CN115590865B - Application of brown alginate oligosaccharides in preparation of product for improving intestinal flora disorder - Google Patents
Application of brown alginate oligosaccharides in preparation of product for improving intestinal flora disorder Download PDFInfo
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/734—Alginic acid
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- 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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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pain & Pain Management (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medical application, and particularly relates to application of brown alginate oligosaccharides in preparation of a product for improving intestinal flora disorder. Among them, mannuronic acid oligosaccharides and guluronic acid oligosaccharides are capable of up-regulating short chain fatty acid production or anti-inflammatory related beneficial bacteria in the cecum to different degrees, down-regulating the relative abundance of harmful bacteria that can cause inflammatory reaction or destroy intestinal barrier, effectively improving and regulating intestinal flora, and thus improving other diseases caused by unbalance of intestinal flora, especially hyperuricemia. The invention provides application of mannuronic acid oligosaccharide and guluronic acid oligosaccharide in improving intestinal flora disorder, and lays a foundation for further application research.
Description
Technical field:
the invention belongs to the technical field of medical application, and particularly relates to application of brown alginate oligosaccharides in preparation of a product for improving intestinal flora disorder.
The background technology is as follows:
the intestinal flora is an important component of human body, the total weight of the intestinal flora of normal adult is about 1-2 kg, the total cell quantity is almost 10 times of that of human body self cells, and the number of encoded genes is more than 100 times of that of human body self genes. The sum of intestinal flora genome information is called an 'intestinal metagenome', which is a 'human second genome' for controlling the health of a human body, and together with the genome of the human body, affects the physiological metabolism of the human body through interaction with environmental conditions. At present, intestinal flora has been reported to be associated with a variety of diseases, such as obesity, diabetes, cardiovascular and cerebrovascular diseases, cancer, autism, depression, etc. Therefore, the intestinal regulation and control of health have become a hot spot for nutrition and health research in recent years. Diet is one of the most important factors affecting intestinal health, and regulating intestinal health becomes an important foothold for functional food development.
Brown algae is one of the most commonly consumed seaweeds in the world. Algin is the most important active ingredient in brown algae extract, and its proportion is about 10% -40% of dry weight of brown algae. China is one of the major production countries of algin from brown algae, and the yield of algin from brown algae is in the forefront of the world. Particularly, enzymatic hydrolysis products of two algins, namely Mannuronate Oligosaccharide (MOS) and Guluronate Oligosaccharide (GOS), have the biological activities of resisting inflammation, resisting insulin resistance, inhibiting obesity, neuroprotection and the like, but the influence of the enzymatic hydrolysis products on the intestinal microorganism types has not been reported yet.
The invention comprises the following steps:
the technical problem to be solved by the invention is that the influence of enzymolysis products of two algins, namely mannuronic acid oligosaccharide (MOS) and guluronic acid oligosaccharide (GOS), on intestinal microorganism types is not reported yet.
In order to solve the problems, the invention discovers that mannuronic acid oligosaccharides and guluronic acid oligosaccharides can up-regulate beneficial bacteria related to short chain fatty acid production or anti-inflammation in cecum to different degrees, down-regulates the relative abundance of harmful bacteria capable of causing inflammatory reaction or destroying intestinal barrier, effectively improves and regulates intestinal flora, and further improves other diseases caused by unbalance of intestinal flora.
The invention aims at achieving the purposes through the following technical scheme, and the application of the brown alginate oligosaccharides in preparing the product for improving the intestinal flora disorder is realized, wherein the brown alginate oligosaccharides are mannuronic acid oligosaccharides and/or guluronic acid oligosaccharides.
Mannuronic acid oligosaccharides (MOS) and guluronic acid oligosaccharides (GOS) are capable of modulating the structure and composition of the intestinal flora, wherein GOS is capable of reducing inflammation and enhancing intestinal barrier by limiting the growth of choledochophilus warrior; MOS increases the production of short chain fatty acid, enhances intestinal barrier and reduces inflammation by up-regulating beneficial bacteria and down-regulating pathogenic bacteria abundance.
Further, the purity of mannuronic acid oligosaccharide and/or guluronic acid oligosaccharide in the preparation is not lower than 80%. Ensures the stability of the main components of the medicine in the treatment process so as to maintain the curative effect.
Further, the mannuronic acid oligosaccharide and/or guluronic acid oligosaccharide in the preparation is used at a dose of 200mg/kg/d. Wherein, the concentration range is 50-800mg/kg/d, but 200mg/kg/d is the optimal dosage.
Use of mannuronic acid oligosaccharide and/or guluronic acid oligosaccharide in the preparation of a product for improving hyperuricemia induced intestinal flora disorder.
Hyperuricemia (HUA) is a metabolic disease caused by a disorder of purine metabolism or a disorder of Uric Acid (UA) excretion. Along with the change of life style and dietary structure, the prevalence of hyperuricemia is increased year by year, and the prevalence of Chinese hyperuricemia reaches 17.4%. Hyperuricemia is a risk factor for cardiovascular disease, kidney disease, and metabolic syndrome. At present, although the medicament effect of the uric acid-reducing medicament XOD inhibitor (such as allopurinol and febuxostat) and uric acid-promoting excreting agent (such as benzbromarone) is obvious, toxic and side effects such as liver function damage are accompanied. Therefore, the development of natural active substances having uric acid lowering effects is an important and hot point of research in recent years.
Research shows that intestinal flora is closely related to the occurrence and development of hyperuricemia. Besides, the intestinal flora can secrete xanthine oxidase to participate in purine metabolism, and can regulate protein expression of uric acid transporter through metabolites such as acetic acid, propionic acid, butyric acid and the like, so that intestinal excretion of uric acid is influenced. There is evidence that there is a difference in the intestinal flora composition of HUA patients from normal individuals, and that an imbalance in the intestinal flora causes UA excretion disorders and activation of inflammation-related signaling pathways, leading to a more severe HUA. In view of the close relationship between the disturbance of intestinal flora and the development of hyperuricemia, the restoration of the disturbance of intestinal flora in patients with hyperuricemia is considered as one of the important ways to improve hyperuricemia. In addition, uric acid is a substance with strong pro-inflammatory response, and persistent hyperuricemia causes deposition in various organs of the human body, leading to systemic inflammatory response and renal inflammation, and further aggravates HUA. As active substances with anti-inflammatory effect, mannuronic acid oligosaccharide (MOS) and guluronic acid oligosaccharide (GOS) have potential improving effect on hyperuricemia, namely, the hyperuricemia is improved through the regulating function of intestinal flora, a new medicine selection is provided for treating the hyperuricemia, and the active substances have important guiding significance on the prevention and treatment of the hyperuricemia and the regulation of intestinal flora disorder.
The beneficial effects of the invention are as follows:
(1) The invention provides the application of mannuronic acid oligosaccharide and guluronic acid oligosaccharide in improving intestinal flora disorder, and lays a foundation for further application research.
(2) The use of mannuronic acid oligosaccharides and guluronic acid oligosaccharides for improving hyperuricemia-induced intestinal flora disorders is presented. For hyperuricemia, mannuronic acid oligosaccharides and guluronic acid oligosaccharides can up-regulate short chain fatty acid production or anti-inflammatory related beneficial bacteria in the cecum to different degrees, down-regulate the relative abundance of harmful bacteria that can cause inflammatory reactions or destroy intestinal barriers, effectively improve and regulate intestinal flora, and further effectively improve hyperuricemia through the action on the intestinal flora.
(3) The potential application value of mannuronic acid oligosaccharide and guluronic acid oligosaccharide is developed, and the method has important guiding significance for improving intestinal flora disorder caused by hyperuricemia.
Drawings
FIG. 1 shows the NMDS analysis results of intestinal flora of mice in the normal group, the model group, the GOS group and the MOS group.
FIG. 2 is a Venn diagram of ASVs from intestinal flora of mice in the normal, model, GOS and MOS groups.
Fig. 3 shows species abundance at the levels of the mouse intestinal flora gate in the normal, model, GOS and MOS groups.
Fig. 4 shows species abundance at mouse intestinal flora level in normal, model, GOS and MOS groups.
FIG. 5 is a graph showing differential species analysis of intestinal flora in mice in normal, model, GOS and MOS groups. A.N vs.m differential species analysis; GOS VS.M differential species analysis; c.mos vs.m differential species analysis; gos vs. mos differential species analysis.
FIG. 6 shows serum uric acid levels in mice from the normal, model, allopurinol, guluronic acid oligosaccharide (GOS) and mannuronic acid oligosaccharide (MOS) groups.
The specific embodiment is as follows:
for the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The invention provides application of mannuronic acid oligosaccharide and guluronic acid oligosaccharide in improving intestinal flora disorder caused by hyperuricemia.
More specifically, the mannuronic acid oligosaccharides and the guluronic acid oligosaccharides are capable of up-regulating the production of short chain fatty acids in the cecum or anti-inflammatory related beneficial bacteria to varying degrees, down-regulating the relative abundance of harmful bacteria that can cause inflammatory reactions or destroy the intestinal barrier, effectively improving and regulating the intestinal flora, and thus effectively improving hyperuricemia through the action on the intestinal flora.
The application of the mannuronic acid oligosaccharide and the guluronic acid oligosaccharide provided by the invention in improving intestinal flora disorder caused by hyperuricemia and the action effect thereof are specifically described below with reference to specific examples.
Examples 1 to 3
Examples 1-3 provide the use of mannuronic acid oligosaccharides and guluronic acid oligosaccharides, respectively, for improving hyperuricemia-induced intestinal flora disorders, with the corresponding mannuronic acid oligosaccharides and guluronic acid oligosaccharides used in an amount of 200mg/kg in examples 1-3.
To verify the effect of mannuronic acid oligosaccharides and guluronic acid oligosaccharides and their effect of dose on the intestinal flora and serum uric acid levels of hyperuricemic mice, the following experiments were performed:
example 1: method for establishing, dosing and sampling hyperuricemia mouse model
1. Experimental animal
55 male Balb/c mice, 18-20g in weight, purchased from Beijing Vetong Liwa Co., ltd., license number: no.110011210108588071. Raising in room with standard environment, maintaining temperature at 22-25deg.C and relative humidity at 40-60%. Mice were kept in separate cages, and were given free water and diet. Animal experiments were approved by the animal laboratory ethics committee of the university of ocean food science and engineering college (SPXY 2021080501).
2. Medicament and reagent
Brown alginate oligosaccharides (Qingdao Bozhishui); potassium Oxazinate (PO), allopurinol (Shanghai source leaf); animal feed (south Tong terlafail).
3. Experimental method
After 7d of adaptive feeding, animals were randomly divided into normal control groups (N groups, 11) and model building groups (44), and the model building groups ingested 25% yeast extract feed, and were started to inject a 0.5% CMC-Na solution of potassium oxazinate (200 mg/kg. BW/2 d) into the abdominal cavity every 2 days 1 am for 4 consecutive weeks to induce hyperuricemia. At the same time, the normal group ingests normal feed, and 1 time per 2 days, the same volume of CMC-Na with the concentration of 0.5 percent is injected into the abdominal cavity. After successful molding, the molding modules were randomly divided into 4 groups (11 per group): hyperuricemia model control group (M group), allopurinol group (AL group), guluronic acid oligosaccharide group (GOS group), mannuronic acid oligosaccharide group (MOS group). The test material is interfered from the 5 th week to the 8 th week, and the molding mode is adopted as before by adopting the molding and the interference. During the intervention period, starting at 3 PM, N groups and M groups are respectively perfused with distilled water (10 ml/kg), with allopurinol (10 mg/kg) which is a positive drug for the stomach perfusion in the AL group, with guluronic acid oligosaccharide (200 mg/kg) in the GOS group and with mannuronic acid oligosaccharide (200 mg/kg) in the MOS group. Mice were sacrificed the following day after the last 8 week dosing. Mice were sacrificed by taking the eyeball and taking blood, cervical dislocation. The blood sample was allowed to stand, and after delamination, serum was obtained by centrifugation at 7500rpm for 15min at 4℃and stored at-80 ℃. The cecum content was stored in a frozen tube at-80 ℃. Each of the above groups was administered by intragastric injection at 0.1mL/10 g.
Experiment 2: intestinal flora 16S rRNA high throughput sequencing of cecal content from experiment one
The microorganisms in the cecal content were subjected to 16S rRNA high-throughput sequencing. Total genomic DNA in the sample was extracted by SDS method. The V3V4 region of the 16S rRNA gene was selected for PCR amplification. UsingUltra TM IIDNA Library Prep Kit library construction is carried out by using a library construction kit, and the constructed library is quantified by using Qubit and Q-PCR; after the library was qualified, on-machine sequencing was performed using NovaSeq 6000. Splitting each sample data from the next machine data according to the barcode sequence and the PCR amplification primer sequence, and cutting off the barcode and the PCR amplification primer sequenceAnd (3) after the primer sequence, splicing reads of the sample by using FLASH (V1.2.11, http:// ccb.jhu.edu/software/FLASH /) software to obtain Raw Tags. And then performing quality control on the obtained Raw Tags by using fastp software to obtain high-quality Clean Tags. And finally, comparing the Clean Tags with a database by using Usearch software to detect the chimera and remove the chimera, thereby obtaining final Effective data, namely Effective Tags. And (3) denoising the obtained Effective Tags by using a DADA2 module in QIIME2 software, and filtering out sequences with abundance less than 5, thereby obtaining final ASVs (Amplicon Sequence Variants, namely amplicon sequence variation) and a characteristic table. The resulting ASVs were then aligned to a database using the classify-sklearn module in QIIME2 software to obtain species information for each ASV. Unifrac distances were calculated using QIIME2 software and NMDS dimension reduction maps were plotted using R software. Group significant differential species analysis was accomplished using DEseq 2. Wherein the DEseq2 analysis is performed by R software.
Experimental results:
beta Diversity is a comparative analysis of the composition of the microbial community for different samples. As shown in fig. 1, the distance between the sample points of the N groups and the M groups is large, and the inter-group difference is significant; and the two test groups also showed significant differences compared to the M group.
Common, unique ASVs between different samples (groups) were analyzed at the subordinate level. As shown in fig. 2, there are 499 ASVs shared among the four groups, 545 for the N groups, 437 for the M groups, 470 for the GOS groups, and 199 for the MOS groups.
The results of species abundance at the gate level are shown in figure 3.
The heat map was used to further determine whether the composition of the intestinal flora was different at the genus level for each group of mice, and the results are shown in fig. 4. The GOS and MOS groups show different flora structures and compositions from those of the M groups, and show that the GOS and MOS groups have a regulating effect on the intestinal flora of HUA mice.
The differential species between groups were analyzed by DEseq2 and the results are shown in fig. 5. At the genus level, the abundance of short chain fatty acid producing-related bacteria clostridium UCG-010, roseburia, mucispirillum, alloprevotella, blautia was reduced in the model group compared to the normal group (fig. 5A). In addition, colidextribacter, bilophila bacterial abundance was decreased in the model group and Akkermansia bacterial abundance was up-regulated in the model group. Wherein the Colidextribacter is capable of producing inosine, and inosine is capable of inhibiting the production of pro-inflammatory factors and chemokines and promoting the production of anti-inflammatory cytokines. GOS, MOS treatment reversed changes in intestinal flora. Compared with the M group (fig. 5B), the abundance of the bilinear volcanic bacteria Bilophila in the GOS group is obviously reduced, the bilinear volcanic bacteria can have adverse effect on liver steady state and has pro-inflammatory effect, which shows that the GOS reduces intestinal inflammation and enhances intestinal barrier by limiting the growth of the bilinear volcanic bacteria. In the MOS group, the abundance of pathogenic bacteria Tuzzerella, bilophila, ASF, bryobacter, comamonas, candidatus _Solibactor, etc. was significantly down-regulated, while the abundance of beneficial bacteria, including short chain fatty acid production-related Muribaculum, ruminococcus, faecalibaculum, etc., anti-inflammatory-related Christensenelaceae_R-7_group, candida_Soleaferea, etc., were significantly up-regulated, and tryptophan metabolism-improving probiotics Clostridia_UCG-014, etc., compared to the M group (FIG. 5C). Comparing the differential flora in the GOS and MOS groups (FIG. 5D), the Candida Soliferrea genus in the GOS group is significantly enriched, and the bacterium is inversely related to colon TNF-alpha and IL-1 beta inflammatory factor levels in the diabetic model mice; bifidobacterium, clostridia _UCG-014 in the MOS group is remarkably enriched, wherein the probiotics Bifidobacterium bifidobacteria can inhibit the growth of harmful bacteria of human body, resist the infection of pathogenic bacteria, synthesize vitamins required by human body, promote the absorption of mineral substances by human body, generate short chain fatty acid and stimulate the immune system of human body; clostridia_UCG-014 was associated with tryptophan metabolism and its abundance was inversely related to ALT and AST levels, associated with liver protection. In conclusion, the beneficial bacteria in the M groups are reduced, the bacteria related to inflammation are increased, the GOS reduces inflammation and enhances intestinal barrier by limiting the growth of the Walker's cholangitis, and the MOS increases the production of short-chain fatty acid, reduces inflammation and enhances intestinal barrier by up-regulating the bacteria and down-regulating the abundance of pathogenic bacteria. And the regulating action of GOS and MOS on flora is different, and the effect of MOS is better than GOS.
Conclusion: mannuronic acid oligosaccharides (MOS) and guluronic acid oligosaccharides (GOS) regulate the structure and composition of the intestinal flora, and simultaneously up-regulate beneficial bacteria, down-regulate pathogenic bacteria abundance, and reverse the intestinal flora disorder caused by hyperuricemia.
Experiment 3: serum uric acid level detection of serum obtained from experiment
1. Medicament and reagent
Uric acid detection kit is purchased from Nanjing built bioengineering institute, and the product number is C012-2-1.
2. Experimental method
Serum obtained by centrifugation was placed on ice, and serum uric acid levels of mice were measured according to the instructions of Nanjing's kit, respectively, and the results are shown in FIG. 6.
3. Experimental results
As can be seen from fig. 6, serum uric acid levels were significantly elevated in the model group compared to the normal group, suggesting that modeling was successful. Allopurinol, mannuronic acid oligosaccharides (MOS) and guluronic acid oligosaccharides (GOS) each significantly reduced serum uric acid levels (p < 0.01) compared to the model group.
Conclusion: based on the dosage provided by the invention, the brown alginate oligosaccharides can obviously reduce the uric acid level of HUA mice and improve hyperuricemia.
In summary, the invention provides an application of mannuronic acid oligosaccharide and guluronic acid oligosaccharide in improving intestinal flora disorder caused by hyperuricemia. The mannuronic acid oligosaccharide and the guluronic acid oligosaccharide can up-regulate the beneficial bacteria related to the production of short chain fatty acid or anti-inflammation in the cecum to different degrees, down-regulate the relative abundance of harmful bacteria which can cause inflammatory reaction or damage intestinal barrier, effectively improve and regulate intestinal flora, and further effectively improve hyperuricemia through the action on the intestinal flora. The invention develops the potential application value of mannuronic acid oligosaccharide and guluronic acid oligosaccharide, provides a new drug choice for treating hyperuricemia, and has important guiding significance for preventing and treating hyperuricemia and regulating intestinal flora disorder.
The above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications and equivalents may be made thereto without departing from the spirit and scope of the technical solution of the present invention.
Claims (4)
1. The guluronic acid oligosaccharide is used as the only active ingredient and is applied to the preparation of medicines for improving hyperuricemia.
2. The use according to claim 1, wherein: the purity of guluronic acid oligosaccharide in the medicine is not lower than 80%.
3. The use according to claim 1, wherein: the dosage of the guluronic acid oligosaccharide in the medicine is 200mg/kg/d.
4. The use according to claim 1, wherein: the application of the guluronic acid oligosaccharide in preparing a product for improving intestinal flora disorder caused by hyperuricemia.
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