Neonatal colonization of germ-free mice with Bifidobacterium longum prevents allergic sensitization to major birch pollen allergen Bet v 1
Introduction
There has been a remarkable increase in allergic diseases over the past few decades, especially in Western countries [1]. Accumulating evidence suggests that environmental changes, rather than genetic factors, are driving the epidemic character of allergy, and events acting within a narrow window of opportunity, either prenatally or early in life, might have major physiological effects [2], [3].
The germ-free status of fetus changes rapidly after birth and the composition of colonizing microbiota can be influenced by multiple factors such as the mode of delivery, dietary changes, high hygiene or over-use of antibiotics [4]. The exposure to microbial stimuli is crucial for the development, maturation and function of the immune system and association between intestinal dysbiosis and allergic disease has been proposed [5]. Several prospective studies have shown lower neonatal colonization by bifidobacteria and lactobacilli species accompanied by higher counts of Clostridium difficile in neonates who developed allergy later in life [6], [7], [8].
Due to the ability of bifidobacteria and lactobacilli to interact with the host immune system and to modulate host immune responses, they have been used with some success in prevention or treatment of allergic disease in infants at risk [9]. Several randomized clinical trials have shown that combined prenatal/postnatal probiotic interventions reduced the cumulative incidence of eczema while less beneficial effects were found in trials using exclusively postnatal treatment approaches (recently reviewed in [10]). These data highlight the importance of the correct timing of probiotic interventions, for which the prenatal period seems to be a significant component.
Dendritic cells (DC) are pivotal in early bacterial recognition through engagement of TLR and C-type lectins, which leads to induction of distinct innate responses that shape the type of T helper cell responses [11], [12]. In this respect, Konieczna et al. recently showed that preconditioning of DC with probiotic Bifidobacterium infantis led to induction of Foxp3 positive regulatory T (Treg) cells with enhanced IL-10 production [13]. Due to the fact that allergic diseases have been associated with a deficiency in Treg cells numbers and/or function [14], specific probiotic strains inducing regulatory immune responses might be beneficial in the prevention of allergic disorders. Indeed, we have previously shown that perinatal administration of Lactobacillus paracasei to pregnant/lactating mice protected against the development of airway inflammation in offspring by activating regulatory pathways [15]. Similarly, neonatal application of Lactobacillus rhamnosus GG or Bifidobacterium lactis Bb-12 suppressed allergic sensitization and airway inflammation in mice by induction of Treg cells associated with increased levels of TGF-β [16].
Germ-free (GF) animals represent a powerful model to study the interaction of a single bacterial strain or a defined mixture of microbial strains with the host immune system [17]. Taking the advantage of this model we have previously shown that neonatal mono-colonization of GF mice with the recombinant bacterial strain Lactobacillus plantarum producing major birch pollen allergen Bet v 1 reduced the development of allergic responses upon systemic sensitization with the same allergen [18].
Bifidobacterium longum subspecies longum CCM 7952 (B. longum) is a commensal bacterial strain originally isolated from the feces of a healthy breast fed infant. This strain has been shown to induce regulatory responses in vitro and to suppress the inflammatory responses in a mouse model of experimental colitis (Srutkova, unpublished results). In the present study we investigated whether neonatal mother-to-offspring mono-colonization of GF mice with B. longum protects the offspring against allergic sensitization to allergen Bet v 1 in a model of type I allergy.
Section snippets
Animals
Germ-free BALB/c mice were kept under sterile conditions and were supplied with water and sterile pellet diet ST1 (Bergman, Czech Republic) ad libitum. Fecal samples were weekly controlled for microbial contamination as previously described [19]. Wild-type (WT) and TLR2−/−, TLR4−/−, and MyD88−/− mice on a C57BL/6 background, obtained from Prof. M. Müller (Vienna, Austria), were kept under SPF conditions. All animal experiments were approved by the local ethics committee.
Bacterial strain
Probiotic strain B.
Neonatal mono-colonization with B. longum prevents systemic sensitization to Bet v 1
Colonization of mice with B. longum remained stable throughout the experiments and reached the level of approximately 5 × 109 CFU/g of feces (data not shown). Sensitization with Bet v 1 induced high levels of allergen-specific antibodies in serum of GF mice. Neonatal mono-colonization with B. longum prevented the development of allergic sensitization as the production of Bet v 1-specific Th2-related IgE and IgG1 as well as Th1-related IgG2a antibodies in serum were reduced in these mice compared
Discussion
In the current study, we demonstrate that neonatal mother-to-offspring mono-colonization with B. longum CCM 7952 significantly reduced the development of allergen-specific immune responses in a gnotobiotic mouse model of type I allergy, which was associated with induction of regulatory milieu. Furthermore we show that TLR2, MyD88 and MAPK signaling pathways are crucial for the recognition of B. longum and induction of IL-10.
Clinical and experimental studies differ greatly regarding the outcome
Acknowledgements
We would like to thank Prof. M. Müller, University of Veterinary Medicine, Vienna, Austria, for providing TLR2-, TLR4- and MyD88-deficient mice. Excellent technical assistance of J. Jarkovska, A. Smolova, I. Grimova, B. Drabonova and O. Ul-Haq is gratefully acknowledged. Supported by grants 303/09/0449 of the Czech Science Foundation, CZ.3.22/2.1.00/09.01574, WTZ CZ16 of the OEAD, NR12-0101-10/2011 of the Republic of Poland, SFB F46 of the Austrian Science Fund (FWF), 7AMB12AT020 of the
References (32)
- et al.
Allergy development and the intestinal microflora during the first year of life
J Allergy Clin Immunol
(2001) - et al.
Distinct patterns of neonatal gut microflora in infants in whom atopy was and was not developing
J Allergy Clin Immunol
(2001) - et al.
Mechanisms of allergen-specific immunotherapy
J Allergy Clin Immunol
(2011) - et al.
Susceptibility to nasal and oral tolerance induction to the major birch pollen allergen Bet v 1 is not dependent on the presence of the microflora
Immunol Lett
(2008) - et al.
Mucosal co-application of lactic acid bacteria and allergen induces counter-regulatory immune responses in a murine model of birch pollen allergy
Vaccine
(2003) - et al.
Distinctive anti-allergy properties of two probiotic bacterial strains in a mouse model of allergic poly-sensitization
Vaccine
(2011) - et al.
Toll-like receptor 2 ligands inhibit TH2 responses to mite allergen
J Allergy Clin Immunol
(2006) - et al.
Exopolysaccharide activities from probiotic bifidobacterium: immunomodulatory effects (on J774A.1 macrophages) and antimicrobial properties
Int J Food Microbiol
(2010) - et al.
TLR signaling pathways
Semin Immunol
(2004) Atopic dermatitis
N Eng J Med
(2008)
Silent mysteries: epigenetic paradigms could hold the key to conquering the epidemic of allergy and immune disease
Allergy
Fetal epigenetic mechanisms and innate immunity in asthma
Curr Allergy Asthma Rep
The ‘hygiene hypothesis’ for autoimmune and allergic diseases: an update
Clin Exp Immunol
Unbalance of intestinal microbiota in atopic children
BMC Microbiol
Gut microbiota composition and development of atopic manifestations in infancy: the KOALA Birth Cohort Study
Gut
Guidance for substantiating the evidence for beneficial effects of probiotics: prevention and management of allergic diseases by probiotics
J Nutr
Cited by (38)
Bifidobacterium longum affects the methylation level of forkhead box P3 promoter in 2, 4, 6-trinitrobenzenesulphonic acid induced colitis in rats
2017, Microbial PathogenesisCitation Excerpt :The effects of intestinal B. longum on preventing the occurrence or exacerbation of UC by attenuating intestinal inflammation are investigated in both animal models and patients with UC [27,28]. In addition, mucosal administration of B. longum prevented the development of experimental allergy in mice [29,30]. Although many studies have demonstrated the immunomodulatory properties of probiotic strains in vitro and their ability to prevent inflammation in colitis mice, no clear association has been established so far.
Murine models for mucosal tolerance in allergy
2017, Seminars in ImmunologyCitation Excerpt :Along these lines, Trompette et al. showed that diet changes the metabolic output of gut bacteria, such as the levels of short-chain fatty acids (SCFA), that protect from allergic airway inflammation [253]. Taking advantage of a GF mouse model, which allows to study the impact of single bacterial strains or a defined mixture of strains on tolerance induction, we demonstrated that neonatal mother-to-offspring mono-colonization of GF mice with B. longum reduced the development of allergic responses to Bet v 1 [254]. Furthermore, we showed that colonization of GF mice with a mixture of three lactobacillus strains ameliorated allergic sensitization to Bet v 1.
Probiotics During the Perinatal Period: Impact on the Health of Mothers and Infants
2017, Prebiotics and Probiotics in Human Milk: Origins and Functions of Milk-Borne Oligosaccharides and BacteriaMicrobiome and Allergy
2016, Encyclopedia of ImmunobiologyThe Use of Adjuvants for Enhancing Allergen Immunotherapy Efficacy
2016, Immunology and Allergy Clinics of North AmericaCitation Excerpt :Thus, the use of immunomodulatory live micro-organisms (probiotics) has been suggested as a new strategy to improve SIT. Bacteria such as Lactobacillus plantarum or Bifidobacterium bifidum were found to modulate systemic cytokine production and decrease allergen-specific IgE production following sublingual immunotherapy in mice sensitized to OVA or Bet v1.74,75 In humans, most clinical trials using selected probiotics as a stand-alone therapy have failed to show clinically relevant beneficial effects on allergy.76,77