A probiotic composition and its application in preparing medicine for depression complicated with diarrhea-type irritable bowel syndrome

Abstract

The present invention provides a probiotic composition and its application in preparing a medicine for treating depression complicated with diarrhea-type irritable bowel syndrome. The composition of the present invention comprises Bifidobacterium lactis U9, Lactobacillus paracasei L55, Lactobacillus rhamnosus LL23, Bifidobacterium longum BB68S, Lactobacillus plantarum CR12 and Lactobacillus acidophilus RA15. Probiotic intervention was performed on patients with depression through a randomized double-blind trial, proving that the probiotic composition can effectively alleviate the gastrointestinal symptoms of people with depression complicated with diarrhea-type irritable bowel syndrome, and improve the depression of people with depression complicated with diarrhea-type irritable bowel syndrome.

Description

Technical Field

[0001] The invention belongs to the technical field of probiotics, and particularly relates to a probiotic composition and application thereof in preparing a medicine for treating depression complicated with diarrhea. Background Art

[0002] According to statistics from the World Health Organization, the number of depression patients is as high as 330 million, which is one of the largest disease burdens in the world. Depression patients not only suffer from mental torture, but also physical symptoms, including gastrointestinal symptoms. It is reported that up to 93.5% of depressed patients have gastrointestinal symptoms, of which 42.3% have diarrhea symptoms. The risk of diarrhea in patients with subclinical depression is twice that of normal people. Improving gastrointestinal symptoms is of great significance for the treatment of depression.

[0003] As humans study intestinal microbial flora, they gradually discover that the intestine is a very complex microenvironment. The intestinal flora has an important influence on human immunity, neurodevelopment, endocrine system, etc. Some people have proposed the gut-brain axis theory, which explains that intestinal microorganisms have an important influence on human health, including emotions.

[0004] Although the results of prior art research have found that probiotics can improve patients' diarrhea symptoms, the improvement effect on diarrhea symptoms in patients with depression is different. The reason for the differences in the effects of these probiotics on depressive symptoms may be due to the characteristics of the probiotics themselves. Although some health-related mechanisms of action are common in multiple probiotic genera and species, some functions may be species-specific or even strain-specific, or may require interactions between different strains to produce effects. On the other hand, depression itself is a very heterogeneous disease. The causes or pathophysiology of different patients are not the same, and even the causes of the same patient's attacks at different times may be different. Social and psychological stress and physiological stress (such as postpartum depression) may lead to different pathogenesis. Summary of the invention

[0005] The purpose of the present invention is to overcome the problem of diarrhea symptoms in depressed patients existing in the prior art, and to provide a probiotic composition and its use in the preparation of a drug for depression complicated with diarrhea. The probiotic composition can effectively alleviate the diarrhea symptoms of depressed people complicated with diarrhea.

[0006] The objective of the present invention is achieved through the following technical solutions:

[0007] A probiotic composition, comprising Bifidobacterium lactis U9, Lactobacillus paracasei L55, Lactobacillus rhamnosus LL23, Bifidobacterium adolescentis BQ23, and Lactobacillus acidophilus RA15, and the composition is as follows in parts by weight:

[0008]

[0009] The Bifidobacterium lactis U9 was deposited in the General Microbiological Center of China Microorganism Culture Collection Administration on November 4, 2015, with the deposit number of CGMCC NO.11560;

[0010] The Lactobacillus paracasei L55 was deposited in the General Microbiology Center of China Microorganism Culture Collection Administration on April 7, 2017, with a deposit number of CGMCC NO.13996;

[0011] The Lactobacillus rhamnosus LL23 was deposited in the General Microbiology Center of China Microorganism Culture Collection Administration on April 7, 2017, with a deposit number of CGMCC NO.13994;

[0012] The Bifidobacterium longum BB68S was deposited in the General Microbiological Center of China Microorganism Culture Collection Administration on May 15, 2017, with the deposit number of CGMCC NO.14168;

[0013] The Lactobacillus plantarum CR12 was deposited in the General Microbiology Center of China Microorganism Culture Collection Administration on April 7, 2017, with a deposit number of CGMCC NO.14000;

[0014] The Lactobacillus acidophilus RA15 was deposited in the General Microbiology Center of China National Microbiological Culture Collection Administration on April 7, 2017, with a deposit number of CGMCC NO.13993.

[0015] A probiotic product comprises the above-mentioned probiotic composition and a food, health product or medically acceptable carrier, auxiliary material or additive.

[0016] Furthermore, the probiotic product includes prebiotics.

[0017] Furthermore, the dosage form of the probiotic product includes capsules, tablets, granules, powders or sustained-release preparations.

[0018] Another aspect of the present invention provides the use of the probiotic composition in the preparation of a drug for treating depression complicated by diarrhea-type irritable bowel syndrome. The probiotic composition can also be used in providing a drug for relieving depression symptoms, preferably depression symptoms of people with depression complicated by diarrhea-type irritable bowel syndrome.

[0019] Biological Deposit Description

[0020] Bifidobacterium lactis U9, classification name: Bifidobacterium animalis subsp. Lactis, deposited in China General Microbiological Culture Collection Center (CGMCC) on November 4, 2015, the address of the collection center is No. 3, No. 1 Beichen West Road, Chaoyang District, Beijing, Institute of Microbiology, Chinese Academy of Sciences, and the collection number is CGMCC NO.11560;

[0021] Lactobacillus paracasei L55, classification name: Lactobacillus paracasei, deposited in China General Microbiological Culture Collection Center (CGMCC) on April 7, 2017, the address of the collection center is No. 3, No. 1 Beichen West Road, Chaoyang District, Beijing, Institute of Microbiology, Chinese Academy of Sciences, and the collection number is CGMCC NO.13996;

[0022] Lactobacillus rhamnosus LL23, classification name: Lactobacillus rhamnosus, deposited in China General Microbiological Culture Collection Center (CGMCC) on April 7, 2017, the address of the collection center is No. 3, No. 1 Beichen West Road, Chaoyang District, Beijing, Institute of Microbiology, Chinese Academy of Sciences, and the deposit number is CGMCCNO.13994;

[0023] Bifidobacterium longum BB68S, classified as Bifidobacterium longum, was deposited in the General Microbiological Center of China Microbiological Culture Collection (CGMCC) on May 15, 2017. The address of the collection center is No. 3, Yard No. 1, Beichen West Road, Chaoyang District, Beijing, Institute of Microbiology, Chinese Academy of Sciences, and the collection number is CGMCC NO.14168;

[0024] Lactobacillus plantarum CR12, classification name: Lactobacillus plantarum, deposited in China General Microbiological Culture Collection Center (CGMCC) on April 7, 2017, the address of the collection center is No. 3, No. 1 Beichen West Road, Chaoyang District, Beijing, Institute of Microbiology, Chinese Academy of Sciences, and the collection number is CGMCC NO.14000;

[0025] Lactobacillus acidophilus RA15, classified as Lactobacillus acidophilus, was deposited in the China General Microbiology Center (CGMCC) on April 7, 2017. The address of the collection center is No. 3, Yard No. 1, Beichen West Road, Chaoyang District, Beijing, Institute of Microbiology, Chinese Academy of Sciences, and the collection number is CGMCC NO.13993.

[0026] Compared with the prior art, the present invention has at least the following beneficial effects:

[0027] Based on existing research, the present invention provides a probiotic composition obtained by compounding multiple probiotics, which can effectively alleviate the depressive symptoms of depressed people with comorbid diarrhea. DETAILED DESCRIPTION

[0028] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0029]

[0030] The inventors of the present invention discovered during the course of research that a probiotic composition obtained by mixing six probiotics, namely Bifidobacterium lactis U9, Lactobacillus paracasei L55, Lactobacillus rhamnosus LL23, Bifidobacterium longum BB68S, Lactobacillus plantarum CR12 and Lactobacillus acidophilus RA15, can replace the existing single probiotic intervention for depression patients, and can effectively alleviate the depressive symptoms of depressed people with comorbid diarrhea.

[0031] The present invention will be described in detail below by way of examples. It should be understood that the following examples are only used to further explain and illustrate the content of the present invention in detail, and are not used to limit the present invention.

[0032] In the following examples, Bifidobacterium lactis U9, Lactobacillus paracasei L55, Lactobacillus rhamnosus LL23, Bifidobacterium longum BB68S, Lactobacillus plantarum CR12 and Lactobacillus acidophilus RA15 are all provided by Beijing Heyiyuan Biotechnology Co., Ltd. All six strains are preserved in the China General Microbiological Culture Collection Management Center. All six strains are derived from the human intestinal tract. Other chemical reagents used are purchased from regular chemical reagent suppliers, and the purity is analytically pure.

[0033] Example 1

[0034] This embodiment provides a probiotic composition, which is composed of Bifidobacterium animalis subsp. lactis U9, Lactobacillus casei L55, Lactobacillus rhamnosus LL23, Bifidobacterium longum BB68S, Lactobacillus plantarum CR12 and Lactococcus acidophilus RA15, each bacterial powder weighs 2g, and the content of each bacterial powder is 3×10 10 CFU;

[0035] The Bifidobacterium lactis U9 was deposited in the General Microbiological Center of China Microorganism Culture Collection Administration on November 4, 2015, with the deposit number of CGMCC NO.11560;

[0036] The Lactobacillus paracasei L55 was deposited in the General Microbiology Center of China Microorganism Culture Collection Administration on April 7, 2017, with a deposit number of CGMCC NO.13996;

[0037] The Lactobacillus rhamnosus LL23 was deposited in the General Microbiology Center of China Microorganism Culture Collection Administration on April 7, 2017, with a deposit number of CGMCC NO.13994;

[0038] The Bifidobacterium longum BB68S was deposited in the General Microbiological Center of China Microorganism Culture Collection Administration on May 15, 2017, with the deposit number of CGMCC NO.14168;

[0039] The Lactobacillus plantarum CR12 was deposited in the General Microbiology Center of China Microorganism Culture Collection Administration on April 7, 2017, with a deposit number of CGMCC NO.14000;

[0040] The Lactobacillus acidophilus RA15 was deposited in the General Microbiology Center of China National Microbiological Culture Collection Administration on April 7, 2017, with a deposit number of CGMCC NO.13993.

[0041] Example 2 Test Example

[0042] In order to explore the effect of the probiotic composition described in Example 1 on patients with depression complicated by diarrhea-type irritable bowel syndrome, this test case conducted a randomized double-blind trial to intervene with probiotics in patients with depression.

[0043] This study was completed under the supervision of the Human Research Ethics Committee of China Agricultural University, in accordance with the Good Clinical Practice Guidelines formulated by the International Association of Pharmaceutical Regulations. The study should be completed in accordance with the operating instructions. The experimental protocol and the informed consent form of the subjects were approved by the ethics committee before the study began (ethics approval number: CAUHR-2018029).

[0044] Patients participating in this study met the following criteria (inclusion criteria for irritable bowel syndrome, i.e., ROME III diagnostic criteria for IBS):

[0045] a) Aged 18 to 60, regardless of gender;

[0046] b) Meet the diagnostic criteria for depressive episodes of the Chinese Classification and Diagnostic Criteria of Mental Disorders (CCMD);

[0047] c) Hamilton Depression Rating Scale (HAMD, 17 items) ≥8 points;

[0048] d) Meet the Rome III diagnostic criteria for IBS: recurrent abdominal pain or discomfort for at least 3 days per month in the last 3 months, and 2 or more of the following symptoms: (1) improvement of symptoms after defecation, (2) change in defecation frequency, (3) change in stool characteristics. Symptoms occurred 6 months before diagnosis, and the onset of symptoms in the last 3 months meets the above diagnostic criteria.

[0049] e) Meet the classification criteria for the diarrhea-predominant IBS (IBS-D) subtype: loose (mushy) or watery stools account for ≥ 25% of the stool volume, and hard or lumpy stools account for < 25% of the stool volume.

[0050] f) Understand and voluntarily participate in this trial and sign the informed consent form.

[0051] The patients participating in this study did not have the following conditions:

[0052] a) Having serious or unstable heart, liver, kidney, endocrine, digestive, blood and other physical diseases;

[0053] b) drug or alcohol abuse in the past year;

[0054] c) Pregnant, breastfeeding women or those planning to get pregnant in the near future

[0055] This study planned to recruit 60 patients with depression, and actually recruited 60 patients with depression. A total of 52 people completed the experiment, all from Beijing Pinggu Hospital of Traditional Chinese Medicine.

[0056] According to the screening criteria, patients with depression who met the diagnostic criteria of the Chinese Classification and Diagnostic Criteria for Mental Disorders (CCMD) were recruited. Eligible subjects signed the informed consent form and were enrolled and randomly divided into the probiotic group and the placebo group. The enrolled patients were required to undergo a 1-week emptying period, during which they could not consume any probiotic products (including yogurt, probiotic tablets, powders, and capsules). After the emptying period, the subjects were tested with the Hamilton's Depression Scale (HAMD) to assess the degree of depression; the ROME III diagnostic evaluation was performed to assess the diarrhea symptoms of the subjects, and the IBS-D (diarrhea-predominant irritable bowel syndrome) population that met the ROME III diagnostic criteria was screened. At the same time, the subjects' demographic information, medical history, and drug treatment were recorded.

[0057] The intervention period was 2 months, during which the probiotic composition composed of 6 probiotic powders described in Example 1 or placebo was taken every day, with a daily dosage of 10 9 -10 10 cfu. During the intervention period, the subjects will continue to eat normally, but cannot eat other fermented dairy products. The subjects will fill in a diary every day, including the intake and bowel movements. At the end of the intervention period, the subjects will be scored for HAMD and gastrointestinal symptoms again to assess their depression level and improvement in gastrointestinal symptoms.

[0058] To study the effect of probiotics on patients with depression-related diarrhea-type irritable bowel syndrome, a randomized blinded population trial of probiotic intervention in depression-related diarrhea-type irritable bowel syndrome was conducted. A total of 60 people met the conditions to participate in the study, and the population was randomly divided into a probiotic group or a placebo group, and 52 people completed the experiment. There was no significant difference in age and gender between the two groups (Table 1). Among them, 26 people met the ROME III diarrhea diagnostic criteria.

[0059] Table 1 Basic information of the population

[0060]

[0061] 1. Effect of probiotics on depressive symptoms in people with IBS-D depression

[0062] After the intervention, the Hamilton Depression Rating Scale (HAMD) scores of both the placebo group and the probiotic group were significantly lower than those of the baseline period. At baseline, there was no difference in the HAMD score between the probiotic group and the placebo group; however, after the intervention, the HAMD score of the probiotic group was significantly lower than that of the placebo group (14.9±7.0 vs 18.8±6.6, p<0.05) (Table 2). The effect of probiotic intervention on the depressed population with concurrent IBS-D was further analyzed. It can be seen that the HAMD score of depressed patients with concurrent IBS-D was significantly lower than that of the placebo group after probiotic intervention (13.1±6.2 vs 18.9±5.9, p<0.05), while the HAMD score of depressed patients without concurrent IBS-D was not significantly lower than that of the placebo group after probiotic intervention.

[0063] Table 2 Effect of probiotics on HAMD depression scores in patients with concurrent IBS-D depression

[0064]

[0065] Note: *Significantly different from the placebo group, p<0.05.

[0066] 2. Effect of probiotics on diarrhea symptoms in depressed patients with IBS-D

[0067] IBS-D symptom score: Score according to the severity of IBS abdominal pain, bloating, and diarrhea. 0 points: no symptoms, 1-3 stools / day, formed; 1 point: mild, with a little attention, symptoms are felt, 4-5 stools / day, <50% unformed; 2 points: moderate, conscious symptoms, no impact on work, 6-8 stools / day, 50%-75% unformed; 3 points: severe, obvious impact on life and work, stools >8 times / day, >75% unformed.

[0068] To be eligible for randomization, daily abdominal pain scores were required to be an average of 4 or higher on an 11-point numeric rating scale (0-no pain, 10-unbearable pain) and average daily stool consistency (assessed by the Bristol Stool Shape Scale (BSFS)) was ≥5.

[0069] The symptom scoring criteria for abdominal distension and abdominal pain are: 3 points (severe), symptoms have a serious impact on the patient's normal life; 2 points (moderate), symptoms have an impact on the patient's normal life but the impact is not obvious; 1 point (mild), symptoms exist but do not affect normal life; 0 points, no symptoms. The sum of the abdominal pain and distension scores plus the stool characteristics score is the gastrointestinal health status score. The reduction rate of the gastrointestinal health status score is [(pre-treatment score - post-treatment score) / pre-treatment score] × 100%, <30% is ineffective, <30%-60% is improvement, and the reduction rate of 60%-100% is effective. The improvement of gastrointestinal symptoms in depressed patients with concurrent IBS-D by probiotic intervention is shown in Table 3. After 8 weeks of intervention, the effective rate of gastrointestinal symptom improvement in the probiotic group was 84.6% (11 / 13), which was much higher than 38.4% (5 / 13) in the placebo group, and the difference between the two groups was statistically significant (p<0.05). It can be seen that probiotics have a significant effect on improving diarrhea symptoms in depressed people with concurrent IBS-D.

[0070] Table 3 Effect of probiotics on improvement of gastrointestinal symptoms in depressed patients with concurrent IBS-D

[0071]

[0072] Note: *Significantly different from the placebo group, p<0.05.

[0073] Based on the above experiments, it is proved that the probiotic composition of the present invention can effectively alleviate the depressive symptoms of depressed people with comorbid diarrhea.

[0074] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A probiotic composition, characterized in that: The composition comprises Bifidobacterium lactis ( Bifidobacteriumanimalis subsp.lactis )U9, Lactobacillus paracasei ( Lactobacillus paracasei ) L55, Lactobacillus rhamnosus ( Lactobacillus rhamnosus LL23, Bifidobacterium longum ( Bifidobacterium longum )BB68S, Lactobacillus plantarum ( Lactobacillus plantarum )CR12 and Lactobacillus acidophilus ( Lactobacillus acidophilus ) RA15, composed by weight: 1 to 10 parts of Bifidobacterium lactis U9; 1 to 10 parts of Lactobacillus paracasei L55; 1 to 10 parts of Lactobacillus rhamnosus LL23; 1 to 10 parts of Bifidobacterium longum BB68S; 1 to 10 parts of Lactobacillus plantarum CR12; 1 to 10 parts of Lactobacillus acidophilus RA15; The Bifidobacterium lactis U9 was deposited in the General Microbiological Center of China Microorganism Culture Collection Administration on November 4, 2015, with the deposit number of CGMCC NO. 11560; The Lactobacillus paracasei L55 was deposited in the General Microbiology Center of China Microorganism Culture Collection Administration on April 7, 2017, with a deposit number of CGMCC NO.13996; The Lactobacillus rhamnosus LL23 was deposited in the General Microbiology Center of China Microorganism Culture Collection Administration on April 7, 2017, with a deposit number of CGMCC NO.13994; The Bifidobacterium longum BB68S was deposited in the General Microbiological Center of China Microorganism Culture Collection Administration on May 15, 2017, with the deposit number of CGMCC NO. 14168; The Lactobacillus plantarum CR12 was deposited in the General Microbiology Center of China Microorganism Culture Collection Administration on April 7, 2017, with a deposit number of CGMCC NO. 14000; The Lactobacillus acidophilus RA15 was deposited in the General Microbiology Center of China Microorganism Culture Collection Administration on April 7, 2017, with the deposit number of CGMCC NO. 13993.

2. The probiotic composition according to claim 1, characterized in that: The weight proportions of the various bacteria in the composition are the same.

3. A probiotic product, characterized in that: The invention comprises the probiotic composition as claimed in claim 1 or 2 and a food, health product or medically acceptable carrier, auxiliary material or additive.

4. The probiotic product according to claim 3, characterized in that The probiotic product includes prebiotics.

5. The probiotic product according to claim 3 or 4, characterized in that: The dosage form of the probiotic product includes capsules, tablets, granules, powders or sustained-release preparations.

6. Use of the probiotic composition according to claim 1 or 2 in the preparation of a drug for alleviating depressive symptoms complicated by IBS-D.

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