NL2039039A

NL2039039A - Food composition capable of ameliorating autism social disorder, preparation method therefor and use thereof

Info

Publication number: NL2039039A
Application number: NL2039039A
Authority: NL
Inventors: Chen Yujiang; Wu Shengxi; Wang Yazhou; Xian Panpan; Wang Mengmeng
Original assignee: Air Force Medical Univ
Priority date: 2024-04-16
Filing date: 2024-11-10
Publication date: 2025-01-27
Also published as: CN118512000A; NL2039039B1

Abstract

Disclosed in the present disclosure are a food composition capable of ameliorating autism social disorder and a preparation method therefor and use thereof, and belongs to the technical ﬁeld of foods. The food composition includes, in percentage by mass, 20% an amino acid complex without methionine and cysteine, 0.15% methionine, 39.45% corn starch, 13% maltodextrin, 10% sucrose, 5% cellulose, 7% soybean vegetable oil and 5.4% vitamins and minerals. By removing cysteine and reducing the methionine content, the food composition formed can reduce the H28 level in the brain of a subpopulation of autistic patients with abnormal H28 metabolism. The autistic mouse model experiments demonstrate that the food 10 composition can signiﬁcantly improve the social ability of autistic mice with abnormal H28 metabolism and thus has good application prospects as a food for ameliorating autism social disorder in human.

Description

FOOD COMPOSITION CAPABLE OF AMELIORATING AUTISM SOCIAL

DISORDER, PREPARATION METHOD THEREFOR AND USE THEREOF

TECHNICAL FIELD

[1] The present disclosure belongs to the technical field of foods, and in particular relates to a food composition capable of ameliorating autism social disorder, a preparation method therefor and use thereof.

BACKGROUND

[2] Autism, also known as autistic disorder and autism spectrum disorder (ASD), is a common developmental mental disorder in children, which is mainly manifested by low social interaction and language communication abilities, and repetitive stereotyped behaviors. Social disorder is the most important clinical symptom of autism. The pathogenic factors of autism are diverse and the pathogenesis is complex. It is generally believed that the abnormality in development or function of synapses in socially related brain regions is the key neurobiological basis of autism social disorder.

[3] Autism usually begins in infancy with symptoms lasting for life. Current treatment mainly includes behavioral interventions, special education, and drug treatment in the early and developmental stages. Mainly through behavioral intervention and special education, adaptive skills, language communication, and emotional control capabilities of pediatric patients are cultivated. In terms of drug treatment, FDA-approved drugs risperidone and aripiprazole are mainly used to improve problems such as emotional control disorder, sleep disorder, and hyperactivity in autistic patients, but so far there has been no drugs that can effectively ameliorate autism social disorder.

[4] In recent years, clinical studies have found that about 30% to 80% of autistic patients have varying degrees of mitochondrial abnormalities in their peripheral blood cells, and some autistic patients have elevated levels of lactic acid in their blood and elevated levels of enzymes related to lactic acid metabolism. In this regard, some studies have proposed to reduce lactic acid and glycolytic metabolism levels by a ketogenic diet, so as to ameliorate the symptoms of autism. However, this method is mainly directed to a subpopulation of autistic patients with abnormal glycolytic metabolism and cannot effectively ameliorate the symptoms of autistic subpopulations with abnormal H>S metabolism.

SUMMARY

[5] In order to overcome the above defects in the prior art, an object of the present disclosure is to provide a food composition capable of ameliorating autism social disorder, a preparation method therefor and use thereof, so as to solve the problem of lack of effective treatment of autism social disorder caused by abnormal H,S metabolism in clinical practice.

[6] In order to achieve the above object, the present disclosure is implemented by adopting the following technical solutions:

[7] In a first aspect of the present disclosure, disclosed is a food composition capable of ameliorating autism social disorder, including, in percentage by mass, 20% an amino acid complex, 0.1%-0.85% methionine, and 79. 15%-79.9% other nutrients, wherein

[8] the amino acid complex is any one or more amino acids other than cysteine and methionine.

[9] Preferably, the other nutrients include maltodextrin, sucrose, cellulose, vegetable oil, and vitamins and minerals.

[10] Preferably, the other nutrients include, in percentage by mass, 38.75-39.5% starch, 13% maltodextrin, 10% sucrose, 5% cellulose, 7% vegetable oil and 5.4% vitamins and minerals.

[11] Preferably, the food composition capable of ameliorating autism social disorder includes, in percentage by mass, 20% an amino acid complex without methionine and cysteine, 0.15% methionine, 39.45% corn starch, 13% maltodextrin, 10% sucrose, 5% cellulose, 7% soybean vegetable oil and 5.4% vitamin and minerals.

[12] Further preferably, 20% the amino acid complex without methionine and cysteine consists of 0.54% L-alanine, 0.75% L-arginine, 1.28% L-aspartic acid, 4.1% glutamic acid, 0.48% glycine, 0.56% L-histidine, 1.10% L-isoleucine, 1.66% L-leucine, 1.85% L-lysine hydrochloride, 0.90% L-phenylalanine, 2.1% L-proline, 1.14% L-serine, 0.88% L-threonine, 0.22% L-tryptophan, 1.14% L-tyrosine and 1.30% L-valine.

[13] In a second aspect of the present disclosure, disclosed is a method for preparing the food composition capable of ameliorating autism social disorder, including uniformly mixing 20% an amino acid complex, 0.1%-0.85% methionine and 79.15%-79.9% other nutrients, and performing granulating and drying to obtain the food composition capable of ameliorating autism social disorder.

[14] In a third aspect of the present disclosure, disclosed is use of the food composition capable of ameliorating autism social disorder as described above in the preparation of a food for ameliorating autism.

[15] Preferably, the food is a food for enhancing the social ability of autistic patients.

[16] Preferably, the food is a food for improving the interaction time and interaction frequency of autistic patients with the outside world. [L7] Preferably, the autism 1s a subgroup of autism caused by abnormal H>S metabolism.

[18] Compared with the prior art, the present disclosure has the following beneficial effects:

[19] According to the food composition capable of ameliorating autism social disorder provided by the present disclosure, the HS level in the brain of a subpopulation of autistic patients with abnormal H:S metabolism will be normalized by removing cysteine and reducing the methionine content. After administration of this modified food to autism mouse models (Shank3b" and FMRI mice), it is found that social preference and social interaction of both autistic mice are significantly improved, indicating that the food composition can effectively improve the social behavior of autistic mice of different ages, and thus has good application prospects as a food for ameliorating autism social disorder.

Given the abnormal H;S metabolism in neurons of autistic mice, the effect of ameliorating autism social disorder can be achieved by limiting the intake of sulfur-containing amino acids in diet in the present disclosure.

BRIEF DESCRIPTION OF DRAWINGS

[20] FIG. 1 is a graph showing the results of a second phase of a 3-chamber assay of juvenile Shank3b mice according to the present disclosure, wherein A and B are trajectory diagrams showing the social preference of two groups of mice in the 3-chamber assay, C shows the residence time in a social contact compartment and a non-social contact compartment, and D is the statistical result of social preference scores;

[21] FIG. 2 is a graph showing the results of a third phase of a 3-chamber assay of juvenile Shank3b"" mice according to the present disclosure, wherein A and B are trajectory diagrams showing the social novelty of two groups of mice in the 3-chamber assay, C shows the residence time in a social contact compartment and a non-social contact compartment, and D is the statistical result of social novelty scores;

[22] FIG. 3 is a graph showing the results of a resident-intruder assay of juvenile

Shank3b mice according to the present disclosure, wherein A is the statistical result of the interaction time with invading mice, B is the statistical result of the interaction frequency with invading mice, and C is a schematic diagram showing the social ability of two groups of mice tested in the resident-intruder assay;

[23] FIG. 4 is a graph showing the results of a resident-intruder assay of juvenile FMRI" mice according to the present disclosure, wherein A is the statistical result of the interaction time with invading mice, B is the statistical result of the interaction frequency with invading mice, and C is a schematic diagram showing the social ability of two groups of mice tested in the resident-intruder assay;

[24] FIG. 5 is a graph showing a third phase of 3-chamber assay of adult Shank3b™ mice according to the present disclosure, wherein A and B are trajectory diagrams showing the social novelty of two groups of mice in the 3-chamber assay, C shows the residence time in social contact compartment and non-social contact compartment, and D is the statistical result of social novelty scores;

[25] FIG. 6 is a graph showing the resident-intruder assay of adult Shank3b™ mice according to the present disclosure, wherein A is the statistical result of the interaction time with invading mice, B is the statistical result of the interaction frequency with invading mice, and C is a schematic diagram showing the social ability of two groups of mice tested in the resident-intruder assay; and

[26] FIG. 7 is a graph showing the resident-intruder assay of adult FMRI" mice according to the present disclosure, wherein A is the statistical result of the interaction time with invading mice, B is the statistical result of the interaction frequency with invading mice, and C is a schematic diagram showing the social ability of two groups of mice tested in the resident-intruder assay.

DETAILED DESCRIPTION OF THE EMBODIMENTS

[27] In order to enable those skilled in the art to understand the features and effects of the present disclosure, only the terms and expressions mentioned in the specification and claims are generally described and defined below. Unless otherwise specified, all technical and scientific words used herein have ordinary meanings as understood by those skilled in the art to the present disclosure, and in case of conflict, the definitions set forth in this specification shall prevail.

[28] The theories or mechanisms described and disclosed herein, whether correct or incorrect, should not limit the scope of the present disclosure in any way, i.e, the present disclosure can be implemented without being limited by any particular theory or mechanism.

[29] All features such as values, quantities, contents, and concentrations defined in the form of numerical ranges or percentage ranges herein are for brevity and convenience only.

Accordingly, the description of the numerical ranges or percentage ranges should be considered to have encompassed and specifically disclosed all possible subranges and individual numerical values (including integers and fractions) within the range.

[30] Herein, unless otherwise specified, "comprising," "including," "containing," "having," or similar terms encompass the meanings of "consisting of" and "consisting 5 essentially of", for example, "A comprises a", which encompasses the meanings that "A comprises a and others" and "A comprises only a".

[31] All possible combinations of the technical features in the embodiments or examples are not described herein for brevity of the description. Therefore, as long as there is no contradiction in the combinations of these technical features, the technical features in the embodiments or examples can be combined arbitrarily, and all possible combinations should be considered within the scope of this specification.

[32] Inthe early stage of the experiment, mitochondrial function and metabolic small molecule changes in anterior cingulate cortexes of two autism model mice (Shark3b"" and

FMRI mice) were studied by using methods such as metabolomics, biochemistry and drug analysis. The results showed that compared with wild-type mice, cystathionine levels in the anterior cingulate cortexes of both autistic mice were significantly increased, and its downstream metabolite hydrogen sulfide (H:S) was also significantly increased in Shank3b™ and FMRI" primary neurons. Considering that HS is a gas transmitter, its abnormal increase will inevitably affect the synaptic function widely, and it is speculated that reducing the HbS level may ameliorate the symptoms of autism.

[33] Based on the principle that HaS inside the brain is mainly produced by metabolism of sulfur-containing amino acids, the present disclosure provides a food composition capable of ameliorating autism social disorder, including, in percentage by mass, 20% an amino acid complex, 0.1%-0.85% methionine, 38.75%-39.5% starch, 13% maltodextrin, 10% sucrose, 5% cellulose, 7% vegetable oil, and 5.4% vitamins and minerals, wherein

[34] the amino acid complex is any one or more amino acids other than cysteine and methionine.

[35] The present disclosure will be further illustrated below with reference to specific examples. It should be understood that these examples are only for illustrating the present disclosure and are not intended to limit the scope of the present disclosure. Furthermore, it should be understood that after reading the teachings of the present disclosure, those skilled in the art may make various changes or modifications to the present disclosure, and such equivalents also fall within the scope defined by the appended claims.

[36] Conventional instruments and equipment in the art were used in the following examples. Experimental methods of which specific conditions were not specified in the following examples were generally performed according to conventional conditions, or according to conditions recommended by the manufacturer. The other raw materials used in the following examples, unless otherwise specified, were conventional commercially available products having specifications conventional in the art. In the specification of the present disclosure as well as in the following examples, "%" represents the mass percentage and a ratio represents a mass ratio unless otherwise specified.

[37] Example 1

[38] A food composition capable of ameliorating autism social disorder includes, in percentage by mass, 20% an amino acid complex without methionine and cysteine, 0.15% methionine, 39.45% corn starch, 13% maltodextrin, 10% sucrose, 5% cellulose, 7% soybean vegetable oil, and 5.4% vitamins and minerals, wherein

[39] the amino acid complex without methionine and cysteine consists of 0.54% L- alanine, 0.75% L-arginine, 1.28% L-aspartic acid, 4.1% glutamic acid, 0.48% glycine, 0.56% L-histidine, 1.10% L-isoleucine, 1.66% L-leucine, 1.85% L-lysine hydrochloride, 0.90% L-phenylalanine, 2.1% L-proline, 1.14% L-serine, 0.88% L-threonine, 0.22% L- tryptophan, 1.14% L-tyrosine and 1.30% L-valine.

[40] A method for preparing the food composition capable of ameliorating autism social disorder includes uniformly mixing 20% an amino acid complex without methionine and cysteine, 0.15% methionine, 39.45% corn starch, 13% maltodextrin, 10% sucrose, 5% cellulose, and 5.4% vitamins and minerals, then adding 7% soybean vegetable oil into the uniformly mixed material, and performing uniform mixing, granulating and drying to obtain the food composition capable of ameliorating autism social disorder.

[41] The prepared food composition capable of ameliorating autism social disorder was administered to two autism models (Shank3b™™ and FMRI" models), respectively, to observe the effect of the food composition on the social behaviors of autistic mice.

[42] 1. Juvenile mouse experiments:

[43] (1) Effect of the food composition on the social function of juvenile Shank3b™ mice. 3-week-old Shank3b male mice were randomly divided into two groups, i.e, a Shank3b™ group (Normal food) fed with a normal mouse food (an experimental mouse maintenance feed purchased by Jiangsu Xietong Pharmaceutical Bio-engineering Co., Ltd.) and a formula feed group (Modified food) fed with the food composition prepared in Example 1. After three weeks of feeding, the social behaviors of the juvenile mice in the groups were analyzed by a 3-chamber assay and a resident-intruder assay.

[44] The 3-chamber assay is primarily used to test the social interaction ability and social novelty of experimental mice. A 3-chamber apparatus used in the experiment is an opaque rectangular box having a length of 63 cm, a width of 43 cm, and a height of 23 cm, and evenly spaced into three areas (an empty compartment, a middle area, and a social contact compartment, respectively) by two partitions in the middle, and the two partitions each are provided with a movable door. Test mice can freely shuttle between the empty compartment, the middle area and the social contact compartment. Prior to the 3-chamberassay, the test mice were allowed to acclimate to the chamber daily for 7 days. On the day of the experiment, the test mice in the groups (the Shank3bh™ group and the formula feed group) were separately placed in a behavior room for acclimation 2 h in advance. The time for each behavioral test was selected between 15:00 and 21:00, the illumination intensity is about 650 lux, the noise does not exceed 30 dB, and after the test mice were placed in the middle area of the 3-chamber apparatus for acclimation for 10 min, a social mouse 1 (S1, 3 weeks old, of the same strain) to which one test mouse has never been exposed was placed in an empty round cage at one corner of the 3-chamber apparatus, and the same vacant round cage was placed at the opposite corner, then the partitions were removed, and timing was started.

Video recording software performed recording for 10 minutes. After the recording was completed, the test mouse was separated again in the middle area and another social mouse 2 (S2, having the same age as that of the previous social mouse and being in different litters and different cages from the previous social mouse) was placed in the vacant round cage.

The partitions were removed, timing was started and a 10 min behavior video was recorded.

The test was completed after the recording. A bottom plate, side walls, and the round cages in the 3-chamber apparatus were cleaned with 75% alcohol. Data recording for a next test mouse were prepared to be performed. After all experiments were completed, behavioral videos of the test mice in the groups were imported into Smart 3.0 analysis software for analysis.

[45] The 3-chamber assay results showed that when the social preference of the test mice to the social mouse 1 (S1) was observed, there was no significant difference in the residence time of the mice in the Shank35"" group in the empty compartment and the social contact compartment, and the residence time of the mice in the formula feed group in the social contact compartment was significantly longer than that in the empty compartment, suggesting a significant increase in social preference (FIG. 1). When the social novelty of the test mice to the social mouse 2 (S2) was observed, there was no significant difference in the residence time of the mice in the Shank3bh™ group in the social contact compartment where the social mouse 2 was placed and the social contact compartment where the social mouse 1 was placed, while the time of the mice spent in the formula feed group in the social contact compartment with social mouse 2 was significantly longer than that in the social contact compartment with social mouse 1, suggesting a significant increase in their social novelty (FIG. 2).

[46] A resident-intruder assay mainly tests the social interaction ability of experimental mice. The resident-intruder assay was performed two days after the end of the 3-chamber assay. The test mice in the groups (the Shank3b™" group and the formula feed group) were housed in single cages one day before the resident-intruder assay, and placed in a test room to acclimate 2 h before the experiment, the experimental time and lighting conditions were the same as those in the 3-chamber assay, after the test mice freely explored in their own cages for 1 min, one male wild-type juvenile mouse (about 3-4 weeks old, significantly smaller than the test mice in size) was taken as an invading mouse and placed in a cabinet with the test mice for free exploration for 10 min (in the experimental stage) and picture recording, and the interaction time and interaction frequency of each pair of mice were counted.

[47] In the resident-intruder assay, the interaction time and interaction frequency of

Shank3h” mice fed with the food composition as prepared in Example 1 with the invading mice were significantly increased, compared with the control group (FIG. 3), demonstrating that the social interaction ability was significantly improved after feeding the juvenile

Shank3b™ mice with the food composition prepared in Example 1.

[48] (2) Effect of the food composition on the social function of juvenile FMRI mice.

Since the social behavior abnormalities exhibited by ZAZR/™" mice in the 3-chamber assay were less obvious, we primarily evaluated their social behaviors by using a resident-intruder assay. 3-weed-old FMRI” male mice were randomly divided into two groups, i.e, an

FMRI" group (Normal food) fed with a normal mouse food and a formula feed group (Modified food) fed with the food composition prepared in Example 1. After 3 weeks, the social behaviors of the juvenile mice in the groups were tested by using the resident-intruder assay with the same steps as those described above.

[49] The experimental results showed that the interaction time and interaction frequency of the mice in the formula food group with the invading mice were increased compared with the control group (FIG. 4). These results suggest that feeding the food composition prepared in Example 1 can significantly enhance the social function of the juvenile FMRI" mice.

[50] 2. Adult mouse experiments:

[51] (1) Effect of the food composition on the social function of adult Shank3bh™ mice. 6- to 8-week-old Shank3b male mice were randomly divided into two groups, i.e., a Shank3b * group (Normal food) fed with a normal mouse food and a formula feed group (Modified food) fed with the food composition prepared in Example 1. The social behaviors of the adult mice were analyzed by 3-chamber assay and resident-intruder test after two weeks of feeding. The procedures of the 3-chamber assay and the resident-intruder assay were the same as those above.

[52] The 3-chamber assay showed that Shank3b™ mice spent similar time in the empty compartment and the social contact compartment during the second phase of social preference. In contrast, the mice in the formula feed group spent significantly longer time in the social contact compartment than that in the empty compartment, suggesting a significant increase in their social preference (FIG. 5). During the third phase of social novelty,

Shank3b™ mice showed no significant difference in the residence time in the social contact compartment where the social mouse 2 was placed and the social contact compartment where the social mouse 1 was placed, while the mice fed with the food composition prepared in Example 1 showed significantly longer time in the social contact compartment where the social mouse 1 was placed than that in the social contact compartment where the social mouse 2 was placed, suggesting a significant increase in their social novelty (FIG. 5).

[53] Inthe resident-intruder assay, both the interaction time and the interaction frequency of the mice in the formula feed group with the invading mice were increased compared with the control group (FIG. 6), indicating that the social ability of the adult SA4ank35"" mice was significantly improved.

[54] (2) Effects of the food composition on the social function of adult FMR/™ Mice. 6- to 8-week-old FMRI male mice were randomly divided into two groups, i.e., an FMRI group (Normal food) fed with a normal mouse food and a formula feed group (Modified food) fed with the food composition prepared in Example 1. The social behaviors were tested by using a resident-intruder assay after 2 weeks. The procedures of the resident- intruder assay were the same as those above.

[55] Both the interaction time and the interaction frequency of the mice in the formula feed group with the invading mice were significantly increased compared with the control group (FIG. 7). These results suggest that feeding with the food composition in Example 1 can also significantly enhance the social function of the adult FEMR/” mice.

[56] The above experimental results show that the food composition provided by the present disclosure can significantly improve the social behaviors of autistic mice.

[57] The above contents are merely to illustrate the technical idea of the present disclosure, and cannot limit the scope of protection of the present disclosure. Any modifications made on the basis of the technical solutions according to the technical idea proposed in the present disclosure fall within the scope of protection of the claims of the present disclosure.

Claims

Conclusions

1. Composition of foodstuffs which can improve the social disorder of autism, containing, as a percentage by mass, 20% of an amino acid complex, 0.1% - 0.85% of methionine and 79.15% - 79.9% of other nutrients, wherein the amino acid complex is one or more amino acids other than cysteine and methionine.

2. The composition of foodstuffs which can improve the social disorder of autism according to claim 1, wherein the other nutrients include maltodextrin, sucrose, cellulose, vegetable oil and vitamins and minerals.

3. The food composition capable of improving the social disorder of autism according to claim 1, wherein the other nutrients contain, in mass percentage, 38.75-39.5% starch, 13% maltodextrin, 10% sucrose, 5% cellulose, 7% vegetable oil and 5.4% vitamins and minerals.

4. The composition of foodstuffs capable of improving the social disorder of autism according to claim 1, containing, in mass percentage, 20% of an amino acid complex without methionine or cysteine, 0.15% of methionine, 39.45% of corn starch, 13% of maltodextrin, 10% of sucrose, 5% of cellulose, 7% of vegetable soybean oil and 5.4% of vitamins and minerals.

5. The composition of food that can improve the social disorder of autism according to claim 4, wherein 20% of the amino acid complex without methionine and cysteine consists of 0.54% L-alanine, 0.75% L-arginine, 1.28% L-aspartic acid, 4.1% glutamic acid, 0.48% glycine, 0.56% L-histidine, 1.10% L-isoleucine, 1.66% L-leucine, 1.85% L-lysine hydrochloride, 0.90% L-phenylalanine, 2.1% L-proline, 1.14% L-serine, 0.88% L-threonine, 0.22% L-tryptophan, 1.14% L-tyrosine and 1.30% L-valine.

6. A method for preparing the food composition capable of improving the social disorder of autism according to any one of claims 1 to 5, comprising uniformly mixing 20% of an amino acid complex without cysteine and methionine, 0.1% - 0.85% of methionine and 79.15% - 79.9% of other nutrients, and carrying out granulation and drying to obtain the food composition capable of improving the social disorder of autism.

7. Use of the composition of foodstuffs capable of improving the social disorder of autism according to any one of claims 1 to 5 in the preparation of a food for improving autism.

8. The use according to claim 7, wherein the food is a food for improving the social capacity of autistic patients.

9. The use according to claim 7, wherein the food is a food for improving the time and frequency of interaction of autistic patients with the outside world.

10. The use according to claim 7, wherein the autism patients are the subgroup of autism associated with abnormal H>S metabolism.