WO2014132982A1 - ストレス軽減剤 - Google Patents
ストレス軽減剤 Download PDFInfo
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- WO2014132982A1 WO2014132982A1 PCT/JP2014/054629 JP2014054629W WO2014132982A1 WO 2014132982 A1 WO2014132982 A1 WO 2014132982A1 JP 2014054629 W JP2014054629 W JP 2014054629W WO 2014132982 A1 WO2014132982 A1 WO 2014132982A1
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- stress
- lactobacillus gasseri
- oll2809
- αla
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
- A61K35/741—Probiotics
- A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
- A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
- A61P5/46—Drugs for disorders of the endocrine system of the suprarenal hormones for decreasing, blocking or antagonising the activity of glucocorticosteroids
Definitions
- the present invention relates to a stress reducing agent containing Lactobacillus gasseri as an active ingredient.
- the present invention also relates to a stress relieving agent further comprising ⁇ -lactalbumin ( ⁇ LA) as an active ingredient.
- ⁇ LA ⁇ -lactalbumin
- Stress is defined as a biological response to a stimulus that impairs homeostasis.
- the cause of stress is called a stressor. From the types of external stimuli, physical stressors (cold, noise, radiation, etc.), chemical stressors (oxygen, drugs, etc.), biological stressors (inflammation, infection), psychological stressors (Anger, anxiety, etc.)
- hypothalamic-sympathetic-adrenal medullary system SAM axis
- HPA axis hypothalamic-pituitary-adrenal cortex system
- the HPA axis which is a non-specific stress reaction, first secretes corticotropin-releasing hormone (CRH) from the hypothalamus.
- CRH corticotropin-releasing hormone
- ACTH adrenocorticotropic hormone
- ACTH promotes secretion of glucocorticoids such as cortisol (mainly corticosterone in rats) from the adrenal cortex. This glucocorticoid is generally called a stress hormone.
- glucocorticoids are involved in physical responses to stress (activation of energy metabolism, promotion of cardiac function) and play an important role in maintaining homeostasis.
- stress activation of energy metabolism, promotion of cardiac function
- glucocorticoids are also known to adversely affect the living body, such as reducing the proliferation ability and function of immune cells.
- persistent secretion of glucocorticoids due to chronic stress causes secondary symptoms such as decreased ability to defend against infection (decreased immune function), emotional disorders such as depression and anxiety, and sleep disorders such as insomnia.
- Non-patent Document 1 Non-patent Document 1
- stress sensitivity is reduced and stress response is reduced by stimulation from the intestine by intestinal bacteria or probiotics.
- the intestine is governed by the brain by autonomic nerves, and when the brain recognizes stress, the information is transmitted to the intestine by information transmission substances such as autonomic nerves, endocrine hormones, and cytokines, causing abnormal peristalsis.
- Non-patent Document 1 Non-patent Document 1
- intestinal bacteria influence signal transmission from the intestine to the brain. From this, it is considered that stress sensitivity is attenuated and stress response is reduced by stimulation from the intestine with probiotics such as lactic acid bacteria.
- Non-Patent Document 2 discloses that when Lactobacillus johnsonii La1 is administered to rats, the activity of parasympathetic nerves governing the functions of the stomach and gastrointestinal tract is enhanced.
- Patent Document 1 discloses that Lactobacillus paracatheis, subspices, paracasei lactic acid bacteria FERM-19169 suppresses excessive production of cytokines such as TNF- ⁇ , IFN- ⁇ , and IL-6, thereby effectively preventing pathogenic infection. It is disclosed to suppress stress by protecting and suppressing excessive inflammatory reactions and minimizing wear due to diseases and the like.
- Patent Document 2 describes the effect that acid milk obtained by fermenting animal milk with lactic acid bacteria of the genus Lactobacillus including Lactobacillus helveticus ATCC8205 prevents or reduces the mental and physical symptoms caused by stress. It is disclosed to have.
- Non-Patent Document 2 is an effort for acute stress such as gastrointestinal disorders and inflammatory reactions
- Patent Document 1 is examining psychological and physical symptoms but has confirmed the effect on temporary stress. It is unclear whether it is effective enough for chronic stress, which is a problem in modern society.
- Lactobacillus gasseri OLL2809 has an effect of stimulating the immune response of the living body, such as strongly inducing IL-12 from mouse splenocytes. .
- This lactic acid bacterium acts on the immune response mechanism of the host and is effective in reducing immediate allergic disease (Patent Document 3), delayed hypersensitivity reaction (Patent Document 4), and endometriosis (Patent Document 5).
- IL-12 has the effect of inducing type I helper T cells (Th1) and enhancing the cytotoxic activity of NK cells (Patent Document 3).
- NK cells play an important role in innate immune mechanisms such as protection from viral infection and elimination of tumor cells.
- ⁇ LA has an action of inhibiting the activity of cyclooxygenase-2 to suppress the production of prostaglandins from arachidonic acid and also to suppress the production of IL-6. Yes. From these effects, it has been clarified that ⁇ LA reduces menstrual pain caused by inflammation and contributes to improving QOL of healthy women at reproductive age (Patent Document 6). Prostaglandins are one of the inflammatory mediators and exert various inflammatory symptoms such as pain.
- Lactobacillus gasseri OLL2809 and ⁇ LA are effective in reducing the immune function caused by the influence of glucocorticoids due to chronic stress (chronic stress), psychological stress such as anxiety and fatigue, etc. There is no mention of effects under stressed conditions.
- JP 2010-96751 A Japanese Patent Laid-Open No. 10-045610 International Publication WO2006 / 093022 Pamphlet International Publication WO2012 / 086150 Pamphlet International Publication No. WO2012 / 073924 Pamphlet International Publication WO2008 / 140041 Pamphlet
- known stress suppressors are known for stimulating the immune system and improving gastrointestinal disorders, but are effective against various stresses, particularly those associated with chronic stress. It is not known at all how it works. Therefore, the present invention regulates physical and mental health by suppressing the excessive response of the HPA axis and decline in immune function due to chronic stress, and also reducing psychological stress represented by fatigue, anxiety and tension. It is an object of the present invention to provide a stress relieving agent that has no side effects as a medicine, can be used regularly, and can be easily taken as a food or drink.
- the present invention which has not been known to Lactobacillus gasseri, suppresses the excessive response of the HPA axis caused by chronic stress and the decline of immune function, and reduces psychological stress such as anxiety and tension And found useful as a stress reducing agent.
- ⁇ LA in combination with Lactobacillus gasseri, we found that it reduces daily fatigue, which is one of the symptoms of chronic stress, and found that it is useful as a stress-reducing agent. It was.
- a stress reducing agent comprising Lactobacillus gasseri as an active ingredient.
- ⁇ LA ⁇ -lactalbumin
- Lactobacillus gasseri having a stress reducing effect.
- the Lactobacillus gasseri according to [4] which has an action of suppressing an increase in blood stress hormone.
- [7] A composition containing 1 ⁇ 10 7 or more of Lactobacillus gasseri and 40% by weight or more of ⁇ LA.
- the agent according to any one of [1] to [3], wherein Lactobacillus gasseri is Lactobacillus gasseri OLL2809 strain deposited under accession number NITE BP-72.
- Lactobacillus gasseri according to any one of [4] to [6], deposited under the deposit number NITE BP-72.
- the composition according to [7] wherein the Lactobacillus gasseri is Lactobacillus gasseri OLL2809 strain deposited under accession number NITE BP-72.
- a stress reducing method using Lactobacillus gasseri [12] The method according to [11], wherein the stress is chronic stress. [13] The method according to [11] or [12], further using ⁇ LA. [14] The method according to any one of [11] to [13], wherein the Lactobacillus gasseri is Lactobacillus gasseri OLL2809 strain deposited under accession number NITE BP-72.
- the present inventors have repeatedly examined the effects of Lactobacillus gasseri or ⁇ LA.
- the present inventors conducted a submerged stress load test in rats administered with Lactobacillus gasseri OLL2809.
- Lactobacillus gasseri OLL2809 is able to suppress NK activity decline due to intense exercise and reduce psychological stress such as anxiety and tension through a test with athletes who are doing intense exercise on a daily basis. I found it.
- the present inventor has found that daily fatigue can be alleviated by the combined use of OLL2809 and ⁇ LA through a test using athletes who are exercising intensely on a daily basis. This effect was objectively demonstrated by a significant decrease in serum derivatives'of'reactive'oxygen'metabolites '(dROMs) and Transforming'growth'factor' (TGF) - ⁇ 1 levels.
- TGF Transforming'growth'factor'
- White, gray, and black bars represent the normal group, the stress group, and the Lactobacillus gasseri OLL2809 group, respectively. Evaluation was performed on the 14th day of the test. a and b indicate that there is a significant difference between different signs (one-way analysis of variance (One-way ANOVA), Fisher's PLSD test, P ⁇ 0.05). It is a graph which shows spleen NK activity after a rat water stress stress test. Results are expressed as mean + standard deviation. White, gray, and black bars represent the normal group, the stress group, and the Lactobacillus gasseri OLL2809 group, respectively. Evaluation was performed on the 14th day of the test.
- a and b indicate that there is a significant difference between different signs (One-wayFiANOVA, Fisher's PLSD test, P ⁇ 0.05). It is a graph which shows the effect of Lactobacillus gasseri OLL2809 and ⁇ LA in ProfilesProfileof Mood States (POMS) for evaluating mood and emotional state. The black dots in the graph indicate the results of each subject, and the bars in the graph indicate the average value. The evaluation was performed before the test substance intake and after the intake for 4 weeks. #, *: P ⁇ 0.1, 0.05.
- stress refers to a stressor, such as a physical stressor (coldness, noise, radiation, etc.), a chemical stressor (oxygen, a drug, etc.), a biological stressor (inflammation, infection), a psychological stressor (anger, anxiety, etc.). This refers to the phenomenon of biological tension caused by such factors.
- the stress reducing agent of the present invention can be used to relieve stress.
- the stress relieving agent of the present invention has no side effects as a medicine, can be used regularly, and can be easily ingested as a food or drink.
- the stress reducing agent of the present invention can suppress, for example, a decrease in immune function due to stress.
- the stress relieving agent of the present invention has a reducing effect on acute stress and chronic stress by the stressor described above, but can be preferably used in the case of chronic stress in which stress persists.
- the stress reducing agent of the present invention is used in the case of chronic stress, for example, NK activity caused by glucocorticoids such as cortisol, corticosterone, and cortisone that are secreted continuously in response to chronic stress. The decrease can be suppressed, and psychological fatigue is also reduced.
- the stress relieving agent of the present invention can improve or prevent secondary symptoms during chronic stress, such as a decrease in immune function, an increase in psychological stress, a delay in wound healing, or a metabolic disorder.
- the stress reducing agent of the present invention can alleviate poor physical condition caused by stress.
- the stress reducing agent of the present invention can reduce, for example, mental stress (psychological stress) such as anxiety, tension, and fatigue, daily fatigue (chronic fatigue), or chronic fatigue syndrome.
- the stress reducing agent of the present invention suppresses an increase in stress hormone caused by stress stimulation such as intense exercise, reduces an increase in oxidative stress markers, suppresses a decrease in immune function due to stress load, and improves physical condition. Is to prepare. Therefore, the stress reducing agent of the present invention can also be used for the purpose of maintaining homeostasis (homeostasis), conditioning and physical condition adjustment.
- the stress relieving agent of the present invention provides an enhanced immune response and reduced physical fatigue in order for athletes to exhibit superior athletic performance or to prevent or reduce overtraining, It can be used as a sports conditioning agent.
- the stress reducing agent of the present invention contains Lactobacillus gasseri, or Lactobacillus gasseri and ⁇ LA as active ingredients.
- the stress reducing agent of the present invention contains Lactobacillus gasseri as lactic acid bacteria. Any Lactobacillus gasseri can be used as long as it has a stress-reducing effect and a chronic fatigue-reducing effect.
- Lactobacillus gasseri that can be particularly preferably used is Lactobacillus gasseri OLL2809, which was independently isolated from human adult feces.
- the strain was founded on February 1, 2005 (original deposit date) at the National Institute of Technology and Evaluation, Japan's Patent Microorganism Depositary Center (Japan: 2-5-8 Kazusa Kamashichi, Kisarazu City, Chiba Prefecture 292-0818) As NITE P-72, it was transferred from the original deposit to a deposit based on the Budapest Treaty on January 18, 2006, and the deposit number was deposited as NITE BP-72.
- a medium usually used for lactic acid bacteria is used. That is, any medium can be used as long as it contains a nitrogen source, an inorganic substance and other nutrients in addition to the main carbon source.
- a nitrogen source lactose, glucose, sucrose, fructose, starch hydrolyzate, waste molasses and the like can be used according to the assimilation ability of the bacteria used.
- organic nitrogen-containing substances such as casein hydrolyzate, whey protein hydrolyzate, and soy protein hydrolyzate can be used.
- meat extract, fish extract, yeast extract and the like are used as growth promoters.
- the culture of Lactobacillus gasseri which is an active ingredient of the stress relieving agent of the present invention, is preferably performed under anaerobic conditions, but may be performed under microaerobic conditions such as liquid stationary culture that is usually used.
- anaerobic culture a known method such as a method of culturing under a nitrogen gas layer can be applied, but other methods may be used.
- the culture temperature is preferably 30 to 40 ° C., but may be other temperature conditions as long as Lactobacillus gasseri grows.
- the pH of the medium during the culture is preferably maintained at 4.0 to 7.0, but may be other pH conditions as long as Lactobacillus gasseri grows. It can also be cultured under batch culture conditions.
- the culture time is usually preferably 10 to 24 hours, but may be any other culture time as long as Lactobacillus gasseri can grow.
- Lactobacillus gasseri which is an active ingredient of the stress reducing agent of the present invention, may be a live cell or a dead cell, and may be a wet cell or a dry cell.
- Lactobacillus gasseri means both Lactobacillus gasseri strains and cells.
- Lactobacillus gasseri which is an active ingredient of the stress reducing agent of the present invention may be a “processed product”.
- the “processed product” of Lactobacillus gasseri is not limited, but, for example, a lactobacillus gasseri suspension (suspension) after completion of the culture, a culture in which the culture solution is used as it is. (Including bacterial cells, culture supernatant and medium components), fermented products (fermented raw milk, skim milk powder or soy milk, etc.), heat-treated products, sterilized or sterilized products by heat, radiation, etc.
- the cell concentration of Lactobacillus gasseri which is an active ingredient of the stress relieving agent of the present invention, is not particularly limited, but it is 1 ⁇ 10 6 cells / g or more in the concentrate and 1 ⁇ 10 7 cells / g or more in the dried product. Is preferred.
- the stress reducing agent of the present invention further comprises ⁇ LA as an active ingredient in addition to Lactobacillus gasseri.
- the ⁇ LA of the present invention is not particularly limited in origin, but is preferably derived from a human and / or non-human mammal (such as bovine, sheep, goat, horse, etc.), more preferably human or bovine ⁇ LA.
- the amino acid sequences and base sequences of these ⁇ LA are already known and are registered in databases such as EMBL, DDBJ, NCBI.
- bovine ⁇ LA is registered with DDBJ as ACCESSION No.J05147.
- ⁇ LA is derived from the milk of mammals such as humans, cows, sheep, and goats, by ammonium sulfate precipitation ("Latest Revised Dairy Technology Handbook” Dairy Technology Promotion Society, pages 122-125, 1975), ultrafiltration 268879), ion exchange method (Japanese Patent No. 2916047) and the like.
- the content of ⁇ LA in milk varies somewhat depending on the production area, feed, etc., but domestic milk is usually 1.2 ⁇ ⁇ g / kg. If milk is used as a raw material for production, a large amount of ⁇ LA can be prepared.
- the stress relieving agent of the present invention may be a drug or food for humans or animals, or may be a material or preparation used by blending with the drug or food.
- the food has the concept of relieving chronic stress, recovering from physical / psychological fatigue, maintaining homeostasis (homeostasis), conditioning and physical condition, and displays that effect when necessary. Functional foods, foods for the sick, and foods for specified health use.
- a dosage form can be selected according to its purpose, administration route, etc., for example, tablets, coated tablets, pills, capsules, granules, Examples include powders, liquids, suspensions, emulsions, syrups, injections, suppositories, soaking agents, decoction, tinctures, etc., but used as parenteral agents such as oral preparations and nutrients by tube feeding It is preferable to do this.
- compositions are prepared according to conventional methods as necessary with respect to the active ingredient, such as fillers, extenders, excipients, binders, humectants, disintegrants, surfactants, lubricants, coloring agents, flavoring agents.
- the pharmaceutical composition can be formulated using known adjuvants that can be usually used in the pharmaceutical preparation technical field, such as solubilizing agents, suspension agents, and coating agents.
- the stress relieving agent of the present invention is a compound or microorganism that is orally administered alone or mixed with other components that can be usually used in pharmaceuticals and foods, or has other immune response enhancing effects and physical fatigue reducing effects. Is effective in enhancing the immune response and reducing physical fatigue in humans and animals.
- anxiolytics eg chlordiazepoxide, oxazolam or diazepam
- hypnotics eg nitrazepam, estazolam or haloxazolam
- vitamins eg vitamin A, vitamin B1, vitamin B2, vitamin B6, niacinamide, pantothenic acid
- Vitamin B12 Vitamin E, biotin, vitamin C, etc.
- the stress-reducing agent according to the present invention has no side effects and can be used regularly, so it can be used not only as a medicine but also as a food and drink.
- foods and drinks milk, soft drinks, milk drinks, fermented milk, yogurt, cheese, ice cream, bread, biscuits, crackers, confectionery, tablet confectionery, pizza crust, prepared milk powder, liquid food, supplements, beauty Foods, health foods, foods for the sick, foods such as infant milk powder, foods such as infant milk powder, nutritional foods, sports foods, etc.
- the stress reducing agent according to the present invention in any of the above states, for example, solid (powder, granule, etc.), paste, gel, jelly, liquid or suspension.
- Such food can be produced in accordance with a conventional method for ordinary food and beverage compositions such as using Lactobacillus gasseri of the present invention, ⁇ LA as it is, or mixing with other foods or food ingredients.
- Other food ingredients are not particularly limited, and examples include water, proteins, carbohydrates, lipids, vitamins, minerals, organic acids, organic bases, fruit juices, and flavors.
- examples of the protein include whole milk powder, skim milk powder, partially skimmed milk powder, casein, whey powder, whey protein, whey protein concentrate, whey protein isolate, ⁇ -casein, ⁇ -casein, ⁇ -casein, ⁇ -Animal and vegetable proteins such as lactoglobulin, lactoferrin, soy protein, chicken egg protein, meat protein, and hydrolysates thereof.
- Sugars include sugars, processed starches (dextrin, soluble starch, British starch, oxidized starch, starch ester, starch ether, etc.), dietary fiber, and the like.
- lipids examples include lard, fish oil, etc., fractionated oils thereof, hydrogenated oils, animal oils such as transesterified oils, palm oil, safflower oil, corn oil, rapeseed oil, coconut oil, fractionated oils thereof, Examples include vegetable oils such as hydrogenated oils and transesterified oils.
- vitamins examples include vitamin A, carotene, vitamin B group, vitamin C, vitamin D group, vitamin E, vitamin K group, vitamin P, vitamin Q, niacin, nicotinic acid, pantothenic acid, biotin, inositol, choline. And folic acid.
- minerals include calcium, potassium, magnesium, sodium, copper, iron, manganese, zinc, selenium, and whey mineral.
- organic acid examples include malic acid, citric acid, lactic acid, and tartaric acid.
- These components can be used in combination of two or more kinds, and synthetic products and / or foods containing a lot of these may be used.
- the intake amount of the stress relieving agent of the present invention varies depending on the sex, age, health condition, etc. of the person who takes it. 1 ⁇ 10 7 or more per day, preferably 1 ⁇ 10 8 or more, more preferably 1 ⁇ 10 9 or more, particularly preferably 1 ⁇ 10 10 or more, more preferably 1 ⁇ 10 11
- ⁇ LA as an active ingredient is 100 mg or more per day, preferably 250 mg or more, more preferably 500 mg or more, and particularly preferably 1000 mg or more.
- the upper limit of intake of these stress relieving agents is not particularly limited because there are Lactobacillus gasseri and ⁇ LA, which are active ingredients, as general food ingredients.
- Lactobacillus gasseri OLL2809 cells include 1 ⁇ 10 15 cells per day, and ⁇ LA includes 2000 mg / kg per day.
- count of ingestion may be once per day, or may be multiple times.
- the term “intake” includes “administration”.
- the stress relieving agent of the present invention can be administered to a patient who is required to be treated with the composition of the present invention at one time or before, before a meal, after a meal, between meals and / or before going to bed.
- the dosage can also be determined individually depending on the age, weight and purpose of administration of the patient being administered.
- Lactobacillus gasseri, or Lactobacillus gasseri and ⁇ LA of the present invention are administered to, eaten or fed to mammals, a method for adjusting physical condition, reduction of chronic stress or Provided are a method for alleviating, an increase in blood stress hormones caused by chronic stress, and a method for alleviating or reducing psychological stress due to chronic stress.
- the effective amount of the Lactobacillus gasseri, or Lactobacillus gasseri and ⁇ LA means the same amount as the intake of the stress relieving agent Lactobacillus gasseri or Lactobacillus gasseri and ⁇ LA.
- the stress to which the method of the present invention is applied includes all the phenomena of biological tension caused by stressors that are physiologically harmful to animals.
- the stress relieving agent of the present invention is particularly useful for a stress response via the HPA axis.
- Symptoms caused by stress include reduced infection protection, delayed wound healing, decreased immune function, metabolic disorders, cardiovascular disorders (eg chest pain, palpitation, arrhythmia, etc.), digestive disorders (Eg, loss of appetite, stomach pain, nausea, stomach ulcer, constipation, diarrhea), shoulder stiffness, headache, dizziness, floating feeling, eye strain, general fatigue, fatigue, psychological stress such as tension and anxiety, depression, etc. Is mentioned.
- the stress relieving agent of the present invention is particularly useful for psychological stresses such as decreased immune function, decreased ability to prevent infection, general malaise, fatigue, tension and anxiety.
- the mitigation or alleviation method of the present invention relieves the stress, suppresses the increase in glucocorticoid, suppresses the decrease in immune function associated with the stress, and relieves psychological stress and fatigue such as anxiety and tension. , Maintain homeostasis in the body and adjust daily physical condition.
- YAC-1 target cells were mixed in a 96-well round bottom plate and cultured for 4 hours in a 37 ° C CO 2 incubator. 15 minutes before the end of the culture, 20 ⁇ L of 0.5 mg / mL propidium iodide (Sigma-Aldrich) was added to stain dead cells. YAC-1 target cell death was analyzed using FACSCalibur flow cytometry and CellQuest software (BD Biosciences, Flanklin Lakes, NJ), and the death rate was defined as NK activity. Three levels of stress hormones in the blood were measured: ACTH (adrenocorticotropic hormone), corticosterone, and 8-OHdG. These were measured using a kit.
- ACTH asdrenocorticotropic hormone
- corticosterone corticosterone
- 8-OHdG 8-OHdG
- ACTH ACTH
- ACTH Rat
- EIA KIT Phoenix Pharmaceuticals, Burlingame, CA
- Corticosterone Corticosterone EIA Kit
- 8-OHdG High-sensitivity 8-OHdG Check, (Nikken Seil, Shizuoka).
- Exclusion (cancellation / dropout) criteria (i) Subjects who declined to continue the study due to free will; (ii) Those who developed allergic diseases such as hay fever during the study period; (iii) Continued the study due to the onset of some disease (Iv) Those who are found to be not in compliance with the instructions of the investigator or investigator; (v) The number of ingestions during the test substance intake period Those who have reached 10% of the scheduled number. In carrying out this case, written consent was obtained from all test subjects who received an explanation of the study content from the investigator. If the subject was under 20 years of age, the consent of the person and their guardians was obtained. This study was conducted in compliance with the Declaration of Helsinki, and was conducted with consideration given to the safety of subjects. This test was conducted with the approval of the Ethics Review Committee of the Meiji Research Headquarters.
- Test method A randomized placebo-controlled double-blind method (parallel comparison test among three groups) was performed. After a 1-week pre-observation period, placebo and Lactobacillus gasseri OLL2809 only group (hereinafter referred to as OLL2809 group), and Lactobacillus gasseri OLL2809 plus ⁇ LA group (hereinafter referred to as OLL2809 + ⁇ LA group) ) 3 groups. Each subject received a placebo or tablet containing the test article for 4 weeks. The test was performed before and after ingestion of the test substance, and exercise load, questionnaire survey, and blood test were performed as described below. The blood test after exercise was performed approximately 1 hour after the completion of 1 hour of exercise.
- VAS was rated on a straight line of 100mm, with the right side “no fatigue” and the left side "the strongest fatigue ever experienced". The subject was marked on the straight line at a position where he felt he best represented his current perception of his condition. Next, the VAS fatigue score was determined by measuring the distance (mm) from the left end of the straight line to the mark.
- [Iii] NK activity In two observation periods before and after ingestion, blood was collected 4 times in total, 2 times before and after exercise, and NK activity was measured by BML.
- Blood and blood biochemistry tests Blood tests (red blood cell count, white blood cell count, platelet count, hemoglobin) and blood biochemistry tests (blood glucose level, total protein, alanine aminotransferase (ALT), asparagine aminotransferase (AST), lactic acid Dehydrogenase (LDH), total bilirubin, ⁇ -transpeptidase, alkaline phosphatase (ALP), blood urea nitrogen (BUN), creatinine, uric acid, total cholesterol, triglycerides, high density lipoprotein (HDL)) 4 weeks later, before exercise. These were mainly evaluated as safety indicators. TGF- ⁇ 1 and dROMs were evaluated by collecting blood 4 times in total, 2 times before and after exercise, in 2 observation periods before and after intake.
- test object was manufactured in Meiji Co., Ltd. Lactobacillus gasseri OLL2809 freeze-dried powder is inoculated with 1% pre-culture of Lactobacillus gasseri OLL2809 in a whey and lactose-based medium (whey decomposition medium), 37 ° C, lower limit pH 4.5 (6 mol / L NaOH automatically adjusted), and cultured for 18 hours under nitrogen aeration. Thereafter, the culture solution was concentrated 20 times and heat-treated at 85 ° C. for 60 minutes. After cooling, it was freeze-dried, and the dried product was pulverized to obtain a freeze-dried Lactobacillus gasseri OLL2809 powder.
- whey and lactose-based medium whey decomposition medium
- pH 4.5 6 mol / L NaOH automatically adjusted
- OLL2809 tablets taken by the OLL2809 group produced 1 mg of Lactobacillus gasseri OLL2809 lyophilized powder and 500 mg tablets per tablet containing excipients and the like.
- OLL2809 + ⁇ LA tablets taken by the OLL2809 + ⁇ LA group produced 16.7 mg of Lactobacillus gasseri OLL2809 freeze-dried powder, 150 mg of ⁇ LA, and 500 mg tablets per tablet containing excipients and the like.
- the placebo tablets ingested by the placebo group were prepared by blending dextrin instead of Lactobacillus gasseri OLL2809 lyophilized powder and ⁇ LA, and adding excipients to give 500 mg per tablet. These made every tablet indistinguishable in appearance, color and taste.
- each tablet was ingested continuously 2 tablets once a day, 3 times a day (morning, noon, evening) for 4 weeks. That is, the daily intake of OLL2809 group is 100 mg (5 ⁇ 10 10 cells) of L. gasseri OLL2809 freeze-dried powder, and the intake of OLL2809 + ⁇ LA group is 100 mg of Lactobacillus gasseri OLL2809 freeze-dried powder. (5 ⁇ 10 10 cells) and ⁇ LA are 900 mg.
- FIG. 5 shows the result of fatigue caused by exercise load using the VAS method.
- FIG. 6 shows the results of peripheral blood NK cell disorder activity before and after exercise performed before the test substance ingestion and peripheral blood NK activity before and after exercise performed 4 weeks after the ingestion.
- NK activity decreased to -12.4 ⁇ 11.0% in the placebo group, -12.2 ⁇ 12.3% in the OLL2809 group, and -14.5 ⁇ 11.4% in the OLL2809 + ⁇ LA group after 1 hour of exercise.
- the difference between before and after exercise at 4 weeks was -8.8 ⁇ 12.0% in the placebo group, -2.7 ⁇ 14.2% in the OLL2809 group, and -4.3 ⁇ 10.2% in the OLL2809 + ⁇ LA group, respectively.
- dROMs is an index indicating the degree of oxidative damage caused by active oxygen and free radicals, that is, the degree of oxidative stress.
- dROMs is an index indicating the degree of oxidative damage caused by active oxygen and free radicals, that is, the degree of oxidative stress.
- TGF- ⁇ 1 is a cytokine that is suggested to be a causative agent of central fatigue.
- TGF- ⁇ 1 was compared to pre-exercise only before taking 1.29 ⁇ 0.35, 1.33 ⁇ 0.27, 1.35 ⁇ 0.32 ng / ml in the placebo group, OLL2809 group, OLL2809 + ⁇ LA group, 1.23 ⁇ 0.18 after 4 weeks of ingestion, There was no significant difference between groups with 1.20 ⁇ 0.15, 1.19 ⁇ 0.19 ng / ml.
- P 0.075
- Lactobacillus gasseri OLL2809 and ⁇ LA have been shown to improve the condition in athletes. Lactobacillus gaselli OLL2809 intake has been found to be effective in reducing mental stress and maintaining immunity that declines after strenuous exercise. It was. In addition to Lactobacillus gasseri OLL2809, ingestion of ⁇ LA was found to reduce daily fatigue.
- the stress reducing agent comprising Lactobacillus gasseri or Lactobacillus gasseri and ⁇ LA provided as an active ingredient according to the present invention alleviates poor physical condition caused by chronic stress when taken orally.
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Abstract
Description
腸は自律神経によって脳に支配されており、脳がストレスを認識するとその情報が自律神経や内分泌ホルモンやサイトカインなどの情報伝達物質によって腸に伝達され、蠕動運動の異常などが引き起こされる。一方、腸において便秘や下痢などの症状が起こると、それがストレスとして脳に伝えられる。この脳と腸の双方向の情報伝達機構は「脳腸相関」と呼ばれている(非特許文献1)。近年、この脳腸相関において、腸から脳へのシグナル伝達に腸内細菌が影響していることが明らかになりつつある。このことから、乳酸菌などのプロバイオティクスによる腸からの刺激により、ストレス感受性を減弱させ、ストレス応答を軽減することが考えられる。
〔1〕ラクトバチルス・ガセリ(Lactobacillus gasseri)を有効成分として含むストレス軽減剤。
〔2〕ストレスが、慢性ストレスである、〔1〕記載の剤。
〔3〕さらにα-ラクトアルブミン(αLA)を有効成分として含む、〔1〕または〔2〕記載の剤。
〔4〕ストレス軽減作用を有するラクトバチルス・ガセリ。
〔5〕血中ストレスホルモンの上昇を抑制する作用を有する、〔4〕記載のラクトバチルス・ガセリ。
〔6〕血中副腎皮質ホルモンおよび/または血中糖質コルチコイドの上昇を抑制する作用を有する、〔4〕または〔5〕記載のラクトバチルス・ガセリ。
〔7〕ラクトバチルス・ガセリを1×107個以上およびαLAを40重量%以上含有する組成物。
〔8〕ラクトバチルス・ガセリが、受託番号NITE BP-72で寄託されているラクトバチルス・ガセリ OLL2809菌株である、〔1〕~〔3〕のいずれかに記載の剤。
〔9〕受託番号NITE BP-72で寄託されている、〔4〕~〔6〕のいずれかに記載のラクトバチルス・ガセリ(Lactobacillus gasseri)。
〔10〕ラクトバチルス・ガセリが、受託番号NITE BP-72で寄託されているラクトバチルス・ガセリOLL2809菌株(Lactobacillus gasseri OLL2809)である、〔7〕記載の組成物。
〔11〕ラクトバチルス・ガセリ(Lactobacillus gasseri)を用いる、ストレス軽減方法。
〔12〕ストレスが、慢性ストレスである、〔11〕記載の方法。
〔13〕αLAをさらに用いる、〔11〕または〔12〕記載の方法。
〔14〕ラクトバチルス・ガセリが、受託番号NITE BP-72で寄託されているラクトバチルス・ガセリOLL2809菌株(Lactobacillus gasseri OLL2809)である、〔11〕~〔13〕のいずれかに記載の方法。
前記ラクトバチルス・ガセリ、またはラクトバチルス・ガセリおよびαLAの有効量とは、上記ストレス軽減剤のラクトバチルス・ガセリ、またはラクトバチルス・ガセリおよびαLAの摂取量と同じ量を意味する。
ラクトバチルス・ガセリOLL2809のストレス軽減および免疫抑制改善効果の検討
[実験方法]
6週齢の雄性Sprague Dawlyeラット(SPF)を個別飼育で馴化した後、ストレス負荷を与えない「通常群」、ストレス負荷を与える「ストレス群」、ラクトバチルス・ガセリOLL2809を投与しつつストレス負荷を与える「OLL2809群」の3群に分けた(Day 1)。全群とも馴化期間中と同様に通常飼育した後、Day 9からストレス群およびOLL2809群において、底面から1.5cmの高さまで水を張ったケージで5日間(Day 9~Day 13)飼育した。Day 1からDay 14まで、OLL2809群に40mg/kg体重/dayのOLL2809株を胃ゾンデを用いて強制胃内投与した。通常群およびストレス群には溶媒の水のみを同様に投与した。Day 14にラットを解剖し、脾細胞のNK活性と血中ストレスホルモンの測定を実施した。
脾細胞のNK活性はYAC-1細胞を標的細胞とし、フローサイトメトリーを使用した方法を用いた。1×106 cellsのラット脾臓エフェクター細胞と、2.5×104 cellsのDio(3,3'-ジオクタデシルオキサカルボシアニン過塩素酸塩(Dio; Sigma-Aldrich, St. Louis, MO))標識YAC-1標的細胞を96ウェル丸底プレートに混合し、37℃のCO2インキュベーターで4時間培養した。培養終了の15分前に0.5mg/mLのヨウ化プロピジウム(Sigma-Aldrich)を20μL添加して死細胞を染色した。YAC-1標的細胞の死滅はFACSCaliburフローサイトメトリーおよびCellQuestソフトウェア(BD Biosciences, Flanklin Lakes, NJ)を用いて解析し、その死滅率をNK活性とした。
血中のストレスホルモンは、ACTH (副腎皮質刺激ホルモン)、コルチコステロン、8-OHdGの3項目を測定した。これらはキットを用いて測定した。ACTH;ACTH (Rat) EIA KIT(Phoenix Pharmaceuticals, Burlingame, CA)、Corticosterone;Corticosterone EIA Kit (Enzo Life Science, Farmingdale, NY)、8-OHdG;高感度8-OHdG Check, (Nikken Seil, 静岡)。
HPA軸のストレス応答伝達物質であるACTH、コルチコステロンを測定した結果、通常群と比較してストレス群で有意な増加が認められた(図1)。一方、OLL2809群でもストレス負荷によりこれらの値は通常群と比較して増加したが、有意ではなかった。また、酸化ストレスマーカーである8-OHdGも同様の推移を示した(図2)。
脾臓のNK活性を測定したところ、通常群と比較してストレス群で有意な低下が認められた(図3)。一方、ストレス群と比較してOLL2809群ではNK活性が有意に亢進しており、通常群と同じレベルにまで回復していた。この変動はコルチコステロンと逆の変動であった。この結果から、OLL2809株の摂取はストレスによって低下するNK活性を高く維持する作用があることが明らかになった。
従って、本結果から、OLL2809株の投与はHPA軸を介したストレス応答を軽減していることが明らかになった。
(1)被験者
以下の基準を満たす健常な大学生を被験者(n=44)として、臨床試験に登録した:(i) 同意取得時の年齢が30歳以下の健常な日本人男性であること、(ii) 持久力を要する運動を日常的に(週5日以上)行っていること。
さらに、以下の除外基準に抵触しない者を被験者とした。除外(中止・脱落)基準:(i) 自由意志により試験継続を辞退した被験者;(ii) 試験期間中に花粉症などのアレルギー疾患を発症した者;(iii) 何らかの疾患の発症により試験を継続することが困難になった者;(iv) 試験責任医師、実施運営責任者の指示に従わずコンプライアンスを遵守していないことが判明した者;(v)被験物摂取期間中の未摂取回数が予定回数の10%に達した者。
本件の実施に際し、治験担当医師より試験内容の説明を受けた被験者群全員から、書面による同意を得た。また、被験者が20歳未満でる場合は、本人とその保護者の同意を得た。本試験はヘルシンキ宣言を遵守して実施され、被験者の安全性を第一に考慮して実施した。本試験は株式会社明治研究本部の倫理審査委員会での承認を得て実施した。
無作為化プラセボ対照二重盲検法(三群間の並行比較試験)を行った。1週間の前観察期間の後、プラセボ群とラクトバチルス・ガセリ OLL2809のみを摂取する群(以下、OLL2809群)、およびラクトバチルス・ガセリ OLL2809に加えてαLAを摂取する群(以下、OLL2809+αLA群)の3群に割り付けた。各被験者にはプラセボまたは被験物を含有する錠剤を4週間摂取させた。被験物の摂取前後で検査を行い、下記のように運動負荷、アンケート調査、血液検査を行った。尚、運動後の血液検査は、1時間の運動終了後、約1時間後に実施した。
電磁ブレーキ式自転車エルゴメーターを用いて、被験者に、運動全体にわたって予測最大心拍予備能の70%を維持する強度(70%HRreserve)で、1時間の自転車エルゴメーター運動を行わせた。尚、70%HRreserveは、以下のカルボーネンの式によって算出した:
70%HRreserve = [(220 - 年齢) - 安静時心拍数] × 0.7 + 安静時心拍数。
心拍数は、運動試験全体にわたって5分おきにモニターした。
[i]POMS
POMS質問紙の記入は、前観察期間、および摂取4週後の運動前の計2回実施した。各得点を合計し、以下の6つの下位尺度を得点化した:T-A(緊張-不安)、D(抑うつ-落込み)、A-H(怒り-敵意)、V(活気)、F(疲労)、およびC(混乱)。POMSマニュアルに従い、パラメトリック統計解析のためにこれらの合計素得点をTスコアに変換した(Yokoyama K, Araki S. POMS Japanese manual. Kaneko Syobo, Tokyo, 1994 (In Japanese).)。
[ii]疲労のVAS
被験者の疲労を測定するために、疲労のVASを用いた。評価は摂取開始前の運動負荷の前後、及び摂取4週後の運動負荷の前後の計4回行った。VASは、右側を「疲労感が全くない」、左側を「これまでに経験した最も強い疲労感」として、100mmの直線上でその程度を評価した。被験者に、該直線上で、現在の自分の状態についての自分自身の認識を最もよく表していると感じる位置に印を付けさせた。次に、該直線の左端から印までの距離(mm)を測定することによって、VAS疲労スコアを決定した。
[iii]NK活性
摂取前後の2回の観察期間においてそれぞれ、運動負荷前後の2回、計4回の採血を行い、NK活性をBML社にて測定した。
[iv]血液・血液生化学検査
血液検査(赤血球数、白血球数、血小板数、ヘモグロビン)および血液生化学検査(血糖値、総タンパク質、アラニンアミノトランスフェラーゼ(ALT)、アスパラギンアミノトランスフェラーゼ(AST)、乳酸脱水素酵素(LDH)、総ビリルビン、γ-トランスペプチダーゼ、アルカリフォスファターゼ(ALP)、血液尿素窒素(BUN)、クレアチニン、尿酸、総コレステロール、トリグリセリド、高密度リポタンパク質(HDL))を摂取前及び摂取4週後の運動前に行った。これらは主に安全性指標として評価した。
またTGF-β1、dROMsは摂取前後の2回の観察期間においてそれぞれ、運動負荷前後の2回、計4回採血を行って評価した。
被験物は株式会社明治で製造した。
ラクトバチルス・ガセリ OLL2809凍結乾燥粉末は、ホエイと乳糖を主成分とする培地(ホエイ分解培地)に、ラクトバチルス・ガセリ OLL2809の前培養液を1%接種し、37℃、下限pH 4.5(6 mol/L NaOHで自動調整)、窒素上面通気下で18時間培養した。その後、培養液を20倍濃縮し、85℃で60分間加熱処理した。冷却後、凍結乾燥し、乾燥物を粉砕してラクトバチルス・ガセリ OLL2809凍結乾燥粉末とした。
OLL2809群が摂取するOLL2809錠は、ラクトバチルス・ガセリ OLL2809凍結乾燥粉末を16.7mgと賦形剤等を配合した1錠あたり500mgの錠剤を製造した。OLL2809+αLA群が摂取するOLL2809+αLA錠は、ラクトバチルス・ガセリ OLL2809凍結乾燥粉末を16.7mgとαLAを150mgならびに賦形剤等を配合した1錠あたり500mgの錠剤を製造した。プラセボ群が摂取するプラセボ錠は、ラクトバチルス・ガセリ OLL2809凍結乾燥粉末およびαLAの代わりにデキストリンを配合し、賦形剤を加えて1錠あたり500mgとしたものを製造した。これらは、どの錠剤も見た目、色、味に見分けがつかないようにした。
いずれの群も、それぞれが摂取する錠剤を1回2錠、1日3回(朝、昼、晩)、4週間にわたって連続摂取させた。つまり、OLL2809群の1日の摂取量は、L. gasseri OLL2809凍結乾燥粉末が100mg(5×1010 cells)であり、OLL2809+αLA群の摂取量は、ラクトバチルス・ガセリ OLL2809凍結乾燥粉末が100mg(5×1010 cells)とαLAが900mgとなる。
盲検結果のレビューはキーオープン前に実施し、脱落症例の取り扱いは盲検データを基に判断した。この評価は試験を終了した全被験者に対して実施した。
結果は平均値±標準偏差で示した。被験者背景因子は一元配置分散分析(One-way ANOVA)を行った。POMS、VAS法による疲労感調査、NK活性は被験物要因と摂取前後の観察期要因の2要因で二元配置反復測定分散分析(Two-way repeated-measures (rm) ANOVA)を行った(疲労感調査、NK活性は各観察期における運動前後の差を用いた)。有意と認められた場合にはpost hoc解析を実施し、群内の摂取前後の比較はStudentの対応のあるt検定(Bonferroni補正)で実施した。P<0.05で有意と判断した。
[被験者の背景因子]
試験には44人(プラセボ群14人、OLL2809群15人、OLL2809+αLA群15人)が参加し、全員が試験期間を終了した。コンプライアンスの違反や有害事象などによる中止・脱落症例はなかった。最終的に全被験者を解析対象とした。摂取前に記録した被験者の背景因子を表1に示す。全項目において3群間で有意差は認められなかった。
POMSの結果を表2および図4に示す。各群内で摂取前と4週後を比較すると、「緊張‐不安」ではプラセボ群は摂取前が44.9±9.9、4週後が43.0±6.0と有意な差は認められなかったが、OLL2809群では摂取前が43.6±8.2、4週後では40.6±6.9と有意な低下が認められた(P=0.006)。さらに、OLL2809+αLA群では摂取前が42.6±6.1、4週後が39.7±6.3と低下する傾向が認められた(P=0.095)。
「疲労」ではプラセボ群、OLL2809群共に摂取前後で有意差は認められなかったが、OLL2809+αLA群のみにおいて摂取前が43.8±6.1、4週後が40.3±5.2と低下する傾向が認められた。
以上の結果から、OLL2809は緊張や不安といった心理的ストレスを軽減し、さらに、OLL2809とαLAでは慢性ストレスで感じられる、日常的な疲労感を軽減する効果が認められた。
VAS法を用いた運動負荷による疲労感の結果を図5に示す。各群内で運動前時の疲労感を摂取前後で比較すると、OLL2809+αLA群において、4週後にVASスコアの有意な低下が認められた(P=0.026)。この結果はPOMSの結果とも一致するものであった。そこで、運動前の検査値について相関解析すると、POMSとVAS法での疲労感に有意な正の相関が認められた(r=0.293、n=88、P=0.0053)。これらの結果から、OLL2809+αLA群では4週間の被験物の摂取により、慢性的な疲労感が軽減していることが示唆された。
被験物質の摂取前に実施した運動前後における末梢血NK細胞障害活性と、摂取4週後に実施した運動前後における末梢血NK活性の結果を図6に示す。
摂取前では、1時間の運動後にNK活性はプラセボ群で-12.4±11.0%、OLL2809群で-12.2±12.3%、OLL2809+αLA群で-14.5±11.4%と低下した。一方、4週後における運動前後の差はそれぞれプラセボ群で-8.8±12.0%、OLL2809群で-2.7±14.2%、OLL2809+αLA群で-4.3±10.2%であった。
各群内で運動負荷の前後で比較を行うと、被験物の摂取前では全群において運動負荷により有意なNK活性の低下が認められた。一方、4週後ではプラセボ群(P=0.016)では摂取前と同様に運動負荷による有意な低下が認められたのに対して、OLL2809群(P=0.476)及びOLL2809+αLA群(P=0.125)ではNK活性の有意な低下は認められなかった。即ち、OLL2809株の摂取によって、運動負荷という慢性ストレスによるNK活性の低下が軽減されることが明らかになった。
末梢血中のdROMs、 TGF-β1の結果を表3に示す。
dROMsは活性酸素・フリーラジカルによる酸化的傷害の度合い、即ち酸化ストレス度を示す指標である。dROMsは運動前の値のみを比較すると、プラセボ群では摂取前では303±56 U.CARR、4週後では298±80 U.CARRと有意な差は認められなかったが、OLL2809群では摂取前が298±50 U.CARR、4週後が283±27 U.CARRと低下する傾向を示した(P=0.089)。さらに、OLL2809+αLA群では摂取前が317±58 U.CARR、4週後では284±53 U.CARRと有意に低下した(P=0.033)。これらの値に運動負荷による影響は認められなかった。
TGF-β1は中枢性疲労の原因物質であることが示唆されるサイトカインである。TGF-β1は運動前のみを比較すると摂取前はプラセボ群、OLL2809群、OLL2809 + αLA群でそれぞれ1.29±0.35、1.33±0.27、1.35±0.32 ng/ml、摂取4週後はそれぞれ1.23±0.18、1.20±0.15、1.19±0.19 ng/mlと共に有意な群間差は認められなかった。各群内で摂取前との比較を行うと、プラセボ群では有意な変化が認められなかったのに対して、OLL2809群で低下する傾向が認められた(P=0.075)。さらに、OLL2809+αLA群では有意な低下が認められた(P=0.035)。
Claims (14)
- ラクトバチルス・ガセリ(Lactobacillus gasseri)を有効成分として含むストレス軽減剤。
- ストレスが、慢性ストレスである、請求項1記載の剤。
- さらにα-ラクトアルブミン(αLA)を有効成分として含む、請求項1または2記載の剤。
- ストレス軽減作用を有するラクトバチルス・ガセリ(Lactobacillus gasseri)。
- 血中ストレスホルモンの上昇を抑制する作用を有する、請求項4記載のラクトバチルス・ガセリ(Lactobacillus gasseri)。
- 血中副腎皮質ホルモンおよび/または血中糖質コルチコイドの上昇を抑制する作用を有する、請求項4または5記載のラクトバチルス・ガセリ(Lactobacillus gasseri)。
- ラクトバチルス・ガセリ(Lactobacillus gasseri)を1×107個以上およびαLAを40重量%以上含有する組成物。
- ラクトバチルス・ガセリが、受託番号NITE BP-72で寄託されているラクトバチルス・ガセリOLL2809菌株(Lactobacillus gasseri OLL2809)である、請求項1~3のいずれか一項記載の剤。
- 受託番号NITE BP-72で寄託されている、請求項4~6のいずれか一項記載のラクトバチルス・ガセリ(Lactobacillus gasseri)。
- ラクトバチルス・ガセリが、受託番号NITE BP-72で寄託されているラクトバチルス・ガセリOLL2809菌株(Lactobacillus gasseri OLL2809)である、請求項7記載の組成物。
- ラクトバチルス・ガセリ(Lactobacillus gasseri)を用いる、ストレス軽減方法。
- ストレスが、慢性ストレスである、請求項11記載の方法。
- αLAをさらに用いる、請求項11または12記載の方法。
- ラクトバチルス・ガセリが、受託番号NITE BP-72で寄託されているラクトバチルス・ガセリOLL2809菌株(Lactobacillus gasseri OLL2809)である、請求項11~13のいずれか一項記載の方法。
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Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20230000933A1 (en) * | 2019-12-02 | 2023-01-05 | Life Quality Institute, Inc. | Agent for prevention or remediation of stress disorders and composition containing same |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002544146A (ja) * | 1999-05-06 | 2002-12-24 | カンパーニ ジェルヴェ ダノン | 抗不安特性を有する乳酸菌及びその使用 |
JP2003095963A (ja) * | 2001-09-20 | 2003-04-03 | Snow Brand Milk Prod Co Ltd | 炎症性腸疾患及び過敏性腸症候群の予防・治療剤 |
JP2008212140A (ja) * | 2007-02-09 | 2008-09-18 | Crossfield Bio Inc | 新規なラクトバチルス属微生物および乳酸菌製剤 |
WO2013031749A1 (ja) * | 2011-08-29 | 2013-03-07 | 株式会社明治 | 身体活動を促進させる乳酸菌 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102726524B (zh) * | 2012-06-19 | 2014-05-28 | 重庆市天友乳业股份有限公司 | 一种益生菌发酵乳 |
-
2014
- 2014-02-26 CN CN201480010243.1A patent/CN105025909B/zh active Active
- 2014-02-26 SG SG11201506640TA patent/SG11201506640TA/en unknown
- 2014-02-26 JP JP2015502944A patent/JP6329125B2/ja active Active
- 2014-02-26 WO PCT/JP2014/054629 patent/WO2014132982A1/ja active Application Filing
-
2016
- 2016-04-01 HK HK16103778.4A patent/HK1215854A1/zh unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002544146A (ja) * | 1999-05-06 | 2002-12-24 | カンパーニ ジェルヴェ ダノン | 抗不安特性を有する乳酸菌及びその使用 |
JP2003095963A (ja) * | 2001-09-20 | 2003-04-03 | Snow Brand Milk Prod Co Ltd | 炎症性腸疾患及び過敏性腸症候群の予防・治療剤 |
JP2008212140A (ja) * | 2007-02-09 | 2008-09-18 | Crossfield Bio Inc | 新規なラクトバチルス属微生物および乳酸菌製剤 |
WO2013031749A1 (ja) * | 2011-08-29 | 2013-03-07 | 株式会社明治 | 身体活動を促進させる乳酸菌 |
Non-Patent Citations (3)
Title |
---|
DAISUKE SAWADA ET AL.: "Continuous oral intake of fermented milk produced with Lactobacillus gasseri strain CP2305: a potential and practical approach to stress protection", JOURNAL OF INTESTINAL MICROBIOLOGY, vol. 23, no. 2, 2009, pages 96 * |
MARKUS C.R. ET AL.: "The bovine protein a-lactalbumin increases the plasma ratio of tryptophan to the other large neutral amino acids,and in vulnerable subjects raises brain serotonin activity, reduces cortisol concentration, and improves mood under stress.", AM.J.CLIN.NUTR., vol. 71, 2000, pages 1536 - 1544 * |
SASHIHARA T. ET AL.: "Effects of Lactobacillus gasseri OLL2809 and alpha-lactalbumin on university-student athletes: a randomized, double-blind,placebo-controlled clinical trial.", APPLIED PHYSIOLOGY, NUTRITION, AND METABOLISM, vol. 38, no. 12, December 2013 (2013-12-01), pages 1228 - 1235 * |
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