Composite prebiotic composition for regulating kidney-intestinal axis and delaying senescence and application thereof

Abstract

The invention belongs to the technical field of functional food, health care products and medicines, and provides a compound prebiotic composition for regulating kidney-intestinal axis and delaying senescence and application thereof. The compound prebiotic composition is prepared from 7.5 parts of fructo-oligosaccharide, 0.035 part of yeast beta-glucan, 17.5 parts of resistant starch and 0.12 part of luteolin. According to the formula, fermentable carbohydrates, immunoregulation polysaccharides and antioxidant polyphenols are combined, and intestinal microecology and whole body state are regulated through multi-target synergistic effects of providing multiple carbon sources, regulating immunity, resisting inflammation and oxidation and the like. Animal experiments show that the compound can intervene in kidney-intestinal axis dysfunction, can delay skin and hair aging and prolong healthy life after being fed to an elderly mouse for a long time, is good in safety and is suitable for developing products related to intestinal health, kidney-intestinal axis diseases and aging resistance.

Description

Technical Field

[0001] This invention belongs to the field of functional food, health product and pharmaceutical technology, and specifically relates to a compound prebiotic composition for regulating the kidney-gut axis and delaying aging and its application. Background Technology

[0002] The gut microbiota interacts closely with distal organs (such as the kidneys) through the "kidney-gut axis." In conditions such as chronic kidney disease (CKD), gut microbiota dysbiosis can lead to increased production of uremic toxins (such as indophenol sulfate and p-cresol), exacerbating systemic inflammation and organ damage. Simultaneously, the aging process itself is accompanied by a decline in gut microbiota diversity and a reduction in beneficial bacteria.

[0003] Prebiotics, serving as "nutrients" for beneficial bacteria, are an effective means of regulating the gut microbiota. Currently, most common prebiotics are single-component (such as inulin and fructooligosaccharides) or simple combinations, resulting in limited effects and a lack of systematic, multi-target design targeting complex physiological networks (such as the kidney-gut axis and aging, which simultaneously involve metabolism, immunity, and oxidative stress). Existing technologies struggle to effectively improve specific pathological models (such as kidney-gut axis dysfunction) while simultaneously obtaining definitive anti-aging phenotype evidence in long-term safety observations.

[0004] Therefore, it is of great significance to develop a compound prebiotic composition with clearly defined ingredients, scientific ratios, and synergistic effects through multiple mechanisms to meet the clinical and health needs for precise and comprehensive regulation of the gut microbiota. Summary of the Invention

[0005] To address the above-mentioned technical problems, this invention proposes a compound prebiotic composition for regulating the kidney-gut axis and delaying aging, and its application. This composition, through multi-target synergistic action, aims to regulate the intestinal microecology, improve kidney-gut axis dysfunction caused by intestinal flora imbalance, and demonstrates physiological benefits in delaying aging in long-term application.

[0006] The technical solution of this invention is: The first aspect of this invention is to provide a complex prebiotic composition, the active ingredients of which include the following components: By weight, it contains 5-10 parts of functional oligosaccharides, 0.03-0.04 parts of polysaccharides, 15-20 parts of dietary fiber, and 0.10-0.14 parts of polyphenols.

[0007] In the above-mentioned compound prebiotic composition, the functional oligosaccharide is selected from any one of fructooligosaccharide, xylooligosaccharide, and galactooligosaccharide, with fructooligosaccharide being preferred. The polysaccharide is selected from any one of yeast β-glucan, mushroom polysaccharide, and Ganoderma lucidum polysaccharide, with yeast β-glucan being the preferred polysaccharide. The dietary fiber is selected from any one of resistant starch, pectin, and alginate. Preferably, the dietary fiber is resistant starch, and more preferably, the dietary fiber is RS2 type resistant starch. The polyphenols are selected from any one of luteolin, catechin, and anthocyanin, with luteolin being the preferred polyphenol.

[0008] The above compositions can be formulated into any conventional oral dosage form, including but not limited to capsules, tablets, powders, solid beverages, or foods for special medical purposes. During preparation, the content of each active ingredient should be calculated based on the recommended daily intake and the strength of the unit dosage form.

[0009] Preferably, the daily intake ratio of the four active ingredients in the compound prebiotic composition is as follows: 7.5 parts of fructooligosaccharide, 0.035 parts of yeast β-glucan, 17.5 parts of resistant starch, and 0.12 parts of luteolin.

[0010] Further preferred, the four active ingredients in this compound prebiotic composition are proportioned according to the following daily intake: 7.5 parts of fructooligosaccharide, 0.035 parts of yeast β-glucan, 17.5 parts of RS2 resistant starch, and 0.12 parts of luteolin.

[0011] A second aspect of the present invention is to provide the use of the compound prebiotic composition in the preparation of pharmaceuticals, health products or foods for special medical purposes for improving and / or treating diseases related to renal-gut axis dysfunction.

[0012] Among them, diseases related to kidney-gut axis dysfunction include chronic kidney disease and its associated gut microbiota dysbiosis, constipation, or systemic microinflammatory states.

[0013] A third aspect of the present invention provides the use of a complex prebiotic composition in the preparation of health products and / or functional foods for delaying skin aging in mammals, maintaining healthy hair, or extending healthy lifespan.

[0014] Compared to existing single or simply compounded prebiotic products, the composition of this invention has the following outstanding beneficial effects, which stem from the fact that the four components form a mutually reinforcing synergistic system: (1) Multiple fermentation and precise regulation of gut microbiota: Fructooligosaccharides, as a high-quality and fast-acting carbon source, can be rapidly utilized by Bifidobacteria and other bacteria to quickly improve the structure of gut microbiota; Resistant starch (RS2 type), as a slow-release carbon source, can reach the distal colon directly, promote the sustained generation of beneficial metabolites such as butyric acid, and nourish colonic epithelial cells. The two complement each other in terms of fermentation rate and space, so as to achieve full-domain and time-space regulation of gut microbiota. (2) Immunomodulation and barrier strengthening: Yeast β-glucan is a well-known immunomodulator that can activate intestinal innate immunity, enhance the function of macrophages, and work with prebiotics to promote beneficial bacteria and their metabolites (such as short-chain fatty acids) to build a healthy intestinal immune microenvironment, synergistically enhance intestinal barrier function, and reduce endotoxin translocation; (3) Enhanced antioxidant and anti-inflammatory effects: As a natural polyphenol, luteolin has strong antioxidant and anti-inflammatory activities. It can directly scavenge free radicals and inhibit inflammatory pathways such as NF-κB. The key is that luteolin can exert a synergistic anti-inflammatory effect with the short-chain fatty acids (especially butyric acid) produced by the aforementioned components, which can more effectively alleviate the chronic inflammatory state of the kidney-gut axis and the whole body. Chronic inflammation is the common soil of aging and a variety of chronic diseases. (4) Clear efficacy in the renal-gut axis model: In a complex renal-gut axis dysfunction mouse model, the intervention group (PF group) of this composition showed an improvement trend in general survival compared with the control group, which proved the effectiveness of this formulation in this complex pathological model; (5) Long-term safety and anti-aging phenotype evidence are conclusive: In long-term animal observation experiments, the healthy skin / hair of elderly mice (Y group) that ingested this composition was maintained for a longer time (the time of skin damage and spontaneous tumor appearance was delayed and the degree was reduced) compared with the normal diet group (P group), and the median survival and maximum survival were significantly prolonged. This provides strong in vivo evidence for the long-term safety and anti-aging effect of the composition. Attached Figure Description

[0015] Figure 1 This is a schematic diagram illustrating the synergistic mechanism of the four active ingredients in the compound prebiotic composition of the present invention; Figure 2 This is a comparison curve of the body weight change of mice in the kidney-gut axis model during treatment with the compound prebiotic formula of this invention; Figure 3 The images show a comparison of the effects of the compound prebiotic formulation of this invention on the intestines and kidneys of mice in a kidney-gut axis model. In A, CKD-induced disordered microvilli arrangement and shedding of intestinal epithelial cells are shown. In B, prebiotic intervention repaired the disordered microvilli arrangement and shedding of intestinal epithelial cells caused by CKD, improving the intestinal barrier structure. In C, CKD-group mice showed significant glomerular sclerosis and mesangial matrix proliferation. In D, CKD-group mice showed a significant reduction in glomerular sclerosis and mesangial matrix proliferation damage after prebiotic intervention. Figure 4 The effect of the compound prebiotic formula of this invention on the content of short-chain fatty acids (SCFAs) in feces of mice with a kidney-gut axis model is shown in Figure A, where A represents the total short-chain fatty acids (SCFAs), acetic acid, and propionic acid in the feces of mice in the prebiotic experimental group (Y group) after 16 weeks of intervention, and B represents the proportion of butyric acid in the feces of mice in the prebiotic experimental group (Y group) to the total short-chain fatty acids. Figure 5 This invention is based on long-term survival curves (Kaplan-Meier curves) derived from animal experimental data. Figure 6 The images show a comparison of the representative appearances of two groups of mice at different stages of the experiment of this invention. Among them, A is an aged C57 mouse that was fed a normal mouse diet every day, B is an aged C57 mouse that was fed a prebiotic mouse diet every day, C is an aged C57 mouse that was fed a normal mouse diet every day, and D is an aged mouse. The images of B are taken when the mice were 52 weeks old. Detailed Implementation

[0016] To enable those skilled in the art to better understand the present invention, the present invention will now be further described in conjunction with specific embodiments.

[0017] Example 1: Preparation of compound prebiotic composition capsules (1) Weigh the active ingredients according to the recommended daily intake ratio: 7.5 parts of fructooligosaccharide, 0.035 parts of yeast β-glucan, 17.5 parts of RS2 resistant starch, and 0.12 parts of luteolin.

[0018] (2) Add the above active ingredients and 50 parts of microcrystalline cellulose (filler) and 2 parts of magnesium stearate (lubricant) into a three-dimensional mixer and mix evenly to obtain a mixed powder.

[0019] (3) Use a capsule filling machine to fill the mixed powder into No. 0 capsules, with each capsule filled with about 0.5 parts of powder, to obtain a compound prebiotic composition capsule.

[0020] Conversion: Each capsule contains approximately 0.1875 parts of fructooligosaccharides, 0.00875 parts of yeast beta-glucan, 0.4375 parts of RS2 resistant starch, and 0.003 parts of luteolin. The recommended daily dose is 40 capsules (divided into several doses) to meet the daily intake requirement (7.5 parts of fructooligosaccharides, 0.035 parts of yeast beta-glucan, 17.5 parts of RS2 resistant starch, and 0.12 parts of luteolin).

[0021] Example 2: Preparation of Compound Prebiotic Solid Beverage Weigh out the following amounts according to daily intake: 7.5 parts fructooligosaccharides, 0.035 parts yeast β-glucan, 17.5 parts RS2 resistant starch, and 0.12 parts luteolin.

[0022] Add flavoring agents (such as 200 parts of steviol glycosides and 1000 parts of natural lemon powder) and 10000 parts of maltodextrin as carriers.

[0023] All materials are thoroughly and evenly mixed in a large mixer after being pulverized by airflow.

[0024] Repackaged into 10 servings / bag. Each bag contains approximately: 2.5 parts fructooligosaccharides, 0.0117 parts yeast beta-glucan, 5.8 parts resistant starch, and 0.04 parts luteolin. The recommended daily intake is 2-4 bags.

[0025] Experimental Example 1: Application of Compound Prebiotic Composition in a Model of Kidney-Gut Axis Dysfunction (Efficacy Verification) A mouse model of renal-gut axis dysfunction was established using conventional fecal microbiota transplantation.

[0026] Preparation of donor microbiota suspension: Fresh fecal samples were taken from patients with uremia and constipation, homogenized and filtered under anaerobic conditions with sterile phosphate buffer (PBS) to prepare fecal microbiota suspension.

[0027] Model construction: Healthy recipient mice (C57BL / 6J) were randomly divided into two groups. The model group was given 200 μL of the above-mentioned pathological bacterial suspension by gavage daily for 3-5 consecutive days; the control group was given an equal volume of sterile PBS by gavage.

[0028] C57 mice that survived the modeling were randomly divided into a control group and an intervention group. The control group was fed a standard maintenance diet; the intervention group (i.e., the experimental group) was fed a customized diet with a composition added at 3-5% of the total feed weight, wherein the mass ratio of each active ingredient was 7.5 parts of fructooligosaccharide, 0.035 parts of yeast β-glucan, 17.5 parts of resistant starch, and 0.12 parts of luteolin.

[0029] Table 1. Effects of the compound prebiotic formulation on body weight in mice with a kidney-gut axis model during treatment.

[0030] Based on the data in Table 1 Figure 2 It was found that there was a significant difference in body weight between the control and experimental groups of mice during treatment. The prebiotic intervention group showed a stable weight gain trend in the later stages of the intervention, while the model control group experienced slow weight gain or even fluctuations. By the end of the intervention (week 6), the average body weight of the prebiotic intervention group was significantly higher than that of the model control group by approximately 8%-15%. p<0.01, independent samples t test ) Figure 3The images show a comparison of the effects of the compound prebiotic formulation of this invention on the intestines and kidneys of mice in a kidney-gut axis model. Scanning electron microscopy (SEM) revealed that the glomeruli of mice in the CKD group showed significant sclerosis and mesangial matrix proliferation, and the damage was significantly reduced after prebiotic intervention (Figure 3, CD). SEM results in A showed that CKD caused disordered arrangement and loss of microvilli in intestinal epithelial cells; SEM results in B showed that prebiotic intervention repaired the disordered arrangement and loss of microvilli in intestinal epithelial cells caused by CKD, improving the intestinal barrier structure; C showed significant sclerosis and mesangial matrix proliferation in the glomeruli of mice in the CKD group; SEM results in D showed that the damage of glomerular sclerosis and mesangial matrix proliferation in mice in the CKD group was significantly reduced after prebiotic intervention.

[0031] During the intervention, the intervention group mice showed better performance than the control group in terms of weight maintenance and activity level. Preliminary analysis of the kidney and intestinal tissues collected after sacrifice at the experimental endpoint showed (…). Figure 3 The intervention group showed a trend of improvement in kidney and intestinal damage. This result validates the effectiveness of this composition in this pathological model.

[0032] Experimental Example 2: Application of Compound Prebiotic Composition in Long-Term Safety and Anti-Aging Observation A long-term natural aging observation model was applied, which was established using conventional long-term natural aging observation models in this field.

[0033] 24-week-old male C57BL / 6J mice were randomly divided into two groups: Normal group (P group): fed standard maintenance rodent food.

[0034] Intervention group (Group Y): Feeding with a customized rodent diet containing a feed composition at 3-5% of the total feed mass, wherein the mass ratio of each active ingredient is 7.5 parts fructooligosaccharide, 0.035 parts yeast β-glucan, 17.5 parts resistant starch, and 0.12 parts luteolin. Long-term observation began from 24 weeks of age.

[0035] The main results are: Table 2. Mouse survival rate (%) Time / Day Group P Group Y 263 60% 80% 516 40% 80% 599 20% 80% 613 0% 60% 689 0% 40%

[0036] Safety: No formulation-related toxic reactions or abnormal deaths occurred in Group Y throughout the entire experimental period.

[0037] Hair and skin health: Mice in the normal control group (P group) began to show obvious skin damage, thinning hair, and spontaneous tumors from about 40 weeks of age. In contrast, mice in the prebiotic intervention group (Y group) showed similar significant aging phenotypes at an average time that was delayed by 10-15 weeks, and the severity was generally milder. Figure 6This study demonstrates representative differences in hair coverage and skin integrity between the two groups of mice at the same age (e.g., 52 weeks).

[0038] Extended lifespan: such as Figure 5 The Kaplan-Meier survival curves shown indicate that the median survival of the prebiotic intervention group (Group Y) was significantly longer than that of the control group (Group P). The median survival of Group Y was approximately 1.2–1.4 times that of Group P. Log-rank test analysis of the survival curves confirmed that the difference between the two groups was highly statistically significant. p <0.001 ).

[0039] Experimental Example 3: Effect of Compound Prebiotic Composition on Short-Chain Fatty Acids (SCFAs) Content in Animal Feces This embodiment aims to directly verify the effectiveness of the formulation in regulating intestinal flora from the functional output level by measuring the content of key metabolites—short-chain fatty acids (SCFAs)—in the feces of mice that have long-term ingested the compound prebiotic composition of this invention, and to quantitatively demonstrate its synergistic effect on the production of beneficial metabolites (especially butyric acid) through the "dual carbon source synergy" mechanism.

[0040] Experimental animals: Sixteen 24-week-old male C57BL / 6J mice were randomly divided into two groups of eight mice each.

[0041] Feed preparation: Normal control group diet (P group): Standard laboratory maintenance rat diet.

[0042] Prebiotic intervention group feed (Group Y): Based on standard maintenance rat diet, the compound prebiotic composition of this invention was added in a certain mass ratio.

[0043] The content of short-chain fatty acids (SCFAs) in the feces of experimental animals was detected using gas chromatography-mass spectrometry (GC-MS). After 16 weeks of intervention, the SCFA content in the feces of two groups of mice was analyzed, and the key data are as follows: Table 3. Effects of compound prebiotic formulation on short-chain fatty acid content in feces of mice in the kidney-gut axis model.

[0044] Combining the data in Table 3 Figure 4 It can be seen that, compared with the normal control group (P group), the total SCFAs content in the feces of mice in the prebiotic intervention group (Y group) was significantly increased. p<0.01 Among them, the butyrate content, which is particularly crucial for gut health, increased most significantly, with the butyrate content in group Y being 2.0-2.5 times that of group P. p<0.001 Meanwhile, the percentage of butyrate in total SCFAs in feces of group Y also significantly increased from approximately 12% in group P to approximately 17%-20%. p <0.01This indicates that the composition can selectively promote the metabolic function of butyric acid-producing bacteria. Meanwhile, the content of branched-chain fatty acids (isobutyric acid, isovaleric acid), which represent protein putrefaction products, showed no significant change.

[0045] The above are merely preferred embodiments of the present invention and do not limit the scope of the patent. All equivalent changes and modifications made within the scope of the present invention should still fall within the scope of the present invention.

Claims

1. A compound prebiotic composition, characterized in that, Its active ingredients are formulated according to the following proportions based on daily intake: 5-10 parts functional oligosaccharides, 0.03-0.04 parts polysaccharides, 15-20 parts dietary fiber, and 0.10-0.14 parts polyphenols.

2. The compound prebiotic composition as described in claim 1, characterized in that, The functional oligosaccharide is selected from any one of fructooligosaccharides, xylooligosaccharides, and galactooligosaccharides; The polysaccharide is selected from any one of yeast β-glucan, lentinan, and Ganoderma lucidum polysaccharide; Dietary fiber is selected from any one of resistant starch, pectin, and alginate; The polyphenols are selected from any one of luteolin, catechin, and anthocyanin.

3. The compound prebiotic composition as described in claim 1, characterized in that, Its active ingredients, according to the daily intake mass ratio, are as follows: 7.5 parts of fructooligosaccharides, 0.035 parts of yeast β-glucan, 17.5 parts of resistant starch, and 0.12 parts of luteolin.

4. The compound prebiotic composition according to any one of claims 2-3, characterized in that, The resistant starch is RS2 type resistant starch.

5. The use of the compound prebiotic composition as described in any one of claims 1-4 in the preparation of pharmaceuticals, health products or foods for special medical purposes for improving and / or treating diseases related to renal-gut axis dysfunction.

6. The application as described in claim 5, characterized in that, The kidney-gut axis dysfunction-related diseases include chronic kidney disease and its associated gut microbiota dysbiosis, constipation, or systemic microinflammatory states.

7. The use of the compound prebiotic composition according to any one of claims 1-4 in the preparation of health products and / or functional foods for delaying skin aging in mammals, maintaining healthy hair, or prolonging healthy lifespan.

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