Composition for improving total attentiveness, cognitive flexibility, and / or execution function

Abstract

The present invention addresses the problem of providing a new means for improving total attention, cognitive flexibility, and / or execution function. The present invention provides a composition for improving at least one selected from the group consisting of total attention, cognitive flexibility, and execution function, the composition containing bifidobacteria and water-soluble dietary fiber.

Description

Compositions for improving general attention, cognitive flexibility and / or executive function

[0001] The present invention relates to compositions for improving general attention, cognitive flexibility and / or executive function.

[0002] Dementia is a disease associated with aging, in which the death and decline of brain cells causes impairment of cognitive functions such as memory and judgment, resulting in interference with social life and interpersonal relationships. Approximately 15% of people aged 65 and over are said to suffer from dementia, and it is estimated that there are approximately 4 million people with mild cognitive impairment (MCI), which is one step away from dementia.

[0003] There are various types of dementia and MCI, including declines in memory functions and declines in reaction time functions, and there are also various types of memory. Specifically, Cognitrax has been developed and is used as a tool to measure these memory and cognitive functions. More specifically, Cognitrax measures the following items to determine which areas of function are declining: overall memory, verbal memory, visual memory, cognitive function speed, reaction time, overall attention, sustained attention, simple attention, cognitive flexibility, processing speed, motor speed, executive function, social cognition, reasoning, working memory, and neurocognitive index. Of these functions, overall attention, cognitive flexibility, and executive function are extremely important because they affect various decisions in social life. Under these circumstances, the development of new methods to improve overall attention, cognitive flexibility, and executive function is highly desirable.

[0004] Jpn Pharmacol Ther (Pharmacology and Therapeutics) vol. 48 no. 4 2020, 685-679; Jpn Pharmacol Ther (Pharmacology and Therapeutics) vol. 47 no. 5 2019, 739-749; Jpn Pharmacol Ther (Pharmacology and Therapeutics) vol. 48 no. 3 2020, 475-486; J Biosci Bioeng. 2012;113:587-91. Biosci Microbiota Food Health. 2016;35(4):163-171. Arch Clin Neuropsychol. 2006, 7, 623-643. Molecules. 2020, 18, 4265. Psychiatry Clin Neurosci. 2007, 1, 112-119. PLoS One. 2014, 4, e95192Microbiome. 2021, 1, 95Nutrients. 2019, 4, 839

[0005] The problem to be solved by the present invention is to provide new means for improving general attention, cognitive flexibility and / or executive function.

[0006] Under these circumstances, the present inventors conducted extensive research and found that combining bifidobacteria with water-soluble dietary fiber can improve overall attention, cognitive flexibility, and / or executive function. More specifically, the inventors found that combining bifidobacteria with water-soluble dietary fiber improves overall cognitive ability (average scores for memory, information processing speed, reaction time, attention, and judgment), and in particular improves attention (the ability to maintain attention and respond accurately), judgment (the accuracy and speed of judgment, and the ability to respond to and process changes in instructions), and / or executive function (the ability to understand rules and concepts and make decisions). The present invention is based on this novel finding. The inventors have found that ingesting the composition of the present invention can improve overall attention, cognitive flexibility, and / or executive function, particularly in healthy middle-aged and elderly people. Accordingly, the present invention provides the following: Item 1. A composition for improving at least one selected from the group consisting of overall attention, cognitive flexibility, and executive function, comprising bifidobacteria and water-soluble dietary fiber.

[0007] Item 2. The composition according to Item 1, wherein the water-soluble dietary fiber comprises inulin.

[0008] Item 3. The composition according to Item 1 or 2, for improving a neurocognitive index.

[0009] Item 4. The composition according to any one of Items 1 to 3, wherein the bifidobacteria have the ability to grow in the intestine.

[0010] Item 5. The composition according to any one of Items 1 to 4, wherein the bifidobacterium has an anti-metabolic syndrome effect.

[0011] Item 6. The composition according to any one of Items 1 to 5, which is a food product.

[0012] Item 7. The composition according to any one of Items 1 to 6, which is a food for preventing, maintaining, or improving cognitive function decline.

[0013] Item 8. Use of bifidobacteria and water-soluble dietary fiber for producing a composition for improving at least one selected from the group consisting of general attention, cognitive flexibility, and executive function.

[0014] Item 9. The use according to Item 8, wherein the water-soluble dietary fiber comprises inulin.

[0015] Item 10. The use according to Item 8 or 9, wherein the composition is a composition for improving a neurocognitive index.

[0016] Item 11. The use according to any one of Items 8 to 10, wherein the bifidobacteria have the ability to grow in the intestine.

[0017] Item 12. The use according to any one of Items 8 to 11, wherein the bifidobacterium has an anti-metabolic syndrome effect.

[0018] Item 13. The use according to any one of Items 8 to 12, wherein the composition is a food product.

[0019] Item 14. The use according to Item 13, wherein the composition is a food for preventing, maintaining, or improving cognitive function decline.

[0020] Item 15. Use of water-soluble dietary fiber for producing a composition for improving at least one selected from the group consisting of overall attention, cognitive flexibility, and executive function, which comprises bifidobacteria.

[0021] Item 16. The use according to Item 15, wherein the water-soluble dietary fiber comprises inulin.

[0022] Item 17. The use according to Item 15 or 16, wherein the composition is a composition for improving a neurocognitive index.

[0023] Item 18. The use according to any one of Items 15 to 17, wherein the bifidobacteria have the ability to grow in the intestine.

[0024] Item 19. The use according to any one of Items 15 to 18, wherein the bifidobacterium has an anti-metabolic syndrome effect.

[0025] Item 20. The use according to any one of Items 15 to 19, wherein the composition is a food product.

[0026] Item 21. The use according to Item 20, wherein the composition is a food for preventing, maintaining, or improving cognitive function decline.

[0027] Item 22. Use of bifidobacteria for producing a composition for improving at least one selected from the group consisting of overall attention, cognitive flexibility, and executive function, which composition contains water-soluble dietary fiber.

[0028] Item 23. The use according to Item 22, wherein the water-soluble dietary fiber comprises inulin.

[0029] Item 24. The use according to Item 22 or 23, wherein the composition is a composition for improving a neurocognitive index.

[0030] Item 25. The use according to any one of Items 22 to 24, wherein the bifidobacteria have the ability to grow in the intestine.

[0031] Item 26. The use according to any one of Items 22 to 25, wherein the bifidobacterium has an anti-metabolic syndrome effect.

[0032] Item 27. The use according to any one of Items 22 to 26, wherein the composition is a food product.

[0033] Item 28. The use according to Item 27, wherein the composition is a food for preventing, maintaining, or improving cognitive function decline.

[0034] Item 29. A method for improving at least one selected from the group consisting of overall attention, cognitive flexibility, and executive function, comprising administering effective amounts of bifidobacteria and water-soluble dietary fiber to a subject in need thereof.

[0035] Item 30. The method according to Item 29, wherein the water-soluble dietary fiber comprises inulin.

[0036] Item 31. The method according to Item 29 or 30, for improving a neurocognitive index.

[0037] Item 32. The method according to any one of Items 29 to 31, wherein the bifidobacteria have the ability to grow in the intestine.

[0038] Item 33. The method according to any one of Items 29 to 32, wherein the bifidobacterium has an anti-metabolic syndrome effect.

[0039] Item 34. The method according to any one of Items 29 to 33, wherein the bifidobacteria and water-soluble dietary fiber are ingested as a food product.

[0040] Item 35. The method according to any one of Items 29 to 34 for preventing, maintaining, or improving cognitive function decline, wherein the bifidobacteria and water-soluble dietary fiber are ingested as food.

[0041] Item 36. A combination of bifidobacteria and water-soluble dietary fiber for use in improving at least one selected from the group consisting of overall attention, cognitive flexibility, and executive function.

[0042] Item 37. The combination for use according to Item 36, wherein the water-soluble dietary fiber comprises inulin.

[0043] Item 38. The combination for use according to Item 36 or 37 for use in improving a neurocognitive index.

[0044] Item 39. The combination for use according to any one of Items 36 to 38, wherein the bifidobacteria have the ability to grow in the intestine.

[0045] Item 40. The combination for use according to any one of Items 36 to 39, wherein the bifidobacterium has an anti-metabolic syndrome effect.

[0046] Item 41. The combination for use according to any one of Items 36 to 40, which is a food product.

[0047] Item 42. The combination for use according to any one of Items 36 to 41, which is a food for use in preventing, maintaining, or improving cognitive function decline.

[0048] Item 43. A water-soluble dietary fiber for use in combination with bifidobacteria in improving at least one selected from the group consisting of overall attention, cognitive flexibility, and executive function.

[0049] Item 44. A water-soluble dietary fiber for use according to Item 43, comprising inulin.

[0050] Item 45. A water-soluble dietary fiber for use according to Item 43 or 44, for use in combination with bifidobacteria in improving neurocognitive indexes.

[0051] Item 46. The water-soluble dietary fiber for use according to any one of Items 43 to 45, wherein the bifidobacteria have the ability to grow in the intestine.

[0052] Item 47. The water-soluble dietary fiber for use according to any one of Items 43 to 46, wherein the bifidobacterium has an anti-metabolic syndrome effect.

[0053] Item 48. The water-soluble dietary fiber for use according to any one of Items 43 to 47, which is a food product.

[0054] Item 49. The water-soluble dietary fiber for use according to any one of Items 43 to 48, which is a food for use in combination with bifidobacteria in preventing, maintaining, or improving cognitive function decline.

[0055] Item 50. Bifidobacterium for use in combination with water-soluble dietary fiber in improving at least one selected from the group consisting of overall attention, cognitive flexibility, and executive function.

[0056] Item 51. The bifidobacterium for use according to Item 50, wherein the water-soluble dietary fiber comprises inulin.

[0057] Item 52. The bifidobacterium for use according to Item 50 or 51, for use in combination with water-soluble dietary fiber in improving a neurocognitive index.

[0058] Item 53. The bifidobacterium for use according to any one of Items 50 to 52, which has the ability to grow in the intestine.

[0059] Item 54. A bifidobacterium for use according to any one of Items 50 to 53, which has an anti-metabolic syndrome effect.

[0060] Item 55. The bifidobacterium for use according to any one of Items 50 to 54, which is in the form of a food product.

[0061] Item 56. The bifidobacterium for use according to any one of Items 50 to 55, which is a food product for use in combination with water-soluble dietary fiber in preventing, maintaining, or improving cognitive function decline.

[0062] The present invention provides a novel means for improving overall attention, cognitive flexibility, and / or executive function. The Cognitrax-based measurement of these parameters is generally independent of each other, and a substance's ability to improve some of these parameters does not necessarily translate to improved performance in other parameters. Specifically, ergothioneine is known to be effective on cognitive function speed but not on overall attention, cognitive flexibility, or executive function (Non-Patent Document 1, Tables 2 and 3, intergroup comparison). Plasmalogen is known to be effective only on verbal memory but not on overall attention, cognitive flexibility, or executive function (Non-Patent Document 2, Table 4, intergroup comparison). GABA is known to be effective only on motor speed but not on overall attention, cognitive flexibility, or executive function (Non-Patent Document 3, Table 1, intergroup comparison). The effects of combining bifidobacteria with water-soluble dietary fiber on improving overall attention, cognitive flexibility, and executive function have not been reported to date, making the effects of the present invention unexpected from the prior art.

[0063] The flow from subject enrollment to analysis in the examples is shown in the flowchart of Figure 1. The results of quantifying bifidobacteria in feces in the examples are shown.

[0064] Composition for improving overall attention, cognitive flexibility and / or executive function The present invention provides a composition for improving at least one selected from the group consisting of overall attention, cognitive flexibility and executive function, comprising bifidobacteria and water-soluble dietary fiber. In the present invention, the type of bifidobacterium is not particularly limited, and examples thereof include Bifidobacterium animalis, Bifidobacterium adolesentis, Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium catenulatum, Bifidobacterium longum, and Bifidobacterium pseudocatenulatum, with Bifidobacterium animalis being preferred. Among Bifidobacterium animalis, Bifidobacterium animalis subsp. lactis is preferred. Furthermore, bifidobacteria that have the ability to grow in the intestine are preferred. More specifically, bifidobacteria that can increase the total number of bifidobacteria in the intestine are preferred. Whether or not a bifidobacterium has the ability to grow in the intestine can be determined, for example, by measuring the number of bifidobacteria in a fecal sample using real-time PCR. More specifically, this can be measured and evaluated in accordance with the method described in Non-Patent Document 4. Furthermore, in the present invention, if an increase in the intestine can be confirmed by the above method, the bifidobacterium can be selected as a preferred bifidobacterium of the present invention. Bacteria that can grow to a value measured by the above method that is at least 2-fold, preferably at least 5-fold, and more preferably at least 10-fold the number of bacteria ingested into the body are preferred. Furthermore, in the present invention, the bifidobacterium preferably has an anti-metabolic syndrome effect. The anti-metabolic syndrome effect can be determined, for example, by measuring visceral fat area, and more specifically, can be measured and evaluated according to the method described in Non-Patent Document 5. In the present invention, if a reduction in visceral fat area can be confirmed by the above method, the bifidobacterium can be selected as a preferred bifidobacterium of the present invention.In a preferred embodiment of the present invention, bifidobacteria that provide a visceral fat area of ​​0.98 times or less, as measured by the above-mentioned method, are preferred, and bifidobacteria that provide a visceral fat area of ​​0.96 times or less are more preferred. Examples of bifidobacteria include GCL2505, which belongs to Bifidobacterium animalis subsp. lactis. The GCL2505 strain has been deposited under accession number FERM ABP-21918. This strain was deposited on February 17, 2010, in accordance with the Budapest Treaty with the Patent Organism Depositary, National Institute of Technology and Evaluation (Room 120, 2-5-8 Kazusa Kamatari, Kisarazu City, Chiba Prefecture, 292-0818, Japan).

[0065] The number of bifidobacteria in the composition of the present invention is not limited, and can be appropriately set within the range of, for example, 10 million cells / g, preferably 30 million cells / g, more preferably 50 million cells / g, even more preferably 80 million cells / g or more, and particularly preferably 100 million cells / g or more. There is no particular upper limit, and examples include 10 trillion cells / g or less, 100 billion cells / g or less, and 10 billion cells / g or less. In a typical embodiment, live bifidobacteria are used in the present invention.

[0066] Examples of water-soluble dietary fibers include inulin, indigestible dextrin, water-soluble soybean polysaccharides, polydextrose, sodium alginate, psyllium, fucoidan, laminaran, sodium carboxymethylcellulose, pullulan, curdlan, low-molecular-weight hemicellulose, etc., and inulin is preferred. These water-soluble dietary fibers may be blended alone or in combination.

[0067] The content of water-soluble dietary fiber in the composition of the present invention is not limited, but can be set, for example, in the range of 0.5 to 10% by weight, preferably 1 to 5% by weight, and more preferably 1.5 to 3% by weight, based on the mass of the total composition.

[0068] In the present invention, a combination of bifidobacteria, which are the active ingredients of the present invention, and water-soluble dietary fiber may be used as a composition for improving at least one selected from the group consisting of overall attention, cognitive flexibility, and executive function, or the combination may be used as a composition combining the combination with various pharmaceutically acceptable carriers that can be added to foods (e.g., isotonicity agents, chelating agents, stabilizers, pH adjusters, preservatives, antioxidants, solubilizers, thickeners, excipients, binders, etc.). In embodiments containing various carriers, the total content of bifidobacteria and water-soluble dietary fiber in the composition is not limited, and can be appropriately set within ranges, for example, 50% by mass or more, 60% by mass or more, 70% by mass or more, 80% by mass or more, 90% by mass or more, 95% by mass or more, 99% by mass or more, etc.

[0069] Examples of the isotonicity agent include sugars such as glucose, trehalose, lactose, fructose, mannitol, xylitol, and sorbitol, polyhydric alcohols such as glycerin, polyethylene glycol, and propylene glycol, and inorganic salts such as sodium chloride, potassium chloride, and calcium chloride. These isotonicity agents can be used alone or in combination of two or more.

[0070] Examples of the chelating agent include edetate salts such as disodium edetate, calcium disodium edetate, trisodium edetate, tetrasodium edetate, and calcium edetate, ethylenediaminetetraacetate, nitrilotriacetic acid or a salt thereof, sodium hexametaphosphate, citric acid, etc. These chelating agents may be used alone or in combination of two or more.

[0071] The stabilizer may, for example, be sodium hydrogen sulfite.

[0072] Examples of pH adjusters include acids such as hydrochloric acid, carbonic acid, acetic acid, and citric acid, as well as alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates or hydrogen carbonates such as sodium carbonate, alkali metal acetates such as sodium acetate, alkali metal citrates such as sodium citrate, and bases such as trometamol. These pH adjusters can be used alone or in combination of two or more.

[0073] Examples of preservatives include sorbic acid, potassium sorbate, parahydroxybenzoic acid esters such as methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, and butyl parahydroxybenzoate, quaternary ammonium salts such as chlorhexidine gluconate, benzalkonium chloride, benzethonium chloride, and cetylpyridinium chloride, alkylpolyaminoethylglycine, chlorobutanol, polyquad, polyhexamethylene biguanide, and chlorhexidine. These preservatives can be used alone or in combination of two or more.

[0074] Examples of antioxidants include sodium hydrogen sulfite, dry sodium sulfite, sodium pyrosulfite, concentrated mixed tocopherols, etc. These antioxidants may be used alone or in combination of two or more.

[0075] Examples of solubilizing agents include sodium benzoate, glycerin, D-sorbitol, glucose, propylene glycol, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, D-mannitol, etc. These solubilizing agents can be used alone or in combination of two or more.

[0076] Examples of thickeners include polyethylene glycol, methyl cellulose, ethyl cellulose, carmellose sodium, xanthan gum, sodium chondroitin sulfate, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, etc. These thickeners may be used alone or in combination of two or more.

[0077] Examples of excipients include lactose, corn starch, L-cysteine, trehalose, maltitol, sorbitol, etc. These excipients may be used alone or in combination of two or more.

[0078] Examples of binders include crystalline cellulose, starch, sucrose, hydroxypropyl cellulose, gelatin, powdered gum arabic, polyvinylpyrrolidone, pullulan, dextrin, cyclodextrin, methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl alcohol, polyethylene glycol, etc. These binders can be used alone or in combination of two or more.

[0079] The intake amount of the composition of the present invention is not limited, but the daily intake of bifidobacteria as an active ingredient can be appropriately set within a range of, for example, 10 million to 10 trillion, preferably 100 million to 1 trillion, more preferably 1 billion to 100 billion, even more preferably 5 billion to 30 billion, and particularly preferably 10 billion to 20 billion. The intake amount of the composition of the present invention based on the weight of bifidobacteria is also not limited, but the daily intake of bifidobacteria as an active ingredient can be appropriately set within a range of, for example, 1 mg to 10 g, preferably 10 mg to 1000 mg, more preferably 40 mg to 300 mg, and even more preferably 200 mg or more.

[0080] The composition of the present invention may further contain a substance other than the bifidobacteria that is known to improve overall attention, cognitive flexibility, and / or executive function. Examples of substances known to improve overall attention, cognitive flexibility, and / or executive function include propolis and chlorogenic acids. These substances can be used alone or in combination of two or more. The composition of the present invention may also contain a substance known to improve functions other than overall attention, cognitive flexibility, and executive function, specifically, overall memory, verbal memory, visual memory, cognitive function speed, reaction time, sustained attention, simple attention, processing speed, motor speed, social cognition, logical thinking, working memory, and neurocognitive index. Examples of substances known to improve these functions include GABA, palatinose, plasmalogen, and ergothioneine. These substances can be used alone or in combination of two or more.

[0081] The composition of the present invention is preferably an oral composition. Oral compositions include food and drink compositions, pharmaceutical compositions, etc. In the present invention, the food and drink compositions also include health functional foods (nutrient functional foods, foods for specified health uses, foods with functional claims), etc.

[0082] Examples of food and beverage compositions include beverages such as vegetable juice drinks, fruit juice drinks, mixed vegetable and fruit juice drinks, fermented milk drinks, and almond-containing drinks; and foods such as ice creams, frozen desserts, candies, gummies, almond-containing foods, biscuits (cream sandwich biscuits, etc.), chocolates (including semi-chocolate), and fermented milk foods (yogurt, cheese). Preferred ice creams include lacto ice cream (lacto ice cream containing fermented milk, etc.). Examples of semi-chocolate include corn-containing semi-chocolate. Examples of dairy products include fermented milk, ice creams, and milk drinks. The food and beverage compositions of the present invention also include supplements, etc.

[0083] In another embodiment, the present invention provides use of bifidobacteria and water-soluble dietary fiber for the manufacture of a composition for improving at least one selected from the group consisting of overall attention, cognitive flexibility, and executive function; use of water-soluble dietary fiber for the manufacture of a composition for improving at least one selected from the group consisting of overall attention, cognitive flexibility, and executive function, comprising bifidobacteria; use of bifidobacteria for the manufacture of a composition for improving at least one selected from the group consisting of overall attention, cognitive flexibility, and executive function, comprising water-soluble dietary fiber; a method for improving at least one selected from the group consisting of overall attention, cognitive flexibility, and executive function, comprising administering (having a subject ingest) an effective amount of bifidobacteria and water-soluble dietary fiber to a subject in need thereof; a combination of bifidobacteria and water-soluble dietary fiber for use in improving at least one selected from the group consisting of overall attention, cognitive flexibility, and executive function; water-soluble dietary fiber for use in combination with bifidobacteria in improving at least one selected from the group consisting of overall attention, cognitive flexibility, and executive function; and bifidobacteria for use in combination with water-soluble dietary fiber in improving at least one selected from the group consisting of overall attention, cognitive flexibility, and executive function. In these embodiments, details (type, amount, etc.) of the bifidobacteria, water-soluble dietary fiber, and optional other ingredients, method of use (medicine, food, drink, etc.), and purpose (improvement of at least one selected from the group consisting of overall attention, cognitive flexibility, and executive function, etc.) are the same as those described above. In the present invention, subjects to which bifidobacteria and water-soluble dietary fiber are administered (ingested) include, for example, mammals such as humans, mice, rats, and guinea pigs (preferably humans). When humans are the subject, the subject includes, but is not limited to, humans without dementia, mild cognitive impairment, etc. Furthermore, the age of the subject is not particularly limited, and examples include age groups in which overall attention, cognitive flexibility, executive function, etc. are generally thought to decline with age. In a preferred embodiment, the present invention can improve such overall attention, cognitive flexibility, and / or executive function.According to the present invention, by using a combination of bifidobacteria and water-soluble dietary fiber, it is possible to improve at least one (preferably two, more preferably three) selected from the group consisting of overall attention, cognitive flexibility, and executive function. According to the present invention, by improving these functions (particularly cognitive flexibility, etc.), judgment can be improved. Furthermore, overall attention and executive function can also be rephrased as attention and executive ability, respectively. Therefore, in one embodiment, the present invention provides a composition for improving at least one selected from the group consisting of attention, judgment, and executive ability, comprising bifidobacteria and water-soluble dietary fiber; use of bifidobacteria and water-soluble dietary fiber for producing a composition for improving at least one selected from the group consisting of attention, judgment, and executive ability; use of water-soluble dietary fiber for producing a composition containing bifidobacteria for improving at least one selected from the group consisting of attention, judgment, and executive ability; use of bifidobacteria for producing a composition containing water-soluble dietary fiber for improving at least one selected from the group consisting of attention, judgment, and executive ability; use of bifidobacteria for producing a composition containing water-soluble dietary fiber for improving at least one selected from the group consisting of attention, judgment, and executive ability; The present invention provides a method for improving at least one selected from the group consisting of attention, judgment, and executive ability, which comprises administering (having a subject ingest) effective amounts of bifidobacteria and water-soluble dietary fiber to a subject in need thereof; a combination of bifidobacteria and water-soluble dietary fiber for use in improving at least one selected from the group consisting of attention, judgment, and executive ability; water-soluble dietary fiber for use in combination with bifidobacteria in improving at least one selected from the group consisting of attention, judgment, and executive ability; and bifidobacteria for use in combination with water-soluble dietary fiber in improving at least one selected from the group consisting of attention, judgment, and executive ability.

[0084] Specific embodiments of the present invention will be described in more detail below using examples, but the present invention is not limited to such examples.

[0085] To evaluate the potential cognitive function-improving effects of GCL2505 and inulin, a randomized, double-blind, placebo-controlled, parallel-group comparative study was conducted.

[0086] Study Methods Subjects (Analysis Population) This study was approved by the Ethics Committee of Kobuna Orthopedic Hospital, Medical Corporation Koyokai, on May 12, 2022 (approval date: March 12, 2022; approval number: MK-2205-01). Written informed consent was obtained from all participants in accordance with the Declaration of Helsinki. Participants were Japanese men and women aged 50 to 80 years at the time of consent, who met the inclusion criteria, did not fall under the exclusion criteria, and were deemed eligible by the principal investigator. The inclusion criteria were: (1) those who score 24 or more on the Mini Mental State Examination-Japanese (MMSE-J) conducted as a screening test, 17 or more on the Japanese version of the Montreal Cognitive Assessment (MoCa-J), or 5 or less on the Geriatric Depression Scale-short Version-Japanese (GDS-SJ), (2) those who have subjective symptoms of forgetfulness or who have been pointed out by a close relative or acquaintance as having objective symptoms of forgetfulness, and (3) those who have been fully informed of the purpose and content of the study, are capable of consent, fully understand the study, voluntarily volunteer to participate, and provide written consent to participate in the study.The exclusion criteria were: (1) those currently receiving treatment for or with a history of psychiatric disorders (including depression), cerebrovascular disease, or sleep disorders; (2) those with serious liver, kidney, heart, respiratory, endocrine, or metabolic diseases; (3) smokers; and (4) regular alcohol users (those with alcohol intakes of 6000 or more pure alcohol equivalents). (5) those who cannot adhere to the restrictions on foods and supplements that affect the intestinal environment during the study period; (6) those who have taken antibiotics within one month prior to the start of the study; (7) those who have undergone gastrointestinal surgery (excluding appendicitis); (8) those who have experienced allergies to the ingredients of the study foods; (9) those taking medications that may affect cognitive function (antipsychotics, antianxiety drugs, antidepressants, antiparkinsonian drugs, antimanic drugs, antiepileptic drugs, anticoagulants, etc.); (10) those with visual or hearing impairments that would interfere with cognitive function tests; (11) those who regularly consume foods or supplements that may affect cognitive function; (12) those with current or past drug or alcohol dependence; (13) those participating in research involving the intake of other foods or the use of medicines, or research involving the application of cosmetics or medicines; those participating in other research while participating in this study; (14) others who the principal investigator deems unsuitable as study subjects.

[0087] Test Food The test food was a milk drink containing inulin (Orafti GR; BENEO GmbH, Mannheim, Germany) and GCL2505 (test drink) or a placebo. The test drink contained 2.0 g / 100 g of inulin and 1 × 10 10 The test food and placebo were designed to contain colony-forming units (cfu) / 100g of GCL2505. The placebo was prepared with the same ingredients as the test food, with food-grade acetic acid and lactic acid added to adjust the flavor and pH. The basic ingredients were skim milk powder, high-fructose corn syrup, sucrose, yeast extract, acidulant, stabilizer, and flavoring. Nutritional details of the test food and placebo are shown in Table 1.

[0088] Experimental Design: This study was a randomized, placebo-controlled, double-blind, parallel-group study. Participants were randomized using a permuted block design stratified by age, sex, and the results of the screening test (Cognitrax® Short, MMSE-J, and MoCa-J). They were assigned to two groups (block size: 4). The controller (principal randomizer) assigned the two groups to the test food group and the control food group. Subjects in the active and placebo groups consumed 100g of milk once daily for 12 weeks. Both subjects and observers were blinded to group assignment throughout the study. Double-blinding was achieved by labeling the test food only with an identification number. The primary outcome was Cognitrax® Long after 12 weeks of study initiation. Secondary outcomes were Cognitrax® Long after 8 weeks of study initiation, fecal bifidobacteria count, and SF-36v2®.

[0089] Cognitrax Test (PC-Based Cognitive Function Test) The participants' cognitive functions were measured using Cognitrax, a Japanese version of the CNS Vital Signs (CNSVS) (Non-Patent Document 6). The Cognitrax cognitive function tests were administered in the following order: Verbal Memory Test (VBM), Visual Memory Test (VIM), Finger Tapping Test (FTT), Symbol Digit Coding Test (SDC), Stroop Test (ST), Shift Attention Test (SAT), Continuous Performance Test (CPT), Perception of Emotion Test (POET), Non-Verbal Reasoning Test (NVRT), and Four-Part Continuous Performance Test (FPCPT). The tests were administered according to previous studies (Non-Patent Document 7).

[0090] Mental health status: Surveys were conducted at weeks 0, 8, and 12 using the World Health Organization (WHO)-Five Well-Being Index (WHO-5-J) (Non-Patent Document 8), and it was confirmed that the subjects had no abnormalities in their mental health status during the study period.

[0091] Biochemical parameters Blood pressure, pulse rate, and weight were measured at weeks 0, 8, and 12. Biochemical parameter concentrations were also measured at weeks 0 and 12. Blood was drawn from each subject in a fasting state after 4 hours of not consuming any food or drink other than water. Biochemical parameters included hematology (white blood cell count, red blood cell count, hemoglobin, hematocrit, total corpuscular volume, myocardial infarction (MCV), myocardial infarction (MCHC), platelet count, and white blood cell picture), biochemistry (total protein, albumin, total bilirubin, AST, ALT, LD (IFCC), ALP (IFCC), γ-GT, urea nitrogen (UN), creatinine, uric acid, sodium, chloride, potassium, calcium, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, phospholipids, glucose, HbA1c (NGSP), and insulin), and urinalysis (protein, glucose, bilirubin, urinary ketone bodies, occult blood test, urobilinogen, pH, and specific gravity). Serum BDNF was also quantified. All of these tests were performed at LSI Medience Corporation (Tokyo, Japan).

[0092] Inflammatory Protein Profile. Circulating inflammatory markers were measured in frozen serum using the Olink® Target 96 Inflammation Panels (Olink Proteomics AB, Uppsala, Sweden), a high-throughput multiplex proteomic immunoassay using proximity expansion technology, according to the manufacturer's instructions (see Non-Patent Document 9). This panel contains 92 immune-related proteins, primarily cytokines and chemokines. The assay utilizes epitope-specific binding and hybridization of a set of paired oligonucleotide antibody probes, followed by amplification using quantitative PCR and conversion to Normalized Protein eXpression (NPX) values, a logarithmic base 2 normalized value and a proprietary Olink unit of relative abundance. Quality control was performed on each sample plate for samples (using spiked internal controls) and external controls. This testing was outsourced to Pharma Foods Co., Ltd. (Tokyo, Japan).

[0093] Stool collection: Stool samples were submitted at weeks 0 and 12. Stool samples were collected at home between 7 and 2 days before the scheduled visit. After collection, the samples were promptly transported to the testing company in a frozen package.

[0094] Fecal DNA Extraction. Bacterial DNA was extracted from fecal samples using the ISOSPIN Fecal DNA Kit (Nippon Gene Co., Ltd., Tokyo, Japan) according to the method described by Tourlousse et al. (10). Specifically, the sample (0.2 g fecal sample), 700 μL of FE1 buffer, and 10 μL of RNase were added to the attached tube with beads. Cells were disrupted by bead-beating using a FastPrep-24 (MP Biomedicals, Irvine, CA) at 6 m / s for 1 minute. This bead-beating was repeated three times, with the sample kept at room temperature for 5 minutes between each bead-beating. Then, 90 μL of FE2 buffer was added, and the sample was centrifuged at 12,000 × g for 15 minutes. The supernatant (up to 500 μL) was collected and mixed with 0.4 volumes of FB buffer and isopropanol. Finally, the sample was loaded onto a spin column and washed according to the manufacturer's instructions. The purified DNA was eluted with 50 μL of Tris-EDTA (pH 8.0) buffer.

[0095] Fecal bifidobacteria real-time polymerase chain reaction (PCR) was performed following the method described by Tanaka et al. using genus-specific primers capable of detecting Bifidobacteria, including GCL2505. The primer sequences were as follows: Bifidobacterium sense primer, 50-GATTCTGGCTCAGGATGAACGC-30; Bifidobacterium antisense primer, 50-CTGATAGGACGCGACCCCAT-30. Each PCR reaction mixture contained 20 pmol of each primer, 5 μL of SYBR® Premix Ex taq (Takara Bio, Shiga, Japan), and 1 μL of DNA solution in a total volume of 10 μL (Non-Patent Document 11). This test was performed by the Nutrition and Pathology Research Institute, Kyoto, Japan.

[0096] Statistical analysis: All measurements were expressed as means and standard deviations (SD). All statistical analyses were performed using IBM® SPSS® Statistics 27 (IBM Corp., Armonk, NY, USA). A P value of <0.05 was used as the threshold for determining significance. For basic statistics, means and SD were displayed to one significant digit or less, and percentages (%) were displayed to one decimal place. Rounding was performed using the nearest neighbor method. Missing data were treated as missing values, and no substitute values ​​were used. For Cognitrax (long), a paired t-test was used to compare test results at the start of intake (week 0) with those at 8 and 12 weeks after initiation of intake. For other items, a Dunnett test (two-tailed test) was used to compare test results at the start of intake (week 0) with those at 8 and 12 weeks after initiation of intake. For qualitative evaluation items, a Wilcoxon signed-rank test was used. In addition, statistical analysis of the comparison between the active and placebo groups at each test was performed using an unpaired t-test (two-tailed test), and the Wilcoxon rank sum test was used for qualitative evaluation items.

[0097] Results Subjects (Analysis Population) An overview of the study period is shown in the flowchart in Figure 1. 255 participants were screened for this study. As a result of the screening, 80 participants were selected: 40 were assigned to the active group and 40 to the placebo group. A significant difference was observed in alkaline phosphatase levels between the active and placebo groups at the start of the study, but this was deemed to be within the normal range and not a problem. There were no differences in the baseline characteristics of the subject data for other items (Table 2).

[0098] Before the end of the study, one participant in the active group withdrew for personal reasons. After the entire study was completed, one participant in the placebo group was discontinued due to compliance reasons. One participant in the active group was excluded due to the diagnosis of a medical condition unrelated to the study, which raised concerns about its impact on the results. Nine participants were also excluded because they were found to have taken medications or foods during the study period that could potentially affect the study results (n = 5 in the active group, n = 4 in the placebo group). One active group participant was also discarded as a case due to missing data on the primary endpoint. Thus, the combined analysis population consisted of 67 participants, consisting of 32 in the active group and 35 in the placebo group. Furthermore, four participants in Cognitrax who demonstrated a decline in their WHO-5-J scores (n = 1 in the active group, n = 3 in the placebo group) were excluded because they met the cutoff score ≤ 50 used to assign a screening diagnosis of depression on the global version of the WHO-5. A decrease in WHO-5-J scores indicates the possibility of elderly depression due to indoor lifestyles caused by the COVID-19 pandemic, suggesting that the Cognitrax test may not have been performed properly on these individuals.

[0099] The change in the Cognitrax Test neurocognitive index score from week 0 to week 12 in the active group (5.5±7.1) was greater than that in the placebo group (2.3±4.0), and a statistically significant difference was observed between the two groups (p=0.027 by the unpaired t-test). Furthermore, the change in the Complex Attention domain score from week 0 to week 12 in the active group (8.3 ± 11.8) was significantly higher than that in the placebo group (3.2 ± 6.9) (p = 0.041 by the unpaired t-test), the change in the Cognitive Flexibility domain score in the active group (9.8 ± 11.5) was significantly higher than that in the placebo group (4.8 ± 6.7) (p = 0.038 by the unpaired t-test), and the change in the Executive Function domain score in the active group (9.5 ± 11.8) was significantly higher than that in the placebo group (4.5 ± 6.9) (p = 0.044 by the unpaired t-test) (Table 3).

[0100] Fecal bifidobacteria counts. The number of bifidobacteria in feces was quantified (Figure 2). The number of bifidobacteria in the active group at week 12 (7.71 ± 0.56 log cells / g feces) was significantly increased compared to week 0 (7.39 ± 0.74 log cells / g feces) (p = 0.005 by the Dunnett multiple comparison test), whereas no change was observed in the placebo group. Additionally, the total number of bifidobacteria in the active group at week 12 was significantly increased compared to the placebo group (7.31 ± 0.90 log cells / g feces) (p = 0.031 by the unpaired t-test).

[0101] The expression levels of a total of 92 inflammatory markers were examined at weeks 0 and 12 using the Olink® Target 96 Inflammation Panels. Seventy-five inflammatory markers deemed quantifiable were analyzed (Supplementary Materials Table S1). Statistically significant differences were observed between the active and placebo groups in the changes in scores from week 0 to week 12 for leukemia inhibitory factor receptor (LIF-R), sulfotransferase 1A1 (ST1A1), CC motif chemokine 23 (CCL23), and tumor necrosis factor (Ligand) superfamily, member 12 (TWEAK). Furthermore, there were no statistically significant differences between the active and placebo groups in the changes in scores from week 0 to week 12 for adenosine deaminase (ADA), osteoprotegerin (OPG), eotaxin (CCL11), glial cell line-derived neurotrophic factor (GDNF), fractalkine (CX3CL1), interleukin-8 (IL-8), CC motif chemokine 28 (CCL28), interleukin-18 (IL-18), interleukin-10 (IL-10), CC motif chemokine 19 (CCL19), and T-cell surface glycoprotein CD5 (CD5). However, because the P value was <0.1, it was determined that there was a significant trend (Table 4).

[0102] "In conclusion, the intake of a synbiotic drink containing GCL2505 and inulin resulted in improvements in overall attention, cognitive flexibility, and executive function, as well as improvements in neurocognitive index scores. These cognitive functions may contribute to improving quality of life, and the results obtained in this study are considered to be clinically significant."

Claims

1. A composition for improving at least one selected from the group consisting of overall attention, cognitive flexibility and executive function, comprising bifidobacteria and water-soluble dietary fiber.

2. The composition of claim 1, wherein the water-soluble dietary fiber comprises inulin.

3. A composition according to claim 1 or 2 for improving neurocognitive indexes.

4. The composition according to claim 1 or 2, wherein the bifidobacteria have the ability to proliferate in the intestine.

5. The composition according to claim 1 or 2, wherein the bifidobacteria have an anti-metabolic syndrome effect.

6. The composition according to claim 1 or 2, which is a food product.

7. The composition according to claim 1 or 2, which is a food for preventing, maintaining or improving cognitive function decline.

8. Use of bifidobacteria and water-soluble dietary fiber for producing a composition for improving at least one selected from the group consisting of overall attention, cognitive flexibility, and executive function.

9. The use according to claim 8, wherein the water-soluble dietary fiber comprises inulin.

10. The use according to claim 8 or 9, wherein the composition is for improving a neurocognitive index.

11. The use according to claim 8 or 9, wherein the bifidobacteria have the ability to grow in the intestine.

12. The use according to claim 8 or 9, wherein the bifidobacteria have an anti-metabolic syndrome effect.

13. The use according to claim 8 or 9, wherein the composition is a food product.

14. The use according to claim 8 or 9, wherein the composition is a food for preventing, maintaining or improving cognitive function decline.

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