A Systematic Review On The Role Of Probiotic Supplementation In Primary Prevention Of Eczema In Infants.

1. Abstract:

Eczema is a hypersensitivity reaction mediated by the immune system and is the most common allergic disease in infancy. The incidence of allergies has been increasing in the Industrialised world due to changes in environment and lifestyle. The ‘hygiene hypothesis’ proposes that the immune system has less exposure to environmental allergens, affecting its development and leading to an imbalance in immune responses and allergic disease. The underlying principle of probiotic use in infancy is to modify the gut microbiota and consequently modulating the immune response and minimising allergy development. Recent studies have shown beneficial effects of probiotic supplementation and eczema development. However the probiotic strain, dosage and time of intervention varies greatly between the different studies, with varying results. Lactobacillus rhamnosus supplemented to mothers before birth and to infants from birth to 6 months has shown the most beneficial results in primary prevention of eczema in infants. Keywords: Eczema, atopic dermatitis, prevention, microbiota, probiotics, prebiotics, immune regulation, infants

Introduction

1. Purpose of the study

The purpose of this research is to determine which probiotics play a role in the prevention of eczema in infants.

1. Context of the study

2.2.1 Aetiology and incidence of allergies and eczema

Eczema is an inflammatory allergic reaction occurring in the skin, mostly in infants and young children. It consists primarily of itchy, inflamed patches on the face and flexural areas like the knees and elbows (Bratman, 2007). It is considered a widespread allergic disease with prevalence of eczema ranging from less than 2% in Iran and China to around 20% in Australasia, England, and Scandinavia (Williams et al, 2008). The clinical pattern of eczema differs with age and infants usually present with erythamatous papules and vesicles on their cheeks, forehead and scalp that are extremely itchy. Approximately 45% of eczema cases occur before 6 months, and later increases to 65% by 1 year of age.

The patho-physiology of eczema is due to a complex interaction between susceptible genes, the environment, microbes, skin barrier function and the immune response (Akdis et al, 2006).

There has been an increase in the prevalence of allergic disease in the industrialized world for many years (Sironi et al, 2010). Pathologically the development of Immunoglobulin E (IgE) antibodies against environmental antigens is a characteristic feature of allergic disease (Valenta et al, 2008).

David Strachan hypothesized in 1989 that there is a connection between the increase in hygiene in the western world and the increased incidence of allergies and asthma, and coined the term the ‘hygiene hypothesis’ (Clough et al, 2011). He postulated that if the immune system had less exposure to various environmental allergens, this may hinder immune development and lead to immune dysregulation. Epidemiological evidence supported the hygiene hypothesis by showing that allergies are less frequent in (Sironi et al, 2010)

• Families with a large number of siblings

• Children who attended day care in early life

• Children who grew up in rural/farm areas compared to those in the city

• Having a pet cat or dog in the first few years of life

The increased hygiene in populations has caused a decrease in various pathogens in the body that resulted in immune dysregulation and an increase in conditions related to an inappropriate immune response (Sironi et al, 2010). Current research is focusing on the role of commensal bacteria or microbiota and the immune system, that may reinforce the hygiene hypothesis.

Immunologists tried to explain this paradoxical phenomena by investigating T-helper lymphocytes type 1(Th1) and T-helper lymphocytes type 2(Th2) reactions of the immune system (Sironi et al, 2010). T lymphocytes mediate cellular immunity and can be divided into two groups, namely CD8+ T-lymphocytes (Tc) and CD4+ T-helper lymphocytes (Th). T-helper lymphocytes are further separated into Th1 and Th2 based on the cytokines they produce. Th1 lymphocytes generate interleukin 2 (IL-2), tumour necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ). Th1 lymphocytes are cell mediated and are associated with the release of pro-inflammatory cytokines, delayed type hypersensitivity responses and autoimmune conditions (Boon et al, 2006). Th2 lymphocytes produce anti-inflammatory cytokines and is part of humoral immunity. Th2 lymphocytes produce cytokines interleukin 4 (IL4), interleukin 5 (IL5) and interleukin 10 (IL10) (Boon et al, 2006). Over activation of these Th2 lymphocytes results in allergic disorders, mainly a type 1 hypersensitivity allergic reaction. However, many chronic inflammatory conditions resemble the delayed cell based hypersensitivities of Th1 mediated reactions (Sironi et al, 2010). Onset of acute eczema has been associated with an increase production of Th2 cytokines IL4 and IL13, however the Th2 cytokine IL5 prevails in chronic eczema (Akdis et al, 2006).

The Th1/Th2 paradigm could not hold up the hygiene hypothesis alone, but the discovery of T regulatory ( T _reg ) cells could help support it. T _reg cells have shown the ability to modulate immune reactivity and inflammation, and therefore are able to dampen the immune response (Boon et al, 2006). Over activation of Th2 type responses leads to an overproduction of cytokines and therefore allergic diseases. However the presence of T _reg cells prevents disease manifestations by suppressing Th2 activity. T _reg cells are divided into natural regulatory T cells (any T cell that can suppress the immune system) and adaptive or induced T regulatory cells (formed due to certain inhibitory cytokines or in the absence of favourable antigen exposure). T _reg cells can move to peripheral circulation and suppress the immune system locally. In individuals affected with atopic dermatitis T _reg cells are absent within the skin lesions (Nandakumar et al, 2009).

The increased hygiene in populations has seemingly caused a decrease in various potentially beneficial pathogens in the body and therefore the T _reg cells were not stimulated to differentiate. This results in an immune dysregulation and an increase in conditions related to an altered immune response (Sironi et al, 2010).

2.2.2. Diagnostic criteria of eczema and treatment

Diagnostic criteria for atopic eczema is itchy skin and at least 3 of the following:

• History of itch in skin creases (or cheeks if < 4 years old)

• History of asthma/hay fever ( or in a first degree relative if <4 years old)

• Dry skin

• Visible flexural eczema ( cheeks, forehead, outer limbs if <4 years)

• Onset in first 2 years of life

(Boon et al, 2006)

Treatment of eczema comprise of topical treatments of emollients, topical glucocorticosteroids and antimicrobials, pimecrolimus and tacrolimus. Systemic treatment in severe eczema includes antibiotic treatment, oral corticosteroids, cyclosporine A and antihistamines. Apart from the high financial cost of eczema treatment, long term corticosteroid therapy has serious side effects. Topical corticosteroids can lead to skin atrophy and secondary infections in infants. And due to the larger skin surface area to body mass seen in infants, their systemic absorption is higher than in adults, leading to possible hypothalamic-pituitary-adrenal axis suppression. (Papp et al, 2005)

Atopic dermatitis has a financial burden that can be compared with that of asthma, and the family stress related to the care of children with eczema is greater than that of the care of children with type 1 diabetes mellitus (Williams et al, 2008). Analysis of the Tasmanian Longitudinal Health Study showed childhood eczema increased the likelihood of childhood asthma. An increased risk of new-onset asthma in later life and asthma persisting into middle age (Burgess et al, 2008). Immunoglobulin E (IgE) is elevated in 80% of patients with eczema and there is a positive family history in two thirds of individuals suffering from eczema (Pizzorno & Murray, 2006).

2.2.3. The role of microbial gut colonisation

Immediately after vaginal birth the process of bacterial colonisation of the infants gastrointestinal tract starts. Apart from birth and type of infant feeding, other environmental factors also play a role in microbiota, as differences are noted between infants born in developed and developing countries (Guarner & Malagelada, 2003). The human intestinal microbiota contains up to 500 species of bacteria with substantial strain variation, as well as archaea and eukarya (Boyle & Tang, 2006).

The bacteria mostly found in the human intestinal tract are from the genera bacteroides, bifidobacterium, eubacterium and clostridium, where anaerobic bacteria outnumber aerobic bacteria 1:10. Adult human microbiota composition at the species level usually remains constant throughout life, but can vary during illness or antibiotic use (Guarner & Malagelada, 2003). The newborn microbiota however changes quickly during the first few weeks and during weaning. This makes the infant gut more inclined to change its microbiota composition by supplementing probiotics (Boyle & Tang, 2006).

An important factor in the initial regulation of the infants developing immune system is the colonisation of the gut by specific species of bacteria. Infants in developed countries are colonized later than those in developing countries by fecal bacteria, and have slower strain turnover in their microbiota (Gore et al, 2008). The composition of the gut flora is very important as some microflora has been associated with disease and the increased incidence of inflammatory conditions in developed countries. Studies have shown the differences in gut microbiota colonisation between healthy and ill individuals. Various factors affect microbial colonisation and type of bacteria present. Foremost the use of antibiotics that reduce the numbers of Bifidobacteria and Bacteroides that cause an overgrowth of pathogenic bacteria. Antibiotic use has also been linked with an increased risk of developing an allergy (Kranich et al, 2011).

2.2.4. Factors that affect microbial colonisation

Various environmental factors affect the composition of the intestinal flora. By altering the intestinal flora of humans, the environment is affecting individuals susceptibility to disease. Diet affects bacterial composition in gut due to the various preferences of bacteria for energy sources.

Beneficial bacteria prefer complex plant polysaccharides that increase their growth over other bacteria in the gastrointestinal tract. Method of delivery, hospital hygiene and breast feeding all contribute to the colonisation of the newborn (Kranich et al, 2011) .Maternal transfer of microbes to the newborn is essential for gut colonisation. The infants colonisation pattern is affected by the method of delivery. Infants delivered vaginally have more Bifidobacteria compared to caesarean born infants, who were more often colonised with Candida difficile (Gore et al, 2008).

Furthermore, breastfeeding compared to formula feeding was associated with colonisation of different bacteria. Clostridium species and Enterobacteriaceae other than E coli were more prevalent after caesarean section, and the ratio of strict anaerobes to facultative anaerobes were lower in these infants. The strict/facultative anaerobe ratio was also strongly decreased initially, and remained low at 12 months of age, indicating a slowed maturation of the intestinal flora (Adlerberth et al, 2007).

Figure 1: Possible effects of microbiota on health (Kranich et al, 2011)

2.2.5. Microbiota and allergies

Recently there has been an increasing number of studies on the commensal gut flora or ‘good bacteria’. Research has shown that the flora in the gut plays a role in immune regulation and can play a role in the development of allergies. Studies of germ free (GF) mice that have no flora has shown that the mice have severe immune abnormalities. Their spleen and lymph nodes have weak B and T cell zones that results in lower serum Immunoglobulin G (IgG) and intestinal Immunoglobulin A (IgA). Cytokine production is also altered towards a more Th2 type response (Kranich et al, 2011).

Some of the mechanisms of immune regulation by the microbiota have been identified. Certain species from the Bacteroidetes phyla show beneficial anti-inflammatory effects by producing beneficial factors such as short chain fatty acids (SCFAs). The SCFAs acetate, butyrate and propionate are produced in the colon by fermentation of plant polysaccharides. SCFAs binds to receptors on innate immune cells and have a systemic anti-inflammatory effect in the body. Other important factors are peptidoglycan that influences neutrophil priming and polysaccharide A that is able to induce T cell responses (Kranich et al, 2011).

The combined analysis of 3 European birth cohorts showed a relationship between increased total serum IgE levels and late gut colonisation by Lactobacillus. They also saw elevated numbers of gram-negative to gram-positive bacteria at 12 months in infants with higher total serum IgE levels at 18 months. (Adlerbert et al, 2007)

The promotion of breastfeeding trial (Probit), where 17 046 mother-infant pairs were studied, showed considerable protection of atopic eczema from prolonged breastfeeding. (Sikorski et al, 2003)

2.3. Review of the literature

2.3.1. Probiotic therapy

The rationale for probiotic supplementation was to alter the microbiota composition from a potentially detrimental composition, towards a microbiota composition that would be beneficial. Generally this would include the reduction of clostridia and coliforms and an increase in the numbers of lactobacilli and bifidobacteria (Ouwehand et al, 2002). The gut microflora plays a central role in the intestinal defence barrier and the development of gut associated lymphoid tissue in infancy. Regulating systemic and local immune responsiveness, as well as hyporesponsiveness to food and micro-organism derived antigens. Probiotic therapy aims to improve intestinal permeability, alter the microbiota and reducing the intestinal inflammatory response (Ouwehand et al, 2002).

The extended hygiene hypothesis is the motivation for the use of probiotics in immune regulation and thus reducing the risk of eczema during a crucial period of immunologic development in infants (Rautava et al, 2005).

Figure 2. The extended hygiene hypothesis (Rautava et al, 2005)

2.3.2. Prenatal supplementation

Prenatal supplementation of Lactobacillus rhamnosus GG (LGG) to 250 pregnant mothers from 36 weeks till delivery, did not show a lower risk of eczema development in the infants at 1 year. Although lower soluble IgA and CD14 levels were seen in the breast milk of mothers supplemented with LGG. (Boyle et al, 2011)

In another study with a smaller sample size, 112 pregnant women were given a 3 strain probiotic mix before delivery and continued for 6 months after birth. The infants were not supplemented but were exclusively breastfed for the first 3 months. Of the 68 infants that finished the study, eczema prevalence was considerably lower in the supplemented group at 1 year of age. Although no difference in total serum IgE was seen in the 2 groups. (Kim et al, 2010)

2.3.3. Pre and postnatal supplementation

A recent double blind, randomised, placebo controlled trial that used Lactobacillus reuteri (L. reuteri) to prevent IgE- associated eczema found that the incidence of eczema was very similar in both groups. However, the infants that received the L. reuteri showed lower rates of IgE associated eczema at 2 years of age. The 188 mothers received L. reuteri1.3x10⁸ CFU from 36 weeks till birth daily and the infants untill 12 months (Abrahamsson et al, 2007).

The importance of supplementing a pre- and probiotic together was shown in a large double blind, placebo controlled trial in Finland. The researchers supplemented 1 223 pregnant woman twice daily for 2-4 weeks before delivery with a 4 strain probiotic mix. Their infants received a 4 strain probiotic mix with a galacto-oligosaccharide probiotic for 6 months.

At 2 years lactobacilli and bifidobacteria more commonly populated the supplemented infants gut. A significant decrease in eczema was seen in the probiotic group, indicating an inverse connection between eczema and gut colonisation (Kukkonen et al, 2007).

The PandA study showed a reduction of eczema at 3 months, along with lowered IL-5 production. Infants were supplemented with a 3 strain probiotic mix for 12 months and the mothers only received probiotic mix prenatally. They concluded that the preventative effect of probiotics is in the first 3 months of life and appears to be maintained through until 2 years (Niers et al, 2009).

However an Australian study showed a considerable reduction in eczema risk by almost half in infants supplemented with Lactobacillus rhamnosus (L. rhamnosus) versus placebo, but not with B animalis.

Interestingly they continued to supplement the mothers till 6 months if they were breastfeeding, along with the infants that received supplementation from birth till 2 years old. They also saw lower numbers of eczema in infants who continually had L. rhamnosus in their feces (Wickens et al, 2008).

2.3.4. Postnatal supplementation

A Finish study of 239 infants with Eczema–dermatitis syndrome (AEDS) looked at the immunological effects of probiotic supplementation. All the infants followed an elimination diet and received either LGG or a 4 strain probiotic mixture, or placebo for 4 weeks. The infants received LGG 5x10⁹ twice daily, or a mix of LGG 5x10⁹ , L. rhamnosus 5x10⁹ , B. breve 2x10⁸ , P. shermanii 2x10⁹ twice daily or placebo. 132 Infants with a mean age of 6.5 months were tested before and after supplementation for various immunological markers. The results showed that infants who received LGG had higher levels of IL-6 than placebo, and those with IgE related AEDS had higher C- reactive protein (CRP) levels. Those who received the probiotic mix had an increase in plasma IL-10, but not IL-6. This study showed slight systemical inflammation that might help explain the clinical effects of probiotic supplementation in infants (Viljanen et al, 2005).

So far, only one trial has shown beneficial effects with probiotic supplementation during weaning and lower eczema risk. Lactobacillus paracasei F19 (L.F19) with 1 x 10⁸ CFU were given to vaginally born infants from 4 months till 13 months in a cereal. At 13 months 11% in the probiotic group developed eczema as compared to 26% in the placebo group of infants at high risk of developing eczema. Not only did this study achieve a clinical outcome, but also showed a higher Th1/Th2 ratio that effects the T-cell mediated immune reaction (West et al, 2009).

Problem statement

Eczema is the most common allergic disease in infancy and the incidence is increasing in the developed world. Eczema is an extremely uncomfortable disease and has been linked with development of allergic rhinitis and asthma in later life. Naturopathic principles include treating the cause of disease and not just the symptoms and in prevention of disease by lifestyle changes. Probiotic supplementation has shown a preventative effect in infants developing eczema. There is however a need for information about the best protocol to follow to help prevent eczema in infants.

Significance of the study

Various studies on probiotic supplementation have been done on the prevention of allergic disease, especially eczema, but the results have been inconsistent. However the studies differ in numerous ways like the species of probiotics used, the dose and duration. This study differs in that it reviews the various studies conducted on probiotic supplementation for eczema prevention. Including start of initiating treatment, dosage and species of probiotics, duration of supplementation and the outcomes in preventing eczema. The study will provide guidance to what measures have the best results in preventing eczema development in infants with high risk of developing allergic disease.

Definition of terms

1. Atopic dermatitis (AD) “is synonymous with eczema and is a chronic inflammatory pruritic skin disease” (PRACTALL consensus report, 2006)

2. Atopy: “ A tendency to develop immediate-type hypersensitivity reactions to common allergens.” (Valenta et al 2008) Atopy causes a proneness to asthma, hay fever and eczema (Collins Dictionary of Medicine, 2005)

3. Allergy: “ the situation of changed reactivity to antigenic stimulation resulting in immunity or hypersensitivity, also known as IgE mediated hypersensitivity.” (Valenta et al 2008)

4. SCORAD: SCORing Atopic Dermatitis. (Wickens et al, 2008)

5. Microbiota: the collective microorganisms that inhabit the human intestine

6. Probiotics: “live microorganisms which when administered in adequate amounts confer a health benefit on the host” (Boyle et al, 2006)

7. Prebiotics: “non-digestible food ingredients that beneficially affect the host by selectively stimulating the growth, and/or activity, of one or a limited number of beneficial bacteria in the colon and thus improve host health” (Gibson & Roberfroid, 1995)

8. C.F.U: Colony forming unit

3. Aim and objectives:

3.1. Aim: To review the use of probiotics, pre- and postnatally, in the prevention of the development of eczema in infants.

3.2. Objectives: To review the various microbiota studies and evaluate which of the various strains, or combination of strains and dosages, have the most beneficial effect on preventing eczema.

To review the various factors that affect microbial gut colonisation in infants and whether breastfeeding plays a role in immune tolerance.

To assess if the stimulation of the immature immune system can create tolerance and therefore prevent or reduce the risk of developing eczema.