**1. Introduction**

352 Atopic Dermatitis – Disease Etiology and Clinical Management

Won,T.J., Kim,B., Lim,Y.T., Song,D.S., Park,S.Y., Park,E.S., Lee,D.I., and Hwang,K.W. (2011).

Woo,S.I., Kim,J.Y., Lee,Y.J., Kim,N.S., and Hahn,Y.S. (2010). Effect of Lactobacillus sakei

Yoo,J., Omori,M., Gyarmati,D., Zhou,B., Aye,T., Brewer,A., Comeau,M.R., Campbell,D.J.,

Zareie,M., Johnson-Henry,K.C., Jury,J., Yang,P.C., Ngan,B.Y., McKay,D.M., Soderholm,J.D.,

Zheng,T., Yu,J., Oh,M.H., and Zhu,Z. (2011). The atopic march: progression from atopic dermatitis to allergic rhinitis and asthma. Allergy Asthma Immunol. Res. *3*, 67-73. Zutavern,A., Brockow,I., Schaaf,B., Bolte,G., von Berg,A., Diez,U., Borte,M., Herbarth,O.,

in NC / Nga mice. J. Appl. Microbiol. *110*, 1195-1202.

Allergy Asthma Immunol. *104*, 343-348.

birth cohort study. Pediatrics *117*, 401-411.

Med. *202*, 541-549.

stress. Gut.

Oral administration of Lactobacillus strains from Kimchi inhibits atopic dermatitis

supplementation in children with atopic eczema-dermatitis syndrome. Ann.

and Ziegler,S.F. (2005). Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin. J. Exp.

Perdue,M.H., and Sherman,P.M. (2006). Probiotics prevent bacterial translocation and improve intestinal barrier function in rats following chronic psychological

Wichmann,H.E., and Heinrich,J. (2006). Timing of solid food introduction in relation to atopic dermatitis and atopic sensitization: results from a prospective Development of the child's immune system tends to be directed toward a T-helper 2 (Th2) phenotype in infants, whereas postnatal maturation is associated with gradual inhibition of Th2 and increasing Th1 affinity [1]. Thus, immature Th2-dominant neonatal responses must undergo environment-driven maturation via microbial contact in the early postnatal period to prevent development of childhood allergic diseases. Nevertheless, nowadays the increased use of antimicrobial medication, the consumption of sterile food, and reduced family size that result in lower rates of infection during childhood also reduce early contact to microbes. Consequentially, at an early age the infant`s immune system results in subsequent polarization toward a Th2 phenotype during postnatal maturation. Among several other phenomena, the present increase in allergic diseases seen in the industrialized countries has been attributed, to a relative lack of microbial stimulation of the infantile gut immune system and the exaggerated hygiene of the typical western lifestyle during early childhood. And this is known as the hygiene hypothesis [2].

The newborn is first colonized by microbes at birth. The colonization of the gut that begins promptly after birth is affected by mode of delivery, early feeding strategies and the hygienic conditions around the child (the early environment). The colonizing bacteria originate mainly from the mother's gut and vaginal tract [3]. For instance, children born by cesarean section are colonized with Bifidobacteria and Lactobacilli later than vaginally delivered children, and are shown to have more frequent respiratory allergies [4]. After delivery, breastfeeding continues to enhance the original inoculum by the introduction of specific lactic acid bacteria, Bifidobacteria and bacteria from the mother's skin, all of which enable the infant gut microbiota that is dominated by Bifidobacteria. Breast milk also contains plentiful indigestible oligosaccharides, which pass through the whole intestine and promote the growth and activity of commensal bacteria; composed mainly of Bifidobacteria [5]. These bacteria set the basis for gut microbiota development and modulation, along with environmental exposures such as antibiotic administration.

The greatest differences between breast-fed and formula-fed infants appear to be in lactic acid bacteria and Bifidobacteria colonization. Usually, Bifidobacteria appear after birth and, within a week, are reported as the dominant bacterial group, with Bifidobacterium (Bfdbm) infantis / longum / breve being the most common species in breast-fed infants [6]. In addition, Lactobacillus (Lctbs) acidophilus is the most common Lctbs in the feces of breast-

The Role of Probiotics in Atopic Dermatitis Prevention and Therapy 355

are able to induce a host response once they enter the intestinal microbial ecosystem;

Atopic dermatitis (AD) is the most common chronic skin condition in infants and children, with a prevalence of 10- 20% in population. Geographic location affects the prevalence of this disease, with the highest prevalence in the United States and Europe [17]. Important factors in the susceptibility to develop AD include a genetic basis and environmental factors. Eczema refers to a chronic or relapsing itchy skin inflammation with typical lesions and locations. AD has been linked to food hypersensitivity, especially milk and egg proteins. However, 40-60% of children with AD may not develop IgE sensitization [18]. The term eczema has been recently proposed, but for practical purposes, both AD and eczema will be

There have been several proposed methods for classifying the severity of AD in various research studies mentioned in this chapter, but only the Scoring of AD Severity Index (SCORAD), established by the European Task Force on AD, has been validated for reproducibility and accuracy in assessing therapeutic response [17,18]. The SCORAD combines objective measures, such as extent and severity of skin lesions, and subjective criteria, such as pruritus and sleep loss. Children with AD can be further classified as having

mild: (≤25), moderate: (25-50), or severe: (≥50) disease based on their SCORAD score.

**2. Experimental and clinical essentials of preventative and therapeutic** 

As briefly mentioned above, there is a good experimental and clinical theoretical basis for using probiotics in the prevention and therapy of AD. Germ-free animal models demonstrate that bacterial gut colonization is essential for maturation of immune function and induction of oral tolerance. It has been proposed that a similar but more subtle process may be occurring in human beings with progressively cleaner environments. Probiotic intestinal flora is arguably the most abundant source of early immune stimulation and contributes significantly to microbial burden in early life. A number of studies have suggested differences in the early colonization patterns of infants who go on to develop allergic disease. These studies strongly suggest that the pattern of colonization in the first weeks of life may influence the patterns of immune development [19,20]. These notions have been supported by observations that gut flora can influence local and systemic immune responses. There has been speculation that intestinal flora may influence the maturing precursor cells that circulate through the gut before they home to other tissues. This may explain how probiotic species can influence systemic immune responses and IgA production in distal sites, such as the respiratory tract. Together with reported clinical effects in early allergic disease, this has logically led to a growing interest in the role of probiotics in allergy

The gastrointestinal tract of the newborn baby is sterile. Soon after birth, however, it is colonized by many different microorganisms. Colonization is complete after around one week, but the numbers and species of intestinal bacteria fluctuate markedly during the first

remain viable and stable after culture, manipulation, and storage before utilization;

yield a functional or clinical benefit to the host when consumed [10-16].

survive gastric, biliary, and pancreatic digestion;

and

used in this chapter.

**probiotic use in AD** 

prevention [13,14].

**1.2 Atopic dermatitis (eczema)** 

fed infants. Formula-fed infants, on the other hand, tend to have a flora that is more complex, consisting mostly of Coliforms and Bacteroides, with significantly lower the prevalence of Bifidobacteria [7]. After weaning, the microflora of children begins to resemble that of adults, with increased Bacteroides, Veillonella, and Fusobacterium [8].

Epidemiologic data showed that atopic children have a different intestinal flora from that of healthy ones, with higher levels of Clostridia and lower levels of Bifidobacteria. Furthermore, other studies have also shown that early colonization with potentially more pathogenic bacteria such as Clostridium difficile and Staph. aureus is more likely to occur in children who go on to develop allergy. In contrast, lactic acid bacteria and Bifidobacteria are found more commonly in the composition of the intestinal flora of non-allergic children. The enhanced presence of these probiotic bacteria in the intestinal microbiota seems to correlate with protection against atopy [9,10]. Based on these data, "harmless" microbial agents that are probiotics have been presently tested for their efficacy in the prevention and therapy of allergy in infants [11-14].

The interest in probiotic therapeutic potential in allergic disorders stemmed from the fact that they have been shown to improve intestinal permeability and reduce inflammatory cytokines. Such effects would be desirable in treating allergic disorders including atopic dermatitis (AD). Therefore, several studies have been designed to examine the efficacy of probiotics in many allergic conditions, such as eczema and food allergies [13,14]. Including the first publication in 1997, over 30 randomized, double-blind, placebo-controlled clinical trials have been conducted to study the effects of various probiotics on treatment and prevention of allergic diseases. In total, almost 3000 individuals (including those in placebo groups) have participated in these studies so far. In the first-time study done by Majamaa and Isolauri in 1997, the administration of LGG to highly selected patients (age <2 years, challenge-proven cow's milk allergy, and mild-to- moderate eczema) significantly improved the total SCORAD score [15]. Later the Finnish study of Kalliomaki was the first report to describe that the frequency of AD in neonates treated with Lctbs rhamnosus GG (LGG) was half that of the placebo [16]. However, these results recently have been questioned by other trials, which reported no difference in the development and therapy of AD in neonates supplemented with LGG or other probiotics. Therefore, an allergen-preventive or therapeutic effect of probiotics in AD could not be consistently established. The aims of this chapter are to comprehensively define probiotic properties and to characterize current knowledge of probiotics, including the key mechanisms of probiotic effects as well as their preventative/ therapeutic role in AD at last.
