Unraveling the gut-skin axis in atopic dermatitis: exploiting insights for therapeutic strategies

ABSTRACT

Gut microbiota exert functions of high importance in the intestine. Furthermore, there is increasing evidence for its role in immune regulation and maintenance of homeostasis in many physiological processes taking place in distant tissues. In particular, in this review, we explore the impact of metabolites produced by the gut microbiota on the development of atopic dermatitis (AD). Probiotics and prebiotics balance the microbiota and promote the generation of bacterial metabolites, such as short-chain fatty acids and tryptophan derivates, which promote the regulation of the exacerbated AD immune response through regulatory T cells and IL-10 and TGF-β cytokines. Metabolites also have a direct action on keratinocytes once they reach the bloodstream. Besides, probiotics decrease the levels of metabolites associated with AD onset, such as phenols. Understanding all these crosstalk processes between the gut and the skin reveals a number of possibilities, mainly through the manipulation of the gut microbiome, which may represent therapeutic strategies that can contribute to the standard treatments of AD patients to improve their quality of life.

Introduction

Atopic dermatitis (AD) represents a chronic inflammatory skin disorder, characterized by dry skin, persistent pruritus, and recurrent eczematous lesions. Worldwide studies have described prevalence of up to 30% in children and 17% in adults, with significant variations both between and within countries.^1,2 AD is a complex and multifactorial pathology that involves a combination of genetic, environmental and immune factors.³ It is initiated through a compromised epidermal structure and function, which subsequently lead to inflammation with dysregulation of lymphocyte T-helper (Th) response that promotes immunoglobulin (Ig)E production, and skin microbiota alteration.^4–7 (Explained in detail in Figure 1). Thus, elevated serum levels of pro-inflammatory cytokines and chemokines, such as IL-4, IL-5, IL-6, IL-13, IL-17, IL-23, tumor necrosis factor (TNF)-α, thymic stromal lymphopoietin (TSLP), thymus and activation regulated chemokine (TARC; CCL17), and macrophage derived chemokine (MDC; CCL22) are detected in AD patients. In contrast, levels of anti-inflammatory cytokines such as IL-10, IL-35, and transforming growth factor (TGF)-β are reduced in these patients.^8–13 This altered cytokine and chemokine profile has gained clinical significance, as it is implicated in the development of itch and skin inflammation in AD.^14,15

Figure 1.

Physiopathology of AD. A defective skin barrier activates keratinocytes (KC) to produce thymic stromal lymphopoietin (TSLP), IL-25, and IL-33. Under these inflammatory stimuli, dendritic cells (DC) uptake penetrating antigen and migrate to skin lymph nodes (LN) to activate and differentiate T cells into Th2 and Th22 profiles. Th2 lymphocytes then promote IgE production by activated B cells (BC). Chemokines produced by keratinocytes (TARC, MDC) attract Th2 cells to dermis. Activated innate lymphoid cells (ILC)2 and Th2 cells release IL-4, IL-5 and IL-13 that trigger mast cells (MC) and eosinophils (Eo) recruitment. These inflammatory cells release factors that contribute to edema, erythema, and pruritus. IL-31 and Th2 cytokines contribute to pruritus, which induces scratching and perpetuates skin barrier disruption. Th2 cytokines disrupt the expression of skin structural proteins, such as filaggrin, enhancing dysfunctional cutaneous barrier and producing transepidermal water loss (TEWL). This inflammatory environment is associated with cutaneous dysbiosis characterized by Staphylococcus aureus colonization. In chronic lesions, Th1 and Th22 responses are enhanced, contributing to epidermal hyperplasia, keratinocyte apoptosis and barrier damage. IFN, interferon; TNF, tumor necrosis factor; AMP, antimicrobial peptides; TARC, thymus and activation regulated chemokine; MDC, macrophage derived chemokine. Created with BioRender.com.

AD is a condition that typically manifests in the early years of life, a critical period during which the microbiota begins to establish in infants.^16,17 The balance of this microbial environment is crucial, and disruptions may contribute to its pathogenesis. Comparisons between individuals with AD and healthy controls reveal distinct alterations in both skin and gut microbiota, with the common signature of decreased bacterial diversity.^18,19 In the skin microbiota of AD patients, there is an overabundance of Staphylococcus aureus (correlated with AD intensity),²⁰ Staphylococcus epidermidis, and Staphylococcus haemolyticus, which aggravate skin inflammation through production of superantigens, cytolytic phenol-soluble modulins and proteases, such as the extracellular serine protease;^21–23 and a deficiency of species of the genera Streptococcus, Acinetobacter, Corynebacterium, and Prevotella, that have an important role in the reduction of AD by inhibiting the production of inflammatory cytokines such as IL-8,^24,25 and stimulating the production of anti-inflammatory molecules, such as IL-10,²⁶ or inhibitory metabolites against S. aureus.²⁷ Additionally, there is a more diverse presence of pathogenic fungal species that can complicate the clinical picture of AD and prompt sensitization to yeast allergens, including Aspergillus, Candida albicans, Cryptococcus diffluens, but excluding Malassezia spp.^18,23 Conversely, in the gut microbiota of individuals with AD, there is an increased colonization with S. aureus, Bifidobacterium pseudocatenulatum, Clostridium spp., and Escherichia coli, along with a deficiency of Bifidobacterium, Enterococcus, Bacteroides, and Ruminococcus genus.^19,28 It is important to highlight, that species belonging to the same genera might have contrasting effects, as the case of Bifidobacterium that is mainly considered an anti-inflammatory genus,²⁹ although B. pseudocatenulatum has been shown to induce IL-10 expression in dendritic cells (DC) in the absence of IL-12, allowing for an expansion of the Th2 response with pro-allergenic consequences.^30,31

Mainstay treatments for AD patients involve topical applied products such as emollients, steroids, calcineurin inhibitors, wet wrap therapy, and dilute bleach baths. These therapies aim to retain and replenish epidermal moisture, decrease skin inflammation, and restore stratum corneum integrity. In refractory AD, ultraviolet phototherapy and systemic immunomodulators are recommended.^32,33 In contrast, an “inside-out” approach to AD therapy is gaining interest and involves the supplementation of nutraceuticals.³⁴ Among these strategies, oral consumption of probiotics and prebiotics has received particular attention because of the potential for local effects in the gut to impact distant organs, including the skin, through mechanisms involving both immune response molecules and compounds generated by the metabolism of these probiotics.^35–38

This novel and important connection between the gut and the skin, commonly referred to as the gut-skin axis, has been supported by solid experimental evidence demonstrating the impact of colonic resident microbiota on skin health.³⁹ Thus, the gut microbiota environment can be reshaped with long term consumption of probiotics and prebiotics, contributing to regulate skin immune response. First, this review highlights the gut-skin connection in AD, showing the beneficial effects of probiotics and prebiotics. Later, the mechanisms that mediate gut-skin communication to maintain healthy skin and its potential as a therapeutic approach in AD are discussed.

Probiotics, prebiotics and atopic dermatitis

The gut microbiota undergoes significant variability throughout life,⁴⁰ influenced by various factors such as the environment, drug and antibiotic use, and diet. Probiotics are defined as “live microorganisms that, when ingested in sufficient quantity, provide a health benefit to the host”.⁴¹ Beyond merely modulating the gut microbiota, probiotics have shown noteworthy effects in both in vitro and preclinical trials.⁴² Notably, certain lactobacilli and bifidobacteria strains (widely documented probiotic genera) have demonstrated significant health benefits. In addition, probiotics exhibit immunomodulatory activities and produce functional molecules such as enzymes, short-chain fatty acids (SCFAs), and vitamins, among other compounds, contributing to broader host health benefits.⁴³

Diet provides the necessary substrates for the selection and growth of diverse microbial strains.^44,45 Dietary fiber, consisting of non-digestible polysaccharides with repeated monosaccharides units such as glucose, fructose, and mannose, is a key substrate fermented by probiotics. These fermentable substrates, termed prebiotics, selectively enhance the growth of beneficial microbes that contribute to the host’s health.⁴¹ Inulin, fructo-oligosaccharides (FOS), oligofructose, galacto-oligosaccharides (GOS), and lactulose are well established prebiotics and have been extensively studied for their health benefits. Other substances such as human milk oligosaccharides, polyphenols, polyunsaturated fatty acids, hydrolyzed protein and peptides are considered new candidates for prebiotics.⁴⁶ Although prebiotics are found in natural foods that are normally included in diets, they can also be consumed in the form of dietary supplements, alone or combined with probiotics, latter preparation named synbiotic.

Probiotics and prebiotics have demonstrated efficacy in alleviating clinical signs of AD in humans. In Table 1, we summarized some clinical trials that show the effectiveness of using probiotics and prebiotics, alone or combined, as their intake remarkably reduce the hallmark clinic symptomatology, and some pro-inflammatory molecules implicated in the disease.

Table 1.

Beneficial effects of probiotics and prebiotics in patients with atopic dermatitis.

Study design	Cohort	Probiotic/prebiotic/synbiotic	Effects	Ref
Randomized double-blind placebo controlled	Patients from 6m to 19y AD mild, moderate or severe - Probiotic (N=24) - Placebo (N=16)	Mix of Lactobacillus acidophilus, Bifidobacterium lactis, Lacticaseibacillus rhamnosus, Lacticaseibacillus paracasei subsp. paracasei Treatment time=6m	-Reduction of 27% on the SCORAD index, that persists after 3m of treatment disruption -Less use of topical immunosuppresants -No differences in IgE levels -No change on serum inflammatory and tolerogenic cytokines	47
Randomized	Newborns (Nb) - no familiar atopy (N=132) - familiar atopy (N=114) - familiar atopy + probiotic (N=111) All breast feeding	Clostridium butyricum Treatment time=10d	-Reduction of AD incidence at 3 to 36m and SCORAD index at 3 to 6m after birth -Lower levels of total IgE and IL-4 at 36m after birth	48
Meta-analysis of randomized double-blind placebo-controlled	Prenatal (mothers) and postnatal (infants) 10 studies up 2y (N = 2572) 3 studies up to 4–5y (N = 1278) 3 studies up to 6–7y (N = 588) 2 studies up to 11y (N = 999)	Lacticaseibacillus rhamnosus (with or without other probiotics)	-Reduction of moderate to severe AD incidence in infants under 7y	49
Randomized double-blind placebo-controlled	Patients >14y AD mild and moderate - Probiotics (N=15) - Placebo (N=15)	Lactiplantibacillus plantarum IS-10506 Treatment time=8w	-Reduction of the SCORAD index -Decreased production of IL-4 and IL-17 -Increased population of IFN-γ CD4+ T lymphocytes	50
Randomized double-blind prospective	Children 2 to 12y AD moderate or severe - Prebiotic (N=22) - Synbiotic (N=17)	Fermentation broth of Lacticaseibacillus rhamnosus Lcr35 with skimmed milk powder, potato starch and lactose or L. rhamnosus Lcr35+ fermentation broth Treatment time=3m	-Reduction of the SCORAD index	51
Randomized double-blind placebo controlled	Children < 6y AD mild or moderate - Placebo (N=29) <1y N=9; 1-2y N=4; 2-5y N=16 - Kestose (N=29) <1y N=8; 1-2y N=9; 2-5y N=12	Kestose (the smallest FOS) Treatment time=12w	-Decrease of 4.05 points of SCORAD index in 2-to-5y infants -Increased amount of intestinal Faecalibacterium prausnitzii*, more significantly in 0-to-1y than 2-to-5y infants	52
Randomized double-blind placebo controlled	Adults 18 to 60y AD moderate or severe - Prebiotic (N=44) - Placebo (N=45)	Lactulose (a synthetic non-digestible disaccharide galactose-fructose) + lignin hydrolyzed Treatment time =21d	-Reduction of SCORAD index by 71% -Elimination of day and night itching -Noticeable clinical improvement -Quality of life improvement	53
Randomized double-blind placebo controlled prospective	Infants >8w, without AD and low atopy risk - Prebiotic (N=414) - Placebo (N=416)	Short chain GOS (scGOS)/long chain FOS (lcFOS) + pectin-derived oligosaccharides Treatment time=6m, from the age of 6m to 1y-old	-Reduction of the incidence of AD up to the first year -A tendency toward less severe AD and SCORAD index. -No change in total IgE and TARC serum levels	54
Randomized Double-blind placebo-controlled prospective	Healthy infants with a parental history of atopy - Prebiotic (N=42) - Placebo (N=50)	scGOS/lcFOS Treatment time=the first 6m of life	After 5-years follow-up, cumulative incidence of AD significantly decreases, and prevalence of persistent AD tends to be lower	55

d, day; w, week; m, month; y, year; FOS, fructooligosaccharides; GOS, galactooligosaccharides; SCORAD, SCORing for Atopic Dermatitis, which is an index that evaluates the extent or intensity of AD through six objective items (erythema, oedema/papulation, excoriations, lichenification, oozing/crusts and dryness on involved skin) and two subjective symptoms (itching and insomnia). The higher the SCORAD index, the greater the severity of the AD.

*F. prausnitzii is the major bacterial source of butyrate in the intestine, which exerts anti-inflammatory effects.

Nevertheless, a few studies have failed to find a beneficial effect of probiotic/prebiotic consumption on AD prevention or alleviation. Thus, in a randomized clinical trial in infants with a positive familiar history of allergy, GOS supplementation in newborns fed with formula with hydrolyzed protein (N = 52) for 6 months did not improve the reduction of the SCORing for AD (SCORAD) index when compared with those who only received the formula (N = 51), although GOS was well tolerated.⁵⁶ Similarly, in a double-blind, placebo-controlled multi-center trial, infants aged <7 months (N = 90) with mild to moderate AD and receiving a formula with hydrolyzed protein supplemented with Bifidobacterium breve M-16 V and a mixture of scGOS/lcFOS for 12 months did not show differences in systemic markers of atopic diseases or T-regulatory cell number compared to placebo group.⁵⁷ The controversial outcomes in clinical trials with prebiotic/probiotic interventions might be associated with genetic, environmental or dietary factors. Larger samples and more accurate experimental design are needed in clinical trials to verify their effectiveness on AD, and whether they may represent a suitable adjuvant strategy to standard therapies. Furthermore, the comprehension of prebiotic/probiotic action mechanisms on the maintenance or recovery of a healthy skin might be helpful to understand the different outcomes of the clinical studies.

Bacterial metabolites

When pro- and prebiotics are incorporated into food or administered orally, an anti-inflammatory effect has been observed in several clinical trials of skin allergic pathologies.^58,59 Following the fermentation of prebiotics, the gut microbiota generates and releases soluble and low molecular weight metabolites that exhibit beneficial bioactivity for the host. These by-products are termed postbiotics.⁶⁰ In this context, several microbial fractions or bacterial components, with beneficial effects, have been defined as postbiotics.^61–63 In the following section, we will discuss various types of metabolites or bacterial components that mediate gut-skin crosstalk and their potential as therapeutics against AD.

Short chain fatty acids

Once dietary fiber is degraded by the gut microbiota, there is an increase in the production of SCFAs. These molecules, small and saturated monocarboxylic fatty acids with up to six carbon atoms, are mainly produced during the fermentation of non-digestible carbohydrates or amino acids by the gut microbiota, including acetic (C2), propionic (C3), and butyric (C4) acids.⁶⁴ Uptake of SCFAs into colonic epithelial cells is mainly mediated via nonionic diffusion, H⁺-dependent monocarboxylate transporters (MCT) or Na⁺-dependent monocarboxylate transporters (SMCT).^65–67 MCT1 and SMCT1 are expressed in the colonocyte apical membrane and are related to the uptake of SCFAs into colonocytes; MCT1 and MCT4 are present in the colonocyte basolateral membrane and might be involved in the transfer of SCFAs to blood circulation⁶⁸ (see Figure 2). SCFAs then serve as a significant source of energy, contributing up to 10% of our daily caloric requirements and being involved in cellular catabolism.⁶⁹

Figure 2.

SCFAs produced through fiber fermentation by gut microbiota exert beneficial effects on AD skin. Short chain fatty acids (SCFAs) generated by microbial fermentation of non-digested fiber are transported into colonic epithelial cells and partly transferred to portal circulation to be systemically distributed. SCFAs induce: i) regulatory T (Treg) lymphocytes in gut-associated lymphoid tissue (GALT) that can migrate to the skin; ii) increased expression of transforming growth factor (TGF)-β in colonic cells; and iii) increased expression of Foxp3 in the skin. In the skin, SCFAs and Treg cells modulate the damage and inflammation associated with AD lesions. Keratinocytes (KC) express free fatty acid receptor (FFAR)2, FFAR3 and hydroxy-carboxylic acid receptor (HCA)2 receptors that in response to SCFAs promote epigenetic changes that elicit gene expression related to immunity, barrier function and keratinocyte differentiation. TEWL, transepidermal water loss; HAT, histone acetyltransferase; SCORAD, SCORing for AD; GPCR, G protein coupled receptors; MCT, H⁺-dependent monocarboxylate transporters; SMCT, Na⁺-dependent monocarboxylate transporters; HDAC, histone deacetylases. Created with BioRender.com.

The distribution of SCFAs in the bloodstream allows them to reach distant organs and modulate immune responses. For example, a prospective study of children born in rural areas of Europe indicated that higher levels of fecal SCFAs at age of 1 year are associated with protection from atopic sensitization later in life.⁷⁰ In the skin, SCFAs have been shown to play a role in modulating the immune response. Thus, in experimental models of AD in which the integrity of the epidermal barrier is compromised, supplementation with inulin or butyrate resulted in less severe disease and a marked reduction in transepidermal water loss (TEWL).³⁸ Lactic acid bacteria may also serve as a source of fermentable fiber, as administration of exopolysaccharides (EPS) produced by Leuconostoc mesenteroides increased SCFAs levels, particularly propionate, in mice feces and plasma.⁷¹ Also, dairy prebiotics, such as glycomacropeptide (GMP), have been associated with SCFAs production.⁷² Oral administration of GMP in a rat model of AD resulted in improved skin barrier function, accompanied by increases in fecal acetate, butyrate, along with a greater Bifidobacterium amount.⁷³ Although the genera Bifidobacterium encompasses non-butyrate producer bacteria, metabolic products produced by Bifidobacterium provide substrates to support growth of butyrate producer bacteria.⁷⁴

SCFAs generated in the colon through the fermentation of dietary fibers can potentially reach keratinocytes to exert their beneficial effects. Indeed, keratinocytes present various receptors where SCFAs act as ligands, including free fatty acid receptor (FFAR)3, also known as G protein-coupled receptor (GPR)41,⁷⁵ FFAR2 (GPR43),⁷⁶ and hydroxy-carboxylic acid receptor (HCA)2 (GPR109a).^77,78 Activation of these receptors has been explored as a potential therapeutic approach. For example, the ligand 4-chloro-α-(1-methylethyl)-N-2-thiazoylylbenzeneacetanilide for FFAR2 has been shown to reduce IgE levels, mast cell infiltration, and Th2 cytokines IL-4 and IL-13 in a mouse model of AD induced by 2,4-dinitrochlorobenzene (Figure 2).⁷⁹

Although direct delivery of SCFAs from the gut to keratinocytes has not been demonstrated to induce epigenetic changes, it is plausible to assume that it occurs as reported for other cell types. In vitro experiments in a panel of epithelial cells have shown that propionate and butyrate induce dose-dependent increases in histone acetylation through the activation of histone acetyltransferases (HATs), particularly the p300/CBP family.⁸⁰ This alteration in chromatin structure modulates gene expression. Specifically, when butyrate is orally administered in a mice model of AD, a change in the skin transcriptomic profile is observed, with enriched pathways related to immunity, barrier function, and keratinocyte differentiation. This leads to an improvement in the signs of AD.³⁸

In fact, butyrate is known for its significant anti-inflammatory activity, particularly through its impact on Treg cells. Studies reported that the butyrate concentration correlates with TGF-β expression in an in vitro model using a colonic cell line. This correlation is mediated by Specific protein 1 and involves the inhibition of histone deacetylases (HDAC).⁸¹ Besides, butyrate derived from commensal microbes induces functional colonic and follicular Treg cells, at least in part through epigenetic upregulation of related genes to Treg differentiation, such as the Foxp3 gene (Figure 2).^82,83 As a result, these Treg cells might acquire the ability to migrate from gut-associated lymphoid tissues to the skin, thereby mediating an indirect anti-inflammatory effect of SCFAs.^84,85 In this context, oral administration of Ruminococcus gnavus (a gut commensal bacterium less abundant in AD than in healthy infants) to AD mice increases cecal butyrate levels, Treg cell number in mesenteric and skin-draining lymph nodes, and Foxp3 expression in skin.⁸⁶ These results highlight the role of SCFAs generated in the gut as a means of communication to support and promote healthy skin in AD patients.

Bioactive tryptophan metabolites

Tryptophan, an essential amino acid crucial for protein synthesis and the generation of bioactive molecules, undergoes metabolism through three different pathways: the kynurenine pathway, the 5-hydroxyindole pathway (serotonin pathway), and the microbial pathway.^87,88 These pathways share a commonality in that their metabolites play crucial roles in the regulation of the immune response.^89–92 Of particular interest is the microbial pathway, as the catabolism of tryptophan by intestinal microbes produces metabolites with both local and distal effects.⁹³

Tryptophan appears through proteolytic degradation in the ascending colon and is then catabolized throughout the colon. Several taxa, including Bacteroides, Klebsiella, Veillonella, Clostridium, Paraprevotella, and Escherichia sp., increase in abundance and work in a sequential and complementary manner to produce indole and indole-derived metabolites. These latter include indole-lactate (ILA), indole-3-carbaldehyde (I3C), and indole-propionate (IPA).⁹⁴ Indole derivatives act as ligands for the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor expressed by various cells in the skin. AhR plays a crucial role in maintaining skin integrity and immunity.^95,96

In keratinocytes, AhR serves as a significant regulator in response to inflammatory stimuli. Ahr-deficient human keratinocytes, when exposed to the inflammatory mediator IL-1β, overexpress CXCL1 and CSF2 (chemokines involved in neutrophil attraction).⁹⁷ Moreover, stimulation of human keratinocytes with the AhR agonist 6-formylindolo(3,2-b)carbazole (FICZ) leads to the upregulation of filaggrin (FLG), and the importance of AhR activation in FLG transcription was corroborated in an in-vitro AD model.⁹⁸ Therefore, the microbial production of indole derivatives from tryptophan represents a pathway that influences skin health through the activation of AhR and its regulatory effects on inflammation and skin barrier function. Although the beneficial effects of AhR activation on keratinocytes open the possibility of a therapeutic intervention in AD, further research is needed to understand the mechanism underlying the physiological consequences of AhR signaling in the immune system.

Probiotic bacteria have been identified as producers of indole derivatives in the gut.^99,100 In a mice model of 2,4-dinitrofluorobenzene (DNFB)-induced AD-like symptoms, mice that were administered orally with the strain Bifidobacterium longum CCFM1029 showed a negative correlation between the reduction of SCORAD and the presence of I3C. Furthermore, when I3C was administered orally, a significant reduction in SCORAD was observed, accompanied by a decrease in ear thickness, serum IgE levels, and downregulation of TSLP and IL-4 expression¹⁰¹ (Figure 3a). This suggests a potential role of indole derivatives produced by probiotic bacteria in mitigating symptoms associated with AD. Consistent with this finding, in an experimental model of food allergy, dietary intake of FOS provides moderate protection from intestinal inflammation, and this protective effect was mediated by modulating the gut microbiota composition and tryptophan metabolites, and was AhR-dependent.¹⁰²

Figure 3.

Effects of tryptophan and tyrosine catabolism by gut microbiota on AD. a) Indol derivates (Indol(d)) generated by microbes during tryptophan metabolism display benefits on atopic dermatitis (AD), through regulation of keratinocyte (KC) gene expression which is reflected in an improvement of AD signs and symptoms. b) Phenol derivates produced by Clostridioides difficile induce changes in the skin that are associated with barrier dysfunction and AD onset. Probiotic administration decreases serum p-cresol and improves cutaneous barrier function. ILA, indole-lactate; IPA, indole-propionate; I3C, indole-3-carbaldehyde; SCORAD, SCORing for AD; PAR-2, proteinase-activated receptor-2; AhR, aryl hydrocarbon receptor. Created with BioRender.com.

Detrimental metabolites: phenol and p-cresol

Bacteria residing in the large intestine play a crucial role in the digestion of dietary and endogenous proteins. Their extracellular proteases produce oligopeptides, which, when internalized, are further degraded into amino acids. These amino acids are then metabolized within the bacteria for protein synthesis or used as sources of carbon and nitrogen.¹⁰³ In the distal colon, certain bacterial families such as Fusobacteriaceae, Enterobacteriaceae, Clostridium, and Coriobacteriaceae have the ability to metabolize tyrosine anaerobically, resulting in the production of phenols [phenol and p-cresol (4-methylphenol)].^103,104 Specifically, Clostridioides difficile, a potent producer of p-cresol, can gain an advantage in its favor by suppressing the growth of other bacterial populations and promoting a state of dysbiosis.¹⁰⁵

The metabolite p-cresol, produced by these bacteria, exerts inhibitory effects on cellular proliferation in colonic epithelial cells through mitochondrial dysfunction.¹⁰⁶ Additionally, serum phenol levels impact skin structure, as women with elevated serum p-cresol levels exhibit reduced corneocyte size. However, in another cohort given a prebiotic beverage containing GOS and polydextrose, serum levels of phenol and p-cresol were reduced. At the same time, corneocyte size and cathepsin-L serum activity, an indicator of keratinocyte differentiation, were increased.¹⁰⁷ This suggests a potential link between gut microbial metabolism, phenols production, and its effects on both colonic epithelial cells and skin structure.

Stimulation of normal human epidermal keratinocytes with p-cresol or uremic sera from chronic kidney disease (CKD) patients, characterized by elevated p-cresol levels, results in increased expression of proteinase-activated receptor-2 (PAR-2).¹⁰⁸ In patients with AD, the enhanced expression of PAR-2 is associated with itching behavior and altered epidermal barrier function when subjected to agonistic stimuli.^109,110 This heightened expression favors skin sensitization,¹¹¹ indicating that high levels of p-cresol might be implicated in influencing the development of AD. It should be noted that these undesirable effects can be reversed by the administration of prebiotics and probiotics. For instance, oral administration of yeast mannan to Japanese females led to an increase in the relative abundance of Bacteroides thetaiotaomicron and Bacteroides ovatus, accompanied by a significant reduction in fecal p-cresol levels. These effects were associated with a decrease in skin dryness.¹¹² Additionally, the consumption of milk fermented with B. breve strain Yakult and GOS promoted keratinocyte differentiation, as evidenced by an increase in cathepsin-L activity. This intervention maintains skin hydration while modulating the presence of phenol in the serum¹¹³ (refer to Figure 3b). These findings highlight the potential of prebiotics and probiotics in mitigating the detrimental effects of p-cresol on skin health and the consequent positive repercussion in AD.

Regulatory cytokines and cells

A substantial body of evidence suggests a close association between skin inflammatory processes and loss of intestinal homeostasis.^114,115 Gut dysbiosis causes “leaky gut syndrome”, characterized by a disruption in the gut epithelial lining that allows the entry of bacteria and other endotoxins into the bloodstream and causes gut and systemic inflammation.¹¹⁶ Gut activated immune cells can migrate into the skin where they cause AD.^117,118 The skin immune response is closely related to the cytokine profile produced in the gut, which is reflected in increased levels of serological inflammatory cytokines.^119–122 Studies using pre- and probiotic administration have demonstrated that the attenuation of gut inflammation leads to a consequent improve in AD symptoms. For example, oral administration of a mixture of probiotics, consisting of Lactobacilli and Bifidobacteria, has been shown to reduce calprotectin levels (a marker for gut inflammation), and exhibited a beneficial effect on the skin, as the SCORAD index and TEWL were reduced.¹²³ In a model of AD induced by DNFB in mice, oral administration of Dendrobium candidum polysaccharides or olive-derived antioxidant dietary fiber led to reduced serum levels of IL-1β, TNF-α, IL-4, IFN-γ, and IL-6, along with increased IL-10. This restoration of cytokine balance contributed to an improvement in AD signs (Figure 4).^124,125

Figure 4.

Modulatory effects of prebiotics and probiotics on Treg cells and cytokines are beneficial in AD. Probiotics and prebiotics decrease levels of gut and systemic inflammatory mediators and increase anti-inflammatory cytokines and Treg cell differentiation. Peripherical Treg (pTreg) Foxp3 cells express molecules of skin recruitment (CLA, CCR4/8), and retention (CD103), and upon arriving in the dermis, are able to modulate atopic dermatitis (AD) inflammation. As result, there is an improvement in the cutaneous barrier and SCORing for AD (SCORAD) index. TNF, tumor necrosis factor; TGF, transforming growth factor; CLA, cutaneous lymphocyte-associated antigen; TEWL, transepidermal water loss. Created with BioRender.com.

Improving the intestinal environment by restoring a balanced microbiota and enhancing intestinal barrier function has been shown to increase the production of regulatory cytokines, which positively impact skin health. Regulatory cytokines, such as IL-10 and TGF-β, are frequently altered in AD patients.^126,127 Therefore, many studies to develop AD therapies focus on restoring the function of regulatory cytokines through probiotic administration.^128,129 This approach aims to rebalance the immune response and improve overall skin health. In AD patients who received the strain L. plantarum CCFM8610, the regulatory cytokine IL-10 increased, accompanied by a reduction in the SCORAD index.¹³⁰ IL-10 is highly expressed by peripherally induced regulatory T cells (pTreg cells) in mesenteric lymph nodes, where they are generated from naive CD4+ T cells into Foxp3+ pTregs. These cells are also detected in the skin.^131,132 As previously mentioned, SCFAs play a remarkable role in the modulation of Treg differentiation. In particular, butyrate has been shown to increase the Foxp3+ cell generation in lymph nodes and spleen, indicating an elevated serum level of IL-10 and facilitating extrathymic differentiation of pTreg. This effect is linked to Foxp3 acetylation, conferring improved stability and function.¹³³ Moreover, butyrate enhances the ability of DCs to promote pTreg differentiation through HDAC inhibition activity, leading to the repression of RelB, a negative regulator of Foxp3 expression.^133,134 In this context, it has been found the orally administered heat-killed L. acidophilus strain L-92 modulates the induction of pTreg in animal models of DNFB-induced dermatitis, increasing the frequency of Foxp3+ cells in spleen and cervical lymph nodes and favoring increased IL-10 and TGF-β expression.¹³⁵

Leukocytes trafficking between lymphoid tissues and peripheral tissues, facilitated by a process known as recirculation, is a crucial aspect of an effective adaptive immune response. This process is tightly regulated by molecules expressed in the target tissue and receptors on immune cells, involving adhesion and migration molecules such as selectins, integrins, and chemokine receptors.¹³⁶ The gut-skin axis describes a mechanism of homeostasis maintenance, where Treg cells migrate from mesenteric lymphoid nodules to the skin to exert their regulatory functions.¹³⁷ Under non-inflammatory conditions, this mechanism enhances tolerance to environmental antigens. During inflammation, the expression of P- and E-selectins in skin microvessels increases, which are essential for leukocyte rolling. Fucosyltransferase VII (FucTVII) expression in Treg cells enables the generation of functional selectin ligands, such as the post-translational modification of the protein core of the P-selectin glycoprotein ligand 1, facilitating the tethering of Treg cells over endothelial cells near inflamed skin.^138,139 Integrins also play a crucial role in the interaction of Treg cells with epithelial cells. The integrin α_E (CD103) β₇ expressed in Foxp3+ Treg cells serves as the ligand for E-cadherin, which is highly expressed in keratinocytes and in dermal DC.^140–143 During the regulation of inflammatory responses, Treg cells, expressing specific chemokine receptors like CCR4 or CCR8, can migrate to the skin. This migration is facilitated by the expression of cutaneous lymphocyte-associated antigen and interaction with E-selectin, particularly in inflamed skin conditions where these molecules are overexpressed.^144–147 When the epithelial barrier is compromised, keratinocytes respond by overexpressing chemokines like CCL22, which attracts Treg cells expressing CCR4 (Figure 4). This orchestrated migration helps in regulating T-cell infiltration, especially Th2 cells, and contributes to the suppression of disease progression.^148,149 Because the migratory capacity of Treg cells induced in the gut plays a crucial role in maintaining cellular communication with the skin, the design of therapeutic strategies for AD directed to target adhesion molecules and chemokines that improve Treg extravasation in skin lesional areas is of great importance. In other skin conditions such as vitiligo, manipulating the expression of chemokines like CCL22 through gene transfers has been shown to impact Treg cell abundance in the skin, suggesting the potential therapeutic implications of modulating these immune responses.¹⁵⁰

In summary, this migratory capacity of Treg cells between the gut and skin exemplifies a dynamic and finely tuned regulatory mechanism that helps to maintain immune homeostasis, prevent inflammation, and contribute to overall skin health, presenting promise potential in the development of AD therapies.

Concluding remarks

The intricate relationship between gut homeostasis and skin health underscores the importance of a balanced microbiota in promoting overall well-being. Disruptions in the gut microbiota can lead to increased intestinal permeability and inflammation, which in turn impact barrier integrity and are linked to the onset of AD. Fortunately, there is substantial evidence highlighting the positive impact of probiotic bacteria and prebiotics in fostering the generation of postbiotic compounds that enhance skin functionality and improve AD symptoms. Their beneficial effects may include a direct increase in the production of structural proteins in keratinocytes or the induction of cytokines and immune cells that play pivotal roles in regulating inflammatory processes in the skin. Understanding the underlying mechanisms of these interactions is crucial for developing effective AD treatment and prevention strategies. This holistic approach, considering the gut-skin axis, holds promise for advancing skin health and addressing various skin conditions. Although much information about the effect of using probiotics and prebiotics points to their usefulness as therapeutic and preventive agents in AD, it is important to consider that other factors such as hygiene and breastfeeding, physical contact with siblings, housing conditions, antibiotic use, cultural dietary habits, contact with pets, use of supplements and hydrolyzed formulas, and genetics, should be considered to implement more integrative strategies that contribute to the patients improvement. As research in this field progresses, it opens exciting opportunities for the development of innovative therapies targeting the skin health of AD patients to achieve outcomes that improve their quality of life.

Funding Statement

The work was supported by a grant from the Autonomous University of Aguascalientes to E.S [PIBB23-1]. Universidad Autónoma de Aguascalientes [PIBB23-1].

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

No new data were created or analyzed in this study. Data sharing is not applicable to this review article.