CN114568528A - Infant formula food capable of regulating and controlling intestinal immunity and application thereof - Google Patents
Infant formula food capable of regulating and controlling intestinal immunity and application thereof Download PDFInfo
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- CN114568528A CN114568528A CN202011381147.1A CN202011381147A CN114568528A CN 114568528 A CN114568528 A CN 114568528A CN 202011381147 A CN202011381147 A CN 202011381147A CN 114568528 A CN114568528 A CN 114568528A
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- infant formula
- parts
- macrophages
- breast milk
- oligosaccharide
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
- A23C9/00—Milk preparations; Milk powder or milk powder preparations
- A23C9/152—Milk preparations; Milk powder or milk powder preparations containing additives
- A23C9/156—Flavoured milk preparations ; Addition of fruits, vegetables, sugars, sugar alcohols or sweeteners
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- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides an infant formula food capable of regulating and controlling intestinal immunity and application thereof. Specifically, the invention provides application of breast milk oligosaccharide in preparation of infant formula food with the effect of regulating macrophages to regulate intestinal immunity, and also provides the infant formula food with the effect of regulating macrophages to regulate intestinal immunity, wherein the infant formula food contains breast milk oligosaccharide, and the breast milk oligosaccharide contains 70.9-1363.7mg/100g, or 0.1-1.8g/L of breast milk oligosaccharide calculated by milk. According to the technology provided by the invention, the breast milk oligosaccharide is added into the infant formula food, so that the response of macrophages can be regulated, the development of the macrophages is supported, immune cells are more active in certain specific activities, or more immune cells are attracted, and an activated state is presented to neutralize pathogenic bacteria, so that the intestinal immunity can be regulated, and more protection is provided for a subject, particularly for an infant with an immune system developing.
Description
Technical Field
The invention relates to a new application of breast milk oligosaccharide, in particular to an application of breast milk oligosaccharide in preparing infant formula food which can regulate and control advocate immunity and the prepared infant formula food.
Background
Breast feeding is an important basis for survival and sustainable development in human society, and no human is self-administered without breast feeding. Even today with scientific development, breast feeding is incomparable with any other artificial feeding method. In infants, breast feeding is enriched with active ingredients against infectious diseases (e.g. gastrointestinal infections) in addition to providing a comprehensive and balanced nutritional composition for newborns and infants. Often, many mothers choose infant formulas to feed babies for a variety of reasons. As a breast milk substitute, the infant formula food can not reach the level of breast milk at present, and the nutrition and functional components are far inferior to those of the breast milk. Therefore, the infinite closeness to breast milk is the ultimate goal of the development of the infant formula industry in the future.
At present, most of the infant formula foods sold in the market are milk-based milk powder products. Human milk proteins, fatty acids, carbohydrates, etc. have been shown to be very different from milk of other mammals. For many years, the development of upstream raw materials in the infant milk powder industry has made a breakthrough based on the continuous and deep research and development of domestic and foreign breast milk, and various breast milk components have been developed to replace the raw materials. Such as 1, 3-dioleoyl-2-palmitoyl triglyceride (OPO), lactoferrin, alpha-lactalbumin, beta-casein, milk fat globule membrane, etc., it is basically possible to achieve a fat and protein emulsion.
Breast Milk Oligosaccharides (HMOs) belong to the third most abundant substances in breast Milk, except lactose and fat. The total content varies at various stages of lactation, and is about 12-14g/L in mature milk and about 20-24g/L in colostrum. Each breast milk oligosaccharide has a lactose at the reducing end, mostly with poly lactosamine as the structural backbone, and fucose, sialic acid, or both at the chain end. Breast milk oligosaccharides are mainly composed of three major groups: fucosyl oligosaccharide, which is a representative substance of 2 '-fucosyl oligosaccharide and 3' -fucosyl oligosaccharide; sialic acid-based oligosaccharides, including 3 '-sialyllactose and 6' -sialyllactose as representative substances; oligosaccharides formed by a core sugar chain structure containing no fucosyl or sialyl group are typified by lacto-N-tetraose and lacto-N-neotetraose. HMOs are present in individual differences in content and are associated with the lewis secretory component of the nursing mother. Since the raw material of infant formula is usually cow's milk, which usually contains no or very little such oligosaccharides, HMOs constitute a gap that infant formula is expected to approach the breast milk.
The immune function of the human body is divided into innate immunity and adaptive immunity. Innate immunity is innate, based on the genetic makeup of an individual. Phagocytic cells are responsible for attacking, phagocytosis, and destroying foreign microorganisms in innate immunity. Adaptive immunity is acquired during life, directly against specific pathogenic microorganisms or other foreign substances. In adaptive immunity, foreign substances (primarily proteins), may act as antigens to trigger an immune response. T lymphocytes are a very important class of cells in adaptive immunity, mature in the thymus and capable of directly attacking foreign cells to produce cell-mediated immunity. Macrophages, which are the progeny of monocytes, are important for the function of T cells, they phagocytose and process foreign antigens; t cells are activated when they come into contact with antigens on the surface of macrophages, together with the body's own proteins.
There are a large number of macrophages in the gut, which may have an important role in maintaining the microecological balance. These macrophages can be divided into two subgroups, Tolerant (Tolerant) macrophages and inflammatory (inflammatory) macrophages. The tolerogenic type is a major subset of homeostasis, and they have a low rate of turnover, mainly located in the submucosa near CD 4T cells. Inflammatory macrophages are not present in homeostasis, but are rapidly recruited when infection occurs with CCR-2 dependent monocyte migration. They are fast in iteration and produce TNF- α and many other proinflammatory factors. Undifferentiated macrophages are commonly designated as M0, inflammatory or traditionally activated macrophages as M1, and tolerogenic or selectively activated macrophages as M2.
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 immune cells and initiate an immune response. Appropriate immune responses may protect the body from infection.
At present, in the fields of infant formula food and the like, a solution for regulating and controlling immune cells in intestinal tracts, relieving infant intestinal discomfort and improving autoimmune capacity is needed.
Disclosure of Invention
The invention aims to provide a new application of breast milk oligosaccharide, in particular to an application of breast milk oligosaccharide in preparing a maternal emulsion infant formula food which can regulate and control macrophage so as to regulate and control intestinal immunity.
Another object of the present invention is to provide a maternal emulsion infant formula.
The invention also aims to provide application of the mother emulsified infant formula food.
The invention discovers that some breast milk oligosaccharides have the effect of remarkably regulating and controlling the response of macrophages, and the breast milk oligosaccharides are particularly characterized in that the gene phenotype of the macrophages can be changed, the macrophages are promoted to release a series of chemotactic factors, and the macrophages are regulated and controlled to be differentiated to M1 type, so that other immune cells can be attracted to jointly resist infection, and the immune activity of the system is activated. These effects will allow the breast milk oligosaccharides to be added to infant formula to provide more protection to infants whose immune system is still developing.
Specifically, the invention provides an application of breast milk oligosaccharide in preparing infant formula food with the efficacy of regulating macrophages to regulate intestinal immunity.
The invention also provides an infant formula food with the efficacy of regulating macrophages to regulate intestinal immunity, which contains breast milk oligosaccharides.
It is known that human milk oligosaccharides include fucosyllactose, sialyllactose, and the basic sugar chain structure of human milk oligosaccharides without fucosyl or sialyl groups (typical representatives include lacto-N-tetraose and its isomer lacto-N-neotetraose).
Wherein 2 ' -fucosyllactose (2 ' -fucosyllactose, 2 ' -FL or 2FL) is a trisaccharide structure formed by fucose and lactose, and is a representative substance of fucosyl oligosaccharide. Commercially available materials are usually prepared by microbial fermentation and have the same structure as oligosaccharides found in human milk.
3-fucosyllactose (3-fucosyllactose, 3 '-FL or 3FL) is a trisaccharide structure formed by fucose and lactose, and is an isomer of 2' -fucosyllactose. Is a representative of fucosyl oligosaccharides. The substance is prepared by microbial fermentation, and has the same structure as oligosaccharide found in human milk.
lacto-N-tetraose (LNT), which is 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 or sialyl group. The substance is prepared by microbial fermentation, and has the same structure as 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 substance is prepared by microbial fermentation, and has the same structure as oligosaccharide found in human milk.
6 ' -sialyllactose (6 ' -sialyllactose, 6 ' -SL or 6SL), which is a trisaccharide structure formed by sialic acid and lactose, is a representative of sialic acid-based oligosaccharides. The substance is prepared by microbial fermentation, and has the same structure as oligosaccharide found in human milk.
According to the specific embodiment of the invention, the infant formula with the function of regulating macrophages to regulate intestinal immunity contains 70.9-1363.7mg/100g of breast milk oligosaccharide, or 0.1-1.8g/L of breast milk oligosaccharide calculated by milk. Preferably, the infant formula of the invention contains 70.9-1060.7mg/100g of breast milk oligosaccharide, or 0.1-1.4g/L of breast milk oligosaccharide calculated by milk; more preferably, the milk oligosaccharide contains 70.9-681.9mg/100g of breast milk oligosaccharide, or 0.1-0.9g/L of breast milk oligosaccharide based on the milk.
According to a specific embodiment of the present invention, the infant formula with the efficacy of regulating macrophages to regulate intestinal immunity according to the present invention is infant formula powder, wherein the infant formula powder contains 70.9-606.1mg/100g of breast milk oligosaccharide, and the infant formula powder contains: 8.5-20g/100g of protein, 13.5-30g/100g of fat and 40-71g/100g of carbohydrate.
According to a specific embodiment of the present invention, the infant formula of the present invention has a function of regulating macrophages to regulate intestinal immunity, and the breast milk oligosaccharide includes sialyl oligosaccharide. Preferably, the sialyloligosaccharide comprises 3-SL and/or 6-SL. More preferably, the content of 3-SL, 6-SL in the infant formula is not lower than 70.9mg/100g, either individually or in total. Specifically, the application amount of the breast milk oligosaccharide 3-SL in the infant formula is 70.9-606.1mg/100g powder, 0.1-0.8g/L converted into milk, preferably 70.9-454.6mg/100g powder, 0.1-0.6g/L converted into milk, more preferably 70.9-227.3mg/100g powder, and 0.1-0.3g/L converted into milk. The application amount of 6-SL in infant formula food is 70.9-757.6mg/100g of powder, converted into milk liquid is 0.1-1.0g/L, preferably 70.9-606.1mg/100g of powder, converted into milk liquid is 0.1-0.8g/L, more preferably 70.9-454.6mg/100g of powder, and converted into milk liquid is 0.1-0.6 g/L.
According to a specific embodiment of the present invention, in the infant formula with the efficacy of regulating macrophages to regulate intestinal immunity according to the present invention, the regulating macrophages comprise: alter the genetic phenotype of macrophages, promote the release of chemokines from macrophages, and/or regulate the differentiation of macrophages to M1 type.
In some embodiments of the invention, the breast milk oligosaccharide in the food product of the invention is used to alter the genetic phenotype of macrophages and/or to promote chemokine release from macrophages to enhance the immune activity of macrophages.
According to a particular embodiment of the invention, the human milk oligosaccharides in the food product of the invention are used to regulate macrophages in the intestine of a subject.
In some embodiments of the invention, the human milk oligosaccharide in the food product of the invention is for promoting macrophage release of one or more of the chemokines CCL17, CXCL9, CXCL10, CXCL11, CXCL1, CXCL5, CXCL8, CCL3, CCL4, CCL5, CCL 20.
In some embodiments of the invention, the human milk oligosaccharide in the food product of the invention is for promoting macrophage release of one or more of the chemokines CXCL9, CXCL10, CXCL 11.
In some embodiments of the invention, the human milk oligosaccharide in the food product of the invention is for promoting macrophage release of one or more of the chemokines CXCL1, CXCL5, CXCL8, CCL3, CCL4, CCL5, CCL 20.
According to a specific embodiment of the invention, the infant formula with the efficacy of regulating macrophages to regulate intestinal immunity provided by the invention is characterized in that the main raw materials of the protein comprise one or more of the following raw materials in parts by weight: 260 parts of whole milk powder 140-.
The protein in the infant formula food can be used by matching the above raw materials, and is not limited to the above types.
The milk raw materials are derived from various mammals, such as cow milk and cow milk products; goat milk and goat milk products. And is not limited to the above raw material species.
According to a specific embodiment of the invention, the infant formula with the efficacy of regulating macrophages to regulate intestinal immunity provided by the invention is characterized in that the main raw materials of fat comprise one or more of the following raw materials in parts by weight: 20-50 parts of corn oil, 40-65 parts of soybean oil, 0-100 parts of sunflower seed oil, 0-115 parts of 1, 3-dioleic acid-2-palmitic acid triglyceride, 5-50 parts of coconut oil and 30-85 parts of low erucic acid rapeseed oil.
The fat in the infant formula food can be used by matching the above raw materials, and is not limited to the above types.
According to a specific embodiment of the invention, the infant formula with the efficacy of regulating macrophages to regulate intestinal immunity according to the invention provides a formula which is characterized in that the main raw materials of carbohydrates comprise one or more of the following raw materials in parts by weight: 80-450 parts of lactose, 50-200 parts of maltodextrin, 50-200 parts of solid corn syrup and 25-200 parts of white granulated sugar.
The carbohydrates in the infant formula milk powder can be used by matching the raw materials.
The infant formula food with the function of regulating macrophages to regulate intestinal immunity can also comprise other common nutritional additives in the infant formula food, for example, 4-20 parts of vitamins and mineral nutrients can be added into the raw materials. In addition, some optional components can be added into the formula, including dietary fiber (fructo-oligosaccharide, galacto-oligosaccharide, polyfructose, etc.), inositol, taurine, L-carnitine, docosahexaenoic acid, arachidonic acid, lutein, lactoferrin, etc. The source, content and usage amount of the nutrient raw materials are in accordance with infant formula food and related national standards.
According to a specific embodiment of the present invention, the infant formula with the efficacy of regulating macrophages to regulate intestinal immunity according to the present invention, wherein the vitamin component comprises one or more of vitamin a, vitamin D, vitamin E, vitamin K1, vitamin B1, vitamin B2, vitamin B6, vitamin B12, niacin, folic acid, pantothenic acid, vitamin C, choline and biotin. The mineral component comprises one or more of sodium, potassium, calcium, phosphorus, copper, iron, zinc, manganese, iodine, selenium, magnesium, potassium and their derivatives.
In some embodiments of the invention, the infant formula is an infant formula suitable for consumption by infants from 0 to 6 months. Preferably, the content of vitamins and minerals in each 100g of infant formula (suitable for infants of 0-6 months) is as follows:
| item | Content/100 g |
| Vitamin A/(mu gRE) | 308～462 |
| Vitamin D/(mug) | 10.32～15.48 |
| Vitamin E/(mg alpha-TE) | 5.6～8.4 |
| Vitamin K1/(ug) | 56～84 |
| Vitamin B1/(mug) | 440～660 |
| Vitamin B2/(mug) | 480～720 |
| Vitamin B6/(mug) | 336～504 |
| Vitamin B12/(mug) | 2.08～3.12 |
| Nicotinic acid/(mug) | 3200～4800 |
| Folic acid/(ug) | 62.4～93.6 |
| Pantothenic acid/(ug) | 2280～3420 |
| Vitamin C/(mg) | 52～78 |
| Biotin/(ug) | 12.8～19.2 |
| Choline/(mg) | 104～156 |
| Sodium/(mg) | 144～216 |
| Potassium/(mg) | 372～558 |
| Copper/(mug) | 308～462 |
| Magnesium/(mg) | 25.6～38.4 |
| Iron/(mg) | 3.8～5.7 |
| Zinc/(mg) | 3.016～4.524 |
| Manganese/(μ g) | 40～60 |
| Calcium/(mg) | 280～420 |
| Phosphorus/(mg) | 176～264 |
| Iodine/(μ g) | 78.4～117.6 |
| Chlorine/(mg) | 260～390 |
| Selenium/(ug) | 15.6～23.4 |
Preferably, the content of the optional components in each 100g of the infant formula (suitable for being eaten by infants of 0-6 months) is as follows:
in some embodiments of the invention, the infant formula is an infant formula suitable for consumption by older infants between 7 and 12 months of age. Preferably, the content of vitamins and minerals in each 100g of infant formula (suitable for 7-12 months old infants) is as follows:
| item | Content/100 g |
| Vitamin A/(mu gRE) | 296～444 |
| Vitamin D/(mug) | 9.92～14.88 |
| Vitamin E/(mg alpha-TE) | 5.6～8.4 |
| Vitamin K1/(ug) | 32～48 |
| Vitamin B1/(mug) | 560～840 |
| Vitamin B2/(mug) | 768～1152 |
| Vitamin B6/(mug) | 320～480 |
| Vitamin B12/(mug) | 2.08～3.12 |
| Nicotinic acid/(mug) | 3280～4920 |
| Folic acid/(mug) | 52～78 |
| Pantothenic acid/(ug) | 2520～3780 |
| Vitamin C/(mg) | 52～78 |
| Biotin/(ug) | 12～18 |
| Choline/(mg) | 99.2～148.8 |
| Sodium/(mg) | 96～144 |
| Potassium/(mg) | 372～558 |
| Copper/(mug) | 222.4～333.6 |
| Magnesium/(mg) | 24.8～37.2 |
| Iron/(mg) | 4.944～7.416 |
| Zinc/(mg) | 2.48～3.72 |
| Manganese/(μ g) | 40～60 |
| Calcium/(mg) | 344～516 |
| Phosphorus/(mg) | 229.6～344.4 |
| Iodine/(μ g) | 74.4～111.6 |
| Chlorine/(mg) | 320～480 |
Preferably, the optional component content in each 100g of the infant formula (suitable for 7-12 month old infants) is as follows:
in some embodiments of the present invention, the infant formula is a formula suitable for infants aged 12-36 months. Preferably, the contents of vitamins and minerals in every 100g of the infant formula food (suitable for infants of 12-36 months of age) are as follows:
preferably, every 100g of the infant formula food (suitable for infants of 12-36 months old) comprises the following optional components:
| item | Content/100 g |
| Choline/(mg) | 96～144 |
| Inositol/(mg) | 26.4～39.6 |
| Taurine/(mg) | 32～48 |
| L-carnitine/(mg) | 6.56～9.84 |
| Docosahexaenoic acid/(mg) | 96～144 |
| Eicosatetraenoic acid/(mg) | 96～144 |
| Galacto-oligosaccharide/(g) | 2.72～4.08 |
| Fructo-oligosaccharide/(g) | 0.288～0.432 |
| OPO/(g) | 4.8～7.2 |
| Nucleotide/(mg) | 28～42 |
On the other hand, the invention also provides a method for preparing the infant formula food, which adopts a wet or dry production process to mix breast milk oligosaccharide with other raw materials in the formula to prepare the infant formula food. Specifically, the wet process generally includes: preparing materials, homogenizing, concentrating, sterilizing, and spray drying to obtain the final product; the HMO can be mixed together during batching, and can also be mixed and added after other materials are powdered. Dry production processes typically include: preparing materials, preheating, homogenizing, concentrating, sterilizing, spray drying, and dry mixing (including adding HMO) to obtain the final product.
On the other hand, the invention also provides application of the infant formula food in preparing infant formula powder with the efficacy of regulating macrophages to regulate intestinal immunity. Wherein the regulatory macrophage comprises: alter the genetic phenotype of macrophages, promote the release of chemokines from macrophages, and/or regulate the differentiation of macrophages to M1 type.
In some embodiments of the invention, the invention demonstrates that breast milk oligosaccharides do not affect monocyte chemotactic factor CCL 2. Breast milk oligosaccharides 3-SL and 6-SL support the release of CXCL8, CCL5, CCL3, CXCL5, CCL20, CXCL1 and CCL4 chemokines. These chemokines may support the attraction of more immune cells, such as may include monocytes and the like.
Therefore, the invention can regulate and control the response of macrophages by adding breast milk oligosaccharide into infant formula food, supports the development of the macrophages, enables immune cells to be more active on certain specific activities, or attracts more immune cells to present an activated state to neutralize pathogenic bacteria, thereby regulating and controlling intestinal immunity and providing more protection for subjects, particularly for infants with the immune system developing.
Drawings
FIG. 1 shows the results of 7-AAD staining of human milk oligosaccharides on macrophages tested for each monomer.
FIG. 2 shows the main component analysis displaying the gene phenotype marker molecules characteristic of M1 and M2-type macrophages.
FIG. 3 shows that a portion of HMO affected the macrophage phenotype after co-culture of breast milk oligosaccharides with macrophages.
FIG. 4 shows the production of the chemokine CCL2 after co-culture of breast milk oligosaccharides with macrophages.
FIG. 5 shows the production of the chemokine CCL11 after co-culture of breast milk oligosaccharides with macrophages.
FIG. 6 shows the production of the chemokine CCL17, representative of a typical M2-type macrophage, following co-culture of breast milk oligosaccharides with macrophages.
FIG. 7 shows the production of the chemokine CXCL9, representative of a typical macrophage of type M1, following co-culture of breast milk oligosaccharides with macrophages.
FIG. 8 shows the production of the chemokine CXCL10, representative of a typical macrophage of type M1, following co-culture of breast milk oligosaccharides with macrophages.
FIG. 9 shows the production of the chemokine CXCL11, representative of a typical macrophage of type M1, following co-culture of breast milk oligosaccharides with macrophages.
FIG. 10 shows the production of the chemokine CXCL1 following co-culture of breast milk oligosaccharides with macrophages.
FIG. 11 shows the production of the chemokine CXCL5 after co-culture of breast milk oligosaccharides with macrophages.
FIG. 12 shows the production of the chemokine CXCL8 after co-culture of breast milk oligosaccharides with macrophages.
FIG. 13 shows the production of the chemokine CCL3 following co-culture of breast milk oligosaccharides with macrophages.
FIG. 14 shows the production of the chemokine CCL4 following co-culture of breast milk oligosaccharides with macrophages.
FIG. 15 shows the production of the chemokine CCL5 following co-culture of breast milk oligosaccharides with macrophages.
FIG. 16 shows the production of the chemokine CCL20 following co-culture of breast milk oligosaccharides with 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
This example provides a powdered infant formula wherein the total protein content is 11.1g/100g powder, the fat content is 28.0g/100g powder; the carbohydrate content was 53.0g/100g powder; the content of oligosaccharide in breast milk is 70.9mg/100g powder.
The infant formula food is prepared by compounding the following raw materials in parts by weight:
1000 parts of raw milk, 327 parts of lactose, 137 parts of sunflower seed oil, 56 parts of soybean oil, 31 parts of corn oil, 171 parts of desalted whey powder (D90), 26 parts of whey protein powder, 24 parts of whey protein powder (WPC80), 21.5 parts of casein and 0.78 part of breast milk oligosaccharide (3-SL).
The infant formula food of the embodiment is prepared by a wet process, and mainly comprises the following steps: mixing (including adding HMO), homogenizing, concentrating, sterilizing, and spray drying to obtain the final product.
Example 2
This example provides a powdered infant formula wherein the total protein content is 8.5g/100g powder, and the fat content is 13.5g/100g powder; the content of carbohydrate is 75g/100g of powder; the milk oligosaccharide content is 606.1mg/100g powder.
The infant formula food is prepared by compounding the following raw materials in parts by weight:
140 parts of whole milk powder, 25 parts of whey protein powder and 120 parts of skimmed milk powder;
20 parts of corn oil, 40 parts of soybean oil, 10 parts of coconut oil and 30 parts of low erucic acid rapeseed oil;
450 parts of lactose, 200 parts of maltodextrin and 100 parts of solid corn syrup;
6.73 portions of breast milk oligosaccharide (3-SL).
The infant formula food of the embodiment is prepared by adopting a dry production process, and mainly comprises the following steps: preparing materials, preheating, homogenizing, concentrating, sterilizing, spray drying, dry mixing, and adding HMO to obtain the final product.
Example 3
This example provides a powdered infant formula wherein the total protein content is 20g/100g powder, the fat content is 30g/100g powder; the carbohydrate content is 40g/100g powder; the milk oligosaccharide content is 227.3mg/100g powder.
The infant formula food is prepared by compounding the following raw materials in parts by weight:
1000 parts of raw milk, 240 parts of skim milk powder and 25 parts of whey protein powder;
50 parts of corn oil, 65 parts of soybean oil, 70 parts of sunflower seed oil, 50 parts of coconut oil and/or 70 parts of low erucic acid rapeseed oil;
2.52 portions of breast milk oligosaccharide (6-SL).
The infant formula food of the embodiment is prepared by a wet process, and mainly comprises the following steps: mixing (including adding HMO), homogenizing, concentrating, sterilizing, and spray drying to obtain the final product.
Experiment on the efficacy of oligosaccharide in breast milk
Experimental methods
Monocyte and macrophage collection and culture were performed as described by Tang et al (2017, j.func.foods) and good et al (2020, Food Funct.). Primary monocytes were isolated and harvested from blood of three healthy donors and M0 was obtained after seven days of monocyte culture with M-CSF. Activation was then performed with control broth or HMO: if cultured with TNF alpha and INF gamma for 24 hours, M1 type macrophage can be obtained; if the culture is carried out for 24 hours with IL-4, M2 type macrophages can be obtained; the experimental group of the present invention cultured the primary monocyte M0 with HMO for 24 hours, and the obtained macrophage was marked as "M (NDP)", and the gene transcription assay was performed to analyze the phenotype change of the macrophage (see whether to shift to the more mature M1 and M2 phenotypes). In the present invention, chemotactic factors produced by macrophages are simultaneously analyzed and migration tests are performed.
The experimental conditions for the specific blood sample collection and culture are as follows:
buffy coat (fraction containing white blood cells and platelets obtained from centrifugation of whole blood samples) was obtained from healthy donor blood samples 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. To this mixture were added 10% fetal bovine serum (FBS, Hyclone, Einhol, Netherlands), 1% MEM nonessential amino acids (Gibco Breusviger, Netherlands), 1% sodium pyruvate (Lonza, Bradar, Netherlands), 1% penicillin/streptomycin (Sigma, St. Louis, Missouri, USA) and 50ng/ml MCSF (R)&D systems, Minneapolis, Minnesota, USA) in RPMI 1640-Glutamax medium (Gibco, Brazivik, Netherlands) at 1X 106Concentration of cells/2 ml/well monocytes differentiated into macrophages after 7 days of culture in 24-well plates. After 3 and 5 days of culture, half of the medium was replaced with medium containing 100ng/ml MCSF. On day 7, the medium was replaced with medium without any other substances added, and macrophages were polarized to M0; the medium was replaced with a medium containing 20ng/ml TNF-. alpha.and 20ng/ml INF-. gamma. (R)&D systems, minneapolis, minnesota, usa), macrophage polarization was M1; the medium was replaced with a medium containing 20ng/ml IL-4 (R)&D systems, minneapolis, minnesota, usa), macrophage polarization was M2; the test substance HMO was added at a concentration of 0.1mg/mL, and cultured with macrophages in the absence of MCSF medium for 24 hours.
Lipopolysaccharide detection
The content of Lipopolysaccharide (LPS) produced by HMO is analyzed, and when the produced lipopolysaccharide meets the detection limit below the detection limit for promoting macrophage response, the lipopolysaccharide can be used for subsequent experiments.
Lipopolysaccharide LPS was tested as described by Govers et al (2016, bioact. Carbohydrat. Diet. fiber.). For the measurement of lipopolysaccharide, a concentration of 0.1mg/mL was used. One endotoxin unit corresponds to 0.1 to 0.2pg LPS, depending on the kind of LPS, and is estimated to reflect 0.2pg LPS.
Macrophage survival assay
To measure macrophage activity after activation, macrophages were washed with PBS without calcium/magnesium. Macrophages were dissociated with EDTA-trypsin, centrifuged and washed with PBS containing calcium/magnesium. The macrophages treated with the medium were divided into two tubes (1 as an unstained control), and all cells were resuspended in PBS containing 5. mu.l of 7-AAD (stain), incubated for 10 minutes, and detected by flow cytometry.
When a cell dies, or is undergoing apoptosis, the cell membrane surface will have pores through which 7-AAD can enter the cell and attach to DNA. Macrophages were exposed to HMO-supplemented environments, cells were harvested and 7-AAD was added. The resulting fluorescent signal was washed off with a flow cytometer and measured. All cells had some background fluorescence generation, and therefore there was a slight increase in fluorescence signal compared to the control without staining, even without excitation by any test substance. Therefore, a slight amount of positive staining is not a negative signal, but only background fluorescence produced by the cells themselves. If the test substance causes cell death, the percentage will be in the interval 20-100%.
Gene expression and inflammatory factor testing
The primary monocytes were isolated and allowed to differentiate towards M0. The cells are then cultured with different HMO monomers. The cells were assayed for activity and the production of chemokines in the medium was analyzed. After RNA extraction, cDNA was synthesized, and gene expression was analyzed using qPCR for detection using specific sequences of M1, M2, and M (ndp). The established fold change for the marker for M1 and the marker for M2 was used to characterize whether the test substance could cause phenotypic differentiation of macrophages towards M1 or M2.
Measurement of macrophage gene transcription is accomplished by the following steps: RNA was obtained using Trizol, Rneasy and Dnase Qiagen kits, as described by Tang et al (2017, j. Gene expression was detected using Q-PCR using markers commonly known as M1-type expressed genes (IDO1, LAMP3, GCH1, CXCL11, and GBP5) and M2-type expressed genes (CD209, CHDH, DCIR, IL-17RB, and MGL), and gene markers were selected as described by Tang et al (2017, J.Funct.foods) (reference genes ACTB, RPLP 0).
The amount of secreted cytokine was determined in the supernatant of activated macrophages using the Multi-plex kit (Legendplex group of human pro-inflammatory chemokine reagents).
Data analysis
A two-sample two-sided T-test was performed on the data results (two tailed, paired T-test). Two groups were marked with an asterisk if they were significantly different and p < 0.05.
Results of experiments on LPS production by various breast milk oligosaccharides
When the concentration of lipopolysaccharide is above 20pg/mL, the macrophage will have a strong response. The purpose of this assay is therefore to control the lipopolysaccharide produced when macrophages are co-cultured with HMO, reducing the impact on subsequent testing. The results are shown in Table 1. When the peak value is between 50% and 200%, the peak value interval is verified to be credible. It can be seen that when the concentration of HMO is 0.1mg/mL, the concentration of lipopolysaccharide produced is below the threshold.
TABLE 1
| HMO | LPS(pg/0.1mg) | Spike(％) |
| 2-FL | 0.8 | 119 |
| 3-FL | 10.9 | 127 |
| 3-SL | 15.9 | 99 |
| 6-SL | 18.4 | 144 |
| LNT | 15.2 | 120 |
Results of macrophage 7-AAD staining experiment by each breast milk oligosaccharide
The preparation steps and specific experimental methods before the experiment are described in the preceding paragraphs.
If the test substance causes cell death, a peak of a certain height is generated to the right of the higher peak on the image generated by the flow cytometer, and the percentage of dead cells can be calculated therefrom.
As a result of the detection, as shown in FIG. 1, the second peak caused by the test substance was extremely small and hardly visible to the naked eye. Macrophages stimulated by various HMO monomers were also calculated to produce a percentage of dead cells that did not substantially exceed 1% (table 2). Therefore, it is believed that co-culture with HMO does not kill macrophages, and that macrophage growth is better.
TABLE 2
| ％ | Medium(M0) | M1 | M2 | 2-FL | 3-FL | 3-SL | 6-SL | LNT |
| HD96 | 1.06 | 0.75 | 0.57 | 0.51 | 0.61 | 0.96 | 0.37 | 0.67 |
| HD97 | 2.38 | 0.47 | 0.8 | 0.69 | 0.68 | 0.37 | 0.71 | 1.04 |
| HD98 | 0.44 | 0.5 | 0.9 | 0.75 | 0.87 | 0.57 | 0.57 | 0.99 |
Testing of the Effect of various Breast milk oligosaccharides on macrophage Gene phenotype
This example examined the effect of various breast milk oligosaccharides on macrophage gene phenotype. The test results are shown in fig. 2 and 3. As shown in FIG. 2, the genetic phenotypes unique to M1 and M2-type macrophages and their marker molecules were determined from prior studies. After co-culturing different HMO monomers with macrophages, it was found that 3-SL and 6-SL affected the genetic phenotype of macrophages, biasing them more towards the phenotypes of M1 and M2, respectively (FIG. 3), whereas the other three tested HMOs (2' -FL, 3-FL and LNT) did not.
Chemokine assay of Co-culture of various human milk oligosaccharides with macrophages
This example examined the expression of chemokines produced by co-culture of various breast milk oligosaccharides with macrophages. The main efficacy of each chemokine as reported in the prior art is seen in table 3.
TABLE 3
The test results are shown in fig. 4 to 16.
CCL2 is an important monocyte chemotactic factor that is chemotactic for monocytes and basophils but not neutrophils and eosinophils. As shown in fig. 4, the breast milk oligosaccharide monomer tested did not affect the release of CCL2, a chemokine.
CCL11 is involved in allergic responses and is an eosinophil chemokine. As shown in fig. 5, HMO resulted in very low release for CCL11 chemokine, with very little effect.
CCL17 is a marker molecule for the typical M2 macrophage subpopulation, which is a chemokine for T cells, not for monocytes or granulocytes. As shown in FIG. 6, only 3-SL and 6-SL affected the release of CCL17 to some extent in all HMOs tested but body weights.
CXCL9, CXCL10 and CXCL11 are typical M1 macrophage subpopulation marker molecules, as shown in fig. 7-9, of all HMOs tested, only 3-SL and 6-SL affected their release, and were more pronounced with CXCL10 and CXCL 11. However, these two HMOs produced relatively low levels of these chemokines after macrophage stimulation compared to the macrophage release from the M1 subpopulation.
As shown in fig. 10-16, 3-SL and 6-SL significantly affected the release of other series of chemokines upon co-culture with macrophages, including CXCL1, CXCL5, CXCL8, CCL3, CCL4, CCL5, CCL20, and the like.
From the above experimental results, it can be concluded that monocyte chemotactic factor CCL2 is not affected by HMO. 3-SL and 6-SL support the release of CXCL8, CCL5, CCL3, CXCL5, CCL20, CXCL1, CCL4 and the like. These chemokines may support the attraction of more immune cells, such as may include monocytes and the like.
Claims (10)
1. Application of breast milk oligosaccharide in preparing infant formula food with effects of regulating macrophage and regulating intestinal immunity is provided.
2. An infant formula food with effect of regulating macrophage to regulate intestinal immunity contains breast milk oligosaccharide, wherein the breast milk oligosaccharide contains 70.9-1363.7mg/100g, or 0.1-1.8g/L based on milk.
3. The infant formula according to claim 2, comprising 70.9-1363.7mg/100g of breast milk oligosaccharides, preferably 70.9-1060.7mg/100g, more preferably 70.9-681.9mg/100 g; the infant formula food contains: 8.5-20g/100g of protein, 13.5-30g/100g of fat and 40-71g/100g of carbohydrate.
4. The infant formula of claim 2 or 3, wherein the breast milk oligosaccharide comprises a sialyl oligosaccharide; preferably, the sialyloligosaccharide comprises 3-SL and/or 6-SL.
5. The infant formula of claim 3, wherein:
the raw materials for providing the protein comprise one or more of the following raw materials in parts by weight: 260 parts of whole milk powder 140-;
the raw materials for providing the fat comprise one or more of the following raw materials in parts by weight: 20-50 parts of corn oil, 40-65 parts of soybean oil, 0-100 parts of sunflower seed oil, 0-115 parts of 1, 3-dioleic acid-2-palmitic acid triglyceride, 5-50 parts of coconut oil and 30-85 parts of low erucic acid rapeseed oil;
providing raw materials of carbohydrate, wherein the raw materials comprise one or more of the following raw materials in parts by weight: 80-450 parts of lactose, 50-200 parts of maltodextrin, 50-200 parts of solid corn syrup and 25-200 parts of white granulated sugar.
6. The infant formula according to claim 3 or 5, wherein the raw materials further comprise 4-20 parts of vitamins, mineral nutrients, or further optionally comprise one or more of dietary fiber (fructo-oligosaccharide, galacto-oligosaccharide, polyfructose, etc.), inositol, taurine, L-carnitine, docosahexaenoic acid, arachidonic acid, lutein, lactoferrin.
7. The method for preparing the infant formula according to any one of claims 2 to 6, wherein the infant formula is prepared by mixing breast milk oligosaccharides with other raw materials in a formula by a wet or dry production process.
8. Use of the infant formula of any one of claims 2 to 6 for preparing an infant formula powder having the efficacy of regulating macrophages to regulate intestinal immunity.
9. The use of claim 8, wherein the regulatory macrophage comprises: alter the genetic phenotype of macrophages, promote the release of chemokines from macrophages, and/or regulate the differentiation of macrophages to M1 type.
10. Use according to claim 8 or 9, wherein the infant formula or the breast milk oligosaccharides thereof are for altering the genetic phenotype of macrophages and/or promoting macrophage release of chemokines to enhance intestinal macrophage immune activity;
preferably, the breast milk oligosaccharide is for promoting macrophage release of one or more of chemokines CCL17, CXCL9, CXCL10, CXCL11, CXCL1, CXCL5, CXCL8, CCL3, CCL4, CCL5, CCL 20.
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| CN115644431A (en) * | 2022-12-29 | 2023-01-31 | 内蒙古伊利实业集团股份有限公司 | Formula food containing breast milk oligosaccharide for premature infant and preparation method and application thereof |
| CN115669732A (en) * | 2022-12-29 | 2023-02-03 | 内蒙古伊利实业集团股份有限公司 | Hypoallergenic infant partially hydrolyzed formula containing the breast milk oligosaccharide LNnT |
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| CN115644431A (en) * | 2022-12-29 | 2023-01-31 | 内蒙古伊利实业集团股份有限公司 | Formula food containing breast milk oligosaccharide for premature infant and preparation method and application thereof |
| CN115669732A (en) * | 2022-12-29 | 2023-02-03 | 内蒙古伊利实业集团股份有限公司 | Hypoallergenic infant partially hydrolyzed formula containing the breast milk oligosaccharide LNnT |
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