CN116439377A - Nutritional composition for relieving dysbacteriosis of infants and application thereof - Google Patents
Nutritional composition for relieving dysbacteriosis of infants and application thereof Download PDFInfo
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Classifications
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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
-
- 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
- A23L33/20—Reducing nutritive value; Dietetic products with reduced nutritive value
- A23L33/21—Addition of substantially indigestible substances, e.g. dietary fibres
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- 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
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Life Sciences & Earth Sciences (AREA)
- Mycology (AREA)
- Health & Medical Sciences (AREA)
- Nutrition Science (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 present invention relates to a nutritional composition, in particular to a nutritional composition comprising breast milk oligosaccharides and probiotics, and to the use of said nutritional composition for alleviating dysbacteriosis caused by early antibiotic exposure in infants and/or for inhibiting the increase of pathogenic and/or drug-resistant bacteria caused by early antibiotic exposure in infants. The invention discovers that the combination of the breast milk oligosaccharide and the probiotics can obviously and synergistically relieve dysbacteriosis caused by early antibiotic exposure of infants, can effectively relieve depletion (reduction of abundance) of intestinal bacteria, can synergistically inhibit pathogenic bacteria and/or increase of drug-resistant bacteria caused by early antibiotic exposure of infants, also increases the abundance of the probiotics, further prevents the possibility of occurrence of various diseases, and has wide application prospect.
Description
Technical Field
The present invention relates to a nutritional composition, in particular to a nutritional composition comprising breast milk oligosaccharides and probiotics, and to the use of said nutritional composition for alleviating dysbacteriosis caused by early antibiotic exposure in infants and/or for inhibiting the increase of pathogenic and/or drug-resistant bacteria caused by early antibiotic exposure in infants.
Background
Infectious diseases are one of the leading causes of death in children worldwide. As the most effective means of inhibiting infection, antibiotics (Abx) are the most commonly prescribed drugs used in the first months of life. Prolonged exposure to Abx therapy results in increased bacterial resistance and increased susceptibility to disease, primarily because Abx can disrupt the microflora, indirectly affecting growth, energy metabolism, nervous system and immune system maturation. However, when microbiota disorders occur within a specific neonatal time window, the development of the intestinal immune system is impaired, thereby indirectly and directly affecting the host immunity throughout the life cycle. Breast feeding has been found to protect infants from antibiotic-resistant bacteria. At the same time, many studies have demonstrated that the long-term metabolic benefit of breast feeding is conveyed by the intestinal flora. Breast milk oligosaccharides (Human milk oligosaccharides, HMOs) are a unique nutritional ingredient in breast milk that can exert a natural prebiotic effect in the large intestine by modulating intestinal flora, which helps prevent bacterial infection in cells, tissues, and is expected to replace antibiotics in the future for the treatment of neonatal infections.
In one study, by studying the development of intestinal flora and its susceptibility to DSS (sodium dextran sulfate) induced colitis in mice at different early stages of life (perinatal, lactating and postweaning nutritional stages), it was found that exposure to early antibiotics aggravated changes in the intestinal flora of mice and susceptibility to DSS induced colitis, while confirming the presence of bacteria in the pre-natal gastrointestinal tract of mice, and that lactating has an important role in developing intestinal flora.
At present, a certain nutrition prevention guidance is lacking for the long-term exposure of antibiotics in the period of infants. Accordingly, there is a great need in the art to develop a nutritional formula that alleviates the dysbacteriosis and increased drug resistance caused by early antibiotic exposure in infants and meets the health needs of infants.
Disclosure of Invention
The present invention aims to provide a nutritional composition comprising breast milk oligosaccharides and probiotics and its use for alleviating dysbacteriosis caused by early antibiotic exposure in infants and/or inhibiting the increase of pathogenic bacteria and/or drug-resistant bacteria caused by early antibiotic exposure in infants.
In a first aspect of the invention, there is provided the use of a nutritional composition for (a) alleviating dysbacteriosis caused by early antibiotic exposure in infants; and/or (b) inhibiting an increase in pathogenic and/or resistant bacteria caused by early antibiotic exposure in infants; wherein the nutritional composition comprises breast milk oligosaccharides and probiotics.
In a preferred embodiment of the present invention, the human milk oligosaccharide comprises at least one of sialylated or fucosylated or N-acetylated oligosaccharides; preferably, the fucosylated oligosaccharide is 2 '-fucosyllactose (2' -FL).
In a preferred embodiment of the invention, the probiotic is Bifidobacterium (Bifidobacterium), lactobacillus (Lactobacillus), or a combination thereof; preferably, the probiotic is bifidobacterium animalis subspecies lactis or bifidobacterium animalis Bb-12 (Bifidobacterium animalis subsp.lacts or Bifidobacterium animalis Bb-12), bifidobacterium longum subsp. Infantis or bifidobacterium infantis R0033 (Bifidobacterium longum subsp.infantis or Bifidobacterium infantis R0033), bifidobacterium bifidum R0071 (Bifidobacterium bifidum R0071), bifidobacterium animalis subsp. Lactis or bifidobacterium lactis HN019 and Bi-07 (Bifidobacterium animalis subsp.lactis or Lactobacillus lactis HN019, bifidobacterium animalis subsp.lactis or Lactobacillus lactis Bi-07), bifidobacterium breve M16V (Bifidobacterium breve M16V), lactobacillus helveticus R0052 (Lactobacillus helveticus R0052), lactobacillus rhamnosus g or GG (Lactobacillus rhamnosus LGG or GG, lactobacillus rhamnosus HN 001), bifidobacterium subsp. Longum Bb536 (Bifidobacterium longum subsp.longum Bb 536), lactobacillus acidophilus NCFM (Lactobacillus acidophilus NCFM) or a combination thereof.
In a preferred embodiment of the present invention, the concentration of the probiotic in the nutritional composition is 1×10 6 -1×10 14 CFU/100g, preferably 1X 10 8 -1×10 14 CFU/100g, more preferably 1X 10 10 -1×10 14 CFU/100g。
In a preferred embodiment of the present invention, the concentration of the breast milk oligosaccharide in the nutritional composition is from 10mg/100g to 10X 10 3 mg/100g, preferably 10X 10 1 ～10×10 3 mg/100g。
In a preferred embodiment of the present invention, the infants are a group of 0 to 3 years old, preferably a group of 0 to 12 months old, more preferably a group of 0 to 6 months old.
In a second aspect of the invention, a nutritional composition is provided, the nutritional composition comprising breast milk oligosaccharide and a probiotic; the breast milk oligosaccharide comprises at least one of sialylated oligosaccharide or fucosylated oligosaccharide or N-acetylated oligosaccharide; the probiotic is Bifidobacterium (Bifidobacterium), lactobacillus (Lactobacillus), or a combination thereof.
Advantageous effects
(1) The invention discovers that the combination of the breast milk oligosaccharide and the probiotics can obviously and synergistically relieve dysbacteriosis caused by early antibiotic exposure of infants, can effectively relieve the exhaustion (the reduction of abundance) of intestinal bacteria, can synergistically inhibit the increase of pathogenic bacteria and/or drug-resistant bacteria caused by early antibiotic exposure of infants, and also increases the abundance of the probiotics, thereby preventing the occurrence of various diseases.
(2) The invention aims at the pain point that the antibiotics are easy to be excessively used by infants, and the raw materials used by the invention are all nutritional raw materials which can be used by infants, so that the infant formula is more suitable for the conditions of real infants, and has wide application prospect.
Drawings
The accompanying drawings are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate the invention and together with the embodiments of the invention, serve to explain the invention. In the drawings:
FIG. 1 is a diagram showing the experimental design of 2' -FL, M16V, R0033, and R0071.
Fig. 2 is a graph showing changes in body weight of mice in the control group (Con), the model group (Abx), and the intervention group (HMObiotics).
Fig. 3 is a graph showing changes in colon length in mice from the blank (Con), model (Abx), and intervention (HMObiotics).
Fig. 4 is a graph of intestinal flora level ASV content in the blank (Con), model (Abx), intervention (HMObiotics).
Fig. 5 is a graph of the intestinal flora seed level bifidobacterium ASV content in the blank (Con), model (Abx), intervention (hmobics).
FIG. 6 is a schematic diagram of the experimental design of 2' -FL and R0052.
Fig. 7 is a graph showing changes in body weight of mice in the control group (Con), the model group (Abx), and the intervention group (HMObiotics).
Fig. 8 is a graph of intestinal flora gate level classification for the blank (Con), model (Abx), intervention (HMObiotics).
Fig. 9 is a graph of intestinal flora level classification for the control group (Con), model group (Abx), intervention group (HMObiotics).
FIG. 10 is a schematic diagram showing the experimental design of 2' -FL, M16V, R0033, R0071 and R0052.
Fig. 11 is a graph showing changes in body weight of mice in the control group (Con), the model group (Abx), and the intervention group (HMObiotics).
Fig. 12 is a graph showing changes in colon length in mice from the blank (Con), model (Abx), and intervention (HMObiotics).
Detailed Description
The following detailed description of the embodiments of the present invention is provided for better illustration of the present invention, but is not to be construed as limiting the invention. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise specified, all reagents involved in the examples of the present invention are commercially available products and are commercially available. The classification units of bacteria are divided into seven basic classification grades, which are sequentially from top to bottom: kingdom, phylum, class, order, family, genus, species.
Example 1
(1) Early antibiotic exposure experimental design for mice
The invention uses SPF-grade healthy gestation C57BL/6 mice, full AIN-93G feed supplementation, maintains the mice in a 12 hour light/dark cycle, and allows for ad libitum access to food and water. As shown in fig. 1, the mice were divided into nine study groups:
(1) blank control (Con), 10-21d mice were perfused with PBS;
(2) model group (Abx), 0-21d master mouse antibiotic drink, 10-21d mice lavage PBS;
(3) - (9) intervention group (hmobiots), 0-21d master mouse antibiotic drink;
2FL group: 2'-FL, 2' -FL gastric lavage treatment of 10-21d mice;
M16V group: M16V,10-21d mice M16V lavage treatment;
FM16V group: 2'-FL+M16V,10-21d mice 2' -FL+M16V lavage treatment;
r33 group: performing intragastric treatment on R0033 and 10-21d mice R0033;
FR33 group: 2'-FL+R0033, 2' -FL+R0033 intragastric treatment of 10-21d mice;
r71 group: intragastric treatment of R0071, 10-21d mice;
FR71 group: 2'-FL+R0071, 10-21d mice 2' -FL+R0071 were lavaged.
Wherein Abx (ampicillin trihydrate (1 g/L) +neomycin sulfate (0.5 g/L)) was dissolved in deionized water and refreshed every two days. 2' -FL (HMO) lavage concentration was 1000 mg/(kg. Bw), M16V, R0033 and R0071 lavage concentration was 1 x 10≡9CFU/d. Fresh feces were collected at postnatal weaning (day 21) and stored at-80 ℃ for later analysis.
(2) Analysis of results
Statistical analysis:
the analysis is carried out by adopting SPSS26.0 statistical software, the measurement is expressed by mean ± standard deviation, the comparison among multiple groups is carried out by adopting a single-factor analysis of variance method, the multiple pairwise comparison adopts an LSD-t method, and the difference of P <0.05 is statistically significant.
(a) Body weight change in mice as shown in fig. 2:
(1) model group (Abx) mice gain slowly in weight compared to the placebo group (Con), indicating that early antibiotic exposure may affect early host growth.
(2) The R33 intervention group had no significant effect on alleviating the slow weight gain caused by early antibiotic exposure.
(3) Compared with the model group (Abx), the weights of mice in the FM16V group, the FR33 group and the FR71 group all show a growing trend, which indicates that the combination of breast milk oligosaccharide and probiotics has a synergistic effect and has a relieving effect on the weight loss of mice caused by early antibiotic exposure.
(b) Colon length changes as shown in fig. 3:
(1) the model group (Abx) mice showed a significantly shorter colon length compared to the placebo group (Con), indicating that early antibiotic exposure may slow intestinal tissue development.
(2) Compared with the model group (Abx), the colon length of the mice in the FM16V group, the FR33 group and the FR71 group all show obvious increasing trend, which shows that the combination of breast milk oligosaccharide and probiotics has synergistic effect and has reducing effect on slow development of intestinal tissues of mice caused by early antibiotic exposure.
(c) Effects on intestinal flora were regulated, supplementing microbiota analysis by 16s rDNA V3-V4 region sequencing of mouse faeces:
from fig. 4, it is seen that higher abundance Morganella and Paenibacillus were found in the gut of early antibiotic exposure model group (Abx) mice. Among them, morganella belongs to gram-negative bacteria and proved to be a potential pathogenic bacterium for depression. Meanwhile, the results of the FM16V group, the FR33 group and the FR71 group in the figure 4 show that the combination of the breast milk oligosaccharide and the probiotics can inhibit the increase of pathogenic bacteria and/or drug-resistant bacteria at the same time of early antibiotic exposure.
Further from the species level (fig. 5) analysis, it was found that the co-intervention of M16V, R0033, R0071, respectively, in combination with 2' -FL, significantly promoted bifidobacteria enrichment. Wherein, FM16V group promotes Bifidobacterium_breve bacterial enrichment notably, FR33 group promotes Bifidobacterium_longum bacterial enrichment notably, FR71 group promotes Bifidobacterium_bifidum bacterial enrichment notably.
These results all indicate that early in life antibiotic exposure can bring about unbalanced pressure of intestinal flora, while intervening in the combination of breast milk oligosaccharides and probiotics while antibiotic exposure can alleviate intestinal bacterial depletion (reduced abundance) and inhibit pathogenic bacteria and/or increase of drug-resistant bacteria to varying degrees, thereby preventing the possibility of occurrence of various diseases.
Example 2
(1) Early antibiotic exposure experimental design for mice
The invention uses SPF-grade healthy gestation C57BL/6 mice, full AIN-93G feed supplementation, maintains the mice in a 12 hour light/dark cycle, and allows for ad libitum access to food and water. As shown in fig. 6, the mice were divided into five study groups:
(1) blank control (Con), 10-21d mice were perfused with PBS;
(2) model group (Abx), 0-21d master mouse antibiotic drink, 10-21d mice lavage PBS;
(3) - (5) intervention group (HMObootics), 0-21d master mouse antibiotic drink,
2FL group: 2'-FL, 2' -FL gastric lavage treatment of 10-21d mice;
r52 group: performing gastric lavage treatment on R0052, 10-21d mice;
FR52V group: 2'-FL+R0052, 10-21d mice 2' -FL+R0052 were subjected to intragastric treatment.
Wherein Abx (ampicillin trihydrate (1 g/L) +neomycin sulfate (0.5 g/L)) was dissolved in deionized water and refreshed every two days. 2' -FL (HMO) lavage concentration is 700 mg/(kg. Bw), R0052 lavage concentration is 1 x 10≡9CFU/d. Fresh feces were collected at postnatal weaning (day 21) and stored at-80 ℃ for later analysis.
(2) Analysis of results
Statistical analysis:
the analysis is carried out by adopting SPSS26.0 statistical software, the measurement is expressed by mean ± standard deviation, the comparison among multiple groups is carried out by adopting a single-factor analysis of variance method, the multiple pairwise comparison adopts an LSD-t method, and the difference of P <0.05 is statistically significant.
(a) Body weight change in mice as shown in fig. 7:
(1) model group (Abx) mice gain slowly in weight compared to the placebo group (Con), indicating that early antibiotic exposure may affect early host growth.
(2) The FR52 group mice showed a clear trend of increasing body weight compared to the model group (Abx), indicating that the combination of breast milk oligosaccharides and probiotics has a synergistic effect and a remission of weight loss in mice caused by early antibiotic exposure.
(b) Effects on intestinal flora were regulated, supplementing microbiota analysis by 16s rDNA V3-V4 region sequencing of mouse faeces:
from figures 8, 9, combined with the classification level of each species, higher abundance of Paenibacillus was found in the early antibiotic exposure model group (Abx) mouse gut, which has been shown to be a super-resistant bacterium with the risk of becoming a pathogen. The relative abundance of Paenibacillus in the 2FL intervention group was significantly reduced suggesting that we 2' -FL might inhibit the growth of drug-resistant bacteria by stimulating other bacteria growth to compete with Paenibacillus, thereby reducing antibiotic exposure risk, and reducing escherichia coli colonization. Analysis of the FR52V intervention group found that the super-resistant bacteria Paenibacillus had not been present in the mouse gut, suggesting that 2' -fl+r0052 intervention could significantly suppress pathogenic and/or drug-resistant bacteria while also significantly increasing beneficial bacterial abundance, including Turicibacter, ruminococcus, oscillospira, lactobacillus, clostridium, lachnospiraceae, etc., which proved to be positively correlated with gut beneficial metabolites and host health. And an enrichment of bifidobacterium animalis was found in the FR52V intervention group, which may be related to simultaneous supplementation with 2' -FL.
These results all indicate that early in life antibiotic exposure brings about unbalanced stress in the intestinal flora, and that 2' -FL single dry prognosis can significantly inhibit the growth of drug-resistant bacteria. Due to the influence of antibiotics, 2' -FL has no bacteria that can utilize it as a fermentation substrate during colonic fermentation. Therefore, the probiotic Lactobacillus helveticus R0052 which can decompose and utilize the 2'-FL is further added while the antibiotics are exposed, and the combination of the 2' -FL and the R0052 is found to relieve the exhaustion (the reduction of the abundance) of intestinal bacteria and inhibit the increase of pathogenic bacteria and/or drug-resistant bacteria, and also increase the abundance of the probiotic, thereby preventing the occurrence of various diseases.
EXAMPLE 3 modification of the probiotic gastric lavage concentration
(1) Early antibiotic exposure experimental design for mice
The invention uses SPF-grade healthy gestation C57BL/6 mice, full AIN-93G feed supplementation, maintains the mice in a 12 hour light/dark cycle, and allows for ad libitum access to food and water. As shown in fig. 10, the mice were divided into eleven study groups:
(1) blank control (Con), 10-21d mice were perfused with PBS;
(2) model group (Abx), 0-21d master mouse antibiotic drink, 10-21d mice lavage PBS;
③-intervention group (hmobiots), 0-21d master mouse antibiotic drink;
2FL group: 2'-FL, 2' -FL gastric lavage treatment of 10-21d mice;
M16V group: M16V,10-21d mice M16V lavage treatment;
FM16V group: 2'-FL+M16V,10-21d mice 2' -FL+M16V lavage treatment;
r33 group: performing intragastric treatment on R0033 and 10-21d mice R0033;
FR33 group: 2'-FL+R0033, 2' -FL+R0033 intragastric treatment of 10-21d mice;
r71 group: intragastric treatment of R0071, 10-21d mice;
FR71 group: 2'-FL+R0071, 10-21d mice 2' -FL+R0071 were lavaged.
R52 group: performing gastric lavage treatment on R0052, 10-21d mice;
FR52V group: 2'-FL+R0052, 10-21d mice 2' -FL+R0052 were subjected to intragastric treatment.
Wherein Abx (ampicillin trihydrate (1 g/L) +neomycin sulfate (0.5 g/L)) was dissolved in deionized water and refreshed every two days. 2' -FL (HMO) lavage concentration was 700 mg/(kg.bw), M16V, R0033, R0071 and R0052 lavage concentrations were 1X 10≡8CFU/d.
(2) Analysis of results
Statistical analysis:
the analysis is carried out by adopting SPSS26.0 statistical software, the measurement is expressed by mean ± standard deviation, the comparison among multiple groups is carried out by adopting a single-factor analysis of variance method, the multiple pairwise comparison adopts an LSD-t method, and the difference of P <0.05 is statistically significant.
(a) Weight change in mice, as shown in FIG. 11, was further found using 1 x 10≡8CFU/d of bacterial concentration intervention:
(1) model group (Abx) mice gain slowly in weight compared to the placebo group (Con), indicating that early antibiotic exposure may affect early host growth.
(2) Compared with the model group (Abx), the weights of mice in the FM16V group, the FR33 group, the FR71 group and the FR52V group all show an increasing trend, which indicates that the combination of breast milk oligosaccharide and probiotics has a synergistic effect, has a relieving effect on the weight loss of mice caused by early antibiotic exposure, and has a certain host protecting effect.
(b) Colon length changes, as shown in FIG. 12, were further found using 1 x 10≡8CFU/d of bacterial concentration intervention:
(1) the model group (Abx) mice showed a significantly shorter colon length compared to the placebo group (Con), indicating that early antibiotic exposure may slow intestinal tissue development.
(2) Compared with the model group (Abx), the colon length of the mice in the FM16V group, the FR33 group, the FR71 group and the FR52V group all show obvious increasing trend, which shows that the combination of breast milk oligosaccharide and probiotics has synergistic effect and has reducing effect on slow intestinal tissue development of the mice caused by early antibiotic exposure.
It is apparent that the above examples are only illustrative of the present invention and are not limiting of the embodiments of the present invention. Various modifications and alterations of this invention may be made by those skilled in the art without departing from the spirit and scope of this invention. Thus, it is intended that the present invention also include such modifications and alterations insofar as they come within the scope of the appended claims or the equivalents thereof.
Claims (10)
1. Use of a nutritional composition, characterized in that the nutritional composition is for:
(a) Alleviating dysbacteriosis caused by early antibiotic exposure of infants; and/or
(b) Inhibiting pathogenic bacteria and/or drug-resistant bacteria from increasing caused by early antibiotic exposure of infants;
wherein the nutritional composition comprises breast milk oligosaccharides and probiotics.
2. The use according to claim 1, wherein the breast milk oligosaccharide comprises at least one of sialylated or fucosylated or N-acetylated oligosaccharides.
3. The use according to claim 1, characterized in that the fucosylated oligosaccharide is 2 '-fucosyllactose (2' -FL).
4. The use according to claim 1, wherein the probiotic is Bifidobacterium (bifidobacteria), lactobacillus (Lactobacillus), or a combination thereof.
5. Use according to claim 1, characterized in that the probiotics are bifidobacterium animalis subspecies lactis or bifidobacterium animalis Bb-12 (Bifidobacterium animalis subsp.lacts or Bifidobacterium animalis Bb-12), bifidobacterium longum subsp. Infantis or bifidobacterium infantis R0033 (Bifidobacterium longum subsp.infantis or Bifidobacterium infantis R0033), bifidobacterium bifidum R0071 (Bifidobacterium bifidum R0071), bifidobacterium animalis subsp. Lactis or bifidobacterium lactis HN019 and Bi-07 (Bifidobacterium animalis subsp.lactis or Lactobacillus lactis HN019, bifidobacterium animalis subsp.lactis or Lactobacillus lactis Bi-07), bifidobacterium breve M16V (Bifidobacterium breve M V), lactobacillus helveticus R0052 (Lactobacillus helveticus R0052), lactobacillus rhamnosus LGG or GG (Lactobacillus rhamnosus LGG or GG, lactobacillus rhamnosus HN 001), bifidobacterium subsp. Longum Bb536 (Bifidobacterium longum subsp.longum Bb 536), lactobacillus acidophilus NCFM (Lactobacillus acidophilus NCFM) or a combination thereof.
6. Use according to claim 1, characterized in that the concentration of probiotics in the nutritional composition is 1 x 10 6 -1×10 14 CFU/100g, preferably 1X 10 8 -1×10 14 CFU/100g, more preferably 1X 10 10 -1×
10 14 CFU/100g。
7. The use according to claim 1, characterized in that the concentration of breast milk oligosaccharide in the nutritional composition is 10mg/100g to 10 x 10 3 mg/100g, preferably 10X 10 1 ～10×10 3 mg/100g。
8. A nutritional composition, characterized in that the nutritional composition comprises breast milk oligosaccharides and probiotics; the breast milk oligosaccharide comprises at least one of sialylated oligosaccharide or fucosylated oligosaccharide or N-acetylated oligosaccharide; the probiotic is Bifidobacterium (Bifidobacterium), lactobacillus (Lactobacillus), or a combination thereof.
9. The nutritional composition according to claim 8, the probiotics being bifidobacterium animalis subspecies lactis or bifidobacterium animalis Bb-12 (Bifidobacterium animalis subsp.lacts or Bifidobacterium animalis Bb-12), bifidobacterium longum subsp. Infantis or bifidobacterium infantis R0033 (Bifidobacterium longum subsp.infantis or Bifidobacterium infantis R0033), bifidobacterium bifidus R0071 (Bifidobacterium bifidum R0071), bifidobacterium animalis subsp. Lactis or bifidobacterium lactis HN019 and Bi-07 (Bifidobacterium animalis subsp.lactis or Lactobacillus lactis HN019, bifidobacterium animalis subsp.lactis or Lactobacillus lactis Bi-07), bifidobacterium breve M16V (Bifidobacterium breve M V), lactobacillus helveticus R0052 (Lactobacillus helveticus R0052), lactobacillus rhamnosus g or GG (Lactobacillus rhamnosus LGG or GG, lactobacillus rhamnosus HN 001), bifidobacterium longum subsp. Bb536 (Bifidobacterium longum subsp.longum Bb 536), lactobacillus acidophilus NCFM (Lactobacillus acidophilus NCFM) or a combination thereof.
10. The nutritional composition according to claim 8, characterized in that the concentration of probiotics in the nutritional composition is 1 x 10 6 -1×10 14 CFU/100g, preferably 1X 10 8 -1×10 14 CFU/100g, more preferably 1X 10 10 -1×10 14 CFU/100g; the concentration of the breast milk oligosaccharide is 10mg/100 g-10 multiplied by 10 3 mg/100g, preferably 10X 10 1 ～10×10 3 mg/100g。
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117337992A (en) * | 2023-09-22 | 2024-01-05 | 合生元（广州）健康产品有限公司 | Probiotic prebiotic composition and application thereof |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120294840A1 (en) * | 2011-05-13 | 2012-11-22 | Glycosyn LLC. Trustees of Boston College | Use Of Purified 2'-Fucosyllactose, 3-Fucosyllactose and Lactodifucotetraose as Prebiotics |
| CN112075637A (en) * | 2020-04-27 | 2020-12-15 | 合生元（广州）健康产品有限公司 | Composition for reducing intestinal gas generation |
| CN113796545A (en) * | 2021-09-13 | 2021-12-17 | 合生元（广州）健康产品有限公司 | Breast milk oligosaccharide composition for regulating intestinal immunity function and application thereof |
| WO2022100758A1 (en) * | 2020-11-16 | 2022-05-19 | 内蒙古伊利实业集团股份有限公司 | Composition containing bifidobacterium lactis and human milk oligosaccharides and application thereof |
| CN114568516A (en) * | 2020-11-30 | 2022-06-03 | 内蒙古伊利实业集团股份有限公司 | Composition containing bifidobacterium longum subsp. infantis and breast milk oligosaccharide and application thereof |
| WO2022161865A1 (en) * | 2021-01-29 | 2022-08-04 | Societe Des Produits Nestle S.A. | Mixture of hmos and bifidobacteria |
| CN115868632A (en) * | 2022-11-29 | 2023-03-31 | 黑龙江飞鹤乳业有限公司 | Nutritional composition containing breast milk oligosaccharide and probiotics, food and application |
-
2023
- 2023-04-21 CN CN202310432108.7A patent/CN116439377A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120294840A1 (en) * | 2011-05-13 | 2012-11-22 | Glycosyn LLC. Trustees of Boston College | Use Of Purified 2'-Fucosyllactose, 3-Fucosyllactose and Lactodifucotetraose as Prebiotics |
| CN112075637A (en) * | 2020-04-27 | 2020-12-15 | 合生元（广州）健康产品有限公司 | Composition for reducing intestinal gas generation |
| WO2022100758A1 (en) * | 2020-11-16 | 2022-05-19 | 内蒙古伊利实业集团股份有限公司 | Composition containing bifidobacterium lactis and human milk oligosaccharides and application thereof |
| CN114568516A (en) * | 2020-11-30 | 2022-06-03 | 内蒙古伊利实业集团股份有限公司 | Composition containing bifidobacterium longum subsp. infantis and breast milk oligosaccharide and application thereof |
| WO2022161865A1 (en) * | 2021-01-29 | 2022-08-04 | Societe Des Produits Nestle S.A. | Mixture of hmos and bifidobacteria |
| CN113796545A (en) * | 2021-09-13 | 2021-12-17 | 合生元（广州）健康产品有限公司 | Breast milk oligosaccharide composition for regulating intestinal immunity function and application thereof |
| CN115868632A (en) * | 2022-11-29 | 2023-03-31 | 黑龙江飞鹤乳业有限公司 | Nutritional composition containing breast milk oligosaccharide and probiotics, food and application |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117337992A (en) * | 2023-09-22 | 2024-01-05 | 合生元（广州）健康产品有限公司 | Probiotic prebiotic composition and application thereof |
| CN117337992B (en) * | 2023-09-22 | 2024-05-17 | 合生元（广州）健康产品有限公司 | Probiotic prebiotic composition and application thereof |
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