Application of probiotic composition in preparation of medicine for preventing and / or treating infant intestinal angina pectoris and related diseases of infant intestinal angina pectoris

Abstract

The invention provides application of a probiotic composition in preparation of medicines for preventing and / or treating infant intestinal angina pectoris and related diseases, and the probiotic composition comprises bifidobacterium infantis, lactobacillus, coccus and bacillus. The probiotic composition can significantly improve the symptoms of abdominal pain, abdominal distension, borborygmus, intestinal flora imbalance and the like of infant patients with intestinal angina pectoris, has high safety, and has a certain treatment prospect for infant intestinal angina pectoris and related diseases thereof.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine. Specifically, the present invention relates to the use of a probiotic composition in the preparation of a drug for preventing and / or treating infantile colic and related diseases. Background Art

[0002] Infantile colic is a common symptom of childhood diseases. Generally, based on the characteristics of the crying behavior of infants, that is, sudden and inconsolable crying, often accompanied by body language, namely knee bending, fist clenching and facial distortion (accompanied by blushing), showing a painful posture. Research has found that the risk of children with infantile colic developing into recurrent abdominal pain increases by 11 times after 10 years, the risk of developing allergic diseases increases, and it is more likely to show emotional and behavioral problems, attention deficit and hyperactive impulse, cognitive dysfunction, and delayed fine and gross motor development in preschool and school-age children. At present, the main methods for relieving infantile colic are to improve nursing and feeding methods, such as infant massage, colic hold, and giving infants more appropriate care. In terms of drug treatment, there is no exact drug that can treat related diseases. For example, anticholinergic drugs have been eliminated due to their adverse reactions such as drowsiness, constipation, and effects on motor and respiratory functions. In addition, many herbal teas or traditional Chinese medicines with anticholinergic and antiadrenergic activities are used to treat infantile colic. Traditional Chinese medicine tastes bitter and is difficult to drink, and it needs to be metabolized by the liver and kidneys. The various systems and organs of newborn infants are not yet sound, and improper use of drugs may have toxic side effects; acupoint application directly contacts the skin of children, and the adhesive tape or drug for application is likely to stimulate and damage the delicate skin of infants; it is difficult to fix the body position of infant acupuncture, so acupuncture and moxibustion operations are difficult and riskier, and the pain caused by acupuncture makes infants cry more during the treatment process, which is generally unacceptable to parents.

[0003] Infantile colic is also likely to cause abnormal immune function, such as excessive immune response or immune tolerance, which will lead to inflammatory reactions. The inflammatory reaction initially causes macrophages to release cytokines such as IL-1β and TNF-α. These inflammatory factors can further stimulate and expand the inflammatory process. If the immunity is excessive, cytokine levels will increase sharply, including the participation of secondary mediators and inflammatory cells, causing tissue damage. Summary of the Invention

[0004] Aiming at the above problems, the object of the present invention is to provide the use of a probiotic composition in the preparation of a drug for preventing and / or treating infantile colic and related diseases. The probiotic composition can significantly improve symptoms such as abdominal pain, abdominal distension, bowel sounds, and intestinal flora imbalance in children with infantile colic, and the probiotic composition has high safety and has a certain therapeutic prospect for infantile colic and related diseases.

[0005] The above object of the present invention is achieved by providing the following technical solutions:

[0006] The present invention provides the use of a probiotic composition in the preparation of a drug for preventing and / or treating infantile colic and its related diseases, wherein the probiotic composition comprises Bifidobacterium infantis, Lactobacillus, coccus and Bacillus.

[0007] Preferably, the present invention provides the use of a probiotic composition as the sole active ingredient in the preparation of a drug for preventing and / or treating infantile colic and its related diseases, wherein the probiotic composition comprises Bifidobacterium infantis, Lactobacillus, coccus and Bacillus.

[0008] Preferably, the probiotic composition consists of Bifidobacterium infantis, Lactobacillus, coccus and Bacillus.

[0009] Preferably, in the probiotic composition, the viable count ratio of Bifidobacterium infantis, Lactobacillus, coccus and Bacillus is (1-100):(1-100):(1-100):1, preferably (1-100):(1-100):(1-10):1.

[0010] Preferably, the total viable count of the drug is not less than 1×10 5 cfu / g, preferably 2×10 5 to 4×10 9 cfu / g, more preferably 1×10 6 to 6×10 6 cfu / g.

[0011] Preferably, the viable count of Bifidobacterium infantis contained in the drug is not less than 1×10 5 cfu / g, preferably 1×10 6 to 1×10 9 cfu / g.

[0012] Preferably, the viable count of Lactobacillus contained in the drug is not less than 1×10 5 cfu / g, preferably 1×10 6 to 1×10 9 cfu / g.

[0013] Preferably, the viable count of coccus contained in the drug is not less than 1×10 4 cfu / g, preferably 1×10 5 to 1×10 8 cfu / g.

[0014] Preferably, the viable count of Bacillus contained in the drug is not less than 1×10 3 cfu / g, preferably 1×104 to 1×10 7 cfu / g.

[0015] Preferably, the lactobacillus is selected from one or more of Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus crispatus, Lactobacillus delbrueckii subsp. Bulgaricus (Lactobacillus bulgaricus), Lactobacillus delbrueckii subsp. Lactis, Lactobacillus fermentium, Lactobacillus gasseri, Lactobacillus helveticus, Lactobacillus johnsonii, Lactobacillus paracasei, Lactobacillus plantarum, Lactobacillus reuteri, Lactobacillus rhamnosus, Lactobacillus salivarius, Lactobacillus sakei, and Lactobacillus curvatus, and preferably Lactobacillus acidophilus.

[0016] Preferably, the coccus (Enterococcus) is selected from one or more of Enterococcus faecalis; Streptococcus, such as Streptococcus thermophilus; Galactococcus, such as Lactococcus Lactis subsp. lactis, Lactococcus Lactis subsp. cremoris, Lactococcus Lactis subsp. diacetylactis; Leuconostoc, such as Leuconostoc mesenteroides subsp. mesenteroides; Pediococcus, such as Pediococcus acidilactici, Pediococcus pentosaceus; and Staphylococcus, such as Staphylococcus vitulinus, Staphylococcus xylosus, Staphylococcus carnosus, preferably Enterococcus faecalis.

[0017] Preferably, the Bacillus is Bacillus cereus and / or Bacillus coagulans, preferably Bacillus cereus.

[0018] More preferably, the Bifidobacterium infantis is Bifidobacterium infantis with the preservation number of CGMCC No. 0460.1.

[0019] More preferably, the Lactobacillus acidophilus is Lactobacillus acidophilus with the preservation number of CGMCC No. 0460.2.

[0020] More preferably, the Enterococcus faecalis is Enterococcus faecalis with the preservation number of CGMCC No. 0460.3.

[0021] More preferably, the Bacillus cereus is Bacillus cereus with the preservation number of CGMCC No. 0460.4.

[0022] Preferably, the drug further comprises a pharmaceutically acceptable excipient.

[0023] Preferably, the pharmaceutically acceptable excipients are selected from one or more of fillers, moisture regulators, sour taste regulators, glidants, and flavors.

[0024] Preferably, the filler is selected from one or more of trehalose, lactose, and mannitol.

[0025] The inventors of the present invention found that if mannitol is included in the pharmaceutically acceptable excipients, mannitol has a high water activity and slightly poor compatibility with Bifidobacterium infantis and Lactobacillus acidophilus. Therefore, a moisture regulator needs to be added to the pharmaceutically acceptable excipients to reduce the moisture and improve the compatibility of mannitol with Bifidobacterium infantis and Lactobacillus acidophilus.

[0026] Preferably, the moisture regulator is soluble starch.

[0027] Preferably, the soluble starch is corn soluble starch and / or potato soluble starch.

[0028] The inventors of the present invention found that the hygroscopicity of potato soluble starch is lower than that of corn soluble starch or soluble starch from other sources in different environments, and thus the stability of the powder preparation prepared with potato soluble starch is higher.

[0029] Preferably, the sour taste regulator is citric acid and / or sodium citrate.

[0030] Preferably, the glidant is silicon dioxide.

[0031] Preferably, the target population of the drug is patients of all ages.

[0032] Preferably, the drug is a tablet, powder, or capsule.

[0033] The present invention has at least the following beneficial effects:

[0034] When the present invention uses a probiotic composition at a low dose alone to intervene in diseased mice, it can effectively increase their pain threshold, reduce the expression of inflammatory factors IL-1β and TNF-α, effectively relieve abdominal pain, and has a certain therapeutic prospect for infantile colic.

[0035] The probiotic composition of the present invention can significantly improve the symptoms such as abdominal pain, abdominal distension, bowel sounds, and intestinal flora imbalance in infants with infantile colic, and the probiotic composition has high safety.

[0036] When the probiotic composition provided by the present invention is used alone, it can achieve a therapeutic effect at a low dose, which is beneficial to reducing the treatment cost and can avoid the adverse reactions caused by current drug treatments. Description of the Drawings

[0037] Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings, where:

[0038] Figure 1 It is the AWR score after modeling with trinitrobenzenesulfonic acid (TNBS) in mice of the non-intervention group and the drug intervention group.

[0039] Figure 2 It is the intestinal inflammatory factor levels after TNBS modeling in mice of the non-intervention group and the drug intervention group. (a) is TNF-α; (b) is IL-1β. Specific Embodiments

[0040] The present invention will be further described in detail below in conjunction with specific embodiments. The examples given are only for clarifying the present invention and not for limiting the scope of the present invention.

[0041] Example 1 Preparation of Probiotic Composition

[0042] 1.1 Freeze-drying of Probiotics

[0043] After secondary activation of Bifidobacterium infantis, Lactobacillus acidophilus, Enterococcus faecalis, and Bacillus cereus, the probiotic powder was made into freeze-dried bacterial powder.

[0044] Among them, the strain preservation number of Bifidobacterium infantis is CGMCC No.0460.1 (preservation unit: General Microbiology Center of China Committee for Culture Collection of Microorganisms, address: No. 3, Courtyard 1, Beichen West Road, Chaoyang District, Beijing, preservation date: June 20, 2000);

[0045] The strain preservation number of Lactobacillus acidophilus is CGMCC No.0460.2 (preservation unit: General Microbiology Center of China Committee for Culture Collection of Microorganisms, address: No. 3, Courtyard 1, Beichen West Road, Chaoyang District, Beijing, preservation date: June 20, 2000);

[0046] The strain preservation number of Enterococcus faecalis (also known as Streptococcus faecalis) is CGMCC No.0460.3 (preservation unit: General Microbiology Center of China Committee for Culture Collection of Microorganisms, address: No. 3, Courtyard 1, Beichen West Road, Chaoyang District, Beijing, preservation date: June 20, 2000);

[0047] The preservation number of the Bacillus cereus strain is CGMCC No. 0460.4 (preservation unit: China General Microbiological Culture Collection Center, address: No. 3, Yard 1, Beichen West Road, Chaoyang District, Beijing; preservation date: June 20, 2000).

[0048] 1.2 Preparation of the probiotic composition bacterial liquid

[0049] Mix the bacterial powders of Bifidobacterium infantis, Lactobacillus acidophilus, Enterococcus faecalis, and Bacillus cereus in ddH2O according to the calculated amounts to obtain the probiotic composition bacterial liquid.

[0050] Among them, the total viable count of the probiotic composition bacterial liquid is 4.22×10 7 cfu / ml, the viable count of Bifidobacterium infantis is 2.0×10 7 cfu / ml, the viable count of Lactobacillus acidophilus is 2.0×10 7 cfu / ml, the viable count of Enterococcus faecalis is 2.0×10 6 cfu / ml, the viable count of Bacillus cereus is 2.0×10 5 cfu / g; the ratio of the viable counts of Bifidobacterium infantis, Lactobacillus acidophilus, Enterococcus faecalis, and Bacillus cereus is 100∶100∶10∶1.

[0051] Example 2 Animal experiment

[0052] 2.1 Experimental animals

[0053] The experimental animals were 6-week-old ICR mice, purchased from Beijing Spey Foster Biotechnology Co., Ltd. and raised in the animal house. The mice were raised in an SPF environment, and the temperature and humidity were controlled (22±2°C, 45%) under a strict 12∶12-hour dark-light cycle. Food and water were available ad libitum. Male and female mice were housed together. All animal experiments were approved by the Animal Experiment Ethics Committee of Qilu Hospital of Shandong University.

[0054] 2.2 Experimental method

[0055] 2.2.1 Grouping

[0056] Grouping of mice: The mice were randomly grouped by body weight into an untreated group and a drug intervention group; the drug intervention group was further divided into: a probiotic group (administered the probiotic composition bacterial liquid prepared in Example 1) and a control probiotic combination group.

[0057] Probiotic group: The mice in the probiotic group were gavaged with the probiotic composition bacterial liquid prepared in Example 1 (both Bifidobacterium infantis and Lactobacillus acidophilus were 2.0×10 7 cfu / kg, and Enterococcus faecalis was 2.0×10 6cfu / kg, and for Bacillus cereus it was 2.0×10 5 cfu / kg), for a total of 4.22×10 7 cfu / kg. They were continuously gavaged for 4 weeks and then the TNBS model was established. The mice were fasted but given water 24 hours before enema. 0.1 mL of 1.75 mg TNBS was injected into the descending colon through the anus, with the end of the catheter 4 cm from the anus. After the procedure, the mice were kept in an inverted position for 30 s. The control group was given the same volume of normal saline.

[0058] Control probiotic combination group: Commercially available products Bifico (Bifidobacterium triple viable capsules) and Shishou (Bacillus cereus viable capsules) were selected for isolation and culture, and a four-strain viable bacteria containing Bifidobacterium longum, Lactobacillus acidophilus, Enterococcus faecalis, and Bacillus cereus (the ratio of the four bacteria was the same as that of the probiotic group) was combined. The gavage dose was controlled at 4.22×10 7 cfu / kg, and then the TNBS model was established in the same way as the probiotic group.

[0059] Non-intervention group: The mice were not intervened with drugs and the TNBS model was directly established in the same way as the probiotic group.

[0060] After modeling, the abdominal wall withdrawal reflex was scored, and the contents of inflammatory factors such as IL-1β and TNF-α in the intestinal tissue were detected by ELISA.

[0061] 2.2.2 Index detection

[0062] 2.2.2.1 Abdominal wall withdrawal reflex (AWR) score

[0063] Before the experiment, the mice were fasted but given water for 24 h. The 6F pediatric urinary catheter with a balloon was lubricated with liquid paraffin and slowly inserted into the colorectum of the mice anesthetized with ether (about 2 cm from the anus) and fixed to the tail of the mice. After the mice woke up and adapted to the balloon for 30 min, air was quickly injected into the balloon until the specified pressure (60 mmHg, 80 mmHg) was reached and maintained for 10 s, with an interval of 60 s. Each pressure was repeated 3 times. The abdominal wall withdrawal reflex was observed and scored, and the average score of the 3 times was taken.

[0064] AWR scoring criteria: 0 point, no response to dilation; 1 point, only slight head movement; 2 points, abdominal muscle contraction; 3 points, abdomen lifted; 4 points, body arched and pelvis lifted.

[0065] 2.2.2.2 Content of inflammatory factors

[0066] Total RNA was extracted from the intestine using TRIzol reagent, and then cDNA was prepared using a Toyobo qPCR kit. All reactions were performed in triplicate on an Applied Biosystems StepOne real-time PCR system. GAPDH was used as an endogenous control.

[0067] 2.2.3 Statistical methods

[0068] The t-test was used for gene expression. Data were expressed as Mean±SEM. Among them, p < 0.05 (*) indicated significant difference, and p < 0.01 (**) indicated extremely significant difference.

[0069] 2.3 Experimental results

[0070] 2.3.1 Abdominal wall withdrawal reflex score

[0071] As Figure 1 shown, when the pressure was 60 mm Hg, the AWR score of mice intervened with probiotics was extremely significantly lower than that of the non-intervened group, and compared with the control probiotic combination group, the reduction amplitude of the probiotic group was greater; when the pressure increased to 80 mmHg, there was still a significant difference in the AWR score between the probiotic group and the non-intervened group, while there was no significant difference between the control probiotic combination group and the non-intervened group, and even slightly higher than the non-intervened group. This indicates that the pain threshold of mice in the probiotic group is higher than that of mice in the non-intervened group, and the probiotic composition of the present invention has a better effect on improving the pain threshold than the control probiotic combination group.

[0072] 2.3.2 Inflammatory factor content

[0073] As Figure 2 (a) shown, the TNF-α level in the probiotic group was extremely significantly lower than that in the non-intervened group, while there was no significant difference between the control probiotic combination group and the non-intervened group.

[0074] As Figure 2 (b) shown, the IL-1β level in the probiotic group was extremely significantly lower than that in the non-intervened group, while the control probiotic combination group was only significantly lower than the non-intervened group.

[0075] This shows that the probiotic composition of the present invention is superior to the control probiotic combination group in alleviating the intestinal inflammation degree caused by TNBS modeling.

[0076] 2.3 Experimental summary

[0077] In this invention, a probiotic composition was used to intervene in mice, and the rectal pain threshold of the mice was reflected by the AWR score 3 weeks after TNBS modeling. When the rectal pressure was relatively high, the score of the mice in the probiotic group was significantly lower than that of the mice in the non-intervened group, indicating that the intervention with the probiotic composition of this invention could effectively increase the pain threshold of diseased mice; in addition, the intervention with the probiotic composition of this invention also significantly reduced the levels of IL-1β and TNF-α, and alleviated the inflammatory reaction to a certain extent.

[0078] Example 3 Population Experiment

[0079] Two hundred and thirty-one infants with infantile colic were selected and treated with oral Sibelium Bifidobacterium quadruple viable bacteria tablets, one tablet each time, three times a day, and each treatment cycle was 7 days. During and after the treatment, the improvement of the symptoms of the children (abdominal pain, abdominal distension, bowel sounds, intestinal flora) and the safety of the probiotic composition were measured.

[0080] The evaluation criteria for abdominal pain indicators refer to the diagnostic criteria for neonatal colic in the "Rome III Diagnostic Criteria for Functional Gastrointestinal Diseases"; the evaluation criteria for abdominal distension indicators refer to "Diagnostic Lectures (28) Abdominal Distension", Zhang Shuji, Chinese Journal of Rural Medicine and Pharmacy, 1997, 4(4): 2; the evaluation criteria for the activity of bowel sounds refer to the diagnostic criteria for bowel sounds in "Diagnostics" (written by Wan Xuehong and Lu Xuefeng); the evaluation criteria for intestinal flora balance refer to "Consensus on the Clinical Application of Probiotics in the Chinese Digestive Tract (2016 Edition)" and "Atlas of Fecal Smear Examination of Intestinal Flora" (edited by Zhang Xiurong); the specific scoring criteria are shown in Table 1.

[0081] Table 1 Scoring Table for Efficacy Observation Indicators

[0082]

[0083] Safety evaluation of the probiotic composition: Blood routine (Hb, RBC, WBC, neutrophil percentage, PLT), urine routine (WBC, RBC, casts, protein, urine sugar), stool routine, liver function (ALT, AST), kidney function (BUN, Cr), blood electrolytes (sodium, potassium, chloride), and electrocardiogram were examined once before medication and after the end of treatment; physical examinations and vital signs (body temperature, respiration, heart rate, blood pressure) were examined before medication, during treatment, and after the end of medication. All adverse events occurring during the medication period of the subjects were recorded, including serious adverse events and important adverse events. Serious adverse events refer to those leading to death, life-threatening situations, disability, loss of function, the need for hospitalization or extended hospitalization, congenital anomalies or birth defects, etc. (ICH E2A), and important adverse events lead to interventions, including discontinuation of the test drug treatment, dose reduction, or other important concomitant treatments (ICH E3), which specifically include 1) adverse events causing trial discontinuation; 2) obvious abnormal laboratory tests requiring symptomatic treatment; 3) adverse events with moderate and severe severity requiring symptomatic treatment; 4) adverse events causing dose reduction of the test drug.

[0084] 3.1 Improvement of abdominal pain before and after treatment

[0085] As shown in Table 2, with the treatment of the probiotic composition, the proportion of children with 0 points for abdominal pain is getting higher and higher. By the 7th day of treatment, the abdominal pain index scores of all children dropped to 0 points, showing a complete clinical control effect, and the treatment effect was also maintained after the end of treatment.

[0086] Table 2 Abdominal pain index score before and after treatment

[0087]

[0088] 3.2 Improvement of abdominal distension before and after treatment

[0089] As shown in Table 3, with the treatment of the probiotic composition, the proportion of children with 0 points for abdominal distension is getting higher and higher. By the 7th day of treatment, the proportion of children with a score of 0 for the abdominal distension index reached 99.1%, showing a good clinical control effect, and the treatment effect was also maintained after the end of treatment.

[0090] Table 3 Abdominal distension index score before and after treatment

[0091]

[0092]

[0093] 3.3 Improvement of hyperactive bowel sounds before and after treatment

[0094] The test results are shown in Table 4. With the treatment of the probiotic composition, the proportion of children with 0 bowel sounds score is getting higher and higher. By the 7th day of treatment, the proportion of all children with a bowel sound index score of 0 reached 72.7%, showing good clinical control effect, and the treatment effect was also maintained after the treatment ended.

[0095] Table 4 Bowel Sound Index Score Table before and after Treatment

[0096]

[0097]

[0098] 3.4 Relief of Dysbacteriosis before and after Treatment

[0099] The test results are shown in Table 5. After the treatment with the probiotic composition, the disorder of the intestinal flora in children has been greatly relieved, and the proportion of normal intestinal flora has increased from 16.9% to 67.1%, showing good clinical control effect.

[0100] Table 5 Scoring Table of Bacteriological Identification Indexes of Direct Stool Smear Staining before and after Treatment

[0101]

[0102]

[0103] 3.5 Safety Evaluation

[0104] There were no obvious abnormalities in the tests of blood routine, urine routine, stool routine, liver function, kidney function, blood electrolytes, electrocardiogram, etc. before and after treatment in the experimental group; there were no abnormalities in vital signs (including body temperature, respiration, heart rate, blood pressure).

[0105] No serious adverse events were seen in this study. Among the 231 cases in the experimental group, 2 people had 2 important adverse events (specific conditions are shown in Table 6). The symptoms of 1 adverse event were upper respiratory tract infection, with mild symptoms, and after evaluation, it was determined that the adverse reaction was not related to the drug; the symptoms of 1 adverse event were fever, with mild symptoms, and after evaluation, it was determined that the adverse reaction might not be related to the drug. Both cases withdrew from the treatment study. The incidence of comprehensive adverse events is shown in Table 7, indicating that the probiotic composition has high safety.

[0106] Table 6 List of Cases with Adverse Events

[0107]

[0108] Table 7 Incidence of Adverse Events

[0109]

[0110]

[0111] In summary, the research of the present invention shows that the intervention with the probiotic composition of the present invention can increase the pain threshold and reduce the levels of inflammatory factors in diseased mice, and can significantly improve the symptoms such as abdominal pain, abdominal distension, bowel sounds, and intestinal flora imbalance in infants with infantile colic. Moreover, this probiotic composition has high safety and has a certain therapeutic prospect for infantile colic and its related diseases.

[0112] The above are only several exemplary embodiments of the present invention, and do not impose any form of limitation on the present invention. Although the present invention is disclosed above with preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some changes or modifications within the scope of the technical solution of the present invention by using the disclosed technical content to obtain equivalent or equivalent embodiments, which all belong to the scope of the present invention.

Claims

1. Use of a probiotic composition in the preparation of a medicament for preventing and / or treating infantile colic and related diseases, wherein, The probiotic composition contains Bifidobacterium infantis, Lactobacillus, coccus, and Bacillus.

2. Use of a probiotic composition as the sole active ingredient in the preparation of a medicament for preventing and / or treating infantile colic and its related diseases, wherein, The probiotic composition contains Bifidobacterium infantis, Lactobacillus, coccus, and Bacillus.

3. The use according to claim 1 or 2, wherein The probiotic composition consists of Bifidobacterium infantis, Lactobacillus, coccus, and Bacillus.

4. Use according to any one of claims 1 to 3, wherein In the probiotic composition, the viable count ratio of Bifidobacterium infantis, Lactobacillus, coccus, and Bacillus is (1 - 100)∶(1 - 100)∶(1 - 100)∶1, preferably (1 - 100)∶(1 - 100)∶(1 - 10)∶1.

5. Use according to any one of claims 1 to 4, wherein The total number of viable bacteria contained in the drug is not less than 1×10 5 cfu / g, preferably 2×10 5 Up to 4×10 9 cfu / g.

6. The use according to any one of claims 1 to 5, wherein The live bacteria count of Bifidobacterium infantis contained in the drug is not less than 1×10 5 cfu / g, preferably 1×10 6 to 1×10 9 cfu / g; Preferably, the viable count of Lactobacillus contained in the drug is not less than 1×10 5 cfu / g, preferably 1×10 6 to 1×10 9 cfu / g; Preferably, the viable count of cocci contained in the drug is not less than 1×10 4 cfu / g, preferably 1×10 5 to 1×10 8 cfu / g; Preferably, the viable count of Bacillus contained in the drug is not less than 1×10 3 cfu / g, preferably 1×10 4 to 1×10 7 cfu / g.

7. Use according to any one of claims 1 to 6, wherein The Lactobacillus is selected from one or more of Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus crispatus, Lactobacillus bulgaricus, Lactobacillus delbrueckii subsp. lactis, Lactobacillus fermentum, Lactobacillus gasseri, Lactobacillus helveticus, Lactobacillus johnsonii, Lactobacillus paracasei, Lactobacillus plantarum, Lactobacillus reuteri, Lactobacillus rhamnosus, Lactobacillus salivarius, Lactobacillus sakei, and Lactobacillus curvatus, preferably Lactobacillus acidophilus; Preferably, the coccus is selected from one or more of Enterococcus faecalis, Streptococcus, Lactococcus, Leuconostoc, Pediococcus, and Staphylococcus, preferably Enterococcus faecalis; Preferably, the Bacillus is Bacillus cereus and / or Bacillus coagulans, preferably Bacillus cereus.

8. The use according to claim 7, wherein The Bifidobacterium infantis is Bifidobacterium infantis with the deposit number of CGMCC No. 0460.1; Preferably, the Lactobacillus acidophilus is Lactobacillus acidophilus with the deposit number of CGMCC No. 0460.2; Preferably, the Enterococcus faecalis is Enterococcus faecalis with the deposit number of CGMCC No. 0460.3; Preferably, the Bacillus cereus is Bacillus cereus with the deposit number of CGMCC No. 0460.

4.

9. Use according to any one of claims 1 to 8, wherein, The drug also contains pharmaceutically acceptable excipients; Preferably, the pharmaceutically acceptable excipients are selected from one or more of fillers, moisture regulators, acid regulators, glidants, and flavors; Preferably, the filler is selected from one or more of trehalose, lactose, and mannitol; Preferably, the moisture regulator is soluble starch; more preferably, the soluble starch is corn soluble starch and / or potato soluble starch; Preferably, the acid regulator is citric acid and / or sodium citrate; Preferably, the glidant is silicon dioxide.

10. Use according to any one of claims 1 to 9, wherein The target group of the drug is patients of all ages; Preferably, the drug is in the form of tablets, powders, or capsules.

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