CN114452296A - Breast milk oligosaccharide composition for improving immune response and application thereof - Google Patents
Breast milk oligosaccharide composition for improving immune response and application thereof Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
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- A23C9/203—Dietetic milk products not covered by groups A23C9/12 - A23C9/18 containing bifidus-active substances, e.g. lactulose; containing oligosaccharides
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- 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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Abstract
The invention provides a breast milk oligosaccharide composition for improving immune response and application thereof. Specifically, the invention provides an application of a breast milk oligosaccharide composition in preparation of a composition for improving immune response, wherein the breast milk oligosaccharide composition comprises 2 '-fucosyllactose, lacto-N-tetraose and 3' -sialyllactose, and the mass ratio of the 2 '-fucosyllactose to the lacto-N-tetraose to the 3' -sialyllactose is 3-5: 1.5-2.5: 1. the invention discovers that the breast milk oligosaccharide composition can be used for improving the immune response function of the differentiation of monocytes into macrophages.
Description
Technical Field
The invention relates to a breast milk oligosaccharide composition for improving immune response and application thereof, in particular to application of the breast milk oligosaccharide composition comprising 2 '-fucosyllactose, lacto-N-tetraose and 3' -sialyllactose in preparing a composition for improving immune response.
Background
The immune function of the human body is divided into innate immunity and adaptive immunity. The mononuclear-macrophage system (MPS) is a major component of the natural immune system and plays an important role in the defense of the body against invasion by foreign microorganisms and in the elimination of pathogens. The monocyte-macrophage system includes monocytes in blood and macrophages fixed or migratory in tissues, in which the monocytes, as immune effector cells, migrate from the blood to the tissues and produce a large amount of inflammatory factors when the body is invaded by an external source; meanwhile, the compound has a phagocytic function and can phagocytize cells and harmful molecules; in addition, monocytes may also differentiate into dendritic cells or macrophages to further exert immune functions. Macrophages have multiple biological functions, and the functions of the macrophages in natural immunity and adaptive immunity mainly comprise the following aspects: nonspecific immunity epidemic prevention, namely phagocytosis and elimination of pathogens before the body is invaded by foreign pathogens to stimulate immune response; clearing the foreign cells; non-specific immune surveillance; presenting the antigen; secretion media cytokines such as IL-1, interferon, and complement (C1, C4, C3, C2, B3 factors). In addition, macrophages also have important functions in the aspects of tissue development, repair, maintenance of body stability and the like.
The process of differentiation of monocytes into macrophages is particularly important because of the importance of the monocyte macrophage system in body function. Disturbance of macrophage differentiation can lead to a variety of diseases, such as inflammatory responses, autoimmune diseases, leukemia, and the like.
Human intestinal tracts contain a large number of macrophages, which are mainly differentiated from monocytes and have a fast iteration rate, and which can produce tumor necrosis factor-alpha (TNF-alpha) and many other proinflammatory factors, and may play an important role in maintaining intestinal health. TNF- α is a cytokine involved in systemic inflammation and is also a member of many cytokines responsible for the acute phase response, and is secreted mainly by macrophages. Dysregulation of TNF- α production is thought to be associated with a number of human diseases, including alzheimer's disease, cancer, major depressive disorder, and inflammatory bowel disease, among others.
The small intestinal epithelium forms the first line of defense against pathogenic bacteria. The adhesion of pathogenic bacteria to the small intestine epithelium, or the subsequent invasion, provides signals to the epithelium and further stimulates the production of cytokines or chemokines. These are soluble regulatory substances that attract cells of the immune system, or activate the monocyte macrophage system and initiate the immune response. Appropriate immune responses may protect the body from infection.
Therefore, there is a need for solutions to maintain normal immune response function after monocyte differentiation to macrophages to promote intestinal health.
Disclosure of Invention
The invention finds that some breast milk oligosaccharide compositions have the function of improving immune response to promote intestinal health.
In particular, in one aspect, the present invention provides the use of a breast milk oligosaccharide composition in the preparation of a composition for improving an immune response, wherein the breast milk oligosaccharide composition comprises 2 '-fucosyllactose, lacto-N-tetraose and 3' -sialyllactose.
2 ' -fucosyllactose (2 ' -fucosyllactose, 2 ' -FL or 2FL) is a trisaccharide structure formed by fucose and lactose, and is a representative substance of fucosyl oligosaccharides. The commercially available material is usually prepared by microbial fermentation and has the same structure as 2' -fucosyllactose found in human milk.
lacto-N-tetraose, a hexasaccharide structure formed by lactose and tetraose, is a representative substance of oligosaccharides having a core sugar chain as a basic structure and containing no fucosyl group or sialyl group. Most of lactose-N-tetraose commodities in the prior art are prepared by a microbial fermentation method, and have the same structure as lactose-N-tetraose oligosaccharide found in human milk.
3 ' -sialyllactose (3 ' -sialyllactose, 3 ' -SL or 3SL) is a trisaccharide structure formed by sialic acid and lactose, and is a representative substance of sialyl oligosaccharides. The commercial products of 3 '-sialyllactose in the prior art are mostly prepared by microbial fermentation methods and have the same structure as 3' -sialyllactose found in human milk.
According to a specific embodiment of the present invention, the breast milk oligosaccharide composition of the present invention is used in a composition for improving an immune response, which is a food composition or a pharmaceutical composition, for improving an immune response activity of monocytes differentiating into macrophages. In some embodiments of the present invention, the improvement of the immune response activity of monocytes to differentiate into macrophages is to increase the immune response activity of monocytes to respond to stimulation after differentiation into macrophages or to prevent the decline of the immune response activity of monocytes after training to differentiate into macrophages. In particular, flora metabolic disturbance can generate abnormal concentrations of toxins such as lipopolysaccharide in human intestinal tracts, and the breast milk oligosaccharide composition can improve the immune response activity of macrophages for the stimulation of the toxins. Furthermore, if monocytes are stimulated by some enterotoxins (i.e. trained conditions), their immune response activity is reduced after re-differentiation into macrophages, whereas the breast milk oligosaccharide composition of the present invention prevents a reduction in immune response activity, even further enhances immune response activity.
According to some embodiments of the invention, the immune response activity is characterized in the present invention by measuring the amount of secreted TNF- α following differentiation of monocytes into macrophages. Experiments prove that the breast milk oligosaccharide composition can improve the secretion of TNF-alpha when monocytes are differentiated into macrophages and then respond to stimulation (such as lipopolysaccharide stimulation).
According to a specific embodiment of the present invention, the breast milk oligosaccharide composition of the present invention is used, wherein the mass ratio of 2 '-fucosyllactose, lacto-N-tetraose and 3' -sialyllactose is 3-5: 1.5-2.5: 1.
according to a preferred embodiment of the present invention, the use of a breast milk oligosaccharide composition according to the invention, wherein the mass ratio of 2 '-fucosyllactose, lacto-N-tetraose and 3' -sialyllactose is 4: 2: 1.
on the other hand, the invention also provides a breast milk oligosaccharide composition, which comprises the following components in a mass ratio of 3-5: 1.5-2.5: 1, preferably 4: 2: 1 of 2 '-fucosyllactose, lacto-N-tetraose and 3' -sialyllactose. The breast milk oligosaccharide composition can be used for improving immune response.
In some embodiments of the present invention, the present invention further provides a food or a pharmaceutical product, wherein the food or the pharmaceutical product comprises breast milk oligosaccharides 2 '-fucosyllactose, lacto-N-tetraose and 3' -sialyllactose, and the mass ratio of the 2 '-fucosyllactose, the lacto-N-tetraose and the 3' -sialyllactose is 3 to 5: 1.5-2.5: 1.
according to a particular embodiment of the invention, the food product comprises one or more of a nutritional supplement, milk powder, liquid milk, a complementary food. The milk powder can be infant formula powder (infant formula food), non-infant milk powder such as milk powder for children or milk powder for adults (including middle-aged and elderly people).
In some embodiments of the invention, the food product is an infant formula powder or an infant liquid milk.
According to some embodiments of the invention, the food product is an infant formula.
According to some embodiments of the invention, the 2' -fucosyllactose is used in the food product in an amount of: the application amount in the milk powder is 14.2-3182.2mg/100g powder, or 0.02-4.2g/L calculated by conversion into milk liquid. In addition, the amounts of lacto-N-tetraose and 3' -sialyllactose were used with reference to the above ratios.
According to some embodiments of the invention, the 2' -fucosyllactose is used in the food product in an amount of: the application amount in the milk powder is 70.9-1818.4mg/100g powder, or 0.1-2.4g/L converted into milk liquid.
According to some embodiments of the invention, the 2' -fucosyllactose is used in the food product in an amount of: the application amount in the milk powder is 70.9-1515.3mg/100g powder, or 0.1-2.0g/L calculated by conversion into milk.
The application amount of each breast milk oligosaccharide in other foods can be properly adjusted according to specific needs.
According to a specific embodiment of the present invention, the food or pharmaceutical product of the present invention may further comprise ingredients conventionally used in the art. For example, for pharmaceutical products, suitable excipients may be included, which may be excipients, diluents, fillers and/or absorption enhancers, and the like. The food or pharmaceutical product may take on different forms depending on the needs of the recipient. Such as powders, lozenges, granules, microcapsules and/or liquid formulations, and the like.
In another aspect, the invention provides a method of improving an immune response, the method comprising: the breast milk oligosaccharide composition of the present invention is contacted with monocytes, thereby increasing the immune response activity of monocytes after differentiation into macrophages. In some embodiments of the invention, the breast milk oligosaccharide composition is contacted with the monocytes for a period of at least 12 hours, preferably at least 24 hours. In some embodiments of the invention, the breast milk oligosaccharide composition is administered to the individual in an amount effective to achieve a concentration of at least 0.02mg/mL, preferably at least 0.05mg/mL, more preferably at least 0.1mg/mL of the breast milk oligosaccharide composition when contacted with monocytes in the body (e.g., in the gut) of the individual.
In conclusion, the invention finds that the composition of 2 '-fucosyllactose, lactose-N-tetraose and 3' -sialyllactose can be used for improving the immune response activity of monocytes differentiated into macrophages, improving the immune response activity of the monocytes after differentiating into macrophages, preventing the reduction of the immune response activity of the monocytes after training and differentiating into macrophages, and being added into food to be beneficial to improving the immune response of individuals.
Drawings
FIG. 1 shows the effect of the immune response of breast milk oligosaccharides of the present invention on monocyte differentiated macrophages.
Detailed Description
For a more clear understanding of the technical features, objects and advantages of the present invention, reference is now made to the following detailed description taken in conjunction with the accompanying specific embodiments, and the technical solutions of the present invention are described, it being understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the present invention. In the examples, each raw reagent material is commercially available, and the experimental method not specifying the specific conditions is a conventional method and a conventional condition well known in the art, or a condition recommended by an instrument manufacturer.
Example 1 Effect of HMO on monocyte differentiation into macrophage immune response Activity
This example examines the effect of HMO on monocyte differentiation into macrophage immune response activity by acclimatization and activation of monocytes.
Collection and culture of monocytes
The experimental conditions for the specific blood sample collection and culture are as follows:
monocytes were isolated from blood samples from multiple healthy adult donors using the quadro macs system and CD14 microbeads magnetic bead sorting kit (Miltenyi Biotec, ledon, the netherlands) using the manufacturer's recommended protocol. Prior to blood collection, written consent was obtained from the donor.
Culturing the mononuclear cells: RPMI 1640-Glutamax medium (Gibco, Blastwick, the Netherlands) supplemented with 10% fetal bovine serum (FBS, Hyclone, Einholwen, the Netherlands), 1% MEM non-essential amino acids (Gibco Blastwick, the Netherlands), 1% sodium pyruvate (Lonza, Braudard, the Netherlands), 1% penicillin/streptomycin (Sigma, St. Louis, Mo., USA) at 1X 106Cells were cultured in 24-well plates at a concentration of 2 ml/well.
Immune response activity study experiments included pretreatment of monocytes and challenge testing of immune responses after 6 days. The specific operation is as follows:
monocytes recovered from liquid nitrogen and after 1 day of recovery, the following groups of experiments were performed, and all HMO starting materials in this experiment were from Jennewein:
group HMO: different HMO test samples (different HMO monomers or HMO compositions in different proportions, wherein the proportions of the monomers in the HMO composition are in mass ratio) were added to the monocyte culture medium at a final concentration of 0.1mg/mL, co-cultured with monocytes for 24 hours, after which the culture medium was replaced with fresh medium (to flush out the HMO under test) and continued for 6 days to differentiate the monocytes into macrophages. Then, lipopolysaccharide (lipopolysaccharide in the culture medium of 10ng/mL final concentration) stimulation for 24 hours, and from the supernatant determination of secreted TNF alpha.
Control group 1 (lipopolysaccharide group): the monocytes were pretreated with lipopolysaccharide by adding lipopolysaccharide to the monocyte culture medium at a final concentration of 0.1mg/mL, co-culturing with monocytes for 24 hours, and then replacing the fresh medium (washing away LPS) for further culturing for 6 days to differentiate monocytes into macrophages. Then, lipopolysaccharide (lipopolysaccharide in the culture medium of 10ng/mL final concentration) stimulation for 24 hours, and from the supernatant determination of secreted TNF alpha. The purpose of this control pre-lipopolysaccharide pretreatment was to reduce the ability of monocytes to respond to subsequent re-stimulation, and it was expected that lipopolysaccharide would reduce the response of monocytes to the second lipopolysaccharide stimulation.
Control group 2 (medium group): monocytes were cultured in a medium without any test substance added for 7 days to differentiate monocytes into macrophages. Then, lipopolysaccharide (lipopolysaccharide in the culture medium of 10ng/mL final concentration) stimulation for 24 hours, and from the supernatant determination of secreted TNF alpha. The experimental method refers to the method reported by Bekkering et al (2016, Clinical and Vaccine Immunology), and TNF-alpha is measured by ELISA (enzyme-linked immunosorbent assay) and a kit special for TNF-alpha, wherein the wavelength of the ELISA is 450nm, the absorption value of the ELISA is measured by a Plate Reader Spark device, the Spark sequence number is 2009003477, and the Spark sequence number is V3.1.
Data analysis
Macrophage immune response data were statistically analyzed using one way ANOVA. Two groups were marked with an asterisk if they were significantly different and p < 0.05. Two asterisks indicate p < 0.01. Three asterisks indicate p < 0.001.
Results of the experiment
See fig. 1 for experimental results. The mass ratio is 4: 2: 2' -FL of 1: LNT: the group of 3' -SL breast milk oligosaccharide compositions showed a significant increase in TNF-alpha secretion in the monocyte trained model (p < 0.05).
In addition, as expected from experiments, the test results of the lipopolysaccharide group showed that lipopolysaccharide reduced the immune response, and it was seen that the lipopolysaccharide group was significantly reduced compared to the medium group without any test substance.
This example demonstrates that the breast milk oligosaccharide composition of the present invention comprising 2 '-fucosyllactose, lacto-N-tetraose and 3' -sialyllactose in a specific ratio has a significant effect on improving the immune response activity of monocytes differentiating into macrophages, embodying the synergistic effect of the composition.
Example 2 infant formula with added Breast milk oligosaccharide combination
The embodiment provides an infant formula milk powder with an age of 0-6 months, wherein the formula milk powder has a total protein content of 11.1g/100g of powder, a fat content of 28.3g/100g of powder, a carbohydrate content of 52.9g/100g of powder, and a breast milk oligosaccharide content of 1.8g/100g of powder, wherein the breast milk oligosaccharide is a combination of 2 '-fucosyllactose (2' -FL), lacto-N-tetraose (LNT) and 3 '-sialyllactose (3' -SL), and the mass ratio of the 2 '-fucosyllactose (2' -FL), the lacto-N-tetraose (LNT) and the 3 '-sialyllactose (3' -SL) is 4: 2: 1.
Claims (10)
1. the application of a breast milk oligosaccharide composition in preparing a composition for improving immune response is disclosed, wherein the breast milk oligosaccharide composition comprises 2 '-fucosyllactose, lacto-N-tetraose and 3' -sialyllactose, and the mass ratio of the 2 '-fucosyllactose to the lacto-N-tetraose to the 3' -sialyllactose is (3-5): 1.5-2.5: 1.
2. the use according to claim 1, wherein the composition for improving an immune response is a food composition or a pharmaceutical composition.
3. The use according to claim 1 or 2, wherein the composition for improving an immune response is for improving the immune response activity of monocytes differentiating into macrophages.
4. Use according to claim 1 or 2, wherein the composition for improving the immune response is for increasing the amount of secreted TNF-a of monocytes after differentiation into macrophages in response to stimulation.
5. Use according to claim 2, wherein the food composition comprises one or more of a nutritional supplement, a milk powder, a liquid milk, a complementary food.
6. Use according to claim 5, wherein the food composition is an infant formula;
preferably, the food composition is an infant formula powder.
7. Use according to claim 5 or 6, wherein the 2' -fucosyllactose is used in the food composition in an amount of: the application amount in the milk powder is 14.2-3182.2mg/100g powder, or 0.02-4.2g/L calculated by conversion into milk;
preferably, the 2' -fucosyllactose is applied in the food composition in an amount of: the application amount in the milk powder is 70.9-1818.4mg/100g powder, or 0.1-2.4g/L converted into milk;
more preferably, the 2' -fucosyllactose is applied in the food composition in an amount of: the application amount in the milk powder is 70.9-1515.3mg/100g powder, or 0.1-2.0g/L calculated by conversion into milk.
8. The use according to claim 2, wherein the pharmaceutical composition further comprises pharmaceutically acceptable excipients comprising excipients, diluents, fillers and/or absorption enhancers.
9. A breast milk oligosaccharide composition comprises the following components in a mass ratio of 3-5: 1.5-2.5: 1 of 2 '-fucosyllactose, lacto-N-tetraose and 3' -sialyllactose.
10. A food comprises breast milk oligosaccharides 2 '-fucosyllactose, lacto-N-tetraose and 3' -sialyllactose, wherein the mass ratio of the 2 '-fucosyllactose, the lacto-N-tetraose and the 3' -sialyllactose is (3-5): 1.5-2.5: 1;
preferably, the food product comprises one or more of a nutritional supplement, milk powder, liquid milk, a complementary food;
preferably, the food is infant formula powder;
preferably, the food product is an infant formula.
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| CN112514997A (en) * | 2020-11-30 | 2021-03-19 | 内蒙古伊利实业集团股份有限公司 | Breast milk oligosaccharide for improving intestinal microenvironment health and application thereof |
| CN112869168A (en) * | 2019-11-29 | 2021-06-01 | 内蒙古伊利实业集团股份有限公司 | Probiotics prebiotics composition capable of improving gastrointestinal tract immunity and application thereof |
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| CN110301646A (en) * | 2012-03-27 | 2019-10-08 | 雅培制药有限公司 | For using human milk oligosaccharides to adjust cell-mediated immune method |
| CN112869168A (en) * | 2019-11-29 | 2021-06-01 | 内蒙古伊利实业集团股份有限公司 | Probiotics prebiotics composition capable of improving gastrointestinal tract immunity and application thereof |
| CN111903766A (en) * | 2020-08-10 | 2020-11-10 | 沈阳农业大学 | Infant formula milk powder and preparation method thereof |
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