CN114452305A - Application of bacteroides uniformis in preparing medicine for preventing and treating anxiety and depression - Google Patents
Application of bacteroides uniformis in preparing medicine for preventing and treating anxiety and depression Download PDFInfo
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- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
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- A61P25/22—Anxiolytics
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
The invention belongs to the field of life science, and particularly relates to a novel application of Bacteroides simplex (Bacteroides unifomis) in the aspect of preventing and treating anxiety and depression. The amount of viable Bacteroides monoides (Bacteroides uniformis) is 1 × 10 per day4‑1×1020CFU/mL。
Description
Technical Field
The invention belongs to the field of microbiology, and particularly relates to application of Bacteroides simplex (Bacteroides unifomis) in medicines for preventing and treating anxiety and depression.
Background
Depression, also known as depressive disorder, is a common mood disorder with symptoms of depressed mood, low-lying, depression, pessimistic and disgusting intention or behavior, and in some cases with obvious anxiety. According to the latest data of the world health organization, the incidence rate of the global depression is 3.1%, the average incidence age is about 25 years old, and people of more than 2.64 billion ages all over the world suffer from the depression and are in a continuous rising trend in recent years.
Life events play an important potential role in the induction and possible cause of major depressive disorders. For example, the impact of stressful life events is closely related to the onset of major depressive disorder one year prior to the onset of depression. Stressful life events include chronic illness, economic instability, loss of employment, living quarters, loss of relatives, and the like. Stressful life events have been found to have a strong link with depression. Most anxiety and depression patients have experienced psychological stress events, and thus stress events are currently considered to be one of the causes of anxiety and depression, which can lead to the development of mood disorders. Depression is also an induction factor for inducing a series of diseases, such as osteoarthritis, cardiovascular diseases, coronary heart disease, parkinson's disease, and the like. Many factors can cause the occurrence of depression, and no clear mechanism can be explained in all aspects at present, and the etiology and pathogenesis of the depression are not clearly researched. Treatment of depression is usually by psychotherapy, drug therapy, or both. The main limitations of psychotherapy are that trained therapists are few and that treatment costs are expensive. Although antidepressant therapies vary widely, a significant proportion of patients do not respond adequately, either partially or not at all, to treatment. Moreover, the medicines can generate a plurality of side effects when being taken for a long time, such as headache, dizziness, hepatotoxicity, hypertension, insomnia and other adverse reactions. The depression affects millions of people all over the world, however, no effective method or medicament for preventing and treating the anxiety depression with small side effect exists in the field, so that the development of a novel method or medicament for preventing and treating the anxiety depression without toxic side effect is urgently needed in the field.
In recent years, the intestinal flora has been found to be closely related to human health, such as irritable bowel syndrome, obesity, heart disease, etc., and particularly the intestinal flora affects brain activities such as stress, fear, cognition, etc., and plays a key role particularly in emotional handling and behavior. In view of the potential influence of the intestinal microorganisms on the central nervous system, particularly on stress, emotion, anxiety and cognition, the intestinal microorganisms have important clinical significance as a potential means for improving or treating mental diseases, and have wide application prospects. However, the probiotics associated with mood improvement are almost all probiotics discovered earlier, and research work on new psychoprobiotics has been rarely reported in recent years. In addition, the prevention effect of the probiotics is not researched in the study of the probiotics related to mood improvement at present, and the prevention effect has important significance for people who experience life stress for a long time.
Disclosure of Invention
In order to solve the technical problems, through intensive research of the inventor, the Bacteroides uniformis found to have the effects of preventing and treating anxious and depressive behaviors, and the Bacteroides uniformis found to be capable of inhibiting the anxious and depressive behaviors and effectively relieving mental disease symptoms by gavaging an experimental subject, so that the Bacteroides uniformis suitable for developing drugs for relieving anxiety and depression. The present invention has been completed based on this finding.
The invention aims to provide application of Bacteroides uniformis in preparing a medicament for preventing and treating anxiety and depression. Wherein the Bacteroides uniformis ATCC8492(Bacteroides uniformis ATCC8492) purchased from China Industrial Culture Collection (China Industrial Culture Collection) and having a deposit number of ATCC8492, the Bacteroides uniformis in the form of living cells, and the effective amount in the medicine is 1X 109CFU/mL。
The medicament comprising bacteroides uniformis ATCC8492 and or metabolites thereof according to the present invention achieves its effects by at least one of the following mechanisms:
1) reducing the level of inflammatory factors in serum or brain tissue;
2) reducing the content of corticosterone in serum;
3) increasing the content of short chain fatty acids;
4) decrease intestinal barrier permeability;
5) reducing blood brain barrier permeability;
specifically, the method comprises the following steps:
1) reducing the content of inflammatory factors in serum of mental patients;
2) reducing the content of inflammatory factors in brain tissue of a patient with mental disease;
3) reducing corticosterone content in brain tissue of a patient with mental disease;
4) increasing the short chain fatty acid content in patients with mental disease;
5) increasing neurotransmitter levels in patients with mental disorders;
6) reducing the intestinal barrier permeability of a patient with a mental disease;
7) reducing blood brain barrier permeability of mental disease patients.
The prepared medicine for preventing and treating anxiety and depression contains effective dose of Bacteroides monomorphus and/or metabolite thereof, and pharmaceutically acceptable carrier and/or excipient. The medicine formula of the invention is 1 multiplied by 104-1×1020CFU/mL Bacteroides monoides (Bacteroides unidentified) and/or metabolites thereof, and the dosage form of the medicament for preventing and treating anxiety and depression comprises the common pharmaceutical dosage forms in the field such as granules, capsules, tablets, powder, oral liquid, suspension or emulsion, and the like, and is characterized in that the medicament is used by oral administration or feeding.
The invention provides application of bacteroides uniformis in preventing and treating anxiety and depression. The subject receives chronic non-precompression for depression modeling and takes Bacteroides uniformis ATCC8492 which has the function of inhibiting anxiety-like and depression-like behaviors of the subject. Meanwhile, the anxiety-like and depression-like behavior of the rats treated with Bacteroides monomorphus ATCC8492 was significantly improved compared to untreated depressed rats. Therefore, the strain can be used for preventing and treating anxiety depression.
The Bacteroides monomorphus ATCC8492 provided by the invention has excellent function of resisting anxiety and depression, can be used for preparing a medicine for preventing and treating anxiety and depression, provides a new idea for clinical intervention and control of mental diseases such as anxiety and depression and the like, and has good industrial prospect.
Drawings
Fig. 1 shows experimental grouping information and processing steps.
FIG. 2 shows the comparative results of rat behavioral tests (elevated plus maze experiment).
FIG. 3 shows the comparative results of rat behavioral testing (open field experiments).
Figure 4 shows the comparative results of rat behavioural tests (forced swimming experiments).
Detailed Description
The inventor finds that Bacteroides simplex (Bacteroides unidentis) has prevention and treatment effects on anxiety-like and depression-like behaviors through extensive and intensive research and experiments, and finds that the Bacteroides simplex (Bacteroides unidentis) can inhibit the anxiety-like and depression-like behaviors and effectively relieve mental disease symptoms by gastric lavage of experimental subjects. The present invention has been completed based on this finding.
As used herein, the term "comprising" means that the various ingredients can be applied together in a mixture or composition of the invention. Thus, the terms "consisting essentially of and" consisting of are encompassed by the term "comprising. As used herein, the terms "Bacteroides simplex", "Bacteroides unidentiformis" are used interchangeably.
The Bacteroides simplex strain is Bacteroides unidentiformis ATCC8492, is sourced from ATCC (American Type Culture Collection), is purchased from China center for Culture Collection of industrial microorganisms, and has the accession number of ATCC 8492.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers.
(I) test materials
SPF grade Sprague Dawley (SD) rats were purchased from Spbefu Biotechnology, Inc. and were normally bred for 70 total rats at 6 weeks of age. The rats were grown in the same environment and fed the same diet.
The strain is as follows: bacteroides unidentifications ATCC8492, which is derived from ATCC (American Type Culture Collection), was purchased from China center for Industrial Culture Collection and has accession number ATCC 8492.
Conventional rat feed sterile rat feed was purchased from sbefu biotechnology limited.
(II) Experimental protocol
After 70 purchased SD male rats of 6 weeks old are placed in the same environment and normally acclimatized for 1 week, the formal experiment is started.
Normally fed SPF-grade 6-week-old SD male rats are selected for experiments, anxiety and depression-like behaviors of the rats are detected through behavioral tests, and Bacteroides uniformis ATCC8492 is introduced into intestinal tracts of the rats through a gavage method.
This example was divided into 7 groups of 2 stages: stage 1 is the prevention experiment stage, and stage 2 is the treatment experiment stage. 3 groups are arranged in the 1 st stage, the experimental period is 4 weeks, 10 rats in each group are randomly selected after the 1 st stage is finished to carry out the ethology test to test the anxiety and depression-like behaviors of the rats, and the rest rats enter the treatment experiment of the 2 nd stage. Stage 1 rats were grouped specifically for each group as follows:
control group (Free-1, n ═ 20): rats were normally housed for 4 weeks without any treatment and were not affected by the other groups.
Chronic non-prestimulated group (CUMS, n ═ 40): rats received 4 weeks of chronic non-pre-stimulation.
Chronic non-prestimulation + Bacteroides unidentiformis ATCC8492 strain group (CUMS + B.U, n-10): rats received 4 weeks of chronic non-prestimulation while they were perfused with 4 weeks of Bacteroides uniformis ATCC8492 bacterial solution.
In the second stage, 4 groups are set, the experimental period is 4 weeks, all rats are subjected to behavioral testing to test anxiety and depression-like behaviors after the 2 nd stage is finished, and each group is specifically divided into the following groups:
control group (Free-2, n ═ 10): the rats continued to be fed normally for 4 weeks without any treatment and were not affected by the other groups.
Gavage saline group (Control, n ═ 10): rats received 4 weeks of chronic non-pre-stimulations and were gavaged with 4 weeks of saline.
Gavage fluoxetine group (Flx, n ═ 10): rats received 4 weeks of chronic non-pre-stimulations followed by gavage of the antidepressant drug fluoxetine (fluoxetine) for 4 weeks.
Gavage Bacteroides uniformis ATCC8492 strain group (B.U, n 10): rats received 4 weeks of chronic non-prestimulation and were gavaged with Bacteroides uniformis ATCC8492 for 4 weeks.
Bacteroides unidentiformis ATCC8492 strain anaerobic culture
Bacteroides uniformis strains were cultured in anaerobic work station (Bactron, Shellab BAC II) at 37 ℃ for 2-3 days in M2GSC medium: casitone,10g/L, Solarbio, China; yeast Extract,2.5g/L, Thermo Fisher, USA; NaHCO3,4.0g/L, Sigma, USA; glucose,2.0g/L, Beijing Chemical Works, Beijing, China; soluble Starch,2.0g/L, Xilong Scientific, Beijing, China; cellobiose,2.0g/L, Thermo Fisher, USA; rumen fluid (cemented), 10g/L, Wiz Biotech, China; resazurin (0.1% w/w),1.0mL/L, Thermo Fisher, USA; cystein HCl,1.0g/L, Innochem, Beijing, China; k2HPO4,0.45g/L,Innochem,Beijing,China；KH2PO4,0.45g/L,Beijing Chemical Works,Beijing,China；(NH4)2SO4,0.9g/L,Guanghua Sci-Tech,Guangdong,China；NaCl,0.9g/L,Beijing Chemical Works,Beijing,China；MgSO4,0.09g/L,Beijing Chemical Works,Beijing,China；CaCl20.09g/L, Beijing Chemical Works, Beijing, China. The concentration of the gavage liquid of each rat is 1 multiplied by 109CFU/mL, gavage volume 1 mL/mouse, frequency once per day. The culture medium is cultured in advance, activated every week to ensure freshness, and the concentration is measured.
Chronic non-precompression
Rats received 4 weeks of chronic non-precompression: (1) fasting for 24 hours; (2) water is forbidden for 24 hours; (3) shake for 1 hour (160 r.p.m); (4) clamping the tail for 1 minute; (5) cold water swimming (4 ℃, 5 minutes); (6) the day and night are reversed; (7) heat stress at 50 ℃. The 7 non-precompressures were randomly scheduled for 1 week, 2 of which were randomly scheduled daily. Rats not receiving chronic non-precompression were raised routinely to ensure that they were not affected by the other groups.
Behavioural test
In order to observe and research the neuropsychiatric changes of experimental animals, a series of behavioral tests are carried out, and the method and the process are as follows:
1) open field experiment (OF)
Open field experimental testing is used to assess anxiety-like behavior of animals, and may be used to assess the degree of anxiety in animals by testing their spontaneous activity and exploratory behavior in a novel open environment. Rats were placed in the center of an open device (50X 45cm), allowed to acclimate for one minute, and then recorded for 5 minutes of spontaneous activity using Ethovsion software (Noldus, TrackSys, Nottingham, UK). The lower central zone (50% from the edge) residence time and number of entries into the central zone were used as indicators of anxiety-like behavior. After the test of each rat is finished, the rat is put back into the feeding cage, the equipment is cleaned, and 75% ethanol is used for wiping the inner wall and the bottom surface of the rat so as to eliminate the influence of excrement, urine, smell and the like of the rat on subsequent experimental animals.
2) Elevated cross maze Experiment (EPM)
The elevated plus maze examines the anxiety state of animals by utilizing the exploration characteristics of the animals to the new and different environment and the fear of high-suspension open arms to form contradiction conflict behaviors. The rats were introduced into the central area of the four-walled maze with the head facing the open arms, after which each rat was placed in the same position with two open arms (50X 10cm) without walls and two closed arms (50X 10X 30cm) with walls, the maze being one meter above the ground. A camera directly above the maze was used to track the movements of each rat and Ethovision software (Noldus, TrackSys, Nottingham, UK) was used to record the residence time of the rat in the open arm and the number of entries into the open arm over 5 minutes. Lower frequency of entry into the open arm and residence time served as indicators of anxiety performance. After each experiment, the maze was cleaned with 70% ethanol to eliminate the influence of the feces and urine, odor and the like of the rats on the following experimental rats.
3) Forced Swimming Test (FST)
Forced swimming experiments are used to evaluate depression-like behavior in animals, and the principle is that when an animal is put into a limited space to swim, the animal tries to escape initially, quickly becomes floating and motionless, only nostrils are exposed to keep breathing, and limbs are occasionally scratched to keep the body from sinking, so that the animal actually hopes to give up escaping, and the behavior hopes are desperate. Rats were placed in clear plastic buckets (40X 70cm) filled with 30cm high water (around 25 ℃), allowed to acclimate for one minute, and then the resting time of the rats was recorded over 5 minutes. Resting means that the animal keeps the head on the water surface without additional movement. Rest time was used as an indicator of the behavior of the rats in the form of depression. The experimental water is replaced once for each test to eliminate the influence of the excrement and urine, the odor and the like of the rat on the subsequent experimental rat.
Results of the experiment
1. The results of the behavioral tests (elevated plus maze) of the rat are shown in FIG. 2
In the prevention experiment, compared with the control group (Free-1), the residence time of the CUMS group rats in the open arm is reduced (fig. 2A, P ═ 0.051, F(2，27)203.29), the number of entries into the open arm decreased significantly (fig. 2B, P0.023, F)(2，27)2.98), suggesting that chronic non-pre-stimulation causes anxiety-like behavior in rats. In contrast, the residence time in the open arms of the rats administered with Bacteroides monomorphus group (CUMS + B.U) was significantly increased compared to the CUMS group (FIG. 2A, P)<0.001,F(2，27)203.29) indicating that Bacteroides monomorphus can prevent and relieve anxiety-like behavior induced by chronic non-prestimulation in rats.
In the treatment experiment, the number of times the rats in Control group entered the open arm was significantly reduced compared to the Control group (Free-2) (fig. 2D, P ═ 0.041, F(3，34)2.98), suggesting that chronic non-pre-stimulation causes anxiety-like behavior in rats. The rats given Bacteroides monorphus (B.U) tended to have an increased residence time in the open arm compared to the rats in the Control group (FIG. 2C, P-0.077, F)(3，35)1.34), the number of entries into the open arm increased significantly (fig. 2D, P0.018, F)(3，34)2.98), indicating that the bacteroides uniformis can treat and relieve anxiety-like behaviors induced by chronic non-pre-stimulation in rats.
2. The comparative results of the behavioral tests (open field experiments) of the rats are shown in FIG. 3
In the prevention experiment, compared with the control group (Free-1), the residence time of the rats in the central area in the CUMS group was determined (fig. 3A, P ═ 0.0027, F)(2，26)5.64) and the number of entries into the central region (fig. 3B, P)<0.001,F(2，27)9.81) showed a significant decrease, indicating that chronic non-pre-stimulations caused anxiety-like behavior in rats. In contrast to the CUMS group, the rats given the bacteroides uniformis group (CUMS + B.U) had a significantly increased residence time in the central region (fig. 3A, P0.046, F)(2，26)5.64), indicating that bacteroides uniformis can prevent anxiety-like behaviors induced by chronic non-prestimulation in rats。
In the treatment experiment, the residence time of rats in the central area was controlled in comparison with that in the Control group (Free-2) (FIG. 3C, P ═ 0.041, F)(3，33)1.79) and the number of entries into the central region (fig. 3D, P0.0074, F(3，34)2.96) showed a significant decrease, indicating that chronic non-pre-stimulations caused anxiety-like behavior in rats. The rats given the Bacteroides monorphus group (B.U) tended to have an increased residence time in the central zone compared to the Control group (FIG. 3C, P ═ 0.071, F)(3，33)1.79), indicating that the bacteroides uniformis can treat and relieve anxiety-like behaviors induced by chronic non-pre-stimulation in rats.
3. The comparative results of the behavioral tests (forced swimming test) of the rats are shown in FIG. 4
In the prevention experiment, compared with the control group (Free-1), the immobility time of the rats in the CUMS group is remarkably increased (figure 4A, P is 0.036, F)(2，27)6.034), suggesting that chronic non-pre-stimulation causes depression-like behavior in rats. In contrast, the administration of bacteroides uniformis (CUMS + B.U) significantly reduced the immobility time of rats compared to the CUMS group (fig. 4A, P0.0019, F)(2，27)6.034), suggesting that bacteroides uniformis can prevent depression-like behavior induced by chronic non-pre-stimulations in rats.
In the treatment experiment, the immobility time of the rats in the Control group was significantly increased compared to that in the Control group (Free-2) (FIG. 4B, P)<0.001,F(3，35)41.87), suggesting that chronic non-pre-stimulation causes the rats to develop depressive-like behavior. Whereas, administration of Bacteroides monorphus (B.U) significantly reduced the immobility time of rats compared to the Control group (FIG. 4B, P)<0.001,F(3，35)41.87) indicating that bacteroides uniformis can treat and relieve depression-like behaviors induced by chronic non-pre-stimulation in rats.
Conclusion
In summary, the above results demonstrate for the first time that Bacteroides monomorphus can prevent and treat anxiety-like and depression-like behavior in rats induced by chronic non-precompression. The result provides powerful experimental support for the application of the bacteroides uniformis in preparing the medicine for preventing and treating the anxiety disorder and the depression.
The application provides a Bacteroides unidentified ATCC8492 with anxiety and depression improving function. SD rats are taken as experimental objects, and the Bacteroides monomorphus ATCC8492 is proved to have the effect of improving anxiety and depression.
It should be understood that the present application is not limited to the bacterial liquid concentrations and/or strains that have been described above. The scope of the application is limited only by the appended claims.
Claims (7)
1. Use of Bacteroides monoides (Bacteroides uniformis) for the manufacture of a medicament for the prevention and treatment of anxiety depression, characterized in that said Bacteroides monoformis is Bacteroides uniformis, purchased from the China center for Industrial Culture Collection of microorganisms, available under ATCC (American Type Culture Collection) and having deposit number ATCC8492, said Bacteroides monoformis is in the form of living cells, said medicament comprises Bacteroides monoformis ATCC8492, and said medicament comprises an effective amount of Bacteroides monoformis of 1X 109CFU/mL。
2. The use according to claim 1, wherein the medicament is for the alleviation of anxiety and depression by at least one of the following mechanisms:
1) reducing the level of inflammatory factors in serum or brain tissue;
2) reducing the content of corticosterone in serum;
3) increasing the content of short chain fatty acids;
4) decrease intestinal barrier permeability;
5) reducing blood brain barrier permeability.
3. The use according to claim 1, wherein the medicament is for the alleviation of anxiety and depression by at least one of the following mechanisms:
1) reducing the serum level of inflammatory factors in a subject with a mental disorder;
2) reducing the level of inflammatory factors in brain tissue of a subject with a psychiatric disorder;
3) reducing the serum corticosterone content of the mental disease subject;
4) increasing short chain fatty acid content in a subject with a psychiatric disorder;
5) reducing intestinal barrier permeability in a subject with a psychiatric disorder;
6) reducing blood brain barrier permeability in a subject with a psychiatric disorder.
4. Use of Bacteroides monorphis (Bacteroides uniformis) according to any one of claims 1 to 3 for the manufacture of a medicament for alleviating anxiety and depression, characterized in that the medicament comprises an effective amount of Bacteroides monorphis (Bacteroides uniformis) and a pharmaceutically acceptable carrier and/or excipient.
5. The medicament of claim 4, wherein the dosage form of the medicament comprises: granules, capsules, tablets, powders, oral liquids, suspensions, or emulsions, and the like.
6. The medicament of claim 5, wherein the effective amount of Bacteroides monoides (Bacteroides unidentiformis) is 1X 104-1×1020CFU/mL。
7. The use of a medicament as claimed in any one of claims 5 to 6, wherein the medicament is administered orally or by feeding.
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