**6. Probiotics in atopic dermatitis**

*Human Microbiome*

bifidobacteria are good candidates as probiotics with an appropriate life span, no toxic or pathogenic properties, and no inflammatory induction. The selection of the bacteria as probiotics is mainly based on no harmful side effects during the history of their use for a long time. Consumption of these probiotics aid in balancing the ratio of the intestinal flora, avoiding the inhabiting of the pathogens by preventing the binding of them to the host cells, and suppressing the inflammation, which all are as the result of immune system regulation [60]. The effects of probiotics vary

But the problem of the probiotics is their longevity and residence in the body of the host, as it was seen that they only remain during the administration period and

Long-term effects of probiotics in different periods of everyone's life need to be

As it was mentioned, immune tolerance is one of the necessary immune reactions to stop excessive inflammatory reactions. Preservation of this tolerance involves the integrity of the epithelial barrier that is heightened by commensal anaerobes, such as *Clostridium* spp. [15, 16, 66, 67], *Bacteroides fragilis* [68], and *Clostridium* spp. [66, 67], which are potent inducers, persuading Foxp3þ Treg differentiation to maintain mucosal tolerance and intestine integrity. Clostridia class also has adaptation properties in the intestinal cells to the routine exposure of an extended range of the antigens. This adaptation is acquired by the effect of IL-22 secreted by innate lymphoid cells which control enterocyte proliferation, activating

Immune homeostasis develops in the gut as a relationship between the intestinal microbiota, the luminal antigens, and the epithelial barrier is established. Microbial intestinal colonization starts after conception. This happens when the newborn's sterile gut is slowly colonized by environmental bacteria and by interaction with the mother's intestinal flora and surroundings and probably by genetic factors [70–72]. Exposure to microbial flora early in life causes a transition in the T helper cell type-1

An infant's immune system at birth is not completely formed and appears to be geared toward a Th2 phenotype to prevent in utero rejection [74]. Nevertheless, the Th2 phenotype results in a stimulated production of IgE by B cells and therefore raises the risk of allergic reactions by mast cells activation [75, 76]. Early in life microbial stimulation will reverse the Th2 bias and promote the expansion of the Th1 phenotype and promote Th3 cell activity [76]. In this way, their combined activity will lead to B-cells releasing IgA. IgA contributes to the elimination of allergens and hence would reduce the immune system's response to antigens. Th1 phenotype-produced cytokines will also reduce inflammation and promote toler-

The hygiene concept states that inadequate or aberrant exposure to environmental microbes is one of the triggers of allergy production and related diseases [78]. As mentioned before, allergic diseases are associated with a change in the Th1/Th2 cytokine balance leading to Th2 cytokine activation and interleukin-4 (IL-4), IL-5, and IL-13 activation as well as IgE production [79, 80]. Probiotics significantly alter the gut microenvironment by encouraging a shift in local microflora and cytokine secretion [81] and can potentially modulate enterocyte Toll-like receptors and proteoglycan recognition proteins, resulting in dendritic cell (DC) activation and a Th1 response. The resulting stimulation of Th1 cytokines can suppress reactions to Th2 [82].

not after that, showing the transient colonization of the probiotics [61–65].

with the dose, strain, and duration of consumption and timing.

the secretion of the mucus and antimicrobial production [16, 69].

**5. Probiotics' mechanisms of action in allergic disorders**

(Th1)/Th2 cytokine balance, promoting a Th1 cell response [73].

ance toward specific antigens [77].

more investigated in complementary studies.

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Atopic dermatitis (AD) is a widespread chronic inflammatory skin condition with a prevalence of around 20% in children and 2–5% in adults worldwide [83]. In recent years, the function of the intestinal microbiota in the aetiopathogenesis of AD has become increasingly important. Atopic dermatitis probiotic therapy is widely studied, with contradictory outcomes [84]. Probiotics containing *Lactobacillus* spp. for the treatment of infantile atopic dermatitis showed beneficial effects in children. Caution should however be raised when treating children under the age of 1 years of age [85]. In addition, mild subjects are exceptions to that beneficial effect. More studies could be informative in investigating the efficacy of *Bifidobacterium* strains. Further larger studies in the treatment of pediatric AD are also required to examine the health, dose-response profile, and long-term impact of probiotics [86].
