CN114886119B - Application of 3' -sialyllactose in preparing functional food for relieving food allergy - Google Patents
Application of 3' -sialyllactose in preparing functional food for relieving food allergy Download PDFInfo
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- CN114886119B CN114886119B CN202210657070.9A CN202210657070A CN114886119B CN 114886119 B CN114886119 B CN 114886119B CN 202210657070 A CN202210657070 A CN 202210657070A CN 114886119 B CN114886119 B CN 114886119B
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- Prior art keywords
- sialyllactose
- mice
- fucosyllactose
- group
- food
- Prior art date
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Classifications
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- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
- A23L2/385—Concentrates of non-alcoholic beverages
- A23L2/39—Dry compositions
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
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- A—HUMAN NECESSITIES
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/20—Reducing nutritive value; Dietetic products with reduced nutritive value
- A23L33/21—Addition of substantially indigestible substances, e.g. dietary fibres
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
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- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an application of 3' -sialyllactose in preparing functional food for relieving food allergy, and belongs to the technical field of functional food. The alleviation effect of 3 '-sialyllactose and the compounding of the 3' -sialyllactose and 2 '-fucosyllactose on sensitized mice is further examined by adopting different dosages of 3' -sialyllactose and different compounding ratios of the 3 '-sialyllactose and 2' -fucosyllactose and combining the aspects of clinical pathological characteristics, beta-Lg specific IgE and IgG1 levels in serum, jejunum tissue H & E staining, toluidine blue staining intestinal permeability, intestinal flora and the like. Experimental results show that the 3 '-sialyllactose and the 2' -fucosyllactose can be compounded to remarkably reduce the content of the sensitized antibodies in serum, improve colon tissue structure and enrich the diversity of intestinal microorganisms. Therefore, the 3 '-sialyllactose and 2' -fucosyllactose (1:6, w/w) can be compounded to be used as a functional food for well relieving food allergy.
Description
Technical Field
The invention relates to an application of 3' -sialyllactose in preparing functional food for relieving food allergy, belonging to the technical field of functional food.
Background
Food allergy is a common allergic disease, and is characterized in that immune disorder driven by allergen causes hypersensitivity reaction, and respiratory tract obstruction (asthma, chest distress, palpitation, dyspnea and the like), skin allergy (allergic dermatitis, urticaria and the like), gastrointestinal diseases (stomachache, abdominal pain, diarrhea and the like) and the like are taken as main clinical manifestations, and severe patients may possibly suffer from anaphylactic shock and even death. In recent years, the incidence of food allergy has shown a significant upward trend, and has become a global public health problem. Infancy is the high-lying stage of food allergy, while severe allergic reactions are common to infants and early school children. There are data showing that in our country and some western countries, the health of more than 8% of children is affected by food allergies, and the prevalence of food allergies is significantly higher within 1 year of age than after 1 year of age. Infant food allergy has a serious influence on physical and mental health of the infant and child-care pressure of parents.
The current treatment methods for the diseases mainly comprise antihistamine drugs, allergic reaction medium release-resistant drugs, antigen-antibody reaction-inhibiting drugs and the like, can relieve allergic symptoms, are mainly histamine H1 receptor antagonists in clinical use, such as diphenhydramine, promethazine, chlorpheniramine and the like, are the most widely used nonspecific abnormal antiallergic drugs at present, have certain curative effects, but can generate side effects of dry mouth, blurred vision, difficult urination, constipation and the like caused by headache and somnolence due to central inhibition effect and anticholinergic effect, and can cause drug failure after long-term administration, and various adverse reactions and even toxic and side effects can occur for serious patients. And infants have high sensitivity to the medicines, so that the medicine is not suitable for use. Under the condition of lacking effective treatment means, strengthening early prevention has important significance for guaranteeing healthy growth of infants. The main prevention strategies of food allergy at present comprise diet avoidance, pure breast feeding, feeding by using hydrolyzed formula milk powder, reasonable utilization of prebiotics and the like. The reasonable utilization of prebiotics is considered to be a more prospective and potential food allergy prevention way by virtue of the characteristics of safety and effectiveness. Related studies have shown that supplementing prebiotics early in life can significantly reduce the incidence of allergic disease in infants within two years of age. The fecal microbiology composition and metabolites of infants fed with hydrolyzed whey protein formulas containing specific prebiotics (short chain neutral Galacto (GOS) and long chain fructo-oligosaccharide mixture (FOS) in a 9:1 ratio) are closer to those of breast fed infants and can effectively prevent the occurrence of infantile eczema. Milk oligosaccharides are a type of prebiotics with which infants are initially exposed, and related studies have demonstrated that 2' -fucosyllactose (Fuc (α1-2) Gal (β1-4) Glc) has the potential to alleviate food allergy, and that 2' -fucosyllactose (2 ' -FL) can reduce the expression of pro-inflammatory factors and alleviate allergic symptoms by inhibiting the pathway signals of TLR4/NF- κb activated by β -Lg allergens. However, 2 '-fucosyllactose is an oligosaccharide having a relatively high content in breast milk, and the content in animal milk is very small, and it is not realistic to obtain a large amount of 2' -FL by separating and extracting from breast milk. Currently, the process for producing 2' -fucose lactose mainly comprises a chemical synthesis method, an enzyme-catalyzed synthesis method and a microbial fermentation method. The raw materials required for chemical synthesis are costly and generally the production process is cumbersome and time consuming. The enzyme catalysis synthesis requires a specific fucosyltransferase, and the reaction condition for synthesizing the 2' -fucosyllactose by an enzyme method is mild and controllable, the time is short, the product is easy to purify, but the cost of glycosyl donors required for production is high, the method depends on the discovery of protein engineering for improving the efficiency of the glycosyltransferase to a large extent, and a certain time day is needed from the industrial production. Microbial fermentation production is the main mode for industrially producing 2' -fucose lactose at present, the production mode has relatively low cost and can realize large-scale production, but the production mode mainly utilizes escherichia coli and transgenic technology, and the national safety regulation is not passed at present.
In view of the variety of oligosaccharides in animal milk, the animal milk oligosaccharide is not only a natural milk source of milk oligosaccharides, but also has higher safety compared with human milk oligosaccharides obtained by the existing biosynthesis method. Based on studies of the structure, content and law of variation along with lactation period of the oligosaccharides in animal milks by the inventor, the inventor finds that 3' -sialyllactose (Neu 5Ac (alpha 2-3) Gal (beta 1-4) Glc) is sialylated oligosaccharide with the content of the animal milks being very dominant, however, whether the sialylated oligosaccharide has a desensitization effect or not and whether the sialylated oligosaccharide has a synergistic effect with other oligosaccharides in desensitization have not been reported yet. In 2016, the European Union has approved 3 '-sialyllactose for use as a "new food ingredient" and 3' -sialyllactose is also declared by "generally recognized as safe" substances in the United states. The 3' -sialyllactose-rich formula produced in the European Union and the United states is currently marketed.
Disclosure of Invention
[ problem ]
Provides a new application of 3' -sialyllactose.
[ technical solution ]
A first object of the present invention is to provide the use of 3' -sialyllactose for the preparation of an allergic reaction health food or an antiallergic drug for alleviating food allergy caused by beta-Lg allergen.
A second object of the present invention is to provide the use of 3' -sialyllactose for the preparation of a health food or an antiallergic agent for alleviating atopic dermatitis caused by beta-Lg allergen.
A third object of the present invention is to provide the use of 3' -sialyllactose for the preparation of an allergic health food or an antiallergic agent for alleviating jejunal inflammation caused by beta-Lg allergen.
A fourth object of the present invention is to provide the use of 3' -sialyllactose for the preparation of a health food or an antiallergic agent for alleviating an increase in the content of beta-Lg specific IgE and IgG1 caused by beta-Lg allergens.
As a preferred embodiment of the present invention, in the aforementioned application, the dosage of 3' -sialyllactose is 200-600. Mu.g/kg.bw.
A fifth object of the present invention is to provide an allergic reaction health food for alleviating food allergy caused by beta-Lg allergen, in which the antiallergic components are 3 '-sialyllactose and 2' -fucosyllactose.
As a preferred embodiment of the present invention, the mass ratio of 3 '-sialyllactose to 2' -fucosyllactose is 1:6 or 1000:1.
As a preferred embodiment of the present invention, the total dose of 3 '-sialyllactose and 2' -fucosyllactose is 400. Mu.g/kg.bw.
A sixth object of the present invention is to provide a composite prebiotic solid beverage for alleviating food allergy caused by beta-Lg allergen, comprising 3' -sialyllactose, fructooligosaccharides, resistant dextrins, mannooligosaccharides and lactobacillus rhamnosus LR863; wherein the mass percentage of the 3' -sialyllactose is 2%.
A seventh object of the present invention is to provide a composite prebiotic solid beverage for alleviating food allergy caused by beta-Lg allergen, comprising 3 '-sialyllactose, 2' -fucosyllactose, fructooligosaccharides, resistant dextrins, mannooligosaccharides and lactobacillus rhamnosus LR863; wherein the total mass percent of 3 '-sialyllactose and 2' -fucosyllactose is 2%; the mass ratio of 3 '-sialyllactose to 2' -fucosyllactose is 1:6.
[ beneficial effects ]
(1) According to the invention, the 3 '-sialyllactose is researched, animal experiments are utilized, and an early skin exposure allergen combined food allergy mouse model is adopted, so that the influence of the intervention of the 3' -sialyllactose on the model mouse is investigated in aspects of specific dermatitis lesion degree, allergy symptoms, jejunum inflammation condition, immune response of organisms and the like, and the experimental researches find that: compared with a model group, the 3' -sialyllactose can improve the pathological changes of atopic dermatitis and jejunum inflammation of allergic mice to a certain extent, relieve the influence of allergic symptoms and allergic reaction on the growth and development of mice, and reduce the level of specific antibodies in serum of the allergic mice. The desensitization effect of 3 '-sialyllactose with different doses is compared with that of a model group, the high dose group (600 mug/kg.bw) and the medium dose group (400 mug/kg.bw) can obviously improve the pathological degree and jejunum inflammation condition of allergic mice, relieve the influence of allergic symptoms and allergic reaction on the growth and development of the mice, and reduce the level of specific antibodies in serum of the allergic mice, wherein the desensitization effect of the high dose 3' -sialyllactose group is optimal, and the level of specific IgE and IgG1 in serum of the mice is reduced to the highest degree than that of the model group, which can reach 70.60% and 49.41%, respectively. Therefore, the invention discovers that the 3' -sialyllactose has obvious relieving effect on the symptoms of beta-Lg allergen combined food allergy for the first time;
(2) The research of the invention finds that 3' -sialyllactose is the oligosaccharide with the highest content in animal milk. The milk source is easier to obtain than breast milk based on animal milk separation, and the research at present shows that the recovery rate of the oligosaccharide can reach 95.6-98.3% by carrying out coarse separation by combining microfiltration with ultrafiltration and nanofiltration, and the oligosaccharide is further enriched by carrying out ion exchange by QFF anion exchange resin (QFF), thus being applicable to industrialized production. The oligosaccharide prepared by separating animal milk has high safety on one hand, and the structure and the function of the separated oligosaccharide are more similar to those of natural oligosaccharide in milk on the other hand, and the mixture of 3' -sialyllactose and other oligosaccharides can be prepared, so that the effect of the natural oligosaccharide compound can be better simulated; compared with 2' -fucose lactose, the preparation method is more beneficial to large-scale production and industrial application;
(3) Based on the effect of 3' -sialyllactose on relieving allergic symptoms, the invention further explores the interaction of 3' -sialyllactose and 2' -fucosyllactose on the effect of relieving food allergy, and further examines the effect of a compound mixture of 3' -sialyllactose and 2' -fucosyllactose in the content ratio of the oligosaccharides in breast milk and animal milk on relieving the allergic symptoms of mice through clinical pathological characteristics. Experimental results show that the 3 '-sialyllactose and 2' -fucosyllactose mixture compounded according to the oligosaccharide content ratio in breast milk can obviously improve the pathological degree of atopic dermatitis and jejunum inflammation condition of allergic mice, reduce the influence of allergic symptoms and allergic reaction on the growth and development of the mice and reduce the specific antibody level in serum of the allergic mice through the synergistic effect of the 3 '-sialyllactose and the 2' -fucosyllactose: in comparison with single 3' -sialyllactose, single 2' -fucosyllactose and different combination ratios (3 ' -sialyllactose: 2' -fucosyllactose=1:6; 3' -sialyllactose: 2' -fucosyllactose=1000:1), the combination ratio of 3' -sialyllactose and 2' -fucosyllactose was found to be 1:6, the group showed the strongest desensitization effect, the reduction of specific IgE and IgG1 in the mouse serum was 55.71% and 51.92% compared to the model group, respectively, the reduction of IgE and IgG1 compared to the model group (45.75% and 34.30%) and the reduction of IgE and IgG1 compared to the model group (36.73% and 30.50%) compared to the model group), and the reduction of IgE and IgG1 compared to the model group (36.73% and 30.50%) was also superior to the combination of 3' -sialyllactose: 2' -fucosyllactose=1000:1 group (animal milk oligosaccharide content ratio group) IgE and IgG1 reduced to a degree (54.34% and 36.10%) compared to the model group. Therefore, the 3 '-sialyllactose and the 2' -fucosyllactose compounded according to the oligosaccharide content ratio in the breast milk have a synergistic effect, and can be used as functional food for well relieving food allergy.
Drawings
FIG. 1 is a graph showing the weight change of mice during molding in example 1;
FIG. 2 is the extent of ear-specific dermatitis lesions of the mice in example 1;
FIG. 3 is allergy score of mice in example 1;
FIG. 4 shows the levels of beta-Lg-specific IgE and IgG1 in the serum of mice in example 1;
FIG. 5 shows the H & E staining results of jejunal tissue of the mice in example 1;
FIG. 6 shows the result of toluidine blue staining of jejunal tissue of the mice in example 1;
FIG. 7 is a graph showing weight change of mice during molding in example 2;
FIG. 8 shows the extent of atopic dermatitis lesions in mice in example 2;
FIG. 9 is allergy score of mice in example 2;
FIG. 10 shows the levels of beta-Lg-specific IgE and IgG1 in the serum of mice in example 2;
FIG. 11 shows the H & E staining results of the jejunal tissue of the mice in example 2;
FIG. 12 shows the result of toluidine blue staining of jejunal tissue in mice in example 2;
FIG. 13 shows Chaol index and Shanon index of the intestinal microorganism test of the mice in example 2.
Detailed Description
The following description of the preferred embodiments of the present invention is provided for better illustration of the invention, and should not be construed as limiting the invention.
The food allergy model of the mice transdermal sensitization used in the invention is a construction method of the food allergy model of the mice transdermal sensitization in the patent with the publication number of CN114010766A, and is modified appropriately.
Example 1: application of 3 '-sialyllactose (3' -SL) in relieving food allergy of mice
Modeling is performed by a method of early exposure of the skin to beta-Lg allergens in combination with food allergies. 60 mice were equally divided into 6 groups of 10 mice each, which were blank group, MC903 group, model group, 3' -sialyllactose low dose (200. Mu.g/kg. Bw), 3' -sialyllactose medium dose (400. Mu.g/kg. Bw) and 3' -sialyllactose high dose (600. Mu.g/kg. Bw), respectively. All mice were fed adaptively for 3 days, and were perfused daily with either normal gastric saline or a corresponding dose of 3' -sialyllactose starting from day 4. The molding process included a sensitization phase (first 14 days) and an excitation phase (last 4 days) for 18 days. In the sensitization phase: except for the blank group and the MC903 group, applying MC903 ethanol solution (with the concentration of 0.1mmol/L and the application amount of 20 mu L for each mouse) to the ears of each mouse every day, and applying PBS solution containing beta-Lg (with the concentration of 10g/L and the application amount of 10 mu L for each mouse) to the ears after the ethanol of each mouse ear is naturally air-dried; for the mice in the blank group, only the same dose of PBS solution without beta-Lg was smeared on both ears of each mouse every morning; the MC903 group of mice is coated with MC903 ethanol solution on the ears of each mouse every day in the morning, and PBS solution without beta-Lg is coated on the ears after the ethanol is naturally dried; after 14 days of continuous application, the excitation phase is entered. Excitation stage: on the following morning when the sensitization phase ended, each mouse of the other groups was primed with a beta-Lg-containing PBS solution for the first time except for the blank group and the MC903 group; in the afternoon of the fifth day at the end of the sensitization phase, except for the blank group and the MC903 group, the PBS solution containing beta-Lg is infused into the stomach of each mouse in the other groups for the second excitation; gastric lavage of β -Lg in PBS (ph=7.4) solution at a concentration of 250g/L, 200 μl per mouse; for the blank and MC903 groups, the two shots were lavaged with PBS without β -Lg; after the second challenge, mice were scored for allergic clinical symptoms, with specific scoring criteria as shown in the following table.
TABLE 3 mice allergy symptoms scoring criteria
The experimental method comprises the following steps: during the animal experiment, the body weight of the mice was weighed daily, a body weight change curve was drawn, and the extent of the lesions of ear-specific dermatitis of the mice was observed. After the second challenge with the high dose allergen, mice were scored for allergic clinical symptoms according to the allergic symptoms scoring table. The following day after the second challenge, mice were sacrificed and blood was collected and the levels of specific IgE/IgG1 in the serum of the mice were determined by ELISA. Meanwhile, taking the jejunum tissue of the mouse to fix in 4% neutral formaldehyde, carrying out tissue section, respectively using H & E staining and toluidine blue staining, and observing the jejunum tissue structure of the mouse and the aggregation condition of mast cells under a biological microscope.
The results obtained in this example were analyzed and are shown in fig. 1 to 6:
(1) The weight change of mice during molding is shown in fig. 1: in the sensitization phase (0-14 d), the body weight of mice in the blank group steadily increased, and the growth rate of mice in other groups obviously decreased, wherein the average body weight of mice in the MC903 group and the model group obviously decreases, and the body weight of mice with low, medium and high doses of 3' -sialyllactose infused daily increases to a certain extent, although the growth rate is reduced compared with that of mice in the blank group. The average body weight of mice in the model group was still continuously reduced during the challenge phase (14-18 d), and no significant reduction in body weight was seen in mice perfused with 3' -sialyllactose daily, although the growth rate was reduced compared to the blank group; the high dose (600. Mu.g/kg. Bw) 3' -sialyllactose group showed a significant increase in growth rate compared to the low dose (200. Mu.g/kg. Bw) 3' -sialyllactose group and the medium dose (400. Mu.g/kg. Bw) 3' -sialyllactose group. The 3 '-sialyllactose can reduce the influence of anaphylactic reaction on the growth and development of mice to a certain extent, and especially, the high-dose (600 mug/kg. Bw) 3' -sialyllactose group can reduce the influence of anaphylactic reaction on the growth and development of mice to the greatest extent.
(2) The extent of ear-specific dermatitis lesions in mice is shown in figure 2: in the sensitization stage, the ear of the allergic mouse has the symptoms of atopic dermatitis lesions such as cochlea dryness, keratinization thickening, obvious dermatoglyph and the like. Wherein, severe keratinization of cochlea of the model group mice is accompanied by obvious crusting; the symptoms of atopic dermatitis lesions in mice infused with 3 '-sialyllactose daily were reduced compared to the model group, and the mice infused with high doses of 3' -sialyllactose had the least degree of atopic dermatitis lesions, and the ears were only slightly keratinized. It was demonstrated that 3 '-sialyllactose was able to reduce the extent of atopic dermatitis lesions in mice to some extent, and in particular that the high dose (600. Mu.g/kg. Bw) of 3' -sialyllactose group was able to minimize the extent of atopic dermatitis lesions in mice.
(3) The allergy symptoms scores of the mice are shown in figure 3: the allergic mice developed obvious allergic symptoms including scratching the head, slow movement, diarrhea, decreased anal temperature, etc. during the challenge phase. The allergy symptoms score of the mice in the model group was significantly higher than that of the mice in the blank group and the MC903 group. Daily mice with gavage of 3 '-sialyllactose had significantly lower scores than the model group, and mice with gavage of high doses of 3' -sialyllactose had the lowest scores for allergic symptoms.
(4) The levels of beta-Lg specific IgE and IgG1 in mouse serum are shown in figure 4: the levels of specific IgE and IgG1 in the serum of allergic mice were significantly higher than in the blank and MC903 groups. Wherein the serum level of specific IgE in mice with low, medium and high daily doses of 3' -sialyllactose is 41.93%, 45.75% and 70.60% lower than in the model group, respectively. The level of specific IgG1 in serum of mice injected with low, medium and high doses of 3' -sialyllactose daily was also significantly lower than in the model group, to 30.44%, 34.30% and 49.41%, respectively. Among the intervention groups, the levels of specific IgE and IgG1 were minimal in serum of mice perfused with high doses of 3' -sialyllactose.
(5) The H & E staining results of the jejunal tissue of the mice are shown in fig. 5: the jejunum tissues of mice in the blank group and the MC903 group have complete morphological structure, and the jejunum tissues of mice in the model group have serious inflammation conditions such as villus cell necrosis, shedding and the like. The daily gastric lavage of 3 '-sialyllactose mice showed a different degree of improvement in jejunal inflammation than the model group, wherein the mice of the group of 3' -sialyllactose with high gastric lavage dose had the lightest jejunal inflammation, and their small intestinal villi had intact structure, and only few villi cells were observed to shed.
(6) The results of toluidine blue staining of the jejunal tissue of the mice are shown in fig. 6: mast cells in jejunum were not significantly aggregated in mice from the blank and MC903 groups. The number of jejunal mast cells in the mice of the model group was significantly increased. The daily gavage of 3 '-sialyllactose in the jejunum of mice showed a different improvement over the model group, wherein the gavage of 3' -sialyllactose group in the high dose group showed less mast cell aggregation.
Taken together, the results show that high doses of 3' -sialyllactose have an effective allergy relieving effect.
Example 2: application of 3 '-sialyllactose and 2' -fucosyllactose compounded mixture in relieving food allergy of mice
Modeling is performed using a method of early exposure of skin to beta-Lg allergens in combination with food allergy. 60 mice were equally divided into 7 groups of 10 mice each, which were a blank group, an MC903 group, a model group, a 3 '-sialyllactose group (400 μg/kg. Bw 3' -sialyllactose), a 2 '-fucosyllactose group (400 μg/kg. Bw 2' -fucosyllactose group), a ratio of breast milk oligosaccharide content group (400 μg/kg. Bw 3 '-sialyllactose and 2' -fucosyllactose complex mixture, 2 '-fucosyllactose: 3' -sialyllactose=6:1, w/w), and a ratio of animal milk oligosaccharide content group (400 μg/kg. Bw 3 '-sialyllactose and 2' -fucosyllactose complex mixture, 2 '-fucosyllactose: 3' -sialyllactose=1:1000, w/w). All mice are subjected to 3-day adaptive feeding, corresponding gastric lavage normal saline or corresponding oligosaccharides are carried out on the mice from the 4 th day, MC903 ethanol solution (the concentration is 0.1mmol/L, the total amount of the ethanol applied is 20 mu L for each double ear) is applied to the double ears of each mouse in the day of the sensitization stage except for a blank group and an MC903 group, after the ethanol of the double ears of the mice is naturally air-dried, PBS solution containing beta-Lg (the concentration is 10g/L, and the total amount of the ethanol applied is 10 mu L for the double ears) is applied to the double ears of the mice; for the mice in the blank group, only PBS solution without beta-Lg is smeared on the two ears of each mouse every morning in the sensitization stage; MC903 ethanol solution is smeared on the ears of each mouse in the day of the sensitization stage, and PBS solution without beta-Lg is smeared on the ears after the ethanol is naturally dried. After two weeks of continuous application, the excitation phase is entered. On the following morning when the sensitization phase ended, each mouse of the other groups was primed with a beta-Lg-containing PBS solution for the first time except for the blank group and the MC903 group; in the afternoon of the fifth day at the end of the sensitization phase, except for the blank group and the MC903 group, the PBS solution containing beta-Lg is infused into the stomach of each mouse in the other groups for the second excitation; gastric lavage of β -Lg was performed in PBS (ph=7.4) solution at a concentration of 250g/L and the amount of lavage per mouse was 200 μl. For the blank and MC903 groups, the stomach was perfused with PBS without β -Lg for both shots. The second challenged mice were scored for allergic clinical symptoms, with specific scores shown in table 1. The body weight of the mice was recorded daily and the extent of skin atopic dermatitis lesions was observed, the mice were sacrificed the following day after the second challenge, blood and tissues were collected, and analysis of allergic immunology index was performed.
The experimental method comprises the following steps: during the animal experiment, the body weight of the mice was weighed daily, a body weight change curve was drawn, and the extent of the lesions of ear-specific dermatitis of the mice was observed. After the second challenge with the high dose allergen, mice were scored for allergic clinical symptoms according to the allergic symptoms scoring table. The following day after the second challenge, mice were sacrificed and blood was collected and ELISA was used to detect specific IgE/IgG in the serum of mice 1 Is measured and analyzed. Simultaneously, the jejunal tissue of the mice was fixed in 4% neutral formaldehyde, and tissue sections were taken, H was used separately&E staining and toluidine blue staining, and observing the jejunum tissue structure of the mice and the aggregation condition of mast cells under a biological microscope. Collecting colon contents of the mice, quickly freezing with liquid nitrogen, storing at-80 ℃, and carrying out subsequent DNA extraction and detection, PCR amplification, product purification, library preparation and detection, and Miseq on-machine high-throughput sequencing.
The results obtained in this example were analyzed and are shown in fig. 7 to 13:
(1) The weight change of mice during modeling is shown in figure 7: in the sensitization phase, the body weight of mice in the blank group steadily increased, and the growth rate of mice in other groups was obviously reduced, wherein the average body weight of mice in the MC903 group, the model group and the single 2' -fucose lactose infused daily was reduced, and the body weight of mice in other groups was still increased, although the growth rate was reduced compared with that in the blank group. The mean body weight of mice in the model group and in the monogastric 2 '-fucosyllactose-infused mice remained continuously decreasing, and the mean body weight of mice in the daily gastric 3' -sialyllactose-infused mice and the mixture of 3 '-sialyllactose and 2' -fucosyllactose slightly increased, although the growth rate was significantly lower than in the blank group; wherein, the ratio group of the content of the breast milk oligosaccharide is obviously better than the ratio group of the content of the animal milk oligosaccharide in the aspect of weight increase.
(2) The extent of ear-specific dermatitis lesions in mice is shown in fig. 8: in the sensitization stage, the ear of the allergic mouse has the symptoms of atopic dermatitis lesions such as cochlea dryness, keratinization thickening, obvious dermatoglyph and the like. Wherein the mice in the model group had severe cochlea keratinization with significant crusting. The symptoms of atopic dermatitis lesions in mice perfused daily with 3 '-sialyllactose, 2' -fucosyllactose, and a mixture of 3 '-sialyllactose and 2' -fucosyllactose are reduced. Atopic dermatitis lesions were less symptomatic in mice perfused with single 3 '-sialyllactose than mice perfused with single 2' -fucosyllactose. Compared with single intervention and compound intervention, the compound intervention has optimal improvement effect, wherein the specific dermatitis lesion degree of the mice of the mixture compounded according to the content ratio of the gastric lavage breast milk oligosaccharides is the least, and the ears only show slight keratinization.
(3) The allergy symptoms scores of the mice are shown in fig. 9: the allergic mice developed obvious allergic symptoms including scratching the head, slow movement, diarrhea, decreased anal temperature, etc. during the challenge phase. The allergy symptoms score of the mice in the model group was significantly higher than that of the mice in the blank group and the MC903 group. Daily lavage of mice with 3 '-sialyllactose, 2' -fucosyllactose, and a mixture of 3 '-sialyllactose and 2' -fucosyllactose was significantly lower than in the model group. The average value of the allergy symptoms scores of the mice with single gastric lavage and 2' -fucose is lower than that of the mice with single gastric lavage and 2' -fucose, but the final score is not obviously different from that of the mice with single gastric lavage and 3' -sialyllactose group due to the large individual difference. Compared with single intervention of 3 '-sialyllactose and 2' -fucosyllactose and compound intervention of 3 '-sialyllactose and 2' -fucosyllactose, the compound intervention has better improvement effect, wherein the allergic symptom score of the mice of the compound mixture with the content ratio of the gastric lavage breast milk oligosaccharides is the lowest. Because allergy symptoms scores are somewhat subjective, the sensitization effect should also be assessed in conjunction with the level of IgE and IgG1 in the blood.
(4) The levels of beta-Lg specific IgE and IgG1 in mouse serum are shown in figure 10: the level of specific IgE and IgG1 in the serum of allergic mice was significantly higher than that of the blank group and MC903 group, and the level of specific IgE and IgG1 in the serum of mice perfused with the mixture of 3 '-sialyllactose, 2' -fucosyllactose and 3 '-sialyllactose and 2' -fucosyllactose per day was significantly lower than that of the model group. The reduction of specific IgE levels in serum from mice perfused with single 3 '-sialyllactose was also significantly higher (45.75%) than in mice perfused with single 2' -fucosyllactose than in the model group (36.73%). The level of specific IgG1 in serum of mice perfused with single 3' -sialyllactose was slightly lower (34.30%) than that of the model group, compared to that of the 2' -fucosyllactose group (30.50%) perfused with single 3' -sialyllactose. Comparison of single and compound interventions of 2 '-fucosyllactose, 3' -sialyllactose found that: compounding 3' -sialyllactose: the reduction of specific IgE and IgG1 in serum from mice in group 2 '-fucosyllactose=1:6 (ratio of breast milk oligosaccharide content) was 55.71% and 51.92%, respectively, compared to the model group, better than the reduction of 3' -sialyllactose IgE and IgG1 alone (45.75% and 34.30%) and the reduction of 2 '-fucosyllactose IgE and IgG1 in the model group (36.73% and 30.50%), respectively, better than the reduction of 3' -sialyllactose: 2' -fucosyllactose=1000:1 group (animal milk oligosaccharide content ratio group) IgE and IgG1 reduced to a degree (54.34% and 36.10%) compared to the model group. The highest reduction of specific IgE and IgG1 was observed in the serum of mice of the mixture of the intragastric breast milk oligosaccharide content ratio (3 '-sialyllactose: 2' -fucosyllactose=1:6).
The H & E staining results of the jejunal tissue of the mice are shown in fig. 11: the jejunum tissues of mice in the blank group and the MC903 group have complete morphological structure, and the jejunum tissues of mice in the model group have serious inflammation conditions such as villus cell necrosis, shedding and the like. Daily lavage of 3 '-sialyllactose, 2' -fucosyllactose and mixtures of 3 '-sialyllactose and 2' -fucosyllactose showed a different degree of improvement in jejunal inflammation than in the model group. The jejunal tissue inflammation of the single gavage 3 '-sialyllactose mice was significantly better than that of the single gavage 2' -fucosyllactose mice compared to the single gavage 3 '-sialyllactose and the single gavage 2' -fucosyllactose. Compared with single intervention and compound intervention, the compound intervention has better improvement effect, wherein the mice with the mixture of the gastric lavage and the compound with the content ratio of the breast milk oligosaccharide has the lightest jejunum inflammation condition, the small intestine villus has complete structure, and only few villus cells are observed to fall off.
The results of toluidine blue staining of the jejunal tissue of the mice are shown in fig. 12: mast cells in jejunum were not significantly aggregated in mice from the blank and MC903 groups. The number of jejunal mast cells in the mice of the model group was significantly increased. Daily lavage of 3 '-sialyllactose, 2' -fucosyllactose, and mixtures of 3 '-sialyllactose and 2' -fucosyllactose in the jejunum of mice showed a different improvement in mast cell aggregation than in the model group. Compared with the single 3 '-sialyllactose and the single 2' -fucosyllactose, the phenomenon of mast cell aggregation in jejunum tissue of the single 3 '-sialyllactose-infused mice is obviously better than that of the single 2' -fucosyllactose-infused mice. Compared with single intervention and compound intervention, the compound intervention has better improving effect, wherein the phenomenon of mast cell aggregation in the jejunum of the mice of the mixture compounded by daily gastric lavage and the content ratio of breast milk oligosaccharide is less.
TABLE 1 relative abundance of intestinal flora phylum in different treatment groups
The analysis of the intestinal microbial composition of the mice is shown in fig. 13 and table 1: as can be seen from the Chaol index and Shanon index, the alpha-diversity of the intestinal flora of allergic mice is significantly reduced compared with that of mice in the blank group, while the Chaol and Shanon indexes of the intestinal flora of mice with the mixture of 3' -sialyllactose, 2' -fucosyllactose and 3' -sialyllactose and 2' -fucosyllactose infused daily are improved compared with that of the model group, which indicates that the intervention of the 3' -sialyllactose and the mixture of 3' -sialyllactose and 2' -fucosyllactose can improve the richness and diversity of the intestinal flora of the mice.
As is clear from Table 1, bacteroides (Bactoidota) and Thick-walled bacteria (Firmics) are the main microorganisms in the intestinal tract of mice. Compared with the mice in the blank group, the intestinal Bactroidota abundance of the allergic mice in the model group is increased, and the Firmicum abundance is reduced. Following intervention with single 2' -fucosyllactose (400 μg/kg. Bw), the abundance of Bacteroidota in the intestinal tract of mice was further increased and the abundance of Firmicute was further decreased than in the model group. Under the intervention of single 3' -sialyllactose (400 mug/kg. Bw), the abundance of Bactoidota in the intestinal tract of the mice is slightly reduced compared with that of the intestinal tract of the mice in the model group, and the abundance of Firmicum is slightly increased, so that the callback from the intestinal flora of the allergic mice to the intestinal flora of the normal mice is realized to a certain extent. Similarly, the gastric lavage intervention is carried out by compounding (3 '-sialyllactose and 2' -fucosyllactose=1:6, 400 mug/kg.bw) according to the content ratio of breast milk oligosaccharide, the abundance of Bactoidota in the intestinal tract of the mice is obviously reduced compared with that of allergic mice, the abundance of Firmicum is obviously increased, and the intestinal flora of the mice is more similar to that of mice in a blank group.
The results show that the 3 '-sialyllactose and 2' -fucosyllactose mixture compounded in the content ratio of breast milk oligosaccharides has excellent allergy relieving effect.
Example 3: compound prebiotic solid beverage rich in 3' -sialyllactose
A composite prebiotic solid beverage (10 g) comprising 0.2g 3' -sialyllactose, 0.5g fructooligosaccharides, 8.6g resistant dextrins, 0.5g mannooligosaccharides and 0.2g lactobacillus rhamnosus LR863, which prebiotic solid beverage has the effect of alleviating food allergies.
Example 4: composite prebiotic solid beverage rich in 3 '-sialyllactose and 2' -fucosyllactose
A composite prebiotic solid beverage (10 g) comprising 3 '-sialyllactose, 2' -fucosyllactose, 0.5g fructooligosaccharides, 8.6g resistant dextrins, 0.5g mannooligosaccharides and 0.2g lactobacillus rhamnosus LR863, wherein the total mass of 3 '-sialyllactose and 2' -fucosyllactose is 0.2g, the mass ratio of the two is 1:6, the prebiotic solid beverage having the effect of alleviating food allergy.
While the invention has been described with reference to the preferred embodiments, it is not limited thereto, and various changes and modifications can be made therein by those skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (6)
- Use of a composition of 3 '-sialyllactose and 2' -fucosyllactose for the preparation of an antiallergic medicament for alleviating food allergy caused by a β -Lg allergen, characterized in that the mass ratio of 3 '-sialyllactose to 2' -fucosyllactose is 1:6.
- Use of a composition of 3 '-sialyllactose and 2' -fucosyllactose for the preparation of an antiallergic agent for alleviating atopic dermatitis caused by β -Lg allergens, characterized in that the mass ratio of 3 '-sialyllactose to 2' -fucosyllactose is 1:6.
- Use of a composition of 3 '-sialyllactose and 2' -fucosyllactose for the preparation of an antiallergic agent for alleviating jejunal inflammation caused by a β -Lg allergen, characterized in that the mass ratio of 3 '-sialyllactose to 2' -fucosyllactose is 1:6.
- Use of a composition of 3 '-sialyllactose and 2' -fucosyllactose for the preparation of an antiallergic agent for alleviating an increase in the content of beta-Lg specific IgE and IgG1 caused by a beta-Lg allergen, characterized in that the mass ratio of 3 '-sialyllactose to 2' -fucosyllactose is 1:6.
- 5. The use according to any one of claims 1 to 4, wherein the total dose of 3 '-sialyllactose and 2' -fucosyllactose is 400 μg/kg.
- 6. A composite prebiotic solid beverage for alleviating food allergy caused by beta-Lg allergen comprising 3 '-sialyllactose, 2' -fucosyllactose, fructooligosaccharides, resistant dextrins, mannooligosaccharides and lactobacillus rhamnosus LR863; wherein the total mass percent of 3 '-sialyllactose and 2' -fucosyllactose is 2%; the mass ratio of 3 '-sialyllactose to 2' -fucosyllactose is 1:6.
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| EP3407741A1 (en) * | 2016-01-26 | 2018-12-05 | Nestec S.A. | Compositions with specific oligosaccharides to prevent or treat allergies |
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