TWI745454B - Composition for inhibiting the reduction of Lactobacillus spp. lactic acid bacteria in the intestinal tract - Google Patents

Abstract

The present invention provides a composition capable of inhibiting the decrease of Lactobacillus lactic acid bacteria in the intestinal tract, and a method for inhibiting the same. In more detail, the composition of the present invention is a composition for inhibiting the reduction of Lactobacillus lactic acid bacteria in the intestinal tract of a subject to which an antibacterial drug is administered, and is characterized in that it contains a composition derived from Propionibacterium Made from fermented whey.

Description

Composition for inhibiting the reduction of Lactobacillus spp. lactic acid bacteria in the intestinal tract [Reference to related applications]

The present application claims priority based on Japanese Patent Application No. 2016-202465 filed in Japan on October 14, 2016, and the content disclosed in the patent application is incorporated into this specification by reference.

The present invention relates to a composition for inhibiting the reduction of Lactobacillus spp. lactic acid bacteria in the intestinal tract in a subject to which an antibacterial drug is administered.

A wide variety of antibacterial drugs are being used for the purpose of treating infections and preventing bacterial infections. For example, the deterioration of the intestinal environment due to the use of antibacterial drugs can be one of the adverse reactions caused by the use of antibacterial drugs. This is because by taking antibacterial drugs, not only pathogenic microorganisms, but also beneficial bacteria that are more useful than Fednerella or lactic acid bacteria, are reduced. It is generally believed that this is due to intestinal flora (intestinal bacteria). Cluster), that is, the ecosystem of the intestinal bacteria is negatively affected. As a result, symptoms such as constipation, diarrhea, nausea, headache, etc. will occur. As a countermeasure for such adverse reactions, it is currently recommended to take antibacterial drugs at the same time. Take live probiotics (probiotics) and/or take in ingredients that can increase probiotics (probiotics) at the same time. As a representative example of probiotics, for example, the proliferation factors of intestinal probiotics such as oligosaccharides or dietary fiber, and probiotics such as lactic acid bacteria or Bifidobacterium are used as nutritional supplements in the form of capsules.

Among the beneficial bacteria, there is also Lactobacillus bacteria (Lactobacillus), which is a kind of lactic acid bacteria, which itself is widely used as the probiotic bacteria. However, the lactic acid bacteria of the genus Lactobacillus are Gram-positive bacilli, and because of their high sensitivity to antibacterial drugs, there have been reports of significant reduction when antibacterial drugs are administered (for example, Non-Patent Document 1). Therefore, it is an important issue to suppress the decrease of Lactobacillus lactic acid bacteria in the intestinal tract of subjects administered antibacterial drugs.

On the other hand, in recent years, a Bifidogenic Growth Stimulator (BGS: Bifidogenic Growth Stimulator) has been reported as a new probiotic component (Non-Patent Document 2). Specifically, Non-Patent Document 2 reports that the supernatant filtrate of the culture of Propionibacterium freudenreichii specifically proliferates Bifidella bacteria. However, the report also pointed out that the growth-promoting substance of Bifeideii has no substantial effect on the growth promotion effect of lactic acid bacteria and other intestinal bacteria other than Bifeideii (refer to Table 1 of Non-Patent Document 2). ). In addition, it has also been reported that the use of a feed composition containing a substance that promotes the growth of Bifidobacterium spp. improves the intestinal flora of young livestock (Patent Document 1). Specifically, Patent Document 1 reported that when young livestock ingested Profec (trademark), a whey fermented product derived from Propionibacterium, the intestinal tract significantly increased compared with Fideella, and it was relative to the total bacterial count. The share has also increased significantly. On the other hand, about the nipple The genus lactic acid bacteria also showed that it did not produce a significant increase (refer to Table 1 of Examples in Patent Document 1). So far, there has not been a report of such a significant increase in ingredients of Lactobacillus genus lactic acid bacteria in the intestinal tract. In addition, there has been no report on the test of inhibiting the decrease of Lactobacillus lactic acid bacteria caused by antibacterial drugs, or the effective method and composition.

[Prior Technical Literature] [Patent Literature]

[Patent Document 1] Japanese Patent No. 4073922

[Non-Patent Literature]

[Non-Patent Document 1] Yakult Research Institute Research Report Collection, No. 30, 1-6, 2012

[Non-Patent Document 2] Bioscience Microflora Vol.18(2), 73-80, 1999

The object of the present invention is to provide a composition capable of inhibiting the decrease of Lactobacillus lactic acid bacteria in the intestinal tract of a subject to which an antibacterial drug is administered, and the inhibiting method.

The present inventors, this time, in a human clinical trial, will make the patients who are administering antibacterial drugs before or during the administration of antibacterial drugs ingest the whey fermented product derived from Propionibacterium, compared with the case of not ingesting the whey fermented product derived from propionic acid bacteria. Comparing patients with acid bacillus fermented whey, it was found that it can significantly inhibit the milk rod in the intestine The reduction of lactic acid bacteria. The present invention is based on this relevant knowledge.

According to the present invention, the following invention is provided.

(1) A composition for inhibiting the reduction of lactic acid bacteria of the genus Lactobacillus in the intestinal tract in a subject to which an antibacterial drug is administered, which contains a fermented whey derived from Propionibacterium.

(2) The composition described in (1), wherein the aforementioned Propionibacterium is Propionibacterium freudenreichii (Propionibacterium freudenreichii).

(3) The composition as described in (1) or (2), wherein the aforementioned antibacterial drug is selected from penicillin antibacterial drugs, cephalosporin antibacterial drugs, cephalosporin antibacterial drugs, hydromycin antibacterial drugs, β -At least one of lactam inhibitors, oxazolidinone antibacterial drugs, new quinolone antibacterial drugs, and macrolide antibacterial drugs.

(4) The composition described in any one of claims (1) to (3), wherein the daily dosage is calculated as the dry mass of the fermented whey derived from Propionibacterium, which is 0.15~200mg /kg body weight.

(5) The composition described in any one of (1) to (4) is a food composition or a pharmaceutical composition.

(6) The composition described in any one of (1) to (5), which is in the form of powder, liquid or lozenge.

(7) A use of a whey fermented product derived from Propionibacterium, which is used in the manufacture of a composition for inhibiting the reduction of the lactic acid bacteria of the genus Lactobacillus in the intestinal tract in subjects to which antibacterial drugs are administered.

(8) A method for inhibiting the decrease of the lactic acid bacteria of the genus Lactobacillus in the intestine in a subject to which an antibacterial drug is administered, characterized in that it comprises making the aforementioned antibacterial drug It is made by ingesting an effective amount of fermented whey derived from Propionibacterium.

(9) The method described in (8), which is a method for improving related diseases or conditions that reduce the intestinal lactobacillus lactic acid bacteria caused by the administration of antibacterial drugs.

(10) A whey fermented product derived from Propionibacterium, which is used to inhibit the decrease in the intestinal lactic acid bacteria of the genus Lactobacillus in a subject to which an antibacterial drug is administered.

(11) A use of a fermented whey derived from Propionibacterium, which is used to inhibit the decrease of Lactobacillus lactic acid bacteria in the intestinal tract in a subject to which antibacterial drugs are administered.

According to the present invention, the use of the fermented whey derived from Propionibacterium can effectively inhibit the decrease of Lactobacillus lactic acid bacteria in the intestinal tract among the subjects administered with antibacterial drugs.

[Figure 1] A graph showing the total number of bacteria and the number of Lactobacillus bacteria in the stool of a patient (control group) fed by a tube to which antibacterial drugs are administered (control group test). *; p<0.05 (compared with day 0 after administration).

[Figure 2] A graph showing the change in the total bacterial count and the number of Lactobacillus bacteria in the feces of a patient (group administered with the composition) via a tube administered with antibacterial drugs (test of the group administered with the composition) . *; p<0.05 (compared with day 0 after administration).

[Figure 3] A graph comparing the total bacterial count and the Lactobacillus bacterial count in the feces of the control group and the group administered with the composition. *; p<0.05.

[Fig. 4] A graph comparing the number of Federella in feces of the control group and the group administered with the composition.

Composition for inhibiting the reduction of lactic acid bacteria of the genus Lactobacillus

The composition of the present invention is a composition for inhibiting the reduction of the lactic acid bacteria of the genus Lactobacillus in the intestinal tract in a subject to which an antibacterial drug is administered, and it is made of a fermented whey derived from Propionibacterium. The use of whey fermented product derived from Propionibacterium as an active ingredient can not only inhibit the reduction of Bifidella in the intestinal tract, but also before, during, or after the administration of antibacterial drugs. It is an unexpected fact that it can significantly inhibit the decrease of Lactobacillus lactic acid bacteria in the intestinal tract.

The so-called "objects who have been administered antibacterial drugs" refer to those who are expected to administer antibacterial drugs (before administration), those who are currently being administered (during administration), or those who have been administered (after administration), preferably Refers to objects that are expected to decrease, decrease, or have decreased the Lactobacillus lactic acid bacteria in the intestinal tract due to antibacterial drugs. Although the subject is preferably human, it is also preferable to other than humans (for example, domestic animals such as horses and cows, pets such as rodents, dogs, cats, etc., and appreciation animals kept in zoos, etc.). Related aspects in the present invention Also included in it.

The antibacterial drug of the present invention is not particularly limited if it is an antibacterial drug to which Lactobacillus lactic acid bacteria is susceptible. However, it is preferably an antibiotic to which Lactobacillus lactic acid bacteria are susceptible. As a more specific example, for example, penicillin antibacterial drugs (for example, amoxicillin (AMPC), Ampicillin (ABPC)), Cephalosporin antibacterial drugs (e.g., Cefpirome (CPR)), Cephalosporin antibacterial drugs (e.g., Ceftazidime (CAZ)), Hydromycin antibacterial drugs ( For example, meropenem (MEPM), β-lactamase inhibitors, oxazolidinone antibacterial drugs (for example, linezolid (LZD)), new quinolone antibacterial drugs (for example, levofloxacin (LVFX), Pa In addition to zufloxacin (PZFX) and macrolide antibacterials (for example, azithromycin (AZM)), lincomycin antibacterials, aminoglycoside antibacterials, and tetracycline antibacterials can be listed , Chloramphenicol antibacterial drugs, peptide antibacterial drugs, sulfa drugs, anti-tuberculosis drugs, quinolones antibacterial drugs, antiviral drugs, antifungal drugs. The antibacterial drugs are preferably penicillin antibacterial drugs (e.g., amoxicillin (AMPC), ampicillin (ABPC)), cephem antibacterial drugs (e.g., cefpirome (CPR)), cephalosporin antibacterial drugs ( For example, ceftazidime (CAZ)), hydrocarbon mycene antibacterial drugs (e.g., meropenem (MEPM)), β-lactamase inhibitors, oxazolidinone antibacterial drugs (e.g., linezolid (LZD) ), new quinolone antibacterial drugs (for example, levofloxacin (LVFX), pazufloxacin (PZFX)), and macrolide antibacterial drugs (for example, azithromycin (AZM)).

The method of administration of antibacterial drugs is not particularly limited as long as Lactobacillus lactic acid bacteria in the intestine show sensitivity. For example, it can be taken orally (or orally administered), intestinal administration, gastrostomy, subcutaneous administration, For intravenous administration, etc., it is appropriately selected according to the object and purpose of administration of the antibacterial drug (for example, the purpose of treatment or the purpose of prevention). If the method of using antibacterial drugs is a general knowledge in the technical field of the present invention, it can be based on the disease of the subject. Diseases, conditions, and uses are appropriately selected. For example, those with general knowledge in the technical field of the present invention can follow the methods described in JAID/JAS Infectious Diseases Treatment Guidelines 2014 (JAID/JAS Infectious Diseases Treatment Guidelines and Guidelines Development Committee) Choose appropriately.

Lactobacillus lactic acid bacteria are Gram-positive bacilli and are known as beneficial bacteria. As preferred specific examples of Lactobacillus lactic acid bacteria, the results of a human clinical trial, there may be exemplified Lactobacillus bulgaricus (Lactobacillus bulgaricus), Lactobacillus johnsonii (L.johnsonii), Lactobacillus casein (of L.casei), sub Lactobacillus casei (L.paracasei), gasseri (L.gasseri), Switzerland Lactobacillus (L.helveticus), Lactobacillus rhamnosus (L.rhamnosus), Lactobacillus acidophilus (L.acidophilus), saliva Lactobacillus (L.salivarius), Lactobacillus pentosus (L.pentosus), Lactobacillus plantarum (L.plantarum), Lactobacillus brevis (L.brevis), by lord Lactobacillus (L.reuteri), Sporolactobacillus ( L. sporogenes ) and so on. Lactobacillus lactic acid bacteria are known to have, for example, intestinal regulation effects (for example, for diarrhea, constipation, and irritable bowel syndrome), immune activation, Helicobacter pylori sterilization, atopic dermatitis, pollen Inhibition of allergic diseases, asthma, etc., improvement of irritable bowel syndrome (IBS), improvement of lipid metabolism or visceral fat accumulation, inhibition of risk of infections such as respiratory diseases, improvement of inflammatory bowel disease, uterine Physiological activities such as improvement of endometriosis, cancer suppression, improvement of stress and QOL, improvement of diabetes, and improvement of oxidative stress. Lactobacillus is a lactic acid bacteria, and because of the characteristics of the above-mentioned physiological activity, it is expected that its bacterial count will exist in a certain number in the intestinal tract.

Lactobacillus is a lactic acid bacteria in the intestinal tract, preferably the lactic acid bacteria of the genus Lactobacillus contained in the bacterial flora in the intestine, preferably, a lactic acid bacteria having a function of maintaining a good balance of the intestinal environment. The number of Lactobacillus lactic acid bacteria in the intestine is ^{preferably Log10 4} or more per 1g of human feces, more preferably Log10 ⁵ or more, even more preferably Log10 ⁶ or more, and even more preferably Log10 ⁷ or more.

The whey fermentation product derived from Propionibacterium used in the present invention is obtained by culturing Propionibacterium on a medium containing whey.

The so-called Propionibacterium is a gram-positive anaerobic bacteria belonging to the genus Propionibacterium. It is a microorganism that anaerobicly produce propionic acid from sugars and has been used since ancient times as bacteria such as Evanda cheese. Yuan, its safety has been confirmed. The Propionibacterium used in the present invention, for example, may be Propionibacterium freudenreichii , Propionibacterium freudenreichii, P. thoenii , P. acidipropionici , and Janssen propionic acid. P.jensenii , P.avidum , P.acnes , P.lymphophilum , P.granulosam , preferably It is Propionibacterium freudenreichii. One of the above can be used, or two or more of them can be used in combination.

Propionibacterium, preferably, is the Propionibacterium freudenreichii Propionibacterium frederi growth promoting substance (BGS) producing bacteria, for example, Propionibacterium freudenreichii ET-3 (deposit organization: independent administrative corporation industry) International Patent Organism Depositary National Institute of Advanced Industrial Science and Technology Technology), Deposit Date: August 9, 2001, Deposit Number: FERM-BP-8115), Propionibacterium frederi ATCC 6207, Propionibacterium frederi ATCC 8262, Propionibacterium frederi IFO 12424, C. frederi Acidobacter IFO 12426, Propionibacterium frederi IFO 12391, more preferably Propionibacterium frederi ET-3 (deposit number: FERM-BP-8115).

The so-called whey, also known as whey, refers to the transparent yellow-green water-soluble components remaining after removing fat, casein, fat-soluble vitamins, etc. from cow milk. The whey used in the present invention can be exemplified by, for example, the original liquid of the whey (sweet whey, yoghurt, etc.), its concentrate, its dried product (whey powder), its frozen product, etc. Reducing solution, and, desalted milk serum, milk serum protein concentrate (WPC), milk serum protein isolate (WPI), α-lactalbumin (α-La), β-lactoglobulin (β-Lg), immune Globulin, lactoferrin, etc., as well as the above-mentioned reducing solution, and the above-mentioned milk serum protein decomposition product. The whey is preferably selected from the original liquid of whey, whey powder, WPC, WPI, and reducing solutions thereof, and proteolytic enzyme decomposition products thereof. Only one of the above can be used, or two or more of them can be used in combination.

The whey system is preferably contained at 1 to 5% by mass, and more preferably 1.5 to 4.0% by mass as the amount of protein relative to the medium. In addition, the carbohydrate system is contained at 1 to 4% by mass, preferably 1.5 to 3.0% by mass with respect to the culture medium. In order to have such a medium composition, what adjusts the addition amount (blending amount) of whey can be used. The carbohydrate is preferably glucose or a monosaccharide obtained by treating lactose with lactase. If the medium is capable of cultivating Gram-positive anaerobic bacteria, it may also contain ingredients other than whey. Here, the amount of protein can be calculated by Kjeldahl method or labor law. In the Kjeldahl method In addition, the nitrogen contained in various proteins is measured, and the value can be calculated by multiplying the value by the nitrogen-protein conversion factor (usually 6.25).

The medium that can be used in the present invention is preferably a medium with a pH of 5 to 8 (preferably 5.5 to 7.5) formed from the proteolytic enzyme decomposition product of 10% by mass of the milk powder reducing solution. The proteolytic enzyme is not particularly limited as long as it can appropriately decompose milk serum protein. As the medium, for example, a 10% by mass reduction solution of milk slurry powder decomposed by proteolytic enzyme AMANO A (Amano Pharmaceutical Co., Ltd.) at 50° C. and pH 7.0 can be used.

In addition to using a medium containing whey, the culture of Propionibacterium can be cultured aerobic or anaerobic (for example, under N ₂ gas pressure (0.5 kg/cm ² )) according to common methods. Typically, the temperature of the culture system will be modulated to 20 ~ 40 ℃, pH6 ~ 8 degrees, in order to make the number of microorganisms became ^{10 7 ~ 10 8 cfu / mL} , as acnes bacteria ingested membered, 3 to 4 days in liquid culture That's it. The concentration of Propionibacterium contained in the culture obtained in this way is about 5 times that of the cells.

The whey fermentation product derived from Propionibacterium of the present invention can be a culture obtained by culturing Propionibacterium, isolated bacterial bodies, culture medium (culture supernatant), or a mixture of the above At least one of the fermented whey derived from Propionibacterium may be an extract, a freeze-dried product or a dilution of these. In addition, the whey fermented product derived from Propionibacterium may be one that has been sterilized. As the sterilization step, for example, low temperature and long time sterilization, high temperature and long time sterilization, high temperature and short time sterilization, and ultra-high temperature instant sterilization can be exemplified.

According to a preferred aspect of the present invention, as the Propionibacterium-derived whey fermentation product of the present invention, Propionibacterium freudenreichii ET-3 (Propionibacterium freudenreichii ET-3) (deposit number: FERM BP- 8115) Propionibacterium-derived whey fermented product obtained by culturing with 10% by mass of milk powder reduction solution, more preferably, Propionibacterium freudenreichii ET-3 can be used, which is made from 10% by mass of milk powder The proteolytic enzyme AMANO A (Amano Pharmaceutical Co., Ltd.) of the reducing solution, a culture medium made of decomposed products at 50°C and pH 7.0, and cultured at 35°C and pH 6.0 for 75 hours, derived from propionic acid Bacillus whey fermented product. In this way, the whey fermented product derived from Propionibacterium can be synthesized, or commercially available products can also be used. As a commercially available product, for example, as a raw material, an example is Profec ("Profec" (trademark), manufactured by Meiji Co., Ltd.), which has a proliferation promoting effect on main intestinal bacteria, especially Bifidella, and is recognized As a related ingredient of specific health foods.

According to one aspect of the present invention, the whey fermented product derived from Propionibacterium of the present invention may also include Bifidella growth promoting substance (BGS). As a substance for promoting the growth of Bifidobacterium spp., for example, 1,4-dihydroxy-2-naphthoic acid (1,4-dihydroxy-2-naphthoic acid, DHNA), 2-amino-3-carboxy-1 ,4-Naphthoquinone (2-amino-3-carboxy-1,4-naphthoquinone, ACNQ) and the above-mentioned analogs, the analogs include 1,4-naphthoquinone, 2-methyl-1,4- Naphthoquinone, 4-amino-2-methyl-1-naphthol and 2-amino-3-chloro-1,4-naphthoquinone. According to a preferred embodiment of the present invention, the whey fermentation product derived from Propionibacterium of the present invention contains 1,4-dihydroxy-2-naphthoic acid.

The fermented whey derived from Propionibacterium used in the present invention, It can be used as a composition for inhibiting the reduction of Lactobacillus lactic acid bacteria.

The composition for inhibiting the reduction of Lactobacillus lactic acid bacteria of the present invention may contain other ingredients acceptable for oral administration in addition to the fermented whey derived from Propionibacterium. Other ingredients are not particularly limited within a range that does not hinder the effects of the present invention. Examples include excipients, stabilizers, preservatives, wetting agents, emulsifiers, lubricants, sweeteners, colorants, fragrances, Additives such as buffers, antioxidants, and pH adjusters.

According to a preferred aspect of the present invention, the composition for inhibiting the reduction of Lactobacillus lactic acid bacteria of the present invention contains functional carbohydrates (for example, oligosaccharides or dietary fiber) that become the "feed" of Lactobacillus lactic acid bacteria . By including the functional sugar that becomes the "feed" of Lactobacillus lactic acid bacteria, it becomes the "feed" of Lactobacillus lactic acid bacteria remaining in the intestinal tract, which can promote the proliferation.

In addition, the form of the composition for inhibiting the reduction of Lactobacillus lactic acid bacteria of the present invention is not particularly limited, and any one of solid form (powder form, lozenge form, etc.), liquid form (cited form, etc.), and semi-liquid form Any of them is acceptable, but it is preferably in the form of powder, lozenge or liquid. Examples of commercially available products of this type are Meiji BGSPOWDER in powder form (manufactured by Meiji Co., Ltd.), gastrointestinal vitality tablets in tablet form (manufactured by Meiji Co., Ltd.), and liquid YH Flore (manufactured by Meiji Co., Ltd.) )Wait.

According to a preferred aspect of the present invention, the composition for inhibiting the reduction of Lactobacillus lactic acid bacteria of the present invention contains 1,4-dihydroxy-2-naphthoic acid, protein, carbohydrate (for example, carbohydrate, dietary fiber) , Depending on the situation, contains vitamins and/or minerals (for example, sodium, calcium, phosphorus, magnesium, potassium). According to a preferred aspect, the present invention inhibits the lactic acid bacteria of the genus Lactobacillus 1.5 g of the composition for reduction contains 0.01 to 1000 μg of 1,4-dihydroxy-2-naphthoic acid, more preferably 0.1 to 100 μg, and even more preferably 0.5 to 50 μg.

Ingestion of the composition for inhibiting the reduction of Lactobacillus lactic acid bacteria of the present invention can effectively inhibit the decrease of Lactobacillus lactic acid bacteria in the intestinal tract among subjects administered antibacterial drugs.

The reduction and inhibitory effect of Lactobacillus lactic acid bacteria in the intestinal tract is as described in Example 1 of the embodiment. The number of Lactobacillus bacteria in the intestinal tract can be quantified by ingested and uningested objects. The number of bacteria in the group in which the composition of the present invention is taken is used as an index, and a comparative test is performed for evaluation. In the comparative test conducted, the number of Lactobacillus bacteria in the group after taking the composition of the present invention was significantly higher than that of the group not taking the composition of the present invention. When the number of Lactobacillus bacteria increases, the composition of the present invention is considered to have a high activity to inhibit the decrease of Lactobacillus lactic acid bacteria.

In addition, the composition for suppressing the reduction of Lactobacillus lactic acid bacteria of the present invention contains a fermented whey derived from Propionibacterium, so it has high compatibility with various food materials and can be safely and easily ingested.

According to one aspect of the present invention, the composition for inhibiting the reduction of lactic acid bacteria of the genus Lactobacillus of the present invention is preferably administered simultaneously or sequentially with the growth of the genus Lactobacillus. If the composition for inhibiting the reduction of Lactobacillus lactic acid bacteria of the present invention and the probiotics of Lactobacillus spp. are ingested simultaneously or sequentially, it can be used in subjects to which antibacterial drugs are administered. The increase in the number of bacteria can also make the balance of the bacterial flora in the intestines become better.

According to one aspect of the present invention, the inhibition of Lactobacillus of the present invention It is a composition for the reduction of lactic acid bacteria. In order to make the whey fermented product derived from Propionibacterium become an effective amount for inhibiting the reduction of the lactic acid bacteria of the genus Lactobacillus in the intestinal tract after the administration of antibacterial drugs, it is preferably taken from 1 day It is constituted by the form of the unit of measure. In the composition for inhibiting the reduction of Lactobacillus lactic acid bacteria of the present invention, the above unit is that the daily intake (administration amount) is calculated as the dry mass of the fermented whey derived from Propionibacterium, which is expected to be an intake of 0.15~ 200 mg/kg body weight, preferably 0.65 to 120 mg/kg body weight, more preferably 1.15 to 70 mg/kg body weight, and even more preferably 1.5 to 20 mg/kg body weight. Here, it is estimated that the representative body weight of the subject is 60 kg.

In addition, the composition for suppressing the reduction of Lactobacillus lactic acid bacteria of the present invention is preferably provided in a packaged form in units of a single intake. As a form of packaging equivalent to a single intake unit, for example, a form in which a certain amount is specified by a packaging bag, container, etc., may be indicated on the surface of the ingredients for the single intake, and the intestinal inhibition may be indicated. Lactobacillus genus lactic acid bacteria in the tract can be used for reducing etc. Examples of suitable examples of the unit packaging form include nutritional supplements, pharmaceutical preparations, and the like.

The method (or method of administration) for ingesting the composition for suppressing the reduction of Lactobacillus lactic acid bacteria of the present invention by a subject is not particularly limited as long as the effects of the present invention are not impaired, and it can be taken orally according to the subject and use ( Or oral administration), administration via tube, administration via intestine, gastrostomy, etc.

The composition for inhibiting the reduction of lactic acid bacteria of the genus Lactobacillus of the present invention can be ingested by the subject before the administration of the antibacterial drug, or by the subject in the administration of the antibacterial drug, or ingested by the subject after the administration of the antibacterial drug. More Preferably, the subject before administration of the antibacterial drug is allowed to ingest the composition of the present invention. In the period before the administration of the antibacterial drug, if the ingestion period of the composition of the present invention is longer, the better. From the perspective of the improvement of the intestinal bacterial flora of the whey fermentation product derived from Propionibacterium, it is better to be before administration 1 day, more preferably 3 days before administration, and still more preferably 5 days before administration. In addition, when the subject who is administering the antimicrobial drug ingests the composition of the present invention, the subject can also take the antimicrobial drug at the same time, but it is preferably within 72 hours, and more preferably within 24 hours.

In addition, the intake plan of the composition for inhibiting the reduction of Lactobacillus lactic acid bacteria of the present invention is not particularly limited. Those with ordinary knowledge in the technical field of the present invention can appropriately set it according to the age, sex, symptoms and conditions of the subject. For example, for a subject, a single oral intake unit can be administered 1 to 10 times a day, but it is preferably 1 to 3 times a day, and more preferably 1 time ingestion. In addition, the composition for suppressing the reduction of Lactobacillus lactic acid bacteria of the present invention can be taken with food.

According to one embodiment of the present invention, the composition for inhibiting the reduction of Lactobacillus lactic acid bacteria of the present invention can be used alone as it is. However, in the subject to which antibacterial drugs are administered, it inhibits Lactobacillus lactic acid bacteria in the intestinal tract. The reduction function can be used as previously mentioned. For various compositions for oral ingestion (for oral administration) such as foods and pharmaceuticals, it can also contain raw materials (materials) or additives, which can be obtained after administration. Among the targets of antibacterial drugs, a composition (for example, a pharmaceutical composition or a food composition) that has the effect of inhibiting the reduction of Lactobacillus spp. lactic acid bacteria in the intestinal tract. Since the composition for inhibiting the reduction of Lactobacillus lactic acid bacteria of the present invention is added to the diet without impairing its taste, it can be added to the usual diet and beverages and can be easily ingested.

According to a preferred aspect of the present invention, there is provided a food containing a fermented whey derived from Propionibacterium, which inhibits the reduction of Lactobacillus lactic acid bacteria in the intestinal tract in subjects to which antibacterial drugs are administered.

The form of "food" (food composition) is not particularly limited. Solutions, suspensions, emulsions, powders, solid molded objects, etc. may be ingested orally. Specific examples include instant noodles, retort food, canned food, electronic microwave food, instant soup, miso soup, freeze-dried food, etc.; refreshing drinks, fruit drinks, vegetable drinks, soy milk drinks, coffee drinks, tea Beverages such as beverages, powdered beverages, concentrated beverages, and alcoholic beverages; wheat flour products such as bread, pasta, noodles, cake mixes, bread flour, etc.; candy, milk candy, chewing gum, chocolate, biscuits, soft pastries, cakes , Pies, snacks, biscuits, Japanese confections, desserts and sweets; sauces, tomato processing seasonings, flavor seasonings, condiments, seasonings, salad dressings, soy sauces, curry and stews Seasonings such as raw materials; processed fats, butter, margarine, mayonnaise and other fats; milk beverages, fermented milk (yogurt, etc.), lactic acid bacteria beverages, natural cheese, processed cheese, ice cream, cream Dairy products such as canned agricultural products, jams, citrus sauces, cereals, and other processed agricultural products; frozen foods, liquid foods, etc.

In addition, foods also include health foods, functional foods, nutritional supplements, foods for specific health use, foods for patients, adjusted milk powders for infants and young children, milk powders for pregnant women or breastfeeding women, or as attached A category of foods whose main purpose is to suppress the decrease of Lactobacillus lactic acid bacteria in the intestinal tract among the objects to which antibacterial drugs are administered.

According to another aspect of the present invention, there is provided a medicinal product containing a fermented whey derived from Propionibacterium, which inhibits the decrease of Lactobacillus lactic acid bacteria in the intestinal tract in subjects to which antibacterial drugs are administered. The so-called "pharmaceuticals" (pharmaceutical compositions) are those that are combined with admissible additives for formulation, and are prepared as oral or parenteral preparations in accordance with common methods. When the medicine is an oral preparation, you can choose the type of solid preparations such as tablets, powders, fine granules, granules, capsules, pills, sustained-release preparations, and liquid preparations such as solutions, suspensions, and emulsions. state. In addition, when the medicine is a parenteral preparation, the form of injection or suppository can be selected. In addition, from the viewpoint of ease of ingestion (administration) to a patient, the pharmaceutical product is preferably an oral preparation. Here, among the additives that can be allowed for formulation, for example, excipients, stabilizers, preservatives, wetting agents, emulsifiers, lubricants, sweeteners, colorants, fragrances, buffers, Antioxidant, pH adjuster, etc. The medicine of the present invention can be used for diseases that are necessary to inhibit the decrease of Lactobacillus lactic acid bacteria in the intestinal tract in subjects to which antibacterial drugs are administered. Specifically, it can be used for diseases caused by the administration of antibacterial drugs. Treatment or prevention of side effects such as constipation, diarrhea, nausea, headache, etc.

The composition for inhibiting the reduction of Lactobacillus lactic acid bacteria of the present invention can be easily manufactured by mixing the fermented whey derived from Propionibacterium with other ingredients that are acceptable for oral administration. Therefore, according to another aspect of the present invention, there is provided a method for producing a composition for inhibiting the reduction of Lactobacillus spp. lactic acid bacteria in the intestinal tract in a subject to which antibacterial drugs are administered, characterized in that the composition contains Propionibacterium whey fermented product Effective amount.

In addition, according to another aspect of the present invention, there is provided a method for inhibiting the decrease of Lactobacillus lactic acid bacteria in the intestinal tract in a subject to which an antibacterial drug is administered, characterized in that it comprises allowing the subject to ingest propionic acid It is made from the effective amount of the fermented whey of bacillus. Herein, according to another preferred aspect of the present invention, the method of inhibiting the decrease of Lactobacillus lactic acid bacteria in the intestinal tract is to eliminate the medical treatment of human beings. Here, the so-called "medical behavior for humans" means that doctors etc. are necessary, and for humans, it means the act of ingesting (administering) medicines. Moreover, in the above-mentioned implementation aspect, the target is preferably healthy ordinary people.

In addition, the method for inhibiting the decrease of Lactobacillus lactic acid bacteria in the intestinal tract of the present invention can also be used to improve the diseases or conditions associated with the decrease of Lactobacillus lactic acid bacteria in the intestinal tract in subjects to whom antibacterial drugs have been administered. Therefore, the method for inhibiting the decrease of Lactobacillus lactic acid bacteria in the intestinal tract of the present invention is a method for improving diseases or conditions associated with the decrease of Lactobacillus lactic acid bacteria in the intestinal tract produced by the administration of antibacterial drugs, and more preferably is How to improve constipation, diarrhea, nausea and the headaches that accompany it. Here, the so-called "improvement" not only refers to the treatment of an established disease or condition, but also includes the prevention of a disease or condition that has the possibility of being established in the future.

In the inhibition method, the effective amount of the fermented whey derived from Propionibacterium can be made the same as the unit of the first intake of the above-mentioned composition.

According to one embodiment of the present invention, it is used to inhibit the reduction of lactobacillus lactic acid bacteria in the intestinal tract in a subject to which antibacterial drugs are administered. few. A method of using whey fermented product derived from Propionibacterium is provided. According to a preferred embodiment of the present invention, the method of use of the present invention is non-therapeutic use.

According to an embodiment of the present invention, the use of a whey fermented product derived from Propionibacterium is provided. The use is a composition for inhibiting the reduction of Lactobacillus spp. lactic acid bacteria in the intestinal tract in subjects to which antibacterial drugs are administered. manufacture. According to a preferred embodiment of the present invention, the use is for the production of foods or medicines for reducing inhibition of Lactobacillus lactic acid bacteria.

According to one embodiment of the present invention, there is provided a whey fermentation product derived from Propionibacterium, which is used for the purpose of inhibiting the decrease of Lactobacillus lactic acid bacteria in the intestinal tract in subjects to which antibacterial drugs are administered.

[Example]

The present invention is explained in detail by the following examples, but the present invention is not limited to these.

Example 1: Preparation of composition (preparation of fermented whey by propionic acid)

In order to make the number of ^{viable bacteria 10 7} ~ 10 ⁸ cfu/mL, Propionibacterium freudenreichii ET-3 (Propionibacterium freudenreichii ET-3) (deposit number: FERM BP-8115) was used as the bacteria, and 10% by mass milk was consumed. The pulp powder reduction solution is cultured with the decomposed product of the proteolytic enzyme AMANOA (Amano Pharmaceutical Co., Ltd.) at 50°C and pH 7.0, and cultured at 35°C and pH 6.0 for 75 hours. The obtained culture supernatant was sterilized and freeze-dried. With respect to 0.2g of freeze-dried product, glucose and dextrin containing dietary fiber are added to obtain a total 1.5g preparation. The composition contains 0.03 g of protein, 0 g of lipids, 0.6 g of carbohydrates, 0.8 g of dietary fiber, 2.6 mg of sodium, 1.0 mg of calcium, 1.3 mg of phosphorus, and 0.2 of magnesium. mg and potassium are 15.8mg.

The obtained preparation is used as the composition of the present invention. Individually packaged with 1.5g unit of aluminum as the preparation.

Example 2: Clinical trial (1) Test object

The clinical trials were conducted separately in two groups: the control group and the group administered with the composition. The subjects in the two groups of trials were all critically ill patients (patients with cerebral hemorrhage, trauma, and cerebral embolism) admitted to the Mishima Life-Saving Center in Osaka Prefecture. In principle, the subjects are managed by tube feeding when they are admitted, and the tube is inserted into the stomach from the nasal cavity. Also, in principle, antibacterial drugs should be administered within one week after the start of the test. In addition, antibacterial drugs are based on the disease and state of the patient, based on the techniques described in the JAID/JAS Infectious Disease Treatment Guidelines 2014 (Edited by the JAID/JAS Infectious Disease Treatment Guidelines and Guidelines Development Committee), as listed in Table 1 below The antibacterial drugs are selected and administered.

Control group and administering group

HP)或MEIN(明治股份公司)等2種類所組成之群組。此些中，不含有對於腸道內細菌叢產生影響之成分，特別是不含使乳桿菌屬乳酸菌減少之成分。另一方面，施予組成物之群中，將於由例1所得之組成物(2包/日(3g/日))添加至流質食物中，施予2週之期間。對照群為46人，施予組成物之群為14人。此外，對照群中之1人，由於於2週之試驗期間中係非施予抗菌藥物，故將此1人除外再進行分析。因此，分析人數之對照群為45人，施予組成物之群為14人。 In the control group, liquid food was administered for 2 weeks. As a liquid food, at least one selected from MEIBALANCE HP (

HP) or MEIN (Meiji Corporation) and other two types of groups. Among these, it does not contain ingredients that affect the bacterial flora in the intestinal tract, and especially does not contain ingredients that reduce the lactic acid bacteria of the genus Lactobacillus. On the other hand, in the group of administered composition, the composition obtained in Example 1 (2 packets/day (3g/day)) will be added to the liquid food and administered for a period of 2 weeks. The control group consisted of 46 people, and the group administered the composition consisted of 14 people. In addition, one person in the control group was not given antibacterial drugs during the 2-week test period, so this one person was excluded for analysis. Therefore, the control group for the analysis population is 45 people, and the group for which the composition is administered is 14 people.

The analyzed results of the background of patients in the control group and the group administered with the composition and the days of administration of antibacterial drugs are shown in Table 2 below.

As shown in Table 2, the composition of 11.5±3.2 days and administration of the control group There was almost no difference in the number of days of antimicrobial administration between the two groups of 11.8±2.9 days in the group of things. In addition, there is almost no difference in the male-to-female ratio and APACHE II.

(2) Analysis of flora in feces Take feces

In the control group and the group administered with the composition, before the start of the test (liquid food administration) (day 0), the third day after the start of the test, the seventh day after the start of the test (1 week), and the first day after the start of the test. Stool collection will be implemented for 14 days (2 weeks).

Analysis of flora in feces

The collected feces should be stored below -20°C immediately after being taken. The bacterial colony DNA in the stool was extracted from the stool of the patient using Multi-Beads Shocker (Yasui Machinery Co., Ltd.) according to the method of QIAamp DNA stool Mini Kit (QIAGEN). In addition, the Real-time PCR reaction was performed using QuantiTect SYBR Green RT-PCR (QIAGEN), and using the primers described in Table 3 below, at 95°C for 15 seconds→(94°C, 15 seconds→each primer The bonding temperature, 30 seconds → 72°C, 30 seconds) × 30~55 cycles, the number of Lactobacillus lactic acid bacteria, the number of Bifidella and the total number of bacteria are quantified by ABI 7300 Real Time PCR System (Applied Biosystems) . The number of bacteria is expressed as the logarithm of the number of bacteria per 1g of feces.

Before and after comparison within each group, the corresponding t test is used for analysis. In addition, the analysis between the two groups of the control group and the group given the composition is evaluated by comparing the test results of the control group and the group given the composition by Students't test (isodispersed) or Welch test (Unequal dispersion) analysis.

The results are shown in Figures 1~4.

Fig. 1 is a graph showing the change in the total bacterial count and the Lactobacillus bacterial count in the feces of the control group. In the control group in Fig. 1, after the third day after the start of the test, the total bacterial count and the number of Lactobacillus bacteria were significantly reduced compared to the beginning of the test.

Fig. 2 is a graph showing the change in the total bacterial count and the Lactobacillus bacterial count in the feces of the group administered with the composition. In the group of administered composition in Fig. 2, compared with before the start of the test, there was no significant decrease in the number of Lactobacillus bacteria during the test period. On the other hand, compared to before the start of the test, although the total bacterial count was significantly reduced on the 7th day after the start of the test, there was no significant difference between the 3rd day and the 14th day.

Figure 3 compares the total bacterial count and the Lactobacillus bacterial count in the feces of the control group and the group administered with the composition. Observe the number of Lactobacillus bacteria in Figure 3, the control group There was almost no difference in the administration composition at the beginning of the test, but after the third day after the start of the test, compared with the administration composition group, one of the control groups was significantly reduced. On the other hand, the total number of bacteria between the two groups did not change significantly during the test period (Figure 3). In this way, although the administration of antibacterial drugs reduces the number of Lactobacillus bacteria in the intestinal tract, it is confirmed that the composition of the present invention is administered before or during the administration of the antibacterial drug to inhibit Lactobacillus in the intestinal tract. The reduction of the number of bacteria.

Fig. 4 is a graph showing the comparison of the number of Bifeidia in the feces of the subject group and the group to which the composition is administered. In Fig. 4, the number of Bifidella bacteria, the control group and the group administered with the composition, decreased significantly after the third day after the start of the test compared to the start of the test. In addition, as a result of comparing the number of Fideella bacteria between the control group and the group to which the composition was administered, no significant change was seen between the two groups.

<110> Meiji Co. LTD.

<120> Composition for inhibiting the reduction of Lactobacillus lactic acid bacteria in the intestinal tract

<150> JP 2016-202465

<151> 2016-10-14

<160> 6

<170> PatentIn version 3.5

<210> 1

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> primer Lactobacillus F

<400> 1

Claims (8)

A use of a whey fermented product derived from Propionibacterium, which is used in the manufacture of a composition for inhibiting the reduction of Lactobacillus genus lactic acid bacteria in the intestinal tract in a subject to which an antibacterial drug is administered. For the use of the whey fermentation product derived from Propionibacterium as described in claim 1, the aforementioned Propionibacterium is Propionibacterium freudenreichii (Propionibacterium freudenreichii). For the use of the whey fermentation product derived from Propionibacterium as described in claim 1 or 2, the aforementioned Propionibacterium is a Propionibacterium that produces Bifidogenic Growth Stimulator (BGS: Bifidogenic Growth Stimulator). The use of a whey fermentation product derived from Propionibacterium as described in claim 1 or 2, wherein the aforementioned antibacterial drug is selected from the group consisting of penicillin antibacterial drugs, cephalosporin antibacterial drugs, cephalosporin antibacterial drugs, and hydrocarbons At least one of antibacterial drugs, β-lactamase inhibitors, oxazolidinone antibacterials, new quinolone antibacterials, and macrolide antibacterials. The use of the whey fermentation product derived from Propionibacterium as described in claim 1 or 2, wherein the daily dosage is calculated by the dry mass of the whey fermentation product derived from Propionibacterium, which is 0.15~200mg/ kg body weight. The use of the fermented whey derived from Propionibacterium as described in claim 1 or 2 is a food composition or a pharmaceutical composition. The use of the whey fermented product derived from Propionibacterium as described in claim 1 or 2 is in the form of powder, liquid or lozenge. A whey fermented product derived from Propionibacterium, which is used to inhibit the decrease of Lactobacillus lactic acid bacteria in the intestinal tract of a subject to which antibacterial drugs are administered.

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