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Reviewed by:
Dr Justyna (Tina) Wojno
Pathologist/Medical
Microbiology
MBBCh (Wits), MMed (Med
Micro), FC Path (SA) UCT
The influence of oral
probiotic administration
in allergy disease
limitation is now being
emphasised more
regularly
This report was made possible
by an unrestricted educational
grant from Cipla. The content
of the report is independent of
the sponsor.
© 2021 deNovo Medica
for Southern African
free CEUs Probiotics
healthcare professionals
Spring fever: probiotics
and allergy
Learning objectives
You will learn:
• To develop an understanding of the role of the gut microbiota in the context of immunity and
allergic disease
• To obtain the latest evidence on the role of probiotic supplementation in children with cow’s
milk allergy
• To assess the role of Lactobacilli replacement in the treatment of allergic disorders in adults,
including allergic rhinitis, allergic skin conditions and asthma.
Introduction
Allergies, although more frequently reported in childhood, affect all age groups and
impair the quality of life of 30-40% of people. Exposure to an allergen may give
rise to a hypersensitivity reaction caused by an immunological response to a specific
antigen acting on innate immune cells; repeated contact with an allergen triggers
the activation of mast cells and basophils and the release of allergic mediators.1
Consequent symptoms range from sneezing and itchy rashes to severe shortness
of breath and anaphylaxis. Alternatives to pharmacological treatment of allergic
diseases and for symptom reduction are desirable.1
In the context of allergic disease, the gut microbiota modulates the immune system
via the production of molecules with immunomodulatory and anti-inflammatory
functions that are capable of affecting immune cells. Gut dysbiosis, characterised by
changes in the quantitative and qualitative composition of microbiota, may lead to
altered host-microbial interaction that can contribute to a disease state.1,2
© shutterstock/1746366068
OCTOBER 2021 I 1
 Spring fever: probiotics and allergy

Probiotics are one of many strategies that may have an effect on dysbiosis, altering the
perturbed intestinal microbiota with specific mechanisms of action that have not been
completely elucidated (Table 1). The influence of oral probiotic administration in allergy
disease limitation is now being emphasised more regularly.1-3

Table 1. Probiotics’ mechanism of action2

• Colonise and normalise perturbed intestinal microbial communities in both children and adults
• Competitively exclude pathogens
• Bacteriocin production
• Modulate enzymatic activities related to metabolisation of carcinogens and other toxic substances
• Produce volatile fatty acids – short-chain fatty acids and branched-chain fatty acids
• Increase intestinal cell adhesion and mucin production
• Modulate activity of gut-associated lymphoid tissue and the immune system.

Allergy, immunity and the microbiome

In allergic diseases there is a disturbance
in the balance between T helper (Th) 1 and
Certain probiotic Th2 lymphocytes, in favour of Th2 lympho-
bacteria might cytes. Th1 lymphocytes are key to infection,
diminish mast cell activating macrophages to defend the body
allergy-related primarily against intracellular microbes.
activation Excess stimulation of Th2 lymphocytes
activates eosinophils and mast cells, which
leads to the secretion of interleukin (IL)-4,
IL-5, and IL-13 and the production of an
allergen-specific immunoglobulin E (IgE)
which drives allergic inflammation. Interferon
(INF)-γ inhibits Th1 activity by inducing
these cytokine responses, thus maintaining an
allergic phenotype (Figure 1).1,4

Figure 1. Mechanism of allergy induction at mucosal surfaces4

2 I OCTOBER 2021

The number of mast cells and the amount
of mast cell-derived mediators such as
histamine, the key mediator in allergy, are
increased at sites of allergic inflammation.
The released mediators induce mucus and
electrolyte secretion, smooth-muscle contrac-
tion, nerve-cell activation and other symp-
toms common in allergic reactions. Certain
probiotic bacteria might diminish mast cell
allergy-related activation by downregulation
of the expression of high-affinity IgE and
histamine receptor genes, and by inducing a
pro-inflammatory response.5
Different studies examining the influence of
Many studies probiotics on allergic diseases are equivocal
have shown that and, as such, few practical recommenda-
probiotic intake tions guiding the use of probiotics in allergic
diseases have been established. The different
at a minimum
effects of the same probiotic bacteria on dif-
of 1×109 cfu per ferent patients seemingly reinforce the idea
day in food and that the efficacy of probiotics is dependent
food supplements on the microbial species or strain, its derived
can support metabolites and by-products, and the gut
maturation and microbiota eubiosis of the patient. Many
modulation of studies have shown that probiotic intake at
the immune a minimum of 1×109 colony forming units
(cfu) per day in food and food supplements
system; the
can support maturation and modulation
most promising of the immune system; the most promising
probiotics are probiotics are those belonging to the genera
those belonging Lactobacillus and Bifidobacterium.1,2
to the genera
Lactobacillus and The most studied allergies on which pro-
Bifidobacterium biotics have been shown to have a benefi-
cial effect are rhinitis, asthma and atopic
Cow’s milk allergy in children: The role of gut
microbiota
Cow’s milk allergy (CMA) is one of the most
common food allergies in early childhood,
affecting 2-3% of the children under three
years of age. IgE-mediated CMA is the most
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Spring fever: probiotics and allergy
dermatitis (AD). Studies have mostly been
on the administration of Lactobacillus and
Bifidobacterium species in children with
atopy and many of these species have shown
beneficial effects, including a reduction in
hyperreactivity and inflammation caused by
allergens and a decrease in cytokine release.
In the studies that have reported beneficial
results in children, these effects were found
to make allergy symptoms less aggressive,
thereby reducing morbidity.1
Lactobacillus reduces proinflammatory
responses by regulating nuclear factor kappa
B signalling and promoting the maturation of
dendritic cells that release IL-10, thus trigger-
ing the differentiation and survival of regula-
tory T (Treg) cells. The regulation of Treg
cells in intestinal immunity at a steady state is
essential for sustaining tolerogenic response
by adaptive immunity.1,6
Microarray analysis has been used to inves-
tigate the effects of Lactobacillus rhamnosus
GG (LGG) on human mast cell gene expres-
sion. LGG was observed to suppress genes
that encode allergy-related high-affinity IgE
receptor subunits α and γ (FCER1A and
FCER1G, respectively) and the histamine H4
receptor, the expression of genes involved
in mast cell immune system regulation, and
several genes that encode proteins with a
pro-inflammatory impact such as IL-8 and
tumour necrosis factor (TNF)-α. LGG also
upregulates genes that encode proteins with
anti-inflammatory functions, such as IL-10.5
common form of CMA, and hypersensitiv-
ity reactions may occur upon exposure to a
single or multiple milk protein(s) while the
immune system is still immature (Figure 2).6,7
OCTOBER 2021 I 3
 Spring fever: probiotics and allergy

ILC: innate lymphoid cells; PAMP: pathogen-associated molecular pattern molecules; Th: T helper cell; Treg: regulatory T cell; TSLP: thymic stromal lymphopoietin.

Figure 2. Immune tolerance (A) and breakdown of tolerance (B) to ingested antigens
https://www.emjreviews.com/allergy-immunology/symposium/human-milk-oligosaccharides-new-ways-to-shape-the-gut-
microbiome-in-cows-milk-protein-allergy/

Children with Typical IgE-mediated CMA symptoms extended hygiene hypothesis considers a lack
include urticaria, angioedema, vomiting, of microbial exposure during infancy to
CMA in the first
diarrhoea, and anaphylaxis. The majority of potentially be one of the factors contributing
year of life have affected children have one or more symptoms to CMA.6,7
an increased risk involving one or more organ systems, usually
of subsequently the gastrointestinal tract and/or skin. Many Allergen avoidance is not ideal in this set-
being affected infants develop symptoms in two or more ting because dairy products constitute a
by other atopic organ systems.6,7 high-quality source of calcium, potassium,
diseases; the protein, and vitamins B and D; avoidance of
extended hygiene Children with CMA in the first year of these foods can increase the risk of morbid-
life have an increased risk of subsequently ity, including bone fracture, osteoporosis and
hypothesis
being affected by other atopic diseases; the nutrient deficiencies.6,7
considers a lack
of microbial
exposure during The gut microbiota of children with CMA versus non-CMA
infancy to Compared to that of healthy children, the A different gut microbiota study of CMA
potentially be gut microbiota of children with CMA shows infants found dysbiosis characterised by
one of the factors enrichment in the relative abundance of fami- a prevalence of Haemophilus, Klebsiella,
contributing to lies Trichocomaceae and Ruminococcaceae as Prevotella, Actinobacillus and Streptococcus.
CMA well as genera Bacteroides and Alistipes, while Interestingly, Haemophilus, Prevotella,
a decrease in that of genus Bifidobacterium Actinobacillus and Streptococcus gradually
suggests that the gut microbiota of children decreased in the gut microbiota from CMA to
with CMA might be in an imbalanced state.5 cow’s milk-sensitised to healthy infants, lead-
A long-term investigation of gut micro- ing to the supposition that there is a correla-
biota of children with CMA showed that tion between these bacteria and allergic status.8
Firmicutes and Clostridia were enriched in
the infant gut microbiome of subjects whose There is some evidence suggesting the clini-
milk allergy resolved by the age of eight cal potential of probiotics for treating lactose
years, whereas Bacteroidetes and Enterobacter intolerance, as some probiotics promote lactose
were characteristic of subjects whose milk digestion by increasing the overall hydrolytic
allergy did not resolve by eight years of age. capacity in the small intestine and increasing
Specifically, there seems to be a link between the colonic fermentation, decreasing lactose
dysbiosis in the composition of the intestinal concentration in fermented products, and also
microbiota and the pathogenesis of CMA.2 increasing active lactase enzymes entering the
small intestine with the fermented products.2

4 I OCTOBER 2021

A randomised, double-blind, placebo-
controlled trial indicated that L. rhamnosus
strains could improve the symptoms of
infants with CMA.9 LGG consumption has
also been shown to increase the abundance
of beneficial Bifidobacterium, Prevotella,
Lactococcus and Ruminococcus species and
decrease the abundance of Escherichia species
when compared with placebo.2
Investigation into the administration of
probiotics such as LGG in an extensively
Some laboratory evidence
The effects of LGG administration on CMA
development have been evaluated in cow’s
milk protein (CMP)-sensitised BALB/c mice
based on the similarity of their immune
system to that of humans, particularly the
Th1 and Th2 responses. Allergic responses
were assessed by monitoring hypersensitivity
scores, measuring the levels of CMP-specific
immunoglobulins (IgG1, IgG2a and IgG)
A randomised,
double-blind, Further clinical evidence
placebo- A multicentre prospective investigation was
controlled trial performed in children 0-12 months of age
indicated that L. diagnosed with CMP allergy. Infants were
rhamnosus strains randomised to LGG daily 1x109cfu/ml with
could improve a CMP-free diet or placebo for four weeks;
the symptoms of symptoms of CMP allergy were recorded
infants with CMA weekly. Daily LGG administration showed
a statistically significant improvement in
Respiratory allergy disorders in adults
Respiratory allergy diseases can be divided
relative to their occurrence within the upper
and lower airways and can display different
forms and symptoms. Respiratory allergies
can be triggered by allergens such as pollen,
house dust mites, animal dander, moulds and
EARN FREE inhaled food proteins. The most common res-
CPD POINTS piratory disorders linked with hypersensitiv-
ity type I are rhinitis and asthma, which can
Join our CPD community at occur together although a direct link between
www.denovomedica.com them has not been proved.3,4
and start to earn today! The role of the microbiome in the respiratory
tract has not been widely studied, espe-
cially in comparison with the role of the gut
microflora.
Spring fever: probiotics and allergy
hydrolysed formula has shown increased
tolerance in infants with CMA compared
with those treated with hydrolysed formula
alone. Extensively hydrolysed casein formula
(eHCF) represents an effective treatment
for infants diagnosed with CMA and sup-
plementation with probiotics, particularly
LGG (eHCF + LGG), seems to promote and
accelerate antigenic tolerance by influencing
the bacterial community structure and the
capacity to produce short-chain fatty acids,
mainly butyrate.2
and total IgE from sera, and cytokines (IL-4
and IFN-γ) from spleen lysates. LGG sup-
plementation favourably modulated immune
reactions by shifting Th2-dominated trends,
with consequent reduced hypersensitivity
scores and lowered serum CMP-specific
IgG1, toward Th1-dominated responses by
causing elevated IFN-γ and CMP-specific
IgG2a levels.10
symptoms of bloody stool, diarrhoea, restive-
ness and abdominal distension (p≤0.001).
A statistically significant improvement was
also observed in symptoms of mucus stool
(p=0.038) and vomiting (p=0.034). No signif-
icant improvements were observed in abdomi-
nal pain (p=0.325), constipation (p=0.917)
and dermatitis (p=0.071).11
The role of the gut-lung axis, however, has
been increasingly emphasised of late; it has
been clinically noted that diseases of the
gastrointestinal tract also have a reflection in
diseases of the respiratory tract although the
direct mechanism of this intercommunication
is not clear. Even though the exact relation-
ship between bacteria and the atopic host
has not been described yet, the clinical and
biomedical evidence for the positive effect
of probiotics has been reported, although
evidence for probiotic prevention of allergic
airway disease remains scarce.3,4
OCTOBER 2021 I 5

Allergic rhinitis and the role of probiotics in its treatment
Allergic rhinitis (AR) is foremost among
the most common allergic diseases affect-
ing 10-20% of the total population. The
most important allergens that trigger AR are
pollens, giving rise to IgE-mediated inflam-
mation of the nasal mucosa characterised
Figure 3. Microbiota in normal and AR nasal mucosa
https://www.mdpi.com/1422-0067/22/9/4744
The investigators A study investigating the role of probiotics in
the treatment of AR when added as adjuvant
concluded that
agents to standard therapy in patients older
NVP-1703, than 15 years found no effect on the outcome
containing B. of AR when using a commercial probiotic,
longum and including strains of L. casei, L. acidophilus,
L. plantarum, L. rhamnosus, L. bulgaricus, B. breve, B.
can be a useful longum and S. thermophilus.13
treatment option
for perennial AR However, the safety and efficacy of probiotic
NVP-1703, a mixture of B. longum and L.
plantarum, has been studied in adult par-
ticipants with perennial AR. Total nasal
symptom scores (TNSS), rhinitis control
assessment test, blood eosinophil count, aller-
gen-specific IgE, and immunological param-
eters in serum and urine were compared at
6 I OCTOBER 2021
Spring fever: probiotics and allergy
by pruritus, sneezing, rhinorrhoea and nasal
congestion (Figure 3). AR is a potential risk
factor for asthma. Although several recent
studies reported that probiotics might be
beneficial for AR, the effect is not consistent
between studies.1,3,12
baseline and after four weeks. TNSS changes
from baseline at weeks 1, 3 and 4 were sig-
nificant between the NVP-1703 and placebo
groups (p=0.033, 0.031, and 0.029, respec-
tively). Serum IL-10 levels were significantly
different between the NVP-1703 and placebo
groups (p=0.033 and p=0.047, respectively).
IL-10/IL-4 and IL-10/IL-13 ratios differed
between the NVP-1703 and placebo groups at
week 4 (p=0.046 and 0.018, respectively). The
investigators concluded that NVP-1703, con-
taining B. longum and L. plantarum, can be a
useful treatment option for perennial AR.12
A trial in adults with Japanese Cedar pollino-
sis showed that daily consumption of 125ml
fermented citrus juice containing a heat-killed
 Spring fever: probiotics and allergy

L. plantarum strain throughout the pollen probiotics to low-dose corticosteroids in the

season significantly improved symptoms, treatment of symptoms and quality of life
medication use and TNSS at weeks 1 and of randomised AR patients receiving either
2, compared to placebo. The percentage of budesonide with probiotic supplements or
Treg cells was significantly higher at week 6, budesonide with placebo for 8 weeks, then
which was the peak of the pollen season, and vice versa for a further 8 weeks, followed by
associated with milder symptoms in the L. an 8-week washout. This study showed that
plantarum group.14 the addition of probiotics to budesonide sig-
nificantly improved quality of life in patients
L. plantarum A study assessed the impact of add-on with persistent AR.15
treatment in mice
with asthma has Asthma – a role for probiotics?
shown significant
Chronic inflammation of the air passages detectable bacterial taxa in the airway, which
efficacy in in the lungs of patients with asthma is might have an impact on susceptibility to
preventing lung reflected in oversensitivity to irritants (Figure infection and the response to asthma treat-
inflammation 4). Asthmatic patients differ in microbiota ment. The usefulness of naturally derived
exacerbated composition; this is seemingly linked with the anti-asthmatic agents to treat patients with
by DEPM phenotype of asthma. Patients with neutro- severe allergic asthma has recently gained
administration phil domination in the sputum are charac- attention and probiotics have been suggested
terised by lower diversity and numbers of as new agents for asthma therapy.3

APC: antigen-presenting cell; CRTH2: chemoattractant receptor-homologous molecule expressed on Th2 cells; dsRNA: double-stranded RNA; PGD2: prostaglandin D2; IFN: interferon; GRO: growth-
regulated oncogene; IL: interleukin; LPS: lipopolysaccharide; PAMP: pathogen-associated molecular pattern; ssRNA: single-stranded RNA; Th: T helper; TLR: Toll-like receptor.

Figure 4. Influence of the airway microbiota on responses to allergens, pollutants and pathogens
https://www.sciencedirect.com/science/article/pii/S0966842X15000591

OCTOBER 2021 I 7

L. plantarum treatment in mice with asthma
has shown significant efficacy in prevent-
ing lung inflammation exacerbated by
diesel exhaust particulate matter (DEPM)
administration. A study investigating the
potential of L. plantarum in preventing
DEPM-exacerbated asthma in ovalbu-
min (OVA)-sensitised BALB/c mice found
that oral administration reduced OVA +
Allergic skin conditions and the role of gut-skin
microbiota
The most common chronic inflammatory
skin disease, AD, is very pruritic and is char-
acterised by erythema and oedema. AD may
have a mixed IgE-mediated and non-IgE-
mediated mechanism.1 Individuals with AD
are commonly stimulated by allergens includ-
ing pollen, dust mite and animal dander. Skin
flora, especially Staphylococcus aureus and
Malassezia, blooms in the lesions and results
in more severe AD clinical symptoms. Recent
advances in sequencing technology have dem-
onstrated that the development of AD is not
only associated with the skin microbiome but
also with gut microbiota.17
In patients with In patients with AD, compared to healthy
AD, compared individuals, gut microbial diversity is
decreased and the relative abundances of the
to healthy
beneficial microbes such as Lactobacillus and
individuals, gut Bifidobacterium are significantly reduced;
microbial diversity proportions of E. coli, Clostridium difficile
is decreased and S. aureus are increased in AD patients.
and the relative The development of gut diseases is commonly
abundances of accompanied by cutaneous lesional manifes-
the beneficial tations and this implies that the association
microbes such as between them may affect the health of each.
The hypothesis of the ‘gut-skin’ axis has
Lactobacillus and
been proposed, the cross-talk mechanism has
Bifidobacterium gradually been demonstrated, and it is now
are significantly recognised as a new target to prevent and
reduced treat AD.17
Recent systematic review of the literature
with regard to diversity of the gut microbiota,
specific bacterial colonisation and subsequent
risk of AD indicated that nearly half of the
interventional studies included showed that
altered gut microbial colonisation due to
use of probiotics had a positive effect on the
severity of AD. The remaining studies did not
8 I OCTOBER 2021
Spring fever: probiotics and allergy
DEPM-induced inflammatory infiltration,
goblet cell hyperplasia, airway remodelling,
and the levels of proinflammatory cytokines
and chemokines in bronchoalveolar lavage
fluid (BALF). The probiotics also attenuated
OVA + DEPM-induced IgE levels in serum
and in BALF, and significantly reduced cas-
pase-3 activity, total collagen level and matrix
metalloproteinase-9 activity.16
show an effect of probiotics on the severity of
AD, despite an alteration in the gut microbial
composition. Data from the observational
studies were conflicting, with some studies
showing that participants who developed
AD had a less diverse gut microbiome than
healthy individuals, while others found no sig-
nificant differences.18
L. plantarum LM1004 supplementation
has been shown to significantly improve
AD-like symptoms, decrease Th2 and Th17
cell transcription factor levels, and increase
the transcription factors of Treg and Th1
cells, galactin-9 and the important epidermal
barrier protein, filaggrin. This implies that
there is an interaction between probiotics, gut
microbiota and the epidermal barrier.17
Of interest, it has been found that the allergic
inflammation process is affected not only by
L. plantarum itself, but also by the extracel-
lular vesicles (EVs) secreted by the bacteria.
Experimental findings in S. aureus-induced
mouse AD models show that L. plantarum-
derived EV administration reduced epidermal
thickening and the level of IL-4; this indicates
the potential to help prevent skin inflamma-
tion.19 Another AD-induced animal model
study has shown significantly reduced vaso-
dilation (in rats) and pruritus, oedema and
serum histamine (in mice) with dietary L.
plantarum supplementation. Further findings
included significantly decreased mRNA levels
of Th2 and Th17 cell transcription factors,
while the transcription factors of Th1 and
Treg cells, galactin-9 and filaggrin increased,
indicative of enhanced immunomodulation
(p<0.05).20
 Spring fever: probiotics and allergy

Key learnings
• In allergic diseases there is a disturbance in the balance between Th1 and Th2 lymphocytes, in favour of
Th2 lymphocytes
• The most studied allergies on which probiotics have been shown to have a beneficial effect are rhinitis,
asthma and AD
• The most promising probiotics for the prevention and treatment of allergy are Lactobacillus and
Bifidobacterium species
• The gut microbiota of infants and children with CMA differs from the microbiota of healthy children;
there is some evidence for the clinical potential of probiotic supplementation against lactose intolerance
• Clinical and biomedical evidence exists for the beneficial effects of probiotics in respiratory allergy
disorders such as AR and asthma; trial evidence for the probiotic prevention of allergic airway disease
remains scarce
• The gut-skin axis is recognised as a new target for the prevention and treatment of AD; L. plantarum
supplementation has been shown to significantly improve symptoms.

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References
Click on reference to access the scientific article
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6. Yang Y, Li X, Yang Y, et al. Advances in the relationships
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between cow’s milk protein allergy and gut microbiota in
infants. Front Microbiol 2021; 12: 716667.
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7. Leis R, de Castro MJ, de Lamas C, et al. Effects of prebiotic and
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 Spring fever: probiotics and allergy

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