Method for treating intestinal microbiota dysbiosis and composition used in such treatment

Abstract

The present invention relates to intestinal microbiota-modulating compositions containing at least one type of polyphenol, at least one type of beta-glucan and at least one type of fermentable fibre, for use in the partial or total reversal of intestinal dysbiosis and in the reduction of symptoms, in supporting treatment and even in the remissive control of health disorders caused by it, such as most autoimmune spectrum diseases, including sleep quality, intestinal and urinary inflammation, chronic pain, muscle mass formation and respiratory capacity. The composition for modulating intestinal microbiota comprises by mass relative to the total mass of the composition: (a) 5% to 55% polyphenols; (b) 5% to 23% beta-glucans; (c) 33% to 93% fermentable fibre.

Description

"METHOD FOR TREATING INTESTINAL MICROBIOTA DYSBIOSIS AND COMPOSITION USED IN SUCH TREATMENT" FIELD OF APPLICATION

[0001] The present invention relates to a composition for the modulation of dysbiotic intestinal microbiota comprising polyphenols, beta-glucans and fermentable fibers, with the use of low daily intake doses and treatment employing such nutraceutical composition. STATE OF THE ART

[0002] The human gut microbiota evolves in species diversity until around age 7, when it stabilizes and the immune system begins to protect it against the entry of new species. This set of species is called alpha diversity, which remains unchanged for the rest of life.

[0003] After the age of 7, variations in the abundance of species within a microbiota can occur. The set of species abundances within a microbiota is called beta-diversity, which can vary due to several stressors.

[0004] Stressors that can cause changes in the beta-diversity of the gut microbiota can be environmental, dietary, chemical, and / or emotional in nature.

[0005] Alterations in the alpha and / or beta diversity of the gut microbiota that cause harm to health are called dysbiosis.

[0006] It is estimated that gut microbiota dysbiosis, or simply gut dysbiosis, affects approximately 50% of healthy people and 70% of people suffering from chronic diseases such as overweight, diabetes, intestinal inflammation, allergies, cancer, and most autoimmune diseases.

[0007] There is a growing understanding of the interrelationships between gut microbiota species and the neurological, endocrine, and immune systems, whether through direct action or through their metabolites.

[0008] The process of partially or completely restoring the alpha and / or beta diversity of a dysbiotic gut microbiota back to the normal levels of a 7-year-old is called modulation.

[0009] Several tools have been used to modulate dysbiotic gut microbiota, such as dietary changes, fecal microbiota transfer (FMT), probiotics, prebiotics, and polyphenols. Taken in isolation, all these methods have limitations, and their effects are only ephemeral or partial. This is due to the sacrifices required to maintain them, as in the case of dietary changes; the risks of sepsis, as in the case of therapeutic monoxide therapy; and the potential side effects, inconsistency, and, especially, the high daily intake required, as in the case of probiotics, prebiotics, and polyphenols when used in isolation.

[0010] Currently, the human microbiota in urbanized regions averages 300 to 400 species, making it difficult to achieve significant and consistent changes over time without acting directly or indirectly on a significant number of these species.

[0011] With the recent advent of genomic analyses of gut microbiota, it has become clear that achieving significant effects in modulating gut microbiota requires significantly altering the abundances of dozens of species and exploiting competitive exclusion among them. Therefore, to target a significant number of species, it is necessary to combine various tools, as each tends to act only on a restricted group of species. Furthermore, the combined use of microbiota modulation tools often exhibits synergy, so that the results tend to be superior to those expected with the use of each tool in isolation.

[0012] The present invention is based on the combination of such tools in proportions that have shown synergy in the modulation of intestinal microbiota, leading to significant results with the use of small daily doses of the composition. Reducing the daily dose is important to maintain patient adherence to the use of the composition for the time necessary to obtain the desired results, which is measured in months and years.

[0013] A low daily intake dose of the composition is also necessary to avoid the side effects that each component usually presents, as the daily intake doses need to be increased when each of the tools is used in isolation.

[0014] Among the most common side effects of using probiotics in isolation are pancreatitis induced by prolonged use and high daily doses of probiotics, or SIBO (small intestinal bacterial overgrowth) caused by high doses. Daily intake of fermentable fibers (prebiotics) and intoxications caused by high daily doses of polyphenols.

[0015] The present invention utilizes three types of tools which, when combined in the correct proportions and used in low daily doses, are able to modulate the intestinal microbiota totally or partially, as well as the respective neuroendocrine-immunological systems related to it.

[0016] Polyphenols are the first tool. Until recently, polyphenols were seen only as substances, usually of plant origin, that acted chemically and directly on the human organism, typically exhibiting antioxidant effects. Currently, with the advent of genomic analyses of the intestinal microbiota, it is possible to observe that these substances are metabolized by the intestinal microbiota, having a great effect on the abundance of various species. Furthermore, it is likely that most of the effects until recently attributed to polyphenols are actually produced by metabolites resulting from their metabolization by the species of the intestinal microbiota. Plasma spectrometric analyses have shown that the absorption of polyphenols by the organism is very small, if not zero. Due to the effect that polyphenols have on the beta diversity of intestinal microbiota, they have been considered new prebiotics.

[0017] Beta-glucans are the second tool. They play several roles in the process of modulating the microbiota and the neuroendocrine-immunological system of the organism. The first role is their ability to directly modulate the enteric immune system, acting as a harmless vaccine that keeps it active and trained. A second role is that of adsorbent of fecal mycotoxins, decreasing the amount of toxins that cross the tight junctions between enterocytes and enter the bloodstream, causing lesions and inflammation. A third role is that they also serve as a substrate for the fermentation of certain species of the intestinal microbiota, whose abundance is desired to be increased.

[0018] Fermentable fibers are the third tool. They are oligosaccharides and polysaccharides that can only be metabolized by certain species of the gut microbiota. For this reason, these saccharides have always been called prebiotics. Each of these saccharides is usually fermented or metabolized by a small group of microbiota species, which are capable of producing the enzymes necessary to break the bonds. chemical compounds that bind together the monosaccharides that form these fibers and which are your food.

[0019] Although much remains to be discovered about their mechanisms of action, it is known that metabolites from the metabolism of polyphenols and fermentable fibers play a significant role in modulating the neuroendocrine-immune system.

[0020] There are countless possible combinations that can be made with polyphenols, beta-glucans, and fermentable fibers, each containing different species, different proportions, and suitable for consumption in varying doses.

[0021] Each different composition containing polyphenols, beta-glucans, and fermentable fibers will produce different modifications in the gut microbiota, with equally different alterations in health, whether these are beneficial or harmful.

[0022] Recently, it has been possible to establish correlations and associations between the abundance of gut microbiota species and health problems, making it clear that different compositions containing polyphenols, beta-glucans, and fermentable fibers are necessary to aid in the treatment of each disease.

[0023] Intestinal dysbiosis is identified as a cause of several chronic diseases, such as: obesity, diabetes, certain types of cancer, chronic intestinal inflammation, allergies / intolerances, and various other autoimmune diseases.

[0024] Several neurological disorders, such as poor sleep quality, mood swings, and a propensity to engage in physical activity, are also cited as consequences of gut dysbiosis.

[0025] Low immunity, especially against viruses and digestive tract cancers, is attributed to an imbalance between the cytokines IL-6, IL-10, and TNF-alpha. In turn, this imbalance is also often a consequence of intestinal dysbiosis.

[0026] The treatment of various health disorders with immunotherapies, chemotherapeutics, analgesics, anxiolytics, etc., has shown low efficiency, since the imbalance of the neuroendocrine-immunological system, caused by intestinal dysbiosis, prevents an adequate response from the organism. This is one of the reasons why many health disorders become chronic.

[0027] Reversing, partially or completely, intestinal dysbiosis is fundamental to increasing the effectiveness of treatments for chronic diseases, especially those related to... autoimmune spectrum.

[0028] Medical research has sought to address health problems stemming from intestinal dysbiosis with chemical substances, which often act quickly on symptoms but without resolving the causes. In addition to being increasingly expensive solutions and having side effects, they are not very effective in achieving remission or partial control of these conditions.

[0029] In a world with an ever-growing elderly population and healthcare systems facing increasing challenges to sustainability, it is imperative that lasting and affordable solutions be found for healthcare problems.

[0030] The inventors are aware of the following documents and assert that the present invention does not infringe upon any of them.

[0031] Document WO 2013 / 032744 A2 describes a formulation with a dosage of less than 200 calories comprising 4 g of indigestible carbohydrates, but fermentable by the intestinal microbiota, 2 g of beta-glucans, and 700 mg of polyphenol compounds. The polyphenols used are derived from berries and are exemplified by quercetin, petunidin, malvidin, delphinidin, and cyanidin. The formulation contains, by mass, 4 to 40% indigestible carbohydrate, 2 to 21% glucan, and 0.5 to 9% polyphenol. The formulation is administered orally in a dosage that, relative to body weight, comprises 2 to 120 mg / kg of indigestible carbohydrate, 2 to 80 mg / kg of beta-glucan, and 2 to 120 mg / kg of polyphenolic extracts from berry-type fruits. The document also indicates the consumption of fermentable fiber, which is 20 to 60 mg / kg BW; beta-glucans, which is 10 to 30 mg / kg BW; and blueberry extract or other polyphenols, which is 20 to 60 mg / kg BW.In the case of the present invention, the main differences from the aforementioned document are that the consumption of the components is significantly lower, the same polyphenols are not used, and the application objective is different. In the case of the present invention, the consumption of fermentable fibers is 5 to 25 mg / kg BW, that of beta-glucans is 1 to 5 mg / kg BW, and that of polyphenols is 1 to 10 mg / kg BW, in addition to the preferred polyphenols being berberine, curcumin, fisetin, and silymarin.

[0032] Document WO 2015 / 200842 A1 concerns a pharmaceutical composition for oral administration based on metformin and a microbiome modulator that may be based on inulin, plant-derived beta-glucan (preferably oat) and polyphenol extracted from berry-type fruit (red fruit, particularly blueberry). In the case of the present invention, the main differences are that metformin is not used and the application is not aimed at diabetes.

[0033] Document BR 112015024846-2 describes a vitamin D-based composition used to enhance one or more polyphenols in bone formation, particularly oleuropein and hydroxytyrosol, and the formulation may also contain prebiotics. In the case of the present invention, the main differences are that most of the components of the aforementioned document, such as hydroxytyrosol, oleuropein, or vitamin D, are not used, and the application is not aimed at bone growth.

[0034] Brazilian patent document BRPI 0416731-7 describes methods for reducing the amount of Desulfovibrio and / or Helicobacter spp. in the GI tract of a pet, for treating inflammation in the GI tract of a pet, and for reducing odor, through the administration of a fiber comprising oligosaccharide, galactan, and beta-glucan, or mixtures thereof. The fiber may be XOS, GOS, FOS, and inulin. The polyphenol is taxifolen. In the case of the present invention, the main differences are that the application is for humans and that beta-glucans are used, which are not used in the aforementioned patent.

[0035] US patent 11730749 B2 describes a composition that modulates the intestinal microbiota in the form of capsules, pills, tablets, etc., of a polyphenol comprising at least 15% by weight of chlorogenic acid, an oligosaccharide (XOS), a phenol extracted from green coffee beans, and chromium polynicotinate. In the case of the present invention, the main difference is that XOS is not used.

[0036] WO 00 / 64282 describes a functional food that, in relation to its dry mass, comprises: (A) 10–90% linear fructans, branched fructans, and / or FOS; (B) 0.1–80% polyphenols (naringin, hesperidin, hesperetin, anthocyanins, and resveratrol). The main differences are that the components used are dried individually, beta-glucans are used in the composition, calcium sources are not used, and the components narangin, hesperidin, hesperetin, and resveratrol are not included.

[0037] WO 2008 / 076579 A2 document deals with a method of weight control for women with estrogen deficiency by administering a composition comprising: (A) solid dried fruits comprising flavonoids, hydroxycyanamic acid and a fiber, wherein at least 20% by weight of the fiber is soluble; and (B) an indigestible and soluble oligosaccharide; wherein the weight ratio of (A) / (B) may vary from 15:1 to 1:15. In the case of the present invention, the main differences are that solid fruits are not used and the document does not use beta-glucans.

[0038] Documents BR 102020008884 and BR 102020016156 describe a regulatory composition for the neuro-immune-endocrine system comprising 3 prebiotics (beta-glucans and GOS and FOS) and a silymarin phytotherapeutic (by weight, 2 to 10% beta-glucans, 38 to 70% prebiotics and 4 to 11% silymarin). In the case of the present invention, the main difference is that it does not use only silymarin and the daily dosage is also lower. OBJECTIVES OF THE INVENTION

[0039] The present invention aims to contribute to reversing intestinal dysbiosis, totally or partially, in a permanent, inexpensive way and without side effects.

[0040] Another objective of the invention was to provide a solution to increase patient adherence to treatment for intestinal microbiota dysbiosis, using small daily doses. PROBLEM SOLVED

[0041] The present invention has demonstrated a lasting solution for reversing intestinal dysbiosis, which is considered the cause of most chronic diseases and, indirectly, the cause of the low efficiency of their treatment. The products of this invention should be used in the prevention and support of the treatment of a large part of the autoimmune spectrum diseases. UNUSUAL EFFECT

[0042] The synergy between the components of the formulations allowed for the use of small daily doses, much lower than those recommended for each component in isolation. This is very important for maintaining patient adherence to the treatment of intestinal dysbiosis, which usually takes months or even years. SUMMARY DESCRIPTION

[0043] The present invention describes a set of prebiotic formulations and a method of use or treatment for modulating the intestinal microbiota, reversing, totally or partially, intestinal dysbiosis and the health disorders it causes. These include sleep quality, intestinal and urinary inflammation, digestive tract cancers, chronic pain, muscle mass formation, and respiratory capacity.

[0044] The treatment method for intestinal microbiota dysbiosis according to the invention. This consists of administering a composition comprising, by mass relative to the total mass of the composition: (a) 5% to 55% polyphenols; (b) 5% to 23% beta-glucans; (c) 33% to 93% fermentable fibers; corresponding to a daily intake dose in milligrams per kilogram of body weight of the consumer, as follows: (d) 1.0 to 10.0 mg / kg body weight of polyphenols; (e) 1.0 to 5.0 mg / kg body weight of beta-glucans; (f) 5.0 to 25.0 mg / kg body weight of fermentable fibers. DETAILED DESCRIPTION

[0045] The present invention is represented by a composition that modulates the intestinal microbiota, containing at least one species of polyphenol, at least one species of beta-glucan, and at least one species of fermentable fiber, in proportions and dosages that can provide a reduction, or even complete control, of intestinal dysbiosis, with modulating effects on the neuroendocrine-immunological system of those who consume it.

[0046] Modulating the neuroendocrine-immunological system is the way to restore the body's homeostasis. The greater the body's homeostasis, the greater its response to medications, such as immunotherapies, chemotherapeutics, antidepressants, analgesics, etc.

[0047] Each person has a unique gut microbiota, different from all others, so the same composition within the scope of this invention, used at the same dosage, may have different effects on each person. Similarly, alternatively, a different composition within the scope of this invention may be required for the same disease or health disorder.

[0048] The usage intervals of the classes and species of components provided for in this invention allow for the creation of different compositions to achieve the reduction and / or remission control of various health problems arising from intestinal dysbiosis.

[0049] The scope of this invention includes the components, their proportions, and the dosages for consumption.

[0050] The overall composition of this invention will always have at least one of each kind. One of the classes of basic components presented in Table 1 (Components and their Species in the Composition), shown below: TABLE 1

[0051] For the purposes of the present invention, the mass proportions between the classes and species of active components in the composition will always comply with the proportional limits of Table 2, presented below, where only the components foreseen in Table 1 are considered, regardless of the presence or absence of other substances that may be added to the final product. That is, the percentages in Table 2 assume that the sum of the proportions of polyphenols, beta-glucans, and fermentable fibers in the composition will always be equal to 100%.

[0052] The limits specified in Table 2 refer to the active components, considering 100% theoretical purity. TABLE 2

[0053] For the purposes of the present invention, the daily consumption limits for each class and type of component of the composition, expressed in milligrams of active product per kilogram of body weight of each consumer (mg / kgBW), are presented in Table 3 below.

[0054] The limits specified in Table 3 refer to the active components, considering 100% theoretical purity. (*) mg / kgBW = milligram / kilogram of live weight of the consumer, per day TABLE 3

[0055] The polyphenol species that represent the scope of the invention are: berberine, curcumin, fisetin, silymarin, cranberry proanthocyanidins (PAC), grape seed proanthocyanidins, pycnogenol, and cocoa extract. Preferably, berberine, curcumin, fisetin, and silymarin are used.

[0056] Berberine (C20H18NO4+, CAS no: 2086–83-1) is a naturally occurring benzylisoquinoline alkaloid with a long history of applications in traditional Chinese medicine (Li, T., Wang, P., Guo, W., Huang, X., Tian, ​​X., Wu, G., et al. (2019). Natural Berberine-Based Chinese Herb Medicine Nanostructures Assembled with Modified Antibacterial Application). As a bioactive natural ingredient, berberine occurs naturally in the roots, rhizomes, and bark of various medicinal plants in the Ranunculaceae family (Wang, L., Deng, L., Lin, N., Shi, Y., Chen, J., Zhou, Y., et al. (2020). Berberine Inhibits Proliferation and Apoptosis of Vascular Smooth Muscle Cells Induced by Mechanical Stretch via the PDI / ERS and MAPK Pathways. Life Sci. 259, 118-253. doi:10.1016 / j.lfs.2020.118253), Rutaceae (Ryuk, JA, Zheng, MS, Lee, MY, Seo, CS, Li, Y., Lee, SH, et al. (2012). Discrimination of Phellodendron Amurense and P. Chinês Based on DNA Analysis and Simultaneous Alkaloid Analysis. Arch. Pharm. Res. 35 (6), 1045–1054. (2020).

[0057] Curcumin, commonly referred to as 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, is a compound commonly known as "curcumin I". Therefore, curcumin is a diferuloylmethane with a crystalline yellow-orange color, a molecular weight of 368.39 g / mol, a melting point of 183°C, and the chemical formula C 21 H 20O6. Chemically, it exhibits keto-enol tautomerism, that is, it has a keto form in acidic and neutral solutions and, in the solid state, in alkaline solutions the enol form predominates. (Anand, P., Kunnumakkara, AB, Newman, RA, Aggarwal, BB (2007). Bioavailability of Curcumin: Problems and Promises. Mol. Pharmacy. 4, 807–818. doi: 10.1021 / mp700113r). There are two other compounds known as curcumin, which are called curcumin II [demethoxycurcumin, 1-(4-hydroxy-3-methoxyphenyl)-7-(4-hydroxyphenyl)-1,6-heptadiene-3,5-dione] and curcumin III [bisdemethoxycurcumin, 1,7-bis(4-hydroxyphenyl)-1,6-heptadiene-3,5-dione] (Buckingham, J. (2018). Dictionary of Natural Products on DVD.

[0058] Proanthocyanidins (PACs), or condensed tannins (CTs), are oligomers of the flavan-3-ol class, naturally produced by plants. Like other polyphenols, PACs have shown promising health benefits and effects on the gut microbiota (Cos, P., De Bruyne, T., Hermans, N., Apers, S., Berghe, DV, Vlietinck, AJ (2004). Proanthocyanidins in health care: current and new trends. Curr. Med. Chem. 11, 1345–1359. doi: 10.2174 / 0929867043365288). Chemically, PACs are formed from the polymerization of flavan-3-ol units and are naturally found in the form of oligomers and polymers (Ou & Gu 2014). Flavan-3-ol derivatives include simple monomers, such as catechin, epicatechins, and gallocatechins, or more complex units, such as polymeric and oligomeric units, consisting of two or more flavan-3-ol monomer units (Del Rio et al. 2013).Including the less bioactive and bioavailable polymers (4 or more catechins), they represent a group of flavan-3-ols. condensates, such as procyanidins, prodelphinidins, and propelargonidins (Del Rio et al. 2013).

[0059] Fisetin is a flavonoid with a diphenylpropanoid structure, containing two aromatic rings connected via a heterocyclic oxygenated ring. It is supplemented with 4 OH group substitutions and one oxo group substitution (Jash, SK, and Mondal, S. (2014). Bioactive flavonoid fisetin–A molecule of pharmacological interest. Cardiovasc Dis. 5, 6.). Fisetin is naturally synthesized in several edible plants and acts as a coloring agent in these plants. (Prabhu, K., and Bhute, AS (2012). Plant based natural dyes and mordants: A review. J. Natl. Prod. Plant Resour. 2 (6), 649–664.). It is commonly found in trees and shrubs of the Fabaceae, Anacardiaceae, and Cupressaceae families (Pal, HC, Pearlman, RL, and Afaq, F. (2016). Fisetin and its role in chronic diseases. Adv. Exp. Med. Biol. 928, 213–244. doi:10.1007 / 978-3-319-41334-1_10). In summary, fisetin (7,3′,4′-flavon-3-ol) serves as a yellow / ochre pigment.It is also found in many fruits, such as strawberries, apples, persimmons, onions, and pumpkins (Sahu et al., 2014). Its chemical formula was first described by the Austrian chemist Josef Herzig in 1891.

[0060] Pycnogenol (PYC) is a plant extract obtained from the bark of the French maritime pine (Pinus maritima), common in the Gasgone region. It grows along the entire southwest coast of France. Extracts from maritime pine bark have been used since Hippocrates (Drehsen, G. (1999). “20-From ancient pine bark uses to Pycnogenol” in Antioxidant food supplements in human health. Eds. Packer, L., Hiramatsu, M., Yoshikawa, T. (San Diego: Academic Press), 311–322). The standardized extract is composed of phenolic components, divided into monomers (catechins, epicatechins and taxophenol), condensed flavonoids (classified as procyanidins / proanthocyanidins) and phenolic acids (cinnamic acid and other glycosides) (Petrassi, C., Mastromarino, A., Spartera, C. (2000). Pycnogenol ® in chronic venous insufficiency. Phytomedicine 7 (5), 383–388. doi: 10.1016 / S0944-7113(00)80059-8). Pycnogenol is the registered trademark of a standardized preparation containing 70% procyanidins.

[0061] The beta-glucan species that represent the scope of the invention are: (1,3 and 1,6) beta-glucans extracted from Saccharomyces cerevisiae and Euglena gracilis. Preferably, the (1,3 and 1,6) beta-glucans are extracted from Saccharomyces cerevisiae.

[0062] (1,3 and 1,6) beta-glucans are polysaccharides present in the cell wall of Fungi and some algae, where they act as the cell's external skeleton. Unlike the 1,3 and / or 1,4 beta-glucans present in cereals, which are more efficient as thickeners and gelling agents, the 1,3 and 1,6 beta-glucans from yeasts and algae are more active as immunomodulators and mycotoxin adsorbents. Within the scope of this invention, the 1,3 and 1,6 beta-glucans from the yeast Saccharomyces cerevisiae and the algae Euglena gracilis are used.

[0063] The fermentable fiber species that represent the scope of the invention are: FOS (fructooligosaccharides), GOS (galactooligosaccharides), inulin, polydextrose, and lactulose. Preferably, FOS (fructooligosaccharides), GOS (galactooligosaccharides), and inulin are used.

[0064] Fermentable fibers are oligosaccharides that serve as a specific substrate for the fermentation of certain species of bacteria and fungi, which produce the right enzymes to break the chemical bonds that unite the monosaccharides that compose them. For example, the fermentation of FOS can only be carried out by microorganisms that produce the extracellular invertase enzyme.

[0065] The mass proportions between the components of the compositions of the invention must respect the following limits: polyphenols representing 5% to 55% of the sum of the active components foreseen in this invention, beta-glucans representing 5% to 23% of the sum of the active components foreseen in this invention, and fermentable fibers representing 33% to 93% of the sum of the active components foreseen in this invention.

[0066] The composition of this invention should be consumed in tablets, capsules, and / or sachets.

[0067] The scope of this invention includes the addition of minerals, vitamins, amino acids, and other bioactive substances that may enhance the effects of the compositions. This also includes aggregators, disaggregators, palatability enhancers, silicon dioxide, and other substances necessary for their transformation into a final product.

[0068] A preferred embodiment of this invention provides that the basic component species of the composition are reduced to those listed in Table 4 below. TABLE 4

[0069] In a preferred embodiment of the invention, the mass ratios between the basic component species of this invention must comply with narrower proportional limits, as presented in Table 5 below, considering that the sum of the proportions of polyphenols, beta-glucans and fermentable fibers in the composition will always be equal to 100%.

[0070] The limits specified in Table 5 refer to the active components, considering 100% theoretical purity. (*) assuming the sum Polyphenols + Beta-glucans + Fermentable Fibers TABLE 5

[0071] Polyphenols (berberine, curcumin, silymarin, and fisetin) can be used separately or in mixtures, provided that the sum of their masses does not exceed 5% to 55% of the total mass of the composition.

[0072] Beta-glucans from Saccharomyces cerevisiae or Euglena gracilis can be used separately, or in mixtures with each other, provided that the sum of their masses do not exceed 5% to 23% of the total mass of the composition.

[0073] Fermentable fibers such as FOS (fructooligosaccharides) and / or GOS (galactoligosaccharides) and / or inulin can be used separately, or in mixtures, provided that the total sum of their masses is between 33% and 93%.

[0074] The daily intake of each basic component of the compositions of this invention should respect the following limits: polyphenols representing an intake of 1 mg / kgBW to 10 mg / kgBW, beta-glucans representing an intake of 1 mg / kgBW to 5 mg / kgBW, and fermentable fibers representing an intake of 5 mg / kgBW to 25 mg / kgBW, as shown in Table 3.

[0075] In a preferred embodiment of the invention, the daily consumption limits for each type of component in the composition of this invention, expressed in milligrams of active product per kilogram of body weight of the consumer (mg / kgBW), should be restricted to those presented in Table 6 below.

[0076] The limits specified in Table 6 refer to the active components, considering 100% theoretical purity. (*) mg / kgBW = milligram / kilogram of live weight of the consumer, per day TABLE 6

[0077] The polyphenols listed in Table 6 (berberine, curcumin, silymarin, fisetin) may be used in the composition in a mixed form provided that they do not exceed the limit of 1.0 to 10.0 mg / kg BW per day.

[0078] The beta-glucans listed in Table 6 can be used individually or in combination with each other, provided that they do not exceed the limit of 1.0 to 5.0 mg / kg BW per day.

[0079] The fermentable or indigestible fibers indicated in Table 6 can be used individually or in combination with each other, provided that they do not exceed the limit of 5.0 to 25.0 mg / kg BW per day.

[0080] According to one embodiment of the invention, the treatment for reducing or reversing intestinal dysbiosis administers a composition comprising by mass relative to the total mass of the composition: (a) 5% to 55% polyphenols; (b) 5% to 23% beta-glucans; (c) 33% to 93% fermentable fibers; corresponding to a daily intake dose in milligrams per kilogram of body weight of the consumer, as follows: (d) 1.0 to 10.0 mg / kg BW of polyphenols; (e) 1.0 to 5.0 mg / kg BW of beta-glucans; (f) 5.0 to 25.0 mg / kg BW of fermentable fibers.

[0081] According to a preferred embodiment of the invention, the treatment of dysbiosis or for modulation of intestinal microbiota consists of administering a composition comprising by mass relative to the total mass of the composition: (a) 5% to 55% of polyphenols selected from the group comprising: 2.1% to 25% berberine; and / or 5% to 36% curcumin; and / or 2.1% to 36% silymarin; and / or 2.1% to 25% fisetin; (b) 5% to 23% of beta-glucans selected from the group comprising: 4% to 21% beta-glucans from Saccharomyces cerevisiae; and / or 4% to 21% beta-glucans from Euglena gracilis; (c) 33% to 93% of fermentable fibers selected from the group comprising: 11% to 93% FOS (fructooligosaccharides); and / or 4% to 21% GOS (galactoligosaccharides); and / or 7% to 86% inulin;corresponding to a consumption dose in milligrams per kilogram of the consumer's body weight, per day, as follows: (d) 1.0 to 10.0 mg / kg BW of polyphenols comprising consumption doses (mg / kg BW) of: 0.4 to 5.0 of berberine; and / or 1.0 to 7.1 of curcumin; and / or 0.4 to 7.1 of silymarin; and / or 0.4 to 5.0 of fisetin; (e) 1.0 to 5.0 mg / kg BW of beta-glucans comprising consumption doses; (mg / kgBW) of: 0.7 to 4.3 mg of beta-glucans from Saccharomyces cerevisiae; and / or 0.7 to 4.3 mg of beta-glucans from Euglena gracilis; (f) 5.0 to 25.0 mg / kgBW of fermentable fiber comprising consumption doses (mg / kgBW) of: 4.3 to 18.6 mg of FOS (fructooligosaccharides); and / or 0.7 to 4.3 mg of GOS (galactoligosaccharides) and / or 4.3 to 17.1 mg of inulin.

[0082] The composition of this invention should be ingested orally, once or twice a day.

[0083] The effects of this invention's composition on the gut microbiota typically take 180 days or more to become fully apparent. The first signs, noticeable within the first 24-48 hours, are improved bowel function, with softer stools and an increased number of bowel movements. Approximately after 20 days, the effects of immune system modulation are already noticeable, with attenuation of inflammatory responses, including autoimmune responses, increased resistance to viruses, and improved response to medications, whether immunotherapeutic, antidepressant, analgesic, or chemotherapeutic. Blood tests show a decrease in the inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), and an increase in the anti-inflammatory cytokine interleukin 10 (IL-10). A reduction in blood levels of the protein NFkappa-B can also be observed after 20 days.

[0084] Starting after 90 days, improvements in sleep begin to be noticed. Initially, with more intense dreams and later with an increase in the proportion of deep NREM sleep ¾.

[0085] Use

[0086] The present invention relates to the use of intestinal microbiota-modulating compositions containing at least one polyphenol species, at least one beta-glucan species, and at least one fermentable fiber species, to treat intestinal dysbiosis, reversing it totally or partially, aiming to achieve remission control of the health disorders caused by it, such as most diseases of the autoimmune spectrum, including sleep quality, cancer, intestinal and urinary inflammation, chronic pain, muscle mass formation, and respiratory capacity.

[0087] The treatment for reversing intestinal dysbiosis described in this invention takes months or years, so to maintain patient adherence to treatment it was necessary to reduce the daily intake. Adherence to treatment is fundamental to its success. In the state of the art, the consumption of the isolated components of the composition usually totals 50 to 100 mg / kg BW, which ends up discouraging patients from maintaining treatment in the long term. In this invention, the recommended dosages are in the range of 10 to 20 mg / kg BW.

[0088] The following examples are for illustrative purposes only and should not be taken as limiting the scope of the invention.

[0089] Examples of Use

[0090] Example 1:

[0091] A clinical trial was conducted with two groups of volunteers, aged 17 to 70 years, suffering from chronic ulcerative colitis and Crohn's disease. The colitis group consisted of 50 volunteers and the Crohn's group of 26 volunteers. Both groups were divided into two subgroups each. Each subgroup was supplemented for 365 days with two different nutraceutical compositions to evaluate the effects of reducing intestinal dysbiosis on the effectiveness of the medication treatments each volunteer was using to control their disease. It was a randomized, double-blind trial, meaning that neither volunteer nor researcher knew which composition each volunteer was consuming, and it was not possible to assign volunteers to specific subgroups. Volunteers were instructed to maintain their usual lifestyle.

[0092] The compositions used to supplement each subgroup of volunteers are shown in Table 7 below. Composition LL1 is similar to a composition already commercially produced by the company Efeom Nutrição SA and does not fall within the scope of this invention, as it does not contain any polyphenols in its formulation. The other composition, LL1 + SF, falls within the scope of this invention, since silymarin and fisetin are two polyphenols that are included in the list of components of this invention and meet the mass proportions and daily consumption foreseen therein. TABLE 7

[0093] As can be seen in Table 7, the polyphenols silymarin and fisetin were added to the formulation of the LL1 + FS composition, diluting the composition similar to LL1, so that the daily intake dose of the supplement for both treatments was maintained at 1473 mg / day.

[0094] At the beginning, at 180 days and at 365 days of the experiment, each volunteer was examined to assess the severity of the two diseases. The indicators used for this were colonoscopy (Mayo score), fecal calprotectin levels, and weight gain.

[0095] Due to the severity of the diseases suffered by the volunteers, the medications each one was taking to control them were maintained, and the nutraceutical compositions of the two treatments were used only as a supplement, aiming to reverse intestinal dysbiosis. Each volunteer ingested the compositions in the form of 4 capsules per day, 2 in the morning and 2 at night.

[0096] Table 8 shows the evolution of the indicators for each disease at the beginning, at 180 days, and at 365 days of supplementation. (*) Mayo Score Disease Activity for Ulcerative Colitis (DAI)TABLE 8

[0097] The results in Table 8 show that the evolution of the indicators for the two diseases is not linear, since the volunteers were at different stages of the evolutionary cycle of each disease and were not taking the same medications.

[0098] The time required for the reversal of dysbiosis with the use of nutraceuticals is also a factor that must be considered in the analysis of the results in Table 8, since signs of reversal begin to be perceived after 180 days.

[0099] The results in Table 8 show that, except for weight gain, the results of treatment with LL1 were not very significant for either disease. However, the results of treatment with LL1 + SF were significant at both 180 and 365 days for both diseases.

[0100] Based on these results, after the experiment ended, in the LL1 treatment group, 1 patient with Crohn's disease (equivalent to 7% of the subgroup) had their medication for disease control discontinued and moved into remission control with the use of the LL1 supplement. In the LL1 + SF treatment group, 3 patients with Crohn's disease (23%) and 7 patients with colitis (28%) had their medications for disease control discontinued and moved into remission control with the use of the LL1 + SF supplement.

[0101] Since these are considered chronic diseases, with rare cases of remission, these remission control rates provided by the LL1 + SF composition can be considered very significant.

[0102] These results open the door to the possibility of new Nutraceutical compositions, within the scope of this invention, can achieve even higher rates of remission, controlled or uncontrolled. Especially when combined with FMT (fecal microbiota transfer).

[0103] Example 2:

[0104] In a clinical trial, a group of 63 volunteers, aged 22 to 51, were divided into 3 random subgroups of 21 people each, to be supplemented for 180 days with compositions containing prebiotics, to evaluate their effects on modulating the gut microbiota before the start (T0) and after 180 days (T180). It was a randomized, double-blind trial, so that neither the volunteer nor the researcher knew which composition the volunteer was consuming, nor was it possible to direct volunteers to specific subgroups. The volunteers were instructed to maintain their usual lifestyle.

[0105] The compositions used to supplement each subgroup of volunteers are shown in Table 9 below. Composition LL1 is similar to that already commercially produced by Efeom Nutrição SA and does not fall within the scope of this invention, as it does not contain any polyphenols in its formulation. The other two compositions, LL1 + Berberine and LL1 + Curcumin, fall within the scope of this invention, as berberine and curcumin are two polyphenols included in the list of components of this invention and meet the mass proportions and daily intakes foreseen therein. (*) mass ratio between the basic components of this invention. TABLE 9

[0106] Table 10 below shows that the proportions between the active components of polyphenols (berberine and curcumin), beta-glucans (from Saccharomyces cerevisiae and Euglena gracilis) and fermentable fibers (FOS and GOS), as well as the respective recommended daily intakes for the volunteers, were within the ranges claimed in this invention.

[0107] Each volunteer was instructed to take 4 capsules of their subgroup's composition per day.

[0108] The average weight of the patients was estimated at 70 kg BW. (*) mass ratio between the basic components of this invention. TABLE 10

[0109] Before the start and after 180 days of using the compositions, stool samples were collected from each volunteer. After the end of the test, genomic analyses of the 16S mRNA segments present in the stool were performed to evaluate the alpha and beta diversity of the volunteers' intestinal microbiota. The average results of the analyses, expressed as the abundance of bacterial phyla, are shown in Tables 11 and 12 below. TABLE 11

[0110] The results shown in Table 11 demonstrate that the commercial composition LL1 showed lower efficiency in modulating the intestinal microbiota, as there was less convergence between the proportions of the Firmicutes and Bacteroidetes phyla after 180 days of use. The two compositions that are part of the scope of this invention, LL1 + Berberine and LL1 + Curcumin, proved to be more efficient, as the abundances of the Bacteroidetes and Firmicutes phyla became quite similar. Although there is still no consensus on how to parameterize dysbiosis, it is considered that the microbiota of healthy individuals contains proportions of Firmicutes and Bacteroidetes close to 45% each.

[0111] The results in Table 12 show the changes in the abundance of bacterial genera in the gut microbiota of the volunteers after 180 days of supplementation with the compositions LL1, LL1 + Berberine, and LL1 + Curcumin. TABLE 12

[0112] The results shown in Table 12 demonstrate that the LL1 + Berberine composition was effective in increasing the abundance of the genera Bacteroides, Parabacteroides, Prevotella, Phascolarbacterium, and Gemmiger, while the LL1 + Curcumin composition was effective in increasing the abundance of the genera Bacteroides, Parabacteroides, Prevotella, Phascolarbacterium, and Akkermansia. Similarly, the LL1 + Berberine composition was effective in reducing the abundance of the genera Clostridium, Coprococcus, Dialister, Lachnospira, Roseburia, Ruminococcus, and Sutterella, while the LL1 + Curcumin composition was effective in reducing the abundance of the genera Coprococcus, Dorea, Dialister, Roseburia, and Sutterella.

[0113] Each genus of bacteria is correlated, or associated, with specific health effects. Thus, for each type of health effect, or for each type of modification of the beta-diversity of an intestinal microbiota, there will be a different ideal composition, within the scope of this invention.

[0114] Example 3:

[0115] A clinical trial was conducted with 63 healthy volunteers, aged 21 to 58 years, divided into 3 treatment groups that were supplemented for 365 days with compositions containing prebiotics, to evaluate the health effects that could be observed at 180 days and 365 days after the start of supplementation, related to the endocrine-immune system and sleep, respectively. It was a randomized, double-blind trial, so that neither volunteer nor researcher knew which composition each volunteer was consuming, and it was not possible to direct volunteers to specific subgroups. The volunteers were instructed to maintain their usual lifestyle.

[0116] Before the start and after 180 days of consuming the formulas, blood samples were collected from all volunteers for analysis of key immune and endocrine system indicators. On the same occasions, each volunteer was asked if they experienced recurrent or chronic pain. In addition, at the beginning and end of 365 days of consuming the formulas, the PSQI (Pittsburgh Sleep Quality Index) questionnaire was administered to each volunteer.

[0117] The compositions used to supplement each treatment are shown in Table 13 below. The 3 compositions tested contained at least one polyphenol, at least one beta-glucan, and at least one fermentable fiber in their composition. The formulation, according to the scope of this invention, is in accordance with the proportions and daily consumption doses foreseen in the scope of this invention. Volunteers were instructed to consume 4 capsules of each composition daily, totaling a daily intake of 1,650 mg / day of each composition. (*) mass ratio between the basic components of this invention. TABLE 13

[0118] Although there were significant differences between the components of each composition, all were within the scope of this invention and, for the purpose of demonstrating results, were given names alluding to the polyphenols that each contained, accompanied by FFBG (fermentable fibers + beta-glucans). Thus, these names were FFBG + Fisetin, FFBG + Curcumin, and FFBG + Berberine.

[0119] Table 14, presented below, shows the mass proportions between the active components of polyphenols (fisetin, curcumin and berberine), (1,3 and 1,6) beta-glucans (from Saccharomyces cerevisiae and Euglena gracilis) and fermentable fibers (FOS and GOS), as well as the respective recommended daily intakes for the volunteers, which were within the ranges claimed in this invention.

[0120] The average weight of the patients was estimated at 70 kg BW. (*) mass ratio between the basic components of this invention. TABLE 14

[0121] The PSQI is obtained through a questionnaire administered to each volunteer at the beginning and end of the test. The PSQI measures the amount of sleep disturbances over a given period of time, so the greater the decrease in the indicator, the greater the improvement in sleep quality. As can be seen in Table 15 below, all treatments showed good efficiency in improving sleep quality, although it is possible to state that the FFBG + fisetin combination was the most efficient.

[0122] Table 15 shows the results of sleep quality observed in the clinical trial, based on the application of the Pittsburgh Sleep Quality Index (PSQI) questionnaire. TABLE 15

[0123] Regarding the effects of the treatments on the immune system of the volunteers, Table 16, presented below, shows that all compositions were effective in reducing the inflammatory state of the volunteers.

[0124] Although all volunteers were classified as healthy, modern lifestyles negatively affect immunity, such that most people tend to have a more inflammatory immune system than ideal, with higher levels of the inflammatory cytokines IL-6 and TNF-alpha and lower levels of the anti-inflammatory cytokine IL-10. As a result, cortisol, CRP, and IgM levels also end up being above ideal.

[0125] Table 16 demonstrates the immunological benefits observed in the clinical trial. TABLE 16

[0126] Based on the results presented in Table 16, it can be concluded that the FFBG + Berberine composition was the most efficient in reducing the inflammatory state of the volunteers' immune system, as it provided the highest IL10 / TNF-alpha ratio. Consequently, it led to the lowest levels of cortisol, IgM, and CRP.

[0127] However, although they were not the most efficient in reducing the inflammatory state of the volunteers, the FFBG + Fisetin and FFBG + Curcumin compositions appear to have been the most efficient in reducing chronic pain. This is further proof that for each gut microbiota and for each health disorder there is an ideal composition within the scope of this invention. TABLE 17

[0128] Table 17, presented above, shows that all treatments had beneficial effects on the endocrine system of the volunteers. However, due to the greater reduction in abdominal circumference and the greater weight loss provided, the FFBG + Berberine composition was the most efficient for weight loss.

[0129] Example 4:

[0130] The following are examples of compositions, within the scope of this invention, designed for specific health effects. For the purpose of the example, but without limiting the scope of this invention, the compositions presented below have been supplemented with bioactive substances that could enhance their effects in the use for which they are indicated.

[0131] The inclusion of substances that may contribute to the desired effects in the compositions of this example can be very important to facilitate dialogue with healthcare professionals and consumers, as they are already part of everyday life. Disruptive innovations, such as this invention, often face difficulties in public acceptance, so dialogue with conventional knowledge can be an effective marketing tool for persuasion.

[0132] Composition 1: Designed for Chronic Intestinal Inflammation.

[0133] Table 18 shows a composition within the scope of this invention, designed for use by patients suffering from inflammatory bowel diseases (IBD), such as irritable bowel syndrome, ulcerative colitis, and Crohn's disease. It is presented in tablets, each containing 631 mg of pure active components, the concentration of which is shown in the last column. The implied dosage of each component of the formulation, expressed in mg / kg BW, is shown in the "Daily Dose" column, and the dosages are within the limits of the scope of this invention, which can be seen in the "Invention" columns. TABLE 18

[0134] Although composition 1 modulates the gut microbiota and thus promotes the modulation of the entire neuroendocrine-immunological system, its composition was designed to promote an increase in the abundance of bacteria that are usually scarcer in the gut microbiota of those suffering from inflammatory bowel diseases (IBD), such as irritable bowel syndrome, ulcerative colitis, and Crohn's disease. Furthermore, it is designed to increase the overall abundance of bacteria with the least possible increase in gas production.

[0135] The recommended dosage for composition 1 is 2 tablets (pills) per day for individuals weighing 70 kg.

[0136] The effects of intestinal modulation are slow and should begin to appear after 180 days of starting to consume the formula, becoming more definitive at 365 days. At that point, the metabolites of the new abundances of bacteria will have already modulated the neuroendocrine-immunological system and can be observed in the decrease in fecal calprotectin levels and in the Mayo score obtained by colonoscopy.

[0137] Composition 2: Designed to improve sleep.

[0138] Table 19 shows a composition within the scope of this invention, designed for use by patients who have poor sleep quality or suffer from insomnia. It is presented in tablets, each containing 621 mg of pure active components, the concentrations of which are shown in the last column “Tablet”. The implied dosage of each component of the formulation, expressed in mg / kg BW, is shown in the column “Daily Dose”, and the dosages are in accordance with the limits of the scope of this invention, which can be seen in the columns “Invention”. TABLE 19

[0139] The recommended dosage for composition 1 is 2 tablets (pills) per day for individuals weighing 70 kg.

[0140] The effects of gut modulation are slow and should begin to appear after 90 days of starting to consume the formula, in the form of more intense dreams. The increase in the amount of NREM ¾ deep sleep should become more evident at 180 days and continue to improve steadily until 720 days, when it should then stabilize.

[0141] Composition 3: Designed to improve the immune response.

[0142] Table 20 shows a composition within the scope of this invention, designed for use by patients who have low immunity to viruses and suffer from chronic autoimmune spectrum diseases. It is presented in tablets, each containing 633 mg of pure active components, the concentrations of which are shown in the last column “Tablet”. The implied dosage of each component of the formulation, expressed in mg / kg BW, is shown in the column “Daily Dose”, and the dosages are in accordance with the limits of the scope of this invention, which can be seen in the columns “Invention”. TABLE 20

[0143] Although composition 3 modulates the gut microbiota and thus promotes the modulation of the entire neuroendocrine-immunological system, its composition was designed to promote a better immune response for patients suffering from chronic diseases who require treatment with immunotherapies, chemotherapeutics, antidepressants, and strong analgesics.

[0144] The recommended dosage for composition 1 is 2 tablets (pills) per day for individuals weighing 70 kg.

[0145] Intestinal modulation is a slow process, and the modulating effects on the immune system should begin to appear 20 days after starting consumption of composition 3, in the form of an increase in the number of lymphocytes and IL-10, and a reduction in TNF-alpha and IL-6.

[0146] Composition 4: Focused on women's health

[0147] Table 21 shows a composition within the scope of this invention, designed to modulate the gut microbiota of women, focusing on the abundance of bacteria that help improve resistance to recurrent urinary inflammation, provide better hormonal balance, and strengthen nails and hair. It is Presented in tablets, each containing 628 mg of pure active components, the concentrations of which are shown in the last column “Tablet”. The implied dosage of each component of the formulation, expressed in mg / kg BW, is shown in the column “Daily Dose”, and the dosages are in accordance with the limits of the scope of this invention, which can be observed in the columns “Invention”. TABLE 21

[0148] The recommended dosage for composition 1 is 2 tablets (“pills”) per day for individuals weighing 70 kg BW.

[0149] Intestinal modulation is a slow process, and the effects on women's health should begin to be noticed 90 days after starting to consume composition 4, in the form of reduced menopausal symptoms and stronger nails and hair.

[0150] Composition 5: Designed to improve the quality of life for the elderly.

[0151] Table 22 shows a composition within the scope of this invention, designed to modulate the gut microbiota of elderly people, focusing on the abundance of bacteria that help improve protein absorption in the small intestine, improve sleep quality, and increase the efficiency of the immune system. It is presented in tablets, each containing 624 mg of pure active ingredients. whose concentrations are shown in the last column “Tablet”. The implied dosage of each component of the formulation, expressed in mg / kg BW, is shown in the column “Daily Dose”, and the dosages are in accordance with the limits of the scope of this invention, which can be seen in the columns “Invention”. TABLE 22

[0152] Although composition 5 modulates the gut microbiota and thus promotes the modulation of the entire neuroendocrine-immunological system, its composition was designed to promote a better immune response to vaccines, improved sleep quality, and better protein absorption in the small intestine, which is essential to prevent sarcopenia.

[0153] The recommended dosage for composition 1 is 2 tablets (pills) per day for individuals weighing 70 kg.

[0154] Intestinal modulation is a slow process, and the modulating effects on the immune system should begin to appear 20 days after starting consumption of composition 5, in the form of an increase in the number of lymphocytes and IL-10, and a reduction in TNF-alpha and IL-6.

[0155] Composition 6: Designed to improve the performance of athletes.

[0156] Table 21 shows a composition within the scope of this invention. Designed to modulate the gut microbiota of athletes, focusing on reducing the inflammatory state by reducing the overall amount of inflammatory cytokines, and increasing mitochondrial biogenesis by reducing the NFkappa-B protein. It is presented in tablets, each containing 644 mg of pure active components, the concentrations of which are shown in the last column "Tablet". The implied dosage of each component of the formulation, expressed in mg / kg BW, is shown in the column "Daily Dose", and the dosages are within the scope of this invention, which can be seen in the columns "Invention". TABLE 23

[0157] Although composition 6 modulates the gut microbiota and thus promotes the modulation of the entire neuroendocrine-immunological system, its composition was designed to promote a reduction in the overall inflammatory state and increase the number of mitochondria per cell in the body, thereby increasing its respiratory capacity and the production of lean mass.

[0158] The recommended dosage for composition 1 is 2 tablets (pills) per day for individuals weighing 70 kg.

[0159] The intestinal modulation effects of composition 6 should only be noticeable, in the form of VO2 measurement, after 180 days from the start of consumption.

Claims

1 / 5 CLAIMS 1. A method for treating intestinal microbiota dysbiosis characterized by administering a composition comprising, by mass relative to the total mass of the composition: (a) 5% to 55% polyphenols; (b) 5% to 23% beta-glucans; (c) 33% to 93% fermentable fibers; corresponding to a daily intake dose in milligrams per kilogram of body weight of the consumer, as follows: (d) 1.0 to 10.0 mg / kg BW of polyphenols; (e) 1.0 to 5.0 mg / kg BW of beta-glucans; (f) 5.0 to 25.0 mg / kg BW of fermentable fibers.

2. A method for treating intestinal microbiota dysbiosis, according to claim 1, characterized in that polyphenols can be chosen from the group comprising: berberine, curcumin, fisetin, silymarin, cranberry proanthocyanidins (PAC), grape seed proanthocyanidins, pycnogenol, and cocoa extract. 3.A method for treating intestinal microbiota dysbiosis, according to claim 2, characterized by employing berberine, curcumin, fisetin, and silymarin.

4. A method for treating intestinal microbiota dysbiosis, according to claim 1, characterized by employing (1,3 and 1,6) beta-glucans extracted from Saccharomyces cerevisiae and Euglena gracilis.

5. A method for treating intestinal microbiota dysbiosis, according to claim 4, characterized by employing (1,3 and 1,6) beta-glucans extracted from Saccharomyces cerevisiae.

6. A method for treating intestinal microbiota dysbiosis, according to claim 1, characterized by the fermentable fibers being chosen from the group comprising: FOS (fructooligosaccharides), GOS (galactooligosaccharides), inulin, polydextrose, and lactulose. 7.A method for treating intestinal microbiota dysbiosis, according to claim 6, characterized by employing FOS (fructooligosaccharides), GOS (galactooligosaccharides), and inulin. 2 / 5 8. Method for treating intestinal microbiota dysbiosis, according to claim 1, characterized by employing by mass in relation to the total mass of the composition: 2.1% to 25% berberine; and / or 5% to 36% curcumin; and / or 2.1% to 25% fisetin; and / or 2.1% to 36% silymarin; provided that the total sum of their masses is from 5% to 55%.

9. Method for treating intestinal microbiota dysbiosis, according to claim 1, characterized by employing by mass in relation to the total mass of the composition: 4% to 21% beta-glucans from Saccharomyces cerevisiae; and / or 4% to 21% beta-glucans from Euglena gracilis; provided that the total sum of their masses is from 5% to 23%. 10.A method for treating intestinal microbiota dysbiosis, according to claim 1, characterized by employing, by mass relative to the total mass of the composition: 11% to 93% FOS (fructooligosaccharides); and / or 4% to 21% GOS (galactoligosaccharides); and / or 7% to 86% inulin; provided that the total sum of their masses is from 33% to 93%.

11. A method for treating intestinal microbiota dysbiosis, according to claim 1, characterized by employing the following daily consumption doses (mg / kg BW): 0.4 to 5.0 of berberine; and / or 1.0 to 7.0 of curcumin; and / or 0.4 to 5.0 of fisetin; and / or 0.4 to 7.1 of silymarin; provided that the daily consumption dose of polyphenols is between 1.0 and 10.

0. 12.A method for treating intestinal microbiota dysbiosis, according to claim 1, characterized by employing the following daily intake doses (mg / kg BW): 0.7 to 4.3 mg of beta-glucans from Saccharomyces cerevisiae; and / or 0.7 to 4.3 mg of beta-glucans from Euglena gracilis; provided that the intake dose of beta-glucans is between 1.0 and 5.0 mg. A method for treating intestinal microbiota dysbiosis, according to claim 1, characterized by employing the following daily intake doses (mg / kg BW): 2.1 to 18.6 mg of FOS (fructooligosaccharides); and / or 0.7 to 4.3 mg of GOS (galactoligosaccharides); and / or 1.4 to 17.1 mg of inulin; provided that the intake dose of fermentable fibers is between 5.0 and 25.0 mg.

14. Method for treating intestinal microbiota dysbiosis, according to claim 1, characterized by administering a composition comprising... 3 / 5 by mass in relation to the total mass of the composition: (a) 5% to 55% of polyphenols selected from the group comprising: 2.1% to 25% berberine; and / or 5% to 36% curcumin; and / or 2.1% to 25% fisetin; and / or 2.1% to 36% silymarin; (b) 5% to 23% of beta-glucans selected from the group comprising: 4% to 21% beta-glucans from Saccharomyces cerevisiae; and / or 4% to 21% beta-glucans from Euglena gracilis; (c) 33% to 93% of fermentable fibers selected from the group comprising: 11% to 93% FOS (fructooligosaccharides); and / or 4% to 21% GOS (galactoligosaccharides); and / or 7% to 86% inulin; corresponding to a consumption dose in milligrams per kilogram of the consumer's live weight, per day, as follows: (d) 1.0 to 10.0 mg / kg BW of polyphenols comprising consumption doses (mg / kg BW) of: 0.4 to 5.0 of berberine; and / or 1.0 to 7.1 of curcumin; and / or 0.4 to 5.0 of fisetin; and / or 0.4 to 7.1 of silymarin;(e) 1.0 to 5.0 mg / kg BW of beta-glucans comprising consumption doses (mg / kg BW) of: 0.7 to 4.3 of beta-glucans from Saccharomyces cerevisiae; and / or 0.7 to 4.3 of beta-glucans from Euglena gracilis; (f) 5.0 to 25.0 mg / kg BW of fermentable fibers comprising consumption doses (mg / kg BW) of: 4.3 to 18.6 of FOS (fructooligosaccharides); and / or 0.7 to 4.3 of GOS (galactoligosaccharides); and / or 4.3 to 17.1 of inulin.

15. Composition for the treatment of intestinal microbiota dysbiosis, described in any of claims 1 to 14, characterized by comprising by mass in relation to the total mass of the composition: (a) 5% to 55% polyphenols; (b) 5% to 23% beta-glucans;(c) 33% to 93% fermentable fiber.

16. Composition for the treatment of intestinal microbiota dysbiosis, according to claim 15, characterized in that the polyphenols can be chosen from the group comprising: berberine, curcumin, fisetin, silymarin, grape seed proanthocyanidins, cranberry proanthocyanidins (PAC), pycnogenol and cocoa extract. 4 / 5 17. Composition for the treatment of intestinal microbiota dysbiosis, according to claim 16, characterized by employing berberine, curcumin, fisetin and silymarin.

18. Composition for the treatment of intestinal microbiota dysbiosis, according to claim 15, characterized by employing (1,3 and 1,6) beta-glucans extracted from Saccharomyces cerevisiae and Euglena gracilis.

19. Composition for the treatment of intestinal microbiota dysbiosis, according to claim 18, characterized by employing (1,3 and 1,6) beta-glucans extracted from Saccharomyces cerevisiae.

20. Composition for the treatment of intestinal microbiota dysbiosis, according to claim 15, characterized in that the fermentable fibers are selected from the group comprising: FOS (fructooligosaccharides), GOS (galactooligosaccharides), inulin, polydextrose and lactulose. 21.Composition for the treatment of intestinal microbiota dysbiosis, according to claim 20, characterized by employing FOS (fructooligosaccharides), GOS (galactooligosaccharides), and inulin.

22. Composition for the treatment of intestinal microbiota dysbiosis, according to claim 15, characterized by comprising, in relation to the total mass of the composition: (a) 5% to 55% of polyphenols selected from the group comprising: 2.1% to 25% berberine; and / or 5% to 36% curcumin; and / or 2.1% to 25% fisetin; and / or 2.1% to 36% silymarin; (b) 5% to 23% of beta-glucans selected from the group comprising: 4% to 21% beta-glucans from Saccharomyces cerevisiae; and / or 4% to 21% beta-glucans from Euglena gracilis; (c) 33% to 93% fermentable fibers selected from the group comprising: 11% to 93% FOS (fructooligosaccharides); and / or 4% to 21% GOS (galactoligosaccharides); and / or 7% to 86% inulin. 23.A method for treating intestinal microbiota dysbiosis, according to any of the preceding claims, characterized by being intended for oral consumption, to treat intestinal dysbiosis, reversing it totally or partially, aiming to achieve remission control of the health disorders caused by it, such as most. 5 / 5 of autoimmune spectrum diseases, including sleep quality, cancer, bowel and urinary inflammation, chronic pain, muscle mass formation, and respiratory capacity.

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