Understanding the Role of Probiotics and Prebiotics in Preventing Allergic Disease

Evidence and Methodological Issues

Hania Szajewska

Immunotherapy. 2013;5(8):869-878.

Abstract and Introduction

Abstract

Research in the area of prevention of allergic disorders through modification of the intestinal microbiota by provision of probiotics and/or prebiotics is relatively new. This paper briefly summarizes evidence regarding the role of probiotics and/or prebiotics in reducing the risk of allergy. There are studies that show a protective effect, no effect or even a predisposing effect of using probiotics and/or prebiotics in preventing allergic disease. A variety of methodological issues are likely to contribute to current uncertainty. These include differences in the study population (high-risk vs unselected population), optimal strain selection (all probiotics are not equal), differences in definitions of outcomes, timing and duration of the interventions, and a lack of repeat studies.

Introduction

The rising number of children and adults with allergic disorders, such as asthma, allergic rhinitis, atopic dermatitis and food allergy, worldwide is a major public health concern.^[1] The origins of this increase are still not well understood. However, it is now clear that, among other factors, impaired oral tolerance, which is a specific suppression of cellular and/or humoral immune responses to an antigen, contributes to the development of allergic diseases. For the development of oral tolerance, contact with microbes is crucial.^[2] It has been hypothesized that, among other causes, aberrant gut microbiota, due to factors such as the mode of delivery (vaginal vs cesarean), use of antibiotics in the early neonatal period and mode of feeding (breast vs formula feedings), contributes to the development of allergic diseases. If so, prevention of allergic disorders through modification of intestinal microbiota via the provision of probiotics and/or prebiotics is of interest.

Probiotics are live microorganisms administered in adequate amounts that confer a beneficial health effect on the host.^[3] In principle, this definition applies to probiotics in food, and it excludes references to the term 'biotherapeutic agents' and beneficial microorganisms not used in food. In practice, however, the definition is used regardless of the delivery mode, and probiotics can be found in food, dietary/nutritional supplements, drugs and medical foods. Prebiotics are "nondigestible food components that beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon and thereby improving host health".^[4] In infants, oligosaccharides, such as galactooligosaccharides and fructooligosaccharides, are commonly used as prebiotics as they increase the fecal counts of bifidobacteria. Finally, the term 'synbiotic' is used "when a product contains both probiotics and prebiotics".^[5]

A number of concepts have been considered as the rationale for using probiotics/prebiotics in the prevention of allergic disorders. Among them are improved hygiene and the reduced exposure of the immune system to the microbial stimulus early in childhood, which may contribute to the rising number of allergic disorders worldwide.^[6] Second, there exists a difference in the neonatal gut microbiota that may occur before or match the timing of the early development of atopy. Atopic subjects have more Clostridia and tend to have fewer bifidobacteria than nonatopic subjects.^[7] Finally, evidence suggests a critical role for a stable commensal gut microbiota in the maturation of the early immune system.

This article briefly summarizes evidence regarding the role of probiotics and/or prebiotics in reducing the risk of allergy, and discusses some methodological issues to help clarify why the data are conflicting.

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Next Section

Abstract and Introduction
Evidence on Probiotics
Evidence on Prebiotics
Evidence on Synbiotics
Methodological Issues
Safety
Recommendations From Scientific Societies
Conclusion & Future Perspective
References
Sidebar

Table 1. Comparison of the meta-analyses on the effects of probiotics on the prevention of allergic diseases.
Study (year)	Question	Methodology	Literature search	Type of study	Unpublished trials	Language	Study quality	Heterogeneity	RCTs/participants	Conclusion	Comment	Ref.
Osborn and Sinn (2007)	Well defined: to determine the effect of probiotics given to infants for the prevention of allergic diseases or food hypersensitivity	Well covered	CENTRAL (issue 1, 2007), MEDLINE and CINAHL (February 2007); EMBASE, PREMEDLINE; reference lists; abstracts from some conferences	RCTs and quasi-RCTs	Not clear	No language restriction	Yes (using standardized criteria)	Heterogeneity discussed or assessed	Six RCTs reported allergic disease and/or food hypersensitivity (in 1549 out of 2080 enrolled infants)	Insufficient evidence to recommend the addition of probiotics to infant feeds for the prevention of allergic disease or food reactions	Concerns regarding the quality of studies and inconsistency of findings between trials. Further studies are needed to confirm the results	[8]
Lee et al. (2008)	Well covered: to summarize clinical trial findings on probiotics for pediatric atopic dermatitis	Well covered	PubMed and Cochrane databases (up to July 2007); reference lists; authors were contacted if the study did not provide sufficient data	RCTs	Not included	English only	Yes (using a standardized protocol)	Heterogeneity considered	Six RCTs (n = 1581)	Current evidence is more convincing for probiotics' efficacy in the prevention rather than the treatment of pediatric atopic dermatitis	Criticism for combining the results from five studies on probiotics with results from one study on synbiotics. Moreover, data from the same study population at different time intervals were combined	[9]
Betsi et al. (2008)	Well covered: to synthesize the evidence of the effectiveness of probiotics for the treatment or prevention of atopic dermatitis in children	Well covered	PubMed, EMBASE and the Cochrane Library (1997–2007)	RCTs	Not clear	English only	Not formally assessed	Narrative synthesis	Three RCTs (n = 1429)	Probiotics, especially LGG, seem to be effective for the prevention of atopic dermatitis	Conclusions based on only three RCTs; the review's methodological limitations call for caution	[10]
Doege et al. (2012)	Well covered: to assess the impact of probiotics intake during pregnancy on the development of eczema in children	Well covered	PubMed and Ovid, including EMBASE (up to June 2009); reference lists	RCTs	Not clear	Not clear	Yes (according to the Centre for Reviews and Dissemination guidance)	Heterogeneity considered	Seven RCTs (n = 2843)	Probiotics, especially Lactobacilli, reduce the risk of atopic eczema	Presents pooled data and separate data from studies that used mixtures of probiotics and studies that used Lactobacilli. Still, different Lactobacilli were pooled together, calling for caution when interpreting the pooled effect	[11]
Pelucchi et al. (2012)	Well covered: to investigate whether probiotic use during pregnancy and early life decreases the incidence of atopic dermatitis and IgE-associated atopic dermatitis	Well covered	MEDLINE, EMBASE, Cochrane Library (up to October 2011); reference lists	RCTs	Not included	English only	Not formally assessed (except for double blinding)	Heterogeneity considered	18 publications based on 14 RCTs	Moderate role of probiotics in the prevention of atopic dermatitis and IgE-associated atopic dermatitis in infants	Different probiotics were pooled together. Caution is needed when interpreting the results	[12]

LGG: Lactobacillus GG; RCT: Randomized controlled trial.

Table 2. Effects of specific probiotics on the prevention of allergic diseases.
Probiotic	Author (year)	Population	Intervention (dose CFU)	Before delivery	After delivery	Follow-up (years)	Atopic dermatitis (effect size)	Ref.
*High-risk population*
LGG	Kalliomäki et al. (2001)	132/159	1 × 10¹⁰	2–4 weeks	6 months (to BF mothers or directly to infants)	2	RR: 0.51 (0.32–0.84)	[29]
	Kalliomäki et al. (2003)					4	RR: 0.57 (0.33–0.97)	[30]
	Kalliomäki et al. (2007)					7	RR: 0.64 (0.45–0.92)	[31]
	Rautava et al.(2002)	57/62	2 × 10¹⁰	2–4 weeks	3 months BF mothers only	1	NS	[33]
	Kopp et al.(2008)	94/105	5 × 10⁹, twice daily	4–6 weeks before delivery	6 months		RR: 0.96 (0.38–2.33)	[25]
	Boyle et al.(2011)	210/250	1.8 × 10⁸	1 month	–	1	NS	[34]
	Ou et al.(2012)	128/191	1 × 10¹⁰	From second trimester	6 months to BF mother or non-BF infant	3	NS	[39]
LGG + Bb12	Rautava et al. (2006)	72/81	LGG 1 × 10¹⁰ Bb12 1 × 10¹⁰	–	From start of infant formula to 12 months	1	NS	[40]
Lactobacillus rhamnosus LP, Bifidobacterium longum BL999	Rautava et al. (2012)	205/241	1 × 10⁹ each	2 months	2 months to BF mother	2	OR: 0.17 (0.08–0.35)	[41]
Lactobacillus paracasei ST11, B. longum BL999							OR: 0.16 (0.08–0.35)
Lactobacillus acidophilus LAVRI A1	Taylor et al.(2007)	178/226	3 × 10⁹	–	6 months	1	NS	[24]
	Prescott et al. (2008)	153/226				2.5	NS	[42]
	Jensen et al.(2012)	123/226				5	NS	[43]
Lactobacillus reuteri ATCC 55730	Abrahamsson et al. (2007)	188/232	1 × 10⁸	1 month	12 months	2	NS (but IgE eczema)	[44]
L. rhamnosus HN001	Wickens et al. (2008)	446/512 (2 years) 425/512 (4 years)	6 × 10⁹	1 month	6 months if BF + to an infant 2 years	2	HR: 0.51 (0.3–0.85)	[26]
	Wickens et al. (2012)					4	HR: 0.57 (0.39–0.83)	[27]
Bifidobacterium animalis HN019	Wickens et al. (2008)		9 × 10⁹			2	NS	[26]
	Wickens et al. (2012)					4	NS	[27]
B. longum BL999, L rhamnosus LPR	Soh et al. (2009)	245/253	2.8 × 10⁸	–	6 months	1	NS	[45]
Bifidobacterium bifidum W23, Bifidobacterium lactis W52, L lactis W58	Niers et al. (2009)	98/156	1 × 10⁹ of each strain	1 month	12 months	2	Reduced at 3 months; later NS	[46]
B. bifidum BGN4, B lactis AD011, L acidophilus	Kim et al. (2010)	68/112	1.6 × 10⁹ of each strain	1–2 months	3 months to BF mother, than to an infant up to age 4–6 months	1	Reduced p < 0.029	[47]
*Unselected population*
LGG + Bb12	Huurre et al. (2008)	140/171	LGG 1 × 10¹⁰Bb12 1 x 10¹⁰	From first trimester	End of BF (two mothers only)	1	NS	[48]
LGG + Bb12 + Lacidophilus La5	Dotterud et al. (2010)	278/415	LGG 5 × 10¹⁰Bb 12 5 × 10⁹ L. acidophilus La5 5 × 10¹⁰	1 month	3 months to BF mothers	2	OR: 0.51 (0.3–0.87)	[49]
Lactobacillus F19	West et al. (2009)	171/179	1 × 10⁸	–	4–13 months in cereals	1	Reduced p < 0.05	[35]

BF: Breastfeeding or breastfed; HR: Hazard ratio; LGG: Lactobacillus GG; NS: Not significant; OR: Odds ratio; RR: Relative risk.

Table 3. Effects of specific prebiotics on the prevention of allergic diseases.
Prebiotic	Author	Population	Intervention (dose CFU)	Before delivery	After delivery	Follow-up	Atopic dermatitis (effect size)	Ref.
*High-risk population*
GOS/FOS (90/10%)	Moro et al. (2006)	206/259	Extensively hydrolyzed formula + GOS/FOS (0.8 g/dl)	–	6 months	6 months	RR: 0.42 (0.2–0.8)	[17]
	Arslanoglu et al. (2008)	134/152				2 years	RR: 0.49 (0.24–1.00)	[50]
*Unselected population*
Polydextrose, GOS	Ziegler et al. (2007)	n = 116	Standard infant formula with polydextrose and GOS	–	4 months	4 months	RR: 1.62 (0.62–4.26)	[18]
Polydextrose, GOS, lactulose		n = 106	Standard infant formula with polydextrose and GOS and lactulose				RR: 0.6 (0.12–3.16)
GOS/FOS, acidic OS	Grüber et al. (2010)	n = 830	Standard infant formula + GOS/FOS (9:1; 6.8 g/l) and acidic OS (1.2 g/l)	–	1 year	1 year	RR: 0.58 (0.35–0.97)	[19]
GOS/FOS, acidic OS	Niele et al. (2013)	n = 94 Preterm or low birth weight infants (<32 weeks or birth weight <1500 g, or both)	Breast milk or preterm formula + GOS/FOS (in increasing doses to a maximum of 1.5 g/kg/d)	–	From day 3 to day 30	1 year	RR: 1.05 (0.41–2.65)	[20]