CN113018318A - Bifidobacterium lactis Probio-M8 and application of product thereof in preparing medicine for treating ASD - Google Patents
Bifidobacterium lactis Probio-M8 and application of product thereof in preparing medicine for treating ASD Download PDFInfo
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Classifications
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- A23G3/34—Sweetmeats, confectionery or marzipan; Processes for the preparation thereof
- A23G3/36—Sweetmeats, confectionery or marzipan; Processes for the preparation thereof characterised by the composition containing organic or inorganic compounds
- A23G3/364—Sweetmeats, confectionery or marzipan; Processes for the preparation thereof characterised by the composition containing organic or inorganic compounds containing microorganisms or enzymes; containing paramedical or dietetical agents, e.g. vitamins
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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- A—HUMAN NECESSITIES
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Abstract
The application discloses application of Bifidobacterium lactis (Bifidobacterium lactis) Probio-M8 and a product thereof in preparing a medicine for treating autism spectrum disorder, wherein the microbial preservation number of the Bifidobacterium lactis (Bifidobacterium lactis) Probio-M8 is CGMCC No.18610, the Bifidobacterium lactis Probio-M8 and a microbial inoculum thereof provided by the application have treatment, alleviation and improvement effects on ASD and can be used for preparing a medicine for treating ASD, and the Bifidobacterium lactis Probio-M8 used by the application has clear sources, has common food properties and microbial strain potential, is low in popularization cost and has a good prospect in preparing products for alleviating and treating ASD such as autism and the like.
Description
Technical Field
The application belongs to the technical field of biology, and particularly relates to application of bifidobacterium lactis Probio-M8 and a product thereof in preparing a medicine for treating ASD.
Background
Autism (Autistic disorder), also known as Autism, is a neurodevelopmental disorder disease whose symptoms are mainly social interaction disorder, speech development disorder, and language communication ability deficiency, accompanied by stereotypical behaviors, and more serious conditions, along with other types of asperger syndrome, childhood schizophrenic disorder, and the like, can be referred to as Autism Spectrum Disorder (ASD). Research shows that ASD has genetic basis and is induced to attack under certain environment, including maternal immunity factor, autoimmune disorder, natural environment factor, etc. and has abnormal brain development. However, the etiology and pathogenesis of ASD are not completely clear.
Most ASD patients suffer from other mental and physical ailments such as: hyperactivity disorders, mood disorders, sleep problems, digestive tract dysfunction, immune problems, and nutritional and metabolic problems, among others. Studies have shown that the digestive tract problems of ASD patients are significant, some ASD patients have significant manifestations, such as constipation, acid reflux or diarrhea, and some ASD patients have no significant symptoms, but when they are examined by gastroscopy or enteroscopy, they find that the digestive tract is abnormal.
Compared with autism patients without obvious symptoms in the gastrointestinal tract, autism patients with certain symptoms in the gastrointestinal tract show more serious symptoms such as irritability, anxiety, social contact avoidance and the like. Through genome detection, the composition of intestinal flora, including the type and the number of flora, of the ASD population is greatly different from that of the healthy population.
With the progress of modern research, especially with the intestinal flora as a research focus, researchers find that the intestinal flora is closely related to the occurrence and development of mental diseases. Related studies have confirmed that the association between intestinal flora and brain affects immunity, metabolism, nerves and behavior, and that the communication between intestinal tract and brain is mediated by nervous system, neuroendocrine and neuroimmune signals.
Disclosure of Invention
The application aims to provide the application of Bifidobacterium lactis (Bifidobacterium lactis) Probio-M8 in preparing a medicament for treating autism spectrum disorder, wherein the microbial preservation number of the Bifidobacterium lactis Probio-M8 is CGMCC No. 18610.
In the application, Bifidobacterium lactis (Bifidobacterium lactis) Probio-M8 is a gram-positive bacterium, an agar plate generates a convex milky-white colony with the diameter of 1-2 mm, the edge is complete, the surface is smooth, the cell shape is dumbbell-shaped, two ends are regular, a plurality of obvious nodes are arranged, Bifidobacterium Probio-M8 is heterotypic fermentation, Bifidobacterium lactis Probio-M8 is separated from breast milk, and the strain is preserved in China Committee for culture Collection of microorganisms, general microbiological culture center of China academy of sciences, China institute of microbiology, Ministry of China, Ministry of Western Lu 1, Ministry of North Cheng Yangye, No. 3, of Beijing, in 2019, 20 days: 100101, classified and named as Bifidobacterium lactis (CGMCC), and its microorganism preservation number is CGMCC No. 18610.
The bifidobacterium lactis Probio-M8 provided by the invention has good tolerance to gastrointestinal digestive juice and bile salt, so that the bifidobacterium lactis Probio-M8 provided by the application belongs to probiotics.
It is also an object of the present application to provide a probiotic formulation for use in the treatment of autism spectrum disorders, said probiotic formulation comprising said bifidobacterium lactis Probio-M8.
In an achievable manner, the number of viable bacteria of the bifidobacterium lactis Probio-M8 in the probiotic preparation is not less than 1 x 10, based on the total weight or the total volume of the probiotic preparation6CFU/g or 1X 106CFU/mL. In particular, if the probiotic formulation is a solid, by weight, if the probiotic formulation is a liquid, by volume.
Optionally, the probiotic preparation further comprises a drug carrier, and the drug carrier comprises microalgae, inulin, protein hydrolysate and the like.
Further, the probiotic formulation may be prepared by a process comprising the steps of:
culturing the Bifidobacterium lactis Probio-M8 to obtain Bifidobacterium lactis Probio-M8 bacterial liquid;
separating the Bifidobacterium lactis Probio-M8 thallus from the obtained Bifidobacterium lactis Probio-M8 bacterial liquid;
the obtained Bifidobacterium lactis Probio-M8 thallus is prepared into probiotic solid preparation.
In the present application, the Bifidobacterium lactis Probio-M8 is a wet cell, and can be cultured by any method known in the art for culturing probiotics, for example, by fermentation.
Alternatively, the cells may be separated by any method known in the art, such as centrifugation, for separating solid cells from a bacterial liquid.
Optionally, the method for preparing the obtained bifidobacterium lactis Probio-M8 thallus into the probiotic solid preparation can adopt any method for preparing live bacteria into a solid microbial inoculum in the prior art, such as freeze-drying, spray-drying or embedding, and the like, so as to achieve the purposes of prolonging the shelf life and reducing the transportation cost.
It is also an object of the present application to provide the use of said bifidobacterium lactis Probio-M8 or said probiotic preparation for the preparation of at least one of the following products:
(A) a BTBR autism model mouse therapeutic drug;
(B) an ASD therapeutic agent.
(C) An intestinal flora modulator;
(D) a functional health product.
In the present application, the four preparations include the viable bacterial cell of Bifidobacterium lactis Probio-M8.
Further, in the preparation, the number of the viable bacteria of the bifidobacterium lactis Probio-M8 is not less than 1 x 10 based on the total weight or the total volume of the probiotic preparation6CFU/g or 1X 106CFU/mL。
Furthermore, the regulator for regulating the balance of intestinal flora prepared from the bifidobacterium lactis Probio-M8 can be compounded with other substances capable of stimulating the growth of beneficial bacteria, such as fructo-oligosaccharide, xylo-oligosaccharide, Chinese herbal medicines and extracts thereof.
Further, the intestinal flora regulator and the functional health product can be candy tablets, probiotic solid beverages and the like; the dosage forms of the BTBR autism model mouse therapeutic drug and the ASD therapeutic drug can be oral dosage forms, and specifically comprise oral liquid, granules, pills, capsules and the like.
It is another object of the present application to provide the use of the probiotic formulation for the preparation of at least one of the following products:
(A) a BTBR autism model mouse therapeutic drug;
(B) an ASD therapeutic agent.
(C) An intestinal flora modulator;
(D) a functional health product.
Optionally, the preparation further comprises a pharmaceutical carrier and/or a pharmaceutical excipient.
In the present application, in the above four preparations, the probiotic preparation is present in a percentage by weight of 6% to 10%, based on the total weight of the preparation.
Further, the intestinal flora regulator and the functional health product can be candy tablets, probiotic solid beverages and the like; the dosage form of the BTBR autism model mouse therapeutic drug and the ASD therapeutic drug can be oral dosage forms, and the oral dosage forms comprise oral liquid, granules, pills, capsules and the like.
Compared with the prior art, BTBR autism mouse model research discovers that the Bifidobacterium lactis Probio-M8 and the microbial inoculum thereof provided by the application have the effects of treating, relieving and improving ASD and can be used for preparing medicines for treating ASD, and the Bifidobacterium lactis Probio-M8 used by the application has clear sources, has the properties of common foods and the potential of microecological medicine strains, is low in popularization cost and has good prospects in preparing products for relieving and treating ASD such as autism and the like.
Drawings
FIG. 1A shows the social behavior of B6 and BTBR in a three-box social test;
FIG. 1B shows the novelty preferences of B6 and BTBR in a three-box social test;
FIG. 2A shows the social behavior of B6, BTBR-vehicle, and BTBR-M8 in a three-box social test (D22-23);
FIG. 2B shows the novelty preferences of B6, BTBR-vehicle, and BTBR-M8 in a three-box social test (D22-23);
FIG. 2C shows the social behavior of B6, BTBR-vehicle, and BTBR-M8 in a three-box social test (D40-41);
FIG. 2D shows the novelty preferences of B6, BTBR-vehicle, and BTBR-M8 in a three-box social test (D40-41);
FIG. 3A shows the social behavior index of B6, BTBR-vehicle, and BTBR-M8 in a three-box social test (D22-23);
FIG. 3B shows the novelty preference indices (D22-23) of B6, BTBR-vehicle, and BTBR-M8 in a three-box social test;
FIG. 3C shows the social behavior index of B6, BTBR-vehicle, and BTBR-M8 in a three-box social test (D40-41;
FIG. 3D shows the novelty preference indices (D40-41) of B6, BTBR-vehicle, and BTBR-M8 in a three-box social test;
FIG. 4A shows the average grooming times for B6 and BTBR in the grooming test;
FIG. 4B shows the number of false teasing by B6 and BTBR in the pile test;
FIG. 5A shows the mean grooming times (D22-23) of B6, BTBR-vehicle and Bifidobacterium Probio-M8 on BTBR in the grooming test;
FIG. 5B shows the number of false teasing (D22-23) of B6, BTBR-vehicle and Bifidobacterium lactis Probio-M8 on BTBR in the hairiness test;
FIG. 5C shows the mean grooming times (D39-40) of B6, BTBR-vehicle and Bifidobacterium lactis Probio-M8 on BTBR in the grooming test;
FIG. 5D shows the number of false teasing (D39-40) of B6, BTBR-vehicle and Bifidobacterium lactis Probio-M8 on BTBR in the hairiness test;
FIG. 6A shows B6 and BTBR exploring times for an object in the familial phase in a cognitive behavioral testing trial;
FIG. 6B shows recognition indices of B6 and BTBR in cognitive behavioral testing trials over the testing period;
FIG. 7A shows the exploration times (D28-31) of BTBR for an object in the familial phase in a cognitive behavioral testing trial for BTBR by B6, BTBR-vehicle, and Bifidobacterium lactis Probio-M8;
FIG. 7B shows the recognition index (D28-31) of B6, BTBR-vehicle and Bifidobacterium lactis Probio-M8 for BTBR in a cognitive behavioral test trial over the test period;
FIG. 7C shows the exploration times (D45-48) of BTBR for objects in the familial phase in cognitive behavioral testing trials by B6, BTBR-vehicle and Bifidobacterium lactis Probio-M8;
FIG. 7D shows the recognition index (D45-48) of B6, BTBR-vehicle and Bifidobacterium lactis Probio-M8 for BTBR in a cognitive behavioral testing assay over the test period;
FIG. 8A shows the total field-open motion path for B6 and BTBR in the field-open test;
FIG. 8B shows the central zone motion path in the open field test for B6 and BTBR;
FIG. 8C shows the central zone motion times for B6 and BTBR in the open field test;
FIG. 8D shows the number of standings of B6 and BTBR in the open field test;
FIG. 8E shows the standing times of B6 and BTBR in the open field test;
FIG. 9Aa shows the total field-open motion path (24D) for B6, BTBR-vehicle and Bifidobacterium lactis Probio-M8 versus BTBR in the field-open test for B6 and BTBR in the field-open test;
FIG. 9Ab shows the total field-open motion path (42D) for B6, BTBR-vehicle and Bifidobacterium lactis Probio-M8 versus BTBR in the open field test for B6 and BTBR in the open field test;
FIG. 9Ba shows the central zone motion distance (24D) for B6, BTBR-vehicle and Bifidobacterium lactis Probio-M8 versus BTBR in the open field test for B6 and BTBR in the open field test;
FIG. 9Bb shows the central region movement path (42D) for B6, BTBR-vehicle and Bifidobacterium lactis Probio-M8 versus BTBR in the open field test for B6 and BTBR in the open field test;
FIG. 9Ca shows the time of central zone movement (24D) of B6, BTBR-vehicle and Bifidobacterium lactis Probio-M8 versus BTBR in the open field test for B6 and BTBR in the open field test;
FIG. 9Cb shows the time of movement of B6 in the open field test and of the central region in the open field test (42D) for BTBR by Bifidobacterium lactis Probio-M8;
FIG. 9Da shows the number of stands of B6, BTBR-vehicle and Bifidobacterium lactis Probio-M8 on BTBR in the open field test B6 and BTBR in the open field test (24D);
FIG. 9Db shows the number of standings (42D) of B6, BTBR-vehicle and Bifidobacterium lactis Probio-M8 against BTBR in the open field test B6 and BTBR in the open field test;
FIG. 9Ea shows the standing time (24D) of B6, BTBR-vehicle and Bifidobacterium lactis Probio-M8 versus BTBR in the open field test for B6 and BTBR in the open field test;
FIG. 9Eb shows the standing times (42D) of B6, BTBR-vehicle and Bifidobacterium lactis Probio-M8 versus BTBR in the open field test of B6 and BTBR in the open field test.
Detailed Description
Reference will now be made in detail to the exemplary embodiments, examples of which are illustrated in the accompanying drawings. When the following description refers to the accompanying drawings, like numbers in different drawings represent the same or similar elements unless otherwise indicated. The embodiments described in the following exemplary embodiments do not represent all embodiments consistent with the present invention. Rather, they are merely examples of methods consistent with certain aspects of the invention, as detailed in the appended claims.
The use of bifidobacterium lactis Probio-M8 in the preparation of a medicament for the treatment of autism spectrum disorders, as provided herein, is illustrated in detail by the specific examples below.
First, a brief description is given of a model used in the present embodiment.
The application is researched by a BTBR T- (+) tf/J (BTBR for short) mouse model, wherein a BTBR mouse is a main application model for researching autism, and the BTBR mouse is an inbred line mouse and has the core symptoms of ASD: social contact is reduced, and the ultrasonic waves emitted in social occasions are less and severe; in addition, the compound also has the brain dysplasia and immune biochemical index abnormality similar to ASD.
In recent years, studies on the association of gut flora imbalance with central nervous system disorders revealed that gut flora imbalance is closely associated with gut-brain axis abnormalities, and therefore, the present applicant has conducted studies with intervention in gut flora balance by probiotics as an entry point for alleviating and/or treating ASD. Due to the differences of physiological and metabolic characteristics among probiotic strains, the probiotic effect is exerted and has strain specificity, so after a large number of researches, the applicant screens the bifidobacterium lactis Probio-M8 to improve the social behaviors and anxiety behaviors of BTBR autism model mice, and plays a certain role in relieving or treating.
The following experimental examples describe the verification process, and the results of the experiments obtained by the other strains with no improvement in social behavior and anxiety behavior of the BTBR autism model mice are not described in the present document.
Specifically, the conclusion obtained by the application is based on the comparison of the difference of intestinal flora of different groups of mice and the combination of the results of the multiomic correlation analysis, and the comprehensive evaluation of the influence of the bifidobacterium lactis Probio-M8 on ASD patients is carried out.
Examples of the experiments
(I) design of the experiment
Animal model: ASD mouse-BTBR, normal developing mouse-B6.
Three groups (13 mice/group):
the first group was the B6 control group: feeding physiological saline;
the second group is BTBR-vehicle group: feeding physiological saline;
the third group was the M8 treatment group: feeding physiological saline and bifidobacterium lactis Probio-M8, wherein the administration dosage is the ratio of bifidobacterium lactis Probio-M8: 5X 109CFU/time, 1 time per day for a total of 21 treatments.
Behavioral test design: three-box social contact, hair-tidying experiment, novel object identification experiment and open field experiment.
Behavioral test time points: before grouping (D-4), after the 21 st dose (D22-31), before the end of the experiment (D39-48).
The sample types and sampling times collected in the experiment are shown in table 1:
TABLE 1 type of sample collected and sampling time information for experiments
(II) test Contents
1. Social behavior test-three-box social test
The test method comprises the following steps:
(1) an adaptation stage: the test mice were placed in a viewing device (40cm x 60cm x 22cm) comprising 3 communicating chambers, which were allowed to move freely in the 3 communicating chambers for 10min to suit the environment.
(2) And (3) a testing stage: well-adapted test mice were removed and randomly placed in the left and right compartments into Empty cages (designated "Empty") and cages with strange mice (designated "Mouse 1"), respectively. Gently placing the well-adapted tested mouse from the middle chamber to make it move for 10min, and recording the times (n) that the tested mouse stays in the left and right chambers respectivelyAir conditionerAnd nA method for preparing a catalyst) And the time of interaction (T) with the empty cage and with the strange Mouse ("Mouse 1"), respectivelyAir conditionerAnd TA method for preparing a catalyst) After completion, the test mice were gently removed. Another strange Mouse (noted "Mouse 2") was placed into the empty cage, and the test Mouse was again gently placed into the middle chamber. The number of times the test mouse stayed in the left and right chambers (n) within the next 10min was recordedCookingAnd nUnfamiliar 2) And the time of interaction with the previous strange Mouse ("Mouse 1") and the new strange Mouse ("Mouse 2"), respectively (T)CookingAnd TUnfamiliar 2)。
And (3) behavior testing:
baseline value determination stage (B6 and BTBR 15 each)
And (3) a testing stage: test early test B6 control and BTBR; mid-test B6 control group, BTBR-vehicle group, and BTBR-M8 treatment group; the end of the trial test B6 control group, BTBR-vehicle group and BTBR-M8 treatment group.
The results are shown in fig. 1A to 3D, in which,
FIG. 1A shows the social behavior of B6 and BTBR in a three-box social test;
FIG. 1B shows the novelty preferences of B6 and BTBR in a three-box social test;
FIG. 2A shows the social behavior of B6, BTBR-vehicle, and BTBR-M8 in a three-box social test (D22-23);
FIG. 2B shows the novelty preferences of B6, BTBR-vehicle, and BTBR-M8 in a three-box social test (D22-23);
FIG. 2C shows the social behavior of B6, BTBR-vehicle, and BTBR-M8 in a three-box social test (D40-41);
FIG. 2D shows the novelty preferences of B6, BTBR-vehicle, and BTBR-M8 in a three-box social test (D40-41);
FIG. 3A shows the social behavior index of B6, BTBR-vehicle, and BTBR-M8 in a three-box social test (D22-23);
FIG. 3B shows the novelty preference indices (D22-23) of B6, BTBR-vehicle, and BTBR-M8 in a three-box social test;
FIG. 3C shows the social behavior index of B6, BTBR-vehicle, and BTBR-M8 in a three-box social test (D40-41;
FIG. 3D shows the novelty preference indices (D40-41) of B6, BTBR-vehicle, and BTBR-M8 in a three-box social test.
As can be seen from FIG. 1A, the experiment before administration found that B6 social interaction behavior was normal, and BTBR social interaction ability was abnormal; b6 was normal in its ability to favor novelty, with obvious social novelty preferences, BTBR impaired novelty preferences. The results show that B6 has obvious social novelty preference and BTBR has no social novelty preference, further indicating that the experimental animal meets the experimental design requirements.
As can be seen from fig. 2A to 3D, at D22-D23, B6 mice performed normal social interactions and had social novelty preferences after dosing, and the BTBR-vehicle group mice had a significantly greater preference for the familiar Mouse ("Mouse 1") than the strange Mouse2 ("Mouse 2") during the second phase of the test;
bifidobacterium lactis Probio-M8 had some improvement in BTBR social behavior after 21 days of continuous administration, but did not have statistical differences (P > 0.05).
In D40-D41, B6 control group mice have normal social interaction behavior and social novelty preference, BTBR-vehicle group has obviously longer contact time to empty cages in the first testing stage than strange mice (P <0.05), and the Bifidobacterium lactis Probio-M8 has certain improvement effect on abnormal social behavior and novelty preference disorder, but has no statistical difference.
In conclusion, bifidobacterium lactis Probio-M8 has a certain improvement effect on social behavior abnormality and novelty preference disorder, but has no statistical difference.
2. Carving behavior test-hair-tidying test
The test method comprises the following steps:
(1) an adaptation stage: the mice were taken from the animal room to the test room 1h before the video recording activity started, and the room was illuminated at about 40Lux for 1h of acclimatization. The testing time is 17: 00-21: 00 each time. For the experiment, the mice were gently transferred into a transparent observation box (specification L.times.WXH: 20 cm. times.20 cm. times.50 cm) and data collection was carried out simultaneously.
(2) And (3) a testing stage: each mouse (15 each of B6 and BTBR) was placed in a clean observation box padded on the bottom, with the camera placed directly above the box. Under low light conditions (about 40Lux), after the observation box is pre-adapted for 10min each time, the behavior of the mouse is recorded for 10min, the testers are kept quiet and far away from the tested mouse in the whole process, the observers keep the standards consistent and the groups are unknown, and the repeated self-combing behavior of the mouse within 10min is scored.
Specifically, 5min is taken as a unit interval, the accumulated hair-combing time and the number of correct/wrong combing actions (rounds) in each interval are recorded, and the average accumulated hair-combing time(s) and the average wrong combing number percentage (%) are calculated, wherein the combing action rounds are analyzed by using a combing analysis algorithm (one round is in sequence from head to tail: paw, face, body, legs, tail/genitals); percent (%) false combing number-total number of times that the normal cranial combing sequence number/combing behavior was not followed.
And (3) a testing stage: test early test B6 control and BTBR; mid-test B6 control group, BTBR-vehicle group, and BTBR-M8 treatment group; the end of the trial test B6 control group, BTBR-vehicle group and BTBR-M8 treatment group.
The results are shown in fig. 4A, 4B, 5A, 5B, 5C and 5D, wherein,
FIG. 4A shows the average grooming times for B6 and BTBR in the grooming test;
FIG. 4B shows the number of false teasing by B6 and BTBR in the pile test;
FIG. 5A shows the mean grooming times (D22-23) of B6, BTBR-vehicle and Bifidobacterium Probio-M8 on BTBR in the grooming test;
FIG. 5B shows the number of false teasing (D22-23) of B6, BTBR-vehicle and Bifidobacterium lactis Probio-M8 on BTBR in the hairiness test;
FIG. 5C shows the mean grooming times (D39-40) of B6, BTBR-vehicle and Bifidobacterium lactis Probio-M8 on BTBR in the grooming test;
FIG. 5D shows the number of false teasing in the haircut test of B6, BTBR-vehicle and Bifidobacterium lactis Probio-M8 on BTBR (D39-40).
As can be seen from FIG. 4A and FIG. 4B, the mean hair-grooming time of BTBR autism model mice before administration is much longer than that of B6 mice (P <0.001), but the two mice have no statistical difference in the ratio of the number of wrong combing times (P >0.05), further indicating that BTBR stereotypy behavior reaches the standard and experimental animals meet the requirements of experimental design.
As can be seen from FIGS. 5A to 5D, Bifidobacterium lactis Probio-M8 did not have a significant improvement in the BTBR average hair-plucking time and the proportion of the number of false combing times after administration of D1-D21.
3. Cognitive behavioral testing-new object recognition
The test method comprises the following steps:
(1) an adaptation period: on day 1, mice (13 each of B6 and BTBR) were acclimated to the test room for 1h, and then acclimated in an open field cabinet (no object in the cabinet) for 20 min.
(2) In the familiarity stage: on day 2, the test mice were acclimated to the test room for 1h, then placed in an open field box for at least 5min, and then removed from the open field box and placed in a clean temporary holding cage for about 2 min. And then placing two yellow cylindrical bottles with the same size, color and texture at the left end and the right end of the same side in the open field box as familiar objects, placing the tested mouse in the box with the back facing the objects, recording the condition of the tested mouse on the objects in 5min, and timing the time within the range that the nose or mouth of the mouse is 2cm away from the objects.
(3) And (3) testing period: after the familiarity period of 2h, a yellow cylindrical bottle in the open field box is randomly replaced by a green conical bottle with the same size as the yellow cylindrical bottle to serve as a novelty object, then the mouse is placed in the box with the back facing the object, and the exploration time (Tn) of the mouse on the novelty object and the exploration time (Tf) of the familiar object within 5min are recorded. The identification index (RI) is used as a detection index of the recognition capability of the novel object, and is calculated according to the formula RI of Tn/(Tn + Tf).
And (3) a testing stage: test early test B6 control and BTBR; mid-test B6 control group, BTBR-vehicle group, and BTBR-M8 treatment group; the end of the trial test B6 control group, BTBR-vehicle group and BTBR-M8 treatment group.
The results are shown in fig. 6A, 6B, 7A, 7B, 7C and 7D, in which,
FIG. 6A shows B6 and BTBR exploring times for an object in the familial phase in a cognitive behavioral testing trial;
FIG. 6B shows recognition indices of B6 and BTBR in cognitive behavioral testing trials over the testing period;
FIG. 7A shows the exploration times (D28-31) of BTBR for an object in the familial phase in a cognitive behavioral testing trial for BTBR by B6, BTBR-vehicle, and Bifidobacterium lactis Probio-M8;
FIG. 7B shows the recognition index (D28-31) of B6, BTBR-vehicle and Bifidobacterium lactis Probio-M8 for BTBR in a cognitive behavioral test trial over the test period;
FIG. 7C shows the exploration times (D45-48) of BTBR for objects in the familial phase in cognitive behavioral testing trials by B6, BTBR-vehicle and Bifidobacterium lactis Probio-M8;
FIG. 7D shows the recognition index (D45-48) of B6, BTBR-vehicle and Bifidobacterium lactis Probio-M8 for BTBR in the cognitive behavioral testing trial over the test period.
As can be seen in fig. 6A and 6B, prior to dosing, BTBR mice had significantly less time to explore objects in the familial phase than B6 mice (P < 0.01); the recognition index of BTBR mice during the test period was significantly less than that of B6 mice (P <0.05), further indicating that BTBR mice have cognitive deficits and experimental animals meet experimental design requirements.
As can be seen from FIGS. 7A to 7D, D1-D21, Bifidobacterium lactis Probio-M8 had no improving effect on the cognitive performance of BTBR mice after administration.
4. Behavioral testing-open field testing
The test method comprises the following steps:
under low light conditions (about 40lux), after 2min adaptation of mice (15 each of B6 and BTBR) in an open field analysis chamber, the number of times the mice stood, the standing time, the total regional activity distance, and the central regional activity distance and the activity time in the open field analysis chamber were measured within 10min using an animal spontaneous activity video analysis system.
Standing standard: the front 2 limbs were all lifted off the ground and kept for 1s and above.
And (3) a testing stage: test early test B6 control and BTBR; mid-test B6 control group, BTBR-vehicle group, and BTBR-M8 treatment group; the end of the trial test B6 control group, BTBR-vehicle group and BTBR-M8 treatment group.
The test data includes: total distance, central area time, standing times and standing time.
The experimental results are shown in FIG. 8A, FIG. 8B, FIG. 8C, FIG. 8D, FIG. 8E, FIG. 9Aa, FIG. 9Ba, FIG. 9Ca, FIG. 9Da, FIG. 9Ea, FIG. 9Ab, FIG. 9Bb, FIG. 9Cb, FIG. 9Db, and FIG. 9Eb, wherein,
FIG. 8A shows the total field-open motion path for B6 and BTBR in the field-open test;
FIG. 8B shows the central zone motion path in the open field test for B6 and BTBR;
FIG. 8C shows the central zone motion times for B6 and BTBR in the open field test;
FIG. 8D shows the number of standings of B6 and BTBR in the open field test;
FIG. 8E shows the standing times of B6 and BTBR in the open field test;
FIG. 9Aa shows the total field-open motion path (24D) for B6, BTBR-vehicle and Bifidobacterium lactis Probio-M8 versus BTBR in the field-open test for B6 and BTBR in the field-open test;
FIG. 9Ba shows the central zone motion distance (24D) for B6, BTBR-vehicle and Bifidobacterium lactis Probio-M8 versus BTBR in the open field test for B6 and BTBR in the open field test;
FIG. 9Ca shows the time of central zone movement (24D) of B6, BTBR-vehicle and Bifidobacterium lactis Probio-M8 versus BTBR in the open field test for B6 and BTBR in the open field test;
FIG. 9Da shows the number of stands of B6, BTBR-vehicle and Bifidobacterium lactis Probio-M8 on BTBR in the open field test B6 and BTBR in the open field test (24D);
FIG. 9Ea shows the standing time (24D) of B6, BTBR-vehicle and Bifidobacterium lactis Probio-M8 versus BTBR in the open field test for B6 and BTBR in the open field test;
FIG. 9Ab shows the total field-open motion path (42D) for B6, BTBR-vehicle and Bifidobacterium lactis Probio-M8 versus BTBR in the open field test for B6 and BTBR in the open field test;
FIG. 9Bb shows the central region movement path (42D) for B6, BTBR-vehicle and Bifidobacterium lactis Probio-M8 versus BTBR in the open field test for B6 and BTBR in the open field test;
FIG. 9Cb shows the time of movement of B6 in the open field test and of the central region in the open field test (42D) for BTBR by Bifidobacterium lactis Probio-M8;
FIG. 9Db shows the number of standings (42D) of B6, BTBR-vehicle and Bifidobacterium lactis Probio-M8 against BTBR in the open field test B6 and BTBR in the open field test;
FIG. 9Eb shows the standing times (42D) of B6, BTBR-vehicle and Bifidobacterium lactis Probio-M8 versus BTBR in the open field test of B6 and BTBR in the open field test.
As can be seen from fig. 8A and 8B, no significant difference was observed between B6 and BTBR in the index of total field movement distance, central field movement distance and time, and standing time before administration, but B6 mice were significantly more than BTBR model mice in the index of standing times (P < 0.05).
As can be seen from FIGS. 9Aa to 9Eb, the number of B6 mice was significantly greater than that of BTBR-vehicle model mice (P <0.05) in terms of the index of standing time. The Bifidobacterium lactis Probio-M8 has no obvious difference in the indexes of total regional movement, central regional movement and time of the open field between D24/D42, B6 and BTBR-vehicle at the end of administration (P > 0.05);
in conclusion, the administration of Bifidobacterium lactis Probio-M8 is safe and can be effectively used for treating BTBR autism model mice, and further, the Bifidobacterium lactis Probio-M8 has a certain improvement effect on ADS patient symptoms.
Through the above experiments of the present application, it is further shown that the intestinal flora can interact with mental diseases through gut-brain related networks, interact with each other, influence each other, and regulate in two directions.
The present application has been described in detail with reference to specific embodiments and illustrative examples, but the description is not intended to limit the application. Those skilled in the art will appreciate that various equivalent substitutions, modifications or improvements may be made to the presently disclosed embodiments and implementations thereof without departing from the spirit and scope of the present disclosure, and these fall within the scope of the present disclosure. The protection scope of this application is subject to the appended claims.
Claims (7)
1. Use of Bifidobacterium lactis (Bifidobacterium lactis) Probio-M8 in the preparation of a medicament for treating autism spectrum disorder, wherein the Bifidobacterium lactis (Bifidobacterium lactis) Probio-M8 has the microbial deposit number of CGMCC No. 18610.
2. A probiotic formulation for use in the treatment of autism spectrum disorders, wherein said probiotic formulation comprises said bifidobacterium lactis Probio-M8.
3. The probiotic formulation according to claim 2, characterized in that the number of viable bacteria of the bifidobacterium lactis Probio-M8 in the probiotic formulation is not less than 1 x 10 based on the total weight or volume of the probiotic formulation6CFU/g or 1X 106CFU/mL。
4. The probiotic formulation according to claim 2, characterized in that it can be prepared by a process comprising the following steps:
culturing the Bifidobacterium lactis Probio-M8 to obtain Bifidobacterium lactis Probio-M8 bacterial liquid;
separating the Bifidobacterium lactis Probio-M8 thallus from the obtained Bifidobacterium lactis Probio-M8 bacterial liquid;
the obtained Bifidobacterium lactis Probio-M8 thallus is prepared into probiotic solid preparation.
5. Use of Bifidobacterium lactis Probio-M8 for preparing at least one of the following products, wherein the microbial deposit number of the Bifidobacterium lactis Probio-M8 is CGMCC No. 18610:
(A) a BTBR autism model mouse therapeutic drug;
(B) ASD therapeutic agents;
(C) an intestinal flora modulator;
(D) a functional health product.
6. The preparation according to claim 5, wherein the Bifidobacterium lactis Probio-M8 is present in an amount of 6 to 10% by weight, based on the total weight of the preparation.
7. Use of a probiotic formulation according to claim 2 for the preparation of at least one of the following products, wherein the Bifidobacterium lactis (Bifidobacterium lactis) probiotic-M8 has the microbial deposit number CGMCC No. 18610:
(A) a BTBR autism model mouse therapeutic drug;
(B) ASD therapeutic agents;
(C) an intestinal flora modulator;
(D) a functional health product.
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