Role of Nutribiotics in Skin Care

Abstract

The study of the human microbiome has been a hot topic during the last decades and more recently the skin microbiome has aroused great interest as well. So that, scientists have turned their attention to the role of the skin microbiome in skin health, and its relationship with different disorders as atopic dermatitis, psoriasis, acne, and rosacea, among others. Numerous studies and investigations have been performed to study the role of pre and probiotics as nutraceuticals in the treatment of skin diseases, with growing evidence along the last ten years. This review gathers information on the use of “nutribiotics” in skin care health, focus on the main dermatological diseases and other skin conditions. Clinical studies show that nutribiotics could be a new tool to improve skin health and pre, pro, syn, post and para-probiotics seem to be beneficial on several skin disorders, as well as repairing the skin barrier, or promoting wound healing. In conclusion, skin microbiome has emerged as a new field with high potential to develop disruptive solutions to manage skin health and disease. Future advances in this field may facilitate the treatment of skin dysbiosis being nutribiotics a suitable method for skin care.

Full text

Review Not peer-reviewed version
Role of Nutribiotics in Skin Care
M. Lourdes Mourelle * , Carmen P. Gómez , José L. Legido , Leonel Pereira
Posted Date: 8 April 2024
doi: 10.20944/preprints202404.0551.v1
Keywords: Nutraceuticals; prebiotics; probiotics; postbiotics; skin microbiome; skin disorders.
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Review
Role of Nutribiotics in Skin Care
M. Lourdes Mourelle 1,*, Carmen P. Gómez 2, José L. Legido and Leonel Pereira 2,3
1 FA2 Research group; Department of Applied Physics, University of Vigo; Spain; carmengomez@uvigo.es;
xllegido@uvigo.es
2 Department of Life Sciences; University of Coimbra; Portugal; leonelpereira@uc.pt
3 Marine Resources; Conservation and Technology-Marine Algae Lab; CFE-Center for Functional Ecology:
Science for People & Planet, Coimbra, Portugal
* Correspondence: lmourelle@uvigo.es; FA2 Research group; Department of Applied Physics, Faculty of
Sciences; University of Vigo; Campus Lagoas-Marcosende s/n; 36310 Vigo (Spain)
Featured Application: This review deals with the use of nutribiotics in skin care, which of the
great interest as nutritional supplement therapy in skin dysbiosis and related diseases.
Abstract: The study of the human microbiome has been a hot topic during the last decades and more
recently the skin microbiome has aroused great interest as well. So, the scientific community has
become interested in the role of the skin microbiome in skin health, and its relationship with
different disorders such as atopic dermatitis, psoriasis, acne, and rosacea, among others. Numerous
studies and investigations have been performed to study the role of pre and probiotics as
nutraceuticals in the treatment of skin diseases, with growing evidence over the last ten years. This
review gathers information on the use of “nutribiotics” in skin care health, focusing on the main
dermatological diseases and other skin conditions. Clinical studies show that nutribiotics could be
a new tool to improve skin health and pre, pro, syn, post, and para-probiotics seem to be beneficial
for several skin disorders, as well as repairing the skin barrier, or promoting wound healing. In
conclusion, skin microbiome has turned up as a new field with great potential to develop innovative
products to manage skin health and diseases. Future advances in this field may facilitate the
treatment of skin dysbiosis being nutribiotics a suitable method for skin care.
Keywords: Nutraceuticals; prebiotics; probiotics; postbiotics; skin microbiome; skin disorders
GRAPHYCAL ABSTRACT
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© 2024 by the author(s). Distributed under a Creative Commons CC BY license.

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1. Introduction
The study of the human microbiome, which began in the last century, has sparked growing
interest given its complexity and its importance in human health.
The main milestone has been the Human Microbiome Project, of the National Institute of Health
in the United States (Human Microbiome Project, NIH), with the aim of identifying and
characterizing the microorganisms that settle in the different structures of the human body and that
can play a role and therefore influence both health and disease. From that moment on, numerous
scientific publications and studies link the imbalance of the microbiome with different diseases.
A recent review related to the role of the human microbiome in health and disease in the United
Kingdom concluded that the human microbiome plays a fundamental role in health and disease with
multiple facets [1]. Various studies have shown that the intricate and complex communities of
microorganisms that live inside and on the surface of our body have important and marked effects
on several aspects of human physiology, from metabolism or digestive processes to immune function.
Furthermore, researchers demonstrated that a balanced and diverse microbiome can contribute to
global well-being by protecting against pathogens, assisting in nutrient absorption, and modulating
immune responses. In contrast, dysbiosis, that is, alterations or imbalances in the microbiome, has
been linked to a wide variety of health conditions, including inflammatory bowel disease, obesity,
allergies, and neurological disorders, among others [2]. One of the objectives of current research is to
deepen our knowledge of the intricate relationships between the microbiome and human health, in
order to develop ways to use the microbiome for therapeutic purposes [1].
The term “human microbiota” has been described as the group of symbiotic microorganisms
that co-occur with the human organism in balance and without causing damage. The term
“microbiome” refers to the entire microbiota habitat, including microorganisms, their genomes, and
the surrounding environment. Likewise, the aim of the use of prebiotics and probiotics in nutritional
therapy is to alleviate these imbalances in the microbiota and, in parallel, an important industry
linked to these nutritional supplements, also called “nutraceuticals”, has emerged.
The role of probiotics in regulating intestinal health has been widely studied in the last decades
[3]. Besides that, the concept of prebiotics has been developed, and, later on, the concept of synbiotics,
postbiotics and paraprobiotics [4-9], in the form of nutraceuticals in the form of oral supplement and
for topical application with the aim of repairing or balancing the microbiota. All these concepts are
summarized in Figure 1.
Figure 1. Concept of prebiotics, probiotics, synbiotics, para-probiotics and postbiotics (adapted from
Mourelle et al., 2023) [10].
Since the Russian scientist Elie Metchnikoff (1845-1916) coined the concept of probiotic in 1907
[11], numerous studies followed and, finally, a consensus definition was proposed by the
International Scientific Association of Probiotics and Prebiotics (ISAPP) in 2014, 2017, and 2021,
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which includes prebiotics, probiotics and postbiotics definitions. Probiotics have been defined as
“live microorganisms that, when administered in adequate amounts, confer a health benefit on the
host” [4]. Prebiotics have been defined as “a substrate that is selectively utilized by host
microorganisms conferring a health benefit” [5]. Postbiotics were defined as follows: “preparation of
inanimate microorganisms and/or their components that confers a health benefit on the host” [8].
Later on, the concept of synbiotics emerged, being defined as the combination of both prebiotics and
probiotics [8].
The current definition of probiotics does not include inactivated or dead cells, therefore more
recently emerges the concept of postbiotic, referring to the use of dead or inactivated cells (non-viable
microorganisms), cell extracts, or metabolites of these microorganisms that can provide favorable
effects on human health, observing that the action of probiotics depends fundamentally on their
metabolites, rather than on living organisms [12-13]. Later on, emerged the concept of para-probiotics
consisting of inactivated, dead, or non-viable microbial cells of intact or broken probiotics containing
cellular components of probiotic cells after lysis [14]; so that, in the last ten years, several studies have
been conducted using inactivated or heat-killed probiotics [15], but the terms ‘postbiotics’, ‘para-
probiotics’, and ‘inactivated probiotics’ have been used indistinctively in multiple research studies
[16-20]. Postbiotics include the metabolites generated by the microbiota, such as exopolysaccharides,
Short Chain Faty Acids (SCFAs), cell wall fragments, enzymes/proteins, and other metabolites [21];
but also as structural, such as teichoic acids, peptides, and plasmalogens, or based on their basic
composition (proteins, carbohydrates, lipids, vitamins, etc.) [22]. In this context, several postbiotics
have been shown to improve gut health by reinforcing the gut barrier, reducing inflammation, and
promoting antimicrobial activity against gut pathogens [23].
According to the most recurrent definition, para-probiotics, also known as non-viable probiotics,
inactivated probiotics, tyndallized probiotics, or ghost probiotics, are “non-viable microbial cells
(either intact or broken), or crude cell extracts, which, when administered (orally or topically) in
adequate amounts, confer a benefit on the human or animal consumer” [7,24]. A recent review by
Mehta et al. [25] focused on the ability of different types of para-probiotics and postbiotics to
modulate the immune system. The most used strains to develop as para-probiotics are Lactobacillus
and Bifidobacterium strains. The postbiotic components that modulate the biological reactions include
lipoteichoic acids, bacteriocins, SCFAs, peptidoglycan, and exopolysaccharides [25]. Some studies
showed that prescribing live probiotic cells to people with weakened immune systems increases
inflammatory responses. In such cases, a combination of dead cells can be a good alternative. Thus,
the use of killed or inactive probiotics created a new field and various scientists tried to come up with
new terms to describe the mentioned cases [26]. Additionally, Lee et al. [9] described the techniques
to obtain para-probiotics, which include thermal treatments, sonication, ionizing radiation, high
pressure, ultraviolet rays, and pH modification.
In terms of efficacy, Cuevas-González et al. [6] revised the bioactivities, health-promoting effects,
and applications, among other issues related to post and para-probiotics, referring that, in vitro and
in vivo studies have shown that some postbiotics and para-probiotics exhibit bioactivities such as
immunomodulatory, anti-proliferative, anti-inflammatory, antimicrobial, and antioxidant. The
authors postulated that these bioactivities could be involved in the observed health-improving
effects, both in clinical trials and in humans, but more investigation is needed, as the mechanisms of
action and the signaling pathways involved have not been fully elucidated. They concluded that
para-probiotics and postbiotics are of great interest for the development of nutraceutical products,
due to their potential for improving health [6].
In the last decade, several studies evaluated the potential uses of pre, pre, syn, post, and para-
probiotics mainly focusing on inflammatory bowel diseases [27], other inflammatory diseases, and
even in brain dysfunction, oral cavity dysbiosis, and a few of them related to skin diseases
[14,9,23,28]. There are also studies in pregnancy, showing that reduced microbiome diversity
(dysbiosis) during pregnancy, cesarean delivery, prematurity, and formula feeding can bring on
dysbiosis in the newborn; so, microbiota therapy may be a path to restore eubiosis in pregnant
women and their babies [29]. Besides, the use of probiotics in the course of antibiotic therapy does
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not have enough evidence. Éliás et al. [30] conducted a systematic review and meta-analysis of
randomized controlled trials that evidenced differences in gut microbiome diversity between patients
receiving antibiotic therapy with and without concomitant probiotic supplementation, showing that
the results of available randomized controlled trials cannot endorse supplementation with probiotics
along antibiotic therapy to avoid decreasing microbiome diversity [30]. On the other hand, other
studies showed that probiotics can be used to change the microbiome, but an individual approach
should be needed. Patil & Singh [31] suggested that by studying and harnessing individualized
microbiota, personalized probiotic therapies could help improve the microbial environment, and aid
in improving overall health. But more studies and partnerships between different fields are needed
[31].
On the other hand, there is a great field of interest in the use of micro-biotics and nutribiotics in
foods, both for animal nutrition and for humans in terms of functional foods [32], and also in the
pharmaceutical industry [33].
Finally, it is worth mentioning that multiomics is a useful tool to select probiotics and
understand their functions in the host microbiome; so that probiotics and the microbiome can be
better understood [34].
This review describes the growing aspects of the use of nutribiotics (general term to refer to the
set of microbiotics for human use, also called microbial biotherapy), within the field of nutraceuticals,
in skin care health, focusing on the main dermatological diseases and other skin conditions.
2. The Skin Microbiome, a Unique Environment
The skin is a protective organ that performs important barrier functions against external agents
in addition to preventing the loss of body fluids. The cells of the epidermis, but also the
microorganisms present on its surface, intervene in the barrier function.
The microbiome and the skin are part of a whole that coexists and interrelates with each other.
This invisible ecosystem of microorganisms performs important functions in the health of the skin,
protecting it against external aggressions and acting as a second genome, interacting with other parts
of the body to ensure healthy functioning. Its main role is the defense of the skin and the interrelation
with the environment that surrounds it. Furthermore, the skin microbiome has been found to play an
important role in pathogen protection, inflammatory regulation, and overall health [35].
The skin microbiome also helps maintain skin homeostasis and the epidermal barrier, aiding in
the process of epidermal renewal by the production of protease enzymes. The secretion of lipases by
the microorganisms present on the skin surface also plays a regulatory role, since they break down
the lipids secreted by the sebaceous gland. In addition, the skin microbiome produces bacteriocins
[36]. Also, quorum sensing seems to exert a critical role in the skin barrier function, as a recent study
showed that interspecies quorum sensing among bacteria in human skin is considered a necessary
defense mechanism to suppress the ability of Staphylococcus aureus to damage the epidermis [37].
Over the past few years, several studies have focused on the composition of the skin microbiome
and how it changes with development or how external factors may affect its diversity. On the other
hand, it is well known that the composition of the skin microbiome varies according to the areas of
the body that constitute various ecological and physicochemical niches, mainly related to moisture
and sebum content on the surface of the skin [38]. These differences influence resident bacteria and
fungi; oily surfaces such as the forehead harbor lipid-loving bacteria that differ from dry areas, such
as the forearm, in which there is lower microbial density [39]. So that, Cutibacterium spp.,
Staphylococcus spp., and Streptococcus spp. are the most abundant bacteria on dry sites; Staphylococcus
and Corynebacterium spp. prefer moist areas, and on sebaceous sites, lipophilic Cutibacterium species
(spp.) are the most abundant [40,41]. Malassezia spp. is the most abundant fungus throughout the
body, except in the areas of the foot that present greater diversity [42-44]. On the other hand, it has
been observed that two phyla, Bacteroidetes and Firmicutes, tend to predominate in the microbiome
of adults, while Actinobacteria and Proteobacteria constitute a smaller portion. Even so, variations
can be found in the proportions of these phyla and the species from person to person [45].
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Mites are also found in the skin microbiome. Demodex spp. are characteristic of sebaceous glands
and hair follicles, the most numerous representatives being D. folliculorum (hair follicles), and D. brevis
(sebaceous and meibomian glands) [45]. The skin virome has also been explored; it is very
heterogeneous and complex with various polyomaviruses (Polyomaviridae), circoviruses
(Circoviridae), and papillomaviruses (Papillomaviridae) [46,47]. Figure 2 summarizes the relative
abundance of bacterial, fungal, and viral components of the microbial community in the different
skin microenvironments.
Figure 2. Relative abundance of bacterial, fungal, and viral components of the microbial community
in the different skin microenvironments: sebaceous (yellow), moist (blue), and dry (green). Toenail
(black) does not match these major microenvironments (Adapted from Belkaid and Segre, 2014) [39].
Studies of the skin microbiome (microbial and genomic components) in different age groups
have shown that skin microbial communities exhibit dynamics that vary throughout life, developing
in the early stages of life after exposure to the maternal microbiome, and following with changes in
terms of diversity and community structure until old age [48].
Thus, it has been observed that the microbiome in neonates looks like maternal vaginal
communities when delivered vaginally (Lactobacillus and Prevotella spp.), or maternal skin
communities if delivered by cesarean section (Staphylococcus, Streptococcus, Corynebacterium, and
Propionibacterium spp.). Staphylococcus, Corynebacterium, and Prevotella abound in premature infants,
while Brevundimonas, Flavobacterium, and Sphingobacterium predominate in full-term infants [41].
At birth, the pH of the skin is neutral, but in the first hours of life, the development of the
cutaneous acid mantle begins, favoring colonization by commensal organisms and inhibiting the
growth of pathogens. Breast milk contains microbes, antimicrobial metabolites, IgA antibodies, and
cytokines that facilitate the development of the microbiome and the neonatal immune response. The
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microbiome is influenced by close contacts, and it evolves throughout childhood; thus, Firmicutes
(Staphylococcus and Streptococcus) predominate in the skin of babies, followed by Actinobacteria,
Proteobacteria, and Bacteroidetes [49,50]. Microbiota diversity increases at least during the first eight
years of life, which appears to be related to a reduced dominance of Lactobacillales (especially of the
genus Streptococcus) in the skin. In 14-year-olds there is greater interindividual variation in diversity
than in younger age groups; the number of Staphylococcus or Streptococcus species decreases, and the
amount of Actinobacteria and Proteobacteria species increases [51].
Puberty is another stage of changes in the skin microbiota; thus, Firmicutes (Streptococcus spp.),
Bacteroidetes, and Proteobacteria are abundant, while the fungal community becomes more diverse
[41]. The hormonal stimulus that occurs in the post-pubertal stage entails the stimulation of the
sebaceous glands, with an increase of sebum production, favoring the overgrowth and spread of
lipophilic microorganisms, such as Propionibacterium spp; Corynebacterium spp. and Malassezia spp.
[41]. At the adult stage Corynebacterium, Propionibacterium, Streptococcus, and Staphylococcus
predominate [49]; and finally, at the senile stage, the number of Firmicutes, including S. aureus and
Cutibacterium species, decreases [52,53], as well as the production of antimicrobial peptides,
increasing susceptibility to bacterial infections [49].
Jo et al. [54] investigated the skin mycobiome, showing that Malassezia predominated on the
scalp, trunk, and arm skin of adults (age 20s-30s), children (age < 14) had more diverse fungal
communities, for example, Eurotiomycetes which includes common dermatophytes, being M. globose
the most predominant in children.
3. Skin Microbiome: Influence of Intrinsic and Extrinsic Factors
Skin microbiome depends on internal (or intrinsic) and external (or extrinsic) factors. Among
the intrinsic factors, genetics, age, gender, hormones, immunity, sleep and stress factors, and
metabolism must be mentioned. The exposure of the skin to external factors (UV, pollution, humidity,
environmental bacteria, cosmetics, etc.) has also a great influence on the skin microbiome. Skowron
et al. [55] reviewed the impact of extrinsic factors (external exposome) on the skin microbiome, and,
in short, the most important are climate, sunlight (UV radiation), hygiene and cosmetics routine,
environment (air and water pollution, exposure to chemicals), and physical activity and diet can also
be added.
Several studies focused on internal factors, finding that among the genetic factors that determine
the skin microbiome, ethnicity seems to be secondary, although not insignificant, since some
differences have been found; for example, the number of Cutibacterium on the armpits and scalp of
males in Africa and Latin America is lower than in other ethnicities (Caucasian, African–American,
East Asian, and South Asian), and also differences have been found in the microbiomes of the arms
of different ethnicities [56].
Differences linked to gender were also found; the female skin microbiome is characterized by a
higher species diversity than that of males, probably due to several factors such as sweat production,
and the influence of hormones [57].
The relationship between skin and gut (the so-called gut-skin axis) could explain the influence
of the stress factors and metabolism in the skin microbiome [58] as well as nutrition [59]. Furthermore,
diet and obesity were found to influence the skin microbiome, such that high-fat diets favor the
growth of Corynebacterium, probably because it promote skin inflammation through the expression
of mycolic acid. Furthermore, the balance between Firmicutes and Bacteroidetes in obese people is
altered, and during weight loss changes occur in the composition of the microbiota, decreasing
Firmicutes and increasing Bacteroidetes [60].
The environment of a given individual has also a great influence on the skin microbiome, as well
as the profession or the type of daily activity. Some studies suggested that the time children spend
outdoors could be relevant, but also other factors (e.g., cultural differences), and the constant and
close contact with animals could influence the composition and diversity of the skin microbial
communities in healthy people [61-62]. Some authors postulate that differences in the skin
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microbiome of urban and rural residents may be related to the exposure to microorganisms from the
soil, water, and other factors as biomass used in agriculture or livestock [63].
The external environmental conditions have also an important influence on the skin microbiome,
including temperature, humidity, and sunlight. When skin is exposed to UV radiation, several
impacts may occur. The exposure of the skin to UV rays inhibited the growth of S. aureus and C. acnes;
the latest is associated with the decreased production of porphyrins [64]. Furthermore, UV exposure
results in a reduction in Lactobacillaceae and Pseudomonadaceae, and an overall increase in
Cyanobacteria [65]. Additionally, it has been shown that repetitive and intense exposure to UV
radiation may increase skin vulnerability to infections and worsen the associated symptoms, e.g.,
herpes simplex virus (HSV) [66]; on the contrary, Staphylococcus aureus was reduced by UVB
radiation. But there are benefits derived from exposure to light; thus, the antimicrobial effects of
photodynamic therapy (APDT) were demonstrated [67]; and some studies suggest that blue light
treatment and conventional UV phototherapy may act beneficially in acne vulgaris by reducing
Corynebacterium acnes density [68-70]. On the other hand, several studies concluded that skin
microbiome has a useful role in protection against UV irradiation, which is linked with immune
responses since important roles of TNF and IL-6 were observed [71].
Furthermore, using 16S ribosomal DNA and internal transcribed spacer ribosomal DNA
sequencing to profile the microbiomes, Li et al. [72] studied the microbial communities of different
ages, and several pathways related to aging (e.g., base excision repair, biosynthesis of amino acids,
pantothenate and CoA biosynthesis, D-arginine and D-ornithine metabolism and oxidative
phosphorylation, among others), concluding that skin microbiomes may play key roles in skin aging
by regulating immune response, UV light resistance, and the biosynthesis of different substances
involved in aging.
Other authors postulated that climate change, pollution, and the loss of biodiversity, together
with other external factors such as the role of environmental substances (pollen, detergents, tobacco,
as well as microplastics and nanoparticles) or the increase in the consumption of fatty acids in the
diet, derange the epithelial barrier which causing a leaky epithelium resulting in microbial dysbiosis,
including commensals and opportunistic pathogens, and translocation of this content into the
interepithelial and sub-epithelial compartments, inducing microinflammation [73].
Finally, the impact of antibiotics on the skin microbiota should be cited. The use of antibiotics in
the treatment of skin diseases is effective but may have a great impact on skin microbiota diversity.
For example, orally administered doxycycline significantly reduced the number of C. acnes [74];
minocycline decreased the abundance of Cutibacterium, Corynebacterium, Prevotella, Lactobacillus, and
Porphyromonas [75]; lymecycline reduced the presence of Cutibacterium and increased the number of
Streptococcus, Staphylococcus, Micrococcus, and Corynebacterium [76], and fluoroquinolones
(pefloxacin), and macrolides (erythromycin) significantly decreased the number of C. acnes [77].
Despite the lack of studies, some research showed that cosmetics may affect the skin microbiome
diversity. For example, Bouslimani et al. [78] reported that antiperspirants and foot powders
increased the diversity of the skin microbiome, but the effect disappeared after stopping
antiperspirant application, and, in contrast, arm and face lotions had little effect on bacterial
communities and archaea.
Other cosmetics as soaps effectively reduce the number of microorganisms but too frequent use
of soap or other antiseptics in hand disinfection can alter the microbiome and reduce its diversity due
to damage to the barrier function [55]. So, more studies are needed to elucidate the effect of cosmetics
on skin microbiota.
Clothing is also of interest when studying skin microbiome. Skin-clothing contact could cause
microorganism transference and the formation of the so-called textile and volatile microbiome.
Microorganisms that adhere to the fibers can use the lipid components of sebum and dirt as a
substrate and produce volatile substances as byproducts that contribute to unpleasant odors [55].
Furthermore, Ferro de Oliveira et al. [79] investigated the role of clothing on the skin microbiome,
finding that different textile compositions can lead to the growth or inhibitions of certain
microorganisms. For example, Staphylococcus hominis had a high affinity for cotton but did not grow
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in fleece and viscose; Staphylococcus spp. showed a significant adhesion to textile fibers; and cotton
and wool enhanced the growth of different bacteria species, including Staphylococcus epidermidis,
Enhydrobacter spp., Cutibacterium spp., and Micrococcus spp. Additionally, cellulose-based fibers
exhibited low microbial growth rates for most axillary bacteria, except for Staphylococcus spp., and
polyester facilitated greater growth for Cutibacterium spp., Enhydrobacter spp., and Micrococcus spp.
So that, authors revised the existing bioactive textiles based on their specificity against
microorganisms, i.e., antifungal, antibacterial, and antiviral textiles, and concluded that this
knowledge may be an opportunity for the development of microbiota-friendly textiles or
antimicrobial textile products capable of targeting specific populations of the skin microbiota with
the aim of alleviating skin disorders, allergies or bad odor, preventing growth and the spread of
pathogenic microorganisms [79].
Figure 3 summarizes the intrinsic (genetics, age, gender, hormones, immunity, sleep and stress
factors, and metabolism), and external factors (climate, sunlight, hygiene, and cosmetics routine,
environment (air and water pollution, exposure to chemicals, physical activity, and diet) that
influence the skin microbiome.
Figure 3. Intrinsic and extrinsic factors that influence the skin microbiome.
4. Skin Microbiome and Dermatological Disorders
It is very well known that the skin microbiome plays an important role in developing and
maintaining homeostasis and regulation of the host immune system. Belkaid & Segre [39]
summarized the “dialogue between skin and immune system” as follows: Microorganisms present
on the surface and skin appendages (bacteria, fungi, viruses) can themselves produce antimicrobial
peptides and also regulate the production of antimicrobial peptides by keratinocytes, as well as the
production of immune mediators such as complement and IL -1. These molecules can directly or
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indirectly improve skin immunity by improving cellular microbicidal function, promoting cytokine
production, and the recruitment of effector cells. Furthermore, IL-17 production by the microbiota
may promote the effector function of keratinocytes against invading microbes. Additionally, skin-
resident microbes can release defined metabolites that could be captured directly by skin-resident
dendritic cells [39].
Skin disorders such as acne, atopic dermatitis, and psoriasis have all been associated with
dysbiosis of the skin microbiota. Dysbiosis is the alteration in the composition, activity, or
distribution of the cutaneous microbiota. According to Mustari et al. [80], 3 mechanisms can be
involved: 1) Overgrowth of a microbiota member (e.g., Cutibacterium acnes in acne); 2) Elimination of
a microbiota member, and 3) Invasion by non-member microorganisms (e.g., Staphylococcus aureus in
atopic dermatitis) [80]. Dysbiosis is associated with various dermatological conditions such as
psoriasis, atopic dermatitis (AD), seborrheic dermatitis, acne, rosacea, vitiligo, hidradenitis
suppurative, lepra, and others linked to viruses, but it is not entirely clear if the changes in the
microbiota cause diseases or whether certain conditions cause an imbalance in microbial
communities [81].
The gut microbiome also plays a role in some skin disorders; there appears to be a bidirectional
link between the gut and the skin which in turn is linked to the body's homeostasis, the so-called gut-
skin axis. The gut microbiota modulates the functionality and composition of the innate and adaptive
immune system, and vice versa. This fact could explain why some skin diseases are linked to
intestinal dysbiosis and an imbalance of skin homeostasis, suggesting a role of the intestinal
microbiota in the pathogenesis of several inflammatory skin diseases [82]. Multiple studies support
a connection between both and several skin diseases associated with gastrointestinal disorders, but
more studies are needed to attribute a cause-and-effect relationship between the gut microbiome and
dermatological conditions. For example, between 10% and 25% of patients with gastrointestinal
diseases, such as Crohn's and celiac disease, and ulcerative colitis, also have associated skin disorders,
specifically skin ulcers and psoriasis [83].
Inchingolo et al. [81] postulated that the intestinal microbiota contributes to the allostasis and
homeostasis of the integumentary system after any inflammatory process due to the relationship with
innate and adaptive immunity. Proinflammatory cytokines could damage the intestinal barrier, and
severe intestinal dysbiosis provokes inflammation beyond the intestinal and therefore low-grade
systemic inflammation with skin involvement.
Many studies have shown that the overgrowth (or decline) of pathogens on the skin is a common
occurrence in various skin diseases and conditions. The main changes are summarized in Table 1.
Table 1. Changes in the skin microbiota profile is the most frequent skin disorders.
Skin Disease or Condition
Microbiome Disbalance
Reference
Acne
Proliferation or presence of certain
strains of Cutibacterium acnes
Sánchez-Pellicer et al.
2022 [82]
Dreno et al. 2017 [84];
2020 [85]; Condrò et al.
2022
[
86
]
The relative abundance of S. epidermidis
increases at the expense of C. acnes
Xu et al. 2019 [75]
C. acnes inhibits development of S.
epidermidis
Dagnielle et al. 2022
[87]; Claudel et al.
2019
[
88
]
Firmicutes spp., Proteobacteria spp.,
Actinobacteria spp., Staphylococcus spp.,
and Streptococcus spp. are increased; S.
epidermidis is decreased
Weng & Cheng, 2022
[89]
Atopic Dermatitis
Staphylococcus aureus skin colonization
Wollina, 2017 [90]
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10
Increase in the abundance of S. aureus
and loss of anaerobic species
Fyhrquist et al. 2019
[91]
Psoriasis
Increase in Streptococcus and
Staphylococcus and decrease in Malassezia
and Cutibacterium
Lewis et al. 2019 [92]
Taxonomic diversity reduction Increase
of Firmicutes and Actinobacteria
Alekseyenko et al.
2013 [93]
Decrease in Staphylococcus epidermidis and
Cutibacterium acnes
Chang et al. 2018 [94]
that leads a higher colonization with
Staphylococcus aureus
Rosacea
Demodex folliculorum mites that are
suspected carriers of Bacillus oleronius
Sánchez-Pellicer et al.
2022
[
82
]
Involvement of Staphylococcus epidermidis
,
Demodex folliculorum, Helicobacter pylori,
Bacillus oleronius, and Chlamydia
pneumonia in the pathogenesis
Zhu et al. 2023; Lacey
et al. 2007; Murillo et
al. 2014; Kim HS et al.
2020; Yuan et al. 2020
[
95, 96,97,98,99
]
Higher proportions of Firmicutes and
Proteobacteria
Lower proportions of Actinobacteria
Weng & Chen, 2022
[89]
Seborrheic Dermatitis
Role of Malassezia
Paulino et al. 2016
[
100
]
Acinetobacter, Staphylococcus, and
Streptococcus dominated the skin
microbiome of lesional
Tanaka
et al. 2016 [101
]
Over-colonization of Staphylococcus
epidermidis
An et al. 2017 [102]
Dandruff (middle SD) increased
colonization with Malassezia restricta and
Staphylococcus species
Wang et al. 2015 [103]
Hidradenitis suppurativa
Propionibacterium may be part of the
pathogenesis via a dysbiotic condition of
the microbiota
Ring
et al. 2017 [104]
Tinea pedis
Increase fungal diversity and decrease
bacterial diversity compared to healthy
controls
Increase in Trichophyton rubrum
Most prevalent bacteria phyla: Firmicutes
,
Actinobacteria, and Proteobacteria;
Staphylococcus (more than 30% of the
bacterial genera)
McLoughlin et al.
2022
[105]
Acne is a chronic inflammatory skin disease characterized by the presence of comedones,
papules, pustules, and sometimes nodules and scars that appear in oily areas s the face and upper
trunk. The pathogenesis of acne vulgaris is multifactorial and involves increased production of
cutaneous sebum, hyperplasia of sebaceous glands due to the androgenic influence, infra-
infundibulum hyper-keratinization which leads to ductal obstruction, proliferation, or presence of
certain strains of Cutibacterium acnes, and infiltration of inflammatory cells. In terms of skin
microbiota changes, C. acnes is considered the most likely acne pathogen but there are several
recognized sub-groups of C. acnes (I, II, and III) and different ribotype [82], so more investigations
are needed to clarify its role in the pathogenesis of acne. In addition to its role in inflammation, C.
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11
acnes also intervenes in the homeostasis of the skin microbiome by interacting with other skin
microorganisms such as Staphylococcus epidermidis, Streptococcus pyogenes,
and Pseudomonas species. In the microbiome of healthy skin, S. epidermidis may limit the over-
colonization with C. acnes strains and reduce C. acnes-induced IL-6 and TNF-α production by
keratinocytes. In turn, C. acnes may limit the proliferation of S. aureus and S. pyogenes by promoting
triglyceride hydrolysis and propionic acid secretion, which collaborates in the maintenance of the
acidic pH in the pilosebaceous follicle. Furthermore, in the pilosebaceous follicles, C. acnes inhibits
the development of S. epidermidis by the same mechanisms, as to say, hydrolyzing sebum
triglycerides, secreting propionic acid, and maintaining the acidic pH of the pilosebaceous follicle
[87,88]. In acne, a modified profile of C. acnes is observed, as different phylotypes have been shown
to differ between patients with and without acne [84-86].
Weng & Cheng [89] carried out a comprehensive review in which studies on the relationships
between the skin microbiome and acne vulgaris, rosacea, and skin aging were included. Authors
summarized that in acne Firmicutes spp., Proteobacteria spp., Actinobacteria spp., Staphylococcus spp.,
and Streptococcus spp. they were increased, while S. epidermidis decreased [89].
Atopic Dermatitis (AD) is a chronic inflammatory skin disease affecting approximately 20% of
children. In 95% of cases, AD’s first manifestation appears within the first 5 years of life, and, in 25%
of the cases, AD continues during adulthood [106]. Genetic and epigenetic factors modulate AD:
exposure to indoor and outdoor allergens and pollutants, nutrition, and microbiome are considered
to influence and contribute to the development and severity of AD [90]. AD is characterized by an
abnormal immune response; high levels of pro-inflammatory cytokines (e.g., IL-4, IL-13, IL-22)
promote skin inflammation and contribute to barrier derangement and dysfunction. Due to
inflammation, the skin may produce antimicrobial peptides (AMPs) such as defensins and
cathelicidins, which can disbalance the skin microbiome [107].
AD has long been linked with Staphylococcus aureus skin colonization; disease outbreaks are
associated with a spread of S. aureus in injured areas of the skin and a substantial loss of biodiversity
in the skin microbiome. Staphylococcal exoproteins and superantigens cause inflammatory reactions
in the host [90]. Fyhrquist et al. [91] also reported a significant increase in colonization by S. aureus
and a loss of anaerobic species in AD. Koh et al. [108] appointed that S. aureus isolated from AD
patients also express higher levels of virulence factors and a propensity to develop biofilms to
promote its colonization. So, the therapies aim to reduce S. aureus (with antimicrobials) but also to
balance the diversity of the skin microbiome.
Psoriasis is an immune-mediated inflammatory skin disease, the development of which is linked
to both genetic factors and external triggers [109,110]. However, its pathogenesis is still not fully
understood, and the influence of gut and skin microbiota is being investigated. Psoriasis is
characterized by multiple erythematous lesions with scaly plaques that arise mainly on the elbows,
knees, scalp, navel, and lower back, but, in some cases, the disease spreads throughout the body in
the form of erythroderma. Increased vascularization could be also found, which allows the
accumulation of inflammatory subpopulations of neutrophils, dendritic cells, and T lymphocytes.
Psoriasis is frequently associated with inflammation in other organ systems. Thus, 7%–11% of
patients with inflammatory bowel disease (IBD) are also diagnosed with psoriasis, reflecting a strong
association with gastrointestinal inflammation. Changes in the gut microbiome in psoriasis are
similar to those observed in patients with IBD; in both diseases, Faecalibacterium prausnitzii,
Bifidobacterium spp., Lactobacillus spp., Parabacteroides and Coprobacillus were underrepresented,
while the abundance of Salmonella sp., Campylobacter sp., Helicobacter sp., Escherichia coli, Alcaligenes
sp., and Mycobacterium sp. was increased [111]. Other studies showed that psoriatic exacerbation was
considered to be associated with increased colonization of Staphylococcus aureus, Candida albicans,
and Malassezia in the skin and gut [112]. Another similarity between psoriasis and IBD is the reduced
abundance of two beneficial bacteria species (Parabacteroides and Coprobacillus) observed in patients
with psoriasis and psoriatic arthritis and in those with IBD [113]. Thus, it is generally accepted that
the inflammatory and immune mechanisms of psoriasis are based on the dysregulation of the gut-
brain-skin axis [114].
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Additionally, a decrease in Bacteroidetes and an increase in Firmicutes in the intestines of
psoriatic patients compared to control patients were also found [116]. Similar findings were reported
by other authors who found an increased abundance of Firmicutes, Proteobacteria, and
Actinobacteria, together with a decrease in Bacteroidetes in the gut microbiome of psoriatic patients
[116,117].
Other recent studies confirmed this relationship between gut microbiota and psoriasis; Zang et
al. [118] identified nominal protective roles of Bacteroidetes and Prevotella in psoriasis risks; and
some bacterial taxa were recognized as risk factors, including Lactococcus, Ruminiclostridium 5, and
Eubacterium fissicatena; but Odoribacter demonstrated a protective effect against psoriasis [119].
When revising the role of skin microbiome in psoriasis, studies have shown relative increases in
Streptococcus and Staphylococcus and decreases in Malassezia and Cutibacterium [92].
On the other hand, Alekseyenko et al. [93], comparing swap samples of patients with psoriasis
and healthy controls, demonstrated that the microbiome of psoriatic lesions is characterized by an
increase of Firmicutes and Actinobacteria, and a general taxonomic diversity reduction. Additionally,
Chang et al. [94] found that the microbiome of psoriatic skin has reduced stability compared to the
microbiome of healthy skin; and loss of community stability and decline of immunoregulatory
bacteria such as Staphylococcus epidermidis and Propionibacterium acnes may result in increased
colonization with pathogens such as Staphylococcus aureus, which could exacerbate skin inflammation
along the Th17 axis [94].
Rosacea is an inflammatory chronic skin disease that appears exclusively on the central area of
the face, such as cheeks, nose, and chin, symmetrically, and also in the central forehead, characterized
by flushing, papules and pustules, telangiectasia, and sometimes phymatous alterations
accompanied by stinging or itching [120]. Generally, rosacea is classified into four morphologic
subtypes: phymatous rosacea, papulopustular rosacea, erythematotelangiectatic rosacea, and ocular
rosacea [121].
The clinical manifestations of rosacea are multifactorial and are linked to abnormal
neurovascular activation, dysregulated production and release of inflammatory molecules, and
overgrowth of microorganisms that naturally inhabit the skin [122].
Demodex folliculorum is found to been implicated in rosacea; still, Demodex is unlikely to be the
only cutaneous microorganism that contributes to the disease, since Demodex mites are suspected of
carrying Bacillus oleronius, a pro-inflammatory gram-negative bacterium that is receptive to many
antibiotics recurrently used to treat rosacea[82], resulting the amelioration of the disease when
treating with antibiotics.
The origin of rosacea development is unclear, but several factors are involved including genetic
factors, local skin immune imbalance, disorders of neuroimmune function, skin barrier dysfunction,
and skin microbiota dysbiosis, as well as alterations of neurovascular circuitry [123]. The role of the
microbiota in the rosacea pathogenesis is supported by several evidence. Studies conducted by
different authors have pointed to the implication of Staphylococcus epidermidis, Demodex folliculorum,
Helicobacter pylori, Bacillus oleronius, and Chlamydia pneumonia in the pathogenesis of rosacea [95-99].
However, there are discrepancies between the results of the investigations, and the specific
mechanisms by which the microorganisms have been involved in the pathogenesis of rosacea are not
clear, as they are commensal microorganisms. More specifically, the distribution, relative abundance,
mechanisms involved, and thus the role of Cutibacterium acnes and S. epidermidis in rosacea need
further investigation to provide evidence for future probiotic therapy [124].
Finally, the aforementioned review by Weng & Chen [89] described that, in the papulopustular
rosacea, the proportions of Firmicutes and Proteobacteria are higher, and Actinobacteria proportions
been lower.
Seborrheic Dermatitis (SD) is an inflammatory rash that appears on sebaceous areas of skin such
as the scalp, face, and trunk [102]. The incidence of SD reaches the highest point at three ages: infancy,
puberty, and adults over 50 years old, suggesting the role of hormones in sebum production in its
pathogenesis [45]. SD is generally associated with Malassezia, however, its role in the development
of SD is still poorly understood [100]. Some studies suggest that there are other microorganisms
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13
involved. For example, Tanaka et al. [101] found that Acinetobacter, Staphylococcus, and
Streptococcus are the dominant genera on the skin microbiome of lesional areas affected with SD
compared to healthy skin; and An et al. [102] found that patients with SD had a significant over-
colonization of Staphylococcus epidermidis, concluding that this high colonization along with alteration
of the skin barrier function, which is more permeable and contributes to the appearance of SD.
Dandruff, considered a form of middle seborrheic dermatitis, has been also found to be linked
to Malassezia. A study performed by Wang et al. [103], using molecular techniques, showed an
increased colonization with Malassezia restricta, and also of Staphylococcus species when compared
to healthy scalps.
Other skin disorders have also been associated with skin microbiome dysbiosis. Hidradenitis
suppurativa was found to be linked to the dermal microbiota as the microbial composition differs
significantly from that of healthy individuals. In total, the following types of 5 microbes were
identified: Corynebacterium spp. (type I), Acinetobacter and Moraxella spp. (type II), Staphylococcus
epidermidis (type III), Peptoniphilus spp. and Porphyromonas (type IV), and Propionibacterium acnes (type
V), suggesting that Propionibacterium may be involved in its pathogenesis [104].
Tinea pedis is a dermatophyte infection that especially affects the interdigital network and/or
the sides of the feet. Different factors have been found that may be related to its appearance as
sweating, occlusive footwear, trauma, and an immunocompromised state, among others. When
studying the skin microbiota, epidermal samples from patients with tinea pedis have been shown to
exhibit decreased bacterial diversity and increased fungal diversity compared to healthy controls; an
increase in Trichophyton rubrum was observed in patients with tinea pedis as compared to healthy
controls, been the most prevalent bacterial phyla Firmicutes, Actinobacteria, and Proteobacteria,
while Staphylococcus constituted more than 30% of the bacterial genera [105].
Finally, it is worth mentioning the relationship between microbiome and melanoma. Fortman et
al. [125] revised the studies related to the microbiome and cancer, showing that there is evidence that
the gut microbiome can alter responses to chemotherapy and immune checkpoint inhibitors (ICIs).
Authors concluded that preclinical and clinical studies have demonstrated the effects of the gut
microbiome modulation upon ICI response and immune-related adverse event development in
advanced melanoma, with significative evidence supporting the ability of the gut microbiome to
improve ICI response in advanced melanoma through increased intake of dietary fiber, and fecal
microbiome transplant.
5. Nutribiotics: An Opportunity to Improve Skin Health
The history of probiotics can be tracked back to ancient times, nearly 10,000 years ago, since
probiotic microorganisms, and fermented products, such as kefir, kumis, bread beer, and wine had
been very frequently used for nutritional and therapeutic purposes [126]. Knowing that the
composition of the human microbiota is directly linked with the development and functioning of the
immune system, prebiotics and probiotics oral supplementation could be a tool for improving overall
human health but more research is needed to better understand the interactions between diet, the
microbiome and the immune system to design specific diets with the aim of improving diseases [127].
Gao et al. [128] explain the immunological pathway of oral probiotics as follows: when the probiotics
enter the intestinal tract can interact with the host improving intestinal homeostasis, and take part in
immunomodulation, gut microbiota homeostasis, digestion, and absorption of nutrients, and also
improving the intestinal mucosal barrier.
The use of probiotics in skin care is more recent since the gut-skin axis was investigated. Polak
et al. [129] revised the use of prebiotics and probiotics in chronic skin diseases, finding studies mainly
in atopic dermatitis (children and adults), but also in acne, chronic ulcers, seborrheic dermatitis, and
burns. Later on, in a similar revision, Kianmehr et al. [130] showed that the administration of
prebiotics, probiotics, and synbiotics has auspicious effects on preventing and treating various
inflammatory skin disorders, such as atopic dermatitis and acne [131,132]. Orally administration of
probiotics affects the intestinal microbiome and can improve skin conditions such as atopic
dermatitis, acne, or rosacea [133,134], and also other studies showed that using probiotics during
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14
gestation and early life could reduce the incidence and severity of atopic dermatitis, by immune
modulation and promoting the maturation of the gut barrier function [135,130,136]. Additionally,
probiotics are investigated to treat different allergy illnesses, including atopic dermatitis, asthma,
allergic rhinitis, and food allergy [137]. Despite of that, Małolepsza & Dembowski [138], after
reviewing several studies, concluded that alterations in the intestinal microbiome play an important
role not only in the development and aggravation of many skin diseases, but also influence skin
aging, although it is necessary more research to evaluate the impact of probiotics.
On the other hand, Pimentel et al. [139] revised the health effect of post-biotics, including skin
conditions both in vitro and in vivo, and Mehta et al. [25] discussed the potential of para-probiotics
and postbiotics to modulate the immune system.
The following sections describe the use of pre, pro, syn, post, and para-probiotics in skin care.
Table 2 summarizes the clinical studies.
Table 2. Oral pre, pro, syn, post, and para-probiotics used in skin care (clinical studies).
Skin Disease or
Condition
Pre / Pro / Synbiotics Key Results* Reference
Acne
Lactobacillus acidophilus and
Lactobacillus bulgaricus
80% of clinical
improvement
Siver 1961 [140]
L. acidophilus and Bifidobacterium
bifidum
Adjuvant in antibiotic
therapy
Marchetti
et al. 1987 [141]
Lactobacillus acidophilus, Lactobacillus
delbrueckii bulgaricus, and B. bifidum
67% reduction in lesion
counts after twelve weeks
Jung et al. 2013 [133]
Lactobacillus rhamnosus SP1
Adult acne improvement
32% reduction in IGF
-
1 and
a 65% increase in FOXO1
Fabbrocini et al. 2016
[142]
B. lactis W51, B. lactis W52, L.
acidophilus W55, L. casei W56, L.
salivarius W57, L. lactis W58
Increase in IL-10 levels Rahmayani et al. 2019
[143]
Lactobacillus paracasei NCC2461
Inhibition of CD-4+ T cell
activation and
induction of
the anti-inflammatory
cytokines IL-10 and TGF-b.
Benyacoub et al. 2014
[144]
Konjac glucomannan hydrolysates +
(L. casei, L. plantarum, L. gasseri, L.
lactis)
Inhibition of bacteria
growth
Al-Ghazzewi et al. 2010
[145]
Escherichia coli Nissle 1917
80% of clinical
improvement
Manzhalii et al. 2016
[
146
]
Bifidobacterium breve BR03 DSM 16604,
Lacticaseibacillus casei LC03 DSM
27537, and Ligilactobacillus salivarius
LS03 DSM 22776 + Solanum melongena
and Echinacea botanical extract
Decrease in the number of
acne lesions, rate of
desquamation, rate of
sebum secretion, and
presence of C. acnes
Rinaldi et al. 2022 [147]
Nitrosomonas eutropha
Significant reduction in
overall severity
Reduction in the number of
inflammatory lesions
AOBiome [148]
Atopic dermatitis
Oligosaccharide prebiotic-
supplemented formula
Lower 5-year cumulative
incidence of AD
Arslanoglu,
et al. 2012
[
149
]
Mixture of neutral oligosaccharides
and pectin-derived acidic
oligosaccharides
Primary prevention of AD
in low atopy risk infants
Grüber et al. 2010 [150]
Lactobacillus rhamnosus GG
Improvement of SCORAD
Isolauri et al. 2000
[
151
]
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15
Decrease TNF-α and fecal
α1-antitrypsin
Lactobacillus rhamnosus GG
Anti-inflammatory activity
Increased levels of IL-10
and (TGF-β2)
Pessi et al. 2000; Rautava
et al. 2002 [152,153]
Lactobacillus rhamnosus 19070-2 and
Lactobacillus reuteri DSM 12246
Moderate improvement in
the clinical severity
Rosenfeldt et al. 2003
[154]
Lactobacillus rhamnosus GG
Decrease proportions of
IgA- and IgM-secreting
cells
Nermes et al. 2011 [155]
Bifidobacterium lactis HN019 and
Lactobacillus rhamnosus HN001
Improvement natural killer
cell and phagocytic activity
Ouwehand et al. 2009
[
156
]
Lactobacillus rhamnosus GG,
Lactobacillus acidophilus GKA7,
Bifidobacterium longum GKL7,
Lactobacillus plantarum GKM3,
Bifidobacterium bifidum GKB2, and
Lactobacillus paracasei GKS6 + inulin,
isomalto-oligosaccharides, and
fructo-oligosaccharides
Improvement EASI with no
adverse effects
Increase Bacteroides fragilis
and Lactobacillus acidophilus
Choy et al. 2023 [157]
Psoriasis
Bacillus indicus (HU36), Bacillus
subtilis (HU58), Bacillus coagulans
(SC208), Bacillus licheniformis
(SL307),
and Bacillus clausii (SC109) +
fructooligosaccharides,
xylooligosaccharides, and
galactooligosaccharides
Improvement PASI, DLQI,
inflammatory markers, and
skin thickness
Buhas et al. 2023 [158]
Lactobacillus sporogenes
Lesions involution in
pustular psoriasis
Vijayashankar and
Raghunath, 2012
[
159
]
Rosacea
Escherichia coli Nissle 1917
Improvement quality of life
and clinical signs of
dermatosis
Increase IgA levels to
normal values Suppression
of the proinflammatory
cytokine IL-8
Manzhalii et al. 2016
[146]
Doxycycline (40 mg/day) +
Bifidobacterium breve BR03 and
Lactobacillus salivarius LS01
No relapse or flare-up of
disease
Fortuna et al. 2016
[160]
Seborrheic dermatitis Lactobacillus paracasei NCC 2461
Improvement adherent
dandruff, erythema and the
global clinical score
Reygagne et al. 2017
[161]
Wound healing
Lactobacillus plantarum, Lactobacillus
casei, Lactobacillus acidophilus, and
Lactobacillus rhamnosus
Lower incidence of surgical
site infections, foot ulcer
infection, or burn infections
Fijan et al. 2019 [162]
Ageing and Photoageing
Lactobacillus plantarum HY7714
Improvement skin
hydration, gloss, elasticity
Decrease wrinkle depth
Lee et al. 2015 [163]
Lactobacillus johnsonii La-1
Restoration CD1a
Langerhans cell markers
after UV radiation
Peguet-Navarro et al.
2008 [164]
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16
Lactobacillus johnsonii La-1, lycopene,
and β-carotene
Increase in intercellular
adhesion molecule-1
(ICAM-1)**
Marini et al. 2014 [165]
Butyrate supplementation
Counterbalance age-related
microbiota dysbiosis
Boyajian et al. 2021 [166]
L. casei Shirota
B. animalis ssp. lactis HN019
Improvement innate
immunity
Dong et al. 2013; Miller
et al. 2017 [167,168]
Bifidobacterium
longum subsp. longum BB536, B.
longum subsp. infantis M-
63, Bifidobacterium breve M-16V and
B.
breve
Improvement mental
condition and bowel
movement
Decrease body mass index
Inoue et al. 2018 [169]
Lactobacillus johnsonii + carotenoids
Prevent UV-DL-induced
decrease in Langerhans cell
density
Increase factor XIIIa+ type I
dermal dendrocytes
Reduce dermal
inflammatory cells
Bouilly-Gauthier et al.
2010 [170]
Other skin care:
Skin barrier and
hydration
B. breve strain Yakult +
galactooligosaccharides
(in fermented milk)
Optimum level of skin
hydration, decreased
cathepsin L-like
endopeptidase activity, and
phenol content in serum
and urine
Kano et al. 2013 [171]
L. casei
Reduction in
transepidermal water loss
(TEWL) and skin flakiness
Saito et al. 2017 [172]
Other skin care:
Melasma
Lactococcus lactis, Lactobacillus
acidophilus, Lactobacillus casei,
Bifidobacterium longum,
Bifidobacterium
infantis, and Bifidobacterium bifidum
, +
fructo-oligosaccharide, skim milk
powder, lactose, maltodextrin, and
citric acid
Reduce melasma score Piyavatin et al. 2020 [173]
Systemic lupus
erythematous
L. helveticus, B. infantis, B. bifidum +
fructo-oligosaccharides
Decrease systemic
inflammation
Mitigate SLE disease
activity
Widhani et al. 2022 [174]
Oral mucositis
L. rhamnosus GG
Protective effect against
oral mucositis in cancer
patients
Österlund et al. 2007
[175]
Kefir containing Lactobacillus spp.,
and Bifidobacterium spp. Topuz et al. 2008 [176]
L. brevis CD2
Sharma et al. 2012 [177]
B. longum, L. lactis, and Enterococcus
faecium
Jiang et al. 2019 [178]
L. brevis CD2
De Sanctis et al. 2019
[
179
]
L. plantarum MH-301, B. animalis
subsp. Lactis LPL-RH, L. rhamnosus
LGG-18, and L. acidophilus
Xia et al. 2021 [180]
Bacillus clausii
Mirza et al. 2022 [181]
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Skin disease or condition
Post / Paraprobiotics
Key results*
Reference
Atopic dermatitis
Heat-killed Lactobacillus plantarum +
mixture of
Lactobacillus rhamnosus
GG,
Lactobacillus acidophilus GKA7,
Lactococcus lactis GKL2, Lactobacillus
casei GKC1, Lactobacillus paracasei
GKS6, Bifidobacterium bifidum GKB2,
and Bifidobacterium lactis GKK2 +
inulin, galacto-oligosaccharides, and
fructo-oligosaccharides
Improvement in AD
severity
Improvement in the
diversity of gut
microbiome
Wang et al. 2022 [182]
Bifidobacterium animalis subsp. lactis
BS01 (LMG P-21384),
Lacticaseibacillus
rhamnosus LR05 (DSM 19739), and
Lactiplantibacillus
plantarum LP14 (DSM 33401)
(Atopicina
®
)
Reduce severity scores:
erythema, edema/papules,
excoriation, TIS, and
PRURISCORE
Colombo et al. 2023 [183]
Aging and Photoaging
Heat-killed cells Lactococcus lactis H61
Antioxidant activity
Kimoto-Nira 2018
[
184
]
Other skin care:
Skin barrier and
hydration
Heat-killed L. lactis
Decrease melanin content
and cheek elasticity
Increase sebum content
Kimoto-Nira et al. 2012
[185]
* Clinical studies. **In prevention of polymorphic light eruption.
4.1. Acne
As mentioned above, the gut and skin microbiomes influence each other and contribute to skin
health through immune modulation. The preservation of skin homeostasis and the reinforcement of
the skin’s barrier function is one of the major objectives in skin care, and the axis gut-skin could take
part in it [186].
Probiotics aim to modify the skin environment to prevent over-colonization of C. acnes and other
bacteria linked to acne. It has been shown that probiotics directly inhibit C. acnes via the synthesis of
antibacterial proteins and organic acids by certain bacterial strains. Additionally, a large-scale review
on acne vulgaris concluded that oral probiotic administration was associated with a decrease in acne
breakouts [187].
One of the first studies was performed by Robert H. Sawyer in 1961, who reported on the
potential benefits of probiotic Lactobacillus. He followed up 300 patients who consumed commercial
probiotics, that is, Lactinex® tablets comprising a mixture of L. acidophilus and L. bulgaricus. The
protocol consisted of 8 days of oral probiotic, a 2-week washout, and another 8 days of treatment. An
improvement of 80% was found, being more notable in cases of inflammatory acne [140]. Later on,
similar results were found in studies performed in patients under antibiotic therapy with
supplementation of oral probiotics L. acidophilus and Bifidobacterium bifidum as adjuvant therapy [141].
In 2018, Mottin et al. [188] carried out a review of the main strains used in the treatment of acne and
atopic dermatitis, finding that those that showed the highest potential to control acne were
Staphylococcus, Streptococcus, Lactococcus, Lactobacillus, and Enterococcus, and Vitreoscilla filiformis,
Staphylococcus epidermidis, and species of Lactobacillus and Bifidobacterium in the treatment of atopic
dermatitis.
In addition, other studies demonstrated that antibiotics and oral probiotic can provide a
synergistic effect, especially in inflammatory acne. A randomized, prospective open-label trial
demonstrated that consumption of Lactobacillus acidophilus, Lactobacillus delbrueckii subsp. bulgaricus,
and B. bifidum was as effective as minocycline in the treatment of acne, with a 67% reduction in lesions
after twelve weeks of oral treatment, finding fewer side effects [133].
Another randomized-controlled study with twenty subjects showed that oral administration
of Lactobacillus rhamnosus SP1 concluded with an improvement or marked improvement of adult acne
compared to placebo [142]. Researchers also measured gene expression on the skin of IGF-1, a
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hormone involved in acne development, and FOXO1, a transcription factor whose deficiency is
associated with acne pathogenesis. The intervention also showed a 32% reduction in IGF-1 and a 65%
increase in FOXO1 [142].
Other studies focused on interleukin-10 serum levels in acne vulgaris before and after 30 days
of oral probiotics, a sachet containing B. lactis W51, B. lactis W52, L. acidophilus W55, L. casei W56, L.
salivarius W57, L. lactis W58 with total bacterial cells > 108 CFU. Results showed a significant increase
in IL-10 levels after this therapy [143].
Additionally, in an in vitro cell culture skin model, the probiotic strain Lactobacillus
paracasei NCC2461 demonstrated dose-dependent inhibition of CD-4+ T cell activation and induction
of the anti-inflammatory cytokines IL-10 and TGF-b [144].
And in a review performed by Goodarzi et al. [189] authors concluded that probiotics can be
effective as an adjunct therapy both topical or oral administrations, by preventing the growth of
opportunistic bacteria or by controlling inflammation. They suggested that, despite numerous in vitro
and in vivo studies, interventional studies are needed using more samples and long-term follow-ups
to demonstrate the effectiveness of these type of probiotics and determine potential advantages and
disadvantages.
Other studies combine probiotics and plants in oral formulations. For example, Tolino et al. [190]
conducted a double-blind clinical trial in men with mild to moderate acne treated with an oral
supplement containing probiotics, biotin, vitamin E, zinc, nicotinamide, beta-sitosterol, and Boswellia
serrata extract. After 12 weeks of treatment, these patients presented clinical improvement being
shown by the reduction of the Global Acne Grading System (GAGS) score [190].
Oral synbiotics were also investigated. In 2010, Al-Ghazzewi et al. [145] studied the capacity of
konjac glucomannan hydrolysates and probiotics (L. casei, L. plantarum, L. gasseri, L. lactis) to inhibit
C. acnes, finding that significantly inhibited the growth of bacteria, suggesting further research to
confirm the use of this type of synbiotics as therapeutics or prophylactics [145].
The Escherichia coli Nissle 1917 strain has also been used in clinical trials in acne patients.
Manzhalii et al. [146] performed a study in which this strain was orally administered to 82 patients
with intestinal-borne dermatoses (some of them were diagnosed with acne, and others with papular-
pustular rosacea and seborrheic dermatitis). They compared two groups of patients; intervention first
was treated with conventional topical therapy, and the second with the probiotic E. coli Nissle 1917
strain administered orally for one month. A total of 89% of the patients treated with E. coli Nissle 1917
improved significantly, while 56% improved in the group treated with the conventional therapy.
After studying the composition of gut microbiota and other parameters, the authors concluded that
the E. coli Nissle 1917 strain was able to restore the intestinal microbiota, protect the intestinal barrier,
and so ameliorate the mentioned diseases [146].
Rinaldi et al. [147] evaluated the efficacy of a mixture of the probiotic strains Bifidobacterium breve
BR03 DSM 16604, Lacticaseibacillus casei LC03 DSM 27537, and Ligilactobacillus salivarius LS03 DSM
22776 combined with a botanical extract of Solanum melongena and Echinacea in subjects with mild to
moderate acne over an 8-week study period through a randomized, placebo-controlled clinical trial.
Results showed a decreased presence of C. acnes, the number of acne lesions, the rate of sebum
secretion, and the rate of desquamation in patients who were treated with the probiotic mixture and
the botanical extract, as well as the mixture of both, concerning placebo treatment. The most notable
effects were observed with the probiotic mix plus the botanical extract [147].
The ammonia-oxidizing bacteria Nitrosomonas eutropha had also been used to treat adult patients
with mild or moderate acne, finding that, after 12 weeks of treatment, a significant reduction in
overall severity, as well as a tendency in the reduction in the number of inflammatory lesions
compared to the control group [148].
Topic probiotics could be also useful in treating acne. The production of short-chain fatty acids
(such as succinic acid) on the skin can inhibit C. acnes growth [191]. Lactic acid [192] and ceramide
[193] produced after topical probiotic administration, showed direct antimicrobial activity against C.
acnes.
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Additionally, Kang et al. [194] used a cell-free culture supernatant from E. faecalis SL-5 in patients
with mild to moderate acne in topical application. The study concluded that this bacteriocin was able
to reduce inflammation, so that, researchers suggested that E. faecalis could be an alternative option
in future acne therapy [194].
Additionally, a bacteriocin produced by Lactococcus sp. HY499 exerted an inhibitory effect on
inflammatory and pathogenic bacteria in the skin such as S. epidermidis, Staphylococcus aureus, S.
pyogenes, and P. acnes without affecting the growth and proliferation of fibroblasts. The authors
recommended this bacteriocin as an antimicrobial in cosmetic formulations [195].
4.2. Atopic Dermatitis
There are few studies about the use of oral prebiotics to prevent atopic dermatitis. A meta-
analysis by Osborn and Sinn [196] analyzed 4 studies (1,218 infants) exploring the effect of specific
prebiotics in the prevention of allergy. They found a significant reduction in eczema when using a
fructooligosaccharide and galactooligosaccharide combination [196]. Additionally, another research
showed that infants at risk of atopy who were fed with an oligosaccharide prebiotic-supplemented
formula during the first 6 months of life had a significantly lower cumulative incidence of AD in 5
years [149]. Furthermore, a formula containing a specific mixture of neutral oligosaccharides and
pectin-derived acidic oligosaccharides was effective as the primary prevention of AD in low atopy
risk infants [150]. Additionally, Kim et al. [197] demonstrated that AD-like skin lesions induced in
NC/Nga mice were reduced by oral administration of a prebiotic diet (long-chain
fructooligosaccharides, inulin or β-glucan), and intestinal microbiota richness and diversity were also
increased with this prebiotic treatment.
Several studies confirm the positive effects of oral probiotics supplementation in AD. Fanfaret
et al. [198] reviewed the most relevant articles related to the use of probiotics or prebiotics alone and
a combination of the two, finding that the most studied probiotics strains were Lactobacilli and
Bifidobacteria. However, the authors conclude that the results are difficult to interpret as in many
studies the authors suggest that the disease may tend to improve over time in some groups of patients
[198].
Oral supplementation with Lactobacillus rhamnosus GG (LRGG) for 1 month caused a significant
improvement in AD severity scoring of atopic dermatitis (SCORAD) index with decreased levels of
inflammatory markers such as tumor necrosis factor (TNF-α) and fecal α1-antitrypsin [151]. LRGG
also demonstrated anti-inflammatory activity with significantly increased levels of IL-10 and
transforming growth factor-β2 (TGF-β2) in AD patients [152,153]. And administration of probiotic
Lactobacillus strains (a mixture of Lactobacillus rhamnosus 19070-2 and Lactobacillus reuteri DSM 12246)
to children with AD has been shown to result in a moderate improvement in the clinical severity
[154].
Other studies in vitro and in vivo confirmed the potential use of probiotics in AD. Lactobacillus
casei (LC) is one of the most studied species. Several studies in vivo and in vitro showed that LC may
exert an immunomodulatory effect, and the active component has been identified as a protein P14
which has been shown to selectively downregulate serum IgE and interleukin-4 cytokine levels, as
well as the AD index and scratching score in AD-like NC/Nga mice [199].
Kim et al. [200,201] investigated the immunomodulatory capacity of Duolac ATP, a mixed
formulation of probiotics, composed of four different strains of probiotics: L. casei CBT LC5
(KCTC12398BP), L. plantarum CBT LP3 (KCTC10782BP), L. rhamnosus CBT LR5 (KCTC12202BP), and
B. lactis CBT BL3 (KCTC11904BP), both in vitro and in vivo [200,201]. Results showed that Duolac ATP
regulated IL-10 and TGF-beta expression and allowed DCs to become functionally tolerant and
potentially induce Treg differentiation. Additionally, this formulation regulated transcription factors
and cytokines to drive naïve T cell differentiation toward Th1 lineages. The authors concluded that
this formula could be a good ally in the management of AD symptoms and serve as an
immunomodulatory agent for AD [201].
In another study, the probiotic strain Lactobacillus rhamnosus GG decreased the proportions of
IgA and IgM-secreting cells in babies with AD. There were no significant differences in the species
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composition of intestinal bifidobacteria between the studied group and the control group. On the
skin, bacterial counts of the genus Bifidobacterium versus Clostridium coccoides in treated and untreated
infants were similar (155). Additionally, oral administration of probiotic bacteria Bifidobacterium lactis
HN019 and Lactobacillus rhamnosus HN001 has been observed to improve natural killer cells and
phagocytic activity [156].
Later studies showed that AD symptoms can be improved using Lactobacillus paracasei KBL382
isolated from the feces of healthy Koreans. In this study, mice with Dermatophagoides farinae extract
(DFE)-induced AD were fed with L. paracasei KBL382 for 4 weeks, demonstrating that oral
administration of L. paracasei KBL382 significantly reduced AD-associated skin lesions, the epidermal
thickening and serum levels of immunoglobulin E, as well as immune cell infiltration. Furthermore,
the administration of L. paracasei KBL382 was able to change the gut microbiota composition in AD
mice [202].
Several studies focus on oral probiotics supplementation during pregnancy and breastfeeding.
D´Elios et al. [203] revised the efficacy of the most commonly studied probiotic strains for the
prevention and treatment of AD, concluding that probiotic supplementation during the prenatal and
postnatal periods seems to reduce the incidence of AD in infants and children who are at high risk,
especially beginning in gestation through the first 6 months of life. The revised studies included
monostrain probiotics as Bifidobacterium dentium [204], Lactobacillus rhamnosus MP108 [205], and heat-
treated Lactobacillus paracasei [206]; multistrain probiotics as Lactobacillus acidophilus La-5, and
Bifidobacterium animalis subsp. lactis Bb-12 [207], Lactobacillus paracasei and Lactobacillus fermentum
[208]; Lactobacillus rhamnosus and Bifidobacterium animalis subsp lactis [209]; and multistrain
Bifidobacterium lactis CECT 8145, B. longum CECT 7347, and Lactobacillus casei CECT 9104 [210].
A systematic review and meta-analysis of randomized controlled trials performed by Cuello-
Garcia et al. [211] concluded that probiotic supplementation during the last trimester of pregnancy
or breastfeeding could reduce the risk of eczema in infants, although the certainty of the evidence
was low. Li et al. [212] achieved similar findings, concluding that the use of probiotics during both
the prenatal and the postnatal period significantly reduced the incidence of AD; however, analysis of
studies of probiotics administered prenatally only or postnatally only did not reach statistical
significance. Similarly, Tan-Lim et al. [213] revised the randomized clinical trials related to the use of
oral probiotics to prevent AD, finding that the top 3 probiotic preparations in terms of efficacy in
reducing the risk of AD are multi-strain: Lactobacillus paracasei ST11, Bifidobacterium longum BL999,
and Lactobacillus paracasei ssp. paracasei F19, and multi-strain: Lactobacillus rhamnosus GG, and
Bifidobacterium animalis ssp. lactis Bb-12.
Recently, a meta-analysis and systematic review performed by Chen et al. [214] evaluated the
efficacy of probiotic supplementation for the prevention of AD in infants, showing that both mothers
and infants oral probiotics supplementation were effective in preventing AD in infants.
Synbiotics seem to be also useful in AD. Children with mild to moderate AD, aged 1 to 10 years,
were treated with one sachet daily of a novel synbiotics formula containing a mixture of 6 types of
gastro-resistant probiotics (not less than 1.5 x 1010 CFU/sachet at the time of production), and triple
prebiotics containing inulin, isomalto-oligosaccharides, and fructo-oligosaccharides for 8 weeks. The
probiotic mixture was composed of Lactobacillus rhamnosus GG, Lactobacillus acidophilus GKA7,
Bifidobacterium longum GKL7, Lactobacillus plantarum GKM3, Bifidobacterium bifidum GKB2, and
Lactobacillus paracasei GKS6. Results showed an important improvement in Eczema Area and Severity
Index (EASI) without any adverse effects. The presence of key microbial drivers including Bacteroides
fragilis and Lactobacillus acidophilus were significantly increased at week 8. The authors also found that
high responsiveness to an 8-week probiotic treatment was associated with improvements in the gut
microbiome profile with greater relative abundance of probiotic species [157].
Post and parabiotics have also been studied. In 2016, Choi et al. [215] assessed the effect of heat-
killed Enterococcus faecalis EF-2001 (EF-2001) on AD in in vivo AD model by repeated local exposure
of Dermatophagoides farinae extract, finding that the symptoms and pathological sings were attenuated
as well as the production of Ig, and the expression of various pathogenic cytokines in the ears, lymph
nodes, and splenocytes. Considering previous studies in allergic diseases which reported that heat-
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killed Lactobacillus casei Shirota suppressed pro-inflammatory, Th1, and Th2 cytokines in splenocytes
[216], authors suggested that EF-2001 is able to significantly inhibit the inflammatory response by
blocking both Th1 and Th2 in AD lesions of the ear tissue as well as in the cervical lymph nodes and
splenocytes [215].
Formulas including a mixture of pre, probiotics, and postbiotics have also been tested. Patients
with a diagnosis of AD were treated for 8 weeks with an oral formula containing 7 types of gastro-
resistant probiotics (mixture of Lactobacillus rhamnosus GG, Lactobacillus acidophilus GKA7, Lactococcus
lactis GKL2, Lactobacillus casei GKC1, Lactobacillus paracasei GKS6, Bifidobacterium bifidum GKB2, and
Bifidobacterium lactis GKK2, not less than 2 x 1010 CFU/capsule), a postbiotic heat-killed Lactobacillus
plantarum (10 mg/capsule), and triple prebiotics containing inulin (22 mg/capsule),
galactooligosaccharides (8.1 mg/capsule), and fructooligosaccharides (0.9 mg/capsule). Results
showed an improvement in the diversity of gut microbiome and significant improvement in AD
severity [182].
Colombo et al. [183], performed a real-life, multicenter, retrospective observational investigation
designed to evaluate the efficacy and tolerability of a commercial pre- and postbiotic supplement.
Patients consumed a daily sachet containing a concentration exceeding 2.5x109 AFU (active
fluorescent units) of three patented probiotic species: Bifidobacterium animalis subsp. lactis BS01 (LMG
P-21384), Lacticaseibacillus rhamnosus LR05 (DSM 19739), and Lactiplantibacillus plantarum LP14 (DSM
33401). Results showed a significant overall and even intra-individual reduction in all severity scores:
erythema, edema/papules, excoriation, TIS (Three Item Severity score), and PRURISCORE [183].
While the use of orally administered probiotics for the prevention and treatment of AD has been
largely studied, only a small number of studies have focused on the topical application of probiotics,
which may be due to the difficulty of delivering viable bacteria to the skin, given that creams and
lotions typically have to be preserved [217].
The most used probiotics and postbiotics for topical application in AD are heat-inactivated
Lactobacillus johnsonii NCC533 [218], Aquaphilus dolomiae and Vitreoscilla filiformis, which was able to
reduce S. aureus colonization [219], and Lactobacillus reuteri DSM 17938, which showed a statistically
and clinically significant improvement of the SCORAD index and local SCORAD in adults suffering
from AD after 4 and 8 weeks of continuous use [220]. Previous studies showed that the production
of the anti-inflammatory molecule IL-10 by dendritic cells was increased after the local application of
Vitreoscilla filiformis extracts on AD [221,222].
In a study performed by Nakatsuji et al. [223] a strain of Staphylococcus hominis A9 (ShA9) was
selected and applied to AD patients, showing that ShA9 can inhibit skin inflammation by inhibiting
quorum sensing. Phase II of clinical trials is ongoing, and results are not still available.
As has been mentioned before, Nitrosomonas eutropha (B244) is a bacterium that produces nitric
oxide, a potential anti-inflammatory molecule. In phase II a randomized controlled trial (RCT) in
adults, B244 administered as a spray induced a significant improvement of the pruritus. Additionally,
an open-label phase Ib pediatric trial showed a similar effect on itching [224].
Finally, it is also worth citing the studies of Myles et al. [225,226] about topical microbiome
transplantation with Roseomonas mucosa, which was able to reduce S. aureus colonization.
4.3. Psoriasis
Chen et al. [227] conducted an in vivo study where oral administration of Lactobacillus pentosus
GMNL-77 was found to significantly decrease erythematous scaling lesions. Real-time polymerase
chain reaction showed that treatment with L. pentosus GMNL-77 significantly decreased the mRNA
levels of proinflammatory cytokines, including interleukin (IL)-6, tumor necrosis factor-alpha, and
the IL-23/IL-17A axis-associated cytokines (IL-23, IL-17A/F, and IL-22) in the skin of imiquimod-
treated mice.
Buhas et al. [158] performed a 12-week open-label, single-center clinical trial with the aim to
evaluate the efficacy of probiotics: Bacillus clausii (SC109), Bacillus coagulans (SC208), Bacillus indicus
(HU36), Bacillus subtilis (HU58), and Bacillus licheniformis (SL307), and prebiotics such as
xylooligosaccharides, fructooligosaccharides, and galactooligosaccharides in patients with psoriasis
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under topical therapy. Results showed that patients with psoriasis receiving anti-psoriatic local
therapy and probiotic and prebiotic supplementation performed better results in Psoriasis Area and
Severity Index (PASI), Dermatology Life Quality Index (DLQI), inflammatory biomarkers, and skin
thickness compared to those who did not receive supplementation [158].
Finally, it is worth mentioning a case report related to the treatment of a case of pustular
psoriasis resistant to steroids, dapsone, and methotrexate responded well to Lactobacillus sporogenes.
The patient was administered one sachet thrice daily with biotin 10 mg, and all other drugs were
stopped immediately. Within fifteen days the fever decreased, the lesions began to regress, and no
new lesions appeared in two weeks. Therefore, the authors concluded that future research should be
conducted in this field [159].
4.4. Rosacea
According to the ROSacea International Expert Group (ROSIE), composed by European and US
rosacea experts, treatment for rosacea aims to reduce symptoms such as facial flushing and
telangiectasias, and eruption of papules and pustules, to prevent or delay exacerbation of the disease
manifestations as well as to maintain remission [228]. Treatments are based on topical and systemic
therapies (antibiotics, retinoids, etc.), light therapies (e.g., laser), and dermocosmetics [228]. In the
literature, there is a lack of studies focused on nutribiotics, although some are promising.
The study mentioned above by Manzhalii et al. [146] in patients with papulopustular exanthema
(including 36% with rosacea) who received the bacteria Escherichia coli Nissle 1917 as an oral probiotic
as well as a standard topical therapy, demonstrated that oral probiotics therapy had better results
than patients who only received standard treatment, improving quality of life and the clinical signs
of dermatosis. Clinical improvement was associated with a suppression of the proinflammatory
cytokine IL-8 and a significant increase of IgA levels to normal values in serum. Fortuna et al. [160]
also reported a case of rosacea with scalp involvement that was treated with a combination of low-
dose doxycycline (40 mg/day) and oral probiotics (Bifidobacterium breve BR03 and Lactobacillus
salivarius LS01) for 8 weeks, followed by probiotics alone. No relapse or worsening of the disease was
observed during the 6 months of follow-up.
4.5. Seborrheic Dermatitis
Dandruff, seborrheic dermatitis, and scalp-associated disorders showed significant
improvements after oral supplementation of Lactobacillus paracasei NCC 2461 ST11, observing that
free and adherent dandruff, erythema and the global clinical score improved significantly after 56
days of oral intake of a sachet containing ST11 (1×109 CFU) compared to placebo [161].
Additionally, Di Domenico et al. [229] assessed the impact of a topical oily suspension containing
Lactobacillus crispatus P17631 and Lacticaseibacillus paracasei I1688 in patients affected by severe to
moderate seborrheic dermatitis, finding that this mixture was able to reduce symptoms and modulate
the microbiome composition, showing that topical administration of probiotics could also be useful
in seborrheic dermatitis.
4.6. Wound Healing
It has been shown that the absence of microbiota can decrease healing time; furthermore, wound
infections appear when exogenous bacteria become dominant over systemic and local host resistance
factors, and only when a balance is achieved between bacteria and the host can healing processes
develop [230].
The most effective wound management strategy is to prevent infections, promote healing, and
prevent excess scarring, and probiotics may aid in skin repair by exerting antagonistic effects against
pathogens and stimulating the production of immune cells [231]. In a comprehensive review
performed by Fijan et al. [162], authors found that the most commonly used probiotics against
pathogens of wound infections were well-known strains of the species Lactobacillus plantarum,
Lactobacillus casei, Lactobacillus acidophilus, and Lactobacillus rhamnosus. All in vitro studies showed
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effective inhibition of wound pathogens by selected probiotics. In all in vivo studies, probiotics
showed strong activities in counteracting wound infections. Most clinical studies showed a mild or
statistically significant lower incidence of surgical site infection, foot ulcers, or burn infections, in
patients using probiotics [162].
Tagliari et al. [232] investigated the effect of perioperative oral administration of probiotics on
the healing of skin wounds in rats. The probiotic group was supplemented with Lactobacillus paracasei
LPC-37, Bifidobacterium lactis HN0019, Lactobacillus rhamnosus HN001, and Lactobacillus acidophilus
NCFM® at a dose of 250 mg/day, and the control group was supplemented with oral maltodextrin
250 mg/day, both daily for 15 days. In the intervention group, a faster reduction of the wound area
was observed, and authors postulated that this may probably be attributed to a reduction of the
inflammatory phase, an acceleration of the fibrosis process, and collagen deposition.
On the other hand, Togo et al. [233] conducted a systematic review focused on the currently
available evidence on the effect of enteral or oral probiotic therapy on wound healing both of the skin
and oral mucosa, which included seven studies involving 348 people. The results showed that four
studies reported positive results for better healing after probiotic therapy, and none of the studies
reported adverse effects or increasing in wound healing time. The authors concluded that the results
do not generate strong evidence regarding the effectiveness of probiotics for wound healing.
Later on, Tembhre et al. [234] revised the role of probiotics in chronic wounds, finding 14 articles
and concluding that probiotics help eliminate pathogenic bacteria and restore normal wound flora
when applied topically. The main probiotic strains were from the Lactobacillus species: L. plantarum,
L. acidophilus, L. rhamnosus, but also Saccharomyces cerevisiae [234]. S. cerevisiae was shown to achieve
an overall improvement in the healing process; specifically provoking an increase in the expression
levels of collagen type 1 and transcription growth factor beta 1 (TGF-β1) as well as an improvement
of the morphological and biomechanical characteristics of the healing wounds [235]. In vitro study L.
acidophilus and L. casei were shown antibacterial activity against Methicillin-resistant Staphylococcus
aureus [236]; and L. reuteri and L. rhamnosus reduced the ability of the pathogen to induce keratinocyte
cell death [237]. Additionally, L. fermentum was shown an increased wound closure concurrent with
production of nitric oxide (gNO) [238].
Recently, Canchy et al. [239] revised the relationship between the skin microbiome and the
wound healing process. Most of the studies (as in the previous revision by Tembhre et al. [234]) are
related to probiotics topical administration, and the main probiotics strains were again from the
Lactobacillus species; authors suggested that probiotics mainly affect the inflammation phase, which
plays an important role in wound healing impairment, and the suspected mechanism of action is
through the regulation of AMPs, and thus control microbial proliferation [239]. In the same revision,
the use of prebiotics and postbiotics in wound healing was revised, finding very little research.
Vitreoscilla filiformis has been shown to increase keratinocyte proliferation, epidermal regeneration in
vitro, and stratum corneum renewal rate in vivo, as well as to stimulate the expression of collagen I
and IV. These results may indicate that this strain could be useful for increasing re-epithelization in
wound healing applications [239,222,240].
Another field of interest is phage-therapy. Bacteriophages are viruses that infect and replicate
within bacteria which have long been used to treat human bacterial infections. Phages are specific to
the species and often the strain level in targeting and infecting bacteria. Topical phage therapies have
been reported for the treatment of several types of refractory chronic skin infections, such as diabetic
ulcer, venous stasis, or burn-mediated [241], and other investigations focused on the benefits of using
phages to reduce S. aureus biofilm mass, and to treat S. aureus infections [242,243].
4.7. Aging and Photoaging
Since Elia Metchnikoff proposed that all microorganisms are not harmful and that several
intestinal bacteria “produce useful substances against a premature aging,” favoring instead a
“healthy aging” [11], several studies were carried out to investigate the effects of oral probiotics
supplementation on skin aging and photoaging [244]. Thus, protection and recovery from sunburn
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have been one of the first research objectives of probiotics for the skin. These first studies were carried
out with fractions of bifidobacteria applied to the skin, with contradictory results [245].
Oral administration of Lactobacillus johnsonii (La1) at 108 CFU/day for 10 days protected against
the UVR-induced suppression of contact hypersensitivity, increasing IL-10 serum levels, and
decreasing epidermal Langerhans cell density [246]. Additionally, another study demonstrated that
Lactobacillus sakei lipoteichoic acid inhibited MMP-1 induced by UVA in normal human dermal
fibroblasts [247].
Kim et al. [248] evaluated the effect of Lactobacillus plantarum HY7714 against UVB-induced
photoaging in human dermal fibroblasts and hairless mice. The results showed that treatment with
L. plantarum HY7714 effectively recovered UVB-reduced procollagen expression by inhibiting UVB-
induced matrix metalloproteinase (MMP)-1 expression in human dermal fibroblasts. Furthermore,
oral supplementation of L. plantarum HY7714 showed an inhibition of the number and depth of
wrinkles in hairless mouse skin and also was able to inhibit UVB-induced epidermal thickness in
mice. In addition, zymography western blot data also demonstrated that L. plantarum HY7714
effectively inhibited MMP-13 expression as well as MMP-2 and -9 activities in dermal tissue [248].
Additionally, a randomized double-blind clinical trial demonstrated the antiaging effect of oral
administration of L. plantarum HY7714 (1010 CFU/day for 12 weeks), with a significant improvement
in the hydration, shine, and elasticity of the skin and also in the reduction of the depth of wrinkles
[163].
Gueniche et al. [246] showed that oral supplementation with Lactobacillus johnsonii at 108
CFU/day for 10 days was able to protect against the UVR-induced suppression of contact
hypersensitivity, decreased epidermal Langerhans cell density and increased IL-10 serum
levels. Furthermore, in a randomized, double-blind controlled trial, oral administration of
Lactobacillus johnsonii La-1 demonstrated restoration of CD1a Langerhans cell markers compared to
placebo on day 4 after UV irradiation [164].
Weill et al. [249] investigated the effect of lipoteichoic acid (LTA) from Lactobacillus rhamnosus
GG against UV-induced carcinogenesis in hairless mice. The results showed that T-cells in the
inguinal lymph node of LTA-treated mice produced higher levels of interferon-gamma in lymph
nodes and numbers of total, helper, and cytotoxic T-cells compared to controls. A delay in tumors
induced by ultraviolet radiation was also found.
Other studies confirmed the use of Lactobacillus to prevent aging. Tyndallized Lactobacillus
acidophilus was shown to suppress matrix metalloproteinases (MMPs) for wrinkle prevention in
photoaged skin through inhibition of elastase activity [250,251], and also exerted anti-melanogenesis
activity by inhibiting the cAMP pathway and suppressing melanin secretion [251].
Bifidobacterium breve strain Yakult (BBY) was also investigated in hairless mice and was shown
to be able to suppress UV-induced elastase and IL-1beta production and prevent the loss of elasticity
associated with exposure to UV [252]. Similar studies demonstrated that administration of
Bifidobacterium breve B-3 to hairless mice suppressed changes in transepidermal water loss, skin
hydration, and epidermal thickening and reduced damage to the basement membrane and tight
junction structure induced by chronic UVB irradiation, showing a protective effect on skin
photoaging [253].
Several studies performed by Kimoto-Nira (2018) focused on Lactococcus lactis H61, finding that
oral intake of heat-killed or live cells improved skin status in Japanese women; in addition, heat-
killed cells of strain H61 demonstrated an antioxidant effect [184].
Prevention of polymorphic light eruption has also been studied. Marini et al. [165], in a study
with light-sensitive patients, investigated the administrations of a combination of Lactobacillus
johnsonii La-1, β-carotene, and lycopene; the results showed that this mixture was able to improve the
alteration and an increase in intercellular adhesion molecule-1 (ICAM-1) was also observed,
suggesting an immunological response.
Prebiotics seem also to be useful for preventing aging. A diet rich in SCFA-producing dietary
fibers may also help age-related microbial dysbiosis and in turn, suppress the senescent phenotype.
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That is the case of butyrate supplementation which demonstrated to be able to counteract age-related
microbiota dysbiosis [166].
Recently, the term “gerobiotics” has been proposed by Tsai et al. [254] to define those probiotic
strains and their derived postbiotics and para-probiotics that have been shown to reduce
physiological aging processes by attenuating the mechanisms of aging, thus improving the health
span of the host. In an extensive review, the authors highlight the importance of the new field of
gerobiotics, research, and updating, biomarkers for potential targets, and provide recommendations
for the development of gerobiotic products, highlighting its potential to improve health and longevity
in the future. In this review, several strains were highlight. B. longum BB68, L. gasseri SBT2055, L.
fermentum MBC2, B. infantis ATCC15697, and B. subtilis PXN21 (in C. elegans model) were able to
increase lifespan. L. brevis OW38, L. paracasei PS23, L. paracasei K71 (in mice model) were able to
increase memory and/or cognition; L. plantarum AR501 (in mice model) reduced the liver damage; L.
helveticus KLDS1.8701 improved the gut microbiota, and also the memory. In rat models, L. plantarum
NDC 75017 increased learning and memory, and L. fermentum DR9 improved exercise capacity [254].
Bifidobacterium animalis ssp. lactis HN019 and L. casei Shirota improved innate immunity in humans
[167,168]. Additionally, supplementation with a mixture of Bifidobacterium longum subsp. longum
BB536, B. longum subsp. infantis M-63, Bifidobacterium breve M-16V, and B. breve was able to improve
mental condition, and decrease body mass index in humans [169].
Teng et al. [255] revised the mechanisms of action of probiotics in photoaging, concluding that
oral and topical probiotics, by modulating the skin microbiome and gut-skin microbial interactions,
could be useful in preventing and treating skin photoaging through multiple pathways, including
reducing oxidative stress, inhibition of ECM remodeling, inhibition of inflammatory cascade reaction
and maintenance of immune homeostasis [255]. Most of the studies are in vitro and in vivo, and a few
of them clinical studies. An example is the investigation performed by Bouilly-Gauthier (2010) to
assess an oral supplement containing Lactobacillus johnsonii and nutritional carotenoids on early UVR-
induced skin damage, finding that intake of this mixture for 10 weeks prevented UV-DL-induced
decrease in Langerhans cell density and increase in factor XIIIa+ type I dermal dendrocytes, and
reducing dermal inflammatory cells [170].
4.8. Other Uses of Nutribiotics
One of the main issues in skin care is the maintenance of skin barrier and hydration. A double-
blind trial involving combinations of probiotic and prebiotic (B. breve strain Yakult +
galactooligosaccharides) supplemented with fermented milk (100 mL/day for 4 weeks) resulted in
the maintenance of an optimal level of skin hydration, a decrease in the activity of cathepsin L-type
endopeptidase and the phenol content in serum and urine, exerting beneficial effects on both the
intestine and the skin [171]. Additionally, a trial with L. casei (1x1011 bacteria/day for 8 weeks)
conducted by Saito et al. [185] demonstrated a significant reduction in TEWL (trans-epidermal water
loss) and skin flakiness [172]. Furthermore, oral administration of heat-killed L. lactis (60 mg/day for
8 weeks) significantly modulated various skin properties, such as skin elasticity, melanin content,
and increasing sebum content, with a notable effect in the younger age groups. And a para-probiotic
prepared from Kimchi-derived Lactobacillus plantarum K8 improved the skin hydration in human
keratinocyte [256].
Taking into account that skin immune conditions, such as acne, rosacea, and atopy are associated
with skin barrier disruption, and the restoration of this barrier is associated with an amelioration of
the conditions [257], topical application of probiotics is also considered. For example, Gueniche et al.
[258] found Lactobacillus paracasei CNCM I-2116 (ST11) to inhibit P-substance-induced skin
inflammation and accelerate the regeneration and contributing to the epidermal barrier repairment;
finding that significantly eliminates all the effects of P-substance, including vasodilatation, edema,
mast cell degranulation, and TNF-α release, compared to the controls. Moreover, the ST11-associated
skin barrier recovery was found to be accelerated in an ex-vivo skin culture [258]. In a review
performed by Benyacoub et al. [144] related to the immune modulation properties of Lactobacillus
paracasei NCC2461 (ST11) strain, authors concluded that this strain contributes to the reinforcement
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of the skin barrier function, and modulates the skin's immune system, reducing skin sensitivity,
which leads to an improvement in defenses and the preservation of skin homeostasis.
Melasma could be also a target for nutribiotics. Piyavatin et al. [173] performed an experimental
study employing a prospective, double-blind, randomized controlled trial in patients suffering from
facial melasma. Participants were randomly treated with oral synbiotics or placebo, 1 sachet daily for
12 weeks; melasma severity and skin health were evaluated at baseline, weeks 4, 8, and 12 weeks.
Synbiotics consisted of a combination of 50 billion CFUs of 6 probiotics strains: Lactobacillus
acidophilus, Lactococcus lactis, Lactobacillus casei, Bifidobacterium bifidum, Bifidobacterium longum, and
Bifidobacterium infantis, with prebiotic fructo-oligosaccharide, skim milk powder, lactose,
maltodextrin, and citric acid. Results showed that melasma score in the synbiotics supplement group
was significantly lower than that in the placebo group [173].
The use of probiotics in systemic lupus erythematosus (SLE). A systematic review performed by
Mirfeizi et al. [259] identified 22 articles examining the effects of probiotics on SLE. These studies,
which include in vivo tests, in vitro research, and clinical trials, indicated that probiotics may be
effective against inflammation, improving immunological responses as well as the metabolic profiles
in SLE patients. The main strains were Lactobacillus delbrueckii and Lactobacillus rhamnosus [260-263];
a mixture of Lactobacillus rhamnosus, Lactobacillus reuteri, Lactobacillus johnsonii, Lactobacillus oris, and
Lactobacillus gasseri [264]; and Lactobacillus plantarum [264]. In a double-blind randomized clinical trial,
Widhani et al. [174] investigated the effect of a synbiotic formula comprising L. helicus, B. infantis, B.
bifidum and fructo-oligosaccharides, finding that this formulation may be effective in decreasing
systemic inflammation, reducing SLE disease activity, and inducing changes in both the composition
and functions of the intestinal microbiota.
Another field of interest is the treatment of oral mucositis. According to Feng et al. [266]
probiotics exerts a significant protective effect against oral mucositis in cancer patients. In recent
review, Liu et al. [267] found eight trials on patients who were treated with chemotherapy or/and
radiotherapy. The oral probiotics used were: L. rhamnosus GG, 1 capsule, 2 times a day during the
whole chemotherapy course [175]; oral lavage with kefir containing Lactobacillus spp., and
Bifidobacterium spp., and swallow, 250 mL, 2 times a day after meal, first 5 days of each chemotherapy
cycle [176]; L. brevis CD2 lozenges, 1 lozenge, 6 times a day to be dissolved in the mouth and then
swallowed for 8 weeks [177]; oral rinse containing L. lactis, 15 mL, 3 or 6 times a day [268];
combination of B. longum, L. lactis, and Enterococcus faecium on capsules 2 times a day for 7 weeks
[178]; L. brevis CD2 lozenges, 1 lozenge 6 times/day to be dissolved in the mouth and then swallowed
up to one week after the end of cancer treatment [179]; probiotic combination of L. rhamnosus LGG-18,
L. plantarum MH-301, B. animalis subsp. Lactis LPL-RH, and L. acidophilus, 1 capsule, 2 times a day for
7 weeks [180]; Bacillus clausii oral suspension, 5 mL, 2 times a day, until the completion of
radiotherapy course [181]. Therefore, nutribiotics may be useful in this type of sequelae of cancer
therapies.
In the scientific literature, oral probiotics in post-surgery can be also found. Trone et al. [269]
scrutinized how prebiotics, probiotics, and synbiotics may play a role in modulating the immune
response in the perioperative period, and the degree to which they may affect surgical outcomes. The
authors suggested that even short-term gut microbiome pre-habilitation could significantly alter
surgical outcomes, and future studies should consider evidence-based formulations comprising
specific strains and also study the optimal treatment duration. In addition, dietary interventions, such
as high-fiber diets and fermented foods should be considered in perioperative regimens [269].
And in terms of topical application, research tried to develop a plaster/bandage for the
application of inhibitory substances produced by probiotics when applied to diseased skin;
Lactobacillales were the most active against Cutibacterium acnes, Staphylococcus aureus, and
Pseudomonas aeruginosa. Authors suggested that probiotic-containing pads can be applied topically
for the treatment of skin disorders either replacing antibiotic treatment or as adjunctive therapy [270].
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6. Conclusions and Future Perspectives
Intense research into the gut microbiome has provided tools to explore the role of the microbiota
in other physiological systems, including the skin. Despite the scarce knowledge about the
physiological role of skin microbiota in cutaneous biology, several strategies have been implemented
to modulate the microbiome and improve skin health. The most recent strategy is the use of pre, pro,
syn, and post and para-probiotics, which seems to be beneficial on different skin disorders as atopic
dermatitis, psoriasis, acne, seborrheic dermatitis, etc., as well as repairing the skin barrier, preventing
aging or promoting wound healing.
Nevertheless, a deeper understanding of the skin microbiome, the distribution of cutaneous
microbial communities, as well as the differences between microbiomes in healthy and altered skin
is needed. Thus, metagenomic technologies could facilitate functional characterization of the
microbiome and perhaps even provide a personalized approach to diagnosing and treating
conditions underpinned by microbial dysbiosis [44].
It should also be considered the potential adverse effects of probiotics, such as risk of systemic
infections, excessive immune stimulation in susceptible individuals, minor gastrointestinal side
effects [271], or disturbances in the abundance in the gut Bifidobacteria [272].
New investigations about the use of nanotechnology in the probiotic’s formulation are also of
great interest as its delivery without any effect on gastrointestinal digestion is one of the most
important points for their application [273]. Additionally, the genetic engineering of microbiomes has
recently become an area of interest for researchers since it provides solutions to a significant health
problem. In this context, strategies such as conjugative plasmids, bacteriophage, mating-assisted
genetically integrated cloning (MAGIC), and environmental transformation sequencing (ETSeq)
could be effective in the genetic modification of the microbiome [2].
In conclusion, skin microbiome has emerged as a new field with high potential to develop
innovative solutions to manage skin health and disease. Future advances in this field may facilitate
the treatment of skin dysbiosis through means that are more respectful of the physiology of the skin,
being nutribiotics a suitable method for skin care.
Author Contributions: MLM: Conceptualization, Methodology, Writing—original draft preparation, Writing—
review and editing. CPG: Methodology, Investigation, Writing—review and editing. JLL: Writing—review and
editing. LP: Writing—review and editing, Supervision. All authors have read and agreed to the published
version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
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