**5. Probitics and atopic disease**

Probiotics acts on atopic diseases modulating initial colonisation, intralumenal degradation of allergens, promoting intestinal barrier function, enhancing immune maturation with induction of IgA production, induction of regulatory T cells. In infancy, food allergy and atopic eczema are the most common atopic disorders. Even though atopic disease often becomes manifest during the course of the first year of life, it is well established that the immune pathology leading to clinical disease has its origins in early life, possibly already in the immune environment prevailing *in utero*. Indeed, infantile food allergy could be considered a manifestation of a primary failure to establish tolerance to dietary antigens rather than loss of tolerance characteristic of allergies in later life. Therefore, measures aimed at reducing the risk of atopic diseases should be started in the perinatal period. Thus far, the rationale of most studies assessing means of primary prevention of atopic diseases has been to reduce exposure to the allergens known to most often be associated with sensitisation and provocation of symptoms in allergic individuals, but the success of such measures has been relatively poor. Consequently, probiotics have been investigated as a novel approach with a number of potential effects which might beneficially affect the host immune physiology to a non-atopic mode.

The immune pathology of atopic diseases is characterised by T helper (Th)2-driven inflammatory responsiveness against ubiquitous environmental or dietary allergens. The factors leading to inappropriate Th2 responsiveness, and thus atopic disease, in early immune development remain poorly understood. Th2-type responsiveness is counterregulated both by Th1 responses, which are usually directed against infectious agents and immunosuppressive, and by tolerogenic regulatory T cell responses. Prescott and colleagues demonstrated that infants with high hereditary risk who subsequently developed atopic disease are characterised by an impaired capacity (compared with healthy infants) to produce both Th1 and Th2 cytokines in the neonatal period. During the first year of life, an increase in Th2 responsiveness is seen in infants developing atopic disease, whereas a reverse development takes place in healthy infants.

In early 2002, the United States Food and Drug administration accepted a "generally regarded as safe (GRAS) the use of *Bifidobacterium lactis* and *Streptococcus thermophilus* in

The clinical efficacy of probiotics in the prevention and treatment of infectious disease in infancy has most comprehensively been documented in diarrhoeal disease. *Lactobacillus* GG or *Lactobacillus reuteri* (ATCC 55730) supplementation has been demonstrated to be effective in the prevention of acute infantile diarrhoea in different settings. *Lactobacillus* GG has also been reported to significantly reduce the duration of acute diarrhoea and the duration of rotavirus shedding after rotavirus infection. Bifidobacteria have also shown promising potential in preventing both nosocomial spread of gastroenteritis and diarrhoea in infants in residential care settings. Meta-analyses of double-blind, placebo-controlled clinical trials have concluded that probiotics, particularly *Lactobacillus* GG, are effective in treatment of acute infectious diarrhoea in infants and children. Probiotics appear also to have some protective effect against antibiotic-associated diarrhoea and acute diarrhoea in children, but the heterogeneity of the available studies precludes drawing firm conclusions (Vanderhoof,

Probiotics acts on atopic diseases modulating initial colonisation, intralumenal degradation of allergens, promoting intestinal barrier function, enhancing immune maturation with induction of IgA production, induction of regulatory T cells. In infancy, food allergy and atopic eczema are the most common atopic disorders. Even though atopic disease often becomes manifest during the course of the first year of life, it is well established that the immune pathology leading to clinical disease has its origins in early life, possibly already in the immune environment prevailing *in utero*. Indeed, infantile food allergy could be considered a manifestation of a primary failure to establish tolerance to dietary antigens rather than loss of tolerance characteristic of allergies in later life. Therefore, measures aimed at reducing the risk of atopic diseases should be started in the perinatal period. Thus far, the rationale of most studies assessing means of primary prevention of atopic diseases has been to reduce exposure to the allergens known to most often be associated with sensitisation and provocation of symptoms in allergic individuals, but the success of such measures has been relatively poor. Consequently, probiotics have been investigated as a novel approach with a number of potential effects which might beneficially affect the host

The immune pathology of atopic diseases is characterised by T helper (Th)2-driven inflammatory responsiveness against ubiquitous environmental or dietary allergens. The factors leading to inappropriate Th2 responsiveness, and thus atopic disease, in early immune development remain poorly understood. Th2-type responsiveness is counterregulated both by Th1 responses, which are usually directed against infectious agents and immunosuppressive, and by tolerogenic regulatory T cell responses. Prescott and colleagues demonstrated that infants with high hereditary risk who subsequently developed atopic disease are characterised by an impaired capacity (compared with healthy infants) to produce both Th1 and Th2 cytokines in the neonatal period. During the first year of life, an increase in Th2 responsiveness is seen in infants developing atopic disease, whereas a

formula milk for healthy infants aged 4 months or more" (Hammerman et al, 2006).

2000).

**5. Probitics and atopic disease** 

immune physiology to a non-atopic mode.

reverse development takes place in healthy infants.

#### **5.1 Use of probiotics for prevention of atopic diseases**

As previously mentioned, the sequence of bacterial intestinal colonization of neonates and young infants is important in the development of the immune response. Recognition by the immune system of self and nonself, as well as the type of inflammatory responses generated later in life, are likely affected by the infant's diet and acquisition of the commensal intestinal bacterial population superimposed on genetic predisposition.

During pregnancy, the cytokine inflammatory-response profile of the fetus is diverted away from cell-mediated immunity (T-helper 1 [Th1] type) toward humoral immunity (Th2 type). Hence, the Th2 type typically is the general immune response in early infancy. The risk of allergic disease could well be the result of a lack or delay in the eventual shift of the predominant Th2 type of response to more of a balance between Th1- and Th2-type responses (Neaville, 2003).

Administration of probiotic bacteria during a time period in which a natural population of lacticacid– producing indigenous intestinal bacteria is developing could theoretically influence immune development toward more balance of Th1 and Th2 inflammatory responses (Majamaa & Isolauri, 1997). The intestinal bacterial flora of atopic children has been demonstrated to differ from that of nonatopic children. Specifically, atopic children have more Clostridium organisms and fewer Bifidobacterium organisms than do nonatopic study subjects ( Björkstén et al, 1999; Klliomaki et al, 2001), which has served as the rationale for the administration of probiotics to infants at risk of atopic diseases, particularly for those who are formula fed.

In a double-blinded RCT, LGG or a placebo was given initially to 159 women during the final 4 weeks of pregnancy. If the infant was at high risk of atopic disease (atopic eczema, allergic rhinitis, or asthma), the treatment was continued for 6 months after birth in both the lactating woman and her infant (Kalliomäki et al, 2003). A total of 132 mother-infant pairs were randomly assigned to receive either placebo or LGG and treated for 6 months while breastfeeding. The primary study end point was chronic recurrent atopic eczema in the infant. Atopic eczema was diagnosed in 46 of 132 (35%) of these study children by 2 years of age. The frequency of atopic eczema in the LGG-treated group was 15 of 64 (23%) versus 31 of 68 (46%) in the placebo group (RR: 0.51 [95% CI: 0.32– 0.84]; P = .01). The number of mother-infant pairs required to be treated with LGG to prevent 1 case of chronic recurrent atopic eczema was 4.5. By 4 years of age, eczema occurred in 26% of the infants in the group treated with LGG, compared with 46% in the placebo group (RR: 0.57 [95% CI: 0.33– 0.97]; P =.01). However, only 67% of the original study group was analyzed at the 4-year follow-up. These results support a preventive effect for giving a probiotic to mothers late in pregnancy and to both mothers and infants during the first 6 months of lactation for the prevention of atopic eczema in infants who are at risk of atopic disease.

Conversely, Taylor et al (2007) found that probiotic supplementation did not reduce the risk of atopic dermatitis in children at high risk with the report of some increased risk of subsequent allergen sensitization. As concluded in a review by Prescott and Björkstén (2007) and in a 2007 Cochrane review (Osborn & Sinn, 2007) despite the encouraging results of some studies, there is insufficient evidence to warrant the routine supplementation of probiotics to either pregnant women or infants to prevent allergic diseases in childhood. Explanations for varied study results include host factors such as genetic susceptibility,

Intestinal Microbial Flora – Effect of Probiotics in Newborns 11

sometimes it is necessary the continuous or discontinuous enteral feeding, via nasal-gastric

The passage from enteral nutrition to nursing depends on the acquisition of sucking, deglutition, epiglottis and larynx closure ability and on the nasal passage, as well as the esophageal motility and a synchronized process is usually absent before 34 weeks of gestation. The sucking ability is usually reached when the infant has a weight over 1500 gr even if sometimes it is necessary to proceed with the tactile stimulation of the infant tongue

Enzymatic digestive functions in preterm more than 28 weeks of gestation are mature enough to allow the adequate digestion and absorption of proteins and carbohydrates. Lipids are well adsorbed and unsaturated fatty acids and lipids in maternal milk are better

The weight gain in infants with a birth weight less than 2000 gr should be adequate when the mother shows a protein intake of 2.25-2.75/Kg/die, because they should provide a good intake of essential aminoacids, in particular tryptophan and threonine, that are important

The maternal milk, through specific immunologic factors, can potentiate the defensive mechanisms of preterms, contributing to ameliorate the immune defense against infectious agents. Recent studies highlighted that the maternal milk not only promote a passive

The maternal milk contains immunologic and non-immunologic factors, and immunemodulant factors, such as the bifidogenic factor, that promotes the development of the *Lactobacillus Bifidus,* that by competition promotes the decrease of the intestinal pH and inhibits the growth of *Escherichia Coli.* The maternal milk must be fortified, while the formula for preterm infants do not contain the bifidogenic factor (Heiman & Schanler, 2007) **.** It is also well established that the composition of the intestinal microbiota is aberrant and its establishment delays in neonates who require intensive care, with an increased risk of developing NEC. As discussed above, probiotics have been shown to enhance the intestinal barrier, inhibit the growth and adherence of pathogenic bacteria and to improve altered gut micro-ecology In preterm infants, administration of the probiotic *Lactobacillus* GG has been shown to affect colonisation patterns. Data from experimental animal models suggest that bifidobacteria reduce the risk of NEC in rats. Consequently, it could be hypothesised that

protection, but can directly modify the immunologic development of the infant.

probiotics might have potential in reducing the risk of NEC in premature infants.

The supplementation of probiotics since the first day of life represents a valid help in influencing the growth of a favourable intestinal ecosystem, decreasing the quote of Clostridium, Bacillus and Bacteroides Fragilis and increasing the rate of bifidobacteria, also improving the intestinal barrier with a way of action similar to that of the maternal milk, protecting the gut from bacteria and fungal colonization, avoiding the development of NEC.

Necrotizing enterocolitis (NEC) is a serious anoxic and ischemic disease particularly affecting premature newborns, affecting almost the ileo-colic area, with bacteria

tube, in order to suspend the parenteral nutrition.

adsorbed than the components of the formula milk.

**7. Probiotics and necrotizing enterocolitis** 

(Tsang et al, 2005).

for the cerebral development.

environmental factors such as geographic region and diet, and study variables including probiotic strains and doses used (Prescott & Björkstén, 2007; Penders, 2007).

#### **5.2 Use of probiotics in the treatment of atopic diseases**

In an RCT, 53 Australian infants with moderate-to-severe atopic dermatitis were given either Lactobacillus fermentum or placebo for 8 weeks. At final assessment at 16 weeks, significantly more children who received the probiotic had improved extent and severity of atopic dermatitis as measured by the Severity of Scoring of Atopic Dermatitis (SCORAD) index over time compared with those who received placebo (P = .01) (Weston et al, 2005; Viljanen et al, 2005). These results are encouraging, but as summarized in a 2008 Cochrane review (Boyle et al, 2008), probiotics have not yet been proven to be effective in the treatment of eczema.
