Can probiotics be used to treat allergic diseases?

Abstract

Probiotics are proprietary formulations of specific microorganisms and quantified populations of live bacteria that are intended to confer a health benefit on the host. These different strains and combinations of microorganisms have a wide and varying range of clinical and immunologic capacities that can modify intestinal microbial populations in ways that can benefit the host. The enhanced presence of probiotic bacteria in the intestinal microbiota has been found to correlate with protection against atopy. The prevalence of allergic diseases such as asthma, allergic rhinitis, and atopic dermatitis has increased sharply over the past 2–3 decades in many countries, and allergies are now the most common chronic disease among children throughout the world. In the past few years, probiotics have been advocated for the management of allergic diseases in many parts of the world. So far, probiotics have shown more promise, albeit limited, in the primary prevention of allergic disease rather than in the treatment of established disease.

Full text

Review Article
Can probiotics be used to treat allergic diseases?
Ren-Bin Tang
a,b,
*, Jia-Kan Chang
a,b
, Hui-Lan Chen
c
a
Division of Pediatrics, Cheng-Hsin General Hospital, Taipei, Taiwan, ROC
b
National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
c
Department of Pediatrics, Keelung Hospital, Ministry of Health and Welfare, Keelung, Taiwan, ROC
Received June 4, 2014; accepted August 21, 2014
Abstract
Probiotics are proprietary formulations of specific microorganisms and quantified populations of live bacteria that are intended to confer a
health benefit on the host. These different strains and combinations of microorganisms have a wide and varying range of clinical and immu-
nologic capacities that can modify intestinal microbial populations in ways that can benefit the host. The enhanced presence of probiotic bacteria
in the intestinal microbiota has been found to correlate with protection against atopy. The prevalence of allergic diseases such as asthma, allergic
rhinitis, and atopic dermatitis has increased sharply over the past 2e3 decades in many countries, and allergies are now the most common
chronic disease among children throughout the world. In the past few years, probiotics have been advocated for the management of allergic
diseases in many parts of the world. So far, probiotics have shown more promise, albeit limited, in the primary prevention of allergic disease
rather than in the treatment of established disease.
Copyright ©2014 Elsevier Taiwan LLC and the Chinese Medical Association. All rights reserved.
Keywords: allergic diseases; allergic rhinitis; asthma; atopic dermatitis; probiotics
1. Introduction
The rapid increase in immune-mediated disorders such as
allergic disease is strongly linked to reduced early microbial
exposure.
1,2
The intestine is the body's largest immune organ;
most of the antibody-producing cells reside in the intestine.
3
The intestinal microbiota represents the body's greatest mi-
crobial exposure by a substantial extent, and in part works to
provide stimulation of the immune system. The specific
composition of the intestinal microbiota may affect the risk of
developing allergic disease.
4e6
This finding provided the
foundation for intervention studies designed to modify gut
microbial composition for the treatment of allergic disease.
The effects of beneficial bacteria (probiotics) or resistant
starches or fiber (prebiotics) that selectively stimulate a
limited number of beneficial bacteria have been evaluated in
allergy treatment studies.
7,8
Several reviews have examined
the evidence for prebiotics and probiotics in the treatment of
allergic disease. However, in the current era of evidence-based
medicine, there remains insufficient evidence to formally
recommend probiotics for the prevention of allergic diseases
or as part of the standard management for any allergic con-
ditions in children.
9
2. Terminology
An allergy is a hypersensitivity reaction initiated by
immunological mechanisms. Such allergies are generally
broken down into two groups: an antibody-mediated allergy or
a cell-mediated allergy. Hypersensitivity causes objectively
reproducible symptoms or signs, initiated by exposure to a
defined stimulus at a dose tolerated by healthy individuals.
Conflicts of interest: The authors declare that there are no conflicts of interest
related to the subject matter or materials discussed in this article.
*Corresponding author. Dr. Ren-Bin Tang, Division of Pediatrics, Cheng-
Hsin General Hospital, 45, Cheng Hsin Street, Pai-Tou, Taipei 112, Taiwan,
ROC.
E-mail address: ch9406@chgh.org.com.tw (R.-B. Tang).
Available online at www.sciencedirect.com
ScienceDirect
Journal of the Chinese Medical Association 78 (2015) 154e157
www.jcma-online.com
http://dx.doi.org/10.1016/j.jcma.2014.08.015
1726-4901/Copyright ©2014 Elsevier Taiwan LLC and the Chinese Medical Association. All rights reserved.

Allergens are antigens that cause allergy.
10
These allergens
can make contact with the immune system through various
routes such as inhalation, ingestion, and skin contact, or enter
directly into the body through an insect bite.
11
Atopy is a
personal or familial tendency, usually in childhood or
adolescence, to produce immunoglobulin E (IgE) antibodies in
response to ordinary exposure to allergens (usually proteins)
and to develop typical symptoms such as asthma, rhino-
conjunctivitis, and eczema/dermatitis. However, not all cases
are attributable to IgE mechanisms.
10,12,13
The mechanisms
leading to the increased incidence of allergic diseases are not
fully understood but are known to involve genetic factors as
well as complex interactions between the host and allergen
exposuredas well as other environmental stimuli such as the
intestinal microbiota and infectious agents.
14e17
3. The intestinal immune system
In the healthy gut, the immune system is able to create a
balance between the level of protective mucosal immunity and
systemic tolerance. Immune homeostasis in the gut develops
as a relationship is established between the intestinal micro-
biota, luminal antigens, and the epithelial barrier.
18
Microbial
colonization of the intestine begins after birth, where the
sterile gut of the newborn is gradually colonized by environ-
mental bacteria and by contact with the maternal intestinal
flora and surroundings and possibly by genetic factors.
19,20
Exposure to microbial flora early in life allows for a change
in the T helper 1 (Th1)/Th2 cytokine balance, favoring a Th1
cell response.
21
At birth, the immune system of an infant is not
fully developed and tends to be directed toward a Th2
phenotype to prevent rejection in utero. The Th2 phenotype,
however, leads to the stimulated production of IgE by B cells
and thus increases the risk for allergic reactions through the
activation of mast cells. Microbial stimulation early in life will
reverse the Th2 bias and stimulate the development of Th1
phenotype and stimulate the activity of Th3 cells.
22
In this
manner, their combined action will lead to the production of
IgA by B cells. IgA contributes to allergen exclusion and will
thereby reduce exposure of the immune system to antigens.
Cytokines produced by the Th1 phenotype will also reduce
inflammation and stimulate tolerance toward common
antigens.
23
4. Mechanisms of action of probiotics in allergic disorders
Although the exact etiology of allergic diseases remains
ambiguous, the mechanisms by which microbial exposure
affects the development and severity of allergic disease needs
to be better understood. The hygiene hypothesis suggests that
insufficient or aberrant exposure to environmental microbes is
one of the causes of the development of allergy and their
associated diseases.
24e26
As described above, allergic disor-
ders are associated with a shift of the Th1/Th2 cytokine bal-
ance leading to activation of Th2 cytokines and the release of
interleukin-4 (IL-4), IL-5, and IL-13 as well as IgE produc-
tion.
21,27
Probiotics administration dramatically alters the gut
microenvironment by promoting a change in the local
microflora and in cytokine secretion, and can potentially
modulate the Toll-like receptors and the proteoglycan recog-
nition proteins of enterocytes, leading to the activation of
dendritic cells and a Th1 response. The resulting stimulation
of Th1 cytokines can suppress Th2 responses.
28
Other effects
of probiotics that make them suitable for modulation of
allergic disease include stimulation of mucosal IgA level as
well as allergen-specific B and T cell responses.
29
Recent
studies suggest that the bacterialehost interaction may induce
the expansion of T regulatory cells and the expression of
immunomodulatory cytokines such as IL-10 and transforming
growth factor-beta; these interactions are very complex and
involve networks of genes, Toll-like receptors, signaling
molecules, an enhanced intestinal IgA response, and the
mechanisms by which probiotics affect innate and adaptive
immune responses and patterns of disease.
30e32
5. Probiotic strains and effects
Probiotic microorganisms are generally lactic acid bacteria
including Lactobacillus acidophilus,Lactobacillus bulgaricus,
Lactobacillus casei,Lactobacillus plantarum, and Lactoba-
cillus rhamnosus. The Lactobacillus species possess several
important properties such as efficient adherence to intestinal
epithelial cells to reduce or prevent colonization of pathogens,
competitive growth, and production of metabolites to inhibit or
kill pathogens and nonpathogens.
33
However, other bacterial
species such as Bacillus,Bifidobacterium spp., and Propioni-
bacterium spp. as probiotic strains have also been described in
several commercial products.
34
The potential use of L. casei
strain Shirota has also been described as a probiotic agent for
stimulating immune responses and preventing enterobacterial
infections,
35
and Lactobacillus GG is likewise used as an
effective oral vaccine for rotaviruses.
36
Before the use of a
probiotic is considered for hospitalized patients, a careful
assessment of risk versus benefit must be made. Additionally,
to ensure patient safety, probiotics should be properly handled
during administration.
37
6. Probiotics'role in allergic disorders
6.1. Probiotics in atopic dermatitis
Numerous animal and in vitro studies, as well as several
human trials, suggest a beneficial effect of probiotics in
allergic diseases. Several randomized studies demonstrated
that when Lactobacillus GG or placebo was given to pregnant
mothers with a strong family history of eczema, allergic
rhinitis, or asthma and to their infants for the first 6 months
after delivery, the frequency of developing atopic dermatitis in
the offspring was reduced in 2 years, 4 years, and 7 years by
50%, 44%, and 36%, respectively.
38,39
However, after Lee
et al
40
searched PubMed and the Cochrane database in 21
trials for review and quality assessment of probiotics in the
prevention and treatment of pediatric atopic dermatitis, current
evidence suggested that probiotics had a superior efficacy in
155R.-B. Tang et al. / Journal of the Chinese Medical Association 78 (2015) 154e157

prevention rather than treatment of the condition. Probiotics
may affect early development of immune tolerance during the
1
st
year of life, explaining their potential effect in children
with atopic dermatitis.
41
However, the European Society of
Paediatric Gastroenterology, Hepatology, and Nutrition Com-
mittee on Nutrition is concerned that the available data are not
sufficient to support the safety of probiotics in healthy
newborn and very young infants with immature defense sys-
tems, infants with immunocompromised systems, premature
infants, and infants with congenital heart disease.
42
6.2. Probiotics in asthma
A small number of studies exist that attempt to address the
efficacy of probiotic supplementation in the treatment or
prevention of asthma. One study using fermented milk con-
taining L. casei and studying its effect on the number of epi-
sodes of asthma and allergic rhinitis found no statistical
difference between intervention and control groups of asth-
matic children. However, the number of rhinitis episodes was
lower in the probiotic group, leading the authors to conclude
that L. casei may benefit children with allergic rhinitis but not
asthmatic children.
21,43
No primary prevention study has been
able to demonstrate an effect of probiotic supplementation for
asthma in humans.
44
6.3. Probiotics in allergic rhinitis
Reports on the efficacy of probiotics in treating allergic
rhinitis are conflicting. Giovannini et al
43
revealed that L. casei
reduced the number of rhinitis episodes in 64 preschool chil-
dren with allergic rhinitis. However, another trial showed that
patients treated with Lactobacillus GG during the birch pollen
season who were allergic to birch pollen and apple food
demonstrated neither reduction of symptom score, nor any
lesser sensitization to birch pollen and apple after probiotics
supplementation.
45
Recently, data from the PubMed database
and published studies indicate that probiotic intake improved
the quality of life score in patients with allergic rhinitis. There
was no significant change in blood or immunologic parameters
in the probiotic group. This suggests that probiotics may be
useful in allergic rhinitis, but the present data are not sufficient
to allow for any treatment recommendations.
46,47
6.4. Probiotics in food allergy
Recent studies suggest that probiotics may have a role in
the treatment of food allergy by maintaining the intestinal
epithelial barrier integrity, suppressing intestinal inflammatory
responses, and inducing mucosal IgA production and tolero-
genic immune responses.
48,49
However, Hol et al
50
found no
effect of L. casei CRL431 and B. lactis Bb-12 supplementation
for 12 months on the acquisition of tolerance in 119 infants
with cow's milk allergy. Another study on children with egg,
peanut, or cow's milk allergy who were treated with a probiotic
mix (predominantly Lactobacillus spp. and Bifidobacterium
spp.) for 3 months showed that the treatment did not influence
sensitization or ex vivo immune responses. This would further
indicate that the evidence as to whether probiotics can induce
tolerance in allergy is currently lacking.
51
In conclusion, probiotics may have a potential role in the
prevention and treatment of atopic dermatitis, but studies to
date have not been conclusive. Currently, there is no role for
probiotic therapy in the treatment of asthma. A World Allergy
Organization Special Committee on Food Allergy and Nutri-
tion reviewed the evidence regarding the use of probiotics for
the prevention and treatment of allergy. The committee
concluded that probiotics do not have an established role in the
prevention or treatment of allergy.
12
The contradictory results
of the studies on the efficacy of probiotics in the prevention
and treatment of allergy may be attributable to the great het-
erogeneity of strains, duration of therapy, and doses used.
Even if there are promising data on the treatment of atopic
dermatitis, little is known about the efficacy of probiotics for
respiratory allergic symptoms and food allergy.
52e54
The
literature associated with probiotic consists primarily of re-
views, and few of them are systematic; meta-analyses are rare.
Explanations for the varied results between studies include
host factors, environmental factors, individual microbiota,
patient diet of prebiotic substances, and treatment with anti-
biotics.
55
Future studies will be important to better understand
and refine the current knowledge base for potential use of
probiotics in allergy.
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