Ginsenoside Composition

Abstract

The present invention relates to the use of ginsenosides to modulate the gut microflora and increase the production of beneficial short-chain fatty acids by said gut microflora.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to the use of ginsenosides to modulate the gut microflora and increase the production of beneficial short-chain fatty acids by said gut microflora. [Background technology]

[0002] Background of the Invention The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an admission that the document is part of the state of the art or is common general knowledge.

[0003] The human intestinal microbiota is composed of trillions of microorganisms, most of which are bacterial and viral in origin and are considered non-pathogenic. The microbiota coordinates with the host defenses and immune system to defend against pathogen colonization and invasion. It serves as a source of basic nutrients and vitamins, such as short-chain fatty acids (SCFAs) and amino acids, from food and performs essential metabolic functions, such as assisting in the extraction of energy and nutrients (see, e.g., Carding, S. et al., 2015. Microb Ecol Health Dis, 26, 26191).

[0004] The gut microbiome, or microbiota, is gaining increasing attention as a factor regulating intestinal homeostasis in healthy individuals. Various lifestyle and environmental factors, such as hygiene and antibiotic use, along with a low-fiber, high-fat, high-sugar "Western" diet, are associated with an imbalanced gut microbiota, or gut dysbiosis, which can lead to chronic inflammation and metabolic dysfunction (Thorburn AN, et al. Immunity. (2014). 40:833-842). Microbiota perturbations can create an inflammatory environment in the gastrointestinal tract and alter intestinal homeostasis (Agus A, et al. Sci Rep. (2016) 6:1-14).

[0005] Bacterial communities maintain intestinal homeostasis through "training" the immune system and participate in inhibiting the growth of pathogens and protozoan commensals (Rakoff-Nahoum S, et al. Cell. (2015) 118:229-41). The intestinal inflammatory response is regulated by the gut microbiome. Of particular importance appear to be bacterial species that provide non-digestible dietary fiber (DF) and produce metabolic products that exert positive effects on the intestinal mucosa; examples include short-chain fatty acids (SCFAs), primarily acetate, propionate, and butyrate. Butyrate is the primary energy source for colonocytes and also maintains intestinal homeostasis through its anti-inflammatory effects (Donohoe DR, et al. Cell Metab. (2011) 13:517-26).

[0006] The present inventors have now surprisingly found that an extract obtained from ginsenoside-rich American ginseng (Panax quinquefolius) (herein referred to as AG) possesses potent activity in regulating or modulating the gut microbiota. The present inventors have now surprisingly found that an extract obtained from ginsenoside-rich American ginseng (Panax quinquefolius) (herein referred to as AG) increases the production of several SCFAs.

[0007] These effects suggest that such ginsenosides and extracts of American ginseng (Panax quinquefolius) may have a myriad of therapeutic and non-therapeutic (e.g., functional food) uses, and uses in the prevention of disease conditions. Summary of the Invention

[0008] Summary of the Invention The term "ginseng" is commonly used to refer to species of the genus Panax in the family Araliaceae. Extracts of Asian ginseng (Panax ginseng) have been used in traditional Chinese medicine for millennia.

[0009] American ginseng (Panax quinquefolius) has a distinct ginsenoside profile similar to Panax ginseng and has been recognized for its cognitive enhancing properties. However, the beneficial effects of ginsenosides from Panax species such as American ginseng on the gut microbiota have not been described until now.

[0010] The inventors of the present invention have now surprisingly found that a ginsenoside-rich extract obtained from American ginseng (Panax quinquefolius) (herein referred to as AG) increases the production of several SCFAs and affects the gut microbiota.

[0011] Thus, in a first aspect, the present invention provides a composition comprising a ginsenoside for use in regulating or modulating the gut microbiota; increasing the concentration of SCFAs in the intestine; increasing the production of SCFAs by the gut microbiota, and / or increasing SCFA blood concentrations.

[0012] In a second aspect, the present invention provides the use of a composition comprising a ginsenoside for modulating or regulating the gut microbiota; increasing the concentration of SCFAs in the intestine; increasing the production of SCFAs by the gut microbiota, and / or increasing SCFA blood concentrations.

[0013] In a third aspect, the present invention provides a method for (i) regulating or modulating the gut microbiota; (ii) increasing the concentration of SCFAs in the gut; (iii) increasing the production of SCFAs by the gut microbiota; and / or (iv) increasing SCFA blood concentrations, comprising administering to a subject in need thereof an effective amount of a composition comprising a ginsenoside.

[0014] In a fourth aspect, the present invention provides a method for improving or increasing cognition / working memory, treating, reducing, preventing, and / or ameliorating fatigue; improving or increasing attention / alertness, and / or improving or increasing self-confidence, comprising administering to a subject in need thereof an effective amount of a composition comprising a ginsenoside, (i) regulating or modulating the gut microbiota; (ii) increasing the concentration of SCFAs in the gut; (iii) increasing the production of SCFAs by the gut microbiota; and / or (iv) increasing SCFA blood concentrations.

[0015] In a further aspect, the present invention provides methods for (i) regulating or modulating the gut microbiota; (ii) increasing the concentration of intestinal SCFAs; (iii) increasing the production of SCFAs by the gut microbiota; and / or (iv) appropriately increasing SCFA blood concentrations, comprising administering to a subject in need thereof an effective amount of a composition comprising a ginsenoside for regulating satiety, reversing obesity-related and / or metabolic syndrome-related gut microbiota-dysbiosis imbalance, treating or preventing gut microbiota-dysbiosis imbalance-induced cardiovascular and / or cardiometabolic disease; treating or preventing low-grade inflammation, treating or preventing obesity, treating or preventing sleep disorders such as insomnia, treating or preventing neuropsychiatric disorders such as depression and anxiety, treating or preventing neurodegenerative diseases such as schizophrenia, Alzheimer's disease, Parkinson's disease, and / or treating age-induced cognitive decline, attention, alertness, and / or mood.

[0016] In a further aspect, the present invention provides a Panax quinquefolius extract for use in regulating or modulating the gut microbiota; increasing the concentration of SCFAs in the gut; increasing the production of SCFAs by the gut microbiota and / or increasing SCFA blood levels.

[0017] In a further aspect, the present invention provides the use of a Panax quinquefolius extract to regulate or modulate the gut microbiota; increase the concentration of SCFAs in the gut; increase the production of SCFAs by the gut microbiota, and / or increase SCFA blood levels.

[0018] In a further aspect, the present invention provides a method for (i) modulating or regulating the gut microbiota; (ii) increasing the concentration of SCFAs in the gut; (iii) increasing the production of SCFAs by the gut microbiota; and / or (iv) increasing SCFA blood concentrations, comprising administering an effective amount of a Panax quinquefolius extract to a subject in need thereof.

[0019] In a further aspect, the present invention provides a method for improving or increasing cognition / working memory, treating, reducing, preventing, and / or ameliorating fatigue; improving or increasing attention / alertness, and / or improving or increasing self-confidence, comprising administering an effective amount of a Panax quinquefolius extract to a subject in need thereof, to (i) regulate or modulate the gut microbiota; (ii) increase the concentration of SCFAs in the gut; (iii) increase the production of SCFAs by the gut microbiota; and / or (iv) increase SCFA blood concentrations.

[0020] In a further aspect, the present invention provides a method for (i) regulating or modulating the gut microbiota; (ii) increasing the concentration of intestinal SCFAs; (iii) increasing the production of SCFAs by the gut microbiota; and / or (iv) appropriately increasing SCFA blood concentrations, comprising administering to a subject in need thereof an effective amount of a Panax quinquefolius extract for regulating satiety, reversing obesity-related and / or metabolic syndrome-related gut microbiota dysbiosis, treating or preventing gut microbiota dysbiosis induced cardiovascular and / or cardiometabolic disease; treating or preventing low-grade inflammation, treating or preventing obesity, treating or preventing sleep disorders such as insomnia, treating or preventing neuropsychiatric disorders such as depression and anxiety, treating or preventing neurodegenerative diseases such as schizophrenia, Alzheimer's disease, Parkinson's disease, and / or treating or preventing age-induced cognitive decline, attention, alertness, and / or mood.

[0021] The details, examples, and preferences provided in connection with any one or more of the specified aspects of the invention are described further herein and apply equally to all aspects of the invention. Any combination of the embodiments, examples, and preferences described herein below, in all possible variations thereof, is encompassed by the present invention unless otherwise indicated herein or clearly contradicted by context.

[0022] Detailed Description of the Invention As asserted, it is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not limiting of aspects. As used herein, the use of the singular includes the plural unless specifically stated otherwise. As used herein, the use of "or" means "and / or" unless stated otherwise. Furthermore, the use of the term "including" as well as other forms such as "includes," "included," etc., is not limiting.

[0023] The section headings used herein are for organizational purposes only and should not be construed as limiting the described subject matter. All documents, or portions of documents, cited in this application, including, but not limited to, patents, patent applications, articles, books, etc., are hereby expressly incorporated by reference in their entirety, as well as for the portions of the documents discussed herein. Compositions containing ginsenosides In accordance with the present invention, a composition comprising ginsenoside is provided, which may hereinafter be referred to as the "first composition of the present invention." Ginsenosides are saponins, which are the main pharmacologically active constituents of the plant genus Panax.

[0024] More than 40 structurally divergent ginsenosides have been isolated and identified from the roots of the Panax genus and are described, for example, in the publication of Razgonova et al., which is incorporated herein by reference. (Razgonova, MP, et al. (2019). Molecular Medicine Reports, 19(4), 2975-2998.) Ginsenosides are divided into three groups based on their chemical structure: protopanaxadiols (PD), including Rb1, Rb2, Rb3, Rc, etc.; protopanaxatriols (PT), including Re, Rf, Rg1, Rg2, and Rh1; and the oleanolic acid group (e.g., Ro) (Qi, LW, Wang, CZ, & Yuan, CS (2011). Isolation and analysis of ginseng: advances and challenges. Natural Product Reports, 28(3), 467-495).

[0025] As used herein, the term "ginsenosides," or "ginsenoside(s)," may refer to any one of over 40 widely described ginsenosides isolated and purified from the roots of the Panax genus (Panax ginseng, Panax notoginseng, and / or Panax quinquefolius), such as Rb1, Rb2, Rb3, Rc, Re, Rf, Rg1, Rg2, Rhl, Ro, etc. It can be only one particular ginsenoside (i.e., for example, greater than 99.9% Rb1), or a mixture of two or more of said ginsenosides (Rb1 and Rb2, etc.).

[0026] Typically, the ginsenoside(s) may be obtained using the processes described herein from any natural source containing ginsenosides, for example from the Panax genus, specifically Panax ginseng (or Korean ginseng, or KG), Panax notoginseng (or South Chinese ginseng, or CHG), and / or Panax quinquefolius (American ginseng, or AG). In a preferred embodiment, ginsenosides are extracted from Panax quinquefolius.

[0027] The ginsenoside-containing composition (or first composition of the present invention) may be obtained directly from the crushed roots of Panax ginseng, Panax notoginseng, and / or Panax quinquefolius.

[0028] The method for preparing a composition containing ginsenosides (or the first composition of the present invention) may be an extraction method using various suitable solvents to extract the ginsenosides from natural sources containing ginsenosides, such as Panax ginseng, Panax notoginseng, and / or Panax quinquefolius.

[0029] In a preferred embodiment, the ginsenosides of the first composition of the present invention may be isolated from ginsenoside containing natural sources (such as the root of American ginseng, especially AG) using a separation technique that can be selected for the required extract, which may be determined by one skilled in the art.

[0030] Typically, the ginsenosides of the first composition of the present invention may be obtained by the extraction and isolation processes generally described herein, or routine modifications thereof.

[0031] For example, a process for the isolation and extraction of ginsenosides included in the compositions of the present invention may comprise (or consist essentially of / consist of) the following steps:

[0032] (i) extraction of natural sources containing ginsenosides, such as Panax ginseng, Panax notoginseng, and / or Panax quinquefolius roots (which may be ground), with a suitable solvent; (ii) evaporation of the solvent; and, if required, (iii) Purification of ginsenosides (e.g., by chromatography).

[0033] Typically, Panax ginseng, Panax notoginseng, and / or Panax quinquefolius roots are ground into granules with particle sizes ranging from about 0.1 mm to about 30 mm to increase the surface area contacted by the solvent and increase extraction efficiency. Specific solvents that may be used in the extraction process include alcohols (e.g., methanol) and alcohol / water mixtures (e.g., a mixture of methanol and water). For example, the extraction solvent can be water, a water-alcohol mixture (e.g., about 1% to about 99% alcohol in water, e.g., about 30% to about 75% alcohol in water, or about 30% to about 50% alcohol in water, about 35% to about 40% alcohol in water, etc.), or alcohol. Particular alcohols that may be mentioned include ethanol (EtOH) and methanol (MeOH).

[0034] In particular embodiments, the extraction solvent may be an ethanol-water mixture, such as about 30% to about 90% ethanol in water, or about 30% to about 50% ethanol in water. For example, about 35% or about 40% ethanol in water. In a preferred embodiment, the extraction solvent is an ethanol-water mixture with about 80% ethanol and about 20% water.

[0035] In one aspect, the temperature of extraction ranges from about 20° C. to about 100° C. In certain embodiments, the temperature for extraction ranges from about 50° C. to about 70° C. Typically, the ratio of plant material to mixed solvent used in the extraction process varies on a gram to milliliter basis from about 1:1 to about 1:10, from about 1:3 to about 1:8, etc. The incubation period (i.e., the period during which the plant material is in contact with the solvent) is typically from about 2 hours to about 24 hours.

[0036] After the plant material and solvent have been incubated, the solvent is separated from the remaining plant material and the extraction composition is concentrated (i.e., the solvent is removed) until the extraction composition has a solid component.

[0037] Typically, the solid component may contain (or consist essentially of / consist of) about 1% to about 35% ginsenosides and other components, and may also present terpenes, phenolic compounds, amino acids, flavonoids, volatile oils, vitamins, minerals, etc. This natural extract containing ginsenosides and other natural components can be used for the formulation of the compositions of the present invention. However, after completion of the extraction process, the ginsenoside(s) can themselves be isolated (i.e., purified) from the extract using a suitable purification process, such as a chromatographic process. For example, purified ginsenosides may be obtained using the following process:

[0038] A natural source containing ginsenosides (i.e., obtained by preparing ground roots), such as Panax ginseng, Panax notoginseng, and / or Panax quinquefolius powder, is dissolved in alcohol, and the ginsenosides are extracted from the powder by the alcohol.

[0039] The alcohol is then evaporated and the remaining residue containing the ginsenoside(s) is loaded onto a chromatography column filled with reversed-phase C-18 resin;

[0040] - Several fractions containing various compounds are eluted with a series of water and 10% MeOH / 90% water and MeOH systems, the fractions are compared by high performance liquid chromatography (HPLC), and those eluates with similar HPLC patterns are combined; - The combined fractions are separated on a normal phase silica gel column chromatography and eluted with chloroform (CHCl3) CHCl;

[0041] -Methanol mixtures starting from 90%, 80% CHCl3 up to 100% MeOH give several subfractions. The subfractions are compared by HPLC and the fractions containing ginsenoside(s) are combined respectively.

[0042] The combined fractions are further purified by a combination of column chromatography on C-18, MCIGELCHP-20P, and / or Sephadex LH-20 resins to provide pure ginsenoside(s). As used herein, the terms "isolated" and "purified" refer to an extract or ginsenoside(s) that has been separated from at least one other component (e.g., polypeptide or cellulose derivative) that is present with the extract or ginsenoside(s) in the natural source. In one embodiment, the extract or ginsenoside(s) is provided in pure form or in the presence of solvents, buffers, ions, or other components that would normally be present in the same solution. In preferred embodiments, the purified ginsenoside is greater than 60%, 70%, 80%, or 99% pure.

[0043] Additionally, fermentation processes can be used as described in Kazuyoshi Kitaoka et al. (Sleep. 2009 Mar. 1; 32(3): 413-421). A culture medium containing an Ag mixture and fermenting organisms is prepared. In a preferred embodiment, the fermenting microorganism is a confirmed probiotic. In a preferred embodiment, the fermenting microorganism is L. paracasei A221, a homofermentative lactic acid bacterium isolated from traditional fermented foods. Its 16S rRNA sequence was deposited in the GenBank database under accession number AB126872. Lactobacillus bacteria are used as starters for fermented foods, including yogurt and cheese. Their safety as probiotics has traditionally been established. L. paracasei A221 hydrolyzed plant glycosides, including ginsenosides, glycyrrhizin (Glycyrrhizae Radix), and soybean isoflavone glycosides (Glycine max). Regarding ginsenosides, L. paracasei A221 hydrolyzed ginsenosides Rb1, Rb2, Rc, and Rd (protopanaxadiol-type), and also ginsenosides Rg1 and Re (protopanaxatriol-type).

[0044] The culture medium typically contains a natural source of ginsenosides (preferably ground root, Panax ginseng, Panax notoginseng, and / or Panax quinquefolius, etc.) and other ingredients necessary for the fermentation microorganism for the fermentation process (i.e., 15% AG, 84%; yeast extract [Asahi Food - Healthcare Co., Ltd, Japan] 6.5%; soybean peptide [Fuji Oil Co., Ltd, Japan] 3% and calcium carbonate 6.5%). Fermentation process conditions (such as temperature, fermentation time, etc.) can be determined by one skilled in the art to obtain concentrations of ginsenosides greater than 3%, greater than 5%, 6%, 7%, 8%, 9%, 10%, 13%, 15%, 18%, 20%, 30%, 40%, 60%, 70%, 80%, 99%. For example, the temperature used can be from 20°C to about 80°C, from 20°C to about 50°C, preferably about 28°C. The fermentation time can be determined by one skilled in the art to obtain a ginsenoside concentration of greater than 3%. The fermentation time can be from about 2 hours to about 10 hours, from about 4 hours to about 20 hours, or from about 1 day to about 10 days.

[0045] After fermentation, the culture medium can be sterilized using methods known in the art (i.e., 121°C for 10 minutes) and spray-dried. The remainder of the yeast cells and other cellular components (such as plant cellulose, etc.) can be removed (i.e., filtration) before or after the sterilization process using separation techniques known in the art. The fermentation culture medium, before or after sterilization, can be processed using the extraction, isolation, and purification methods described herein to obtain extracts of AG with ginsenoside concentrations of greater than 3%, greater than 4%, 5%, 6%, 7%, 8%, 9%, 10%, 13%, 15%, 18%, 20%, 30%, 40%, 60%, 70%, 80%, or greater than 99%.

[0046] The ginsenoside(s) can be of synthetic origin. Alternatively, biotechnology can be used for the biosynthesis of ginsenosides, as reported by Wang, P. et al. (Wang, P. Wei, W., Ye, W. et al. Synthesizing ginsenoside Rh2 in a Saccharomyces cerevisiae cell factory at high efficiency. Cell Discov 5, 5 (2019)). Purification of the resulting ginsenosides can be achieved using the purification techniques already described herein.

[0047] A composition comprising ginsenosides (or the first composition of the present invention) may have a purity (based on total ginsenosides) of about 3% to about 100% by weight, such as from 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of the total ginsenosides in the composition to about 95%, 85%, 75%, 70%, 65%, 60%, 55%, 50%, 40%, 35%, 30%, 25%, 20%, 15%, or 10%. In preferred embodiments, the total ginsenosides are from about 9% to about 15% by weight, and in more preferred embodiments, the total ginsenosides are from about 10% to about 13% by weight.

[0048] In some embodiments, the ginsenoside-containing composition (or first composition of the present invention) may comprise (or consist essentially of / consist of) the following compounds (ginsenosides):

[0049] a) Rg1: from about 0.5% to about 8% of total ginsenosides by weight, such as from about 1% to about 4% of total ginsenosides by weight, preferably from about 2% to about 4% of total ginsenosides by weight

[0050] b) Re: from about 4% to about 50% by weight of total ginsenosides, such as from about 4% to about 35% by weight of total ginsenosides, preferably from about 10% to about 20% by weight of total ginsenosides, etc.

[0051] c) Rb1: from about 10% to about 100% by weight of total ginsenosides, such as from about 30% to about 80% by weight of total ginsenosides, preferably from about 40% to about 70% by weight of total ginsenosides,

[0052] d) Rc: from about 0.5% to about 40% by weight of total ginsenosides, such as from about 5% to about 35% by weight of total ginsenosides, preferably from about 10% to about 20% by weight of total ginsenosides

[0053] e) Rb2: from about 0.5% to about 20% by weight of total ginsenosides, such as from about 2% to about 15% by weight of total ginsenosides, preferably from about 2% to about 8% by weight of total ginsenosides; and / or

[0054] f) Rd: from about 5% to about 50% of total ginsenosides by weight, such as from about 9% to about 30% of total ginsenosides by weight, preferably from about 10% to about 20% of total ginsenosides by weight.

[0055] In a preferred embodiment, the composition containing ginsenosides (or the first composition of the present invention) comprises: Rg1 at about 3% to 4% by weight of total ginsenosides, preferably 3.6% by weight of total ginsenosides; Re at 12% to 17% by weight of total ginsenosides, preferably 16% by weight of total ginsenosides;

[0056] Rb1 of 40% to 50% by weight of total ginsenosides, preferably 48% by weight of total ginsenosides; Rc of 12% to 17% by weight of total ginsenosides, preferably 16% by weight of total ginsenosides; Rb2 of 2% to 5% by weight of total ginsenosides, preferably 4% by weight of total ginsenosides; and / or Rd of 12% to 15% by weight of total ginsenosides, preferably 14% by weight of total ginsenosides.

[0057] As mentioned above, ginsenosides can be of natural origin and chemically synthesized ginsenosides. In a preferred embodiment, the source of ginsenosides is natural, and in a more preferred embodiment, ginsenosides are extracted from Panax genus members, preferably from roots, such as Panax ginseng, Panax notoginseng and / or Panax quinquefolius. For the avoidance of doubt, ginsenosides can be obtained not only from Panax quinquefolius, Panax ginseng, or Panax notoginseng, but also from any ratio of two of them (i.e., Panax ginseng and Panax notoginseng, Panax notoginseng and Panax quinquefolius), or from three of them: Panax ginseng, Panax notoginseng, and Panax quinquefolius.

[0058] For the avoidance of doubt, the ginsenoside may be only one type of ginsenoside or a mixture of two or more of the various ginsenosides reported in the literature, such as Rb1, Rb2, Rb3, Rc, Re, Rf, Rg1, Rg2, Rhl, Ro, etc. For the avoidance of doubt, any choice, option, special feature, or the like indicated for a given aspect, feature, or parameter of the invention shall be deemed to be disclosed in combination with any and all other choices, options, special features, or the like, as indicated for the same or other aspects, features, and parameters of the invention, unless the context indicates otherwise.

[0059] When the terms "comprising" or "comprises" are used, it means that the extract or composition described must contain the listed ingredient(s), but may optionally contain additional ingredients. When the terms "consisting essentially of" or "consists essentially of" are used, the extract or composition described must contain the listed ingredient(s) and may contain small amounts (e.g., up to 5% by weight, or up to 1% or 0.1% by weight) of other ingredients, provided that any additional ingredients do not affect the essential properties of the extract or composition. When the terms "consisting of" or "consists of" are used, it means that the extract or composition described must contain only the listed ingredient(s). As used herein, the term "about," when referring to a measurable value (such as the amount or weight of a particular component in a reaction mixture), for example, refers to a variation of ±20%, ±10%, ±5%, ±1%, ±0.5%, or, especially, ±0.1% of the specified amount.

[0060] Additionally, other compounds may be present in the extracts of the present invention, including, but not limited to, terpenes, phenolic compounds, amino acids, flavonoids, volatile oils, vitamins, and minerals.

[0061] Such compositions described herein may contain one or more additional ingredients selected from the group consisting of food ingredients, such as sweeteners, flavoring agents, coloring agents, preservatives, and the like.

[0062] Those skilled in the art will appreciate that the extracts of the present invention may be provided in solid or liquid form. By solid form, it is included that the compound may be provided as an amorphous solid, or as a crystalline or partially crystalline solid. Extract of Panax quinquefolius and process for obtaining the extract

[0063] In accordance with the present invention, there is provided a Panax quinquefolius (American ginseng) (AG) extract (particularly a Panax quinquefolius leaf-stem or root extract), which may hereinafter be referred to as the "extract of the present invention."

[0064] Typically, the extract of the present invention may be an extract obtained from American ginseng (particularly the root of AG) using the process described herein. For the avoidance of doubt, all references herein to Panax quinquefolius (AG) extract will refer to extracts obtained from, inter alia, the leaf-stem or root (more particularly, the root) extract of AG. The extract of the present invention may also be the crushed root of American ginseng, which contains between about 3 and 15% of ginsenosides.

[0065] Other methods for preparing the extract of the present invention may include aqueous, alcoholic, or hydroalcoholic extraction. Preferably, the extract of the present invention is a hydroalcoholic extract, such as a hydromethanolic or hydroethanolic extract. For example, the extract of the present invention may be a hydroethanolic extract obtained using an extraction solvent containing about 1% to about 99% ethanol in water, such as about 30% to about 75% ethanol in water, or about 30% to about 50% ethanol in water, such as about 35% or about 40% ethanol in water.

[0066] As used herein, the term "water extract" refers to an extract obtained from Panax quinquefolius (AG) when extraction from the plant (especially the root) is carried out using water as the only solvent.

[0067] As used herein, the term "alcoholic extract" refers to an extract obtained from Panax quinquefolius (AG) when the plant (especially the root) is extracted using alcohol as the only solvent. For example, 100% methanol and / or 100% ethanol. As used herein, the term "hydroalcoholic extract" refers to an extract obtained from Panax quinquefolius (AG) when the plant is extracted using a mixture of water and alcohol. For example, from about 1% to about 99% alcohol (e.g., ethanol) in water, such an extract is called a hydroethanol extract.

[0068] The extracts of the present invention may be isolated from American ginseng (particularly the root of AG) using separation techniques to select the desired extract, which may be determined by one skilled in the art. Typically, the extracts of the present invention may be obtained by the extraction and isolation processes generally described herein, or routine modifications thereof. For example, a process for the extraction and isolation of the extract of the present invention may comprise (consist essentially of / consist of) the following steps: (i) extraction of AG roots (which may be ground) with a suitable solvent; (ii) evaporation of the solvent; and, if required, (iii) Purification of the extract (e.g., by chromatography).

[0069] Typically, AG roots are ground into granules with particle sizes ranging from about 0.1 mm to about 30 mm to increase the surface area that the solvent comes into contact with and increase extraction efficiency.

[0070] Particular solvents that may be used in the extraction process include alcohols (such as methanol) and alcohol / water mixtures (such as a mixture of methanol and water). For example, the extraction solvent can be water, a water-alcohol mixture (from about 1% to about 99% alcohol in water, e.g., from about 30% to about 75% alcohol in water, or from about 30% to about 50% alcohol in water, from about 35% to about 40% alcohol in water, etc.), or alcohol. Particular alcohols that may be mentioned include ethanol (EtOH) and methanol (MeOH).

[0071] In particular embodiments, the extraction solvent may be an ethanol-water mixture, such as about 30% to about 90% ethanol in water, or about 30% to about 50% ethanol in water. For example, about 35% or about 40% ethanol in water. In a preferred embodiment, the extraction solvent is an ethanol-water mixture with about 80% ethanol and about 20% water.

[0072] In one aspect, the temperature of extraction ranges from about 20° C. to about 100° C. In certain embodiments, the temperature for extraction ranges from about 50° C. to about 70° C. Typically, the ratio of plant material to mixed solvent used in the extraction process varies on a gram to milliliter basis from about 1:1 to about 1:10, from about 1:3 to about 1:8, etc. The incubation period (i.e., the period during which the plant material is in contact with the solvent) is typically from about 2 hours to about 24 hours.

[0073] After the plant material and solvent have been incubated, the solvent is separated from the remaining plant material, and the extract composition is concentrated (i.e., the solvent is removed) until the extract composition comprises a solid component. Typically, the solid component may comprise (or consist essentially of) about 1% to about 35% of AG ginsenoside. Other components include terpenes, phenolic compounds, amino acids, flavonoids, volatile oils, vitamins, and minerals.

[0074] After completion of the extraction process, the ginsenoside(s) can themselves be isolated (ie, purified) from the AG extract using chromatographic processes, if desired.

[0075] Typically, the extract of the present invention may be obtained using the following process: The -AG extract powder (i.e., obtained by preparing ground roots) is dissolved in alcohol and the ginsenoside(s) are extracted with alcohol from the powder.

[0076] The alcohol is then evaporated and the remaining residue containing the ginsenoside(s) is loaded onto a chromatography column filled with reversed-phase C-18 resin; -Several fractions containing various compounds are eluted with a series of water and 10% MeOH / 90% water and MeOH systems. Fractions are compared by high performance liquid chromatography (HPLC) analysis, and those eluates with similar HPLC patterns are combined; The combined fractions are separated on a normal-phase silica gel column chromatography, eluting with CHCl3, 90%, 80% CHCl3, and CHCl-methanol mixtures up to 100% MeOH, to give several subfractions. The subfractions are compared by HPLC, and the fractions containing ginsenoside(s) are combined. The combined fractions are further purified by a combination of column chromatography on C-18, MCIGEL CHP-20P, and / or Sephadex LH-20 resins to provide pure ginsenoside(s).

[0077] As used herein, the terms "isolated" and "purified" refer to an extract or ginsenoside(s) that has been separated from at least one other component (e.g., a polypeptide or cellulose derivative) that is present with the extract or ginsenoside(s) in a natural source. In one embodiment, the extract or ginsenoside(s) is provided in pure form or in the presence of solvents, buffers, ions, or other components that would normally be present in the same solution.

[0078] In addition, a fermentation process can be used as described in Kazuyoshi Kitaoka et al. (Sleep. 2009 Mar. 1; 32(3): 413-421). A culture medium containing an Ag mixture and a fermenting organism is prepared. In a preferred embodiment, the fermenting microorganism is a safety-certified probiotic. In a preferred embodiment, the fermenting microorganism is L. paracasei A221, a homofermentative lactic acid bacterium isolated from traditional fermented foods. Its 16S rRNA sequence was deposited in the GenBank database under accession number AB126872. Lactobacillus bacteria are used as starters for fermented foods, including yogurt and cheese. Their safety as probiotics has traditionally been established.

[0079] L. paracasei A221 hydrolyzed plant glycosides, including ginsenosides, glycyrrhizin (Glycyrrhizae Radix), and soybean isoflavone glycosides (Glycine max). Regarding ginsenosides, L. paracasei A221 also hydrolyzed ginsenosides Rb1, Rb2, Rc, and Rd (protopanaxadiol-type), and ginsenosides Rg1 and Re (protopanaxatriol-type).

[0080] The culture medium typically contains AG (ground AG is preferred) and other components required by the fermenting microorganism for the fermentation process (i.e., 15% AG, 84%; yeast extract [[Asahi Food - Healthcare Co., Ltd, Japan] 6.5%; soybean peptide [Fuji Oil Co., Ltd, Japan] 3%; and calcium carbonate 6.5%). Fermentation process conditions (such as temperature, fermentation time, etc.) can be determined by those skilled in the art to obtain a ginsenoside concentration of more than 3%, more than 5%, 6%, 7%, 8%, 9%, 10%, 13%, 15%, 18%, 20%, 30%, 40%, 60%, 70%, 80%, or 99%. For example, the temperature used can be from 20°C to about 80°C, from 20°C to about 50°C, preferably about 28°C. The fermentation time can be determined by those skilled in the art to obtain a ginsenoside concentration of more than 3%. The fermentation time can be from about 2 h to about 10 h, from about 4 h to about 20 h, from about 1 day to about 10 days.

[0081] After fermentation, the culture medium can be sterilized using methods known in the art (i.e., 121°C for 10 minutes) and spray-dried. The remainder of the yeast cells and other cellular components (such as plant cellulose, etc.) can be removed (i.e., filtration) before or after the sterilization process using separation techniques known in the art. The fermentation culture medium, before or after sterilization, can be processed using the extraction, isolation, and purification methods described herein to obtain extracts of AG with ginsenoside concentrations of greater than 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 13%, 15%, 18%, 20%, 30%, 40%, 60%, 70%, greater than 80%, or greater than 99%.

[0082] Thus, the terms "isolated" and "purified" do not refer to extracts or ginsenosides present in natural sources. Similarly, the term extract refers to components of natural materials obtained through the process of extraction, rather than those components present in their natural source (e.g., AG root). In particular embodiments, the extract of the present invention obtained from such a method may be: Substantially free of other plant material (e.g., no plant cellulose); Substantially free of plant cells; and / or Substantially free of plant cell material, It is substantially free of toxic ingredients such as quintozene, aflatoxin, ochratoxin A, cadmium, arsenic, or mercury.

[0083] As used herein, reference to a material that is "substantially free" of another material may refer to a material that consists of less than 1% by weight of that other material (e.g., less than 0.1%, such as less than 0.01% or less than 0.001% by weight).

[0084] In an alternative embodiment, the method of extracting and isolating an AG extract from AG roots may be described as comprising (or consisting essentially of / consisting of) the following steps: (a) Grinding the roots of AG into particles; (optionally carrying out a fermentation process as described above) (b) containing the particles in a mixed solvent; (c) separating the ground particles from the solvent mixture; and (d) Evaporating the mixed solvent. Further in such embodiments, the process may comprise (or consist essentially of / consist of) the following steps: (e) dissolving the product of (d) in alcohol; and (f) Evaporating the alcohol.

[0085] Typically, in extracting an AG extract from AG roots (i.e., steps (a) to (d) as described herein above): the ground particles have a diameter of about 0.1 mm to 30 mm; and / or the temperature is from about 20°C to about 100°C; and / or the ratio of ground particles to mixed solvent is from about 1 g to 1 ml to about 1 g to 8 ml; and / or the ground particles are contacted with the mixed solvent for about 2 hours to about 24 hours; and / or the mixed solvent is water, a water-alcohol mixture, or an alcohol.

[0086] In a particular embodiment, the extract of the present invention as described herein may be an extract obtained from (or obtained by) a process as described herein.

[0087] Those skilled in the art will understand how to make American ginseng extracts using various extraction techniques (other powders, extracts, and modified products) to obtain American ginseng containing ginsenosides.

[0088] Ginsenosides can be classified into three groups based on their chemical structure: the panaxadiol group (Rb1, Rb2, Rb3, Rc, etc.), the panaxatriol group (Re, Rf, Rg1, Rg2, Rh1), and the oleanolic acid group (e.g., Ro). American ginseng (Panax quinquefolius) has its own distinctive profile, exhibiting high expression of ginsenoside Rb1.

[0089] The Panax quinquefolius extracts of the present invention may have a purity (based on total ginsenosides) of about 3% to about 100% by weight, such as from 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of the total ginsenosides in the extract to about 95%, 85%, 75%, 70%, 65%, 60%, 55%, 50%, 40%, 35%, 30%, 25%, 20%, 15%, or 10%. In preferred embodiments, the total ginsenosides are from about 9% to about 15% by weight, and in more preferred embodiments, the total ginsenosides are from about 10% to about 13% by weight. In certain embodiments, the extracts of the invention may comprise (or consist essentially of / consist of) the following compounds (ginsenosides): a) from about 0.05% to about 0.8% by weight of Rg1, such as from about 0.1% to about 0.4% by weight, preferably from about 0.3% to about 0.5% by weight b) from about 0.3% to about 5% by weight, such as from about 1% to about 3.5% by weight, preferably from about 0.4% to about 3.5% by weight, of Re c) from about 1% to about 10% by weight of Rb1, such as from about 3% to about 8% by weight, preferably from about 4% to about 7% by weight d) Rc from about 0.05% to about 5% by weight, such as from about 0.3% to about 4% by weight, preferably from about 0.5% to about 3.5% by weight e) from about 0.05 to about 3% by weight of Rb2, such as from about 0.1 to about 2% by weight, preferably from about 0.2% to about 1.5% by weight, and / or f) Rd from about 0.5% to about 5% by weight, such as from about 0.7% to about 4% by weight, preferably from about 0.9% to about 3% by weight.

[0090] In a preferred embodiment, the AG extract contains about 10% to 13% ginsenosides by weight, preferably about 10%, and includes the following ginsenosides: about 0.1% to about 0.4%, preferably about 0.36%, Re about 0.4% to 3.5%, preferably about 1.6% Rg1, about 4% to about 7%, preferably about 4.8% Rb1, about 0.5% to about 3.5%, preferably about 1.6% Rc, about 0.2% to about 1.5%, preferably about 0.4% Rb2, and / or about 0.9% to about 3%, preferably about 1.4% Rd. Unless otherwise stated herein, the weight percentages listed are based on the total weight of the (dry) extract obtained.

[0091] In certain embodiments, the extracts of the invention may comprise (or consist essentially of / consist of) the following compounds (ginsenosides): a) Rg1: from about 0.5% to about 8% of total ginsenosides by weight, such as from about 1% to about 4% of total ginsenosides by weight, preferably from about 2% to about 4% of total ginsenosides by weight

[0092] b) Re: from about 4% to about 50% by weight of total ginsenosides, such as from about 4% to about 35% by weight of total ginsenosides, preferably from about 10% to about 20% by weight of total ginsenosides, etc.

[0093] c) Rb1: from about 10% to about 100% by weight of total ginsenosides, such as from about 30% to about 80% by weight of total ginsenosides, preferably from about 40% to about 70% by weight of total ginsenosides,

[0094] d) Rc: from about 0.5% to about 40% by weight of total ginsenosides, such as from about 5% to about 35% by weight of total ginsenosides, preferably from about 10% to about 20% by weight of total ginsenosides

[0095] e) Rb2: from about 0.5% to about 20% of total ginsenosides by weight, such as from about 2 to about 15% of total ginsenosides by weight, preferably from about 2% to about 8% of total ginsenosides by weight; and / or

[0096] f) Rd: from about 5% to about 50% of total ginsenosides by weight, such as from about 9% to about 30% of total ginsenosides by weight, preferably from about 10% to about 20% of total ginsenosides by weight.

[0097] In a preferred embodiment, the AG extract comprises: Rg1 at about 3% to 4% by weight of total ginsenosides, preferably 3.6% by weight of total ginsenosides; Re at 12% to 17% by weight of total ginsenosides, preferably 16% by weight;

[0098] Rb1 of 40% to 50% by weight of total ginsenosides, preferably 48% by weight; Rc of 12% to 17% by weight of total ginsenosides, preferably 16% by weight; Rb2 of 2% to 5% by weight of total ginsenosides, preferably 4% by weight; and / or Rd of 12% to 15% by weight of total ginsenosides, preferably 14% by weight of total ginsenosides.

[0099] For the avoidance of doubt, any selection, option, special feature, or the like indicated for a given aspect, feature, or parameter of the invention should be deemed to be disclosed in combination with any and all other selections, options, special features, or the like, as indicated for the same or other aspects, features, and parameters of the invention, unless the context dictates otherwise.

[0100] Additionally, other compounds may be present in the extracts of the present invention, including, but not limited to, terpenes, phenolic compounds, amino acids, flavonoids, volatile oils, vitamins, and minerals.

[0101] Those skilled in the art will appreciate that the extracts of the present invention may be provided in solid or liquid form. By solid form, it is included that the compound may be provided as an amorphous solid, or as a crystalline or partially crystalline solid.

[0102] Pharmaceutical and Food Compositions and Administration According to the present invention, the ginsenoside-containing composition (or the composition of the present invention) or the extract of the present invention (extract from Panax quinquefolius) may be provided in the form of a (suitable) composition, such as a "pharmaceutical composition" or a "food composition". In particular embodiments, the ginsenoside-containing composition (or the composition of the present invention) or the extract of the present invention (extract from Panax quinquefolius) may be provided in the form of a pharmaceutical composition (which may also be referred to as a pharmaceutical formulation or a veterinary composition), a dietary supplement composition or a functional food composition comprising the extract of the present invention, and optionally a pharmaceutically acceptable additive or acceptable ingredient of a (functional) food, as appropriate.

[0103] As used herein, "nutraceutical composition" refers to a dietary supplement composition, a functional food composition, a meal or food for humans or animals (such as a functional food composition, i.e., a food, beverage, feed, or pet food, or a supplement to a food, beverage, feed, or pet food) or nutritional agent. The functional food composition can be presented as a beverage, dairy product, bakery product, etc.

[0104] As used herein, reference to a pharmaceutically (or veterinarily) acceptable excipient may refer to a pharmaceutically (or veterinarily) acceptable adjuvant, diluent, and / or carrier known to those skilled in the art.

[0105] Food-acceptable ingredients include those known in the art (including those referred to herein as pharmaceutically acceptable additives), and can be natural or non-natural, i.e., their structure may or may not occur in nature. In some instances, they can originate from naturally occurring compounds that are subsequently modified (e.g., maltodextrin).

[0106] In particular embodiments, the composition containing ginsenosides (or the composition of the present invention) or the extract of the present invention (extract from Panax quinquefolius) may be provided in the form of a pharmaceutical composition or a functional food composition, and further comprises a non-natural carrier or a modified natural carrier, such as maltodextrin or gum arabic. In a preferred embodiment, the extract of the present invention is formulated with maltodextrin, and in another preferred embodiment, the extract of the present invention is formulated with gum arabic.

[0107] By "pharmaceutically acceptable" (or veterinarily acceptable) is meant that the additional components of the composition are sterile and pyrogen-free. Such components must be "acceptable" in the sense of being compatible with the extract of the present invention and not harmful to their recipient. Thus, "pharmaceutically acceptable" includes any compound used in forming part of a formulation that is intended merely to act as an additive, i.e., not to have biological activity itself. Thus, a pharmaceutically acceptable additive is generally safe, non-toxic, and not biologically or otherwise undesirable. Those skilled in the art will understand that the extract of the present invention (e.g., in the form of a composition such as those described herein, e.g., a pharmaceutical composition known to those skilled in the art) can be administered to a patient or subject (e.g., a human or animal patient or subject) by any suitable route, such as oral, rectal, nasal, pulmonary, buccal, sublingual, transdermal, intracisternal, intraperitoneal, and parenteral (including subcutaneous, intramuscular, intramedullary, intravenous, and intradermal) routes. In particular, the extract of the present invention may be administered orally. In such an instance, the pharmaceutical composition according to the present invention may be specifically formulated for administration by the oral route.

[0108] Pharmaceutical (or veterinary) compositions for oral administration include solid dosage forms such as hard or soft capsules, tablets, troches, dragees, pills, lozenges, powders, and granules. If desired, they can be prepared with coatings, such as enteric coatings, or they can be formulated to provide controlled release, such as sustained or extended release of the active ingredient, according to methods well known in the art. Liquid dosage forms for oral administration include solutions, emulsions, aqueous or oily suspensions, syrups, and elixirs.

[0109] Compositions described herein, such as those intended for oral administration (e.g., pharmaceutical or food compositions), may be prepared by bringing the components of the composition into admixture according to methods known to those skilled in the art.

[0110] Such compositions described herein may contain one or more additional ingredients selected from the group consisting of food ingredients, such as sweeteners, flavoring agents, coloring agents, and preservatives. Tablets may contain the active ingredient mixed with non-toxic pharmaceutically acceptable additives (or ingredients) that are suitable for tablet manufacture. These additives (or ingredients) may be, for example: inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch, maltodextrin, or alginic acid; binders such as starch, gelatin, or acacia; and lubricating agents such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time-delay material, such as glyceryl monostearate or glyceryl distearate, may be used.

[0111] Suitable pharmaceutical (or veterinary) carriers include inert solid diluents or fillers, sterile aqueous solutions, and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, maltodextrin, talc, gelatin, silica, agar, pectin, acacia, magnesium stearate, stearic acid, gum arabic, modified starch, and lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene, and water. In addition, carriers or diluents may include any sustained-release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with wax.

[0112] The extract of the present invention may be administered in varying doses (i.e., therapeutically effective doses when administered to a patient in need thereof) to be treated depending on the disorder and the patient, as well as the route of administration. In this regard, those skilled in the art will recognize that the dose administered to a mammal, particularly a human, in the context of the present invention must be sufficient to affect the therapeutic response of the mammal over a reasonable time frame. Those skilled in the art will recognize that the selection of the exact dose and composition, and the most appropriate delivery regimen, will also be influenced by, among other things, the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical condition and intelligence of the recipient, as well as the capacity, age, condition, weight, sex, and response of the patient being treated with the specific compound, and the stage / severity of the disease.

[0113] Typically, in the uses or methods of the invention described herein, the composition containing ginsenoside (or composition of the invention), the extract of the invention (extract from Panax quinquefolius), or the pharmaceutical or food composition described herein is administered in an amount of from about 100 mg / day to about 200 mg / day, or from about 500 mg / day to about 1500 mg / day, or about 1000 mg / day.

[0114] In a preferred embodiment, the amount is about 100 mg / day to about 400 mg / day, more preferably about 150 mg / day to about 250 mg / day, more preferably 200 mg / day. In any case, a practitioner or other skilled artisan will be able to routinely determine the actual dosage, which will be most suitable for each individual patient. The above dosages are exemplary of the average case; of course, there may be individual instances where higher or lower dosage ranges are merited, which are within the scope of the present invention.

[0115] When included in a composition described herein (e.g., a pharmaceutical composition), the ginsenoside-containing composition (or composition of the present invention), the extract of the present invention (extract from Panax quinquefolius) is typically present in an amount of from about 1% to about 100% by weight, e.g., from about 10% to about 90% by weight, or from about 20% to about 80% by weight, or from about 30% to about 70% by weight, or from about 40% to about 60% by weight.

[0116] Uses and Methods of the Invention As described herein, the first composition of the present invention (a composition containing ginsenosides) or the extract of the present invention (AG extract), as well as the "pharmaceutical composition" or "food composition" described herein, may have particular biological effects, which may be useful in the treatment of pathological conditions.

[0117] The first composition of the present invention (composition containing ginsenoside) or the extract of the present invention (AG extract), as well as the "pharmaceutical composition," "nutraceutical composition," or "food composition" described herein, may have the effect of increasing SCFAs (as shown in Figures 12 to 14) and the effect of increasing certain taxa of the gut microbiota (as shown in Figures 15 and 16).

[0118] Thus, in a first aspect, the present invention provides a composition comprising ginsenoside (first composition of the present invention), or a pharmaceutical or food composition comprising said first composition of the present invention, for use in regulating or modulating the intestinal microbiota; increasing the concentration of SCFAs in the intestine; increasing the production of SCFAs by the intestinal microbiota, and / or increasing SCFA blood concentrations.

[0119] In one aspect, there is provided use of a composition comprising ginsenoside (first composition of the present invention), or a pharmaceutical or food composition comprising said first composition of the present invention, for regulating or modulating the intestinal microbiota; increasing the concentration of SCFAs in the intestine; increasing the production of SCFAs by the intestinal microbiota, and / or increasing SCFA blood concentrations.

[0120] In one aspect, a method is provided which comprises administering to a subject in need thereof an effective amount of a composition comprising ginsenoside (first composition of the present invention) or a pharmaceutical or food composition comprising said first composition of the present invention, to (i) regulate or modulate the gut microbiota; (ii) increase the concentration of SCFAs in the gut; (iii) increase the production of SCFAs by the gut microbiota; and / or (iv) increase SCFA blood concentrations.

[0121] In one aspect of the invention, there is provided a Panax quinquefolius extract (i.e., an extract of the present invention), or a composition comprising a Panax quinquefolius extract (i.e., a pharmaceutical, dietary supplement, or food composition) for use in regulating or modulating the gut microbiota, increasing the concentration of SCFAs in the gut, increasing the production of SCFAs by the gut microbiota, and / or increasing SCFA blood concentrations.

[0122] In an alternative aspect of the invention, there is provided the use of a Panax quinquefolius extract (i.e., the extract of the present invention), or a composition comprising a Panax quinquefolius extract (i.e., a pharmaceutical, dietary supplement, or food composition), in the manufacture of a medicament for regulating or modulating the gut microbiota, increasing the concentration of SCFAs in the gut, increasing the production of SCFAs by the gut microbiota, and / or increasing SCFA blood concentrations.

[0123] In a further alternative aspect of the present invention, there is provided the use of a Panax quinquefolius extract, or a composition (i.e., a pharmaceutical or food composition) comprising a Panax quinquefolius extract, to regulate or modulate the gut microbiota; increase the concentration of SCFAs in the gut, increase the production of SCFAs by the gut microbiota, and / or increase SCFA blood concentrations.

[0124] In a further alternative aspect of the present invention, there is provided a method comprising administering to a subject in need thereof an effective amount of a Panax quinquefolius extract, or a composition (i.e., a pharmaceutical or food composition) comprising a Panax quinquefolius extract, to (i) regulate or modulate the gut microbiota; (ii) increase the concentration of SCFAs in the gut; (iii) increase the production of SCFAs by the gut microbiota; and / or (iv) increase SCFA blood concentrations.

[0125] As described herein, changes in the composition of the gut microbiota, such as alterations in the typical environmental mechanisms of the gut microbiota (dysbiotic gut microbiota), are associated with conditions such as obesity, insulin resistance, impaired glucose tolerance, prediabetes, etc. It has also been reported that changes in the composition of the gut microbiota and SCFAs are associated with conditions such as: sleep disorders such as insomnia, neuropsychiatric disorders such as depression and anxiety, schizophrenia, neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, age-induced cognitive decline, attention and alertness, mood, etc. Therefore, the possibility of restoring an optimal gut microbial system provides a strategy to prevent such conditions. Furthermore, this effect may be useful in promoting the general health of patients who are not suffering from a specific medical disease or disorder.

[0126] Thus, in a further aspect of the present invention, there is provided a composition comprising ginsenoside (first composition of the present invention), or a pharmaceutical, dietary supplement or food composition comprising said first composition of the present invention, or Panax ginsenoside for use in reversing obesity-related and / or metabolic syndrome-related gut microbiota dysbiosis imbalance, treating or preventing gut microbiota dysbiosis imbalance-induced cardiovascular and / or cardiometabolic diseases; treating or preventing low-grade inflammation, treating or preventing obesity, treating or preventing sleep disorders such as insomnia, treating or preventing neuropsychiatric disorders such as depression and anxiety, treating or preventing neurodegenerative diseases such as schizophrenia, Alzheimer's disease, Parkinson's disease, treating or preventing age-induced cognitive decline, attention, alertness and / or mood, treating, reducing, preventing and / or ameliorating fatigue, improving or increasing cognition / working memory, improving or increasing attention / alertness and / or improving or increasing self-confidence. A composition (ie, a pharmaceutical or food composition) comprising a Panax quinquefolius extract (ie, an extract of the present invention) or a Panax quinquefolius extract is provided.

[0127] In an alternative aspect of the present invention, a composition comprising ginsenoside (first composition of the present invention), or a pharmaceutical, dietary supplement, or food composition comprising said first composition of the present invention, in the manufacture of a medicament for use in reversing obesity-related and / or metabolic syndrome-related gut microbiota dysbiosis imbalance, treating or preventing gut microbiota dysbiosis imbalance-induced cardiovascular and / or cardiometabolic disease; treating or preventing low-grade inflammation, treating or preventing obesity, treating or preventing sleep disorders such as insomnia, treating or preventing neuropsychiatric disorders such as depression and anxiety, treating or preventing neurodegenerative diseases such as schizophrenia, Alzheimer's disease, Parkinson's disease, treating or preventing age-induced cognitive decline, attention, alertness, and / or mood, treating, reducing, preventing, and / or ameliorating fatigue, improving or increasing cognition / working memory, improving or increasing attention / alertness, and / or improving or increasing self-confidence, is provided. The use of a Panax quinquefolius extract (ie, the extract of the present invention) or a composition (ie, a pharmaceutical or food composition) comprising a Panax quinquefolius extract is provided.

[0128] In an alternative further aspect of the present invention, a composition comprising ginsenoside (first composition of the present invention), or a pharmaceutical, dietary supplement, or food composition comprising said first composition of the present invention, is provided for reversing obesity-related and / or metabolic syndrome-related gut microbiota dysbiosis imbalance, treating or preventing gut microbiota dysbiosis imbalance-induced cardiovascular and / or cardiometabolic diseases; treating or preventing low-grade inflammation, treating or preventing obesity, treating or preventing sleep disorders such as insomnia, treating or preventing neuropsychiatric disorders such as depression and anxiety, treating or preventing neurodegenerative diseases such as schizophrenia, Alzheimer's disease, Parkinson's disease, treating or preventing age-induced cognitive decline, attention, alertness, and / or mood, treating, reducing, preventing, and / or ameliorating fatigue, improving or increasing cognition / working memory, improving or increasing attention / alertness, and / or improving or increasing self-confidence. Uses of a P. quinquefolius extract (ie, the extract of the present invention) or a composition (ie, a pharmaceutical or food composition) comprising the extract of the present invention are provided.

[0129] Thus, in a further alternative aspect of the present invention, there is provided a composition comprising ginsenoside (first composition of the present invention), or a pharmaceutical or food composition comprising said first composition of the present invention, or Panax ginsenoside, for use in regulating satiety, reversing obesity-related and / or metabolic syndrome-related gut microbiota dysbiosis imbalance, treating or preventing gut microbiota dysbiosis imbalance-induced cardiovascular and / or cardiometabolic diseases; treating or preventing low-grade inflammation, treating or preventing obesity, treating or preventing sleep disorders such as insomnia, treating or preventing neuropsychiatric disorders such as depression and anxiety, treating or preventing neurodegenerative diseases such as schizophrenia, Alzheimer's disease, Parkinson's disease, treating or preventing age-induced cognitive decline, attention, alertness, and / or mood, treating, reducing, preventing and / or ameliorating fatigue, improving or increasing cognition / working memory, improving or increasing attention / alertness, and / or improving or increasing self-confidence. A composition (ie, a pharmaceutical or food composition) comprising an extract of A. quinquefolius (ie, an extract of the present invention) or an extract of the present invention is provided.

[0130] In a further alternative aspect of the present invention, a composition comprising ginsenoside (first composition of the present invention), or a pharmaceutical or food composition comprising said first composition of the present invention, or Panax and / or a pharmaceutical or food composition comprising an extract of A. quinquefolius (i.e., an extract of the present invention) or a composition comprising the extract of the present invention (i.e., a pharmaceutical or food composition) is provided.

[0014] Methods for regulating satiety, reversing obesity-related and / or metabolic syndrome-related gut microbiota dysbiosis, treating or preventing gut microbiota dysbiosis induced cardiovascular and / or cardiometabolic diseases; treating or preventing low-grade inflammation, treating or preventing obesity, treating or preventing sleep disorders such as insomnia, treating or preventing neuropsychiatric disorders such as depression and anxiety, treating or preventing neurodegenerative diseases such as schizophrenia, Alzheimer's disease, Parkinson's disease, treating or preventing age-induced cognitive decline, attention, alertness, and / or mood, treating, reducing, preventing, and / or ameliorating fatigue, improving or increasing cognition / working memory, improving or increasing attention / alertness, and / or improving or increasing self-confidence are provided.

[0131] In a further alternative aspect of the present invention, there is provided the use of a composition comprising a ginsenoside (first composition of the present invention), or a pharmaceutical or food composition comprising said first composition of the present invention, or a Panax quinquefolius extract (i.e., extract of the present invention), or a composition comprising the extract of the present invention (i.e., pharmaceutical or food composition), as a satiety control agent.

[0132] As shown herein, an extract of Panax quinquefolius (i.e., an extract of the present invention) increases the production of the short chain fatty acids (SCFAs) butyrate, acetate, and propionate (Figures 12, 13, and 14).

[0133] "SCFA" refers to carboxylic acids with aliphatic tails of 1 to 6 carbons, with acetate (C2), propionate (C3), and butyrate (C4) being the most abundant, produced by anaerobic fermentation of dietary fiber (DF) in the intestine. Intestinal butyrate and propionate formation arises primarily from carbohydrate metabolism in glycolysis, but can also occur from organic acid and amino acid metabolism. In addition, acetate is the most abundant SCFA in the intestine, produced from acetyl-CoA derived from glycolysis, and can also be converted to butyrate by the enzyme butyryl-CoA:acetyl-CoA transferase. (Louis P, Flint HJ. Formation of propionate and butyrate by the human colonic microbiota. Environ Microbiol. (2017) 19:29-41.; den Besten G, van Eunen K, Groen AK, Venema K, Reijngoud DJ, Bakker BM. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J Lipid Res. (2013) 54:2325-40).SCFAs

[0134] In certain embodiments of the uses and methods described herein, the increased SCFAs are selected from isobutyrate, valerate, isovalerate, isocaproate, acetate, propionate, and / or butyrate. In a more preferred embodiment, the increased SCFAs are acetate, propionate, and / or butyrate.

[0135] SCFAs appear to be highly involved in microbiota-gut-brain signaling pathways, including immune (neuroinflammatory response, mood), endocrine (learning and memory), vagal / neural (learning and memory), and humoral (stress, neuroprotection) pathways (Dalile, B., Van Oudenhove, L., Vervliet, B. et al. The role of short-chain fatty acids in microbiota-gut-brain communication. Nat Rev Gastroenterol Hepatol 16, 461-478 (2019)).

[0136] SCFA production appears to be mediated by Akkermansia muciniphila and is also related to obesity-induced cognitive deficits in response to food intake (Yang, Y., Zhong, Z., Wang, B., Xia, X., Yao, W., Huang, L. & Ding, W. (2019). Early-life high-fat diet-induced obesity programs hippocampal development and cognitive functions via regulation of gut commensal Akkermansia muciniphila. Neuropsychopharmacology, 1-11.). Increased Akkermansia muciniphila levels are also associated with obesity, overweight, and liver dysfunction, as well as a reduction in inflammatory markers (Depommier, C., Everard, A., Druart, C., Plovier, H., Van Hul, M., Vieira-Silva, S., & de Barsy, M. (2019). Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study. Nature medicine, 25(7), 1096-1103.).Lactobacillus is also known to produce vitamins B3, B6, and B9 in cotyledons (Hamzehlou, P., Sepahy, AA, Mehrabian, S., & Hosseini, F. (2018). Production of vitamins B3, B6, and B9 by Lactobacillus isolated from traditional yogurt samples from 3 cities in Iran, winter 2016. Applied Food Biotechnology, 5(2), 107-120.), which have also been linked to brain health (Hutto, BR (1997). Folate and cobalamin in psychiatric illness. Comprehensive psychiatry, 38(6), 305-314).

[0137] As shown herein, an extract of Panax quinquefolius (i.e., an extract of the present invention) increases some taxa of the gut microbiota (Figures 15 and 16). Thus, administration of a Panax quinquefolius extract (i.e., an extract of the present invention) or a composition containing ginsenoside (composition of the present invention) may result in an increase and / or decrease of some taxa (phyla, classes, orders, families, and genera) present in the gut, such as an increase (enrichment) and / or decrease of some operational taxonomic units (OTUs) present in the gut.

[0138] As used herein, the terms "modulate" (or "modulation") or "regulate" (or "modulation") may refer to an increase (enrichment) and / or reduction of certain taxa (phyla, classes, orders, families, and genera) present in the gut. For example, reference to modulation or modulation may refer to the effect of increasing and / or reducing certain operational taxonomic units (OTUs) present in the gut (gut microbiota). Correlations of fecal enrichment microbiota with gut microbiota can be established, and fecal microbiota measurements can be analyzed as described in Sarah L. Hagerty, et al. (2020 PLoS One. 2020; 15(3)) or as described in the results of this document (Microbial community analysis).

[0139] In certain embodiments of the methods and uses described herein, the modulating or regulating effect on the gut microbiota is the modulation or regulation of isobutyrate-producing gut microbiota, valerate-producing gut microbiota, isovalerate-producing gut microbiota, isocaproate-producing gut microbiota, acetate-producing gut microbiota, propionate-producing gut microbiota, and / or butyrate-producing gut microbiota. In a more preferred embodiment, the modulating or regulating effect on the gut microbiota is the modulation or regulation of butyrate-producing gut microbiota, acetate-producing gut microbiota, and / or propionate-producing gut microbiota.

[0140] "Butyrate-producing gut microbiota" refers to those intestinal bacteria and other intestinal microorganisms that can synthesize butyrate through various pathways, such as the butyryl-CoA-acetyl-CoA transferase pathway for butyrate production. Those skilled in the art can isolate and determine if a microorganism can produce butyrate using, for example, the method described in Barcenilla A. et al. (APPLIED AND ENVIRONMENTAL MICROBIOLOGY, April 2000, pp. 1654-1661). For example, a bacterial sample can be grown in a rumen secretion-based medium that has been shown to support the growth of a wide range of anaerobic bacteria, and then colonies can be selected and purified. Selected samples can be grown in broth culture and tested for the production of volatile fatty acids.

[0141] Examples of butyrate-producing microorganisms are bacteria such as Eubacterium rectale, Eubacterium ramulus, and Roseburia cecicola, sugar- and / or lactate-utilizing bacteria that produce butyrate from lactate and acetate, such as Eubacterium hallii and Anaerostipes spp., from the phylum Firmicutes, especially the family Ruminococcaceae, Faecalibacterium prausnitzii and Clostridium leptum from the family Lachnospiraceae, Clostridium coccoides, and members of the families Actinobacteria, Bacteroidetes, Fusobacteria, Proteobacteria, Spirochaetes, and Thermotogae.

[0142] "Propionate-producing gut microbiota" are those enterobacteria and other gut microorganisms that can synthesize propionate through various pathways. Those skilled in the art can isolate and determine if a microorganism can produce butyrate using, for example, the method described in Barcenilla A. et al. (APPLIED AND ENVIRONMENTAL MICROBIOLOGY, April 2000, pp. 1654-1661). For example, a bacterial sample can be grown in a rumen fluid-based medium that has been shown to support the growth of a wide range of anaerobic bacteria, and then colonies can be selected and purified. The selected sample can be grown in broth culture and tested for the production of volatile fatty acids.

[0143] An example of a propionate-producing microorganism is a bacterium such as Akkermansia muciniphila (phylum Verrucomicrobia), which produces both propionate and acetate.

[0144] "Acetate-producing intestinal microflora" refers to those intestinal bacteria and other intestinal microorganisms that can synthesize acetate through various pathways. Those skilled in the art can isolate and determine if a microorganism can produce butyrate, for example, using the method described above (Barcenilla A. et al.). An example of a propionate-producing microorganism is the Bifidobacterium species (belonging to the Actinobacteria phylum), which produces acetate and lactate during carbohydrate fermentation.

[0145] "Isobutyrate-producing gut microbiota" are those gut bacteria and other gut microorganisms that can synthesize isobutyrate by various pathways. "Valerate-producing gut microbiota" are those gut bacteria and other gut microorganisms that can synthesize valerate by various pathways. "Isovalerate-producing gut microbiota" are those gut bacteria and other gut microorganisms that can synthesize isovalerate by various pathways. "Isocaproate-producing gut microbiota" are those gut bacteria and other gut microorganisms that can synthesize isovalerate by various pathways. Those skilled in the art can isolate and determine if a microorganism is capable of producing valerate, isobutyrate, isovalerate, isocaproate, etc., using, for example, the methods described previously (Barcenilla A. et al.).

[0146] Some bacteria can produce one or more of the SCFAs (such as isobutyrate, valerate, isovalerate, isocaproate, acetate, propionate, and / or butyrate) and thus can belong to one or more of the groups described above.

[0147] In particular embodiments, modulation or regulation refers to increasing the levels of butyrate-producing gut microbiota, acetate-producing gut microbiota, and / or propionate-producing gut microbiota, particularly the genus Akkermansia, more particularly Akkermansia muciniphila and / or Lactobacillus.

[0148] In some embodiments of the uses and methods described herein, the increased SCFA is selected from isobutyrate, valerate, isovalerate, isocaproate, acetate, propionate, and / or butyrate. In more preferred embodiments, the increased SCFA is acetate, propionate, and / or butyrate.

[0149] Microbial metabolites, short-chain fatty acids (SCFAs), have been implicated in gastrointestinal function, (neuro)immune regulation, and host metabolism (Dalile, B., et al. Nat Rev Gastroenterol Hepatol 16, 461-478 (2019).).

[0150] Both propionate and butyrate increase intestinal production of glucose and inhibit the activity of enzymes involved in a range of neuropsychiatric disorders, including depression, schizophrenia, and Alzheimer's disease. In a mouse model of Alzheimer's disease, butyrate administration rescued memory function and increased the expression of genes involved in learning. In an animal model of mania, butyrate reversed behavioral hyperactivity.

[0151] Van de Wouw et al. (Van de Wouw, M., et al. 2018. The Journal of Physiology, 596(20), 4923-4944) found that psychosocial stress affected reward-seeking behavior and increased both stress response and in vivo intestinal permeability, all of which were improved by SCFA treatment. They found that the SCFA group showed reduced gene expression of receptors involved in stress signaling in the hypothalamus, hippocampus, and colon.

[0152] SCFA supplementation can improve acute stress-induced hyperthermia and corticosterone levels in mice under prolonged stress (Van de Wouw et al., 2018). SCFAs can downregulate stress signaling and the HPA-axis response, an important pathway in the microbiota-gut-brain axis communication (Wiley, NC, et al. (2017). Journal of Animal Science, 95(7), 3225-3246). The HPA-axis represents the interaction between the hypothalamus, pituitary gland, and adrenal gland, which plays an important role in stress responses. SCFAs reduced anxiety-like behavior in the open-field test and depression-like behavior in the forced swim test in control mice. Animal studies provide direct evidence of the effects of SCFAs on neuropsychiatric disorders and psychogenic function.

[0153] In the periphery, SCFAs affect systemic inflammation by regulating interleukin secretion. SCFAs can modulate neuroinflammation and affect the immune system by regulating the differentiation, recruitment, and activation of immune cells, such as neutrophils, macrophages, and T cells. SCFAs also affect neuroinflammation by affecting microglial morphology and function, potentially affecting emotion, cognition, and the pathophysiology of psychiatric disorders.

[0154] SCFAs increase several hormones in the gastrointestinal tract, and these hormones affect mood and cognition. In addition, SCFAs regulate peripheral levels of serotonin, which may in turn control brain function by influencing the immune system (Stasi, C., et al. 2014. Techniques in coloproctology, 18(7), 613-621) or by transmitting to the brain via 5-HT3 receptors on vagal afferent fibers (Browning, KN (2015) Role of central vagal 5-HT3 receptors in gastrointestinal physiology and pathophysiology. Frontiers in neuroscience, 9, 413).

[0155] Recent evidence supports a role for SCFAs as mediators of microbiota-gut-brain interactions. Through their putative effects on brain function via various gut-brain signaling pathways, they may act as mediators of the effects of probiotics, prebiotics, and dietary interventions on a range of mental functions. In summary, SCFAs may directly affect the brain by crossing the blood-brain barrier, reinforcing BBB integrity, modulating neurotransmission, influencing neurotrophic factor levels, and promoting serotonin biosynthesis.

[0156] Thus, because SCFAs are linked to gut-brain regulation and have positive effects on mood and cognition, neuroinflammation, depression, anxiety-like behaviors and neuropsychiatric disorders including schizophrenia, and Alzheimer's, enrichment of certain bacterial taxa that produce these SCFAs as a result of modulation by ginsenosides and the extracts of the present invention, or compositions comprising the extracts of the present invention, may prevent or treat such conditions.

[0157] Thus, in particular embodiments of the uses and methods described above, the modulation or regulation of gut microbiota (particularly of the genus Akkermansia, more particularly Akkermansia muciniphila and / or Lactobacillus, in particular butyrate-producing gut microbiota, acetate-producing gut microbiota, and / or propionate-producing gut microbiota) is for use in (i.e., results in or has an effect on) treating or preventing sleep disorders such as insomnia, treating or preventing neuropsychiatric disorders such as depression and anxiety, treating or preventing neurodegenerative diseases such as schizophrenia, Alzheimer's disease, Parkinson's disease, and / or treating or preventing age-induced cognitive decline, attention, alertness, and / or mood, comprising administering to a subject in need thereof an effective amount of a composition comprising ginsenoside (first composition of the present invention), a pharmaceutical or food composition comprising said first composition of the present invention, a Panax quinquefolius extract (i.e., extract of the present invention) or a composition comprising the extract of the present invention (i.e., pharmaceutical or food composition).

[0158] In a further aspect of the present invention, there is provided a method for regulating or adjusting gut microbiota (particularly butyrate-producing gut microbiota, acetate-producing gut microbiota, and / or propionate-producing gut microbiota; more particularly Akkermansia genus, more particularly Akkermansia muciniphila; and / or Lactobacillus) for treating or preventing sleep disorders such as insomnia, treating or preventing neuropsychiatric disorders such as depression and anxiety, treating or preventing neurodegenerative diseases such as schizophrenia, Alzheimer's disease, Parkinson's disease, and / or treating or preventing age-induced cognitive decline, attention, alertness, and / or mood, comprising administering to a subject in need thereof an effective amount of a composition comprising ginsenoside (first composition of the present invention), a pharmaceutical or food composition comprising said first composition of the present invention, a Panax quinquefolius extract (i.e., the extract of the present invention), or a composition comprising the extract of the present invention (i.e., the pharmaceutical or food composition).

[0159] In a further aspect of the present invention, there is provided a method for increasing the production of SCFAs by the gut microbiota and / or increasing SCFA blood concentrations (particularly butyrate, acetate, and / or propionate) for treating or preventing sleep disorders such as insomnia, treating or preventing neuropsychiatric disorders such as depression and anxiety, treating or preventing neurodegenerative diseases such as schizophrenia, Alzheimer's disease, Parkinson's disease, and / or treating or preventing age-induced cognitive decline, attention, alertness, and / or mood, comprising administering to a subject in need thereof an effective amount of a composition comprising ginsenosides (first composition of the present invention), a pharmaceutical or food composition comprising said first composition of the present invention, a Panax quinquefolius extract (i.e., the extract of the present invention), or a composition comprising the extract of the present invention (i.e., the pharmaceutical or food composition).

[0160] The effects of a composition comprising ginsenoside (first composition of the invention), a pharmaceutical or food composition comprising said first composition of the invention, a Panax quinquefolius extract (i.e., the extract of the invention), or a composition comprising the extract of the invention (i.e., the pharmaceutical or food composition) in treating or preventing sleep disorders such as insomnia, treating or preventing neuropsychiatric disorders such as depression and anxiety, treating or preventing neurodegenerative diseases such as schizophrenia, Alzheimer's disease, Parkinson's disease, and / or treating or preventing age-induced cognitive decline, attention, alertness, and / or mood may be achieved by: (i) increasing the level of gut microbiota; in particular, butyrate-producing gut microbiota, acetate-producing gut microbiota, and / or propionate-producing gut microbiota; more in particular, the genus Akkermansia, more in particular Akkermansia muciniphila and / or Lactobacillus; (ii) by increasing intestinal SCFA concentrations; (iii) by increasing SCFA production by the gut microbiota; and / or (iv) by increasing SCFA blood concentrations (especially butyrate, acetate, and / or propionate). Moreover, the inventors of the present invention have also demonstrated the effect of the extract of the present invention or the composition of the present invention in reducing fatigue (as shown in Figure 9).

[0161] The extract of the present invention may have the effect of improving the mood of a subject. Typically, the extract of the present invention may reduce negative emotions and increase self-confidence (as shown in Figure 10). The extract of the present invention also increases attention and alertness after chronic treatment (as shown in Figures 2, 3, 4, 5, 6, 7 and 8).

[0162] Because SCFAs are linked to gut-brain regulation, and because the present invention has shown, in particular embodiments of the uses and methods described above, the surprising effects of ginsenoside-rich Panax quinquefolius extract in reducing fatigue, improving self-confidence, and improving alertness / alertness in a subject, modulating or regulating the gut microbiota (particularly butyrate-producing gut microbiota, acetate-producing gut microbiota, and / or propionate-producing gut microbiota; more particularly Akkermansia genus, more particularly Akkermansia muciniphila; and / or Lactobacillus) is for use in (i.e., results in or has the effect of) treating, reducing, preventing, and / or ameliorating fatigue; improving or increasing alertness / alertness, and / or improving or increasing self-confidence in a subject.

[0163] In a further aspect of the present invention, there is provided a method for regulating or adjusting gut microbiota (particularly butyrate-producing gut microbiota, acetate-producing gut microbiota, and / or propionate-producing gut microbiota; more particularly Akkermansia genus, more particularly Akkermansia muciniphila and / or Lactobacillus) for treating, reducing, preventing, and / or ameliorating fatigue, improving or increasing cognition / working memory, improving or increasing attention / alertness, and / or improving or increasing self-confidence in a subject, comprising administering to a subject in need thereof an effective amount of a composition comprising a ginsenoside (first composition of the present invention), a pharmaceutical or food composition comprising said first composition of the present invention, or a Panax quinquefolius extract (i.e., the extract of the present invention) or a composition comprising the extract of the present invention (i.e., the pharmaceutical or food composition).

[0164] In a further aspect of the present invention, there is provided a method for increasing the production of SCFAs by the gut microbiota and / or increasing SCFA blood concentrations (particularly butyrate, acetate, and / or propionate) in a subject in need thereof, comprising administering to a subject an effective amount of a composition comprising a ginsenoside (first composition of the present invention), a pharmaceutical or food composition comprising said first composition of the present invention, or a Panax quinquefolius extract (i.e., the extract of the present invention) or a composition comprising the extract of the present invention (i.e., the pharmaceutical or food composition).

[0165] The effect of a composition comprising ginsenoside (first composition of the invention), a pharmaceutical or food composition comprising said first composition of the invention, a Panax quinquefolius extract (i.e., the extract of the invention), or a composition comprising an extract of the invention (i.e., the pharmaceutical or food composition) in treating, reducing, preventing and / or ameliorating fatigue, improving or increasing cognition / working memory, improving or increasing attention / alertness, and / or improving or increasing self-confidence in a subject may be achieved by: (i) increasing the level of gut microbiota; in particular, butyrate-producing gut microbiota, acetate-producing gut microbiota, and / or propionate-producing gut microbiota; more particularly, the genus Akkermansia, more particularly Akkermansia muciniphila and / or Lactobacillus; (ii) increasing SCFA production by the gut microbiota; (iii) increasing intestinal SCFA concentrations; and / or (iv) increasing SCFA blood concentrations (especially butyrate, acetate, and / or propionate).

[0166] Because the presence of certain bacterial taxa is linked to satiety control, obesity-related and metabolic syndrome-related gut microbiota dysbiosis imbalance, gut microbiota dysbiosis imbalance-induced cardiovascular disease, gut microbiota dysbiosis imbalance-induced cardiometabolic disease, low-grade inflammation, and obesity, the enrichment of certain bacterial taxa resulting from modulation or regulation by the extract of the present invention, or a composition comprising the extract of the present invention, may regulate satiety and treat or reverse obesity-related and metabolic syndrome-related gut microbiota dysbiosis imbalance, microbiota dysbiosis imbalance-induced cardiovascular disease, gut microbiota dysbiosis imbalance-induced cardiometabolic disease, low-grade inflammation, and obesity.

[0167] Thus, in particular embodiments of the uses and methods described above, modulating or regulating the gut microbiota (particularly butyrate-producing gut microbiota, acetate-producing gut microbiota, and / or propionate-producing microbiota; more particularly Akkermansia genus, more particularly Akkermansia muciniphila and / or Lactobacillus) is for use in controlling satiety, reversing obesity-related and metabolic syndrome-related gut microbiota dysbiosis, treating or preventing microbiota dysbiosis-induced cardiovascular disease and / or gut microbiota dysbiosis-induced cardiometabolic disease, treating or preventing low-grade inflammation, and / or treating or preventing obesity.

[0168] In a further aspect of the present invention, there is provided a method for modulating or controlling gut microbiota (particularly butyrate-producing gut microbiota, acetate-producing gut microbiota, and / or propionate-producing gut microbiota; more particularly Akkermansia genus, more particularly Akkermansia muciniphila and / or Lactobacillus) for controlling satiety, reversing obesity-related and metabolic syndrome-related gut microbiota dysbiosis, treating or preventing microbiota dysbiosis imbalance-induced cardiovascular disease and / or gut microbiota dysbiosis imbalance-induced cardiometabolic disease, treating or preventing low-grade inflammation, and / or treating or preventing obesity, comprising administering an effective amount of a Panax quinquefolius extract (or a composition comprising a Panax quinquefolius extract) to a subject in need thereof.

[0169] In a further aspect of the present invention, there is provided a method for increasing the production of SCFAs by the gut microbiota, increasing the concentration of SCFAs in the intestine, and / or increasing SCFA blood concentrations (particularly butyrate, acetate, and / or propionate) for controlling stomach discontent, reversing obesity-related and metabolic syndrome-related gut microbiota-dysbiosis imbalance, treating or preventing microbiota-dysbiosis imbalance-induced cardiovascular disease and / or gut microbiota-dysbiosis imbalance-induced cardiometabolic disease, treating or preventing low-grade inflammation, and / or treating or preventing obesity, comprising administering to a subject in need thereof an effective amount of a composition comprising ginsenosides (first composition of the present invention), a pharmaceutical or food composition comprising said first composition of the present invention, a Panax quinquefolius extract (i.e., the extract of the present invention), or a composition comprising the extract of the present invention (i.e., the pharmaceutical or food composition).

[0170] The effects of a composition comprising ginsenoside (the first composition of the invention), a pharmaceutical or food composition comprising said first composition of the invention, a Panax quinquefolius extract (i.e., the extract of the invention), or a composition comprising the extract of the invention (i.e., the pharmaceutical or food composition) in controlling satiety, reversing obesity-related and metabolic syndrome-related gut microbiota-dysbiosis imbalance, treating or preventing microbiota-dysbiosis imbalance-induced cardiovascular disease and / or gut microbiota-dysbiosis imbalance-induced cardiometabolic disease, treating or preventing low-grade inflammation, and / or treating or preventing obesity in a subject may be achieved by: (i) increasing the level of gut microbiota; in particular, butyrate-producing gut microbiota, acetate-producing gut microbiota, and / or propionate-producing gut microbiota; more in particular, Akkermansia genus, more in particular Akkermansia muciniphila and / or Lactobacillus; (ii) increasing intestinal SCFA concentrations; (iii) increasing SCFA production by the gut microbiota; and / or (iv) increasing SCFA blood concentrations (especially butyrate, acetate, and / or propionate).

[0171] In some embodiments of the uses and methods described herein, the increased SCFA is selected from isobutyrate, valerate, isovalerate, isocaproate, acetate, propionate, and / or butyrate. In more preferred embodiments, the increased SCFA is acetate, propionate, and / or butyrate.

[0172] For the avoidance of doubt, in particular embodiments of the uses and methods described herein, the composition of the invention comprising ginsenosides, the pharmaceutical or food composition comprising said first composition of the invention, the Panax quinquefolius extract (i.e., the extract of the invention), or the composition comprising the extract of the invention may comprise (or consist essentially of / consist of) the following compounds (ginsenosides): from about 3% to about 100% by weight of total ginsenosides, such as from 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% to about 95%, 85%, 75%, 70%, 65%, 60%, 55%, 50%, 40%, 35%, 30%, 25%, 20%, 15%, or 10%. In preferred embodiments, the total ginsenosides in the ginsenoside-containing compositions or extracts of the present invention are from about 9% to about 15% by weight, and in more preferred embodiments, the total ginsenosides are from about 10% to about 13% by weight.

[0173] For the avoidance of doubt, in particular embodiments of the uses and methods described herein, the composition of the invention comprising ginsenosides (or pharmaceutical or food composition comprising said first composition of the invention), or Panax quinquefolius extract (i.e., the extract of the invention or the composition comprising the extract of the invention) may comprise (or consist essentially of / consist of) the following compounds (ginsenosides): a) from about 0.01% to about 0.8% by weight of Rg1, such as from about 0.05% to about 0.4% by weight, preferably from about 0.1% to about 0.4% by weight; b) from about 0.1% to about 5% by weight Re, such as from about 0.4% to about 4% by weight, preferably from about 0.8% to about 3.5% by weight; b) from about 1% to about 10% by weight of Rb1, such as from about 3% to about 8% by weight, preferably from about 4% to about 7% by weight; c) Rc from about 0.05% to about 5% by weight, such as from about 0.1% to about 4% by weight, preferably from about 0.5% to about 3.52% by weight; d) from about 0.05 to about 3% by weight, such as from about 0.1 to about 2% by weight, preferably from about 0.2% to about 1.5% by weight, of Rb2; and / or e) Rd from about 0.5% to about 5% by weight, such as from about 0.7% to about 4% by weight, preferably from about 0.9% to about 3% by weight.

[0174] In preferred embodiments of the uses and methods described herein, the composition of the present invention containing ginsenosides, the pharmaceutical or food composition containing the first composition of the present invention, the Panax quinquefolius extract (i.e., the extract of the present invention), or the composition containing the extract of the present invention contains, by weight, about 10% to 13%, preferably about 10%, of ginsenosides, and about 0.1% to 0.4%, preferably 0.36%, of Rg1, 0.8% to 3.5%, preferably 1.6%, of Rb1, 4% to 7%, preferably 4.8%, of Re, 0.5% to 3.5%, preferably 1.6%, of Rc, 0.2% to 1.5%, preferably 0.4%, of Rb2, and / or 0.9% to 3%, preferably 1.4%, of Rd. Unless otherwise stated herein, the weight percentages listed are based on the total weight of the (dry) extract obtained.

[0175] For the avoidance of doubt, in particular embodiments of the uses and methods described herein, the composition of the invention comprising ginsenosides, the pharmaceutical or food composition comprising said first composition of the invention, the Panax quinquefolius extract (i.e. the extract of the invention), or the composition comprising the extract of the invention may comprise (or consist essentially of / consist of) the following compounds (ginsenosides):

[0176] a) Rg1: from about 0.5% to about 8% of total ginsenosides by weight, such as from about 1% to about 4% of total ginsenosides by weight, preferably from about 3% to about 4% of total ginsenosides by weight

[0177] b) Re: from about 5% to about 50% by weight of total ginsenosides, such as from about 10% to about 35% by weight of total ginsenosides, preferably from about 12% to about 20% by weight of total ginsenosides, etc.

[0178] c) Rb1: from about 10% to about 100% by weight of total ginsenosides, such as from about 30% to about 80% by weight of total ginsenosides, preferably from about 40% to about 60% by weight of total ginsenosides, etc.

[0179] d) Rc from about 0.5% to about 40% by weight of total ginsenosides, such as from about 5% to about 35% by weight of total ginsenosides, preferably from about 10% to about 20% by weight of total ginsenosides

[0180] e) Rb2: from about 0.5% to about 20% of total ginsenosides by weight, such as from about 2 to about 10% of total ginsenosides by weight, preferably from about 2% to about 5% of total ginsenosides by weight and / or

[0181] f) from about 5% to about 50% of total ginsenosides by weight, such as from about 7% to about 30% of total ginsenosides by weight, preferably from about 10% to about 20% of total ginsenosides by weight.

[0182] In preferred embodiments of the methods and uses described herein, the AG extract comprises: Rg1: approximately 3% to 4% of total ginsenosides by weight, preferably 3.6% of total ginsenosides by weight; Re: 12% to 17% of total ginsenosides by weight, preferably 16% by weight; Rb1: 40% to 50% of total ginsenosides by weight, preferably 48% by weight; Rc: 12% to 17% of total ginsenosides by weight, preferably 16% by weight; Rb2: 2% to 5% of total ginsenosides by weight, preferably 4% by weight; and / or Rd: 12% to 15% of total ginsenosides by weight, preferably 14% of total ginsenosides by weight.

[0183] Moreover, for the avoidance of doubt, the Panax quinquefolius extract may be in the form of a composition (e.g. a pharmaceutical composition, a dietary supplement or a food composition) as described herein.

[0184] In preferred embodiments of the uses and methods described herein, the composition of the present invention containing ginsenosides, the pharmaceutical or food composition containing the first composition of the present invention, the Panax quinquefolius extract (i.e., the extract of the present invention), or the composition containing the extract of the present invention is administered in an amount of about 100 mg / day to about 2000 mg / day, or about 500 mg / day to about 1500 mg / day, or about 200 to about 1000 mg / day. In preferred embodiments, the amount is about 100 mg / day to 400 mg / day, preferably 200 mg / day. In any case, a practitioner or other skilled artisan will be able to routinely determine the actual dosage, which will be most suitable for each individual patient. The dosages listed above are illustrative of the average case; of course, there can be individual instances in which higher or lower dosage ranges are merited, and are within the scope of the present invention.

[0185] The composition of the present invention comprising ginsenosides, the pharmaceutical or food composition comprising the first composition of the present invention, the Panax quinquefolius extract (i.e., the extract of the present invention), or the composition comprising the extract of the present invention may provide ginsenosides in an amount of from about 0.11 to about 10 mg / kg of body weight, such as from 2.5 to about 6 mg / kg of body weight, or about 3 mg / kg.

[0186] In a preferred embodiment, the composition of the present invention containing ginsenoside, the pharmaceutical or food composition containing the first composition of the present invention, the Panax quinquefolius extract (i.e., the extract of the present invention), or the composition containing the extract of the present invention is administered for a long period of time. Typically, in the uses of the present invention described herein, the duration of administration of the composition of the present invention containing ginsenoside, the pharmaceutical or food composition containing said first composition of the present invention, the Panax quinquefolius extract (i.e., the extract of the present invention), or the composition containing the extract of the present invention is more than 2 days, more than 3 days, more than 4 days, more than 5 days, more than 6 days, more than 7 days; more than 1 week, more than 2 weeks, more than 3 weeks, more than 4 weeks, more than 5 weeks, more than 6 weeks, more than 7 weeks, more than 8 weeks, more than 9 weeks, more than 10 weeks, more than 1 month, more than 1 month, more than 2 months, more than 3 months, more than 4 months, more than 5 months, more than 6 months, more than 7 months, more than 8 months, more than 9 months, more than 10 months ...1 months, more than 12 months. As used herein, the terms "subject" and "patient" may be used interchangeably and may include mammalian species, particularly humans.

[0187] "Mammal" refers to a human or non-human animal, including, but not limited to, mice, rats, rabbits, dogs, cats, pigs, cows, and non-human primates, including, but not limited to, monkeys and chimpanzees.

[0188] The term "effective amount" refers to the amount of the extract of the present invention, or a composition comprising the extract of the present invention, that confers an effect on a subject to which the extract or composition is administered (e.g., an amount sufficient to cause a desired effect, such as increasing and / or decreasing the presence of certain taxa (phylum, class, order, family, and genus) in the intestine). The effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject gives symptoms or feels an effect).

[0189] "Administration" or "administering" refers to the route of introducing a compound or composition provided herein into an individual to perform its intended function. Examples of administration routes that can be used include, but are not limited to, oral, parenteral administration (for example), such as subcutaneous, intravenous, intramuscular injection, or infusion, etc. A "healthy subject" refers to an individual who is not known to suffer from any serious disease and who corresponds to the general population.

[0190] As used herein, the term "treatment" (and, similarly, "treating") takes its ordinary meaning in the medical field. In particular, the term may refer to achieving a reduction in the severity of one or more clinical symptoms associated with a disease or disorder (e.g., obesity), as may be determined using techniques known to those skilled in the art (e.g., by a physician) and / or slowing the progression of the disease or disorder (i.e., increasing the amount of time the disease or disorder takes to progress to a more severe state, as compared, for example, to the time taken in a less treated patient). As used herein, the term "protection" (and, similarly, "protecting") includes reference to prevention of a disease or disorder (and vice versa). In particular, the term may refer to achieving a reduction in the likelihood of a patient (or healthy subject) developing a condition (e.g., at least a 10% reduction, at least a 20%, 30%, or 40% reduction, etc., for example, at least a 50% reduction).

[0191] For the avoidance of doubt, in the context of the present invention, the terms "treating" and "preventing" include the cure, or palliative treatment, of patients in need, as well as the prophylactic treatment and / or diagnosis of susceptible patients, associated disease states.

[0192] As used herein with respect to a disease state, the term "reducing" may refer to making the observed amount less or reducing in size (i.e., reducing gut microbiota dysbiosis imbalance-induced cardiovascular disease in a subject).

[0193] As used herein with respect to a disease state, the term "increasing" may refer to a greater observed amount or an increase in size (i.e., increasing the concentration of SCFAs in the intestine or increasing the production of SCFAs by the intestinal microbiota). The concentration of blood SCF can be measured in general blood, or in portal, aortic and / or hepatic vein blood.

[0194] Measurement of SCFA concentration can be made from blood (i.e., serum) or fecal samples using any suitable technique used in the art, such as gas chromatography-mass spectrometry (GCM), as described in (Garcia-Villalb R, et al. 2012. J Sep Sci. 2012;35(15):1906-13). Correlation has been established between the cecum level of SCFA and the portal vein and aortic blood level of SCFA in rats (Jakobsdottir G, et al. 2013. Br J Nutr. 2013;110(9):1565-72.). Thus, the increase in SCFA concentration in the intestine can be calculated by correlating the SCFA concentration in the blood or feces of the subject.

[0195] As used herein, the term "fatigue" may refer to a general feeling of tiredness or lack of energy in healthy subjects, but is also associated with some medical conditions. Fatigue is a common symptom of many medical conditions, ranging in severity from mild to severe. Many medical conditions can also cause fatigue. Examples include anemia, arthritis, fibromyalgia, chronic fatigue syndrome, infections such as colds and influenza, Addison's disease, hypothyroidism or hyperthyroidism, sleep disorders such as insomnia, eating disorders such as anorexia, autoimmune disorders, congestive heart disease, cancer, diabetes, kidney disease, liver disease, chronic obstructive pulmonary disease (COPD), aging, neuropsychiatric disorders such as depression and anxiety, neurodegenerative diseases such as schizophrenia, Alzheimer's disease, Parkinson's disease, or emphysema. Fatigue can also be described as a condition in which a subject experiences, among other symptoms, a feeling of sleepiness, tiredness, sluggishness, and / or drowsiness. Fatigue (general lack of energy) can be measured using standard methods known by those skilled in the art. Examples of methods that can be used include, but are not limited to, the PANAS-X (Watson, D., & Clark, LA (1994). The PANAS-X: Manual for the positive and negative affect schedule-expanded form) and the mental fatigue visual analogue scale (Scholey, AB, et al. (2010). Journal of Psychopharmacology, 24(10), 1505-1514). The PANAS-X scale consists of a number of phrases (sleepy, tired, sluggish, drowsy) that describe a variety of sensations and feelings, including self-confidence.

[0196] Participants read each item and then record the appropriate response (giving a score from 1 to 5) in the space provided, indicating how much they felt this way during the past week. Higher ratings indicate higher fatigue states.

[0197] Fatigue can also be measured via a mental fatigue visual analogue scale: participants rate their current subjective mental fatigue state by marking a 9-point Likert scale with 'not at all' (far left) and 'totally' (far right) (Scholey, A. B et al. (2010) Journal of Psychopharmacology, 24(10), 1505-1514).

[0198] As used herein, the terms "attention" and "alertness" are interchangeable and may refer to an overall state of greater awareness or greater focus, concentration, or decision-making in healthy subjects, as well as in relation to some medical conditions. Deficits in attention / alertness are common symptoms of many medical conditions, ranging in severity from mild to severe. Many medical conditions can also cause attention / alertness deficits. Examples include anemia, arthritis, fibromyalgia, chronic fatigue syndrome, infections such as colds and influenza, Addison's disease, hypothyroidism, or hyperthyroidism, sleep disorders such as insomnia, eating disorders such as anorexia, autoimmune disorders, congestive heart disease, cancer, diabetes, kidney disease, liver disease, chronic obstructive pulmonary disease (COPD), aging, neuropsychiatric disorders such as depression and anxiety, schizophrenia, neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, or emphysema. Attention and alertness can also be described as the ability to process tasks with high cognitive demands, such as, but not limited to, response time to process complex information or a correct response to a complex task that requires the synthesis of multiple pieces of information. Attention / alertness status can be measured using standard methods known by those skilled in the art. Examples of methods that can be used include, but are not limited to, accuracy and response time in a modified attention network task described in the examples of this application. Attention and alertness can also be described as the ability to process tasks with high cognitive demands, such as a rapid visual information processing task. In this sustained attention task, a series of digits is presented continuously on the screen. Participants are required to monitor the digits in a sequence of three consecutive even digits or three consecutive odd digits. Participants indicate the end of the target sequence by pressing the space bar as quickly as possible.The dependent variables were response time, accuracy, and commission errors. (Watson, AW, et al. (2015). Acute supplementation with blackcurrant extracts modulates cognitive functioning and inhibits monoamine oxidase-B in healthy young adults. Journal of functional foods, 17, 524-539.)

[0199] As used herein, the term "confidence" may refer to an overall feeling of being sure, proud, strong, bold, fearless, and courageous in a subject who is healthy or who is also affected by some medical conditions. Lack of confidence is a common symptom of many medical conditions, ranging in severity from mild to severe.

[0200] Many medical conditions can also cause low self-confidence. Examples include: anemia, arthritis, fibromyalgia, chronic fatigue syndrome, infections such as colds and influenza, Addison's disease, hypothyroidism or hyperthyroidism, sleep disorders such as insomnia, eating disorders such as anorexia, autoimmune disorders, congestive heart disease, cancer, diabetes, kidney disease, liver disease, chronic obstructive pulmonary disease (COPD), aging, neuropsychiatric disorders such as depression and anxiety, schizophrenia, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, or emphysema. Self-confidence can also be described as the ability to overcome challenges by surpassing oneself.

[0201] Self-confidence can be measured using standard methods known by those skilled in the art. Examples of methods that can be used include, but are not limited to, the PANAS-X (Watson, D., & Clark, LA (1994). The PANAS-X: Manual for the Positive and Negative Affect Schedule - Expanded Form), described in the examples of this application. This scale consists of a number of phrases that describe various sensations and emotions, including self-confidence (proud, strong, confident, bold, fearless, courageous). Participants read each item and then record the appropriate response (giving a score from 1 to 5) in the space provided thereafter. They indicate how much they felt this way during the past week. A higher rating indicates a higher self-confidence state.

[0202] Depending on the disorder and patient to be treated and the route of administration, the first composition of the present invention, the extract of the present invention, and the pharmaceutical or food composition comprising the extract or the first composition of the present invention may be administered at varying doses (i.e., therapeutically effective doses when administered to a patient in need thereof).In this regard, those skilled in the art will recognize that in the context of the present invention, the dose administered to a mammal, particularly a human, must be sufficient to affect the therapeutic response of the mammal over a reasonable time frame.Those skilled in the art will recognize that the selection of the exact dose and composition, and the most appropriate delivery method will also be influenced by, among other things, the pharmacological properties of the formulation, the nature and severity of the condition to be treated, and the physical condition and intelligence of the recipient, as well as the capacity, age, condition, weight, sex, and response of the patient to be treated with the specific compound, and the stage / severity of the disease.

[0203] Typically, in the uses or methods of the invention described herein, the first composition of the present invention, the extract of the present invention, and pharmaceutical or food compositions containing the extract or first composition of the present invention are administered in an amount of about 100 mg / day to about 2000 mg / day, or about 500 mg / day to about 1500 mg / day, or about 1000 mg / day. In preferred embodiments, the amount is about 100 mg / day to about 400 mg / day, more preferably about 150 mg / day to about 250 mg / day, more preferably 200 mg / day. In any case, a practitioner or other skilled artisan will be able to routinely determine the actual dosage, which will be most suitable for each individual patient. The above dosages are illustrative of the average case; of course, there may be individual instances in which higher or lower dosage ranges are merited, and these are within the scope of the present invention. [Brief explanation of the drawings]

[0204] [Figure 1] Figure 1 shows the study design of the Cereboost Longitudinal Study. [Figure 2a] Figure 2a shows that after 4 and 6 h, Cereboost improves the percentage of correct responses compared to placebo. [Figure 2b] Figure 2b shows that after 2 h, Cereboost improves response time compared to placebo. [Figure 3a] Figure 3a shows that Cereboost improves the percentage of correct responses compared to placebo after 2, 4, and 6 h. [Figure 3b] Figure 3b shows that Cereboost improves response times compared to placebo after 2, 4, and 6 h. [Figure 4] FIG. 4 shows that after 4 h, Cereboost improves the percentage of correct responses compared to placebo. [Figure 5] Figure 5 shows that after 4 hours, Cereboost improves response times compared to placebo. [Figure 6a]6a shows that after 6 h, Cereboost in Rush 2 improves the percentage of correct responses compared to placebo and compared to Rush 1. [Figure 6b] 6b shows that after 4 hours, Cereboost in Rush 2 improves response times compared to placebo and compared to Rush. [Figure 7] FIG. 7 shows that long-term Cereboost intake improves the percentage of correct responses compared to placebo. [Figure 8] Figure 8 shows that long-term Cereboost intake limits the number of errors compared to placebo. [Figure 9] Figures 9a, b, and c show that long-term Cereboost intake reduces pre-fatigue during and after a series of cognitively demanding tasks. [Figure 10] FIG. 10 shows that long-term Cereboost intake increases muscle mass. [Figure 11] FIG. 11 shows that long-term Cereboost intake increases cheerfulness. [Figure 12] FIG. 12 shows that Cereboost increased acetate levels in both the distal and proximal colonic regions. [Figure 13] FIG. 13 shows that Cereboost increased propionate levels in both the distal and proximal colonic regions. [Figure 14] FIG. 14 shows that Cereboost increased butyrate levels in both the distal and proximal colonic regions. [Figure 15] FIG. 15 shows that Cereboost increased Akkermansia muciniphila levels in the distal colon. [Figure 16] FIG. 16 shows that Cereboost increased Lactobacillus levels in the distal colon.

[0205] example Example 1 Study design The purpose of the study was to evaluate the effects of ingestion of 200 mg of American ginseng extract called Cereboost in healthy adults (n=60) on attention / alertness and mood. Mood was defined as how participants felt at specific times: energized, confident, sad, hostile, and withdrawn.

[0206] The American ginseng extract (Cereboost) used in this study has a total ginsenoside content of approximately 10% to 12% (by HPLC). Specific ginsenoside concentrations are: Rg1 0.1 to 0.4%, R2 0.4 to 3.5%, Rf not detected, Rb1 4 to 7%, Rc 0.5 to 3.5%, Rb2 0.2 to 1.5%, and Rd 0.9 to 3% by weight of the extract. The extract is quintozene-free and has a particle size of <250 micrometers. The study design is depicted in Figure 1.

[0207] Following recruitment to the study, participants (N = 60) began a 1-week "run-in" phase where they completed a food frequency questionnaire, administered habitual eating measures, and attended the laboratory for the first "performance" session of a cognitive task sequence. They then attended the laboratory for two additional testing days over a 2-week period. On the first testing day (Crisis 1, Baseline), participants arrived at the laboratory in a fasting state where they received a standard breakfast, followed by a cognitive and mood task sequence. Subjects then administered their assigned intervention and were retested at 2-hour intervals over a 6-hour period during the task sequence (Crisis 1, Outcome vs. Baseline). Before leaving the laboratory, participants were given enough capsules to consume one capsule of their assigned intervention per day with breakfast for the next 13 days. After two weeks of treatment, subjects returned to the laboratory and repeated the procedures for Study Day 1—a baseline test session to assess the effects of the 14-day treatment on cognition (baseline scores for Long-Term Outcome vs. Baseline Acute 1 and Acute 2), followed by test sessions 2, 4, and 6 hours after administration to assess the effects of the final dose of their assigned intervention and tolerance (Acute 2, Outcome vs. Baseline 2). For all test sessions, a computerized test battery was used to assess cognitive and mood effects.

[0208] The work included: 1)Positive and Negative Affect schedule Now(PANAS-NOW): The Positive and Negative Affect Scale (PANAS-N) will be used to investigate mood states at the beginning and end of the cognitive task sequence.

[0209] It is considered a reliable instrument in non-clinical populations (Crawford, JR, & Henry, JD (2004). The Positive and Negative Affect Schedule (PANAS): Construct validity, measurement properties and normative data in a large non-clinical sample. British journal of clinical psychology, 43(3), 245-265.). Participants were asked to rate the extent to which they experienced each of 20 emotions on a 5-point Likert scale ranging from "very little" to "very much." Half of the emotion words presented relate to negative emotions (distressed, upset, guilty, embarrassed, hostile, irritable, nervous, nervous, scared, fearful), and the other half relate to positive emotions (interested, alert, attentive, excited, enthusiastic, inspired, proud, determined, strong, active). The PANAS-X may be used to measure characteristic mood. In addition, fatigue 1 and 2 will be rated before and after the cognitive session using a visual analogue scale from 1 to 9.

[0210] 2) immediate and delayed word memory; Using the methodology outlined in Scholey et al. (2010) (Scholey, A et al. (2010). Psychopharmacology, 212(3), 345-356.), participants would be presented with a serial list of 15 words at a rate of 1 word per second. They would then be given 60 seconds to type as many words as possible, with the resulting score recorded as a percentage of accuracy. Approximately 35 minutes after the immediate word recall task, participants would be allowed 60 seconds to record as many items they could remember from the immediate word recall test.

[0211] 3) CORSI blocks task, This task investigates visuospatial memory. Nine identical squares are fixed in a random arrangement on the screen. Participants are asked to observe the spatial arrangement between 2 and 9 blocks. Four versions of each array length are presented during the task. The task is to reproduce the array immediately after each presentation by pressing the relevant square on the screen. The dependent variable is the number of blocks pointed to in the correct order. A novel array will be presented each time, and the order will be counterbalanced across participants.

[0212] 4) Rapid Visual Information Processing task (RVIP), This task will assess attentional processes. In this task, a series of digits is presented one by one on the screen in rapid succession at a rate of 100 / min. Participants must search the sequence for a series of three consecutive even or three consecutive odd digits. Once they detect the sequence string, participants must respond by pressing the space bar as quickly as possible. The task will last approximately six minutes, with up to eight correct target strings presented per minute. The task will be scored for accuracy.

[0213] 5) Modified attention network task (MANT), This task investigates executive function, attention, and inhibition. In this task, participants must respond to a centrally presented arrow by indicating left or right by pressing the corresponding key on a keyboard. The central arrow is flanked by arrows pointing in the same (congruent) or opposite (incongruent) direction. To perform the task effectively, participants must ignore the flanking arrows. Previous studies have found that participants show greater latency and more errors on incongruent trials compared to congruent trials due to the conflicting interference of the incongruent opposing arrows. Response latency on congruent trials reflects processing speed, while the amount of interference during incongruent trials indicates susceptibility to interference.

[0214] 6) Task Switch task (TST). This task measures executive function and attention. Participants view eight equally spaced radii of which two form a bold bisecting line. Numbers are randomly selected from the set 1–4 and 6–9 and presented sequentially in a clockwise direction. Responses higher or lower than 5 are made for trials below the bold line and for even or odd numbers above the line. General measures of accuracy and response time, along with specific measures of switching sacrifice, are obtained for the first trial after each task change.

[0215] Data were analyzed using Linear Mixed Modeling for each outcome variable, with post-hoc analyses to further explore several main or interactive effects between variables. Using the design outlined above, the following three comparisons were available to be made:

[0216] 1) Assessment of the acute effects of Cereboost treatment by comparing performance at baseline on study day 1 with performance at 2, 4, and 6 hours after treatment (Session 1 vs. Sessions 2, 3, and 4);

[0217] 2) Assessment of the acute effects of Cereboost treatment after prolonged treatment, comparing performance at baseline on study day 14 with performance at 2, 4, and 6 hours post-treatment (Session 5 vs. Sessions 6, 7, and 8).

[0218] 3) Assessment of improvement during Urgent 1 vs. Urgent 2, comparing urgent performance during and at the same time as treatment-free or prolonged treatment days (Session 2 vs. Session 6; Session 3 vs. Session 7; Session 4 vs. Session 8).

[0219] 4) Evaluation of the effect of repeated Cereboost treatment, comparing baseline performance on Study Day 1 with baseline performance on Study Day 14 (i.e., after 2 weeks of daily treatment: (Session 1 vs. Session 5)).

[0220] result 1- Urgent 1 Results: MANT task: Cereboost was shown to increase the percentage of correct responses and improve response times in the MANT (Figures 2a and 2b). Overall, participants taking Cereboost responded faster and more accurately, and demonstrated greater alertness and alertness compared to the placebo. 2-Emergency 2 Results: MANT task: Cereboost showed an increase in the percentage of correct responses and an improvement in response time in the MANT (Figures 3a and 3b). Overall, participants taking Cereboost responded faster and more accurately and demonstrated greater alertness and alertness compared to the placebo.

[0221] CORSI task: Cereboost demonstrated an increase in the percentage of correct responses in the CORSI task (Figure 4). Overall, participants taking Cereboost responded more accurately and demonstrated greater alertness and alertness compared to placebo. Interestingly, 4 h corresponds to postprandial hypoglycemia occurring in the placebo group, but not after Cereboost intake.

[0222] Switch task: Cereboost was shown to increase response times in the Switch task (Figure 5). Overall, participants taking Cereboost responded faster and demonstrated greater alertness and alertness compared to placebo.

[0223] 3- Urgent 1 vs. Urgent 2: MANT task: From Urgent 1 to Urgent 2, Cereboost demonstrated an increase in the percentage of correct responses and improved response times in the MANT (Figures 6a and 6b). Overall, participants taking Cereboost responded faster and more accurately, and demonstrated greater attention and alertness compared to placebo. These improvements were augmented by 14 days of Cereboost pretreatment, which helped them excel on the cognitive tasks.

[0224] 4-Long-term results: MANT task: Long-term Cereboost intake was shown to increase the percentage of correct responses in the MANT (Figure 7). Overall, participants taking Cereboost responded more accurately over time and demonstrated greater alertness and alertness compared to the placebo. RVIP task: Long-term Cereboost intake was shown to limit the number of errors in the RVIP task (Figure 8). Overall, participants taking Cereboost responded more accurately over time and demonstrated greater alertness and alertness compared to the placebo.

[0225] Fatigue 1 and 2 / PANAS X Fatigue tasks: Prolonged Cereboost intake was shown to limit fatigue before (Fatigue 1: Figure 9a), during (PANAS-X Fatigue, sensations and emotions: measures of sleepy, tired, sluggish, drowsy, etc., Figure 9b), and after (Fatigue 2: Figure 9c) the task. Generally, participants who took Cereboost over the long term felt more energized compared to the placebo.

[0226] PANAS X Self-assurance task: Long-term Cereboost intake has been shown to increase self-confidence by reorganizing sensations and emotions within PANAX-X: proud, strong, confident, bold, fearless, courageous, etc. (Figure 10). Overall, increased self-confidence means participants who take Cereboost long-term feel more confident and determined.

[0227] PANAS X Joviality task: Long-term Cereboost intake has been shown to increase cheerfulness by reorganizing sensations and emotions within PANAX-X: cheerful, happy, joyful, joyous, enthusiastic, inspired, active, energetic, etc. (Figure 11). Generally, participants who took Cereboost for a long period of time felt more pleased.

[0228] Example 2 The purpose of the experiment was to evaluate the effect of an American ginseng extract named Cereboost on the gut microbiota. material and method The American ginseng extract (Cereboost) used in this study has a total ginsenoside content of approximately 10% to 12% (by HPLC). Specific ginsenoside concentrations are: Rg 10.1 to 0.4%, R2 0.4 to 3.5%, Rf not detected, Rb 14 to 7%, Rc 0.5 to 3.5%, Rb 2 0.2 to 1.5%, and Rd 0.9 to 3% by weight of the extract. The extract is quintozene-free and has a particle size of <250 micrometers.

[0229] Simulator of the Human Intestinal Ecosystem (SHIME®) The reactor configuration was adapted from SHIME® (ProDigest and Ghent University, Belgium) as described by Molly et al. (1993) (Molly, K., Woestyne, MV, & Verstraete, W. (1993). Development of a 5-step multi-chamber reactor as a simulation of the human intestinal microbial ecosystem. Applied microbiology and biotechnology, 39(2), 254-258). Each SHIME segment consisted of a series of three reactors simulating the stomach and small intestine, the proximal colon (PC), and the distal colon (DC), respectively. Inoculum preparation, retention time, pH, temperature settings, and reactor feed composition were previously described in Possemiers, S., Verthe, K., Uyttendaele, S., & Verstraete, W. (2004). PCR-DGGE-based quantification of stability of the microbial community in a simulator of the human intestinal microbial ecosystem. FEMS Microbiology Ecology, 49(3), 495-507. Following inoculation with a fecal sample from a healthy human adult, a 2-week stabilization period was initiated to allow differentiation of the fecal microbial community into colonic region-specific microbiota. During the subsequent control period, baseline values ​​for microbial activity and composition were established. After the control period, a 3-week treatment period began, during which Cereboost was administered.

[0230] Microbial metabolic activity Samples for microbial metabolic activity were collected from each colonic segment three times per week, starting with the control phase. Analysis of SCFA levels, including acetate, propionate, butyrate, and branched SCFAs (isobutyrate, isovalerate, and isocaproate), was performed as described by De Weirdt, R., Possemiers, S., Vermeulen, G., Moerdijk-Poortvliet, TC, Boschker, HT, Verstraete, W., & Van de Wiele, T. (2010). Human faecal microbiota display variable patterns of glycerol metabolism. FEMS microbiology ecology, 74(3), 601-611. Lactate concentrations were determined using a commercially available enzyme assay kit (R-Biopharm, Darmstadt, Germany) according to the manufacturer's instructions.

[0231] Microbial community analysis Samples for microbial community analysis were collected from each colonic reactor once per week, starting from the control phase. DNA was isolated from pelleted cells from 1 mL luminal samples as previously described in Vilchez-Vargas, R., Geffers, R., Suaerez-Diez, M., Conte, I., Waliczek, A., Kaser, VS & Pieper, DH (2013). Analysis of the microbial gene landscape and transcriptome for aromatic pollutants and alkane degradation using a novel internally calibrated microarray system. Environmental microbiology, 15(4), 1016-1039. Subsequently, quantitative polymerase chain reaction (qPCR) for Akkermansia muciniphila and Lactobacillus spp. was performed on a QuantStudio 5 Real-Time PCR system (Applied Biosystems, Foster City, CA USA). Each sample was analyzed in technical triplicate and outliers (differences of more than 1 CT) were removed.qPCR for Akkermansia muciniphila and Lactobacillus, respectively, was performed by Collado et al. (2007) (Collado, MC, Derrien, M., Isolauri, E., de Vos, WM, & Salminen, S. (2007). elderly. Appl. Environ. Microbiol., 73(23), 7767-7770) and Furet et al. (2009) (Furet, JP, Firmesse, O., Gourmelon, M., Bridonneau, C., Tap, J., Mondot, S., ... & Corthier, G. (2009). microbiota using real-time quantitative PCR. The study was carried out using the protocol as described by FEMS microbiology and ecology, 68(3), 351-362.

[0232] Results and Discussion As required during the control period, all SCFA and microbiota compositions were extremely stable. This indicated that the SHIME model was operated under its most optimal conditions. This stability is a prerequisite for asserting that the effects observed during treatment truly result from the administered test product. Upon initiating Cereboost treatment, we observed that basal consumption in the proximal colon increased moderately with treatment, indicating stimulation of microbial fermentation. This was accompanied by a moderate increase in gas production. While basal consumption and gas production are only crude indicators of microbial fermentation, SCFA measurements provide more detailed insight into the fermentation process.

[0233] Cereboost significantly increased acetate, propionate, and butyrate levels towards the end of the treatment period in both colonic regions (Figures 12, 13, and 14).

[0234] Acetate can be produced by a wide range of intestinal microorganisms, including Bacteroides spp. (phylum Bacteroidetes) and Bifidobacter, among many others (Figure 12). It follows that the test product significantly increased acetate levels in the proximal colon toward the end of the treatment period. A mean increase of 7.8 mM (or +42.0%) was observed. Similar effects were observed in the distal colon as in the proximal colon. Again, a large mean increase in acetate levels was observed upon treatment with Cereboost, namely a mean increase of 6.2 mM (or +21.2%).

[0235] Propionate (Figure 13) can be produced by a wide range of gut microorganisms, with the most abundant propionate producers being Bacteroides spp. (phylum Bacteroidetes), Veillonella (phylum Firmicutes), and Akkermansia muciniphila (phylum Verrucomicrobia). Treatment with Cereboost followed, resulting in significantly increased propionate levels in the proximal colon, an average increase of +1.77 mM (or +37.9% compared to the control period). In the distal colon, Cereboost treatment also resulted in a significant increase in propionate levels, with an average increase of 1.96 mM (or +24.1%).

[0236] Butyrate (Figure 14) is produced by members of Clostridium clusters IV and XIVa (phylum Firmicutes). In a process referred to as cross-feeding, these microorganisms convert acetate and / or lactate (along with other substrates) to butyrate, which is associated with health. It was found that Cereboost significantly increased butyrate levels in the proximal colon, resulting in an average increase of 3.0 mM (or +22.6%). In the distal colon, Cereboost supplementation resulted in significantly increased butyrate levels, an average increase of 1.1 mM (or +10.5%).

[0237] Akkermansia muciniphila remained below the detection limit in the proximal colon in this study. In the distal colon, Akkermansia muciniphila levels significantly increased in response to treatment with Cereboost. This indicates that Akkermansia muciniphila likely contributed (at least in part) to the increased acetate and propionate concentrations observed in the distal colon upon treatment (Figure 15).

[0238] Lactobacillus is considered a beneficial saccharolytic bacterium capable of producing high concentrations of lactate, an important metabolic product in the human colonic environment due to its antimicrobial properties, but also because it is the driver of a series of trophic interactions with other bacteria, resulting in the production of downstream metabolites.

[0239] Regarding Lactobacillus levels (Figure 16), levels remained unaffected by Cereboost treatment in the proximal colon. In the distal colon, Cereboost supplementation increased luminal Lactobacillus levels, reaching a significant increase in the mucosal compartment (Figure 16).

[0240] As required during the control period, acid / base consumption, SCFAs, lactate, ammonium, and microbiota composition were all highly stable and reproducible between each SHIME unit.

[0241] This demonstrated that the SHIME model was operated under the most optimal conditions, resulting in a stable and reproducible colonic microbiota. This stability is a prerequisite for asserting that the effects observed during treatment truly result from the administered test product. Upon initiating Cereboost treatment, we observed that basal consumption in the proximal colon increased moderately with treatment, indicating stimulation of microbial fermentation. This was accompanied by a moderate increase in gas production. While basal consumption and gas production are only crude indicators of microbial fermentation, SCFA measurements provide more detailed insight into the fermentation process.

[0242] It was found that Cereboost significantly increased acetate, propionate, and butyrate levels toward the end of the treatment period in both colonic regions. Regarding acetate and propionate production in the distal colon, this could be linked to significantly increased levels of acetate- and propionate-producing, mucin-degrading Akkermansia muciniphila in the distal colon. Furthermore, it was found that lactate levels remained low throughout the treatment period in the proximal colon, indicating appropriate cross-uptake with other metabolites. On the other hand, a significant increase in lactate was observed toward the end of the treatment period in the distal colon, which could be linked to elevated Lactobacillus levels. Finally, regarding markers of proteolytic fermentation, only minor effects were observed in response to treatment with the various test ingredients.

Claims

1. A composition comprising ginsenoside and not containing Dendrobium for use as a pharmaceutical or dietary supplement composition for increasing the concentration of SCFA in the intestine; increasing the production of SCFA by the intestinal microflora, and / or increasing SCFA blood concentrations.

2. 2. The composition for use according to claim 1, wherein the gut microbiota is an isobutyrate-producing gut microbiota, a valerate-producing gut microbiota, an isovalerate-producing gut microbiota, an isocaproate-producing gut microbiota, an acetate-producing gut microbiota, a propionate-producing gut microbiota, and / or a butyrate-producing gut microbiota.

3. The composition for use according to claim 1 or 2, wherein the intestinal microflora is of the genus Ackermansia and / or Lactobacillus.

4. 4. The composition for use according to any one of claims 1 to 3, wherein the SCFA is isobutyrate, valerate, isovalerate, isocaproate, acetate, propionate, and / or butyrate.

5. The composition for use according to any one of claims 1 to 4, wherein the ginsenoside is of synthetic or natural origin.

6. A composition for use according to any one of claims 1 to 5, wherein the ginsenoside is obtained from the root of Panax quinquefolius.

7. The composition for use according to any one of claims 1 to 6, wherein the composition is an extract of Panax quinquefolius.

8. A composition for use according to any one of claims 1 to 7, comprising from 3% to 100% ginsenoside by weight.

9. A composition for use according to claim 8, comprising from 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% by weight to 99%, 95%, 85%, 75%, 70%, 65%, 60%, 55%, 50%, 40%, 35%, 30%, 25%, 20%, 15%, or 10% by weight of ginsenosides.

10. A composition for use according to any one of claims 1 to 9, comprising the following ginsenosides: Rg1, from 1% to 4% of total ginsenosides by weight; Re from 4% to 35% of total ginsenosides by weight; Rb1, 40% to 70% of total ginsenosides by weight; Rc from 5% to 35% of total ginsenosides by weight; Rb2, from 2% to 15% of total ginsenosides by weight; and / or Rd from 9% to 30% of total ginsenosides by weight.

11. 11. The composition for use according to claim 10, comprising the following ginsenosides: Rg1, 3% to 4% of total ginsenosides by weight; Re from 12% to 17% of total ginsenosides by weight; Rb1, 40% to 50% of total ginsenosides by weight; Rc from 12% to 17% of total ginsenosides by weight; Rb2, from 2% to 5% of total ginsenosides by weight; and / or Rd from 12% to 15% of total ginsenosides by weight.

12. The composition for use according to any one of claims 1 to 11, wherein the composition is administered in the form of: (a) a pharmaceutical or nutraceutical composition comprising a pharmaceutically acceptable excipient; or (b) A food composition comprising a food-acceptable ingredient.

13. The composition for use according to any one of claims 1 to 12, wherein the composition comprising ginsenoside is administered in an amount of from 100 mg / day to 2000 mg / day, or from 500 mg / day to 1500 mg / day.

14. The composition for use according to any one of claims 1 to 13, wherein the subject is a human.

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