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Anti‐allergic effects of Lactobacillus crispatus KT‐11 strain on ovalbumin‐sensitized BALB/c mice
Abstract
In this study, we investigated the effects of oral ingestion of Lactobacillus crispatus KT-11 strain (KT-11) on the immune response in an allergic rhinitis mouse model, ovalbumin (OVA)-sensitized BALB/c mice. Sneezing activity in mice that were administered a KT-11-supplemented diet was significantly lower than that in mice administered a KT-11-free diet (control diet) at age 11 weeks. We found that serum OVA-specific immunoglobulin E (IgE) levels and total number of interleukin (IL)-4(+) CD4(+) spleen cells in mice that were administered a KT-11-supplemented diet were significantly lower than in mice administered a control diet. The ratio of spleen interferon-γ(+) CD4(+) /IL-4(+) CD4(+) cells was higher in the mice administered the KT-11-supplemented diet compared to that in mice administered the control or L. rhamnosus GG-supplemented diet. In contrast, the number of CD11b(+) CD80(+) and FcεRIα(+) CD117(+) cells was significantly lower in mice administered the KT-11-supplemented diet. These results suggested that KT-11 reduced OVA-induced allergic symptoms in BALB/c mice via the adjustment of the T helper type 1/T helper type 2 balance, and a decrease in the number of antigen-presenting cells and high affinity IgE receptor-positive mast cells.
... Th1 cytokines IFNγ and IL-12 ↑ [35][36][37][38][39] ↔ [5,11,14,17,20,44] ↓ [41] Th2 cytokines IL-4, IL-5 and IL-13 ↓ [5, 11, 14, 35-37, 39, 41, 44, 46, 50, 51, 53] ↔ [20,38] amounts" [7]. With their long track records for safety, strains of Lactobacilli and Bifidobacteria are widely used [8] and administered as drugs, medical or probiotic food [9]. ...
... Th1 cytokines, IFNγ and IL-12, have been found to be downregulated in AR patients [34]. A significant decreased Th2 cytokine profile in response to probiotic treatment was found in 5 animal trials [35][36][37][38][39]. Moreover, significantly higher levels of IFNγ were found after the intake of L. plantarum [36], L. helveticus, and L. gasseri [35], and in vitro experiments with L. plantarum birch pollen allergy in a murine model showed similar augmenting effects on IL-12 and IFNγ [37]. ...
... The considerable reduction of IgE levels in animal studies [32,36,38,39,44,45] and in human trials [22,23,41,46] indicates a reduction of IgE-producing B cells by Lactobacillus bacteria. In vivo experiments with L. paracasei KW3110 revealed significant lower total IgE and reduced antigen-specific IgE levels (p < 0.05) than control animals without oral administration of this type of LAB [43]. ...
Since conventional allergy medication for asthma or allergic rhinitis (AR) can cause side effects which limit the patients’ quality of life, it is of interest to find other forms of therapy. In particular, probiotic bacteria, such as Lactobacillus species, have shown anti-allergic effects in various mouse and human studies. For instance, administration of some Lactobacillus species resulted in nasal and ocular symptom relief and improvement of quality of life in children and adults suffering from rhinitis. Different changes in cytokine profiles, such as elevated Th1 and decreased Th2 cytokines, reduced allergy-related immunoglobulins and cell immigration have been found in both human and murine studies. Positive effects on patients like less activity limitations or fewer rhinitis episodes and longer periods free from asthma or rhinitis were also described following oral administration of Lactobacillus bacteria. However, it is still unclear how this type of lactic acid bacteria leads to changes in the immune system and thus inhibits the development of allergies or relieves their symptoms. This review gives an overview of current studies and draws conclusions concerning the usage of probiotic Lactobacillus strains in AR.
Keywords:
Allergic rhinitis · Allergy · Lactobacillus · Lactobacillus casei · Lactobacillus paracasei · Probiotics
... Mice were immunized and boosted with OVA (MP Biomedicals, Santa Ana, CA, USA) in order to induce type I allergic rhinitis according to the method of Tobita et al. [23]. As shown in Fig. 1C, AqMOL at low (0.6 mg/ml) and high (6 mg/ml) doses and distilled water as a control were continuously ingested ad libitum by mice (10 mice/each group) as drinking water from day 0 to day 45. ...
... The OVA-specific IgE level was measured using an enzyme-linked immunoassay (ELISA) according to the previously reported method [23]. Briefly, the wells of 96-well microtiter plates were coated with 100 µL OVA (100 mg/mL) in 0.1 mol/L carbonate buffer (pH 9.6) overnight at 4°C and washed five times with PBS containing 0.05% Tween 20 (PBS-T ...
... In the present study, we focused on the antiviral effects of the SLP of Lactobacillus crispatus strain KT-11, a probiotic strain isolated from a healthy infant (Tobita et al., 2009(Tobita et al., , 2010(Tobita et al., , 2018. Lithium chloride extract (LE) containing SLP (Johnson et al., 2013) was prepared from the KT-11 strain and evaluated for its inhibitory effect on human rotavirus infection in human intestinal epithelial cells. ...
S-layer proteins (SLPs), which are present in the external layer of certain strains of lactic acid bacteria isolated from the intestinal tract, are known to recognize and bind to specific proteins and glycan structures and contribute to adsorption to the host intestinal mucosa. The binding properties of certain SLPs are considered to exert a competitive inhibitory effect on infection because similar properties are involved in the infection mechanisms of several viruses. However, little is known regarding whether SLPs directly inhibit viral infection. In the present study, we investigated the effect of an SLP of the Lactobacillus crispatus KT-11 strain, a probiotic strain isolated from a healthy human infant, on human rotavirus infection. The impact of KT-11 lithium chloride extract (KT-11 LE), which contains SLP, on the infection of the P[4] genotype human rotavirus strain DS-1 was evaluated by monitoring the amplification of viral protein 6 (VP6) expression in human intestinal epithelial Caco-2 cells by quantitative reverse transcription-polymerase chain reaction assay after infection. KT-11 LE showed a significant suppressive effect on DS-1 infection in a dose-dependent manner with pre-infection treatment, whereas post-infection treatment was not effective. A 45 KDa protein isolated from KT-11 LE was investigated for homology using the BLAST database and was found to be a novel SLP. KT-11 SLP concentrate (KT-11 SLP) significantly inhibited the proliferative process of the DS-1 strain but not that of the P[8] genotype human rotavirus strain Wa. KT-11 SLP exerted significant inhibitory effect on DS-1 infection by pre-infection treatment even after digestion with gastric juice up to 2 h. Our results provided crucial evidence that SLPs from certain Lactobacillus strains can inhibit human rotavirus infection of intestinal epithelial cells.
... Lactobacillus crispatus is an obligately homofermentative, catalase-negative, Gram-positive bacterium [1]. Numerous studies have shown the considerable probiotic potential of L. crispatus, such as modulating the host's immune system [2], reducing allergic symptoms in mice [3], down-regulating The study (Ethical No. KS202006) was approved by the clinical new technology and scientific research ethics committee of the Wuxi People's Hospital, Wuxi, Jiangsu province, China. ...
Lactobacillus crispatus colonizes the human feces, human vagina, and the crops and ceca of chicken. To explore the genetic characteristics and evolutionary relationships of L. crispatus isolated from different niches, we selected 37 strains isolated from the human vagina (n = 17), human feces (n = 11), and chicken feces (n = 9), and used comparative genomics to explore the genetic information of L. crispatus from the feces and vagina. No significant difference was found in the three sources of genomic features such as genome size, GC content, and number of protein coding sequences (CDS). However, in a phylogenetic tree constructed based on core genes, vagina-derived L. crispatus and feces-derived strains were each clustered separately. Therefore, the niche exerted an important impact on the evolution of L. crispatus. According to gene annotation, the L. crispatus derived from the vagina possessed a high abundance of genes related to acid tolerance, redox reactions, pullulanase, and carbohydrate-binding modules (CBMs). These genes helped L. crispatus to better adapt to the acidic environment of the vagina and obtain more nutrients, maintaining its dominance in the vagina in competition with other strains. In feces-derived bacteria, more genes encoding CRISPR/Cas system, glycoside hydrolases (GHs) family, and tetracycline/lincomycin resistance genes were found to adapt to the complex intestinal environment. This study highlights the evolutionary relationship of L. crispatus strains isolated from the vagina and feces, and the adaptation of L. crispatus to the host environment.
... Bifidobacterium longum BB536 alleviated allergic symptoms in mice by suppressing Th2 activation (Iwabuchi et al., 2007). Lactobacillus crispatus KT-11 attenuated OVA-induced allergic nasal symptoms in mice by correcting Th1/Th2 balance and suppressing MCs population (Tobita, Yanaka, & Otani, 2010). Lactobacillus rhamnosus Lcr35 reduced OVA-induced AR in mice by inhibiting IL-4 expression. ...
We examined the effects of Bifidobacterium longum IM55, Lactobacillus plantarum IM76, and their (1:1 and 1:9) mixtures (PMs) on house dust mite allergen extract (HDMA)-induced allergic rhinitis (AR) in mice. Oral administration of IM55, IM76, or PM significantly suppressed HDMA-induced allergic nasal symptoms, IL-4 and IL-5 expression in the nasal mucosa, bronchoalveolar lavage fluid (BALF), and blood, and IgE level in blood. They suppressed HDMA-induced eosinophil, mast cell, and Th2 populations in BALF while the regulatory T cell population and IL-10 expression were increased. Treatment with IM55, IM76, or PM significantly reduced HDMA-induced IL-4, IL-5, IL-13, and eosinophil peroxidase expression and increased IL-10 expression in the colon. Furthermore, their treatments suppressed HDMA-induced Proteobacteria population and Proteobacteria to Bacteroidetes ratio in the gut microbiota. In conclusion, IM55 and IM76 may mitigate AR by suppressing IL-4, IL-5, and IL-13 expression and inducing IL-10 expression through the inhibition of gut Proteobacteria population.
... These results suggest that fRG can alleviate MC-mediated AR. We also observed that ovalbumin-treated mice exhibited AR symptoms and increased Th2 cell population and IL-4, IL-5, IL-13, and IgE expression, as previously reported [40,41]. Furthermore, the induction of AR by ovalbumin treatment altered gut microbiota composition: it increased the Firmicutes population and reduced Bacteroidetes and Actinobacteria populations. ...
Background:
To increase the pharmacological effects of red ginseng (RG, the steamed root of Panax ginseng Meyer), RG products modified by heat process or fermentation have been developed. However, the antiallergic effects of RG and modified/fermented RG have not been simultaneously examined. Therefore, we examined the allergic rhinitis (AR)-inhibitory effects of water-extracted RG (wRG), 50% ethanol-extracted RG (eRG), and bifidobacteria-fermented eRG (fRG) in vivo.
Methods:
RBL-2H3 cells were stimulated with phorbol 12-myristate-13-acetate/A23187. Mice with AR were prepared by treatment with ovalbumin. Allergic markers IgE, tumor necrosis factor-α, interleukin (IL)-4, and IL-5 were assayed in the blood, bronchoalveolar lavage fluid, nasal mucosa, and colon using enzyme-linked immunosorbent assay. Mast cells, eosinophils, and Th2 cell populations were assayed using a flow cytometer.
Results:
RG products potently inhibited IL-4 expression in phorbol 12-myristate-13-acetate/A23187-stimulated RBL-2H3 cells. Of tested RG products, fRG most potently inhibited IL-4 expression. RG products also alleviated ovalbumin-induced AR in mice. Of these, fRG most potently reduced nasal allergy symptoms and blood IgE levels. fRG treatment also reduced IL-4 and IL-5 levels in bronchoalveolar lavage fluid, nasal mucosa, and reduced mast cells, eosinophils, and Th2 cell populations. Furthermore, treatment with fRG reduced IL-4, IL-5, and IL-13 levels in the colon and restored ovalbumin-suppressed Bacteroidetes and Actinobacteria populations and ovalbumin-induced Firmicutes population in gut microbiota. Treatment with ginsenoside Rd significantly alleviated ovalbumin-induced AR in mice.
Conclusion:
fRG and ginsenoside Rd may alleviate AR by suppressing IgE, IL-4, IL-5, and IL-13 expression and restoring the composition of gut microbiota.
... Lactobacilli colonize the gastrointestinal tract, including the oral cavity (36), and vagina (37) (38), and it has also been evaluated as a possible treatment of allergic rhinitis (39), demonstrating that supplementation with L. gasseri may be beneficial because of its effect on nasal blockage (39), and decreased nasal clinical symptoms scores in children suffering from allergic rhinitis. (40) As L. crispatus and L. gasseri were also observed to suppress allergic responses (41) and reduce mite-induced airway inflammation and hyperresponsiveness in mice models (42), these species may have a protective role in asthma development and deserve to be further investigated. ...
Background
Allergic diseases have become a major public health problem in affluent societies. Microbial colonization early in life seems to be critical for instructing regulation on immune system maturation and allergy development in children. Even though the oral cavity is the first site of encounter between a majority of foreign antigens and the immune system, the influence of oral bacteria on allergy development has not yet been reported.
Objective
We sought to determine the bacterial composition in longitudinally collected saliva samples during childhood in relation to allergy development.
Methods
Illumina sequencing of the 16S rDNA gene was used to characterize the oral bacterial composition in saliva samples collected at 3, 6, 12, 24 months and 7 years of age from children developing allergic symptoms and sensitization (n=47) and children staying healthy (n=33) up to seven years of age.
Results
Children developing allergic disease, particularly asthma, had lower diversity of salivary bacteria together with highly divergent bacterial composition at 7 years of age, showing a clearly altered oral microbiota in these individuals, likely as a consequence of an impaired immune system during infancy. Moreover, the relative amounts of several bacterial species, including increased abundance of Gemella haemolysans in children developing allergies and Lactobacillus gasseri and L. crispatus in healthy children, was distinctive during early infancy, likely influencing early immune maturation.
Conclusion
Early changes in oral microbial composition seem to influence immune maturation and allergy development. Future experiments should test the probiotic potential of L. gasseri and L. crispatus isolates.
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... Researchers reported that OVA was administered through various routes such as inhalation or injection to Balb-c mice in experimental animal studies to generate an allergic reaction, it was shown that these routes resulted with OVA specific IgE levels. We used OVA through intraperitoneal injections in Balb-c mice to stimulate an allergic response [17][18][19][20][21]. ...
Objectives: To investigate the effects of a probiotic mixture thatwas isolated from human gut flora, and a standard probiotic strainLactobacillus GG (LGG) on allergic immune responses in ananimal model.Materials and Methods: Three Enterococcus faecalis, 8Lactobacillus plantarum, and 2 Lactobacillus rhamnosus strainswere included in the mixture. Balb-c mice in the study groupswere given the probiotic mixture, and standard strain LGG, andanimals in the control groups were given skimmed milk for 28days. The mice in the study groups and the positive control groupwere immunized with an intraperitoneal injection of ovalbumin(OVA) on days 14 and 21. An enzyme-linked immunosorbentassay was used to study the OVA-specific IgE levels in the miceserums.Results: The most remarkable results were that OVAspecificIgE levels were significantly higher (P<0.001) inthe positive control group compared with the nonimmunizednegative control group, and OVA-specific IgE levels in thestudy groups were significantly lower than the positive controlgroup (P<0.001).Conclusion: The data of the present study suggest thatoral administration of probiotics prevents IgE-mediated OVAhypersensitivity;however, the immunoregulatory effects ofstrains must be described in detail while preparing probioticmixtures.
... The cytokine secretions from the spleen cells were not measured in the present work, but in a similar study, the administration of probiotic strains promoted the Th1 immune response by increasing the IFN-c/IL-4 secretion ratio from the spleen cells of OVAsensitized mice (Takeda et al., 2014). Other authors also recognized that some probiotic strains may reduce allergic symptoms by shifting the Th1/Th2 balance from a Th2-dominant state to a Th1dominant state (Forsythe, Inman, & Bienenstock, 2007;Hougee et al., 2010;Kang et al., 2016;Lin et al., 2013;Takeda et al., 2014;Tobita, Yanaka, & Otani, 2010). Yet, in the present study, we observed a greater effect on humoral immunity, as oral administration of both OVA and Leu. ...
The present study aimed to assess the immunomodulatory properties of Leuconostoc citreum L3C1E7, isolated from Pico cheese. In vitro tests showed a significant (P < 0.05) effect of live strain on reducing pro-inflammatory cytokine IL-8 secretion by lipopolysaccharide-induced HT-29 cells. The probiotic activity of the strain was further investigated in two rat models. Rats fed with ovalbumin (OVA), with/without the strain, were vaccinated subcutaneously with OVA on day 7 and 14. Allergen-specific IgG1 and IgG2a responses were restored after pre-feeding the strain. In a second experiment, an OVA-induced asthma model was used. Plasma levels of allergen-specific IgG1 and IgG2a were significantly (P < 0.05) raised in the OVA-fed group, while co-feeding with the strain significantly (P < 0.05) reduced plasma levels of these antibodies. Moreover, plasma OVA-specific IgE was significantly (P < 0.05) reduced by feeding the strain. These data show that feeding Leu. citreum L3C1E7 suppresses allergen-specific IgE synthesis and may alleviate Th2-mediated allergic symptoms.
... The proportion of several bacterial genera (Lactobacillus, Alistipes, Roseburia, Adlercreutzia and Clostridium) known to have immunomodulatory properties [25] was significantly different between farm and AF mice. Immunomodulatory properties have in particular been shown for Lactobacillus Crisptatus [26], and for Clostridia colonization in relation to IL-22 up-regulation in lamina propria lymphocytes [27]. In contrast to AF mice whose microbiome had higher diversity at 4 weeks than at 20 weeks of age (P = 0.0079), the Shannon diversity index of farm mice significantly (P = 0.032) increased during this time interval from 2.89 (range 1.8-3.18) to 3.97 (range 3.84-4.16). ...
Background:
Being born and raised in a farm provides a long-lasting protection for allergies. The microbial environment provided by farm animals is crucial to induce this protective effect, although underlying immune mechanisms remain elusive.
Objective:
To establish a mouse model of global exposure to the farming environment and to study immunologic changes linked to protection of allergy.
Methods:
Mice colonies were bred in parallel in a farm cowshed and the University animal facility (AF). Mice from both locations were subjected to a skin contact allergy model. Peripheral blood cells and cell cytokine production were assessed in both populations. In addition, the gut microbiome at various ages was characterized.
Results:
Mice born in the farm were less prone to develop allergy than mice bred in the AF. Mice transfers between the AF and the farm showed a better protection when mice were moved to the farm early in life. As compared to AF-bred mice, farm mice displayed early immune activation with higher CD4(+) T cell population, in particular CD4(+) CD25(+) FoxP3(-) (activated cells). The cytokine profile of mice from the farm was skewed towards an IL-17, and IL-22 secreting cell profile accompanied by increased IL-10 secretion. These differences were mostly seen within a specific age window between birth and 8 weeks of age. Microbiome analysis showed differences between 4 and 20-weeks old mice and between farm and AF mice with an increased number of Murine mastadenovirus B in young farm mice exclusively.
Conclusion:
The farming environment provides a strong, allergy protective IL-22 stimulus and generates activated CD4+ T cells. Exposure to the farm environment early in their life may also provide a better protection for contact skin allergy. Whether a viral trigger might decisively influence protection for allergies remains to be determined. This article is protected by copyright. All rights reserved.
... This shows that hydrolysates of NTU 101 induce the proliferations of macrophage and splenocyte and the release of IL-10 and IL-12 cytokines to modulate the innate and adaptive immune systems and inflammatory response (Chiang et al. 2012). The allergic response may be induced by intraperitoneal injection or by oral or nasal administration of OVA in mice (Bae et al. 2007; Kim et al. 2008; Medeiros et al. 2008; Tobita et al. 2010a, b). Orally administered L. paracasei subsp. ...
Probiotics have a number of beneficial health effects in humans and animals, such as reducing lactose intolerance symptoms and enhancing the bioavailability of nutrients. Probiotics help regulate intestinal microflora and immunomodulatory properties. Probiotics also decrease the prevalence of allergies in susceptible individuals, inhibit the inflammatory responses in the gut, and have antagonistic effects against intestinal and food-borne pathogens. Bacteria typically colonize the intestinal tract first and then reinforce the host defense systems by inducing generalized mucosal immune responses, including modulation of DC/NK interaction, a balanced T-helper cell response, self-limited inflammatory response, and the secretion of polymeric IgA. A lot of reports showed that lactic acid bacteria (LAB) as Lactobacillus and Bifidobacterium and their fermented products are effective at enhancing innate and adaptive immunity, prevent gastric mucosal lesion development, alleviate allergies, and put up defense against intestinal pathogen infection. In this review paper, we compared the influence of immunomodulatory effects on the function and efficacy of lactobacillus products with different strains. We also discuss the beneficial effects of several LAB strain and its derivative products for human immunity and related diseases.
... Cell function analysis. Cell surface markers and intracellular cytokines were labeled according to a previously described procedure (10). The cell number was determined using a Guava personal cell functional analyzer (Guava PCA, Guava Technologies, Hayward, CA, USA). ...
The effects of oral ingestion of a hot water extract of matured fruit of the date palm tree (Phoenix dactylifera L.) on allergic responses were investigated in mite-sensitized mice. Sneezing and nose rubbing events in mice given a date extract-added diet were significantly lower than in those given an extract-free (control) diet. The serum total and mite antigen-specific immunoglobulin (Ig) E levels, and the number of spleen interleukin-4(+)CD4(+), IgE(+)B220(+) and FcεRIα(+)CD117(+) cells was significantly lower in mice given the date extract-added diet than in those given the control diet. Chlorogenic acid, pelargonin and ferulic acid significantly reduced the number of IgE(+)B220(+) cells, while chlorogenic acid and pelargonin significantly decreased the number of FcεRIα(+)CD117(+) cells in mouse spleen cell cultures. These results suggest that some polyphenols in the date may reduce mite-induced allergic symptoms in mice via a decrease in the number of IgE-producing plasma cells and high-affinity IgE receptor-expressing mast cells.
... In addition, orally administered heat-killed Lactobacillus pentosus strain S-PT84 has been shown to lower serum IgE levels, to suppress the active cutaneous anaphylaxis reaction and splenic IL-4 production and to upregulate IL-10 production in OVA-immunised mice (Nonaka et al. 2008). It has also been shown that the allergic response may be induced by intraperitoneal injection or by oral or nasal administration of OVA in mice (Bae et al. 2007; Kim et al. 2008a; Medeiros et al. 2008; Hougee et al. 2010; Tobita et al. 2010a, b). In a previous study, 3-month-old male and female BALB/c mice were divided into two groups: a presensitised group and a post-sensitised group. ...
It is well-known that probiotics have a number of beneficial health effects in humans and animals, including the reduction of symptoms in lactose intolerance and enhancement of the bioavailability of nutrients. Probiotics have showed to possess antimutagenic, anticarcinogenic and hypocholesterolemic properties. Further, they were also observed to have antagonistic actions against intestinal and food-borne pathogens, to decrease the prevalence of allergies in susceptible individuals and to have immunomodulatory effects. Typically, the bacteria colonise the intestinal tract first and then reinforce the host defence systems by inducing a generalised mucosal immune response, balanced T-helper cell response, self-limited inflammatory response and secretion of polymeric IgA. Scientific reports showed that the Taiwan native lactic acid bacterium from newborn infant faeces identified as Lactobacillus paracasei subsp. paracasei NTU 101 and its fermented products proved to be effective for the management of blood cholesterol and pressure, prevention of gastric mucosal lesion development, immunomodulation and alleviation of allergies, anti-osteoporosis and inhibition the fat tissue accumulation. This review article describes that the beneficial effects of this Lactobacillus strains and derivative products may be suitable for human and animals.
This study aimed to examine whether probiotics, which suppressed the differentiation of splenic T cells into type 2 helper T (Th2) cells and induced into regulatory T cells in vitro, alleviate allergic rhinitis (AR) and gut microbiota disturbance. We isolated Bifidobacterium longum IM55 and Lactobacillus plantarum IM76 from human faecal microbiota and kimchi, respectively, and examined their effects on ovalbumin (OVA)-induced AR and gut microbiota disturbance in mice. Treatment with IM55, IM76, or their probiotic mixture (PM) significantly reduced OVA-induced allergic nasal symptoms and blood immunoglobulin E (IgE) levels in mice. These also reduced OVA-induced interleukin (IL)-4 and IL-5 levels in nasal tissues and bronchoalveolar lavage fluid (BALF) but increased OVA-suppressed IL-10 levels. Treatment with IM55, IM76, or PM reduced OVA-induced increase in the populations of mast cells, eosinophils, and Th2 cells and increased OVA-suppressed population of regulatory T cells in the BALF. Treatment with IM55, IM76, or PM also inhibited OVA-induced expression of IL-5 in lung and colon tissues and restored OVA-disturbed composition of gut microbiota Proteobacteria, Bacteroidetes, and Actinobacteria. These results suggest that IM55 and IM67 can alleviate AR by restoring Th2/Treg imbalance and gut microbiota disturbance.
Heat-treated lactic acid bacteria is added to some foods because it is easier to store and transport, and have less interference with other food ingredient compared with living lactic acid bacteria. We have reported that oral administration of heat-treated Lactobacillus crispatus KT-11 strain (KT-11) suppressed the symptoms of periodontal disease in mice orally infected with Porphyromonas gingivalis. However, the preventive effect of KT-11 on periodontal disease in human is unclear. The aim of this randomised double-blind clinical trial was to examine the effects of KT-11 consumption on the oral environment in healthy volunteers. Sixteen healthy volunteers were randomly assigned to two groups (KT-11 or placebo), and they consumed a KT-11 food tablet (1.2×1010 KT-11 cells) or a placebo food tablet (without KT-11) every day for 4 weeks. Clinical parameters including numbers of major periodontopathic bacteria in saliva, plaque score, gum conditions, and oral mucosal fluid level were evaluated at weeks 0 and 4. Amount of change in P. gingivalis numbers decreased in the KT-11 group compared to that in the placebo group at week 4. Female participants in the KT-11 group had decreased plaque scores, reddish tinge, and gingival swelling scores compared to those in the placebo group at week 4. Furthermore, male participants in the KT-11 group demonstrated increased oral mucosa fluid scores. These clinical findings suggest that daily KT-11 intake can prevent periodontal disease through the improvement of oral conditions.
In this study, we investigated the effect of Lactobacillus crispatus KT-11 strain (KT-11) on production of interleukin (IL)-12 produced from a mouse macrophage-like cell line, J774.1stimulated with a few lactic acid bacteria and some bacteria cell components.
The amount of IL-12 was significantly higher in J774.1 cell cultures with KT-11 than in those without KT-11. The amount of IL-12 was also significantly higher in J774.1 cell cultures with a few lactic acid bacteria and Toll-like receptor (TLR) 2 ligand in the presence of KT-11 than in those in the absence of KT-11. On the other hand, KT-11 stimulated the expression of TLR2 on J774.1 cells.
These results suggest that KT-11 promotes IL-12 produced from the J774.1 cells stimulated with a few lactic acid bacteria and TLR2 ligand via an up-regulation of TLR2 expression.
Lactobacillus crispatus KT-11, which was originally isolated from the feces of healthy infants, has been reported to show multiple immunoregulatory effects. However, there have been no reports about the effect of the Lactobacillus on periodontal disease, a chronic destructive inflammatory disease of the tissues supporting the teeth. We used a model of periodontal disease in which mice were infected with Porphyromonas gingivalis. As we report here, oral ingestion of KT-11 exerted inhibitory effects on alveolar bone resorption in this model, suggesting potential preventive activity of the Lactobacillus in periodontal disease.
Mice were given free access to feed containing dead Lb. crispatus KT-11 over 6 weeks, and were then orally infected with P. gingivalis 10 times for 2 weeks from 4 weeks later of Lb. crispatus KT-11 administration. The results showed a marked attenuation of alveolar bone resorption in mice that ingested the Lb. crispatus KT-11-containing feed. Induction of total IgG in plasma and total secretory IgA in saliva was observed. A specific plasma IgG antibody response to P. gingivalis also was induced.
Based on the immune response to P. gingivalis infection induced by ingestion of Lb. crispatus KT-11, this study suggests that oral administration of Lb. crispatus KT-11 is effective in preventing chronic periodontitis.
The effects of heat-treated Lactobacillus (Lb.) crispatus KT-11 on influenza virus infection and macrophage cytokine production in mice were investigated. The mice were orally administered saline containing heat-treated Lb. crispatus KT-11 (0, 1 or 10mg). Then, the mice were intranasally inoculated with influenza H1N1 virus and assessed for survival rate and changes in body weight. The mouse macrophage cell line RAW264 was cultured in the presence of heat-treated lactic acid bacteria for 48 hours. Cytokine levels in the cell culture supernatant were determined using ELISA. The area under the curve of changes in body weight (AUCW) in mice infected with influenza virus and orally administrated heat-treated Lb. crispatus KT-11 (1mg) was significantly higher than that in mice not administered any bacterium (control group). The concentrations of IFNα, TNFα, IL-1α and IL-6 were higher in the RAW264 cells cultured with heat-treated Lb. crispatus KT-11 than in control (non-addition of bacteria) or in those with other heat-treated bacteria. These results suggest that heat-treated Lb. crispatus KT-11 enhances macrophage cytokine production and protects against influenza virus infection.
Antiallergic activities of 10 lactic acid bacteria strains prepared from Mongolian dairy products as orally administered probiotics were examined in three murine type I allergy models (compound 48/80 stimulation, passive cutaneous anaphylaxis reaction, and ovalbumin sensitization models). Among the 10, only Lactobacillus plantarum strain 06CC2 significantly alleviated allergic symptoms in all three models and reduced the levels of total IgE, ovalbumin-specific IgE, and histamine in the sera of ovalbumin-sensitized mice. In vitro study, interferon-γ and interleukin-4 secretions from spleen cells of ovalbumin-sensitized mice administered the 06CC2 strain were significantly enhanced and suppressed, respectively, in the presence of ovalbumin. In Peyer's patches of ovalbumin-sensitized mice, strain 06CC2 significantly enhanced mRNA expressions of interferon-γ and interleukin-12 receptor β2, but suppressed that of the interleukin-4. Thus, strain 06CC2 probably promoted Th1 immunity through intestinal immunity and improved the Th1/Th2 balance in type I allergic mice, resulting in alleviation of allergic symptoms.
We investigated 10 lactic acid bacteria strains with probiotic potential prepared from Mongolian dairy products for their ability to induce T helper type-1 (Th1) cytokine production in mouse immune cells in vitro and in vivo. Among these strains, the Lactobacillus plantarum 06CC2 strain was effective in elevating the level of interleukin (IL)-12p40 in co-culture with J774.1 cells and the levels of IL-12 and interferon (IFN)-γ in co-culture with mouse spleen cells in vitro. Oral administration of this strain augmented the gene expression of IFN-γ and IL-12p40 and enlarged the population of CD4(+), CD25(+), and CD49b(+) cells in the spleens of normal mice. It also significantly elevated the gene expression of IL-12 receptor β2 as well as IL-12p40 and IFN-γ in Peyer's patches. Thus oral administration of strain 06CC2 was effective in inducing Th1 cytokine production activating the Th1 immune response associated with intestinal immunity in normal mice.
Type-1 allergic diseases consist of two phases. An inductive phase comprises IgE formation to allergens based on the immune system being biased to predominant T-helper type 2 responses. In a triggering phase allergic symptoms are triggered due to a robust secretion of mediators from mast cells and other cells after re-exposure to the same allergen. Various polyphenols, found in foods and plant sources, have potent anti-allergic activities that have been shown in different disease models and in human clinical trials. The present review summarizes the recent findings and progress in the research about polyphenols and natural products, and their role in allergic diseases. Intake of representative polyphenols (flavones, flavone-3-ols, catechins, anthocyanidins, flavanones, procyanidins, and resveratrol) can improve a skewed Th1/Th2 balance and suppress antigen-specific IgE antibody formation. Oral administration of fermented grape foods (FGF), one example of natural products fermented by lactic acid bacteria, is effective for decreasing allergic symptoms in the effector phase. Inhibitory mechanisms of polyphenols are also discussed.
A high-fat diet disturbs the composition and function of the gut microbiota and generates local gut-associated and also systemic responses. Intestinal mast cells, for their part, secrete mediators which play a role in the orchestration of physiological and immunological functions of the intestine. Probiotic bacteria, again, help to maintain the homeostasis of the gut microbiota by protecting the gut epithelium and regulating the local immune system. In the present study, we explored the effects of two probiotic bacteria, Lactobacillus rhamnosus GG (GG) and Propionibacterium freudenreichii spp. shermanii JS (PJS), on high fat-fed ApoE*3Leiden mice by estimating the mast cell numbers and the immunoreactivity of TNF-α and IL-10 in the intestine, as well as plasma levels of several markers of inflammation and parameters of lipid metabolism. We found that mice that received GG and PJS exhibited significantly lower numbers of intestinal mast cells compared with control mice. PJS lowered intestinal immunoreactivity of TNF-α, while GG increased intestinal IL-10. PJS was also observed to lower the plasma levels of markers of inflammation including vascular cell adhesion molecule 1, and also the amount of gonadal adipose tissue. GG lowered alanine aminotransferase, a marker of hepatocellular activation. Collectively, these data demonstrate that probiotic GG and PJS tend to down-regulate both intestinal and systemic pro-inflammatory changes induced by a high-fat diet in this humanised mouse model.
We investigated the effect of Lactobacillus crispatus KT-11 (KT-11) on intestinal immune systems in C3H/HeN mice. The level of intestinal total immunoglobulin (Ig) A was significantly higher in mice given KT-11 than in mice not given KT-11. Gene expression relating to antibody production and innate immune response increased more than 2-fold in the former compared with the later. Moreover, the number of IL-6(+)CD11b(+) cells was significantly higher in Peyer's patch cells cultured with KT-11 than in those cultured without KT-11, although the number of CD4(+) cells and the cell ratio of CD4(+)/CD8(+) were remarkably lower in the culture with KT-11. These results indicate that KT-11 enhances intestinal IgA production and innate immune response in C3H/HeN mice.
We synthesized a medium consisting of commercial food supplements (food grade medium) that could be used to cultivate Lactobacillus crispatus KT-11 (KT-11), and investigated the antiallergic effects and acute toxicity of KT-11 cultured in this medium. We found that the growth of KT-11 in the food grade medium was comparable to that in DeMan-Rogosa-Sharpe (MRS) medium. Sneezing event was reduced in ovalbumin (OVA)-sensitized BALB/c mice given a diet supplemented with KT-11 grown in the food grade medium (FG-KT-11 group) when compared to mice given a diet supplemented with KT-11 grown in MRS medium (MRS-KT-11 group). The number of CD80(+)CD11b(+) Peyer's patch cells was significantly lower in the FG-KT-11 group than in the MRS-KT-11 group, while IL-12(+)CD11b(+) Peyer's patch cells were higher in the FG-KT-11 group. Only minimal acute toxicity was observed in ICR mice given 1000 or 2000 mg of FG-KT-11/kg body weight. These results suggest that FG-KT-11 represents a safe antiallergic food material.
The effect of human recombinant interleukin 4 (IL-4) on antibody production by normal peripheral blood mononuclear cells enriched for B cells was investigated. IL-4 preferentially induced IgE synthesis in vitro. In addition, a low induction of IgG production was observed, whereas IL-4 had no effect on IgA and IgM synthesis. The IL-4-induced IgE production by B cells required T cells and monocytes but was specifically inhibited by an anti-IL-4 antiserum indicating that, although IL-4 acts indirectly, it is responsible for the induction of IgE synthesis. IL-4-induced IgE production was blocked in a dose-dependent way by interferon gamma (IFN-gamma), interferon alpha (IFN-alpha), and prostaglandin E2. IFN-gamma also inhibited IL-4-induced IgG production. These inhibitory effects of IFN-gamma and IFN-alpha on IgE production cannot be attributed to toxic effects since IFN-alpha induced IgM production in the presence of IL-4, whereas IFN-gamma was ineffective in inhibiting IgG production induced by IL-2. IFN-gamma, IFN-alpha, and prostaglandin E2 also inhibited IL-4-induced expression of the low-affinity receptor for the Fc portion of IgE (CD23) on B cells, indicating that there is an association between CD23 expression and IL-4-induced IgE production. This theory was supported by the finding that IL-4-induced IgE production was inhibited by F(ab')2 fragments of an anti-CD23 monoclonal antibody.
The rRNA-targeted oligonucleotide probes are useful for the identification of Lactobacillus acidophilus, L. gasseri, L. johnsonii, L. crispatus, and L. amylovorus. However, the oligonucleotide probe designed for L. helveticus hybridized with nucleic acids of type strains of L. gallinarum and L. helveticus. Hence, the similarity among the 73 strains of lactobacilli was evaluated on the basis of their randomly amplified polymorphic DNA (RAPD) profiles derived from five single-primer reactions. These strains were grouped into seven clusters at a similarity level of 30%, which corresponded to six separate species of the L. acidophilus complex (L. johnsonii, L. gallinarum, L. amylovorus, L. crispatus, L. acidophilus, and L. gasseri, respectively) and L. helveticus. For the first time, strains of L. gallinarum were characterized by RAPD and PFGE analyses. The genome length in that species was estimated to be near 1.45 Mb with the summation of ApaI fragments, and near 1.95 Mb with the summation of SmaI fragments.
Lactobacillus acidophilus NCFM is a probiotic strain available in conventional foods (milk, yogurt, and toddler formula) and dietary supplements. Its commercial availability in the United States since the mid-1970s is predicated on its safety, its amenability to commercial manipulation, and its biochemical and physiological attributes presumed to be important to human probiotic functionality. The strain has been characterized in vitro, in animal studies, and in humans. NCFM is the progenitor of the strain being used for complete chromosome sequencing and therefore will be a cornerstone strain for understanding the relationship between genetics and probiotic functionality. Both phenotypic and genotypic techniques have verified its taxonomic status as a type A1 L. acidophilus strain. It adheres to Caco-2 and mucus-secreting HT-29 cell culture systems, produces antimicrobial compounds, and is amenable to genetic manipulation and directed DNA introduction. NCFM survives gastrointestinal tract transit in both healthy and diseased populations. NCFM inhibits aberrant crypt formation in mutagenized rats, indicative of activity that could decrease the risk of colon cancer. A blend of probiotic strains containing NCFM decreased the incidence of pediatric diarrhea. NCFM led to a significant decrease in levels of toxic amines in the blood of dialysis patients with small bowel bacterial overgrowth. At adequate daily feeding levels, NCFM may facilitate lactose digestion in lactose-intolerant subjects. Further validation of the probiotic properties of NCFM in humans and clarification of its mechanisms of probiotic action are needed to better understand the role this strain might play in promoting human health.
Human immune responses are heterogeneous and may involve antagonism between T helper (TH) lymphocyte subsets and their cytokines. Atopy is characterized by immediate immunoglobulin E (IgE)-mediated hypersensitivity
to agents such as dust mites and pollen, and it underlies the increasingly prevalent disorder asthma. Among Japanese schoolchildren,
there was a strong inverse association between delayed hypersensitivity to Mycobacterium tuberculosis and atopy. Positive tuberculin responses predicted a lower incidence of asthma, lower serum IgE levels, and cytokine profiles
biased toward TH1 type. Exposure and response to M. tuberculosis may, by modification of immune profiles, inhibit atopic disorder.
Background:
Alveolar macrophages (AMs) are more efficient antigen-presenting cells in allergic individuals than in nonatopic subjects.
Objective:
We studied whether this difference may be correlated to increased expression of membrane costimulatory molecules, such as the B7 molecules (CD80 and CD86).
Methods:
Eleven subjects with allergic asthma sensitized to Dermatophagoides pteronyssinus and 5 healthy nonatopic volunteers underwent bronchoalveolar lavage, and the costimulatory molecule expression on AMs was evaluated. Peripheral blood T cells, either freshly isolated or as established D pteronyssinus -specific cell lines, were cultured with autologous monocytes or AMs as antigen-presenting cells. In vitro allergen-induced proliferation and cytokine production were evaluated in the presence of B7-blocking reagents.
Results:
Allergic individuals had a significantly higher proportion of AMs expressing the CD80 molecule than control subjects (28.5% +/- 14.8% vs 1.4% +/- 1.2%; P <.001), whereas no difference was observed in CD86 expression (2.0% +/- 2.3% vs 1.1% +/- 0.6; P >.1). In a large proportion of the asthmatic subjects we studied, AMs were presenting soluble antigens (tetanus toxoid and streptolysin-O) to freshly isolated T cells more efficiently than AMs from nonatopic control subjects. Finally, both T-cell proliferation and cytokine production of D pteronyssinus- specific established T-cell lines were inhibited by a CD80-blocking antibody in a dose-dependent manner.
Conclusion:
Costimulation by means of CD80 expressed by AMs is probably involved in the amplification of the allergen-specific T-lymphocyte response in the airways of asthmatic subjects.
The type strain of Lactobacillus crispatus (VPI 3199, parent strain of strain ATCC 33820) and the deoxyribonucleic acid homology reference strain of "Lactobacillus acidophilus" group A2 (strain ATCC 33197) have 100% deoxyri- bonucleic acid homology. L. crispatus and strains in "L. acidophilus" group A2 also produce similar polyacrylamide gel electrophoresis patterns of soluble cellular proteins and are similar in other phenotypic characteristics. Therefore, the group A2 strains are members of the species L. crispatus (Brygoo and Aladame 1953) Moore and Holdeman 1970.
Recent interest has focused on the importance of intestinal immunity for the host defense, but to date, not much is known about the underlying mechanisms. The toll-like receptor (TLR) family plays an important role in host defense through recognizing bacterial pathogen-associated molecular patterns. Our recent research on the physiological function of food products has investigated the immunoregulatory effects of probiotic lactic acid bacteria (LAB) via TLR. Studies of swine, which often substitute for a human model, have demonstrated intestinal immunoregulation by the probiotic LAB mediated by TLR in the gut. On the basis of our study, efforts have also been made to develop a molecular immunoassay system for probiotic LAB and find novel immunostimulatory DNA sequences from probiotics and high potential immunobiotic LAB strains via TLR signaling. These findings may provide important clues at the molecular level on TLR signal transduction pathways and recognition mechanisms for the ligands. They also provide impetus to further delineate the activation mechanism of the innate immune response. In addition to identifying immunoregulatory factor immunogenics from LAB, a better understanding of intestinal immune regulation through cytokine networks holds out promise for basic food immunology research and the development of immunobiotic foods to prevent specific diseases.
The role of inflammatory effector cells in the pathogenesis of airway allergy has been the subject of much investigation. However, whether systemic factors are involved in the development of local responses in both upper and lower airways has not been fully clarified. The present study was performed to investigate aspects of the pathogenesis of isolated allergic rhinitis in a murine model sensitized to ovalbumin (OVA). Both upper- and lower-airway physiological responsiveness and inflammatory changes were assessed, as well as bone marrow progenitor responses, by culture and immunohistological methods. Significant nasal symptoms and hyper-responsiveness appeared after intranasal OVA challenge (P < 0·0001 and P < 0·01, respectively), accompanied with significant nasal mucosal changes in CD4+ cells (P < 0·001), interleukin (IL)-4+ cells (P < 0·01), IL-5+ cells (P < 0·01), basophilic cells (P < 0·02) and eosinophils (P < 0·001), in the complete absence of hyper-responsiveness or inflammatory changes in the lower airway. In the bone marrow, there were significant increases in CD34+ cells, as well as in eosinophils and basophilic cells. In the presence in vitro of mouse recombinant IL-5, IL-3 or granulocyte–macrophage colony-stimulating factor (GM-CSF), the level of bone marrow eosinophil/basophil (Eo/Baso) colony-forming cells increased significantly in the OVA-sensitized group. We conclude that, in this murine model of allergic rhinitis, haemopoietic progenitors are upregulated, which is consistent with the involvement of bone marrow in the pathogenesis of nasal mucosal inflammation. Both local and systemic events, initiated in response to allergen provocation, may be required for the pathogenesis of allergic rhinitis. Understanding these events and their regulation could provide new therapeutic targets for rhinitis and asthma.
In the current study, we investigated the effects of heat-treated Lactobacillus crispatus KT strains on allergic response in mice. We found that the number of interferon (IFN)-gamma(+)CD4(+) cells was higher in C3H/HeN mouse spleen cultures incubated with L. crispatus KT strains than in those cultured with Lactobacillus JCM type cultures. The serum immunoglobulin E levels in NC/Nga mice that were administered KT strains were lower than those in the mice that were not given any bacterium. The ratio of spleen IFN-gamma(+)CD4(+)/interleukin-4(+)CD4(+) was highest in mice given L. crispatus KT-11. L. crispatus KT-11 also increased the expression of Toll-like receptor (TLR) 2, nucleotide-binding oligomerization domain (NOD) 1, and NOD2 in C3H/HeN mouse Peyer's patch cells. These results suggest that the L. crispatus KT-11 strain reduces allergic symptoms in NC/Nga mice via the adjustment of the type 1 helper T cell and type 2 helper T cell balance via TLR2, NOD1, and NOD2.
The Bifidobacterium breve M-16V strain has previously been shown to be effective in infants in improving the symptoms of allergic hypersensitivity to cow's milk and atopic dermatitis. In the current study, we investigated the effect of an oral administration of M-16V on immunoglobulin (Ig) E production in BALB/c mice. Live M-16V was orally administered to ovalbumin (OVA)-immunized mice for 3 weeks at a dose level of 5x10(8) colony-forming unit (cfu)/0.5 ml/d/animal. While M-16V treatment significantly reduced the serum levels of total IgE, OVA-specific IgE and OVA-specific IgG1, as compared to controls, it did not affect the serum level of OVA-specific IgG2a. In M-16V-administered mice, there was a significant decrease in the serum OVA-specific IgG1/IgG2a ratio. In addition, while ex vivo production of interleukin (IL)-4 by the splenocytes from M-16V-administered mice was significantly lower as compared to controls, there was no difference in the production of gamma-interferon (IFN-gamma) and IL-10. We also examined the effect of M-16V on cytokine and IgE production from OVA-sensitized splenocytes via restimulation with OVA in vitro. While M-16V suppressed OVA-induced total IgE and IL-4 production and induced secretion of IFN-gamma and IL-10 in a dose-dependent manner, it was not able to induce IL-12. We concluded that oral administration of M-16V suppressed the T-helper type (Th) 2 immune response and IgE production and modulated the systemic Th1/Th2 balance, and which was at least partially independent of the Th1 cytokine induction. These results suggest that M-16V may potentially have an antiallergic activity.
Among the factors potentially involved in the increased prevalence of allergic diseases, modification of the intestinal flora or lack of microbial exposure during childhood has been proposed. TH2-cytokines increase the production of IgE and stimulate mast cells and eosinophils, whereas TH1-cytokines, such as IFN-γ, may suppress IgE synthesis and stimulate the expression of the secretory piece of IgA. Thus, a dysregulation in the expression of TH1- and TH2-cytokines may contribute to the initiation and maintenance of allergic diseases. Lactobacilli belonging to the natural intestinal microflora were reported to reduce the incidence of atopic dermatitis and the severity of allergic manifestations and to modulate TH1/TH2 responses. The mechanisms still remain to be elucidated.
Background:
The idea that the innate and adaptive immune systems are not separate entities is no longer new. In fact, it is surprising that this paradigm was accepted without question for so long. Many innate cells express cell surface molecules and soluble mediators that are essential for the development and activation of T cells and B cells. Yet among the innate cell populations, mast cells may play the major role in regulating adaptive immune cell function.
Discussion:
This role first came to light in studies of mast cells and their involvement in the autoimmune disease experimental allergic encephalomyelitis, the major rodent model of multiple sclerosis and has subsequently been verified in many in vitro and in vivo model systems.
Human immune responses are heterogeneous and may involve antagonism between T helper (TH) lymphocyte subsets and their cytokines. Atopy is characterized by immediate immunoglobulin E (IgE)-mediated hypersensitivity to agents such as dust mites and pollen, and it underlies the increasingly prevalent disorder asthma. Among Japanese schoolchildren, there was a strong inverse association between delayed hypersensitivity to Mycobacterium tuberculosis and atopy. Positive tuberculin responses predicted a lower incidence of asthma, lower serum IgE levels, and cytokine profiles biased toward TH1 type. Exposure and response to M. tuberculosis may, by modification of immune profiles, inhibit atopic disorder.
Allergic asthma is associated with TH2-like cell responses and increased IgE production. Recent studies in mice have suggested that the costimulatory molecule B7.2 (CD86) may influence the development of TH2 cells.
We sought to determine the potential role of B7.2 in patients with asthma.
We performed an analysis of B cells from patients with allergic asthma and healthy control subjects for expression of B7.1 and B7.2 on B cells using five-parameter flow cytometry.
We report that atopic patients with asthma who are exposed to allergens have significantly (p < 0.005) higher levels of B7.2 expression on B cells than atopic asthmatic subjects not exposed to allergen in vivo or nonatopic control subjects. In contrast, there were no differences in B7.1 (CD80) expression among the three study subject groups. When peripheral blood mononuclear cells from asthmatic patients or normal control subjects were stimulated with IL-4 or IL-13, the expression of B7.2, but not B7.1, was significantly increased (p < 0.005) on B cells. Interferon-gamma or IL-12 did not affect the expression of either molecule. The functional significance of B7.2 induction by IL-4 in allergic disease was suggested by the increased expression of this molecule on CD23+, but not CD23-, B cells.
These results indicate that the same B cell involved in allergen presentation also expresses the costimulatory molecule B7.2 and support the hypothesis that this molecule is an important costimulatory molecule in allergic responses, the expression of which can be modulated by TH2-like cytokines.
The current taxonomy of probiotic lactic acid bacteria is reviewed with special focus on the genera Lactobacillus, Bifidobacterium and Enterococcus. The physiology and taxonomic position of species and strains of these genera were investigated by phenotypic and genomic methods. In total, 176 strains, including the type strains, have been included. Phenotypic methods applied were based on biochemical, enzymatical and physiological characteristics, including growth temperatures, cell wall analysis and analysis of the total soluble cytoplasmatic proteins. Genomic methods used were pulsed field gel electrophoresis (PFGE), randomly amplified polymorphic DNA-PCR (RAPD-PCR) and DNA-DNA hybridization for bifidobacteria. In the genus Lactobacillus the following species of importance as probiotics were investigated: L. acidophilus group, L. casei group and L. reuteri/L. fermentum group. Most strains referred to as L. acidophilus in probiotic products could be identified either as L. gasseri or as L. johnsonii, both members of the L. acidophilus group. A similar situation could be shown in the L. casei group, where most of the strains named L. casei belonged to L. paracasei subspp. A recent proposal to reject the species L. paracasei and to include this species in the restored species L. casei with a neotype strain was supported by protein analysis. Bifidobacterium spp. strains have been reported to be used for production of fermented dairy and recently of probiotic products. According to phenotypic features and confirmed by DNA-DNA hybridization most of the bifidobacteria strains from dairy origin belonged to B. animalis, although they were often declared as B. longum by the manufacturer. From the genus Enterococcus, probiotic Ec. faecium strains were investigated with regard to the vanA-mediated resistance against glycopeptides. These unwanted resistances could be ruled out by analysis of the 39 kDa resistance protein. In conclusion, the taxonomy and physiology of probiotic lactic acid bacteria can only be understood by using polyphasic taxonomy combining morphological, biochemical and physiological characteristics with molecular-based phenotypic and genomic techniques.
In the past 20-30 years, there has been an increase in prevalence of allergic respiratory diseases, particularly amongst children. This study is a prospective analysis of the postnatal maturation of T-helper cell (Th) responses to aeroallergens in atopic and non-atopic infants.
We measured mononuclear-cell proliferative and cytokine responses to specific allergens and tetanus toxoid in blood samples from atopic and non-atopic infants every 6 months from birth to 2 years of age. Cytokine analyses of responses to housedust-mite allergen used ELISA and reverse-transcriptase PCR. We also measured responses to Fel d1 (cat allergen) and tetanus toxoid.
Samples from 18 atopic and 13 non-atopic infants showed low-level Th2-skewed allergen-specific responses at birth, with little accompanying specific interferon-gamma production. Neonatal Th2 responses were lower in the atopic group than in the non-atopic group; the differences were significant for interleukin-4 (mRNA: beta-actin ratio 0.48 [SE 0.15] vs 0.15 [0.06], p=0.049), interleukin-6 (4750 [48] vs 1352 [51] pg/mL culture fluid, p=0.003), interleukin-10 (1162 [228] vs 485 [89], p=0.015), and interleukin-13 (7.1 [0.9] vs 0.9 [0.3], p=0.008). There was rapid suppression of Th2 responses during the first year of life in non-atopic children, but there was consolidation of responses in atopic children, associated with defective neonatal interferon-gamma production.
The continuation of fetal allergen-specific Th2 responses during infancy is a defining feature of the inductive phase of atopic disease, and is associated with decreased capacity for production of the Th1 cytokine interferon y by atopic neonates. These findings provide a plausible mechanism for persistence of the fetal Th2 responses during early childhood in atopic individuals and subsequent expression of disease.
These studies were conducted to investigate the potential use of a flow cytometric analysis method for the identification and differentiation of chemicals with the capacity to induce irritation, IgE- or T cell-mediated hypersensitivity responses. An initial study investigated the ability of equally sensitizing concentrations (determined by local lymph node assay) of IgE-mediated (Toluene Diisocyanate-TDI) and T cell-mediated (Dinitrofluorobenzene-DNFB) allergens to differentially modulate the IgE+B220+ population in the lymph nodes draining the dermal exposure site. Sodium lauryl sulfate (SLS) was also tested as a nonsensitizing irritant control. Female B6C3F1 mice were dermally exposed once daily for 4 consecutive days, with the optimum time point for analysis determined by examining the IgE+B220+ population 8, 10, and 12 days post-initial chemical exposure. At the peak time point, day 10, the IgE+B220+ population was significantly elevated in TDI (41%), while moderately elevated in DNFB (18%) exposed animals when compared to the vehicle (0.8%), and remained unchanged in SLS (2.2%) exposed animals when compared to the ethanol control (2.5%). Experiments in our laboratory and others have demonstrated that the draining lymph node B220+ population becomes significantly elevated following exposure to allergens (IgE- and T cell-mediated), not irritants, allowing for their differentiation. An existing mouse ear swelling assay was used to identify chemical irritants. Therefore, using the endpoints of percent ear swelling, percent B220+ cells, and percent IgE+B220+ cells, a combined irritancy/phenotypic analysis assay was developed and tested with tetradecane (irritant), toluene diisocyanate, trimellitic anhydride (IgE-mediated allergens), benzalkonium chloride, dinitrofluorobenzene, oxazolone, and dinitrochlorobenzene (T cell-mediated allergens) over a range of concentrations. Based upon the pattern of response observed, a paradigm was developed for continued evaluation: Irritant exposure will result in significant ear swelling without altering the B220+ or IgE+B220+ populations. Exposure to sensitizers (IgE-mediated or T cell-mediated) will increase the B220+ population and the percent ear swelling will remain unchanged or will significantly increase, depending on the irritancy capacity of the chemical. Both the IgE+B220+ and B220+ populations will become elevated at the same test concentration following exposure to IgE-mediated, hypersensitivity inducing allergens. At its peak, the percent of IgE+B220+ cells will be equal to the percent of B220+ cells. The B220+ population will increase at a lower test concentration than the IgE+B220+ population, following exposure to T cell-mediated, hypersensitivity inducing allergens. At its peak, the percent of IgE+B220+ cells will reach less than half that of the percent of B220+ cells. The irritancy/phenotypic analysis method may represent a single murine assay able to identify and differentiate chemicals with the capacity to induce irritation, or IgE-mediated or T cell-mediated responses.
Evidence for positive health benefits of Lactobacilli applies to only a few strains used for commercial applications. It is generally agreed that a probiotic must be capable of colonizing the intestinal tract to influence human health; this requirement disqualifies many of the strains currently used in fermented dairy products. Lactobacillus GG, a variant of L. casei sps rhamnosus, has been studied extensively in adults and children. When consumed as a dairy product or as a lyophilized powder, LGG colonizes the gastrointestinal tract for 1-3 days in most individuals and up to 7 days in about 30% of subjects. Traveler's diarrhea, antibiotic-associated diarrhea, and relapsing Clostridium difficile colitis are improved with LGG. In infantile diarrhea, the severity and duration of the attack is reduced. LGG-fermented milk lessens the intestinal permeability defects caused by exposure to cows milk or rotavirus infection. LGG has proven beneficial effects on intestinal immunity. It increases the numbers of IgA and other immunoglobulin-secreting cells in the intestinal mucosa. LGG stimulates local release of interferon. It facilitates antigen transport to underlying lymphoid cells, which serves to increase antigen uptake in Peyer's patches. LGG also acts as an immunoadjuvant for oral vaccines. In an animal model of colon cancer, LGG reduced the incidence of chemically induced tumors in the large bowel of rodents. Extensive safety testing has shown no pathogenic potential in humans or animals. Probiotic cultures of Lactobacilli have the potential to bring substantial health benefits to the consumer. The purported benefits for any probiotic must pass the highest standards of scientific scrutiny before the claims can be accepted.
Oral Lactobacillus rhamnosus GG ingestion for 5 days to 4 weeks has been shown to alleviate clinical symptoms of gastrointestinal inflammation and atopic dermatitis.
To determine whether oral Lactobacillus rhamnosus GG may act by generating immunosuppressive mediator in atopic children.
Lactobacillus rhamnosus GG (ATCC 53103) at a daily dose of 2 × 1010 cfu was added for 4 weeks to the diets of nine children (mean age, 21 months) with atopic dermatitis. Blood and faecal samples were collected before supplementation and at early (2 weeks) and late stage (4 and 8 weeks from the beginning). The concentrations of interleukin-6 (IL-6), IL-10, IL-12, tumour necrosis factor-α (TNFα) and interferon-γ (IFNγ) in sera, as well as the production of IL-2, IL-4, IL-10 and IFNγ in mitogen-induced peripheral blood mononuclear cells, were assessed. Secretory IgA and TNFα were also determined in faeces.
The serum IL-10 concentration differed significantly between before, early and late samples (P < 0.001) due to the elevation of serum IL-10 in the later phase of oral Lactobacillus rhamnosus GG ingestion. The enhancement of IL-10 production in mitogen-induced cultures preceded the rise in serum IL-10.
The enhanced IL-10 generation in vivo substantiates the anti-inflammatory properties of specific probiotic bacteria strains, and provides an additional reason for considering such treatments for patients with intestinal inflammation.
The role of inflammatory effector cells in the pathogenesis of airway allergy has been the subject of much investigation. However, whether systemic factors are involved in the development of local responses in both upper and lower airways has not been fully clarified. The present study was performed to investigate aspects of the pathogenesis of isolated allergic rhinitis in a murine model sensitized to ovalbumin (OVA). Both upper- and lower-airway physiological responsiveness and inflammatory changes were assessed, as well as bone marrow progenitor responses, by culture and immunohistological methods. Significant nasal symptoms and hyper-responsiveness appeared after intranasal OVA challenge (P < 0.0001 and P < 0.01, respectively), accompanied with significant nasal mucosal changes in CD4+ cells (P < 0.001), interleukin (IL)-4+ cells (P < 0.01), IL-5+ cells (P < 0.01), basophilic cells (P < 0.02) and eosinophils (P < 0.001), in the complete absence of hyper-responsiveness or inflammatory changes in the lower airway. In the bone marrow, there were significant increases in CD34+ cells, as well as in eosinophils and basophilic cells. In the presence in vitro of mouse recombinant IL-5, IL-3 or granulocyte-macrophage colony-stimulating factor (GM-CSF), the level of bone marrow eosinophil/basophil (Eo/Baso) colony-forming cells increased significantly in the OVA-sensitized group. We conclude that, in this murine model of allergic rhinitis, haemopoietic progenitors are upregulated, which is consistent with the involvement of bone marrow in the pathogenesis of nasal mucosal inflammation. Both local and systemic events, initiated in response to allergen provocation, may be required for the pathogenesis of allergic rhinitis. Understanding these events and their regulation could provide new therapeutic targets for rhinitis and asthma.
It has been nearly a century since the first suggestion that a soluble factor in plasma or serum might be responsible for the symptoms of allergic disease and asthma, and more than 30 yr since immunoglobulin E (IgE) was identified as the key molecule in mediating what are now described as type 1 hypersensitivity reactions (allergic asthma, allergic rhinitis, food allergy, atopic dermatitis, some forms of drug allergy, and insect sting allergy). Since that time, many of the details of the inflammatory cascade underlying allergy and asthma have been elucidated, and IgE is now known to play a key upstream role. The goals of this report are to review the cellular and molecular events set in motion by IgE and to examine the evidence for its participation in both the immediate allergic response and the late-phase or chronic inflammatory response in the skin and lungs.
Atopy is the state of allergy to common environmental antigens. Genetic and environmental factors promote the disorder. The impressive rise in prevalence, mainly centred on socio-economically developed communities around the world, emphasizes the potent action of environmental factors in moulding this immune disorder which is characterized by inadequately restrained Th-2 immune mechanisms and IgE production. Reversing the epidemiological trend depends on our identifying the major environmental inputs and acting against these. As yet, the nature of these environmental factors remains to be clarified. Candidate factors include changes in diet, chemical air pollution and microbial exposures in developed countries. This article limits its scope to changing microbial exposures as a potential mechanism. (a) It records epidemiological data that have associated atopic status with less natural exposure to pathogens, parasites and commensal micro-organisms, but with more exposure to certain antibiotics and public health immunizations in early life. (b) It records studies in mice that support the concept that certain microbial exposures can inhibit experimental allergy. (c) It considers potential immune mechanisms for such an action, including the possibility that certain natural infections promote immune regulatory processes that can restrain atopy. It is concluded that the hypothesis that changing patterns of microbial exposure may have promoted the rise in atopy is viable, and that exciting possibilities for reversing the rise of atopy may be derived from further studies.
To be able to draw the right conclusions from clinical research, it is essential that words have the same meaning to all researcher and clinicians.
To present the new nomenclature for allergy and discuss its influence on conclusions drawn from clinical studies with one example illustrating that conclusions change with the use of definitions and nomenclature.
To review one recent study at odds with the new allergy nomenclature. Atopy is defined as a personal or familial tendency to produce immunoglobulin (Ig)E antibodies in response to low doses of allergens, usually proteins, and to develop typical symptoms such as asthma, rhinoconjunctivitis, or eczema/dermatitis. Allergy is defined as a hypersensitivity reaction initiated by immunologic mechanisms and divided into IgE-mediated and non-IgE-mediated allergy. What has been called atopic diseases, eg, infantile eczema, can be caused by both IgE-mediated allergy (atopy) and non-Ig-mediated mechanisms. In the study, two groups of mothers/infants were given either Lactobacillus GG or placebo with the incidence of infantile eczema as primary outcome parameter.
The study analyzed concludes that probiotic bacteria supplied to mother and child prevents infantile eczema development caused by both IgE-mediated (atopy) and non-IgE-mediated allergic mechanisms. The study also shows that IgE sensitization was similar in the two groups. Thus, "atopic disease" was prevented (subjective evaluation), whereas atopy, ie, IgE induction was not prevented.
Nomenclature is of utmost importance to interpret results in allergy research. If preventive measures, such as oral treatment with Lactobacilli, have an effect, this should be tested against a single mechanism of disease rather than against a disease caused by several mechanisms. However, in the study Lactobacilli are said to prevent atopic disease, and also that Lactobacilli do not hinder development of IgE sensitization, one of the mechanisms causing this disease.
Allergen-specific CD4+ T-helper (Th) 2 cells are involved in the induction and effector phase of allergic asthma. It is well established that T cells activation requires interaction of T cell receptor (TCR) and MHC-peptide complex, as well as costimulatory signal delivered by antigen presenting cells (APCs). There is increasing evidence that CD80 (B7.1) and CD86 (B7.2), as the most important costimulatory molecules, are involved in the allergic immune responses. In the present study, we investigated the CD80 and CD86 expression of spleen-derived dendritic cells (DCs) in a murine model of allergic asthma. We first established a murine model of ovalbumin (OVA)-allergic asthma that showed unique histological characteristic of allergic inflammation in the lung, high serum OVA-specific IgE level, high numbers of eosinophils in the bronchoalveolar lavage (BAL) and high production of Type 2 cytokines in the splenic T cells. In this model, we found that CD80 were significantly upregulated on the spleen-derived DCs from OVA-sensitized and challenged mice compared with that from PBS-treated or non-treated mice, while CD86 is not different among three groups. Furthermore, we demonstrated that Th2 immune responses were elicited by these DCs with high expression of CD80, even to nai;ve T cells from non-treated mice. Our results suggest that DCs in the spleen of allergic mice, via upregulation of CD80 might play a pivotal role in the maintenance and amplification of allergic immune response, namely Th2 immune response.
There is growing interest in the immune-stimulating effect and in particular, the anti-allergic effect, of lactic acid bacteria (LAB). However, no comprehensive studies have been done that compare the immune-stimulating potential of LAB strains.
The in vitro immune-stimulating effects on Th1/Th2 balance of more than 100 LAB strains were compared in splenocytes from ovalbumin-sensitized Th2-polarized mice. The in vivo anti-allergic ability of strain KW3110 was studied in the Th2-polarized model by detecting serum IgE concentration, Th1/Th2 cytokine secretion from splenocytes, and the expression of co-stimulatory molecules on macrophages.
In vitro studies from Th2-polarized splenocytes, using IL-12 as a Th1 parameter and IL-4 secretion as a Th2 parameter revealed a wide variety of IL-12-inducing and IL-4-repressing activities, depending on the strain of LAB, not depending on the species. However, evaluation of individual strains in vivo revealed that after exposure to Lactobacillus paracasei KW3110 strain, the serum IgE elevation elicited by repeated OVA injection of mice was strongly inhibited. Cytokine secretion from splenocytes 20 weeks after KW3110 administration showed increased IL-12 and decreased IL-4 expression. Both CD40 and B7-1 expression on macrophages was upregulated by administration of KW3110.
Improving the consequences of the Th1/Th2 imbalance by administration of LAB was dependent upon the LAB strain rather than the LAB species. Oral KW3110 administration in the mouse allergy model directed the Th1/Th2 balance toward Th1 through the maturation of APCs and inhibition of serum IgE elevation.
Continuous oral administration of live Lactobacillus rhamnosus GG (L. GG) to pregnant subjects with atopic dermatitis and their children, suppressed the frequency of atopic dermatitis. The details of mechanisms and immune systems involved in this suppressive effect, however, remain speculative.
We sought to clarify suppressive mechanisms of L. GG on atopic dermatitis by using NC/Nga mice, a model of human atopic dermatitis.
Maternal mice and infant mice were fed with food containing or not containing heat-treated L. GG during pregnancy and breastfeeding, and after weaning.
Control NC/Nga mice raised under an air-uncontrolled condition spontaneously manifested typical skin lesions very similar to those in patients with atopic dermatitis. On the other hand, administration of food containing heat-treated L. GG inhibited the onset and development of atopic skin lesions, accompanied by smaller numbers of mast cells and eosinophils in the affected skin sites. Mice fed with L. GG showed a significant increase in plasma IL-10 levels compared with control mice, while there was no significant difference in the proportion of splenic CD4(+)CD25(+) regulatory T cells between mice fed with L. GG and control mice. The IL-10 mRNA expression was enhanced in both Peyer's patches and mesenteric lymph nodes in mice fed with L. GG.
These findings suggest that some components of heat-treated L. GG may have an ability to delay the onset and suppress the development of atopic dermatitis, probably through a strong induction of IL-10 in intestinal lymphoid organs and systemic levels.
As an important subset of regulatory T (Treg) cells, IL-10-producing type 1 regulatory T cells (Tr1), have some different features to thymic-derived naturally occurring CD4+CD25+Foxp3+ Treg cells(nTreg cells). Similar to nTreg cells, Tr1 also play important roles in the control of allergic inflammation in several ways. There is a fine balance between Tr1 and Th2 responses in healthy subjects. Skewing of allergic-specific effector T cells to a Tr1 phenotype appears to be a critical event in successful allergen-specific immunotherapy and glucocorticoids and beta2-agonists treatment. Tr1 suppress Th2 cells and effector cells of allergic inflammation, such as eosinophils, mast cells, basophils, through producing IL-10, and perhaps TGF-beta. Understanding of Tr1 may be helpful in developing new strategies for treatment of allergic diseases.
Eicosanoids (prostaglandins and leukotrienes) are important mediators of inflammatory responses. These lipid mediators may also regulate the production of peptide mediators of the immune system. In this study, we investigated the effect of the absence of 5-lipoxygenase (5-LO)-derived leukotrienes on interleukin (IL)-10 production. IL-10 is a key regulator of immune and inflammatory responses, and previous studies have suggested that prostaglandins effect their immunosuppressive functions in part by stimulation of IL-10 production. We therefore investigated whether leukotriene production would have a similar role in regulation of IL-10 production. We have made the striking observation that absence of 5-LO-derived leukotrienes results in increased IL-10 production with a concomitant decrease in the production of pro-inflammatory cytokines, including tumour necrosis factor (TNF)-alpha and IL-12. Moreover, T-cell cytokine production in the absence of 5-LO-derived leukotrienes results in increased IL-4 production and decreased interferon (IFN)-gamma production. This may be in part secondary to increased IL-10 production and its effects on dendritic cell function resulting in altered T-cell differentiation. These findings indicate that, in addition to the central role leukotrienes play in the acute inflammatory response, endogenous leukotrienes are also important regulators of inflammatory cytokine production, via regulation of IL-10 production and in vivo differentiation of T cells.
We examined the effect of 59 strains of heat-killed Lactobacillus brevis on interleukin (IL)-12 and interferon (IFN)-gamma production from mouse Peyer's patch (PP) cells. L. brevis has a great variety of strains that induce the production of these cytokines. Some L. brevis strains, which were selected for their ability to induce a strong Th1 immune response, inhibited both total immunoglobulin E (IgE) and antigen specific IgE production, and improved the Th1/Th2 balance by enhancing IL-12 and IFN-gamma and inhibiting IL-4 production from ovalbumin (OVA)-sensitized mouse splenocytes. Based on the results of this screening, we selected L. brevis SBC8803 as a potent inhibitor of IgE production, and investigated the effect of oral administration of heat-killed SBC8803 on IgE production in OVA-sensitized mice. OVA-sensitized mice were fed SBC8803 0% (control), 0.05%, or 0.5% added diet for 4 weeks during the period of the experiment. Total and OVA-specific IgE in the serum of mice, which were fed the 0.5% added diet, was significantly lower than that of the control diet fed mice. The IFN-gamma/IL-4 value, which represents the Th1/Th2 balance, from the 0.5% added diet fed mice splenocytes was also significantly higher than that of the control diet fed mouse splenocytes. Histamine release from OVA-sensitized mice into sera that were induced by the intraperitoneal antigen challenge decreased following the oral administration of SBC8803. The inhibition of IgE production and histamine secretion by the oral administration of heat-killed SBC8803 was probably due to the improvement of the Th1/Th2 balance toward Th1 dominance.
A halophilic lactic acid bacterium, Tetragenococcus halophilus, was found to possess an immunomodulatory activity that promotes T helper type 1 (Th1) immunity in addition to its important roles in soy sauce brewing. Strain Th221 was selected from 151 strains isolated from soy sauce (shoyu) moromi, since it induced strong interleukin (IL)-12 production by mouse peritoneal macrophages in vitro. The relationship between the salt concentration in the medium and the IL-12 production-inducing activity of this strain was investigated, and the activity was found to be strong when the bacteria were grown in medium containing > or =10% (w/v) salt. The Th1-promoting activity was also manifested in an in vivo mouse study, since Th1-dependant contact sensitivity was augmented and Th2 immunity, as evaluated by specific immunoglobulin E production, was suppressed following oral ingestion of Th221. Based on these findings, Th221 administration may be useful for improving allergic symptoms.
In a previous study of the immunoregulatory properties of commensal bacterial DNA, we identified the strong immunostimulatory oligodeoxynucleotide (ISS-ODN) ID35 in the genomic DNA of Lactobacillus rhamnosus GG (LGG). The observed effects of ID35 are because of the unique TTTCGTTT motif located at the 5' end of the ODN, which is different from the previously identified ISS motifs in humans and mice. In the present study, we used an ovalbumin (OVA)-sensitized mouse model to show that ID35 is a potent suppressor of antigen-specific immunoglobulin E (IgE) production in vivo. This effect was toll-like receptor 9-dependent, as GpC negID35 failed to suppress antigen-specific IgE production. ID35 activated the specific subset of CD11c+CD8a+ dendritic cells, which are associated with T-helper 1 (Th1)-type systemic responses, and effectively induced interferon-gamma (IFN-gamma) production by CD4+ T cells in OVA-challenged mice. These immunoregulatory effects of ID35 were comparable with those induced by the murine prototype ODN 1826. Thus, ID35 is the first ISS-ODN with such a strong immunostimulatory and IgE suppressor activity to be found in immunobiotic bacterial DNA.
Activation of type 1 immunity plays a critical role in host defense mechanisms against infectious disease and tumor. Lactic acid bacteria, existing in the gastrointestinal tract, are one of the powerful tools to induce a type-1-dominant immunity, which may improve Th2-dependent allergic diseases. In the present work, we found that an oral intake of Lactobacillus pentosus strain, S-PT84 into mice significantly enhanced NK activity of spleen cells in vivo. We further revealed that NK1.1 positive NK cells and NKT cells are responsible cells for producing IFN-gamma after stimulation with S-PT84 in vitro. S-PT84 induced IFN-gamma-producing cells through activation of IL-12 production by CD11c(+)DCs in Toll-like receptor (TLR) 2- and/or TLR4-dependent manner. Interestingly, direct interaction between DCs and NK1.1(+) cells was also essential for the IFN-gamma production in response to the S-PT84 stimulation. Therefore, we concluded that S-PT84 effectively promoted type 1 immunity through IL-12 and IFN-gamma which were produced by DCs and NK1.1(+) cells, respectively. Thus, S-PT84 would be a nice immune modulator for improving immunobalance, which plays a pivotal role for controlling allergy, infectious diseases and tumor.
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