Gut microbiome provides numerous biological and metabolic functions; the alteration of the intestinal bacteria balance may initiate inflammation through the activity of lipopolysaccharide (LPS), a component of the cell wall of gram-negative bacteria that triggers the inflammatory process by binding to the CD14/Toll-like receptor 4 (TLR-4) complex. GM may influence the metabolism of the host by modulating the tissue composition of fatty acids; the species of Lactobacilli and Bifidobacteria produce bioactive isomers of conjugated linoleic acid with immunomodulating properties, reducing the proinflammatory cytokines. Additionally, intestinal microbiome synthesizes a significant amount of glycosidic hydrolases that decompose plant complexes into monosaccharides and short chain fatty acids (SCFAs) (acetate, propionate, butyrate). SCFAs play an important role in energy metabolism; butyrate provides energy for colonic epithelial cells; propionate affects lipogenesis and hepatic gluconeogenesis, while acetate, at the peripheral level, functions as a substrate for cholesterol synthesis. The mucosal colon depends on the presence of butyrate as a source of energy on the lumen level, and the lack of these SCFAs is considered to play an important role in the pathogenesis of intestinal disease and inflammatory bowel disease.

Probiotics modulate the intestinal microbiome and immune status by improving the intestinal barrier; these effects are responsible for reducing allergic phenomenon and AD severity (6).

Intestinal permeability is increased in AD patients (7). In addition, babies born by caesarean section have a lower colonization with Bacteroides and higher with Clostridium (8). Also, early colonization with Escherichia coli has a protective role for AD (9).

There are 4 strains prevailing on the skin surface: Firmicutes (Staphylococcus, Streptococcus, Anaerococcus, Finegoldia, Veillonella, Lactobacillus, Peptoniphilus), Actinobacteria (Propionibacterium, Corynebacterium, Micrococcus, Kocuria, Actinomyces, Rothia), Proteobacteria (Acinetobacter, Haemophilus, Enhydrobacter, Neisseria, Microvirgula), and Bacteriodetes (Prevotella, Chryseobacterium, Fusobacteria, Leptotrichia). The most common genus is Staphylococcus; within the Staphylococcus genus, the most common species in healthy skin is Staphylococcus epidermidis (10–12).

A reduction of the cutaneous microbiome diversity was reported in AD patients (13), AD being associated with early colonization with Staphylococcus aureus. The cutaneous presence of Staphylococcus epidermidis and Staphilococcus cohnii (11) has proven a protective effect against AD in children. Increased colonies of S. aureus, S. epidermidis, Propionibacteria, Corynebacteria and Streptococcus (11) were isolated in the atopic dermatitis lesions. Another study has found an association between AD severity and the abundance of the genus Corynebacterium and the phylum Proteobacteria. The presence and chronicity of eczema appear to be more important determinants of skin microbiome configuration (14,15).

Other studies have shown that there is also an increase in fungal diversity, as Malassezia restricta, Malassezia globosa and Malassezia dermatis have been isolated in ~90% of patients with atopic dermatitis (16). Several studies have described M. sympodialis as the most abundant in patients with atopic dermatitis and the possibility of its coexistence with a non-Malassezia species called Cryptococcus diffluens (17). In addition, many patients with AD have associated IgE mediated sensitization to Malassezia species, with positive skin prick tests (18,19). The rate of IgE mediated Malassezia sensitization correlates with disease severity (18,20).

The presence of Demodex mites (Demodex folliculorum and Demodex brevis) was not associated with an increased prevalence of AD (21).

Changes in skin microbiome composition were also observed in other dermatological conditions such as rosacea, acne, psoriasis, or seborrheic dermatitis; Demodex folliculorum, Bacillus oleronius, Helicobacter pylori, Staphylococcus epidermidis and Chlamydophila pneumonia were associated with rosacea (14,22–24). In adolescence and adults with acne in the affected areas there were mostly lipophilic Propionibacterium (15).

Preventive/prophylactic avoidance of major allergens during pregnancy and lactation does not protect against AD development during the first 18 months of life (results from a systematic review that included 5 clinical trials, 952 participants) (25).

World Allergy Organisation (WAO) does not recommend the use of prebiotics neither during pregnancy nor during lactation as a preventive measure against atopic dermatitis for lack of solid scientific evidence (26).

In a meta-analysis led by Pelucchi et al (1,619 patients treated/1,475 placebo), there was a modest role of diet supplementation with probiotics in pregnancy to prevent AD in infants (27).

In another meta-analysis published in 2012, conducted by Doege et al (28), that included seven randomised, double-blind, placebo-controlled trials, only the supplementing with Lactobacilli during pregnancy prevented AD in children aged 2–7 years; other probiotic supplements, with or without Lactobacilli, have proven no favorable results (28).

The beneficial effects of the administration of probiotics during pregnancy have been reconfirmed by a recent meta-analysis; this meta-analysis that included over 19 trials (4,076 persons exposed to probiotics/3,700 control group) reported the effect of probiotic consumption during the last part of pregnancy and during the lactation period to decrease AD incidence in children under five years (29).

In some studies, the administration of probiotics started during the first trimester, or after the 36th week of gestation, and continued during breastfeeding (27–29).

Prebiotics administered in the first year of life reduce the risk of asthma or food allergy but the results on atopic dermatitis were inconclusive (26,30).

A systematic review of a meta-analysis that included 8 clinical trials totaling 741 infants, demonstrated the beneficial effect of Lactobacillus-containing probiotics on AD severity reduction (31). Probiotics with Bifidobacterium (3 studies, 73 infants) did not prove beneficial effects; this result should be interpreted with caution due to the small number of subjects included and the heterogenity of the studies. Most studies included in meta-analysis followed patients for a limited time (under 8 weeks). Data previously published revealed a smaller number of Bifidobacteria strains in the children's feces with atopic dermatitis (32,33). However, the conclusion of this article was that infants with moderate and severe AD presented a protective effect of probiotics (28).

In a recent meta-analysis (568 children, 1–18 years; intervention group, 296; control group, 272), there was an improvement in SCORAD reported in children (1–18 years) with AD given probiotics (34). Lactobacillus fermentum, Lactobacillus and a mixture of different strains (Bifidobacterium bifidum, Lactobacillus acidophilus, Lactobacillus casei and Lactobacillus salivarius) improved significantly the SCORAD values in children (34). These data reconfirm the results of the previously published studies (35).

A recent randomized, double-blind, placebo-controlled intervention trial, that included 50 children aged between 4–17 years, reported that the mixture of probiotics (Bifidobacterium lactis CECT 8145, Bifidobacterium longum CECT 7347, and Lactobacillus casei CECT 9104) was effective in reducing SCORAD index (36). The probiotic was administered between 4–12 weeks.

We found several randomized clinical trials and one meta-analysis that have reported beneficial effects of probiotics in AD adult patients (35).

Roessler et al (37) in a double-blind, placebo-controlled, randomized cross-over study, using a combination of the probiotics (Lactobacillus paracasei Lpc-37, Lactobacillus acidophilus 74-2, and Bifidobacterium animalis subsp. lactis DGCC 420) for 8 weeks, observed that the SCORAD tended to decrease. There was an increased number of L. paracasei and B. lactis isolated in AD patient's faeces after supplementation.

Another study conducted by Yoshida et al that used Bifidobactrium breve for 8 weeks in AD patients reported that the severity scoring for atopic dermatitis significantly improved and the proportion of B. breve in intestinal microflora was increased in the probiotic group (38).

Drago et al using L. salivarius for 16 weeks in 38 patients with moderate to severe AD reported an improvement in SCORAD and a significant decrease of T-helper cell type-1 (Th1) cytokines [interleukin-12 (IL-12), interferon (INF)-γ] and Th1/Th2 (IL-12, IFN-γ/IL-4, IL-5) ratio (39); they also reported a significant reduction of staphylococci in faeces in the probiotic treated group.

Iemoli et al (40) using a specific mixture of probiotics (L. salivarius LS01/B. breve BR03) for 12 weeks in 48 adults suffering from moderate to severe AD reported an improvement in SCORAD and of the immunological profile [Th1/Th2 ratio, T-helper cell 17/regulatory T cell (Treg) ratio] and a reduced microbial translocation.

Matsumoto et al (41) reported that oral intake of Bifidobacterium animalis subsp. lactis LKM512 may exert antipruritic effects in adults with atopic dermatitis.

Although these studies are promising, the small number of subjects is limiting the generalization of the results.

Probiotics can reduce the severity of AD by inhibiting the T-helper cell type-2 (Th2) mediated response and improving the Th1/Th2 ratio (46); inhibiting Th2 cell response, cytokines such as IL-4, IL-5, IL-6 and IL-13 are no longer released (47–49), INF-γ decrease (cytokine released by Th1 cells), phagocytosis is stimulated, serum IgA is increased (50). Probiotics also stimulate the secretion of IL-10 and transforming growth factor-β (TGF-β) (22). Probiotics can reduce inflammation by reducing proinflammatory cytokines, IL-4, IL-6, tumor necrosis factor-α (TNF-α), INF-γ and high sensitivity C reactive protein (hsCRP) (51) and by increasing expression of IL-10 and Treg-related cytokines at mesenteric lymph nodes. A new mechanism proposed to demonstrate the effectiveness of probiotics is the inhibition of the mature dendritic cell differentiation and transformation of naive T cells into Th2 (52). Immunomodulation decreases the susceptibility to inflammatory and allergic factors modulating the intestine-skin axis. Probiotics also modulate brain function including stress response on the intestine-brain axis (53).

In newborns, the distribution of different Bifidobacterium species in the faeces influences the prevalence of allergic diseases. In a study that proposed to detect differences in levels of different Bifidobacterium species in faeces of children with allergies compared to healthy ones, significantly higher levels of Bifidobacterium longum were isolated in healthy children, suggesting the role of this strain in preventing the occurrence of bronchial asthma and allergic dermatitis (54).

Medical nutrition therapy plays an important role in modulation of the intestinal microflora. The use of ‘functional food’ as prebiotics, probiotics, natural antioxidant (55,56) was associated with good metabolic effects such as improving digestion and absorbtion of food ingredients and minerals, vitamin synthesis, and thereby improving overall nutritional status and health.

Probiotic consumption can be associated with reduction of blood glucose, insulinemia and insulin resistance (IR) (57). Some probiotic strains have antioxidant effects (58). A recent meta-analysis has shown favorable effects of alanine aminotransferase decrease and IR reduction in patients with non-alcoholic fatty liver disease (59).

In another meta-analysis, the administration of probiotics was associated with a decrease in total cholesterol, triglycerides and low-density lipoprotein (LDL)-cholesterol and increase in high-density lipoprotein (HDL)-cholesterol (60); beneficial effects on the lipid profile are secondary to reducing intestinal absorption of dietary cholesterol and suppressing bile acid reabsorption.

In a systematic review and meta-analysis, Zhang and Silverberg concluded that patients with overweight and obesity had a higher risk of AD; the association was significant in North America and Asia but not Europe (61). The major limitations of this meta-analysis are related to the cross-sectional design of the included studies. A study published in Germany, did not observe an increase in prevalence of AD in patients with metabolic syndrome (obesity, diabetes, hypertension and hyperlipidemia) (62).

The relationship between metabolic disorders (obesity, dyslipidemia) and atopic dermatitis can be mediated by chronic systemic inflammation, proinflammatory cytokines (IL-6, TNF-α and CRP), increased oxidative stress and consequent change in expression of inflammatory genes.