NL2035174A - Lactobacillus fermentum and applications of lactobacillus fermentum in preparation for improving hyperlipidemia - Google Patents
Lactobacillus fermentum and applications of lactobacillus fermentum in preparation for improving hyperlipidemia Download PDFInfo
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- NL2035174A NL2035174A NL2035174A NL2035174A NL2035174A NL 2035174 A NL2035174 A NL 2035174A NL 2035174 A NL2035174 A NL 2035174A NL 2035174 A NL2035174 A NL 2035174A NL 2035174 A NL2035174 A NL 2035174A
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- lactobacillus fermentum
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- cholesterol
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Abstract
The present application belongs to the technical field of microorganisms, and specifically, relates to a lactobacillus fermentum and applications of the lactobacillus fermentum in a preparation for improving hyperlipidemia. The strain is deposited with the China General Microbiological Culture Collection Center (CGMCC), and is assigned with the accession number of CGMCC No. 25738. The cholesterol removal rate of the strain is up to 55.2%, the strain may significantly reduce the levels of triglycerides, cholesterol and low-density lipoprotein in the serum of the human body, promote the secretion of a short-chain fatty acid in the intestinal tract, and obviously improve liver pathology in mice, such that hyperlipidemia is effectively improved, and the strain has no side effects and high safety.
Description
I
LACTOBACILLUS FERMENTUM AND APPLICATIONS OF
LACTOBACILLUS FERMENTUM IN PREPARATION FOR
IMPROVING HYPERLIPIDEMIA
The present application belongs to the technical field of microorganisms, and specifically, relates to a lactobacillus fermentum and applications of the lactobacillus fermentum in a preparation for improving hyperlipidemia.
Hyperlipidemia is a disease caused by disorders of lipid metabolism of the human body; such disorders include abnormal elevation of Total Cholesterol (TC), Triglyceride (TG) and
Low-Density Lipoprotein Cholesterol (LDL-C) in the serum, and abnormal reduction of
High-Density Lipoprotein Cholesterol (HDL-C); and if the hyperlipidemia is not controlled and treated in a timely manner, more serious diseases may be caused. The current prevalence of dyslipidemia among adults in China is 18.6%, with an estimated 160 million people suffering from dyslipidemia nationwide. The prevalence of different types of dyslipidemia is 2.9% for hypercholesterolemia, 11.9% for hypertriglyceridemia, and 7.4% for low- and high-density lipoproteinemia, with another 3.9% having edge elevated blood cholesterol. The incidence of hyperlipidemia has been increasing year by year in recent years, and the population affected is getting younger and younger.
At present, the hyperlipidemia may be improved by diet treatment and other lifestyle changes. If, after improvement, the blood lipid of patients is still abnormal, additional lipid-lowering drugs should be used appropriately according to the presence and amount of coronary heart diseases and diseases and risk factors equivalent to the coronary heart diseases.
However, many of the drugs on the market today that can lower blood lipids may cause serious side effects, even in healthy people, and these drugs often cause abdominal pain, allergic reactions, emotional imbalances, hair loss, visual changes, headaches, sore throats, and muscle degeneration.
Through researches, it has found that people who regularly drink yogurt generally have relatively-low blood lipid levels; and correlation analysis shows a correlation between yogurt drinking and low blood lipid levels, thus revealing the possibility that probiotics have the potential to lower the blood lipid level of the human body. In addition, the metabolite of the probiotics, namely a short-chain fatty acid, has also been reported to have a modulating effect on blood lipids; and the intaking of the probiotics is usually not accompanied by side effects and has high safety guarantee for the human body.
Therefore, excavating a probiotic that may improve hyperlipidemia is of great significance.
In view of the above problems, one of the objectives of the present application is to provide a lactobacillus fermentum, which may significantly reduce the levels of triglycerides, cholesterol and low-density lipoprotein in the serum, may significantly promote the secretion of a short-chain fatty acid in the intestinal tract, and obviously improve liver pathology in mice, such that hyperlipidemia is effectively improved.
In order to achieve the above purpose, the present application may use the following technical solutions.
One aspect of the present application provides a lactobacillus fermentum. The lactobacillus fermentum is deposited with the China General Microbiological Culture Collection Center (CGMCC) and is assigned with the accession number of CGMCC No. 25738.
Another aspect of the present application further provides a composition. The composition may include one or a combination of a plurality of the following substances: (a) the lactobacillus fermentum; (b) lysate of the lactobacillus fermentum; (c) a culture of the lactobacillus fermentum; and (d) a fermentation broth of the lactobacillus fermentum.
Still another aspect of the present application provides a preparation. The preparation includes the lactobacillus fermentum or the composition, and a carrier. The carrier is a medicinal carrier or an edible carrier.
Still another aspect of the present application provides applications of the lactobacillus fermentum or the composition in preparation of preparations for improving hyperlipidemia.
The collection information of the lactobacillus fermentum in the present application includes the following. The lactobacillus fermentum is deposited with the CGMCC at No. 3,
Yard 1, BeiChen West Road, Chaoyang District, Beijing on September 16, 2022 and is assigned with the accession number of CGMCC No. 25738, with the classification name being lactobacillus fermentum.
The beneficial effects of the present application include the following. The cholesterol removal rate of the lactobacillus fermentum provided in the present application is up to 55.2%; the strain may significantly reduce the levels of triglycerides, cholesterol and low-density lipoprotein in the serum of the human body, promote the secretion of the short-chain fatty acid in the intestinal tract, and obviously improve liver pathology in the mice, such that hyperlipidemia is effectively improved; and the strain has no side effects and high safety.
Fig. 1 1s a colonial morphology diagram of lactobacillus fermentum TY-S11.
Fig. 2 is a gram staining result diagram of lactobacillus fermentum TY-S11.
Fig. 3 is a standard curve of a cholesterol-ODss50nm value.
Fig. 4 shows in-vitro cholesterol removal rates of 74 strains.
Fig. 5 is a curve graph of food intake of mice in each group.
Fig. 6 is a curve graph of water intake of mice in each group.
Fig. 7 is a curve graph of weights of mice in each group.
Fig. 8 shows a triglyceride level in the serum of mice in each group.
Fig. 9 shows a total cholesterol level in the serum of mice in each group.
Fig. 10 shows a low-density lipoprotein level in the serum of mice in each group.
Fig. 11 shows a triglyceride level in the liver of mice in each group.
Fig. 12 shows a cholesterol level in the liver of mice in each group.
Fig. 13 is an oil red staining diagram (200x) of the liver of mice in each group.
Fig. 14 shows a propionic acid level in feces of mice in each group.
Fig. 15 shows an acetic acid level in feces of mice in each group.
Fig. 16 shows a butyric acid level in feces of mice in each group.
In the drawings, experimental data is expressed as mean + standard error (mean = SEM).
Am “oek v> and "FERRE all represent that there is a statistical difference between two groups, representing p<0.05, p<0.01, p<0.001, and p<0.0001, respectively.
The embodiments are given to better describe the present application, but the content of the present application is not limited only to the embodiments given. Therefore, non-essential improvements and adjustments to the embodiments made by a person skilled in the art in accordance with the content of the above present application still fall within the scope of protection of the present application.
The terms used herein are only intended to describe specific embodiments and are not intended to limit the present disclosure. Expressions in the singular form include those in the plural form unless the expressions have a distinctly different meaning in the context. As used herein, it is to be understood that terms such as "include", "have", "contain", and the like are intended to indicate the presence of features, figures, operations, components, parts, elements, materials, or combinations. The terms of the present application are disclosed in the specification and are not intended to exclude the possibility that one or more other features, figures, operations, components, parts, elements, materials, or combinations thereof may exist or may be added. As used here, "/" may be interpreted as "and" or "or", as appropriate.
An embodiment of the present application provides a lactobacillus fermentum (also known as a lactobacillus fermentum TY-S11). The lactobacillus fermentum is deposited with the
CGMCC and is assigned with the accession number of CGMCC No. 25738.
It is to be noted that, the lactobacillus fermentum is derived from feces of the longevous in
Jiangjin, Chongqing. After being detected by means of gram staining results, the lactobacillus fermentum is found to be in a rod-like shape, and is determined as gram-positive bacteria (G*).
In addition, by means of PCR amplification of a 16SrDNA sequence, the I6SrDNA sequence is detected to include a sequence shown as SEQIDNO. 1.
Another embodiment of the present application further provides a composition. The composition includes one or a combination of a plurality of the following substances: (a) the lactobacillus fermentum; (b) lysate of the lactobacillus fermentum; (c) a culture of the lactobacillus fermentum; and (d) a fermentation broth of the lactobacillus fermentum.
It is to be noted that, in the composition, the lactobacillus fermentum TY-S11 may be prepared into an edible or medicinal composition. In addition, when the lactobacillus fermentum TY-S11 is prepared into the composition, the lactobacillus fermentum may achieve an effect by being directly introduced into the composition in the form of viable bacteria, may achieve an effect by being introduced into the composition in the form of inactivated bacteria after inactivation by means of the existing technology, may achieve an effect by introducing the lysate of the lactobacillus fermentum into the composition, may achieve an effect by introducing products such as proteins, peptides, secretions or metabolites obtained from the culture of the lactobacillus fermentum into the composition, or may achieve an effect by introducing the fermentation broth from the fermentation of the lactobacillus fermentum into the composition. In a specific use process, different forms of the lactobacillus fermentum may be selected for the preparation of the composition according to specific requirements.
In some specific embodiments, the composition may further include one or a combination of probiotics, prebiotics, dietary fiber and traditional Chinese drugs.
It is to be noted that, the lactobacillus fermentum TY-S11 and different forms thereof may also be used in combination with one or the combination of probiotics, dietary fiber and a pharmacologically active compound. For example, the lactobacillus fermentum TY-S11 may be used in combination with bacillus subtilis, bi-fidobacterium or lactobacillus, so as to cause the composition to simultaneously have the effects of the lactobacillus fermentum TY-S11 and other probiotics. For another example, the lactobacillus fermentum TY-S11 may be used in combination with the prebiotics, and the prebiotics may provide an energy source for the lactobacillus fermentum TY-S11, such that the effect of the lactobacillus fermentum TY-S11 is improved. For another example, the lactobacillus fermentum TY-S11 may be used in combination with the dietary fiber, and the dietary fiber may assist in colonization of the lactobacillus fermentum TY-S11, such that the effect of the lactobacillus fermentum TY-S11 is improved. For another example, the lactobacillus fermentum TY-S11 may also be used in 5 combination with the traditional Chinese drugs to form the composition, such that the effects of the lactobacillus fermentum TY-S11 and the traditional Chinese drugs are simultaneously achieved.
Still another embodiment of the present application provides a preparation. The preparation includes the lactobacillus fermentum TY-S11 or the composition, and a carrier. The carrier is a medicinal carrier or an edible carrier.
It is to be noted that, drugs or edible food or health care products may be prepared by adding the medicinal carrier or the edible carrier to the composition including the lactobacillus fermentum TY-S11 and different forms thereof. The medicinal carrier or the edible carrier is known in the art and may be selected according to the dosage form as needed. For example, the preparation of tablets mainly uses a diluent (such as starch, dextrin, sucrose or sugar), an absorbent (such as calcium sulfate, calcium hydrogen phosphate or light magnesium oxide), an adhesive (such as povidone, syrup or hydroxypropyl methylcellulose), a wetting agent (such as water), or a disintegrating agent (such as dry starch, sodium hydroxymethyl starch or cross-linked povidone). For example, the preparation of the liquid preparation mainly uses a bulking agent, a suspending agent, an emulsifying agent, a colorant, or the like.
In some specific embodiments, the preparation may be tablets, pills, capsules, powder, gel, granules or a liquid preparation. It is to be noted that, solid dosage forms such as the tablets, the pills, the granules or the capsules may be product forms such as probiotic tablets, probiotic sugar pills, probiotic powder or probiotic capsules. The liquid preparation may be a product form such as a probiotic beverage. The gel may be product forms such as probiotic jelly, probiotic milk foam or solidified yogurt.
Still another embodiment of the present application provides applications of the lactobacillus fermentum or the composition in preparation of preparations for improving hyperlipidemia.
In some specific embodiments, the applications includes: an application of the lactobacillus fermentum TY-S11 or the composition in preparation of preparations for reducing a triglyceride level and/or a total cholesterol level and/or a low-density lipoprotein level in serum.
It is to be noted that, hyperlipidemia generally includes high cholesterol, the total cholesterol level in the human body is elevated, that is, when the total cholesterol level in the human body (total cholesterol is the sum of cholesterol contained in all lipoproteins in the blood, the total cholesterol level in the population mainly depends on genetic factors and lifestyle, a recommended adult cholesterol value should not be too high, and the ideal value is less than 5.17 mmol/L) is greater than 5.17 mmol/L, it is considered hyperlipidemia; and reducing the cholesterol level in the serum is one of the effective ways to treat the hyperlipidemia. The lactobacillus fermentum TY-S11 in the present application may significantly reduce the total cholesterol level in the serum of the human body. In some specific embodiments, compared with the total cholesterol level in the serum of high fat and high cholesterol model mice that do not use the lactobacillus fermentum TY-S11, the total cholesterol level in the serum of high fat and high cholesterol model mice that use the lactobacillus fermentum TY-S11 in the present application is reduced by approximately 39.1%, such that it indicates that the lactobacillus fermentum TY-SII in the present application has a significant effect on reducing the total cholesterol in bile serum.
It is further to be noted that, triglyceride is a risk factor for cardiovascular disease; the triglyceride level in the serum is affected by ages, genders and diet; and increased serum triglyceride may be seen with high triglyceride intake and secondary to certain diseases such as diabetes and atherosclerosis. The lactobacillus fermentum TY-S11 in the present application may significantly reduce the triglyceride level in the serum of the human body. In some specific embodiments, compared with the triglyceride level in the serum of the high fat and high cholesterol model mice that do not use the lactobacillus fermentum TY-S11, the triglyceride level in the serum of the high fat and high cholesterol model mice that use the lactobacillus fermentum TY-S11 in the present application is reduced by approximately 19.3%, such that it indicates that the lactobacillus fermentum TY-S11 in the present application has a significant effect on reducing the triglyceride in the serum.
It is further to be noted that, low-density lipoprotein is lipoprotein particles that carry the cholesterol into peripheral histiocyte, which may be oxidized to oxidized low-density lipoprotein; and when the low-density lipoprotein, especially the low-density lipoprotein modified by means of oxidization, is in excess, the cholesterol carried by the low-density lipoprotein accumulates on the arterial wall, easily causing arteriosclerosis. The lactobacillus fermentum TY-SI1 in the present application may significantly reduce the low-density lipoprotein level in the serum of the human body. In some specific embodiments, compared with the low-density lipoprotein level in the serum of the high fat and high cholesterol model mice that do not use the lactobacillus fermentum TY-S11, the low-density lipoprotein level in the serum of the high fat and high cholesterol model mice that use the lactobacillus fermentum
TY-SI1I in the present application is reduced by approximately 37.9%, such that it indicates that the lactobacillus fermentum TY-S11 in the present application has a significant effect on reducing the low-density lipoprotein.
In some specific embodiments, the applications include applications of one or a combination of a plurality of the following: (a) an application of the lactobacillus fermentum
TY-SII or the composition in preparation of preparations for reducing a triglyceride level and/or a cholesterol level in the liver; and (b) an application of the lactobacillus fermentum
TY-S11 or the composition in preparation of preparations for promoting the secretion of the short-chain fatty acid in the intestinal tract.
It is to be noted that, lipids may be divided into two categories: fat and lipids. The fat includes the triglyceride, and the lipids include the cholesterol. The triglyceride easily accumulates in the fat, and there is even a risk of fatty liver when the triglyceride is excessively high. The liver is the center of lipid metabolism, and 70%-80% of cholesterol in the human body is synthesized by the liver, such that testing lipid levels in the liver is of great significance.
The lactobacillus fermentum TY-S11 in the present application may significantly reduce the triglyceride and cholesterol levels in the liver of the human body. In some specific embodiments, compared with the triglyceride level in the liver of the high fat and high cholesterol model mice that do not use the lactobacillus fermentum TY-S11, the triglyceride level in the liver of the high fat and high cholesterol model mice that use the lactobacillus fermentum TY-S11 in the present application is reduced by approximately 19.4%, such that it indicates that the lactobacillus fermentum TY-S11 in the present application has a significant effect on reducing the triglyceride in the liver. In addition, compared with the cholesterol level in the liver of the high fat and high cholesterol model mice that do not use the lactobacillus fermentum TY-S11, the cholesterol level in the liver of the high fat and high cholesterol model mice that use the lactobacillus fermentum TY-SI1 in the present application is reduced by approximately 52.2%, such that it indicates that the lactobacillus fermentum TY-S11 in the present application has a significant effect on reducing the cholesterol in the liver.
It is further to be noted that, the short-chain fatty acid is the final metabolite of carbohydrates that the human body cannot digest on its own and are produced by intestinal bacteria after fermentation, including acetic acid, propionic acid, isobutyric acid, butyric acid, isovaleric acid, and valeric acid, among which more than 90% of the short-chain fatty acid is acetic acid, propionic acid, and butyric acid. The short-chain fatty acid may affect the synthesis of lipid substances, may improve abnormal lipid metabolism caused by high-fat diet, may also increase the excretion of bile acid, and reduce the total cholesterol level in the blood. The lactobacillus fermentum TY-S11 in the present application may significantly promote the secretion of the short-chain fatty acid in the intestinal tract, thereby improving the short-chain fatty acid level in the intestinal tract. In some specific embodiments, compared with the acetic acid, propionic acid, and butyric acid levels in the liver of the high fat and high cholesterol model mice that do not use the lactobacillus fermentum TY-S11, the acetic acid, propionic acid, and butyric acid levels in the liver of the high fat and high cholesterol model mice that use the lactobacillus fermentum TY-S11 in the present application are respectively reduced by approximately 28.5% (acetic acid), approximately 68.2% (propionic acid), and approximately 78.2% (butyric acid), such that it indicates that the lactobacillus fermentum TY-SII in the present application has a significant effect on promoting the secretion of the short-chain fatty acid in the intestinal tract of the human body.
It is further to be noted that, the lactobacillus fermentum TY-S11 in the present application may simultaneously reduce the triglyceride and cholesterol levels in the liver of the human body and promote the secretion of the short-chain fatty acid in the intestinal tract, such that the triglyceride, total cholesterol and low-density lipoprotein levels in the serum of the human body are simultaneously reduced, thereby achieving the purpose of improving the hyperlipidemia by means of synergism.
In order to better understand the present application, the content of the present application is further described below with reference to specific embodiments, but is not only limited to the following examples.
In the following embodiments, an MRS liquid culture medium is provided by Beijing Land
Bridge Technology Co., Ltd.
In the following embodiments, the lactobacillus fermentum used in the present application is also called a TY-S11 or a lactobacillus fermentum TY-S11.
Embodiment 1: Separation, purification and identification of TY-S11 (1) Experimental material
A feces sample from the longevous in Jiangjin, Chongqing was collected; feces without urine contamination was collected, a spoon of a feces sampler was used to collect 4 to 5 spoons (about 20 grams) of feces to put into a 20 mL feces sampler containing 30% glycerol, and a cap was tightened up. (2) Separation and purification of TY-S11 1 mL of the sample was pipetted to 9 mL of sterile saline, so as to obtain 10°! diluent; then, 1 mL of the 10°! diluent was pipetted to 9 mL of the sterile saline, so as to obtain 107 diluent; and according to the operation, 10” diluent, 10% diluent, 10% diluent, and 10-6 diluent were successively obtained. 200 pL of the diluent with different dilutions (10%, 107%, 10%, and 10%) was separately spread on the MRS solid culture medium for anaerobic culture at 37°C for 24h; colonial morphology on a plate was observed; single colonies with different morphology were selected, and a streak plate method was used to isolate strains; then, a single colony was selected from the streak-purified plate to continue perform streaking purification, so as to obtain purified strains; the streaking operation was repeated until purified strains were obtained; and then, morphological observation was performed by means of gram staining.
The colonial morphology of the strains was shown in Fig. 1. The single colonies were formed in solid culture medium after the strains were purified, and the colonies were consistent in morphology, hemispherical in shape, white and translucent, smooth and moist in surface, and neat in edge.
The gram staining results were shown in Fig. 2. After gram staining, purple cell morphology (grey processing was performed in Fig. 2, and an original drawing was purple) with a rod-like shape was observed under a microscope, such that the strain was determined as gram-positive bacteria (G*). (3) PCR amplification of 16S rDNA sequence
PCR amplification was performed by using a 25 pL of a reaction system, including 1 pL of atemplate, 1 pL of an upstream primer (SEQIDNO.2 (agagtttgatcctggctcag) (10 uM), 1 uL of a downstream primer (SEQIDNO.3 (tacgacttaaccccaatcge) (10 pM), and 12.5 pL of 2xTaq PCR
Master Mix, and making up to 25 pL with sterile ultrapure water. PCR amplification conditions included: performing pre-denaturation at 94°C for 5 min, performing denaturation at 94°C for 30 s, performing annealing at 55°C for 30 s, and performing extension at 72°C for 1 min, where there was a total of 35 cycles; and performing end extension at 72°C for 10 min. After sequence amplification, Sangon Biotech (Shanghai) Co, Ltd. was entrusted to sequence qualified PCR amplification products, and the obtained sequence was shown as SEQIDNo.1; and after the sequence was obtained, searching and similarity comparison were performed in
GenBank by using BLAST(http://www.ncbi.nlm nih.gov/BLAST). 16S rDNA homology analysis results showed that, the TY-S11 was a lactobacillus fermentum.
Embodiment 2 Degradation of TY-S11 to cholesterol (1) Culture and treatment of strains
Strains that were stored in glycerol at -80°C were taken, and inoculated to the 5 mL MRS liquid culture medium according to 2% of the inoculation amount, anaerobic culture was performed for 24h at 37°C; and the strains were activated for 3 generations. (2) Preparation of reagent 0.5g of cholesterol powder was weighed, heated and dissolved in anhydrous ethanol, and made up to 50 mL, so as to obtain 10.0 mg/m L of a cholesterol solution; and the above solution was sterilized with 0.45, that is, a microporous filter membrane, and added to the sterile MRS liquid culture medium according to 1%(v:v), so as to obtain a 0.1mg/mL cholesterol culture medium, and the culture medium was prepared while being used. 50 mg of o-phthalaldehyde was weighed and made up to 50 mL by using the anhydrous ethanol, so as to obtain a 1 mg/mL o-phthalaldehyde working solution; and the working solution was refrigerated at 4°C for later use.
Glacial acetic acid and concentrated sulfuric acid were taken and well mixed according to
L:1(v:v), so as to obtain a mixed acid, and the mixed acid was stored at room temperature. (3) Standard curve plotting 5 test tubes were taken and numbered according to 1-5, and were respectively added to 0, 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL and 0.5 mL cholesterol culture media in sequence; the 5 test tubes were all made up to 0.5 mL by adding the glacial acetic acid; each test tube was added with 0.2 mL of the o-phthalaldehyde working solution and well mixed by means of shaking; the test tubes were allowed to stand for 10 min, then respectively added with 4.0 mL of the mixed acid, and well mixed; standing was performed for 10 min at room temperature, the reaction solution was placed in a 96-well plate; and a standard curve was plotted by using the concentration of cholesterol as a horizontal coordinate and an ODssonm value as a longitudinal coordinate, as shown in Fig. 3. (4) Measurement of cholesterol removal rate
The well activated bacterial suspension was added to a 5 mL cholesterol culture medium according to 3% of the inoculation amount (v:v), the inoculated culture medium was centrifuged for 10 min at 4°C and 9000r/min, and 0.5 mL of supernatant was taken; 0.2 mL of the o-phthalaldehyde working solution was added; standing was performed for 10 min after full oscillation; 4.0 mL of the mixed acid solution was added, and allowed to stand for 10 min at room temperature; the reaction solution was placed in the 96-well plate, and the ODssoum value was measured; the ODssonm value of the cholesterol culture medium that was inoculated with bacteria and incubated at 37°C for 24h was also measured according to the above steps; and the cholesterol content in the fermentation broth was determined according to a fitting equation of the cholesterol standard curve, and a cholesterol removal rate was calculated according to the equation below. ]
Cholesterol removal rate (%) - BA, 00%
B
Wherein, A is the cholesterol content in the supernatant after culture is performed for 24h at 37°C; and B is the cholesterol content in the supernatant before the strains are incubated.
The cholesterol removal rates of 74 strains of the lactobacillus were calculated according to the above calculation method. Results were shown in Fig. 4, the TY-S11 had the highest cholesterol removal rate (55.2%), such that it indicated that the TY-S11 had a high cholesterol degradation capability and has the potential to alleviate hyperlipidemia.
Embodiment 3 Improvement of TY-S11 to hyperlipidemia (1) Culture and treatment of strains
Strains that were stored in glycerol at -80°C were taken, and inoculated to the 5 mL MRS liquid culture medium according to 2% of the inoculation amount, anaerobic culture was performed for 24h at 37°C; and the strains were activated for 3 generations. The well activated bacterial fluid was centrifuged for 10 min at 4°C and 10000r/min, and bacteria were collected by discarding supernatant; the bacteria were washed with normal saline and then centrifuged again; and the operation was repeated twice to obtain bacterial sludge; the bacterial sludge was resuspended by using a 30%(m/v) sucrose solution, and was cryopreserved at 80°C for later use of intragastric administration of animal experiments; before use, centrifugation was performed for 10 min at 4°C and 10000r/min, supernatant was discarded, gradient dilution was performed by using the normal saline, and the number of viable bacteria was counted by means of a pour-plate method to calculate a Colony Forming Unit (CFU); and the concentration of the bacterial fluid was adjusted to 10° CFU/mL by using the normal saline according to a counting result, so as to obtain bacterial suspension for intragastric administration. (2) Experimental mouse grouping and intervention 10 SPF-grade wild-type male C57BL/6 mice and 20 SPF-grade male ApoE” mice were selected, which were all 8 weeks old; the mice were raised in a standardization laboratory at room temperature of 25+2°C and relative humidity of 50+5% and under a condition of 12h light/12h dark, and an experiment started after a week of adaptive feeding; and after the adaptive phase ended, the C57BL/6 mice were grouped in Group Blank; and the ApoE” mice were grouped in Group Model and Group TY-S11, and each group had 10 mice.
An experimental period was 42 days, during the experiment, the mice in Group Blank were fed with ordinary feed, the mice in Group Model and Group TY-S11 were fed with high fat and high cholesterol feed, and specific recipes were shown in Table 1; and in addition, an intragastric administration operation was performed on the mice in all groups every day, the mice in Group Blank and Group Model were intra-gastrically administered with the normal saline (200pL), the mice in Group TY-S11 were intra-gastrically administered with the bacterial suspension (200uL), and the time for intragastric administration is the same every day.
Table 1 High fat and high cholesterol feed recipe table
L-cystine 3 12
Cellulose BW00 wb oben o
Calcium bieabonate [BB]
Clmmautorte ee
Possum rare Jes p
Ntised vitamin VI000]
Choline bitarrat rh]
Cholesterol ns ob]
Blue dye oes bo]
Yellow dye 00s Ho]
Red ie oo]
Toul ors os (3) Growth performance monitoring of the mice during experiment
The weights of the mice were recorded each week within 42 days of the experimental period, and the food intake and water intake of the mice were recorded every day (the changes in the food intake, water intake, and human body weight of the mice could reflect the health status of the mice to some extent).
Statistical diagrams of changes in the food intake, water intake, and human body weight of the mice during experiment were shown in Fig. 5, Fig. 6 and Fig. 7. During the entire experiment, compared with the mice in Group Normal, the food intake and water intake of the mice in Group Model and Group TY-S11 showed no significant decrease; compared with the mice in Group Normal, the weights of the mice in Group Model and Group TY-S11 were slightly increased; and the above results showed that the high fat and high cholesterol feed does not affect the normal feeding of the mice, and a lactobacillus paracasei TY-G05 had no side effects. (4) Mouse sample collection and treatment
The experimental period lasted 42 days, and then the mice were sacrificed; the mice were fasted for 16h but could drink water before being sacrificed, feces of the mice was collected into a centrifuge tube, and the centrifuge tube was immediately frozen with liquid nitrogen and stored in a refrigerator at -80°C; eyeball blood was extracted, the blood was allowed to stand for
Ih at 4°C and centrifuged for 15 min at 3000r/min, and upper serum was collected carefully; and the mice were dissected to separate liver tissue, which was immediately frozen with the liquid nitrogen and stored in the refrigerator at -80°C.
(5) Measurement of lipid level in serum of the mice
The serum frozen in (4) was taken out, and blood lipids (the blood lipids mainly including total cholesterol, triglyceride, and low-density lipoprotein cholesterol, and being one of the core indicators for evaluating the severity of hyperlipidemia) were detected by using a fully-automatic biochemical analyzer.
A detection result of the triglyceride level in the serum was shown in Fig. 8. The triglyceride level in the serum of the mice in Group Blank was 0.71 mmol/L, and was 1.19 mmol/L in Group Model, such that the triglyceride level in the serum of Group Model was significantly increased compared with that of Group Blank (p<0.0001), and the triglyceride level in the serum of the mice in Group TY-S11 was 0.96 mmol/L and was significantly reduced (by approximately 19.3%) compared with Group Model (p<0.01).
A detection result of the total cholesterol level in the serum was shown in Fig. 9. The total cholesterol level in the serum of the mice in Group Blank was 2.55 mmol/L, and was 27.76 mmol/L in Group Model, such that the total cholesterol level in the serum of Group Model was significantly increased compared with that of Group Blank (p<0.0001), and the total cholesterol level in the serum of the mice in Group TY-S11 was 16.91 mmol/L and was significantly reduced (by approximately 39.1%) compared with Group Model (p<0.05).
A detection result of the low-density lipoprotein level in the serum was shown in Fig. 10.
The low-density lipoprotein level in the serum of the mice in Group Blank was 0.24mmol/L, and was 15.45 mmol/L in Group Model, such that the low-density lipoprotein level in the serum of Group Model was significantly increased compared with that of Group Blank (p<0.0001), and the low-density lipoprotein level in the serum of the mice in Group TY-S11 was 9.59 mmol/L and was significantly reduced (by approximately 37.9%) compared with Group Model (p<0.0001).
The above results showed that the lactobacillus fermentum TY-S11 has the effect of regulating the blood lipids. (6) Measurement of lipid level in liver of the mice
The liver frozen in (4) was taken out, cut and accurately weighed 0.5g; 5 mL of a mixed solution of methanol and chloroform (a volume ratio being 2:1) was added; a tissue homogenizer (60 HZ, homogenization time being 10s/time, with an interval being 30s, homogenization being performed for 5 times continuously at 4°C) was used for full grinding, so as to homogenize liver tissue; after complete grinding, the ground mixed solution was transferred into a graduated test tube, 4.5 mL of the mixed solution of the methanol and the chloroform (the volume ratio being 2:1) was used to wash a grinder, and the washing solution was transferred to the graduated test tube together; the ground mixed solution that was collected before and after was made up to 10 mL, and placed in a water bath to perform warm bath for 1h at 45°C, and then 8000 g was centrifuged for 10 min at 4°C, and then supernatant was collected; and the cholesterol level of the liver and the triglyceride level of the liver were detected by using the fully-automatic biochemical analyzer.
A detection result of the cholesterol level of the liver was shown in Fig. 11. The triglyceride level of the liver of the mice in Group Blank was 5.22 umol/g, and was 7.10umol/g in Group Model, such that the triglyceride level of the liver of Group Model was significantly increased compared with that of Group Blank (p<0.01), and the triglyceride level of the liver of the mice in Group TY-S11 was 5.72 umol/g and was significantly reduced (by approximately 19.4%) compared with Group Model (p<0.05).
A detection result of the triglyceride level of the liver was shown in Fig. 12. The cholesterol level of the liver of the mice in Group Blank was 2.40 umol/g, and was 7.70 umol/g in Group Model, such that the cholesterol level of the liver of Group Model was significantly increased compared with that of Group Blank (p<0.0001), and the cholesterol level of the liver of the mice in Group TY-S11 was 3.68 umol/g and was significantly reduced (by approximately 52.2%) compared with Group Model (p<0.01).
The above results showed that the lactobacillus fermentum TY-S11 has the effect of regulating liver lipids. (7) Oil red O fat staining of liver of mice
A liver frozen section was taken out from the -80°C refrigerator, and dried for 10 min at room temperature; an oil red O working solution was used to stain the section for 45 min at room temperature; washing was performed for 5 times by using 60% isopropanol and was then performed for 3 times by using ddH2O, and staining was performed for 1 min by using hematoxylin; washing was slowly performed for 3 min with tap water, until the running water is colorless; the section was air-dried and then sealed; and pathological changes in the liver of the mice were observed under a microscope. It is to be noted that, oil red O fat staining is a method that is used for displaying the fat in tissue. Oil red O is a fat soluble dye, can be highly dissolved in the fat, and may specifically stain neutral fat such as the triglyceride in the tissue.
A detection result was shown in Fig. 13. Hepatocytes of the mice in Group Blank were arranged normally and no significant abnormalities were observed; and hepatocyte swelling and lipid deposition were observed in the mice of Group Model, and hepatocyte swelling and lipid deposition of the mice in Group TY-G05 were improved.
The above results showed that the lactobacillus fermentum TY-SI1 has the effect of improving liver pathology in the mice. (8) Detection of short-chain fatty acid content in mouse feces using gas chromatography
500 uL of a saturated NaCl solution was added in a 50 mg of mouse feces sample, and was shaken until there were no obvious lumps (a tissue crusher, 60 HZ, homogenization time being 10s/time, with an interval being 30s, homogenization being performed for 5 times continuously at 4°C). 40 pL of 10% sulfuric acid was added to perform acidification, shaken and well mixed.
Then, 1000 uL of ether was added for extraction, shaken and well mixed, and centrifugation was performed for 15 min at 4°C and 12000 rpm. Supernatant was taken and added to an EP tube containing 0.25 g of anhydrous sodium sulfate to stand for 15 min, and centrifugation was also performed with same conditions. Supernatant was taken and added to a gas-phase vial for analysis. Gas chromatographic detection conditions were shown in Table 2 below.
Table 2 Gas chromatographic detection condition table
Chromatographic DB-FFAP30m=320um=0.25um | Detector FID
RE
Temperature program | 100°C for 5 min, a temperature is raised to 250°C at 10°C/min for 12 en a
Heater temperature 300°C Inlet 250°C ee
Split ratio 15:1 Make-up gas Nitrogen te
The content of the short-chain fatty acid (acetic acid, propionic acid, and butyric acid) in mouse feces were detected by means of gas chromatography, and the concentration was calculated by means of an external standard method.
A calculation result of the acetic acid level was shown in Fig. 14. The acetic acid level in the mouse feces in Group Blank was 385.86 ng/g, and was 129.32ug/g in Group Model, such that the acetic acid level of Group Model was significantly reduced compared with that of
Group Blank (p<0.0001), and the acetic acid level in the mouse feces in Group TY-S11 was 166.14 ng/g and was significantly increased (by approximately 28.5%) compared with Group
Model.
A calculation result of the propionic acid level was shown in Fig. 15. The propionic acid level in the mouse feces in Group Blank was 157.07 ng/g, and was 58.48ug/g in Group Model, such that the propionic acid level of Group Model was significantly reduced compared with that of Group Blank (p<0.0001), and the propionic acid level in the mouse feces in Group TY-S11 was 98.38 ug/g and was significantly increased (by approximately 68.2%) (p<0.001) compared with Group Model.
A calculation result of the butyric acid level was shown in Fig. 16. The butyric acid level in the mouse feces in Group Blank was 140.70 ng/g, and was 55.08ug/g in Group Model, such that the butyric acid level of Group Model was significantly reduced compared with that of
Group Blank (p<0.0001), and the butyric acid level in the mouse feces in Group TY-S11 was 98.16 ug/g and was significantly increased (by approximately 78.2%) (p<0.01) compared with
Group Model.
The above results showed that the lactobacillus fermentum TY-S11 has the effect of promoting the secretion of the short-chain fatty acid in the intestinal tract.
To sum up, the lactobacillus fermentum TY-S11 in the present application may simultaneously reduce the triglyceride and cholesterol levels in the liver of the human body and promote the secretion of the short-chain fatty acid in the intestinal tract, such that the triglyceride, total cholesterol and low-density lipoprotein levels in the serum of the human body are simultaneously reduced, thereby achieving the purpose of improving the hyperlipidemia by means of synergism.
It is finally to be noted that, the above embodiments are merely for describing and not intended to limit the technical solutions of the present application. Although the present application is described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present application can be modified or equivalently replaced without departing from the purpose and scope of the technical solutions of the present application, and shall all fall within the scope defined by the claims of the present application.
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| KR20180011490A (en) * | 2016-07-25 | 2018-02-02 | 명지대학교 산학협력단 | Novel Lactobacillus fermentum with probiotic activities and use thereof |
| WO2020080736A1 (en) * | 2018-10-19 | 2020-04-23 | Clinical Nutrition Intl (M) Sdn Bhd | Probiotic strain for ageing, muscle and bone, gut, hyperlipidemia, skin and brain |
| CN114621896A (en) * | 2022-03-23 | 2022-06-14 | 广东省科学院微生物研究所(广东省微生物分析检测中心) | Lactobacillus plantarum84-3 with blood sugar and blood fat reducing functions and application thereof |
| TWI784621B (en) * | 2021-07-16 | 2022-11-21 | 大江生醫股份有限公司 | Chinese medicine fermentation liquid and its uses for refreshing, improving fatigue, protecting liver, boosting immunity, and lowering blood lipids |
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|---|---|---|---|---|
| KR20180011490A (en) * | 2016-07-25 | 2018-02-02 | 명지대학교 산학협력단 | Novel Lactobacillus fermentum with probiotic activities and use thereof |
| WO2020080736A1 (en) * | 2018-10-19 | 2020-04-23 | Clinical Nutrition Intl (M) Sdn Bhd | Probiotic strain for ageing, muscle and bone, gut, hyperlipidemia, skin and brain |
| TWI784621B (en) * | 2021-07-16 | 2022-11-21 | 大江生醫股份有限公司 | Chinese medicine fermentation liquid and its uses for refreshing, improving fatigue, protecting liver, boosting immunity, and lowering blood lipids |
| CN114621896A (en) * | 2022-03-23 | 2022-06-14 | 广东省科学院微生物研究所(广东省微生物分析检测中心) | Lactobacillus plantarum84-3 with blood sugar and blood fat reducing functions and application thereof |
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| DATABASE CNKI [online] 10 April 2019 (2019-04-10), HUANG WENLI ET AL: "Cholesterol-Lowering Effects of Two Lactobacillus Strains in Hyperlipidemia Mice", XP093140574, retrieved from https://oversea.cnki.net/kns/defaultresult/index Database accession no. 10.13255/j.cnki.jusst.2019.06.003 * |
| HUANG WENLI ET AL: "Cholesterol-Lowering Effects of Two Lactobacillus Strains in Hyperlipidemia Mice - CNKI", JOURNAL OF UNIVERSITY OF SHANGHAI FOR SCIENCE AND TECHNOLOGY, 10 April 2019 (2019-04-10), XP093140580, Retrieved from the Internet <URL:10.13255/j.cnki.jusst.2019.06.003> [retrieved on 20240312] * |
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