Application of microbial agent in relieving and treating METH heart addiction

Abstract

The invention provides application of a microbial agent in relieving and treating METH heart addiction, the microbial agent comprises a microorganism Bacteroides eggerthii, and the microbial agent can be used for relieving or treating symptoms such as anxiety, depression and behavioral cognitive impairment, is further suitable for relieving or treating METH heart addiction of patients, and has important significance in treatment and rehabilitation of METH heart addiction.

Description

Background Art

[0001] Methamphetamine (METH) is a central nervous system stimulant belonging to the amphetamine class. Long-term use will produce neurotoxicity and cause brain neuropathy, resulting in abnormal brain function, psychology, and physiology in users, which will then become a chronic, recurrent brain disease.

[0002] The brain has receptors that regulate human emotions and behaviors. When drugs enter the human body, they act on and affect these receptors, gradually forming a state of equilibrium under the action of drugs. Once the effect of drugs disappears, mental symptoms such as restlessness and anxiety and physical symptoms such as nausea, vomiting, and abdominal pain will appear, making drug addicts constantly desire to take drugs to balance the state. This is psychological dependence, also known as mental addiction. Drug addiction is a major problem worldwide. Among them, physical addiction is easy to quit, but "mental addiction" is difficult to quit, which is an important reason for relapse.

[0003] The existing treatments for METH addiction are a combination of medication, psychotherapy, and physical therapy. In terms of medication, antidepressants and antianxiety drugs are mainly used to help relieve withdrawal symptoms, but these drugs are often accompanied by certain side effects and have limited efficacy. Psychological therapy includes cognitive behavioral therapy, motivational enhancement therapy, etc., which help drug addicts resist the temptation of drugs by changing their thinking patterns and behavioral habits. However, these treatments have problems such as unstable efficacy and high relapse rate. Physical therapy includes transcranial magnetic stimulation, neurofeedback and other technologies, which aim to affect brain neural activity through external physical means, but also face the challenges of uncertain effects and high promotion costs. Therefore, there is no unified and effective standard for the treatment of METH addiction, and the relapse rate remains high.

[0004] Based on the view put forward by predecessors that "there may be an interesting connection between intestinal microorganisms and addiction", there are currently few integrative studies on "mental addiction" withdrawal. Therefore, it is necessary to adopt a bacterial intervention method for the "mental addiction" withdrawal of drug rehabilitation students, which is of great significance to the treatment and rehabilitation guidance of METH mental addiction. Summary of the invention

[0005] The purpose of the present invention is to propose the role of bacterial agents in alleviating or treating patients' METH addiction and to provide guidance for the treatment and rehabilitation of METH addiction.

[0006] In view of this, the scheme of the present invention is:

[0007] In a first aspect of the present invention, a bacterial agent is provided for use in preparing a medicine for alleviating and treating behavioral and cognitive disorders, wherein the bacterial agent comprises Bacteroides eggerthii.

[0008] The second aspect of the present invention provides an application in the preparation of a drug for alleviating or treating METH addiction, wherein the bacterial agent comprises Bacteroides eggerthii.

[0009] Furthermore, the bacterial agent is used to improve behavioral and cognitive disorders in subjects.

[0010] Furthermore, the bacterial agent produces butyrate, thereby reducing the level of inflammatory factors, thereby regulating kynurenine metabolism, reducing the presence of neurotoxic metabolites in the kynurenine pathway, and thus reducing behavioral cognitive disorders caused by addiction.

[0011] Furthermore, for the drug described in the first aspect or the second aspect, the drug can improve the exercise time and exercise distance of the subject.

[0012] Furthermore, for the drug described in the first aspect or the second aspect, the drug includes a pharmaceutically acceptable adjuvant.

[0013] Furthermore, for the drug described in the first aspect or the second aspect, the drug is a solid or liquid preparation.

[0014] Furthermore, for the drug described in the first aspect or the second aspect, the drug is for oral administration.

[0015] Preferably, the oral administration form includes, but is not limited to, pills, capsules, tablets, granular powders, film-coated preparations, orally disintegrating granules, sachets or drinkable preparations.

[0016] Compared with the prior art, the present invention has the following beneficial effects:

[0017] By analyzing the differences in relevant indicators between METH addiction patients and normal people after treatment, the present invention finds that supplementing with Bacteroides eggerthii microbial agents can be used to alleviate behavioral and cognitive disorders, and further can be used to alleviate or treat METH addiction, which is of great significance for the treatment and rehabilitation guidance of METH addiction. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 This is a schematic diagram of the comparison of butyrate content between heart addiction patients before and after treatment and healthy people in Example 1 of the present invention; *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.

[0019] Figure 2 This is a schematic diagram comparing the 3HAA content in heart addiction patients before and after treatment and in healthy people according to Example 1 of the present invention; *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.

[0020] Figure 3 This is a schematic diagram of the comparison of TNF-α levels in heart addiction patients before and after treatment and in healthy people in Example 1 of the present invention; *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.

[0021] Figure 4 This is a correlation diagram of the metabolite content of the heart addiction patients before and after treatment and the healthy population in Example 1 of the present invention.

[0022] Figure 5 This is a schematic diagram of the comparison results of the center area time of the open field test between PA rats, healthy rats and rats gavaged with Bacteroides eggerthii in Example 2 of the present invention; *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.

[0023] Figure 6 This is a schematic diagram of the comparison results of the total movement distance of PA rats, healthy rats and rats gavaged with Bacteroides eggerthii in the open field test in Example 2 of the present invention; *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001. DETAILED DESCRIPTION

[0024] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0025] In one embodiment, by analyzing the differences in relevant indicators between patients with addiction and normal people after treatment, it was found that compared with the normal population, the butyrate level of patients with addiction was significantly reduced, but the content would increase significantly after addiction treatment. Studies have shown that in the process of addiction treatment, it is mainly Bacteroides eggerthii that drives the production of butyrate, thereby reducing the level of inflammatory factors, and then regulating kynurenine metabolism, reducing the presence of neurotoxic metabolites in the kynurenine pathway, thereby reducing the behavioral cognitive disorders caused by addiction. Therefore, by establishing a behavioral addiction rat model, it was verified that supplementation with Bacteroides eggerthii microbial agents can be used to alleviate behavioral and cognitive disorders, and then can be used to alleviate or treat METH addiction, which is of great significance for the treatment and rehabilitation of METH addiction.

[0026] In the above embodiments, it can be understood that the main feature of METH addiction is behavioral cognitive disorder. The addiction rat model can simulate the characteristics of behavioral cognitive disorder of METH addiction. Therefore, it is objectively shown that supplementation with Bacteroideseggerthii microbial agents can be used to alleviate or treat METH addiction.

[0027] In the above embodiment, the microbial agent containing Bacteroides eggerthii can be prepared as a drug for alleviating behavioral and cognitive disorders, or alleviating or treating METH addiction.

[0028] In a preferred embodiment, the drug further comprises a pharmaceutically acceptable adjuvant, wherein the adjuvant comprises a carrier and / or an excipient and / or a diluent, and provides the drug with a solid or liquid preparation.

[0029] In a preferred embodiment, the drug is for oral administration. Preferably, the oral administration form includes but is not limited to pills, capsules, tablets, granular powders, film-coated preparations, orally disintegrating granules, sachets or drinkable preparations.

[0030] In a preferred embodiment, the content of the Bacteroides eggerthii microbial agent contained in the medicine can be adjusted as needed, or prepared with a fixed content, and the subject takes it according to the required dose.

[0031] In order to make the experimental methods, technical solutions and advantages and disadvantages in the embodiments of the present invention clearer, the specific experimental steps in the embodiments of the present invention are described in detail and completely below. If the manufacturer of the reagent or instrument is not indicated in the embodiments, conventional products can be purchased from the market. If the specific conditions are not indicated, they can be carried out according to conventional conditions or conditions recommended by the manufacturer.

[0032] Example 1 Analysis of the differences in related indicators between healthy people and patients with addiction

[0033] In this example, 60 METH psychological addicts (MPA) and 17 healthy controls (HC) were selected, 20 METH psychological addicts were treated (MPA+treat), and their serum metabolites and neurotransmitter contents were compared. Butyric acid, tumor necrosis factor-α (TNF-α), and 3-hydroxyanthranilic acid (3HAA) were selected as representative difference indicators to measure the degree of psychological addiction.

[0034] Short-chain fatty acids represented by butyric acid can reflect the intestinal health status and the balance of intestinal microorganisms. Inflammatory factors such as TNF-α play a core role in regulating immune response and inflammation. 3HAA can reflect the level of kynurenine pathway in human tryptophan metabolism. The data show the changes in indicators of heart addiction patients compared with healthy people compared with normal people, providing a theoretical basis for supplementing bacterial compositions. Among them, the comparison results of butyric acid content, 3HAA content and TNF-α content in heart addiction patients and healthy people are as follows: Figure 1 , Figure 2 and Figure 3 shown.

[0035] like Figure 1 As shown in the study, compared with normal people, the butyrate level of patients with addiction is significantly lower, but it will increase significantly after addiction treatment. Figure 2 , Figure 3 In the experiment, the levels of TNF-α and 3HAA were significantly higher than those in normal people, and decreased significantly after treatment.

[0036] At the same time, we collected stool metagenomic samples from 77 people before, during and after treatment, and performed species and functional annotations. The results showed that the lysine synthesis module of intestinal microorganisms was significantly positively correlated with the content of butyrate, and significantly negatively correlated with the level of 3HAA. 3HAA and butyrate were significantly negatively correlated. By leaving one out, we found that Bacteroides eggerthii was the main driver of the lysine synthesis module. Existing studies have shown that short-chain fatty acids in the human body can regulate the level of inflammatory factors in the body, and inflammatory factors can regulate the key enzyme IDO1 in the tryptophan metabolic pathway. 3HAA is a downstream metabolite in tryptophan metabolism. In our data, butyrate and TNF-α were significantly negatively correlated, while the ratio of kynurenine to tryptophan in the reaction catalyzed by TNF-α and IDO1 was positively correlated ( Figure 4 ).

[0037] In summary, our research has shown that in the process of treating addiction, it is mainly Bacteroideseggerthii that drives the production of butyrate, thereby reducing the level of inflammatory factors, and then regulating kynurenine metabolism, reducing the presence of neurotoxic metabolites in the kynurenine pathway, thereby reducing the behavioral and cognitive disorders caused by addiction.

[0038] Example 2 Verification of the effect of supplemental bacterial agents on METH addiction

[0039] According to the exploration of Example 1, it is proposed that the bacterial agent Bacteroides eggerthii has a relieving and inhibitory effect on mental addiction, and can improve the behavioral cognitive disorders of patients with mental addiction. This example uses a sugar water addiction rat model, which simulates the main characteristics of METH mental addiction, including depression and anxiety-like behaviors and cognitive disorders, to verify the role of Bacteroides eggerthii. The experiment is as follows:

[0040] 1. Experimental Preparation

[0041] Eight-week-old female C57BL / 6 rats (n=15) were used. Rats were housed under standard conditions (room temperature 22±1°C, humidity 55±5%, free access to food), with a 12-hour light cycle (6:00 am to 6:00 pm), and free access to food and water. An adaptive feeding period lasted for one week before the start of the experiment. The experimental animals were randomly divided into three groups: a healthy control group (HC, n=5), a psychological addiction group (PA, n=5), and a PA and Bacteroides eggerthii group (PA+BE, n=5).

[0042] 2. The PA rat model was established. The modeling process was divided into the following stages:

[0043] Sugar water adaptation phase (Days 1-7): Two drinking bottles were placed in the rat cage, one containing ordinary water and the other containing 10% sugar water solution. The intake of the two liquids and body weight were recorded.

[0044] Sugar water preference induction phase (Days 8-14): Regular water and sugar water were continuously provided to observe the rats' preference for sugar water. The drinking water bottles were changed regularly every day, and the sugar water intake and body weight were recorded.

[0045] Sugar water restriction phase (Days 15-21): Sugar water was provided only within a fixed hour every day to induce a strong sugar water demand in rats. The intake and behavioral performance were recorded.

[0046] Extinction stage (22-28 days): stop supplying sugar water, provide only ordinary water, observe behavioral changes, and record behavior-related indicators.

[0047] Addiction stage (29th day and later): After stopping sugar water for a period of time, sugar water is briefly provided, and the sugar water intake, weight changes and behavioral performance are recorded.

[0048] 3. Treatment and behavioral experiments

[0049] 1) PA rats were gavaged with 100 μL PBS every day for 4 weeks; PA+BE rats were gavaged with 1x 10 9CFUbacteroides eggerthii for 4 weeks. HC rats always had free access to food and water.

[0050] 2) An open field test was conducted after the end of the fourth week. The floor of the apparatus was thoroughly cleaned with 75% ethanol and dried before each new animal was tested. The rats were allowed to adapt to the environment in the testing room for more than 30 minutes, and the tests were performed in a random order. The activities of the animals were recorded and analyzed using a computer-automated video tracking system (Tracking Master V4.0-OF, VanBi, Shanghai, China). The rectangular test cage (50 cm × 50 cm × 40 cm) was divided into 9 squares, and the middle square was designated as the center area. The rat was gently placed in the center area to start the test, and the rat's behavior was monitored for 5 minutes by the tracking system to quantify the rat's movements. The time spent in the center area and the total distance of movement in the open field can be used to assess the behavioral cognitive impairment of the rats, and the results are as follows: Figure 5 , Figure 6 shown.

[0051] 3) Compared with the HC group, the PA group spent more time in the center zone in the open field test ( Figure 5 ) and the total distance traveled ( Figure 6 ), indicating increased anxiety-like behavior and decreased motor activity. The PA+BE group was able to significantly increase the time spent in the center area and the total distance traveled in the open field test relative to the PA group. Our results showed that Bacteroides eggerthii could effectively alleviate PA, as evidenced by the rats staying longer in the center area and moving a longer total distance. PA+BE rats showed significant improvement compared with PA rats. At the same time, no significant differences were observed between the PA+BE group and the HC group in terms of center area time and total distance, indicating that Bacteroides eggerthii could restore normal behavioral functions in PA rats. The results of this study indicate that Bacteroides eggerthii can be used as a therapeutic target.

[0052] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. Use of a bacterial agent in preparing a drug for alleviating or treating behavioral and cognitive disorders, wherein the bacterial agent comprises Bacteroideseggerthii.

2. Use of a bacterial agent in the preparation of a drug for alleviating or treating METH addiction, wherein the bacterial agent comprises Bacteroideseggerthii.

3. The use according to claim 2, characterized in that: The bacterial agent is used to improve behavioral and cognitive disorders of a subject.

4. The use according to claim 3, characterized in that: The bacterial agent produces butyrate, thereby reducing the level of inflammatory factors, and further regulating kynurenine metabolism, reducing the presence of neurotoxic metabolites in the kynurenine pathway, thereby reducing behavioral cognitive disorders caused by addiction.

5. The use according to claim 1 or 3, characterized in that: The bacterial agent is used to improve the exercise time and exercise distance of the subject.

6. The use according to claim 1 or 3, characterized in that: The medicament includes a pharmaceutically acceptable adjuvant.

7. The use according to claim 1 or 3, characterized in that: The medicine is a solid or liquid preparation.

8. The use according to claim 1 or 3, characterized in that: The drug is for oral administration.

9. The use according to claim 8, characterized in that: The oral administration form is a pill, capsule, tablet, granule powder, film-coated preparation, orally disintegrating granule, sachet or drinkable preparation.

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