurt) and acn e [103-105 ]. It has
been postulated that milk is associated with acne because
it contains growth hormones (both synthetic ally added
and naturally occurring) [106]. Acne is certainly driven
by insulin-like growth factor I (IGF-I) [107], and IGF-I
can be absorbed across colonic tissue [108]. Therefore, it
is interesting to note that probiotic bacteria ( Lactobacilli
in particular) utilize I GF-I during the fermentation pro-
cess when added to milk, with a resulta nt 4-fold lower
level of IGF-I in fermented vs. skim milk [109]. If, as we
suspect, ther e i s increased intestinal permeability in acne,
the intestinal absorptio n of IGF-I would likely be
enhanced in general, and more specifically, when milk
(rather than fermented dairy) is orally consumed. In sum,
researchers may need to look more closely at why fer-
mented milk/dairy has escaped association with acne,
while other forms of dairy have not.
Intervention Studies
The first formal investigation of the potential psycholo-
gical benefits of probiotic supplementation in humans
involved 132 otherwise healthy adults; those who had
more depressive sympotoms at baseline had significant
improvement in mood scores after taking a probio tic
Lactobacillus cas ei fermented beverage compa red to the
placebo group [110]. A separate placebo-controlled
study i nvolved 39 chronic fatigue syndrome patients
who were administered the same oral Lactobacillus casei
probiotic vs. placebo. At the conclusion of the 8-week
study, depression scores remained unchanged between
the g roups, however there were significant i mprove-
ments in anxiety as measured via the Beck Anxiety
Inventory vs. placebo [111].
Even more recently, French researchers evaluated a
Lactobacillus helveticus and Bifidobacterium longum
combination probiotic which was orally administered for
Figure 1 Potential Pathways of the Gut-Brain-Skin Axis in Acne Vulgaris: [1] Psychological distress alone or in combination with [2] high fat
diet, processed comfort foods devoid of fiber, cause alterations to [3] gut motility and microbiota profile [4]. Loss of normal microbial biofilm
(Bifidobacterium in particular) causes intestinal permeability and endotoxins gain systemic access [5]. Burden of inflammation and oxidative stress
is increased, substance P is elevated, insulin sensitivity is decreased due to endotoxemia [6]. In those genetically susceptible to acne vulgaris, this
cascade increases the likelihood of excess sebum production, exacerbations in acne and additional psychological distress. Both probiotics and
antimicrobials may play a role in cutting off this cycle at the gut level.
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one month in a placeb o-controlled study. Using a variety
of validated anxiety, stress, and depression scales,
researchers reported significant improvements i n day-to-
daydepression,anger,anxiety,aswellaslowerlevelsof
the stress hormone cortisol among otherwise healthy
adults taking a daily probiotic supplement vs. placebo. In
addition, an experimental arm of this study also con-
firmed that the prob iotic added to the chow of rats did
indeed decrease behaviors indica tive of a nxiety [11 2]. In
a study involving 44 patients with irritable bowel syn-
drome, the oral consumption of a prebiotic fiber (trans-
galactooligosaccharide) significantly reduced anxiety in
conjunction with the expected marked elevations in fecal
bifidobacteria levels [113]. Finally, research has also
shown that the administration of the soil-based organism
Mycobacterium vaccae can significantly improve quality
of life , d epression and anxiety (vs. control) in patients
receiving chemotherapy for lung cancer [114].
Surely the publication of these studies must allow us to
consider the possibility that the psychological impair-
ment in acne could be, at least to some degr ee, mediated
by endogenous factors that include the gut microbiota.
Over t he years some researchers and clinicians have sug-
gested the existence of an ‘acne personality’, one that pre-
dates the disease onset and subsequently increases the
likelihood of stress reactivity, anxiety and depression
associated with acne [115-119]. Sin ce most investigations
have looked at the post-acne psychol ogical impairments,
a largely justifiable view is that the risk of anxiety and
depression is strictly associated with a disease that p re-
sents itself so visibly in most cases. It is not our position
to infer that this view is incorrect; rather we contend that
endogenous factors may al so play a mediating role in the
elevated risk. We must ask why is it that despite marked
clinical success with topical and oral interventions, a
number of studies using validated measurements of
depression, m ood and quality of life, indicate that the
mental outlook remains unchanged [120-123] ? Indeed, in
one of the studies cited [120], mood scores declined
despite significant clinic al improvement with topical
interventions. In a systematic review examining depres-
sion and isotretinoin, only 1 out of 4 studies using vali-
dated depression instruments showed a statistically
significant reduction in depressive symptoms [124]. It
seems remarkable that an agent with such obvious clini-
calbenefitwouldonlyshowatrendtowardimproving
depressive symptoms and mental outlook.
Future Directions
It seems obvious that we can no longer offhandedly dis-
miss a p otential relationship between the GI microflora,
mental health and acne vulgaris. Just a few short years
ago, the suggestion that the gut microbiota might be a
significant factor in the development of obesity seemed
obscure. Yet, in the last 48 months, a growing body of
research is underscoring a ve ry significant rela tionship
between gut microflora, systemic low-grade inflamma-
tion, metabolism, blood lipids and fat storage [125,126].
At p resent, there are m any questions tha t require reso-
lution. Are the regional differences in acne, for now
linked to a high fiber, low glycemic load diet, in any way
connected to the relationship between such diets and
the intestinal microflora? Rates of acne have been docu-
mented to be extremely low in isolated hunter-gatherer
communities [127] - dietary and lifestyle habits in these
locations would almost cer tainly alter intestinal micr o-
flora directly via r oot fiber and also bring individuals
into greater contact with a variety of soil-based organ-
isms. We know that the ty pical Weste rn diet, high in
sugar and fat, devoid of fiber, the very one correlated
with risk of acne, is associated with lower levels of Lac-
tobacillus and Bifidobacterium [128-131]. The mechan-
ism(s) o f action of oral antibiotics in acne remains a
mystery - is it a systemic effect against P. acnes, an anti-
inflammatory influence, ability to lower sebum free fatty
acids, or via antioxi dant activities [132,133]? Could it be
duetotheinfluenceofantibioticsonthegutmicro-
biota, which in turn improves glycemic control and
decreases LPS endotoxin encroachment into the periph-
ery [134]? Is there a sizeable sub-population of acne
patients wherein i ntestinal permeability and SIBO are
playing a contributing role, connecting acne itself with a
pred etermi ned higher risk of depression and anxiety? In
other words, might the gut-brain-ski n triangle play even
a small role in the much higher rates of depression and
anxiety in acne? We suspect that it does. As we dis-
cussed, the gut microbiota influences systemic lipids and
tissue fatty acid profiles; therefore it is reasonable to ask
if it might influence overall sebum production and spe-
cific free fatty acids within sebum. It would be interest-
ing to determine if oral rifaximin, an antibiotic which
has no systemic antimicrobial activity, is effective in
acne vulgaris, mood and quality of life.
Moving forward we must attempt to answer these and
many other plausible questions. Acne vulgaris is a com-
plexdiseasewithoutasingleavenueofpathogenesis,
therefore scientists and clinicians must remain open-
minded to unexpected therapeutic pathways. To date,
Stokes, Pillsbury and other dermatology elders have
been valida ted in many aspects. However, we cann ot
rely on anecdotes, i nferences and uncontrolled observa-
tions; we must approach this hypothetical la ndscape, the
gut-brain-skin triangle, with scientific vigor.
Conclusion
The scientist and philosopher Goethe is quoted as say-
ing ‘everything has bee n th ought of before, but the diffi-
culty is to think of it again’. Based on our review of the
Bowe and Logan Gut Pathogens 2011, 3:1
http://www.gutpathogens.com/content/3/1/1
Page 7 of 11

original hypotheses of Stokes, Pillsbury and their peers,
it seems much of the recent scientific endeavors in the
area of the gut-brain-skin axis, in the broad sense, have
been thought of before. The difference, of course, is the
degree of scientific sophistication with which we can
now see an undeniable l ink betwee n these major organ
systems. The lines of communication, as m ediated by
gut microbes, may be direct and indirect - ultimately
influencing the degre e of acn e by a systemic effect on
inflammation, oxidative stress, glycemic control, tissue
lipid levels, pathogenic bacteria, as well as levels of neu-
ropeptides and mood-regulating neurotransmitters. It
was not the contention of Stokes and Pillsbury, nor is it
ours, that acne is a disease of the gastrointestina l tract.
Yet, there appears to be more than enough supportive
evidence to suggest that gut microbes, and the integrity
of the gastrointestinal tract itself, are contributin g fac-
tors in the acne process. Only well designed trials
can determine what, if any, the degree of contribution
might be.
Author details
1
Department of Dermatology, State University of New York Downstate
Medical Center, Brooklyn, New York, 11203, USA.
2
Integrative Care Centre of
Toronto, 3600 Ellesmere Road, Unit 4, Toronto, ON M1C 4Y8, Canada.
Authors’ contributions
WPB and ACL contributed equal time and effort in the investigation,
research and drafting of this manuscript. All authors read and approved the
final manuscript.
Competing interests
The authors declare that they have no competing interests.
Received: 27 December 2010 Accepted: 31 January 2011
Published: 31 January 2011
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doi:10.1186/1757-4749-3-1
Cite this article as: Bowe and Logan: Acne vulgaris, probiotics and the
gut-brain-skin axis - back to the future? Gut Pathogens 2011 3:1.
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