CN115989874B - Protein composition for improving intestinal barrier health and application thereof - Google Patents
Protein composition for improving intestinal barrier health and application thereof Download PDFInfo
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- CN115989874B CN115989874B CN202211088823.5A CN202211088823A CN115989874B CN 115989874 B CN115989874 B CN 115989874B CN 202211088823 A CN202211088823 A CN 202211088823A CN 115989874 B CN115989874 B CN 115989874B
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Classifications
-
- 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
-
- 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
- A23C9/16—Agglomerating or granulating milk powder; Making instant milk powder; Products obtained thereby
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23J—PROTEIN COMPOSITIONS FOR FOODSTUFFS; WORKING-UP PROTEINS FOR FOODSTUFFS; PHOSPHATIDE COMPOSITIONS FOR FOODSTUFFS
- A23J3/00—Working-up of proteins for foodstuffs
- A23J3/04—Animal proteins
- A23J3/08—Dairy proteins
-
- 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
- A23L33/17—Amino acids, peptides or proteins
-
- 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
- A23L33/17—Amino acids, peptides or proteins
- A23L33/19—Dairy proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/40—Transferrins, e.g. lactoferrins, ovotransferrins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- 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
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Zoology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nutrition Science (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Mycology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Biochemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses a protein composition for improving intestinal barrier health and application thereof, wherein the protein composition comprises osteopontin and lactoferrin; the composition has the technical effects of rapidly repairing intestinal barrier, improving intestinal barrier permeability under bad external stimulus, or using the protein composition to provide epithelial barrier protection when the intestinal tract is affected by inflammation, and/or reducing the expression level of inflammatory factors to reduce intestinal inflammation, or using the protein composition to regulate the beneficial expression amount of the tight junction protein in the intestinal barrier.
Description
Technical Field
The invention relates to the field of biological products, in particular to a protein composition for improving intestinal barrier health and application thereof.
Background
Osteopontin (OPN) is a biologically active protein in breast milk, which contains higher levels of OPN but whose concentration decreases with the progression of lactation, and this dynamic change suggests that OPN may provide critical protection in early infant development, especially in the establishment of the early immune system. It has been found that the addition of OPN in milk isolated and purified from milk in infant formulas has better tolerability and that OPN fortified formulas significantly reduce the incidence of illness in infants and make the immune cell composition ratio closer to that of breast fed infants than ordinary formulas. A plurality of animal experiments show that OPN can provide immune protection for early intestinal development by stimulating the growth of small intestinal villi, reducing inflammatory reaction of intestinal tracts and the like. In addition, it is reported in the literature that most of OPN is absorbed in the small intestine after oral ingestion. However, most of the related researches on OPN digestion and metabolic processes are animal experiments at present, in vitro digestion simulation based on physiological characteristics of infants is not seen, and the protection effect on intestinal epithelial cells and the action mechanism thereof are still very little known.
OPN is highest in breast milk, and the biological activity of the OPN plays a main role in early life, but most of the prior art is based on in vitro simulation of adult physiological states or exploration of OPN digestion characteristics through animal experiments, and the methods have larger differences from the real in-vivo environment of infants in aspects of in-vivo pH, digestive enzyme activity, bile salt concentration and the like. According to the prior art, OPN is reported to mainly play an immune function in an infant body and is mainly absorbed in small intestine, but the infant immune system is immature, the intestinal barrier is imperfect, gaps exist among small intestine epithelial cells, the permeability is high, and the like, so that various intestinal diseases such as intestinal leakage diseases (the components such as proteins, toxins, microorganisms and the like which are not completely digested in the intestinal tract, and the like, are caused by leak in the intestinal wall) are easily caused to enter the body through leak holes, and inflammation and immune response are caused. Therefore, improving and repairing intestinal wall barrier function is very important for infants. However, the prior art only explores which active fragments remain after the digestion of OPN, whether the intestinal proliferation and differentiation can be promoted, explores the nutritional effect of OPN, and focuses on the protection of the small intestinal barrier and the improvement of the intestinal immune function with less mention. In addition, there is little research on what kind of repair action OPN has on small intestine barrier destruction caused by external inflammatory stimuli under different administration conditions and in combination with other active proteins.
Disclosure of Invention
In order to overcome the deficiencies of the prior art, the present invention provides a protein composition useful for improving intestinal barrier health and uses thereof. Specifically, the invention provides the following technical scheme:
in a first aspect of the invention, a protein composition for improving intestinal barrier health is provided, the protein composition comprising osteopontin.
In a preferred embodiment, the protein composition further comprises lactoferrin, wherein the mass ratio of osteopontin to lactoferrin is 1 (0.6-1.8).
In a preferred embodiment, the ratio of the mass of osteopontin to lactoferrin is 1 (1.2-1.8).
In one embodiment, the osteopontin is present in the composition in an amount of 30-300mg/100g of composition.
In one embodiment, the protein composition is a nutritional supplement, a formula, and/or a complementary food.
In a second aspect of the invention there is provided the use of osteopontin and lactoferrin together for the preparation of a composition for repairing the intestinal barrier.
In one embodiment, the improving intestinal barrier health means:
(a) Improving intestinal barrier permeability under adverse external stimuli;
(b) Providing epithelial barrier protection when the gut is affected by inflammation, and/or reducing inflammatory factor expression levels to reduce gut inflammation;
(c) Regulating and controlling the beneficial expression amount of the tight junction protein in the intestinal barrier;
(d) Promoting the intestinal barrier maturation of infants.
In one embodiment, the beneficial tight junction protein comprises at least one of Occludin and ZO-2.
Compared with the prior art, the invention has the following outstanding characteristics and remarkable progress：
(1) The method determines the digestion characteristics of OPN in the stomach and intestine stages based on the infant static gastrointestinal model, is more fit with the real infant internal environment, and is more fit with the market audience group of OPN;
(2) The invention constructs a small intestine epithelial cell model by Caco-2/HT-29 co-cultured cells, which accords with the characteristic that OPN is mainly digested and absorbed in small intestine;
(3) The invention researches the treatment potential of the gastrointestinal digestive products of OPN and LF composition on the damage of intestinal barrier caused by chronic inflammation, which accords with the main functions: the main biological activity of immunity, and the research content mainly aims at the pain point that the infants are easy to produce inflammatory intestinal discomfort;
(4) In addition to validating the anti-inflammatory effect of OPN and LF compositions, the present invention predicts other bioactive functions, such as having potential as ACE inhibitors, antioxidant, dipeptidyl peptidase inhibitors, immunomodulating, alpha-glucosidase inhibitors, regulatory peptides, vasoactive substance stimulating peptides, anti-amnestic peptides, antithrombotic peptides, neuropeptides and renin inhibiting peptides.
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 shows the toxic effects of osteopontin, lactoferrin and protein compositions on cells at various conditions of administration after 24h exposure;
FIG. 2 is an analysis of the protective effect of protein digests on inflammatory bowel epithelial cells;
FIG. 3 effects of different conditions of administration of osteopontin, lactoferrin, and protein compositions on IL-8 protein secretion under inflammatory factor stimulation;
FIG. 4 effects of different conditions of administration of osteopontin, lactoferrin, and protein compositions on the relative expression levels of IL-8 gene under inflammatory factor stimulation;
FIG. 5 effect of different application conditions of osteopontin, lactoferrin and protein composition on ZO-2 gene relative expression levels under inflammatory factor stimulation (6 h);
FIG. 6 effect of different application conditions of osteopontin, lactoferrin and protein composition on ZO-2 gene relative expression levels under inflammatory factor stimulation (12 h);
FIG. 7 effect of different application conditions of osteopontin, lactoferrin and protein composition on ZO-2 gene relative expression levels under inflammatory factor stimulation (18 h);
FIG. 8 effect of different application conditions of osteopontin, lactoferrin and protein composition on ZO-2 gene relative expression levels under inflammatory factor stimulation (24 h);
FIG. 9 effect of different application conditions under inflammatory factor stimulation on the relative expression level of Occludin gene (6 h) by osteopontin, lactoferrin and protein composition;
FIG. 10 effect of different application conditions under inflammatory factor stimulation on the relative expression level of Occludin gene (12 h) by osteopontin, lactoferrin and protein composition;
FIG. 11 effect of different application conditions under inflammatory factor stimulation on the relative expression level of Occludin gene (18 h) by osteopontin, lactoferrin and protein composition;
FIG. 12 effect of different administration conditions of osteopontin, lactoferrin and protein composition on the relative expression level of Occludin gene under inflammatory factor stimulation (24 h).
Detailed Description
The preferred embodiments of the present invention will be described below with reference to the accompanying drawings, it being understood that the preferred embodiments described herein are for illustration and explanation of the present invention only, and are not intended to limit the present invention.
Example 1 in vitro digestion study based on infant static gastrointestinal model
Since proteins are difficult to resist hydrolysis by digestive enzymes, prior to assessing the effect on improving intestinal barrier health, in vitro gastrointestinal digestion of protein samples is required to prepare digestive fluids, and the ion concentration, pH, digestive enzymes and their enzymatic activities of the present digestive system have been adjusted to be as close as possible to physiological conditions of term infants.
Commercial OPN and LF were supplied by Arla Foods Ingredients (denmark) and Warrnambool Cheese and Butter Factory (australia), respectively, with protein contents of 78% and 95% (w/w), respectively, as determined by the kjeldahl method, and nitrogen conversion coefficients of 6.38.
First, the above-mentioned osteopontin and lactoferrin (OPN and LF) were mixed with water (so that the final concentration of OPN and LF in the digestive juice was 2000 mg/L), and then simulated gastric juice (reference (A first step towards a consensus static in vitro model for simulating full-term infant digestion) was added for preparation, which was prepared with ultrapure water, in which the NaCl concentration was 94mM and the KCl concentration was 13 mM). The pH of the digested chyme was adjusted to 5.3 with 0.05M HCl and then diluted porcine pepsin (ex sigma) in simulated gastric fluid was added to bring the whole system to 268U/mL enzyme activity, and the mixture was gently shaken at 37℃for 1 hour. In the second stage, chyme was adjusted to pH 6.6 with 0.5M hydrochloric acid, followed by addition of simulated intestinal fluid (prepared with ultrapure water (A first step towards a consensus static in vitro model for simulating full-term infant digestion) in which NaCl concentration was 164mM, KCl concentration was 10mM, and NaHCO3 concentration was 85 mM), and pH was adjusted to 6.6. Porcine pancreatin (ex sigma) was then added to bring the trypsin activity in the system to 16U/mL. Adding bile salt (purchased from source leaves) and CaCl 2 And water (bile salt was added to bring the whole digestive system concentration to 3.1mM; caCl2 was added to bring the whole digestive system concentration to 0.1 mM), and finally the digested chyme was gently digested with shaking at 37℃for 1 hour. Immediately after incubation was completed, the samples were heated to 95 ℃ for 5 minutes to give products of OPN and LF after gastrointestinal digestion, which were stored at-80 ℃ for subsequent analysis.
1. NanoLC-MS/MS analysis, database search and bioactivity analysis of digestive juice
For 2 protein gastrointestinal digests, 2. Mu.L total peptide was isolated from each sample by nano-UPLC liquid phase system EASY-nLC 1200. The data acquisition was performed using a mass spectrometer equipped with a nanoliter ion source. The chromatographic separation was carried out using a 100 μm ID. Times.15 cm reverse phase chromatography column. The mobile phase adopts an acetonitrile-water-formic acid system, wherein the mobile phase A is 0.1% formic acid-98% water solution (acetonitrile is 2%), and the mobile phase B is 0.1% formic acid-80% acetonitrile solution (water is 20%). After the chromatographic column is balanced by 100% of phase A, a sample is directly loaded to the chromatographic column by an automatic sampler, and then is subjected to gradient separation by the chromatographic column, wherein the flow rate is 300nL/min, and the gradient time is 60min. Mobile phase B ratio: 2-5% for 2min,5-22% for 34min,22-45% for 20min,45-95% for 2min,95% for 2min. The mass spectrometry uses a data-dependent acquisition mode, the total analysis time is 60min, and a positive ion detection mode is adopted. The primary scanning range is 350-1600m/z, the resolution is 120k, the AGC is 1E6, and the maximum ion implantation time is 50ms; the 20 ions with highest intensity in the primary scan were screened by quadrupole rods and then split using HCD for fragment ion scanning. The quadrupole isolation window was 1.2m/z, the normalized collision energy was 30%, the AGC was 1E5, and the max IT was 100ms. The secondary scan resolution 15k. According to the peak width of the chromatographic peak, the dynamic exclusion time is set to be 30s; the singly charged and >6 valent ions do not undergo secondary scanning.
The raw data file was subjected to library search analysis using Proteome Discoverer software and a built-in sequence HT search engine. Using the AIPpred platform, the AllergenFP platform and the Toxinpred platform, the identified polypeptide sequences were entered to predict the anti-inflammatory potential, sensitization and potential toxicity of the bioactive peptides. The potential of the identified peptide fragments as a source of bioactive peptides was predicted using on-line data of the BIOPEP-UWM protein and bioactive peptide sequences.
2. Experimental results:
(1) Peptides with multiple biological activities are released after digestion of proteins
The bioactive peptides released after digestion are shown in table 1 below:
TABLE 1 analysis of bioactive peptide data after digestion
After the end of gastrointestinal digestion, OPN and LF were separated by nano-UPLC liquid phase system, and the data in Table 1 shows that 8 polypeptides were identified by osteopontin digest and 2 polypeptides were identified by lactoferrin digest. In addition, the osteopontin and lactoferrin polypeptide have low possibility of allergy, no potential toxicity and high safety. Except NSVSSEETDDN and RSNVQSPDATEED, all polypeptides have anti-inflammatory effects, suggesting that osteopontin and lactoferrin have broad host immune response modulating activity, and that the inhibition of inflammation by the composition may be better.
In addition, as can be seen from the above table, the polypeptides released by the OPN after gastrointestinal digestion have a wide spectrum of biological functions such as ACE inhibitors, antioxidant, dipeptidyl peptidase inhibitors, α -glucosidase inhibitors, regulatory peptides and vasoactive substance stimulating peptides, in addition to a broad spectrum of anti-inflammatory effects. In addition to anti-inflammatory effects, the polypeptides released after gastrointestinal digestion of LF may have potential as ACE inhibitors, α -glucosidase inhibitors, anti-amnestic peptides, antithrombotic peptides, regulatory peptides, neuropeptides, dipeptidyl peptidase inhibitors and renin inhibitory peptides. So it is speculated that OPN and LF have a strong anti-inflammatory effect and have a variety of bioactive functions after gastrointestinal digestion, and that both may have synergistically enhanced effects in combating intestinal inflammation and the like.
Example 2 cell experiment
1. Construction of small intestine epithelial cell model
This example was performed using human colon cancer cell lines Caco-2 and HT-29 (available from Heteropoly Biotech Co., ltd. Beijing, cell line Caco-2: ATCC HTB37; cell line HT-29: ATCC HTB 38), and the culture environment was given to the cells for the desired nutrients and suitable growth:
culture medium: RPMI1640 basal medium+10% fetal bovine serum+1% neaa and 1% penicillin/streptomycin;
culture conditions: constant temperature and humidity incubator (37 ℃,5% co 2).
70% Caco-2 and 30% HT-29 cells were seeded in transwell plates and co-cultured for 14 days to construct a cell model with characteristics similar to human small intestine and to simulate the destruction of the intestinal barrier by adverse external stimuli by intervention of differentiated co-cultured cells with the addition of pro-inflammatory factor mixture (TNF-. Alpha. + IL-. 1β. + IFNγ).
2. Construction of inflammatory intestinal cell model
The differentiated co-cultured cells were subjected to intervention for 24 hours with the addition of a mixture of pro-inflammatory factors (50 ng/mL TNF-. Alpha. +25ng/mL IL-1β+50ng/mL IFN-. Gamma.) to simulate chronic intestinal barrier dysfunction associated with chronic inflammation, and cells without any treatment were used as negative controls, and the integrity of the co-cultured cell monolayers was assessed by measuring transepithelial resistance (TEER) values using an EVOM epithelial voltage/ohm meter.
3. Protein digestive juice toxicity detection
Because protein digests may exert toxic inhibition effects on cells under certain administration conditions, their beneficial effects are limited. Therefore, firstly, the CCK8 kit is used for detecting the cell viability, and the bone bridge protein and the protein composition thereof under different application conditions (32.5 mg/L,65mg/L, 130mg/L, 200mg/L, 270mg/L, 400mg/L OPN,65mg/L, 130mg/L LF, OP N: LF=1:0.6, OPN: LF=1:1.2, OPN: LF=1:1.5, OPN: LF=1:1.8, and the OPN application conditions in the latter five groups are all 65 mg/L) are evaluated to have adverse effects on the intestinal cell viability.
4. Protection of inflammatory intestinal epithelial cells by protein digests
TEER values are sensitive indicators reflecting the integrity of the intestinal barrier and can be used to monitor dynamic changes in paracellular permeability. The digests of proteins or protein compositions were co-cultured with inflammatory factor-stimulated cells at a concentration for 24 hours, after which the TEER value was measured and the cell culture supernatant was collected, centrifuged for 10 minutes (600×g,4 ℃) and the supernatant was analyzed for the concentration of inflammatory factor IL-8 according to the ELISA kit manufacturer's method.
Furthermore, tight junctions are one of the important components of the intestinal barrier, and their damage can lead to significant increases in the incidence of Inflammatory Bowel Disease (IBD), necrotizing Enterocolitis (NEC), and the like. Thus, RNA was also obtained by lysing the cells in this example, and the amount of mRNA expressed by cytokines, tight junctions (detected at 6, 12, 18, 24h, respectively) was measured by RT-qPCR, and each experimental group was repeated 3 times.
5. Results
(1) Successful construction of inflammatory bowel model
The TEER value of the normal small intestine epithelial cell model which is not treated is 100%, and after the co-cultured cells are respectively interfered for 24 hours by using low-concentration and high-concentration cytokines, the transepithelial resistance value of the cells can be obviously reduced, which indicates that the inflammatory intestinal model is successfully built.
(2) Cytotoxicity of protein digests at different concentrations
The activity of >80% can be considered nontoxic to cells, and as shown in figure 1, the osteopontin, lactoferrin and protein composition have no cytotoxicity under different application conditions after 24 hours of exposure, i.e. have no adverse effect on the vitality of intestinal cells.
(3) Protection of inflammatory intestinal epithelial cells by protein digests
As shown in fig. 2, untreated monolayer film bypass remained at normal levels. However, the inflammatory cytokine stimulated co-cultured cells have a significant 31.6% decrease in TEER value, indicating an abnormally elevated paracellular permeability of the intestinal epithelium and a disruption in integrity. However, the TEER values were significantly increased for all experimental groups when incubated for 24 hours with digests of OPN, LF and opn+lf compositions, indicating that OPN, LF and opn+lf compositions were effective in restoring intestinal barrier permeability and protecting intestinal barrier integrity. And further, the effect of the protein composition is more remarkable when the application ratio is 1:1.2-1.8.
Effects of inflammatory factor secretion and Gene expression: inflammatory mediators such as IL-8 are produced when the intestine is poorly stimulated from the outside, but over-expression of inflammatory mediators destroys the intestinal barrier function, and IL-8 is known to be a major target for the treatment of intestinal inflammation. As shown in fig. 3-4, stimulation of cytokines resulted in significant increases in protein secretion levels and gene expression levels of co-cultured cell IL-8 compared to the control group. When OPN is administered at lower doses (32.5-200 mg/L), the level of inflammatory mediators is significantly inhibited at both the protein and gene levels (p < 0.05), and further this effect is more pronounced at an administration concentration of 130mg/L, but at the same time OPN at higher administration conditions (> 200 mg/L) may lead to a loss of inhibition of IL-8 levels, which can be explained by the intestinal self-protection mechanism. Furthermore, from the standpoint of IL-8 secretion, the anti-inflammatory effect of OPN and LF compositions is superior to that of OPN and LF single action, and the level of inflammatory mediators (p < 0.05) is significantly suppressed at both the protein and gene level after administration of the osteopontin and lactoferrin compositions under different conditions, and further, this effect is more prominent at an administration ratio of 1:1 to 1:1.2.
Effects of tight junction protein gene expression: the increase in intercellular permeability is generally due to the low expression of the tight junction proteins. After the pro-inflammatory cytokines stimulate the co-cultured cells, the expression of ZO-2 and Occludin protein genes can be obviously reduced, so that the permeability among intestinal cells is increased, the co-cultured cells show leakage of intestinal connection, and the damage of intestinal barrier is aggravated. After OPN administration under different conditions, the gene expression levels of ZO-2, occludin were increased in concentration-dependent manner (P < 0.05), enhancing intestinal barrier structure. Wherein the administration effect at 130-200mg/L is better, and there is a dose effect of a certain extent of such effect. In addition, when the intervention concentration of the protein digestive juice is consistent, the LF can also improve the expression quantity of the tight junction proteins ZO-2 and Occlutin, and the intestinal barrier structure is enhanced, similar to the OPN effect. Meanwhile, the results show that after the composition of the osteopontin and the lactoferrin under different conditions is applied, the gene expression levels of the Occludin and the ZO-2 are enhanced, and the strength of the intestinal barrier is improved. And further, this effect is more pronounced at an administration ratio of 1:1-1.8, i.e. has a synergistic effect of repairing the intestinal barrier relative to the OPN or LF alone. Furthermore, the applicant has unexpectedly found that when OPN and LF are used in combination as a composition, the expression levels of several tight junctions due to inflammation can be rapidly increased, and that the expression levels of both tight junctions secreted by cells of the OPN and LF composition groups are near peak at 12 hours, whereas the other groups are near peak at 18 hours (fig. 5-12), so enhancement of intestinal barrier strength, repair of intestinal barrier can be most rapidly achieved with OPN and LF compositions.
It will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the spirit or scope of the 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 (4)
1. Use of osteopontin and lactoferrin as active ingredients together for the preparation of a composition for improving intestinal barrier health, characterized in that the improving intestinal barrier health is:
(a) Improving intestinal barrier permeability under adverse external stimuli;
(b) Regulating and controlling the beneficial expression amount of the tight junction protein in the intestinal barrier;
wherein the mass ratio of the osteopontin to the lactoferrin is 1 (0.6-1.8).
2. The use according to claim 1, wherein the osteopontin is present in the composition in an amount of 30-300mg/100g of composition.
3. The use of claim 1, wherein the beneficial tight junction protein comprises at least one of Occludin and ZO-2.
4. The use according to any one of claims 1 to 3, wherein the composition is a nutritional supplement, a formula or a complementary food.
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| CN113575686A (en) * | 2020-09-21 | 2021-11-02 | 黑龙江飞鹤乳业有限公司 | Nutrient component for improving immunity, food or health product containing nutrient component and application of nutrient component |
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| CN113575686A (en) * | 2020-09-21 | 2021-11-02 | 黑龙江飞鹤乳业有限公司 | Nutrient component for improving immunity, food or health product containing nutrient component and application of nutrient component |
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