| |

Received: 4 February 2019    Revised: 2 July 2019    Accepted: 27 July 2019

DOI: 10.1111/exd.14016

VIEWPOINT

Targeting the gut‐skin axis—Probiotics as new tools for skin

disorder management?

Magdolna Szántó1 | Anikó Dózsa2 | Dóra Antal1 | Kornélia Szabó3,4 | Lajos Kemény3,4 |

Péter Bai1,5

1
Department of Medical Chemistry, Faculty
of Medicine, University of Debrecen, Abstract
Debrecen, Hungary The existence of a gut‐skin axis is supported by increasing evidence, but its transla‐
2
Paediatric Dermatology, Borsod‐Abaúj‐
tional potential is not widely recognized. Studies linked inflammatory skin diseases
Zemplén County Hospital and University
Teaching Hospital, Miskolc, Hungary to an imbalanced gut microbiome; hence, the modulation of the gut microbiota to
3
Department of Dermatology and improve skin condition seems to be a feasible approach. Today, there is a growing
Allergology, University of Szeged, Szeged,
Hungary
interest in natural products as alternatives to synthetic drugs. In this respect, oral
4
MTA‐SZTE Dermatological Research Group, probiotics could be a simple, safe and cheap modality in the therapeutic management
Szeged, Hungary of skin inflammation. Unfortunately, very few studies have looked into how probiotic
5
MTA‐DE Lendület Laboratory of Cellular
supplementation influences inflammatory skin disorders. The result, though promis‐
Metabolism, Debrecen, Hungary
ing, are difficult to implement in clinical practice due to the heterogeneity of the
Correspondence
applied supplemental regimen in the different studies. In this Viewpoint, we aim to
Magdolna Szántó and Peter Bai, Department
of Medical Chemistry, Faculty of Medicine, encourage the conduction of more research in that direction to explore unambigu‐
University of Debrecen, Debrecen, Egyetem
ously the therapeutic potential of oral probiotics in dermatology. We focus on the
tér 1., Hungary.
Email: [email protected] (M. S.); most common inflammatory skin diseases (atopic dermatitis, psoriasis, rosacea, acne
[email protected] (P. B.)
vulgaris) with an associated  gut dysbiosis, but we also discuss some less common,
Funding information but very serious skin pathologies (eg erythema nodosum, pyoderma gangrenosum,
NKFIH, Grant/Award Number: K123975,
hidradenitis suppurativa) that are possibly linked to a disturbed gut flora composi‐
PD121138, GINOP‐2.3.2‐15‐2016‐00006,
GINOP‐2.3.2‐15‐2016‐00015 and tion. We dissect the possible mechanisms along the gut‐skin axis and highlight novel
EFOP_363_VEKOP_16201700009;
points where probiotics could interfere in this communication in the diseased state.
Momentum fellowship and the Taiwanese‐
Hungarian Bilateral program, Grant/Award
Number: PROJEKT2017‐44; Hungarian KEYWORDS
Academy of Sciences and a NKFIH Bridging atopic dermatitis, inflammatory skin diseases, pathogenesis, psoriasis
fund from the University of Debrecen;
János Bolyai Research Scholarship of the
Hungarian Academy of Sciences; UNKP‐18‐4
New National Excellence Program of the
Ministry of Human Capacities

1 |  I NTRO D U C TI O N The gut microbiome greatly influences the host immune system by
providing protection against exogenous pathogens and by priming
Research in the past decade highlighted the importance of the gut immunoprotective responses[60] Hence, an altered gut flora may
microbiota to our health. There is a delicate interaction between the contribute to the development of autoimmune and inflammatory
host and the microbiota, and the disruption of this balance can com‐ diseases, even in organs distant from the gut, such as the skin.[60]
[7]
promise the homeostasis and survival of the entire human organism Indeed, a growing body of evidence supports that intestinal dysbio‐
and can contribute to the development of severe pathologies[36] sis, a state of microbial imbalance, can almost invariably be observed

Experimental Dermatology. 2019;00:1–9. wileyonlinelibrary.com/journal/exd   © 2019 John Wiley & Sons A/S. |  1
Published by John Wiley & Sons Ltd
 |
2       SZÁNTÓ et al.

in common inflammatory skin pathologies, such as atopic dermatitis and the secretion of health‐stimulating hypothalamic hormones
[58,91] [51,112] [82] [16]
(AD) psoriasis rosacea and acne vulgaris. This reali‐ leading to improved epithelial integrity and immune toler‐
zation gave rise to the recognition of the gut‐skin axis. [62,86] Actually, ance. [63] Unfortunately, the study does not go into detail if the
this notion is not a new one. In 1930, the two dermatologists, John application of the probiotic modulated the composition of the
H. Stokes and Donald M. Pillsbury, proposed their groundbreaking gut microbiota. Nor do we know, whether the observed phe‐
theory about an interrelationship between emotional states, the notype can be generalized after probiotic consumption or it is
intestinal flora and systemic and skin inflammation,[108] which was specific for Lactobacillus reuteri intake. Nevertheless, it is easy
later unified as the gut‐brain[103] and the gut‐brain‐skin axis models[4] to realize that benefits gained upon probiotic supplementation
Most recently, similar crosstalk has also been postulated between in mice would be a desirable improvement in human skin health,
the gut microbiome and the lungs (gut‐lung axis)[23] or cancer cells with obvious implications in the therapy of inflammatory skin
(cancer‐gut axis).[75] conditions.
Although many reports associate the gut microbiota compo‐ Currently, the recommendation of oral probiotics as a treat‐
sition with human health and disease, the causative relationships ment or adjuvant strategy in skin disorders is not usual. Given
remain to be elucidated. There is a need for manipulation strate‐ that gut dysbiosis is commonly observed in skin pathologies, the
gies to clarify the involvement of the gut microbiome in diseases. crosstalk between gut and skin could offer targetable pathways
These strategies may be the use of orally administered antibiotics, with obvious therapeutic potential in dermatological practice.
prebiotics, probiotics and most recently faecal transplantation.[76] However, the molecular mechanism of the crosstalk is not well
Antibiotics are commonly involved in the management of cutane‐ understood. The gut is considered as a major immune organ, with
ous inflammation, but their use should be limited, due to the risk of the gut‐associated lymphoid tissue (GALT) being the most complex
developing resistance. Though the concept of using faecal trans‐ immune compartment. Parts of the GALT are Peyer's patches that
plantation for treating abdominal diseases dates back to mediaeval are organized lymphoid tissues known as the primary inductive
[45]
China faecal transplantation maturated into a medically ac‐ sites for the mucosal immune response.[3] It has long been demon‐
cepted approach only in the recent years as an effective treatment strated that dendritic cells of the Peyer's patches synthesize IL‐10
strategy in Clostridium difficile infection.[106] Though a promising and induce the differentiation of T helper cells.[55] Cytokines and
treatment modality in gastrointestinal disorders associated with primed immune cells from the Peyer's patches may be transported
a disturbed gut flora and skin symptoms, faecal transplantation via the circulation to the skin, where they could modulate the im‐
is unlikely to enter dermatology and cosmetology clinical practice mune status and improve defense mechanisms, providing a pos‐
rapidly. In terms of modulating the gut microbiome with potential sible link in the gut‐skin communication[9] Reports suggest that
beneficial effects on the skin, prebiotics represent an appealing probiotics trigger immunomodulation through the components
set of compounds. Prebiotics are dietary components fermented of the GALT, and the Peyer's patches may have special signifi‐
by gut microbes, and nutritional elements that support the growth cance.[44] Contributing to our understanding of probiotic action,
of bacteria. Among others, prebiotics involve fructooligosaccha‐ evidence has been presented that probiotics ameliorate intesti‐
rides, galactooligosaccharides, inulin, polydextrose, lactulose, sor‐ nal inflammation by local stimulation of the gut epithelial innate
[21]
bitol or xylitol. immune responses.[88] The presented mechanism of probiotics in‐
Probiotics by definition are ‘live microorganisms, which, volves the improvement of epithelial barrier function, increased
when consumed in adequate amounts, confer a health effect production of TNF‐alpha by epithelial cells and activation of the
on the host’. [41] Actual health effects have been reported for NF‐kappaB pathway.[88]
specific strains of the following genera: anaerobic microbes: Beyond immune modulation, one has to take into consideration
Lactobacillus, Bifidobacterium, Saccharomyces, Enterococcus, that when we are talking about the microbiota of the gut, we are
Streptococcus, Pediococcus, Leuconostoc, Escherichia coli; and the talking about probably trillions of microorganisms that obviously
aerobic Bacillus strains. [38] The bacterial probiotic genera demon‐ have huge metabolic capacity. The bioactive metabolites produced
strated to exert beneficial effects on skin health after oral appli‐ by bacteria upon interaction with dietary components are the most
cation are the Bifidobacterium and Lactobacillus (for an overview probable signalling links between the gut microbiota and the host.[28]
[97]
on the subject readers are referred to . In an interesting Faecal and serum metabolomics should be conducted from patients
paper  Levkovich et al, reports that feeding mice with yogurt with dermatological diseases to gain insight into the correlation of
containing the probiotic Lactobacillus reuteri induces a general intestinal bacterial metabolism and skin condition. These analyses
‘glow of health’ phenotype in the animals, which was character‐ could help to better understand probiotic action, and to better de‐
ized by epithelial follicular shift to anagen phase with increased sign probiotic application.
folliculogenesis and sebocytogenesis resulting in thick, radiant In this viewpoint essay, we dissect the possible mechanisms and
fur. The probiotic strain exerted these effects through the mod‐ pathways through which the gut and skin may communicate, and we
ulation of the immune system; the application of the probiotic try to shed light on the significance of these pathways in the path‐
increased the production of the anti‐inflammatory cytokine omechanisms of the most common inflammatory skin diseases, and
IL‐10 that induced peripheral regulatory T (Treg) lymphocytes how probiotics may intervene in the gut‐skin axis.
SZÁNTÓ et al. |
      3

Taken together, gut flora composition is probably key in the devel‐

1.1 | Atopic dermatitis
opment of the disease.
Atopic dermatitis (AD) or eczema is a chronic inflammatory skin dis‐ The gut flora produces a vast amount of metabolites, which
ease where the initial symptoms commonly occur in the first 5 years may enter the circulation, travelling throughout the body and af‐
of life, that affects about 20% of children in developed countries,[119] fecting distant sites of the organism. This process can reach high
and the prevalence of adulthood AD is estimated around 2%‐5% levels when the epithelial barrier integrity of the gut is disrupted,
across different countries[6] Skin of patients with AD exhibits a sig‐ leading to increased intestinal permeability, a condition called as
nificant barrier dysfunction, which is a result of a specific combi‐ the "leaky gut syndrome."[68] When a "leaky gut" develops, the
[22]
nation of genetic and environmental factors. A well‐established penetration of immunogenic molecules, including dietary antigens,
genetic determinant of skin barrier impairment is the deficiency of bacterial toxins and pathogens increases. These antigens may ac‐
the structural protein filaggrin.[22] Environmental factors, such as the cumulate in the skin, may disturb the epidermal barrier, leading
use of hygienic products, may further exacerbate epidermal barrier to chronic skin inflammation and continuous immune response.[68]
[22]
disruption. Application of soaps and detergents is very frequently For example, the bacterial metabolites, free phenol and para‐
associated with the appearance of irritant contact dermatitis on the cresol, are considered as biomarkers of an imbalanced gut flora,
hands, which can aggravate AD.[73] The negative effect of the use of since the production of these molecules is triggered by infection
soaps and detergents on skin is most possibly due to the consequent of the pathogen Clostridium difficile after antibiotic treatment.[24]
marked increase (3 U) of skin surface pH that can last for almost These metabolites can access the blood stream and accumulate in
[80]
two hours, and an elevated pH is detrimental on epidermal barrier the skin.[78] Data suggest that phenol and para‐cresol can disrupt
[34]
function. It is of note that AD‐affected patients have a higher skin epidermal barrier integrity by reducing the expression of keratin
surface pH than individuals with normal skin.[32] Whether the preva‐ 10 in keratinocytes.[78] It has been demonstrated that daily intake
lent cutaneous dysbiosis of AD patients is a cause or a consequence of the probiotic Bifidobacterium breve together with the prebiotic
of the elevation of skin pH is not yet clarified. It is interesting though galactooligosaccharide reduced serum total phenol levels and
that topical application of a probiotic strain, Lactobacillus johnsonii, improved skin hydration in healthy adult women.[78] Besides, a
for 3 weeks was shown to be effective in reducing Staphylococcus randomized double‐blind placebo‐controlled clinical study demon‐
aureus colonization and improving symptoms of AD patients,[13] and strated that oral supplementation with a probiotic Lactobacillus
metabolites of Lactobacilli may reduce skin surface pH. paracasei strain decreased skin sensitivity and increased barrier
In this context, we have to mention the so‐called ‘hygiene hy‐ function in the treated group,[49] pointing to the importance of oral
pothesis’, according to which there is an inverse relationship be‐ probiotics in skin health.
tween AD and an early exposure to microbial agents. Exposure to The gut microbiota and their metabolites can affect the intestinal
microbes starts at birth, when the mode of delivery greatly influ‐ barrier function.[79] Therefore, gut dysbiosis may disturb the intes‐
[29]
ences both the gut and skin microbiota of the newborn. Vaginally tinal barrier in a way that unwanted immunogens, such as bacterial
delivered infants harbour bacterial communities resembling their products, could escape the lumen and influence the state of the
mother's vaginal microbiota, with the dominant species being of the skin. We are aware that it is speculative to make direct association
genera Lactobacillus and Prevotella, while infants born by Caesarian‐ between gut dysbiosis, a "leaky gut" and AD. However, there is evi‐
section acquire microbial species characteristic of the mothers’ dence in the literature that intestinal permeability is increased in AD
skin surface, dominated by Staphylococcus, Corynebacterium and patients compared to control subjects.[69] We do not know whether
[29]
Propionibacterium spp. Caesarian‐section delivery has been asso‐ it is a consequence of a gut dysbiosis in patients, but there are some
ciated with an increased risk for immune disorders, such as asthma, suggestive data in the literature.
allergy and even inflammatory bowel disease.[102] Although there is The short‐chain fatty acids (SCFAs), such as butyrate, propi‐
no clear correlation between  Caesarian‐section and AD, it is very onate, acetate and lactate, are products of fibre fermentation by
likely that Lactobacilli of vaginal origin play a protective role in the in‐ the gut microbiota,[71] and SCFAs are known to promote epithelial
fant by priming the immature immune system against pathogens like barrier integrity of the gut and exert anti‐inflammatory effects.[71]
Staphylococcus aureus, which may have relevance in skin disorders. Intriguingly, intestinal dysbiosis has been demonstrated in AD pa‐
No wonder then that several studies point to the importance of tients by the analyses of their faecal samples, and a clear reduc‐
an early‐life, proper establishment of a diverse gut microbial com‐ tion of SCFAs has been detected.[93,107] Therefore, it is tempting
munity in the prevention of AD.[12,85,117] Numerous clinical trials to hypothesize that any agent, able to  influence gastrointestinal
support this hypothesis by demonstrating that very early‐life (pre‐ microbiota and the production of SCFAs, might be expected to af‐
and postnatal) probiotic supplementation  of the children could re‐ fect inflammatory responses, which may also affect skin condition.
duce the risk of developing AD[2,30,56,59,61,83,118] We presume that Butyrate is mainly produced by species belonging to the Firmicutes
Lactobacilli have pivotal role in protection against AD, since under phylum, such as Roseburia intestinalis, Faecalibacterium prausnitzii
natural circumstances, Lactobacilli are the major microbes trans‐ and Eubacterium hallii.[64] Propionate originates mainly from the pro‐
mitted from mother to baby, hence it seems logical to assume that duction by species of the Bacteroidetes phylum, involving Bacteroides
these are the bacteria that serve the baby's immune system the best. uniformis, Prevotella copri, and by Akkermansia muciniphila of the
4      | SZÁNTÓ et al.

Verrucomicrobia phylum.[64,75] With the use of probiotics, we may supported by the growing literature about the beneficial effects of
[91]
restore a  healthy gut flora and increase the ratio of SCFA‐secret‐ probiotics on AD, overviewed in . In order to better exploit pro‐
ing bacteria in the gastrointestinal tract in AD patients. Indeed, biotics in AD, better characterization of their gut microbiota com‐
according to a recent report, five doses of a cocktail containing 5 position and metabolome is necessary. Besides, carefully designed
Lactobacillus and 5 Enterococcus probiotic strains were successful clinical investigations are required, because the studies conducted
in significantly enhancing the microbial diversity and consequently so far with oral probiotics are highly heterogeneous. The enrolled
SCFAs production in the gut.[81] Furthermore, probiotics can also subjects, the probiotic strains used, the formulation of the probiot‐
promote epithelial barrier integrity by inducing mucus production ics, and the timing and duration of the probiotic intervention vary
[67]
and tight junction function.[101] between the studies. Therefore, comprehensive studies are needed
Among the bacterial metabolites in the colon, secondary bile to assess clinical applicability.
acids (such as litocholic acid and deoxycholic acid) may also have
impact on skin physiology.[77,95] The most important secondary bile
1.2 | Psoriasis
acid‐producing bacteria belong to the Bacteroidetes and Firmicutes
phyla.[95] It has been reported that a Firmicutes species, Clostridium Psoriasis is an immune‐mediated inflammatory skin disease, the
scindens, confers resistance against Clostridium difficile infection pathogenesis of which involves numerous environmental and internal
in a secondary bile acid‐dependent manner,[18] which affects skin factors.[89] Psoriatic lesions are characteristic of the hyperprolifera‐
function as it was discussed above. Besides, litocholic acid has been tion of keratinocytes with a consequent keratinocyte hyperplasia.[8]
reported to influence adaptive immune response by affecting the Ample data point to the critical role of the cytokine network of Th17
activation of Th1 cells.[90] In this fashion, replenishing bacteria capa‐ cells in the pathogenesis of the disease.[66,84] Psoriasis has been as‐
ble of the biosynthesis of secondary bile acids may contribute to the sociated with gut dysbiosis.[51] It is of note that SCFAs potentially
maintenance of skin homeostasis. Currently, we do not know bacte‐ regulate the generation and function of Th17 cells,[87] and the loss or
ria with probiotic characteristics that could do that, but these data depletion of Faecalibacterium prausnitzii, a major source of the pro‐
could be used to develop targeted probiotics to manipulate intestinal tective SCFAs in the gut, is associated with psoriasis,[35] suggesting a
bile acid metabolism. link between gut dysbiosis, SCFAs and Th17‐mediated inflammation
Diet may affect the development of AD across the gut‐skin axis. in the pathomechanism of the disease.
Dietary gluten can damage the intestinal barrier leading to a leaky The development of psoriasis often accompanies gastrointes‐
gut, even in individuals that do not suffer from coeliac disease.[115] It tinal inflammation, such as inflammatory bowel disease (IBD),[53]
[11]
is of note that both coeliac and non‐coeliac[14] gluten sensitivity the aetiology of which is closely associated with the dysbiosis of
have been associated with severe cutaneous manifestations resem‐ the gut.[50] Moreover, the reduction in bacterial diversity of the gut
bling AD. Of further importance, gluten sensitivity has been linked found in psoriatic patients strongly resembles the pattern of dysbi‐
to intestinal dysbiosis,[25] and certain probiotics have been found to osis observed in cases of IBD.[99] Besides, similarly to AD, psoriasis
[25]
be able to hydrolyze gluten polypeptides. Therefore, the use of has also been associated with low vitamin D levels, both in children
probiotics as an adjuvant therapy in gluten sensitivity‐associated AD and adults.[94]
seems to be an interesting approach. Taken together, these data suggest the significance of the gut‐
Another intriguing piece of the puzzle is the demonstration that skin axis in the pathophysiology of psoriasis and raises the relevance
low vitamin D level seems to correlate with the severity of AD.[5] of the application of oral probiotics in the management of the dis‐
It is of great significance that the gut microbiota may regulate sys‐ ease. To date, only three studies have looked into the effects of
[15]
temic vitamin D metabolism, and the vitamin D pathway might be orally administered probiotics on psoriasis, using three distinct pro‐
an important signalling mechanism between the microbiota and the biotic species affecting distinct pathways of the pathomechanism of
host.[65] Hence, we might assume that low vitamin D levels observed psoriasis.[19,48,116] All three studies have shown improvement in the
in these patients may be a consequence of a dysbiosis in their gut. course of the disease. However, as the available data are limited and
Interestingly, a study performed on cystic fibrosis patients suggests heterogeneous, it would be difficult to suggest a proper supplemen‐
that vitamin D deficiency of patients is associated with alterations tation protocol with probiotics in psoriasis‐affected patients.
in microbiota composition that may promote inflammation and that
supplementation with vitamin D has the potential to impact micro‐
1.3 | Rosacea
biota composition.[57] Moreover, growing body of evidence suggests
that probiotics can increase serum levels of vitamin D and expres‐ Rosacea is a chronic inflammatory skin disease characterized by ery‐
sion of vitamin D receptor, protecting against gastrointestinal in‐ thema and telangiectasia predominantly on the face.[17] An associa‐
flammation.[104] These data definitely warrant investigations on the tion between gastrointestinal microbial status and rosacea has been
effects of probiotics on vitamin D homeostasis in case of AD. postulated, in particular the role of Helicobacter pylori infection has
The multifaceted interactions between the gut microbiota and long been suggested in the pathogenesis of rosacea.[92] Like psoriasis,
AD skin clearly point out that modulation of the gut flora  may be rosacea was associated with IBD.[33] However, the pathogenic role of
utilized as adjuvant therapy in disease management. This is also intestinal dysbiosis in rosacea is a debated issue, and comprehensive
SZÁNTÓ et al. |
      5

studies are missing. A recent Korean metagenomic study observed a further investigation. However, it is reasonable to assume that the
link between intestinal microbial alterations and rosacea in a group two mechanisms act through a synergistic loop. Gut dysbiosis may
of 12 Korean women with rosacea[82] Besides, a case study reported induce IGF‐1 that may trigger a change in the quantity and/or quality
an effective treatment of one rosacea affected patient with a com‐ of the lipid‐rich sebum,[105] which may favour the colonization of the
[42]
bination of orally administered doxycycline and probiotics, which pilosebaceous unit by distinct C. acnes phylotypes,[46] disturbing the
might give us a hint about the potential of oral probiotics in rosacea tight equilibrium among members of the skin flora. This might be a
management. feasible mechanism for the possible interconnectedness of gut and
skin flora.
Other explanations for a possible causation of gut microbial im‐
1.4 | Acne vulgaris
balance and inflammatory acne involve the role of lipopolysaccha‐
Acne vulgaris is a disease of the pilosebaceous unit, manifesting in rides (LPS), as LPS biosynthesis pathways have been found to be
non‐inflammatory comedones or inflammatory pustules and pap‐ upregulated in acne patients, which may be a consequence of the
ules. The pathophysiology of acne is characterized by sebum over‐ increased abundance of the main LPS‐producing Bacteroidetes spe‐
secretion, follicular hyperkeratinization and increased production of cies in the intestine of the individuals.[26] In our point of view, these
[10]
pro‐inflammatory cytokines. Acne is quite commonly associated pathways (IGF‐1 and LPS pathways) are possibly not independent of
with microbial dysbiosis. each other. Even if there is still no direct evidence that gut dysbio‐
One of the most investigated subjects in acne studies is the role sis contributes to the pathogenesis of acne, the association seems
of a commensal cutaneous bacterium, Cutibacterium acnes (C. acnes, to be clear, and suggest the relevance of a probiotic‐based supple‐
reclassified from Propionibacterium acnes as proposed in [100] ) in the mental therapy in acne treatment. Supporting this theory, one study
pathogenesis of acne, which is still not fully elucidated. C. acnes is a demonstrated that the consumption of the probiotic Lactobacillus
predominant species of the skin microbiota and an important pro‐ rhamnosus SP1 for 12 weeks resulted in a decreased expression of
ducer of SCFAs on skin surface; hence, C. acnes is essential in the IGF‐1 in the skin, and in an improvement of acne symptoms.[37]
[20]
maintenance of skin homeostasis. Nevertheless, C. acnes can also
act as an opportunistic pathogen.[96] It was a long‐standing theory
1.5 | Other skin diseases
that an increased sebum and fatty acid production favours the pro‐
liferation of C. acnes in the hair follicles and associated sebaceous In addition to those common disorders detailed above, we would
glands, which induces the production of inflammatory mediators.[10] also like to draw the readers’ attention to some less common, though
However, the most recent findings on C. acnes suggest that it is not more serious skin pathologies, including hidradenitis suppurativa
the proliferation of the bacterium, rather the presence of certain C. (HS), erythema nodosum (EN) and pyoderma gangrenosum (PG).
[31]
acnes phylotypes that determines acne onset, as no quantitative These disorders are frequently associated with intestinal inflamma‐
difference of C. acnes abundance between acne patients and healthy tion, such as IBD.[40] Their aetiology is complex, and not fully clari‐
[31]
individuals has been found. Phylotype IA1 was the most strongly fied. So far, a correlation between these diseases and gut dysbiosis
associated with acne, while phylotypes IA2, IB and II were less rep‐ has not been made,however, the common association with IBD raises
[72]
resented in acne‐affected skin. the possibility of the involvement of a disturbed gut microbiome in
There is a long‐standing association between diet and acne. Since their pathogenesis. The beneficial effects of probiotics on IBD have
the prevalence of acne is noticeably higher in developed countries, been suggested,[1] but data of the effects of probiotics on the occur‐
it is believed that the high glycemic or Western‐type diet triggers rence of cutaneous manifestations in IBD patients is missing. The
[74,110]
acne formation. A high glycemic load drives the production only study evaluating the association between probiotic use and
of insulin and insulin‐like growth factor‐1 (IGF‐1) that promotes the skin lesions in IBD patients has been published very recently, and it
proliferation of sebocytes and keratinocytes, as well as inducing lipid demonstrates a negative correlation between the use of probiotics
synthesis in the sebaceous glands.[27] and the occurrence of skin lesions,[98] prompting the importance of
The gut microbiota has been shown to induce IGF‐1.[120] research to be made in this direction. In addition, it would be very
Hypothetically, we may assume that Western diet affects the gut intriguing to see the gut microbial status of HS‐, EN‐ or PG‐affected
flora in a way that may lead to the increased induction of the IGF‐1 patients without IBD.
pathway. Adding to the picture, a recent study demonstrated that in
the gut flora of acne patients the ratio of the phyla Bacteroidetes to
Firmicutes increased,[26] which is consistent with the enterotype of 2 | CO N C LU S I O N S
the Western diet.
Interestingly, C. acnes has been shown to stimulate the IGF‐1/ We outlined here a framework of how an imbalanced gut flora may
[54]
IGF‐1‐receptor system in the skin, suggesting a dual activation contribute to the development of inflammatory skin diseases, and we
of the IGF‐1/IGF‐1‐receptor pathway by the gut and skin microbi‐ propose a scheme of the benefits of probiotic intervention on these
ota, which may contribute to the pathophysiology of acne. Whether disorders (illustrated on Figure 1). We are aware that inflammatory
these mechanisms act independently or are interrelated needs skin conditions are all multifactorial diseases, the pathophysiology
 |
6       SZÁNTÓ et al.

An issue with probiotic supplementation is that the coloniza‐

tion of probiotic bacteria in the gut is mostly transient as they are
only detectable for less than 2 weeks after cessation of intake.[39,43]
Researchers tried to answer the question of what may determine
the successful colonization by a given species. It has been suggested
that it lies with the ability of the probiotic to adapt to the ecosys‐
tem of the gut, which is determined by intestinal phylogenetic
limiting and resource availability in the individual.[70] The study by
Maldonado‐Gómez et al demonstrated that a certain Bifidobacterium
longum (B. longum) strain was able to persist for over 6 months in a
subset of subjects in whom that was originally absent. Moreover,
the persistent B. longum bacteria enriched the faecal microbiome
with functional genes associated with B. longum.[70] This study pro‐
vides an important discovery which can be helpful in the prediction
of the outcome of supplementation with a specific bacterial strain,
which could be used in the personalized application of probiotics.
Additionally, it also needs clarification whether and how the ma‐
F I G U R E 1   A proposed scheme of the contribution of a dysbiotic nipulation of the gut microbiome affects the microbiome of the skin.
gut to the onset of cutaneous inflammation, highlighting the Given the delicate nature of the interaction between host and the
potential sites of action of probiotic intervention that may result in microbiome to maintain the homeostasis of the human organism,
the alleviation of the inflammatory condition
we presume that the different microbial communities (eg gut, skin,
oral, vaginal) should not be considered as separate, but rather as a
of which cannot be simplified solely to the disruption of the gut mi‐ complex, interacting ecosystem of the commensals inhabiting dis‐
crobiota. Nonetheless, a disturbance in the homeostasis of the gut tinct body regions. In the above‐described skin diseases, bacterial
flora may contribute to the development and symptoms of these pa‐ dysbiosis may not be restricted to the gut, but communities at dis‐
thologies. As a logical continuation to these, oral probiotics have an tant body sites could also be affected. Therefore, modulation of the
obvious translational potential in dermatology. Since adverse effects gut microbiota by the application of oral probiotics may impact upon
have not been recorded in relation with the application of oral probi‐ the skin microbiota, as well. In this regard, it is an intriguing issue
otics, we think that probiotic supplementation could be a cheap and whether this plausible interaction between the gut and skin micro‐
simple modality in the management of skin diseases. biota is uni‐ or bidirectional. Hypothetically, the synthesis of vitamin
For the sake of completeness of the concept of probiotic appli‐ D in the skin upon UV irradiation might be exploited as adjunctive
cation, we have to mention that the concept of probiotics has been in case of gastrointestinal inflammation, such as IBD, where vitamin
re‐examined since the now widely adopted definition by the WHO D deficiency occurs.[114] These are fascinating fields of microbial re‐
that we also cited in the introduction. In 2013, The International search yet to be explored.
Scientific Association for Probiotics and Prebiotics (ISAPP) orga‐ This line of research though has to face many challenges. For
nized a panel meeting to define clearer guidelines and standards for one, the skin flora is considered to be highly diverse and variable.[47]
using of probiotics, and for the determination of what products can There are topographical differences on different body sites that
[52]
be included in the scope of probiotics. The panel proposed a slight allow only a certain set of microbes to colonize certain skin regions.
modification of the original 2001 definition, that is, probiotics are More importantly, there are many individual‐specific factors, includ‐
‘live microorganisms that, when administered in adequate amounts, ing sex, age, occupation, clothing, the usage of hygienic products
confer a health benefit on the host’. It is important that this defini‐ that determine the variability seen in the cutaneous flora.[47,109] The
tion differentiates between commensal microorganisms and probi‐ aforementioned factors create an individual‐specific micro‐envi‐
otics. Although probiotics are usually derived from gut commensals, ronment on the skin that may require personalized solutions for the
until these strains are properly characterized and their health effects management of any skin conditions with oral probiotics.
are clearly demonstrated, they cannot be called 'probiotics'.[52] It is A major area in this subject, which surpasses the capacity of
important to adopt the criteria defining probiotics to avoid the mis‐ the current essay, is the translational potential of the use of topical
leading of consumers and researchers, resulting from the misuse of probiotics, oral and topical prebiotics or the combination of pre‐
the term in the absence of proved health effects. and probiotics, called synbiotics, for the manipulation of micro‐
There are many outstanding questions as for the mechanism of bial communities. The use of topical probiotics may have special
action of probiotics yet to be answered. Even though we outlined sev‐ subclinical significance, for example to improve skin defense with
eral pathways where probiotics could interfere with the gut‐skin axis probiotic‐containing cosmeceuticals. It has been reported that
modulating host immune and metabolic processes, further studies are B. longum strains exert pro‐differentiating and pro‐regenerating
required to uncover their exact mechanisms of action. effects on primary human epidermal keratinocytes.[111] However,
SZÁNTÓ et al. |
      7

topical applications of probiotics can create challenges, not only REFERENCES

because of the problem of proper formulation, but also the envi‐
[1] BP Abraham, E Quigley, Gastroenterol. Clin. North. Am. 2017, 46,
ronmental conditions of the skin that may prevent colonization by 769.
the probiotic.[113] It seems probable though that using the most [2] TR Abrahamsson, T Jakobsson, MF Böttcher, M Fredrikson, MC
suitable oral probiotic strain in combination with topical probiotics Jenmalm, B Björkstén, G Oldaeus, J. Allergy. Clin. Immunol. 2007,
and/or prebiotics might help in the individualized design of treat‐ 119, 1174.
[3] B Ahluwalia, MK Magnusson, L Öhman, Scand. J. Gastroenterol.
ment of skin disorders.
2017, 52, 1185.
To better exploit the potential within oral probiotics in derma‐ [4] P Arck, B Handjiski, E Hagen, M Pincus, C Bruenahl, J Bienenstock,
tology, clinical trials should be conducted in order to optimize the R Paus, Exp. Dermatol. 2010, 19, 401.
intervention protocols involving the determination of the optimal [5] JH Baek, YH Shin, IH Chung, HJ Kim, EG Yoo, JW Yoon, HM Jee,
YE Chang, MY Han, J. Pediatr. 2014, 165, 849.
formulation of the most effective probiotic strain or the combi‐
[6] S Barbarot, S Auziere, A Gadkari, G Girolomoni, L Puig, EL
nation of certain strains, the duration of the supplementation or Simpson, DJ Margolis, M de Bruin‐Weller, L Eckert, Allergy 2018,
treatment, and also the inclusion criteria of the subjects in the 73, 1284.
study. [7] KE Barrett, FK Ghishan, JL Merchant, HM Said, J Wood, Physiology
of the gastrointestinal tract, vol. 1‐2, Elsevier, Cambridge, MA
The described diseases are all common, affecting a substantial
2013.
proportion of the population of developed countries. Even though [8] Z Bata‐Csorgo, C Hammerberg, JJ Voorhees, KD Cooper, J. Clin.
their pathomechanisms are getting well characterized, effective and Invest. 1995, 95, 317.
well‐tolerated treatment modalities are currently lacking. Oral probi‐ [9] J Benyacoub, N Bosco, C Blanchard, A Demont, D Philippe, I
Castiel‐Higounenc, A Guéniche, Benef. Microbes. 2014, 5, 129.
otic supplementation is relatively cheap and if proven to be effective,
[10] K Bhate, HC Williams, Br. J. Dermatol. 2013, 168, 474.
it could serve as a useful, supportive therapy for the management [11] BK Bhatia, JW Millsop, M Debbaneh, J Koo, E Linos, W Liao, J. Am.
of microbiome‐associated cutaneous disorders. Our opinion is that Acad. Dermatol. 2014, 71, 350.
both gastroenterology and dermatology should better understand [12] H Bisgaard, N Li, K Bonnelykke, B Chawes, T Skov, G Paludan‐
Müller, J Stokholm, B Smith, KA Krogfelt, J. Allergy. Clin. Immunol.
the translational potential of the gut‐skin axis for the perks of a bet‐
2011, 128, 646.
ter therapeutic strategy. [13] S Blanchet‐Réthoré, V Bourdès, A Mercenier, CH Haddar, PO
Verhoeven, P Andres, Clin. Cosmet. Investig. Dermatol. 2017, 10,
249.
AC K N OW L E D G E M E N T S
[14] V Bonciolini, B Bianchi, E Del Bianco, A Verdelli, M Caproni,
Nutrients 2015, 7, 7798.
The authors are grateful to Dr Attila Szöllősi (Department of
[15] SA Bora, MJ Kennett, PB Smith, AD Patterson, MT Cantorna,
Immunology, University of Debrecen) for valuable pieces of ad‐ Front. Immunol. 2018, 9, 408.
vice on manuscript preparation. Our work was supported by grants [16] WP Bowe, AC Logan, Gut. Pathogens. 2011, 3, 1.
from NKFIH (K123975, PD121138, GINOP‐2.3.2‐15‐2016‐00006, [17] SA Buechner, Dermatology 2005, 210, 100.
[18] CG Buffie, V Bucci, RR Stein, PT McKenney, L Ling, A Gobourne,
GINOP‐2.3.2‐15‐2016‐00015, EFOP_363_VEKOP_16201700009),
D No, H Liu, M Kinnebrew, A Viale, E Littmann, M van den Brink,
the Momentum fellowship and the Taiwanese‐Hungarian Bilateral RR Jenq, Y Taur, C Sander, JR Cross, NC Toussaint, JB Xavier, EG
program (PROJEKT2017‐44) of the Hungarian Academy of Sciences Pamer, Nature 2015, 517, 205.
and a NKFIH Bridging fund from the University of Debrecen for MS. [19] YH Chen, CS Wu, YH Chao, CC Lin, HY Tsai, YR Li, YZ Chen, WH
MS and KS are recipients of the János Bolyai Research Scholarship Tsai, YK Chen, J. Food. Drug. Anal. 2017, 25, 559.
[20] GJ Christensen, H Brüggemann, Benef. Microbes. 2014, 5, 201.
of the Hungarian Academy of Sciences, and KS is also supported by
[21] S Collins, G Reid, Nutrients 2016, 8, 523.
the UNKP‐18‐4 New National Excellence Program of the Ministry of [22] MJ Cork, SG Danby, Y Vasilopoulos, J Hadgraft, ME Lane, M
Human Capacities. Moustafa, RH Guy, AL MacGowan, R Tazi‐Ahnini, SJ Ward, J.
Invest. Dermatol. 2009, 129, 1892.
[23] AT Dang, BJ Marsland, Mucosal. Immunol. 2019, 12(4), 843.
C O N FL I C T O F I N T E R E S T [24] LF Dawson, EH Donahue, ST Cartman, RH Barton, J Bundy, R
McNerney, NP Minton, BW Wren, BMC Microbiol. 2011, 11, 86.
The authors declare that they have no conflict of interest. [25] LF de Sousa Moraes, LM Grzeskowiak, TF de Sales Teixeira, M
Gouveia Peluzio, Clin. Microbiol. Rev. 2014, 27, 482.
[26] Y Deng, H Wang, J Zhou, Y Mou, G Wang, X Xiong, Acta. Derm.
AU T H O R C O N T R I B U T I O N S Venereol. 2018, 98, 783.
[27] D Deplewski, RL Rosenfeld, Endocr. Rev. 2000, 21, 363.
Wrote the manuscript: MS, AD, DA, KS, LK, PB. Designed and cre‐ [28] M Derrien, P Veiga, Trends Microbiol. 2017, 25, 100.
ated the figure: MS. All authors have read and approved the final [29] MG Dominguez‐Bello, EK Costello, M Contreras, M Magris, G
manuscript. Hidalgo, N Fierer, R Knight, Proc. Natl. Acad. Sci. U S A. 2010, 107,
11971.
[30] CK Dotterud, O Storro, R Johnsen, T Oien, Br. J. Dermatol. 2010,
ORCID 163, 616.
[31] B Dréno, S Pécastaings, S Corvec, S Veraldi, A Khammari, C
Péter Bai  https://orcid.org/0000-0002-6191-6616 Roques, J. Eur. Acad. Dermatol. Venereol. 2018, 32, 4.
 |
8       SZÁNTÓ et al.

[32] B Eberlein‐Konig, T Schafer, J Huss‐Marp, U Darsow, M [64] P Louis, HJ Flint, Environ. Microbiol. 2017, 19, 29.
Möhrenschlager, O Herbert, D Abeck, U Krämer, H Behrendt, J [65] NP Ly, A Litonjua, DR Gold, JC Celedón, J. Allergy. Clin. Immunol.
Ring, Acta. Derm. Venereol. 2000, 80, 188. 2011, 127, 1087.
[33] A Egeberg, LB Weinstock, EP Thyssen, GH Gislason, JP Thyssen, [66] HL Ma, S Liang, J Li, L Napierata, T Brown, S Benoit, M Senices, D
Br. J. Dermatol. 2017, 176, 100. Gill, K Dunussi‐Joannopoulos, M Collins, C Nickerson‐Nutter, LA
[34] PM Elias, J. Invest. Dermatol. 2004, 122, xxxvi. Fouser, DA Young, J. Clin. Invest. 2008, 118, 597.
[35] H Eppinga, C Weiland, HB Thio, CJ van der Woude, TE Nijsten, MP [67] DR Mack, S Ahrne, L Hyde, S Wei, MA Hollingsworth, Gut 2003,
Peppelenbosch, SR Konstantinov, J. Crohns. Colitis. 2016, 10, 1067. 52, 827.
[36] SE Erdman, T Poutahidis, Benef. Microbes. 2014, 5, 109. [68] M Maguire, G Maguire, Arch. Dermatol. Res. 2017, 309, 411.
[37] G Fabbrocini, M Bertona, Ó Picazo, H Pareja‐Galeano, G [69] H Majamaa, E Isolauri, J. Allergy. Clin. Immunol. 1996, 97, 985.
Monfrecola, E Emanuele, Benef. Microbes. 2016, 7, 625. [70] MX Maldonado‐Gómez, I Martínez, F Bottacini, A O’Callaghan, M
[38] S Fijan, Int. J. Environ. Res. Public. Health. 2014, 11, 4745. Ventura, D van Sinderen, B Hillmann, P Vangay, D Knights, RW
[39] O Firmesse, A Mogenet, JL Bresson, G Corthier, JP Furet, J. Mol. Hutkins, J Walter, Cell Host Microbe 2016, 20, 515.
Microbiol. Biotechnol. 2008, 14, 90. [71] KM Maslowski, AT Vieira, A Ng, J Kranich, F Sierro Di Yu, HC
[40] M Fleisher, J Marsal, SD Lee, LE Frado, A Parian, BI Korelitz, BG Schilter, MS Rolph, F Mackay, D Artis, RJ Xavier, MM Teixeira, CR
Feagan, Dig. Dis. Sci. 2018, 63, 825. Mackay, Nature 2009, 461, 1282.
[41] Food and Agriculture Organization of the United Nations/World [72] A McDowell, I Nagy, M Magyari, E Barnard, S Patrick, PLoS ONE
Health Organization (FAO/WHO). Evaluation of health and nu‐ 2013, 8, e70897.
tritional properties of powder milk and live lactic acid bacteria; [73] B Meding, G Swanbeck, Br. J. Dermatol. 1987, 116, 627.
(2001). http://www.fao.org/tempr​ef/docre​p/fao/meeti​ng/009/ [74] BC Melnik, Hautarzt 2013, 64, 252.
y6398e.pdf (accessed January 2019). [75] E Mikó, T Kovács, É Sebő, J Tóth, T Csonka, G Ujlaki, A Sipos, J
[42] MC Fortuna, V Garelli, G Pranteda, F Romaniello, M Cardone, M Szabó, G Méhes, P Bai, Cells 2019, 8, 293.
Carlesimo, A Rossi, Dermatol. Ther. 2016, 29, 249. [76] E Mikó, A Vida, P Bai, Cell Biol. Toxicol. 2016, 32, 153.
[43] SA Frese, RW Hutkins, J Walter, Adv. Microbiol. 2012, 2, 399. [77] E Mikó, A Vida, T Kovács, G Ujlaki, G Trencsényi, J Márton, Z Sári, P
[44] A Friedrich, M Paz, J Leoni, D González Maglio, Int. J. Mol. Sci. 2017, Kovács, A Boratkó, Z Hujber, T Csonka, P Antal‐Szalmás, M Watanabe,
18, 1067. I Gombos, B Csoka, B Kiss, L Vígh, J Szabó, G Méhes, A Sebestyén, JJ
[45] S Gaines, JC Alverdy, Crit. Care. Med. 2017, 45, 1106. Goedert, P Bai, Biochim. Biophys. Acta. Bioenerg. 2018, 1859, 958.
[46] EM Gribbon, WJ Cunliffe, KT Holland, J. Gen. Microbiol. 1993, 139, [78] K Miyazaki, N Masuoka, M Kano, R Lizuka, Benef. Microbes. 2014,
1745. 5, 121.
[47] EA Grice, JA Segre, Nat. Rev. Microbiol. 2011, 9, 244. [79] Q Mu, J Kirby, CM Reilly, XM Luo, Front. Immunol. 2017, 8, 598.
[48] D Groeger, L O'Mahony, EF Murphy, JF Bourke, TG Dinan, B Kiely, [80] H Mucke, KT Mohr, A Rummler, P Wutzler, Pharmazie 1993, 48,
F Shanahan, EM Quigley, Gut. Microbes 2013, 4, 325. 468.
[49] A Gueniche, D Philippe, P Bastien, G Reuteler, S Blum, I Castiel- [81] R Nagpal, S Wang, S Ahmadi, J Hayes, J Gagliano, S
Higounenc, L Breton, J Benyacoub, Benef Microbes. 2014, 5, 137. Subashchandrabose, DW Kitzman, T Becton, R Read, H Yadav, Sci.
[50] J Halfvarson, CJ Brislawn, R Lamendella, Y Vázquez‐Baeza, WA Rep. 2018, 8, 12649.
Walters, LM Bramer, M D'Amato, F Bonfiglio, D McDonald, A [82] JH Nam, Y Yun, HS Kim, HN Kim, HJ Jung, Y Chang, S Ryu, H Shin,
Gonzalez, EE McClure, MF Dunklebarger, R Knight, JK Jansson, HL Kim, WS Kim, Exp. Dermatol. 2018, 27, 37.
Nat. Microbiol. 2017, 2, 17004. [83] L Niers, R Martín, G Rijkers, F Sengers, H Timmerman, N van Uden,
[51] C Hidalgo‐Cantabrana, J Gómez, S Delgado, S Requena‐López, R H Smidt, J Kimpen, M Hoekstra, Allergy 2009, 64, 1349.
Queiro‐Silva, A Margolles, E Coto, B Sánchez, P Coto‐Segura, Br. J. [84] KE Nograles, LC Zaba, E Guttman‐Yassky, J Fuentes‐Duculan, M
Dermatol., 2019, https​://10.1111/bjd.17931​ Suárez‐Fariñas, I Cardinale, A Khatcherian, J Gonzalez, KC Pierson,
[52] C Hill, F Guarner, G Reid, GR Gibson, DJ Merenstein, B Pot, L TR White, C Pensabene, I Coats, I Novitskaya, MA Lowes, JG
Morelli, RB Canani, HJ Flint, S Salminen, PC Calder, ME Sanders, Krueger, Br. J. Dermatol. 2008, 159, 1092.
Nat. Rev. Gastroenterol. Hepatol. 2014, 11, 506. [85] L Nylund, M Nermes, E Isolauri, S Salminen, WM de Vos, R Satokari,
[53] BL Huang, S Chandra, DQ Shih, Front. Physiol. 2012, 3, 13. Allergy 2015, 70, 241.
[54] O Isard, AC Knol, MF Ariès, JM Nguyen, A Khammari, N Castex‐ [86] CA O’Neill, G Monteleone, JT McLaughlin, R Paus, BioEssays 2016,
Rizzi, B Dréno, J. Invest. Dermatol. 2011, 131, 59. 38, 1167.
[55] A Iwasaki, BL Kelsall, J. Exp. Med. 1999, 190, 229. [87] C Ohnmacht, JH Park, S Cording, JB Wing, K Atarashi, Y Obata,
[56] M Kalliomaki, S Salminen, H Arvilommi, P Kero, P Koskinen, E V Gaboriau‐Routhiau, R Marques, S Dulauroy, M Fedoseeva, M
Isolauri, Lancet 2001, 357, 1076. Busslinger, N Cerf‐Bensussan, IG Boneca, D Voehringer, K Hase,
[57] M Kanhere, J He, B Chassaing, TR Ziegler, JA Alvarez, EA Ivie, LI K Honda, S Sakaguchi, G Eberl, Science 2015, 349, 989.
Hao, J Hanfelt, AT Gewirtz, V Tangpricha, J. Clin. Endocrinol. Metab. [88] C Pagnini, R Saeed, G Bamias, KO Arseneau, TT Pizarro, F
2018, 103, 564. Cominelli, Proc. Natl. Acad. Sci. U S A 2010, 107, 454.
[58] BJ Kim, SY Lee, HB Kim, E Lee, SJ Hong, Allergy Asthma Immunol. [89] R Parisi, D Symmons, C Griffiths, DM Ashcroft, J. Invest. Dermatol.
Res. 2014, 6, 389. 2013, 133, 377.
[59] JY Kim, JH Kwon, SH Ahn, SI Lee, YS Han, YO Choi, SY Lee, KM [90] T Pols, T Puchner, HI Korkmaz, M Vos, MR Soeters, C de Vries,
Ahn, GE Ji, Pediatr. Allergy Immunol. 2010, 21, e386. PLoS ONE 2017, 12, e0176715.
[60] MM Kosiewicz, AL Zirnheld, P Alard, Front Microbiol. 2011, 2, 180. [91] IA Rather, VK Bajpai, S Kumar, J Lim, WK Paek, YH Park, Front.
[61] K Kukkonen, E Savilahti, T Haahtela, K Juntunen‐Backman, R Microbiol. 2016, 7, 507.
Korpela, T Poussa, T Tuure, M Kuitunen, J. Allergy Clin. Immunol. [92] A Rebora, F Drago, A Parodi, Dermatology 1995, 191, 6.
2007, 119, 192. [93] S Reddel, F Del Chierico, A Quagliariello, S Giancristoforo, P
[62] SY Lee, E Lee, YM Park, SJ Hong, Allergy Asthma Immunol Res. Vernocchi, A Russo, A Fiocchi, P Rossi, L Putignani, M El Hachem,
2018, 10, 354. Sci. Rep. 2019, 9, 4996.
[63] T Levkovich, T Poutahidis, C Smillie, BJ Varian, YM Ibrahim, JR [94] F Ricceri, L Pescitelli, L Tripo, F Prignano, J. Am. Acad. Dermato.
Lakritz, EJ Alm, SE Erdman, PLoS ONE 2013, 8, e53867. 2013, 68, 511.
SZÁNTÓ et al. |
      9

[95] JM Ridlon, DJ Kang, PB Hylemon, J. Lipid Res. 2006, 47, 241. [112] L Tan, S Zhao, W Zhu, L Wu, J Li, M Shen, L Lei, X Chen, C Peng,
[96] M Rosenthal, D Goldberg, A Aiello, E Larson, B Foxman, Infect. Exp. Dermatol. 2018, 27, 144.
Genet. Evol. 2011, 11, 839. [113] RF Tester, FH Al‐Ghazzewi, Inside Cosmeceuticals. 2012, 1, 5.
[97] MR Roudsari, R Karimi, S Sohrabvandi, AM Mortazavian, Crit. Rev. [114] M Torki, A Gholamrezaei, L Mirbagher, M Danesh, S Kheiri, MH
Food Sci. Nutr. 2013, 55, 1219. Emami, Dig. Dis. Sci. 2015, 60, 3085.
[98] R Satta, GM Pes, C Rocchi, MC Pes, MP Dore, J. Dermatol. Treat. [115] M Uhde, M Ajamian, G Caio, R De Giorgio, A Indart, PH Green, EC
2018, 19, 1. Verna, U Volta, A Alaedini, Gut 2016, 65, 1930.
[99] JU Scher, C Ubeda, A Artacho, M Attur, S Isaac, SM Reddy, S [116] M Vijayashankar, N Raghunath, Our Dermatol. 2012, 3, 326.
Marmon, A Neimann, S Brusca, T Patel, J Manasson, EG Pamer, DR [117] M Wang, C Karlsson, C Olsson, I Adlerberth, AE Wold, DP
Littman, SB Abramson, Arthritis Rheumatol. 2015, 67, 128. Strachan, PM Martricardi, N Åberg, MR Perkin, S Tripodi, AR
[100] CF Scholz, M Kilian, Int. J. Syst. Evol. Microbiol. 2016, 66, 4422. Coates, B Hesselmar, R Saalman, G Molin, S Ahrné, J. Allergy Clin.
[101] A Seth, F Yan, DB Polk, RK Rao, Am. J. Physiol. Gastrointest. Liver Immunol. 2008, 121, 129.
Physiol. 2008, 294, G1060. [118] K Wickens, PN Black, TV Stanley, E Mitchell, P Fitzharris, GW
[102] A Sevelsted, J Stokholm, K Bønnelykke, H Bisgaard, Pediatrics Tannock, G Purdie, J Crane, J. Allergy Clin. Immunol. 2008, 122,
2015, 135, e92. 788.
[103] F Shanahan, Semin. Gastrointest. Dis. 1999, 10, 8. [119] U Wollina, Clin. Cosmet. Invest. Dermatol. 2017, 10, 51.
[104] M Shang, J Sun, Curr. Med. Chem. 2017, 24, 876. [120] J Yan, JW Herzog, K Tsang, CA Brennan, MA Bower, WS Garrett,
[105] TM Smith, Z Cong, KL Gilliland, GA Clawson, DM Thiboutot, J. BR Sartor, AO Aliprantis, JF Charles, Proc. Natl. Acad. Sci. USA.
Invest. Dermatol. 2006, 126, 1226. 2016, 113, E7554.
[106] LP Smits, KE Bouter, WM de Vos, TJ Borody, M Nieuwdorp,
Gastroenterology 2013, 145, 946.
[107] H Song, Y Yoo, J Hwang, Y Na, HS Kim, J. Allergy Clin. Immunol.
How to cite this article: Szántó M, Dózsa A, Antal D, Szabó K,
2016, 137, 852.
Kemény L, Bai P. Targeting the gut‐skin axis—Probiotics as
[108] JH Stokes, DH Pillsbury, Arch. Dermatol. Syphilol. 1930, 22, 962.
[109] K Szabó, L Erdei, BS Bolla, G Tax, T Bíró, L Kemény, Br. J. Dermatol. new tools for skin disorder management? Exp Dermatol.
2017, 176, 344. 2019;00:1–9. https​://doi.org/10.1111/exd.14016​
[110] K Szabó, L Kemény, Hum. Immunol. 2011, 72, 766.
[111] AG Szöllősi, A Gueniche, O Jammayrac, J Szabó‐Papp, C Blanchard,
N Vasas, M Andrási, I Juhász, L Breton, T Bíró, Exp. Dermatol. 2017,
26, 92.