The adult human intestine includes a complex ecosystem of microorganisms referred to as gut microbiota (1). The intestinal microbiota is linked to important functions in the host, including digestion of fermentable carbohydrates into short-chain fatty acids (SCFAs) used as an energy source for intestinal cells; production of key nutrients such as essential vitamins and amino acids; protection against pathogens and regulation of the immune system (2,3,4,5). Under normal conditions, intestinal barrier function is highly efficient due to a complex network of mechanisms including a mucus layer, junction proteins, antimicrobial factors, and adaptive immune cells (5,6). However, changes in both the quantitative and qualitative composition of the microbiota, designated as intestinal dysbiosis, potentiates the disruption of these conditions, resulting in loss of homeostasis and, consequently, contributing to a disease state (4,7,8,9). This connection between the gut microbiome and human health foresees that the factors affecting microbial composition can indirectly modulate disease states. Among these, the inclusion of probiotics in the host's diet plays a prominent role, both for its nutritional value and easy digestion, and for the growing predisposition of individuals to consume foods perceived as healthy (3,6,10,11,12). Traditional kefir, originating in the Caucasus Mountains, has been consumed for centuries. Current knowledge supports the historical consideration of kefir as a health-promoting natural food (13,14,15), and this review aimed to explore the impact of probiotics from kefir as regulators of the gut-skin axis.
The intestinal microbiota and its by-products have been shown to affect other organic systems, including the skin, thus demonstrating the existence of a gut-skin relationship (16,17,18). This influence can manifest itself directly via modulation of the immunological response, or indirectly through the secretory activity of the intestinal epithelium and the impact of the host's diet (19,20,21).
Alterations in the balance of the gut-skin relationship are associated with dysfunctions both at the gastrointestinal and skin levels. Changes in the intestinal microbiota associated with increased intestinal permeability can impact the immune system, thus promoting systemic inflammation, and allowing the direct migration of inflammatory products into the circulation. When these products reach the skin, skin homeostasis can be impaired, thus reinforcing the existence of a link between the intestinal microbiota and dermatological diseases (1,3,4,22,23). Although the mechanisms of action are still unclear, considering the current knowledge, the response to intestinal environmental changes seems to involve a combination of factors that lead to a state of systemic inflammation, thus affecting the skin. Moreover, intestinal dysbiosis has been found to be a common factor in inflammatory skin diseases such as atopic dermatitis, rosacea, acne, and psoriasis, thus supporting the bidirectionality of this axis (22,24,25,26).
Probiotics in the modulation of the gut
By definition, probiotics are live microorganisms that confer a health benefit to the host when administered in adequate amounts (27). However, growing evidence suggests that non-microbial components, such as microbial metabolites and cell wall compounds, can also positively affect human health (16,28,29). In addition to their nutritional benefits, the use of probiotics has been widely associated with improved intestinal health, whether by improving the intestinal barrier function, modulating the immune system and antimicrobial effect against intestinal pathogens, or by producing metabolites with anti-inflammatory action, such as SCFA acetate, propionate, and butyrate (5,28,30,31,32,33,34,35). The mechanisms of action, however, have yet to be fully identified. Moreover, no product with health claims associated with the administration of probiotics has yet been approved by the European Food Security Authority (EFSA) (36).
Probiotics and skin health
The integrity of the skin barrier is critical for skin defense and immune performance (35,37,38). Immune skin diseases such as rosacea, acne, and atopic dermatitis are associated with the breakdown of the skin barrier, whereas its restoration is associated with an improvement in clinical outcomes (38,39,40,41).
Probiotics can modulate the immune response locally or systemically (1,6,23,24,40). Topical application of probiotics reduces pro-inflammatory molecules, hence controlling the spread of skin inflammation in acne, and produces anti-inflammatory molecules via dendritic cells in atopic dermatitis (AD) (16,22,42). In addition to improving the intestinal barrier function, oral administration of probiotics can modulate the immune response and reduce systemic inflammation, thereby improving skin health through the gut-skin axis (22,23,41). Research on the contribution of probiotics to skin health has focused on skin conditions such as AD, acne, wound healing, and skin barrier improvement (17,18,22,26,41,43,44). Furthermore, increasing evidence suggests that in addition to the microbial effect, non-microbial components such as microbial metabolites and cell wall compounds may also have beneficial effects, including benefits to skin health (16,28,29,45).
Immunological modulation of probiotics and skin health
The immunological impact of probiotics has been demonstrated by their ability to upregulate regulatory T cells (Treg) and Type-1 T-helper (Th1) cells, responsible for the production of anti-inflammatory cytokines such as interleukin-10 (IL-10), in addition to their ability to downregulate Type-2 and Type-17 T-helper cells (Th2 and Th17, respectively) responsible for the production of pro-inflammatory cytokines such as interferon (INF)-γ, interleukin-4 (IL-4) and interleukin-5 (IL-5) (5,46). Furthermore, probiotics also suppress the maturation of dendritic cells leading to inhibition of naive T cell differentiation into Th2 cells, thus fighting skin inflammation (35,47,48,49).
The role of microbial metabolites of probiotics in skin health
Several bacterial metabolites can enhance immunological response, thus leading to beneficial dermal effects (29). Lactic acid is the major product of metabolization of carbohydrates by either homo- or heterofermentative lactic-acid bacteria (LAB), which can be produced in sufficient concentrations to exhibit antibacterial activity against most pathogenic dermal bacteria (29,45,50,51). Lactic acid has been documented as part of the natural moisturizing factor (NMF) that retains moisture in the skin, and it plays important roles in the physical properties of the stratum corneum (29). Acetic acid, also produced by heterofermentative LAB, has been shown to exert antibacterial effects on different bacterial species, likely due to its pH lowering capability, thereby creating an environment unsuitable for pathogen growth (29,45). Diacetyl can also be produced by some strains of Lactobacilli and Bifidobacteria at concentrations that suggest its potential dermal antimicrobial activities (45). Lipoteichoic acid (ALT) and peptidoglycan (PG) are structural components of cell walls and play a vital role in their growth and physiology, with evidence that their production by LAB can be sufficient to increase the dermal cell defense against bacterial infection (29,45). Moreover, PG from Lactobacilli demonstrated the ability to stimulate an immune response, thus contributing to skin protection (2,9,23), and can be effective even at low concentrations by synergism with LTA (25). Hyaluronic acid (HA), widely utilized in dermatology as a biomaterial and in the promotion of wound healing due to its highly osmotic nature, is relevant in controlling tissue hydration during inflammatory processes (52). To date, only certain strains of Lactobacilli are known to produce HA (45). Finally, sphingomyelinase (SMase), an enzyme that generates ceramides and sphingomyelin precursors necessary for the development of extracellular lipid bilayers in the stratum corneum, has demonstrated important activity for skin barrier function (29,53). SMase can be produced by strains of Lactobacilli and Bifidobacteria at sufficient concentrations to promote ceramide production in skin cells with the possibility to improve barrier properties (45).
Probiotics in Atopic Dermatitis
AD is a chronic inflammatory skin disease associated with an exacerbated skin response to environmental agents that, together with the disruption of the skin barrier integrity, promote a decrease in the antimicrobial response, thus enabling abnormal skin inflammation (38,54). Although the etiology remains unclear, AD onset points towards a complex interaction between skin barrier dysfunction, immune dysregulation, environmental risk factors, and dysbiosis of the intestinal and skin microbiota, which correlates with its clinical severity (54,55,56,57).
Immunological imbalance has been reported in AD patients, namely a decrease in Treg cells and an increase in Th2 cells and Th17 cells in the acute phase of the disease, whereas Th1 cells were associated with the chronic phase (23,26). Th17 cells were also positively correlated with AD severity (58). Current research has focused on the immunomodulatory effect of probiotics, as they are able to stimulate Treg cells and suppress Th2 cells mediated responses, which are the predominant immune responses in AD (23,26,41,46,59,60,61,62,63). However, evidence supporting their use for the treatment and prevention of AD is limited (40,41,61,64,65,66,67,68).
The composition of the gut microbiota has been shown to be different in AD patients, which helps support the hypothesis that aberrant gut microbiota may underlie the onset or worsening of AD (23,59,69). Through the gut-skin axis, intestinal dysbiosis has the ability to negatively impact skin function, either by increasing epithelial permeability via pro-inflammatory cytokines, thus promoting immune dysregulation and contributing to the chronic systemic inflammation in AD, or by perpetuating pruritus via secretion of neuroendocrine itch mediators, leading to a chronic itch-scratch cycle, thus further disrupting the skin barrier (47,54,70,71). Consequently, the gut-skin axis may be receptive to modulation via dietary modification, which represents a potential complementary alternative in AD therapy (6,13). Despite growing evidence that probiotics can improve the intestinal disorders associated with AD, their use has not always proven to be effective, as the observed decrease in gut permeability may be insufficient to cause a discernible disease improvement (59,63,65).
To date, research conducted in vivo in human adults on the impact of probiotics on AD is scarce (40,41,48,59,61). Typically studied probiotics are Lactobacillus, Bifidobacterium and Saccharomyces boulardii, both isolated or in combination. In this sense, and due to the lack of consistency of the results obtained, it is plausible that some of the observed effects may be dependent on strains or species used, as well as on the microbial diversity and potential synergisms between microbes (26,44,63,72,73,74).
Kefir, a traditional and trendy probiotic beverage
Traditional kefir production uses kefir grains as a starter culture for the fermentation of milk, differentiating it from other fermented foods (75). The microorganisms present in the grains are responsible for the lactic, acetic, and alcoholic fermentation of the milk, originating a product with a viscous texture, a sour and slightly acidic taste, and a low alcohol and carbonation content (76,77). Although these microbiological mixtures may not be fully defined, this product is considered acceptable for human consumption by EFSA due to its long tradition of food production using the traditional fermentation substrate (e.g., cow milk) (36,78).
Currently, the growing demand for healthy foods has encouraged the consumption of kefir, drawing the attention of the food industry into its industrial production. However, due to the microbiological complexity of the kefir grains, maintaining the product quality in industrial production is problematic (79). Additionally, secondary yeast fermentation during storage compromised attempts to package traditionally produced kefir, further contributing to limit its large-scale production (80). Thus, pure cultures, composed of a mixture of bacteria with or without yeast, are used in current kefir-like industrial products. Despite their similar flavor, some of the health benefits typically ascribed to traditional kefir may not occur, in part due to this change in microbial diversity (77,81,82).
The microbiological composition of the fermented beverage is different from that of the grains and varies depending on its origin and cultivation method (75,83). The nutritional composition is influenced by the type of milk, the time and temperature of fermentation, and the storage conditions (51,84,85). Even so, traditionally produced kefir fulfills both microbiological and nutritional requirements (86,87).
The lactic acid produced by LAB and the presence of acetic acid produced by acetic-acid bacteria act as natural preservatives, resulting in a low contamination risk for the traditional homemade product (31,88). LAB also contribute to the organoleptic properties of the beverage by producing volatile compounds (e.g., acetaldehyde and acetyl), exopolysaccharides, and free amino acids (89,90). Yeasts produce alcohol and carbon dioxide that contribute to the characteristic mouth feel and taste of kefir (51). The biochemical composition of kefir is reflected in its nutritional value, which is typically around 3% protein, less than 10% fat, and at least 0.6% lactic acid, according to the Codex criteria (86). Kefir can be refrigerated to maintain a shelf life of 3–12 days (77,81,91).
Health effects of kefir
Several health-promoting properties have been ascribed to kefir consumption (14,50,51,84,92,93,94,95). However, to date, most studies have been conducted in vitro with undigested kefir, or in animal models, thus limiting the prediction of the biological activity of kefir in humans (96,97,98). Among the reported health activities of kefir are the improved lactose digestion, hypocholesterolemic effect, reduction of insulin resistance and antihypertensive effect, anti-inflammatory effect, antimicrobial activity, antioxidant activity, antitumor activity, endothelial dysfunction, wound healing, modulation of the immune system and inhibition of pathogenic microorganisms (28,31,52,88,99,100,101,102,103,104). In vivo human studies using kefir, however scarce, have been able to support some of these health benefits such as anti-inflammatory activity, hypocholesterolemic effect, and intestinal integrity conditions (107,109,126,127).
These putative beneficial health properties can be attributed both to the complex microbial fraction of kefir that has shown in vitro an ability to colonize the human gut and modulate intestinal microbiota composition (98,112,124), and to the non-microbial fraction containing bioactive metabolites resulting from fermentation (32,76,100,102,105,106), including lactic acid, acetic acid, ethanol and CO2, vitamins, peptides, polysaccharides (such as kefiran), bacteriocins, acetaldehyde and diacetyl (74,98,108,110,111). The role of the lactic acid has been highlighted. In addition to down-regulating pro-inflammatory responses at intestinal level (33,34,108), lactic acid can be used by the gut microbiota to produce acetate, propionate, and butyrate. These SCFAs are highly associated with intestinal health and the modulation of the immune response (5,62,98,112). Furthermore, the antimicrobial capacity of kefir, mainly attributed to the presence of organic acids and other inhibitor compounds such as bacteriocins, has also been demonstrated in vitro (28,31,106). Its peptides have been linked to anti-hypertensive, antimicrobial, immunomodulatory, and anti-oxidative properties (14,108,113,114). Moreover, the water-soluble polysaccharide kefiran has demonstrated in vitro resistance to enzymatic intestinal hydrolysis (77,89,108,115,116,117), therefore becoming available to act as a substrate to the beneficial gut microbiota (118). Additionally, anti-tumor, anti-fungal, anti-bacterial, anti-hypertensive, anti-glycemic, laxative, immunomodulatory, anti-inflammatory, healing, and antioxidant properties of kefiran have been reported (100,102,116,118,119,120).
Modulation of the gut by kefir
The ability of kefir to positively impact both the intestinal microbiota and the general condition of the digestive system has been demonstrated in vitro, in animal models, and in a limited number of human trials, where its potent anti-inflammatory effect has been frequently noted (93,96,98,108,112,121,122,123,124,125). Recent research in humans on the putative modulation of intestinal microbiota showed that after the consumption of kefir, individuals with metabolic syndrome presented positive correlations between the composition of the intestinal microbiota and improvement of the insulin profile, decreased levels of pro-inflammatory cytokines (such as Tumoral Necrosis Factor (TNF)-α and IFN-γ) and lower blood pressure (126). In addition, another study in humans demonstrated the ability of kefir to modulate the composition of the intestinal microbiota by increasing the concentration of serum zonulin, thus avoiding disruption of the intestinal permeability (109). Thereby, the positive impact of kefir in the host’s gut microbiota suggests that regular kefir consumption may reduce the risk of intestinal dysbiosis and, consequently, could improve the outcome of diseases, such as those with an inflammatory component (127,128).
Effect of kefir on the skin
Research regarding the impact of kefir on the skin thus far has been limited to in vitro and animal studies and to the beneficial effect of its topical application on wound healing (52,102) and anti-inflammatory and antimicrobial activity (52,102,119). A recent study exploring the impact of oral administration of a kefir yeast (Kazachstania turicensis) in AD using an animal model verified a beneficial effect on the modulation of the gut microbiota as well as in the immune response, thus increasing the potential of kefir as a possible application in AD (121).
Noteworthy, none of the in vivo human studies found in the literature assessed the impact of a diet containing traditionally homemade kefir as the probiotic, neither in healthy nor atopic skin (5,112).
This work provided an overview of the impact of probiotics on the gut, and their potential effects on the skin, as a gut-skin axis appears to exist. In addition, current knowledge regarding the role of probiotics in skin health was presented.
Intestinal dysbiosis promotes the occurrence of low-grade systemic chronic inflammation; hence modulation of the intestinal microbiota may represent a promising strategy for the prevention and treatment of cutaneous and non-cutaneous disease states. The use of fermented foods with probiotic activity, such as kefir, may represent an excellent nutritionally based alternative therapeutic strategy via intestinal modulation. Kefir stands out as a probiotic with potential to regulate the gut-skin axis, both for its nutritional and microbiological value, and supported by the historical safety of its consumption and its wide availability and growing popularity. However, scientific literature regarding the impact of a diet containing kefir on skin health is limited, making it essential to identify the effects of kefir in greater depth, as well as its mechanisms of action, in well-controlled human intervention studies. Thus, this review demonstrates the need for further in vivo studies in humans to assess the impact of traditional kefir on skin conditions both in healthy and diseased skin, particularly in individuals presenting AD.
Conflict of Interests
The editors involved in this manuscripts’ authorship had no participation in the review or decision process. All authors have stated that there are no financial and/or personal relationships that could represent a potential conflict of interest.
Author Contributions Statement
CR, LMR, PR and EA: conceptualization and study design; EA: drafting; EA, PR and CR: drafting editing and reviewing.
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