CN114642684A - Eubacterium rectal for preventing and treating anxiety and depression - Google Patents
Eubacterium rectal for preventing and treating anxiety and depression Download PDFInfo
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Abstract
The invention belongs to the field of life science, and particularly relates to a new application of Eubacterium rectus (Eubacterium repeat) in the aspect of preventing and treating anxiety and depression. The viable Eubacterium rectum (Eubacterium repeat) is applied in an amount of 1 × 10 per day4‑1×1020CFU/mL。
Description
Technical Field
The invention belongs to the field of microbiology, and relates to a Eubacterium rectale (Eubacterium rectale) strain JCM1746 which is used for preventing and treating anxiety and depression and preparing medicines for related diseases.
Background
Depression is the third of the global burden of disease, seriously affecting quality of life, with a incidence of about 3.1% and an average age of about 25 years. Depression, a disorder that is based on dysfunction, such as a decreased ability to experience pleasure, often manifests as multiple forms and different combinations of symptoms, but its recognition and diagnosis criteria are not uniform since these symptoms are also often present in other mental disorders. Anxiety is common in depression, with almost two-thirds of major depressive patients having clinical anxiety, with symptoms of anxiety becoming more prominent in major depressive episodes as they age. At present, no clear model can comprehensively explain the disease of depression, and social stressors and biological stressors can cause different pathogenesis.
Stressful life events are found to have potential effects in the induction and possible cause of depression. For example, the impact of stressful life events is closely related to the onset of depression one year before the onset of depression. Adult stress life events include life threatening events, chronic illness, economic instability, unemployment, loss of affinity to violence, and the like. Events in childhood, such as loss and neglect, may also be associated with a depressive tendency in the adult period when faced with stressful life events. For example, early childhood trauma has been associated with depression in late life and stress in early childhood has been found to cause DNA methylation at key sites in the GR gene by studying the changes in the hypothalamic-pituitary-adrenal axis (HPA), particularly Glucocorticoid Receptor (GR) function.
The goal of treating depression is to completely relieve the symptoms of depression, and current methods mainly include psychological treatment, drug treatment or both. Among psychotherapies, cognitive behavioral therapy is the most widely used psychotherapy, which teaches depressed patients how to recognize negative thinking patterns that lead to their depressed mood, replacing them as much as possible with healthier, more positive ideas. However, in practice, the limitations of psychotherapy are the lack of availability, since there are few trained therapists and the cost of treatment is expensive. In drug therapy, the relevant drugs are mainly: bupropion (Bupropion), Citalopram (Citalopram), Fluoxetine (Fluoxetine), and the like. The exact mechanism by which antidepressants improve mood is not known, but most antidepressants acting on monoaminergic neurotransmission produce an initial effect in the synapse, which then affects intracellular signaling and secondary signaling pathways, resulting in changes in gene expression, neurogenesis and synaptic plasticity, ultimately achieving a therapeutic effect. Although the available treatments vary widely, a significant proportion of patients do not respond adequately to treatment, either partially or not at all. For example, a randomized trial study found that the cumulative remission after four treatment steps was still only 67%. The drug therapy also has adverse reactions such as digestive tract symptoms, headache, dizziness, hepatotoxicity, hypertension, insomnia, sexual dysfunction and the like. In addition, drug therapy is not suitable for certain special groups, such as pregnant women and children. Because of the physiological and psychophysiological differences and limited language and experience of children and adolescents, meaning that they may express their suffering in different ways, children and adolescents should be cautious with antidepressants.
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. There is increasing evidence that the gut microbiota plays a role not only in regulating host physiology, particularly metabolism and immunity, but also in central nervous system and brain function, e.g. Lactobacillus rhamnosus (Lactobacillus rhamnosus) is able to significantly improve animal anxiety-like behavior, depression-like behavior, social interaction cognitive memory, etc. 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, little research work has been reported in recent years on new probiotic bacteria. 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 the intensive research of the inventor, the Eubacterium rectus rectum (Eubacterium repeat) is found to have the effect of preventing and treating anxiety and depression-like behaviors, and the Eubacterium rectus rectum (Eubacterium repeat) is perfused into a stomach experimental object, so that the Eubacterium rectus rectum (Eubacterium repeat) is found to be capable of inhibiting the anxiety and depression-like behaviors and effectively relieving mental disease symptoms, and is suitable for developing drugs for relieving anxiety and depression-like behaviors. The present invention has been completed based on this finding.
The invention aims to provide real rectum bacillus for preventing and treating anxiety depression and a medicine for preparing related diseases, and is characterized in that the real rectum bacillus is Eubacterium repeat, is purchased from China center for culture Collection of Industrial microorganisms, is sourced from JCM (Japan Collection of microorganisms), has the accession number of JCM17463, is used for preparing the medicine for preventing and treating the anxiety depression and comprises the real rectum bacillus JCM17463 and/or metabolites thereof, and the effective amount of the real rectum bacillus (Eubacterium repeat) and/or the metabolites thereof in the medicine is 1 x 104-1×1020CFU/mL。
The eubacterium rectum of the invention is in a living cell form.
In the medicine, the eubacterium proctosigmus JCM17463 and/or the metabolite thereof relieve anxiety and depression through 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.
The invention relates to a medicine prepared by using Eubacterium rectale (Eubacterium rectale) for manufacturing the medicine for relieving anxiety and depression, which is characterized in that the medicine contains an effective amount of Eubacterium rectale (Eubacterium rectale) and/or metabolites thereof, and a pharmaceutically acceptable carrier and/or excipient.
The drug is characterized in that the dosage form of the drug comprises: granules, capsules, tablets, powders, oral liquids, suspensions, or emulsions, and the like.
The invention provides application of eubacterium procumbens in preventing and treating anxiety and depression. The test subject takes Eubacterium proctosum JCM17463 while receiving chronic non-preperable stimulation to perform depression molding, and the Eubacterium proctosum JCM17463 has the behavior of inhibiting anxiety and depression of the subject. Meanwhile, the anxiety and depression-like behavior of the rats treated by the eubacterium proctosum JCM17463 is obviously improved compared with that of untreated depressed rats. Therefore, the strain can be used for preventing and treating anxiety depression.
The eubacterium proctosicum JCM17463 provided by the invention has an 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 has a 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 Eubacterium proctosigmum has the effect of preventing and treating anxiety and depression-like behaviors through extensive and intensive research and experiments, and the Eubacterium proctosigmum can inhibit the anxiety and depression-like behaviors and effectively relieve mental disease symptoms by gavage an experimental object with the Eubacterium proctosigmum. 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 "Eubacterium proctosicum", "Eubacterium repeat" are used interchangeably.
The strain of the Eubacterium rectus is Eubacterium repeat JCM17463 which is derived from JCM (Japan Collection of microorganisms) and purchased from China center for culture Collection of industrial microorganisms with the accession number of JCM 17463.
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 Male Sprague Dawley (SD) rats were purchased from Beijing Sibefu Biotechnology, Inc. at 6 weeks of age for a total of 70. All rats were grown in the same environment and fed the same sterile diet.
Strain: eubacterium recycle JCM17463, available from JCM (Japan Collection of microorganisms), and purchased from China center for Industrial collections of microorganisms under accession number JCM 17463.
Conventional rat feed sterile rat feed was purchased from sbefu biotechnology limited.
(II) Experimental protocol
1. Design of experiments
1) The rats were placed in the same environment and were acclimatized for 1 week before the start of the official experiment.
2) Normally fed rats were selected for the experiment, and anxiety-like and depression-like behavior was detected by behavioral testing, and Eubacterium repeat JCM17463 was introduced into the rat intestinal tract by the gavage method.
3) This example is divided into 2 stages: stage 1 is the prevention experiment stage, and stage 2 is the treatment experiment stage.
4) The rats in stage 1 are randomly divided into 3 groups, the experimental period is 4 weeks, 10 rats in each group are randomly selected after stage 1 is finished to perform a behavioral test to test anxiety-like and depression-like behaviors of the rats, and the rest rats enter the treatment experiment in stage 2. The first stage 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, unpredicted mild stimulation.
Chronic non-prestimulation + Eubacterium repeat JCM17463 strain group (CUMS + E.R, n 10): rats received 4 weeks of chronic, unpredictably mild challenge and were gavaged with 4 weeks of Eubacterium repeat JCM 17463.
5) The rats in the second stage are randomly divided into 4 groups, the experimental period is 4 weeks, the rats are subjected to a behavioral test to test the anxiety-like behavior and the depression-like behavior of the rats after the 2 nd stage is finished, and each group is specifically divided into the following groups:
control group (Free-2, n-10): rats were normally housed 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 were gavaged with the antidepressant fluoxetine for 4 weeks after receiving 4 weeks of chronic unpredicted mild stimulation.
Gavage Eubacterium repeat JCM17463 strain group (E.R, n 10): rats received 4 weeks of chronic non-prestimulation followed by gavage of 4 weeks of Eubacterium recale JCM17463 strain.
Anaerobic culture of Eubacterium repeat JCM17463 Strain
The Eubacterium repeat strain was cultured in an anaerobic workstation (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. Advanced culture of bacterial liquidThe cells were maintained, activated weekly to ensure freshness, and the concentrations were measured separately.
3. Chronic non-pre-stimulation
Rats received 4 weeks of chronic non-pre-stimulation: (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) swimming in cold water (4 ℃, 5 minutes); (6) the day and night are reversed; (7) heat stress at 50 deg.C. The 7 non-prestimulatable random schedules were set at 1 week, 2 of which were randomly scheduled daily. Rats not receiving chronic non-prepegiable mild stimulation were kept on a routine basis to ensure that they were not affected by the other groups.
4. 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 testing
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 plus maze test
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 the residence time of the rat in the open arm, and the number of entries into the open arm, was recorded within 5 minutes using Ethovision software (Noldus, TrackSys, Nottingham, UK). 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
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. The rats were placed in clear plastic buckets (40X 70cm) containing 30cm of 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 frequency of the rats entering the open arm in the CUMS group is reduced (fig. 2B, P is 0.062, F)(2，27)5.86), indicating that chronic non-pre-stimulation causes anxiety-like behavior in rats. In contrast to CUMS group, rats administered with Eubacterium rectal group (CUMS + E.R) had a retention time in the open arm (FIG. 2A, P)<0.001,F(2，27)54.23) and the number of entries into the open arm (fig. 2B, P0.00204, F)(2，27)5.86), indicating that eubacterium recta can prevent anxiety-like behavior induced by chronic non-prestimulation in rats.
In the treatment experiment, the residence time of the rats in the Control group in the open arm tended to decrease compared to the Control group (Free-2) (FIG. 2C, P-0.095, F)(3，35)1.61), the number of entries into the open arm decreased significantly (fig. 2D, P)<0.001,F(3，35)5.37), indicates thatChronic non-pre-stimulation resulted in anxiety-like behavior in rats. The residence time in the open arm was significantly increased in the rats given eubacterium proctosigmans (E.R) compared to the rats in Control group (fig. 2C, P ═ 0.049, F)(3，35)1.61), indicating that eubacterium recta can treat and relieve anxiety-like behavior induced by chronic non-pre-stimulative stimulation in rats.
2. The comparative results of rat behavioral tests (open field experiment) are shown in FIG. 3
In the prevention experiment, the residence time of the rats in the central region in the CUMS group was compared with that in the control group (Free-1) (FIG. 3A, P)<0.001,F(2，26)24.61) and the number of entries into the central region (fig. 3B, P)<0.001,F(2，26)9.74) is significantly reduced. In the treatment experiment, the residence time of the rats in the central area was controlled in comparison with that in the Control group (Free-2) (FIG. 3C, P-0.011, F)(3，33)3.87) and the number of entries into the central region (fig. 3D, P0.0059, F)(3，34)3.71) showed a significant decrease, indicating that chronic non-pre-stimulation caused anxiety-like behavior in rats. In contrast to the Control group, the residence time of the rats (CUMS + E.R) administered with Eubacterium rectus rectum in the central area was significantly increased (FIG. 3A, P)<0.001,F(2，26)24.61), the number of entries into the central region tends to increase (fig. 3B, P0.078, F)(2，26)9.74), indicating that eubacterium proctosicum can prevent anxiety-like behavior induced by chronic non-prestimulation 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 (FIG. 4A, P ═ 0.022, F)(2，27)3.54), indicating that chronic non-pre-stimulation causes the rats to develop depressive-like behavior. In contrast, administration of eubacterium proctosphasum (CUMS + E.R) significantly reduced immobility time in rats compared to CUMS group (fig. 4A, P0.0401, F)(2，27)3.54), indicating that eubacterium proctosigmus 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)38.86), indicating chronic incoordinationPre-stimulation resulted in depression-like behavior in rats. In contrast, administration of Eubacterium proctosicum (E.R) significantly reduced the immobility time of rats compared to Control group (FIG. 4B, P)<0.001,F(3，35)38.86), indicating that eubacterium proctosigmum can treat and relieve depression-like behavior induced by chronic non-pre-stimulations in rats.
Conclusion
In summary, the results of the above studies demonstrate for the first time that Eubacterium recta JCM1746 can prevent and treat anxiety-like and depression-like behavior induced in rats by chronic non-pre-stimulations. The result provides a powerful experimental support for the application of the eubacterium proctosigmatum JCM1746 in preparing the medicines for preventing and treating depression and anxiety.
The application provides a strain of Eubacterium repeat JCM17463 with anxiety and depression improving effect. SD rats are taken as experimental objects, and the effect of the eubacterium proctosigmus JCM17463 on improving anxiety and depression is proved.
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 (6)
1. The Eubacterium proctosigmatum JCM17463 is used for preventing and treating anxiety depression and preparing the related diseases, and is characterized in that the Eubacterium proctosigmus is Eubacterium repeat, is purchased from China Industrial microorganisms Collection management center, is derived from JCM (Japan Collection of microorganisms) with the accession number of JCM17463, is used for preparing the medicines for preventing and treating the anxiety depression related diseases and comprises the Eubacterium proctosigmus JCM17463 and/or metabolites thereof, and the effective amount of the Eubacterium proctosigmus (Eubacterium repeat) in the medicines is 1 multiplied by 104-1×1020CFU/mL。
2. The use according to claim 1, wherein the eubacterium recta is in the form of living cells.
3. The use according to claim 1, wherein the medicament is for the alleviation of anxiety depression by at least one of the following mechanisms, eubacterium proctosigmum JCM17463 and/or its metabolites:
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.
4. Use of Eubacterium recta (Eubacterium repeat) according to any of claims 1-3 for the manufacture of a medicament for the relief of anxiety and depression, characterized in that the medicament comprises an effective amount of Eubacterium recta (Eubacterium repeat) and/or metabolites thereof, together with 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. Use of a medicament according to any one of claims 4 to 5, wherein the medicament is administered orally or by feeding.
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