Synergistic composition including butyric acid and agave fructan

Abstract

The present invention relates to a composition, foodstuff, food supplement, or pharmaceutical composition comprising butyric acid or a derivative thereof and agave fructan, and its use for maintaining and / or enhancing proper gastrointestinal function. Figure for the abstract: Fig. 1

Description

Title of the invention: Synergistic composition comprising butyric acid and agave fructan. TECHNICAL FIELD OF THE INVENTION

[0001] The present invention relates to a composition, a foodstuff, a food supplement or a pharmaceutical composition, comprising butyric acid or a derivative thereof and agave fructan, and its use for maintaining and / or enhancing gastrointestinal health. Previous technique

[0002] Humans and animals live in symbiosis with their gut microbiome. One of the essential functions of the gut microbiome is microbial fermentation, primarily of indigestible complex carbohydrates to short-chain fatty acids (SCFAs), such as acetic acid, propionic acid, valeric acid, caproic acid, and butyric acid. SCFAs are produced mainly in the colon and therefore have numerous local and systemic effects on the body. Locally in the intestines, SCFAs are an essential source of energy for colonocytes (cells of the colonic mucosa) and participate in maintaining the intestinal epithelial barrier, regulating intestinal motility, and producing anti-inflammatory substances (Barko, PC, McMichael, MA, Swanson, KS, & Williams, DA (2018)). The gastrointestinal microbiome: a review.Journal of Veterinary International Medicine, 32(1), 9-25). At the systemic level, SCFAs participate, in particular, in energy homeostasis, metabolism and immunity and have a positive effect on the functioning of the respiratory tract and the nervous system (Koh, A., De Vadder, F., Kovatcheva-Datchary, P., & Bâckhed, F. (2016). From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell, 165(6), 1332-1345).

[0003] The composition of the gut microbiome is impacted by various factors, including genetic predisposition, type of delivery, age, diet, geolocation, cultural background, medication use, and physical and psychological stress. The diversity of the gut microbiome is essential for good health and has an immediate impact on, among other things, the brain, joints, immune system, liver, skin, metabolism, athletic performance, respiratory system, etc. Loss of this diversity is associated with a large number of gastrointestinal and systemic diseases, including inflammatory and neoplastic bowel diseases, asthma, obesity, and syndrome metabolic, cardiovascular diseases, immune-mediated diseases, as well as neurodevelopmental abnormalities, such as autism spectrum disorder.

[0004] A disrupted gut microbiome is defined as an alteration of the gut microbiome that leads to adverse health consequences. A disrupted gut microbiome is characterized by significant changes in microbial composition, a decrease in diversity, and changes in the relative proportions of certain microorganisms, resulting in the onset of a negative effect from pathogenic microorganisms, which are usually present in small quantities. This decrease in diversity, in turn, leads to a reduction in SCFA production and, consequently, a decrease in SCFA concentration in the colon, with the resulting negative consequences.

[0005] A disrupted gut microbiome may be asymptomatic, but generally results in a wide range of gastrointestinal and general symptoms. Gastrointestinal symptoms include, but are not limited to, halitosis, abdominal cramps, abdominal pain, flatulence, diarrhea, constipation, food intolerances, malabsorption, anorectal infections and itching, as well as weight loss. General symptoms include, but are not limited to, difficulty urinating, urogenital infections and itching, skin rashes, arthralgia, and chronic fatigue.

[0006] SCFA supplementation in the colon is difficult to achieve. When administered orally, SCFAs are generally absorbed before they reach the colon; and when administered rectally, SCFAs only reach the most distal part of the colon, so that most of the intestinal mucosa cannot benefit from these essential substances.

[0007] Instead of administering SCFAs directly, there is also a possibility of indirectly promoting their production by stimulating the beneficial gut microbiome. To this end, probiotics or substances that stimulate the presence and proper functioning of the beneficial gut microbiome (prebiotics) can be administered. When using probiotics, they are generally administered orally. The drawback of this approach is that the exogenous flora must survive the acidic conditions of the stomach and then colonize the existing ecosystem. In practice, only a very limited number of strains manage to withstand stomach conditions, and colonization of the intestines is very short-lived, so at least one readministration per day is necessary.Although the administration of probiotics is often effective, it can nevertheless be associated with serious complications, mainly in individuals with a weakened immune system, in cases of malnutrition. severe or in cases of impaired intestinal epithelial barrier. These serious complications include, in particular, bacteremia, septicemia, and endocarditis.

[0008] Prebiotics are molecules that promote the growth and activity of beneficial microorganisms, such as bacteria and yeasts, and frequently inhibit the growth of harmful microorganisms. They are generally of plant origin and, in the case of fermentation, lead, in particular, to the production of short-chain fatty acids (SCFAs). Prebiotics can thus promote gastrointestinal health in both healthy individuals and those suffering from various diseases, including gastrointestinal disorders. Since prebiotics are not microorganisms, they are safer than probiotics.When using prebiotics, plant extracts shown to be used solely as substrates by the body's own beneficial microbiome are typically added through food. This results in an increase in the beneficial microbiome at the expense of the harmful one. These extracts are unaffected by stomach conditions and can therefore be easily added to food or dietary supplements, which is technically less the case for probiotics. Most prebiotics are carbohydrates, such as fructans, galacto-oligosaccharides, resistant starch, and glucose-derived oligosaccharides. The effect of these different types of carbohydrates is often unpredictable and can vary significantly depending on the type of microorganism being stimulated and the production of short-chain fatty acids (SCFAs).Different species of bacteria are, for example, supported by linear fructans with different chain lengths (Davani-Davari, D., Negahdaripour, M., Karimzadeh, I., et al. (2019). Prebiotics: definition, types, sources, mechanisms, and clinical applications. Foods, 8(3), 92).

[0009] Given the considerable role that the gut microbiome plays in gastrointestinal health and the overall health of the individual, there is a continuing need to explore compositions that have a beneficial effect on the gut microbiome. This refers, in this case, to compositions, foodstuffs, and food supplements that have a therapeutic and / or prophylactic effect on the gut microbiome, and which are capable, in particular, of increasing the concentration of SCFAs in the colon. Summary of the invention

[0010] The inventors have now surprisingly found that the simultaneous administration of a short-chain fatty acid, in particular butyric acid or a derivative thereof, and agave fructan has a beneficial synergistic effect on the gut microbiome. As shown by the examples, the simultaneous administration of a butyric acid derivative and agave fructan resulted in a There was an unexpected and significant increase in the concentration of SCFAs in the colon. This increase was, moreover, significantly lower, or even non-existent, when butyric acid derivative or agave fructan were administered alone.

[0011] It should be noted that a previous study by Overland et al. 2008 ("Organic acids in diets for entire male pigs: Effect on skatole level, microbiota in digesta, and growth performance," Livestock Science, Elsevier, 2008, Part 115, No. 23, 169-178) shows that a composition of inulin (a fructan from chicory) and butyric acid is less effective at influencing the gut microbiome than the administration of a single dose of an organic acid or a fructan (i.e., inulin). As explained in more detail elsewhere, inulin and agave fructan differ structurally and are metabolized in different ways. The synergistic effect of butyric acid or a derivative thereof and agave fructan, which has been established by the inventors, is also astonishing, even in light of previous results that have been described with inulin.

[0012] A particular embodiment of the present invention therefore comprises a composition containing butyric acid or a derivative thereof and agave fructan as active ingredients in effective amounts, wherein the butyric acid derivative is selected from the group consisting of a salt, an ester, and an amide of butyric acid. According to a further embodiment, the butyric acid derivative is glycerol monobutyrate or a mixture of glycerol butyrates.

[0013] According to one particular embodiment, the present invention provides a composition comprising agave fructan in an amount from 20 to 500 g / l and butyric acid or a derivative thereof in an amount from 5 to 100 g / l. According to yet another particular embodiment, the composition of the invention contains agave fructan in an amount from 50 to 200 g / l and butyric acid or a derivative thereof in an amount from 10 to 80 g / l.

[0014] The composition of the present invention can, moreover, be included in a foodstuff, a food supplement, or a pharmaceutical composition. In one particular embodiment, a foodstuff is provided containing the composition according to the invention. In another particular embodiment, a food supplement is provided containing the composition according to the invention. In yet another particular embodiment, a pharmaceutical composition is provided containing the composition according to the invention and a pharmaceutically acceptable vehicle.

[0015] The present invention further provides the composition, foodstuff, food supplement, or pharmaceutical composition for use as described herein. According to a particular embodiment, the invention provides the use of the composition, foodstuff, or food supplement. or the pharmaceutical composition for the treatment, improvement and / or prevention of a disturbed gut microbiome. According to another particular embodiment, the invention provides the use of the composition, the foodstuff, the food supplement or the pharmaceutical composition to increase the concentration of short-chain fatty acids in the gastrointestinal system, preferably in the colon.

[0016] According to one particular embodiment, the invention provides for the use of the composition, foodstuff, dietary supplement, or pharmaceutical composition for maintaining and / or enhancing gastrointestinal health. According to a further particular embodiment, maintaining and enhancing gastrointestinal health includes treating and / or preventing a disrupted gut microbiome. According to another particular embodiment, maintaining and enhancing gastrointestinal health includes improving intestinal wall function. According to a further particular embodiment, maintaining and enhancing gastrointestinal health includes increasing the concentration of short-chain fatty acids in the gastrointestinal system, preferably in the colon.According to a particular embodiment, the use according to the invention involves the oral administration of the composition.

[0017] According to a particular embodiment, the present invention provides a composition that is an aqueous solution containing 50 to 200 g / L of agave fructan and 10 to 80 g / L of glycerol monobutyrate. According to a further particular embodiment, the composition according to the invention is administered orally.

[0018] According to a particular embodiment, the composition of this invention is administered to a mammal. According to a preferred embodiment, the mammal is a horse. According to another preferred embodiment, the mammal is a dog.

[0019] According to one particular embodiment, the present invention provides the composition, foodstuff, food supplement, or pharmaceutical composition for the described use, wherein the composition is an aqueous solution containing 50 to 200 g / L of agave fructan and 10 to 80 g / L of glycerol monobutyrate, and wherein the use includes the oral administration of the composition to a mammal, such as a horse or dog. According to a further particular embodiment, the composition contains 100 g / L of agave fructan and 30 g / L of glycerol monobutyrate. According to a preferred embodiment, the composition for the described use is administered at a dose of 5 to 100 mL per day.According to yet another embodiment, this composition for the use described is administered at a dose of 2 to 200 ml per day or at a dose which contains 1 to 500 mg / kg body weight of agave fructan and 0.5 to 150 mg / . kg body weight of glycerol monobutyrate. According to a further preferred embodiment, this invention provides the composition for the described use, in which the mammal is a horse. According to another further preferred embodiment, this invention provides the composition for the described use, in which the mammal is a dog. BRIEF DESCRIPTION OF THE FIGURES

[0020] [Fig.1] Variation in total SCFA concentration in a horse stool sample related to the administration of glycerol monobutyrate and / or agave fructan.

[0021] [Fig.2] Variation in the concentration of propionic acid in the sample of horse stools related to the administration of glycerol monobutyrate and / or agave fructan.

[0022] [Fig.3] Variation in the concentration of butyric acid in the stool sample of a horse related to the administration of glycerol monobutyrate and / or agave fructan.

[0023] [Fig.4] Variation in the total concentration of SCFAs in the stool sample of a dog related to the administration of glycerol monobutyrate and / or agave fructan.

[0024] [Fig.5] Variation in the concentration of acetic acid in the stool sample of a dog related to the administration of glycerol monobutyrate and / or agave fructan.

[0025] [Fig.6] Variation in propionic acid concentration in a dog's stool sample related to the administration of glycerol monobutyrate and / or agave fructan.

[0026] [Fig.7] Variation in the concentration of isobutyric acid in the sample of dog stools related to the administration of glycerol monobutyrate and / or agave fructan.

[0027] [Fig.8] Variation in the concentration of isovaleric acid in the stool sample of a dog related to the administration of glycerol monobutyrate and / or agave fructan. DETAILED DESCRIPTION OF THE INVENTION Definitions

[0028] In the context of the present invention, the term "gut microbiome" refers to the diverse collection of bacteria, archaea, fungi, protozoa and viruses, which are capable of living in the gastrointestinal system of a subject, preferably a mammal, which may have a beneficial, adverse or neutral effect on the health of that subject.

[0029] In the context of the present invention, the term "subject" means any human being or animal, in particular a mammal, preferably a dog or a horse, for which The gastrointestinal system is populated by an intestinal microbiome. The individual can be of any age and have a competent or compromised immune system.

[0030] In the context of the present invention, the term "gastrointestinal health" refers to the state of health of the gut microbiome and all the organs belonging to the digestive system: the mouth, pharynx, esophagus, stomach, small intestine (duodenum, jejunum, ileum), colon (appendix, cecum, colon, rectum), and anus. Preferably, it refers to the state of health of the gut microbiome and all the organs belonging to the gastrointestinal system: the stomach, small intestine (duodenum, jejunum, ileum), colon (appendix, cecum, colon, rectum), and anus.

[0031] In the context of the present invention, the term "colon" refers to the following parts of the digestive system: the appendix, the cecum, the colon and the rectum.

[0032] In the context of the present invention, the term "intestinal wall" refers to the various layers of tissue surrounding the lumen of the intestinal tract: the mucosa or intestinal mucosa (including the epithelium, the lamina propria, the muscularis mucosae), the submucosa, the muscularis propria (inner circular muscular layer, intermuscular space, outer longitudinal muscular layer) and the serosa or adventitia, as well as the blood and lymphatic vessels located therein and the nerves.

[0033] In the context of the present invention, the term "intestinal wall function" refers to all bodily processes involving the intestinal wall of the subject. These processes include, in particular, grinding, digestion (production and secretion of intestinal juices), propulsive movements (peristalsis), nutrient absorption, and excretion of digestive waste. The intestinal wall also forms a barrier between the contents of the intestinal lumen and the subject's body and participates in the defenses of the immune system.

[0034] In the context of the present invention, the term "short-chain fatty acid" or "SCFA" refers to a saturated aliphatic organic acid having one to six carbon atoms. SCFAs may be branched or unbranched. A branched-chain SCFA is also called a branched-chain fatty acid (BCFA).

[0035] In the context of the present invention, the term "disrupted gut microbiome" refers to a condition in which the composition of the gut microbiome is detrimental to the health of the individual. A disrupted gut microbiome is usually characterized by a decrease in bacterial diversity, a pathogenic effect on the individual, and / or a decrease in the production of short-chain fatty acids (SCFAs). This pathological condition may be symptomatic or asymptomatic and may or may not lead to other gastrointestinal and / or systemic diseases.

[0036] In the context of the present invention, the terms "treatment," "treat," and similar terms refer to achieving a desired pharmacological and / or physiological effect in a living subject, particularly a dog or a horse. On the one hand, this effect may be prophylactic when it can partially or completely prevent a disease and / or its symptoms or enhance the well-being of a healthy subject (for example, through a more optimal quality of life and / or a correspondingly longer life expectancy). On the other hand, this effect may be therapeutic when it is able to partially or completely cure a disease and / or eliminate its symptoms. This includes any form of treatment, such as improving the normal state of health, as well as preventing, slowing, halting, or reversing the development of a disease in a living subject that may be predisposed to it.

[0037] In the context of the present invention, the terms "butyric acid" and "butyric acid derivatives" refer to synthetic or natural compounds of butyric acid. These butyric acid compounds may be synthetic or natural. A synthetic butyric acid compound may be produced chemically (e.g., by oxidation of butyric aldehyde, extracted from butter). A natural butyric acid compound may be produced by fermenting bacteria, including Bacillus, Bacteroidetes, spirochetes, actinobacteria, chloroflexus, and proteobacteria, through anaerobic digestion or anaerobic fermentation, primarily anaerobic fermentation of biopolymers (e.g., polysaccharides, proteins, lipids).

[0038] In the context of the present invention, the term "agave fructan" refers to any fructan compound of any chain length, whether branched or unbranched, that may occur naturally in any agave plant. Agave fructan and its isolation are described, for example, in patent WO2022043965A1 and in the article by Lopez et al. 2003 (J. Agric. Food Chem. 2003, 51, 7835-7840). Agave fructan is preferably a branched fructan compound.

[0039] In the context of the present invention, the term "probiotic" refers to a microorganism which is supplemented and which in the intestinal microbiome can have a beneficial effect on the health of the subject in which it lives.

[0040] In the context of the present invention, the term "prebiotic" refers to molecules that stimulate the growth or activity of beneficial microorganisms, such as bacteria and yeasts, particularly in the gastrointestinal system. Prebiotics usually contain complex carbohydrates, but may also consist of other biopolymers, such as proteins, lipids, and nucleic acids.

[0041] In the context of the present invention, the term "foodstuff" refers to a composition that is suitable for use as a food source, preferably as the main source of food. Therefore, a foodstuff contains essential nutrients along with other components, all of which are suitable for consumption by the subject, preferably a mammal, and more preferably a horse or a dog.

[0042] In the context of the present invention, the term "food supplement" refers to a composition that is suitable for addition to food or that can be consumed alone as a supplement. Therefore, a food supplement contains only components that are suitable for consumption by the subject, preferably a mammal, and more preferably a horse or a dog.

[0043] In the context of the present invention, the term “pharmaceutically acceptable vehicle” means any material which, when associated with an active substance, enables that active substance to maintain its biological activity; in particular, any material which can strengthen or stabilize the composition or which can be used to facilitate the preparation of the composition. Gastrointestinal health

[0044] As described above, the term "gastrointestinal health" refers to the good health and normal functioning of the intestinal microbiome, as well as all organs that belong to the digestive system.

[0045] A particular embodiment of the invention is designed for use in maintaining and / or enhancing gastrointestinal health. The term "maintaining" here refers to keeping the proper functioning of the gastrointestinal system stable without it deteriorating or improving. The term "enhancing" refers to improving the health of the gastrointestinal system.

[0046] The subject's gastrointestinal system may be healthy, or the subject may have a condition affecting one or more organs of the gastrointestinal system. In one particular embodiment, the invention is designed for use in maintaining and / or improving gastrointestinal health in which the subject is healthy. In another particular embodiment, the invention is designed for use in maintaining and / or improving gastrointestinal health in which the subject's gastrointestinal system is functioning properly. In yet another particular embodiment, the invention is designed for use in maintaining and / or improving gastrointestinal health in which the subject has one or more conditions affecting one or more organs of the gastrointestinal system.These conditions can be, in particular, infectious, inflammatory, autoimmune, neoplastic, vascular, neurogenic, and / or muscular in nature. Furthermore, these conditions can be functional (without structural changes to the intestinal wall) and / or structural (with structural changes to the intestinal wall). Functional gastrointestinal disorders include, but are not limited to, functional dyspepsia, irritable bowel syndrome, functional abdominal pain, and functional constipation. Structural gastrointestinal disorders include, but are not limited to, inflammatory bowel diseases (e.g., ulcerative colitis, Crohn's disease), colon polyps, and bowel cancer. A disrupted gut microbiome

[0047] As described above, the term "disrupted gut microbiome" refers to a condition in which the composition of the gut microbiome is detrimental to the subject's health. A disrupted gut microbiome is frequently associated with a decrease in the level of beneficial and / or neutral microorganisms in the subject's gastrointestinal system, and with an increase in the level of microorganisms harmful to the body, i.e., (entero)pathogens.

[0048] The microbiome beneficial to the body is known to those skilled in the art and includes, but is not limited to, the genera Bifidobacteria, Lactobacilli, Faecalibacterium, Bacteroides, and Bacillus. A microbiome beneficial to the body has a directly positive effect on, among other things, the brain, joints, immune system, liver, skin, metabolism, athletic performance, respiratory system, etc.

[0049] Enteropathogens are microorganisms of the subject's gastrointestinal system that generally have an adverse effect on the subject's health and, in particular, can cause diseases or conditions. Other forms of adverse effects include, for example, a decrease in daily food intake, a decrease in daily weight gain, a decrease in food absorption, and a general deterioration in the subject's health and well-being.Enteropathogens include, but are not limited to, bacterial pathogens of the genera Staphylococcus, Brachispira, Vibrio, Escherichia, Salmonella, Shigella, Klebsiella, Erwinia, Yersinia, Campylobacter, Helicobacter, Pseudomonas, Enterococcus and Clostridium; fungal pathogens and yeasts of the genera Penicillium, Aspergillus, Fusarium, Cephalosporium, Candida, Fungi Imperfecti and Hemiscomycetes; and viral pathogens of the genera Norovirus and Rotavirus.

[0050] According to a particular embodiment, the composition according to the invention is designed to be used to stimulate and / or maintain the presence of one or more beneficial microorganisms, in particular beneficial microorganisms in the gut microbiome. According to a particular embodiment, the composition according to the invention is designed to be used to stimulate and / or maintain the presence of one or more bacteria beneficial to the body. According to a further particular embodiment, the composition according to the invention is designed to be used to stimulate and / or maintain the presence of one or more bacteria beneficial bacteria selected from the genera Bifidobacteria, Lactobacilli, Faecalibacterium, Bacteroides, and Bacillota. In a further embodiment, the composition according to the invention is designed to stimulate and / or maintain the presence of beneficial bacteria from the genera Bifidobacteria and / or Lactobacilli. In another embodiment, the composition according to the invention is designed to stimulate and / or maintain the presence of one or more beneficial bacteria in the colon.

[0051] According to a particular embodiment, the composition according to the invention is designed to be used to inhibit and / or eliminate one or more enteropathogens. According to a further particular embodiment, the composition according to the invention is designed to be used to inhibit and / or eliminate one or more enteropathogens selected from the genera Staphylococcus, Brachispira, Vibrio, Escherichia, Salmonella, Shigella, Klebsiella, Erwinia, Yersinia, Campylobacter, Helicobacter, Pseudomonas, Enterococcus and Clostridium; Penicillium, Aspergillus, Fusarium, Cephalosporium, Candida, Fungi Imperfecti and Hemisamicocycetes; and Norovirus and Rotavirus. According to a particular embodiment, the composition according to the invention is designed to be used to inhibit and / or eliminate one or more enteropathogens in the colon.

[0052] According to a particular embodiment, the composition according to the invention is designed to be used to stimulate and / or maintain the presence of one or more intestinal bacteria beneficial to the body and / or inhibit and / or eliminate one or more enteropathogens. According to a particular embodiment, the composition according to the invention is designed to be used to stimulate and / or maintain the presence of one or more intestinal bacteria beneficial to the body and / or inhibit and / or eliminate one or more enteropathogens in the colon. Topics

[0053] As described above, the term "subject" refers to any human being or animal, in particular a mammal, preferably a dog or a horse, whose gastrointestinal system is populated by a gut microbiome. The subject may be of any age and may have a competent or compromised immune system.

[0054] According to one particular embodiment of this invention, the subject is a mammal. According to a further particular embodiment, the mammal is a human being. According to yet another further particular embodiment, the mammal is a pet. Pets include, but are not limited to, canids, felines, lagomorphs, rodents, equines, ruminants, and swine. Canids include, but are not limited to, dogs. Felines include, but are not limited to, cats. Lagomorphs include, but are not limited to rabbits. Rodents include, but are not limited to, rats, mice, groundhogs, hamsters, and guinea pigs. Equids include, but are not limited to, horses, ponies, and donkeys. Ruminants include, but are not limited to cattle, sheep, goats, and deer. In a preferred embodiment, the mammal is a canid or an equid. In a further preferred embodiment, the mammal is a dog or a horse.

[0055] The subject may have a healthy gut microbiome or a disrupted gut microbiome. In one particular embodiment, the subject has a healthy gut microbiome. In another particular embodiment, the subject has a disrupted gut microbiome. The subject with a disrupted gut microbiome may be symptomatic or asymptomatic. In one particular embodiment, the subject with a disrupted gut microbiome is asymptomatic. In another particular embodiment, the subject with a disrupted gut microbiome is symptomatic. Symptoms related to a disrupted gut microbiome may be gastrointestinal or general. Gastrointestinal symptoms include, but are not limited to, halitosis, abdominal cramps, abdominal pain, flatulence, diarrhea, constipation, food intolerances, malabsorption, anorectal infections and itching, as well as weight loss.General symptoms include, but are not limited to, difficulty urinating, urogenital infections and itching, skin rashes, joint pain, and chronic fatigue. In one particular embodiment, the subject with a disturbed gut microbiome suffers from one or more gastrointestinal symptoms, such as halitosis, abdominal cramps, abdominal pain, flatulence, diarrhea, constipation, food intolerances, malabsorption, anorectal infections, and itching, as well as weight loss.

[0056] In a particular embodiment, the subject presents with a suspected or confirmed disrupted gut microbiome. A disrupted gut microbiome may be suspected, in particular, based on the subject's symptoms and clinical examination (e.g., excessive gas concentration in the abdomen, pain on palpation, hypoperistalsis or hyperperistalsis syndrome). A disrupted gut microbiome may be confirmed (diagnosed) by means of laboratory tests, such as urinalysis (e.g., determination of the concentration of various acids in the urine), stool analysis (e.g., determination of the bacteria, fungi, and protozoa present), or a breath test (e.g., determination of gases produced by bacteria present in exhaled air). In a particular embodiment, the subject has been diagnosed with a disrupted gut microbiome.According to a particular embodiment. Additionally, the subject was diagnosed with a disturbed gut microbiome by urine analysis, stool analysis, or breath test. Butyric acid

[0057] As described above, the terms "butyric acid" and "butyric acid derivatives" refer to synthetic or natural compounds of butyric acid. These butyric acid compounds may be synthetic or natural. A synthetic butyric acid compound may be produced chemically (e.g., by oxidation of butyric aldehyde, extracted from butter). A natural butyric acid compound may be produced by fermenting bacteria, including Bacillota, Bacteroidota, spirochetes, actinobacteria, chloroflexus, and proteobacteria, through anaerobic digestion or anaerobic fermentation, primarily anaerobic fermentation of biopolymers (e.g., polysaccharides, proteins, lipids). Butyric acid derivatives include a salt, an ester, or an amide of butyric acid.

[0058] According to a particular embodiment, the composition according to the invention comprises a butyric acid derivative, which is selected from the group consisting of a salt, an ester, and an amide of butyric acid. According to a preferred embodiment of the invention, the composition comprises an ester derivative of butyric acid. According to a further preferred embodiment, the composition comprises glycerol monobutyrate or a mixture of glycerol monobutyrate, glycerol dibutyrate, and glycerol tributyrate, of which monobutyrate is the main component. The composition preferably comprises glycerol monobutyrate. Agave fructan

[0059] As described above, the term "agave fructan" refers to any fructan compound that can occur naturally in any agave plant. Agave fructans differ from other fructans, such as inulins, by their type of beta linkages between fructose units, both [3(2->1) and [3(2->6) linkages, and by a significantly higher number of branches (Lopez et al. J. Agric. Food Chem. 2003, 51, 7835-7840). The properties of inulin do not apply to agave fructan and vice versa. Agave fructan is, in terms of spatial structure, distinctly different from inulin. Inulin has longer, purely linear chains of fructose molecules joined by beta-2,1 bonds, which make it poorly soluble and it is metabolized elsewhere in the intestines by other microorganisms.Agave fructan is branched and consists of fructose molecules linked by beta-2,6, beta-2,1 bonds. Unlike inulin, it is therefore highly soluble and is metabolized more rapidly in the intestines by (partly) other microorganisms. This different structure thus has some advantages. significant consequences on both the physical and nutritional properties of fructan.

[0060] In order to metabolize agave fructan or inulin, microorganisms must first hydrolyze the substrate using fructanase enzymes. The structure and mechanism of action of these enzymes, which hydrolyze beta-2,1 and / or beta-2,6 bonds, differ for each microorganism, resulting in variations in microorganism growth when inulin and agave fructan are used as substrates. These differences between microorganisms, their localization in the intestines, and their growth rate vary depending on the type and quantity of metabolites produced, such as volatile fatty acids.

[0061] The agave plants are plants belonging to the Agave genre. Les agave plants including, but not limited to the plants A. tequilana, A. sisalana, A. angustifolia, A. parryi, Agave salmiana, A. geminiflora, A. potatorum, A. fourcroyd.es, A. muxii, A. bovicornuta, A. cupreata, A. filifera, A. utahensis, A. deserti, A. bracteosa, A. chapensis, A. neglecta, A. decipiens, A. anomala, A. eggersiana, A. Americana, A. rzedowskiana, A. omithobroma, A. barbadensis, A. impressa, A. marmorata, A. intermixta, A. schidigera and A. schotti.

[0062] According to a particular method of production, the composition according to the invention includes an agave fruit derived from A. tequilana.

[0063] According to a particular method of production, the agave fruit includes a formula composition I

[0064] [Chem.l]

[0065] in which n represents a natural integer. According to a particular embodiment, n represents a number between 2 and 40, more particularly between 5 and 35, preferably between 10 and 30. Compositions

[0066] A further objective of the invention is to provide compositions for its described use, comprising butyric acid or a derivative thereof and agave fructan as active ingredients in effective amounts, wherein the butyric acid derivative is selected from the group consisting of a butyric acid salt, ester, and amide. Therefore, the present invention also provides a food product, a food supplement, and a pharmaceutical composition comprising butyric acid or a derivative thereof and agave fructan, as described herein, for the applications of the invention. The food product, food supplement, or pharmaceutical composition may, in addition to the aforementioned active ingredients, also include a pharmaceutically acceptable vehicle for the applications of the invention.

[0067] As mentioned above, the term “pharmaceutically acceptable vehicle” means any material which, when combined with an active substance, allows that active substance to maintain its biological activity. The pharmaceutically acceptable vehicle usually enhances or stabilizes the composition, or is used to facilitate the preparation of the composition. Pharmaceutically acceptable vehicles include solvents, dispersing media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption retardants and analogues that are physiologically compatible, as known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329; Remington: The Science and Practice of Pharmacy, 21st Ed. Pharmaceutical Press 2011; and subsequent editions thereof).Non-limiting examples of said pharmaceutically acceptable vehicle include each of the pharmaceutically acceptable vehicles, such as phosphate-buffered saline, physiological saline, water, emulsions, such as an oil-water emulsion, and various types of wetting agents. According to a particular embodiment, the present invention provides a composition that is an aqueous solution.

[0068] Compositions containing the compounds according to the invention can take any form suitable for the intended route of administration, including, for example, a solution, a suspension, or an emulsion. Liquid vehicles are generally used in the preparation of solutions, suspensions, and emulsions. Liquid vehicles for use in the present invention contain, for example, water, saline solution, pharmaceutically acceptable organic solvents, pharmaceutically acceptable oils or greases and the like, as well as mixtures of two or more of these. The liquid vehicle may contain other suitable acceptable pharmaceutical additives, such as solubilizing agents, emulsifying agents, nutrients, buffers, preservatives, suspending agents, thickeners, viscosity regulators, stabilizers, and the like.Suitable organic solvents include, for example, monoalcohols, such as ethanol, and polyalcohols, such as glycols. Suitable oils include, for example, soybean oil, coconut oil, olive oil, safflower oil, cottonseed oil, and similar oils. For parenteral administration, the vehicle may also be an oily ester, such as ethyl oleate, isopropyl myristate, and similar oils. The compositions according to the present invention may also be in the form of microparticles, microcapsules, substances encapsulated in liposomes and similar oils, as well as combinations of two or more of these.

[0069] The compositions according to the invention can be administered enterally, parenterally, or topically in formulations that optionally contain conventional, non-toxic, pharmaceutically acceptable vehicles and adjuvants. According to a In a preferred embodiment, the compositions according to the invention are administered enterally. Enteral administration includes oral, sublingual, and anal or rectal administration (e.g., enema, suppository, aerosol), as well as administration via a feeding tube (e.g., gastric tube, duodenal tube). In a further preferred embodiment, the compositions according to the invention are administered orally.

[0070] Solid dosage forms may include capsules, tablets, pills, suppositories, powders, and granules. In similar solid dosage forms, the active compounds may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Similar dosage forms may also contain, as is customary, substances other than inert diluents, for example, lubricants such as magnesium stearate. In the case of capsules, tablets, pills, and suppositories, the dosage forms may also contain buffers. Furthermore, tablets and pills may be prepared using enteric coatings. In one particular embodiment, the compositions according to the invention are a powder.

[0071] Liquid dosage forms may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, creams, foams, ointments, and gels containing inert diluents commonly used in the field, such as water. Similar compositions may also contain excipients, such as wetting agents, emulsifying agents and suspending agents, cyclodextrins and sweeteners, flavorings, and fragrances. In one particular embodiment, the compositions according to the invention are a liquid, especially an aqueous solution.

[0072] The foodstuffs according to the invention may include prepared meals, wet food, lump food, maintenance pellets, snacks, nibbles or sweets, preferably lump food, maintenance pellets or snacks.

[0073] The effective amounts of active substances according to the invention generally include any amount that is sufficient for the maintenance and / or enhancement of gastrointestinal health, in particular for the treatment and / or prevention of a disturbed intestinal microbiome or for the improvement of intestinal wall function.

[0074] A successful treatment of a mammal according to the invention can prevent or treat gastrointestinal disorders, in particular a disturbed intestinal microbiome or an abnormality of intestinal wall function or the symptoms that are associated with these disorders.

[0075] The amount of active substance that can be combined with pharmaceutically acceptable vehicles to produce a unique dosage form may vary depending on the individual being treated and the route of administration. It is clear, however, that the specific dose level for a particular individual depends on a variety of factors, including the form of the composition (food supplement, foodstuff, pharmaceutical composition), the activity of the specific compound used, the animal species, age, body weight, general health, sex, diet, time of administration, route of administration, excretion rate, drug interactions, and the severity of any underlying condition. The therapeutically effective amount for a given situation can be easily determined using routine tests and falls within the competence and judgment of a person skilled in the art.

[0076] For the purposes of the present invention, a dose containing classical agave fructan in an amount ranging from 1 to 500 mg / kg body weight per day and butyric acid or a derivative thereof in an amount ranging from 0.5 to 150 mg / kg body weight per day may be administered in one or more doses.

[0077] For the purposes of the present invention, a dose containing conventional agave fructan in an amount from 50 to 200 g / L and butyric acid or a derivative thereof in an amount from 10 to 80 g / L can be administered in one or more doses. According to a preferred embodiment, the present invention comprises agave fructan in an amount from 50 to 200 g / L and glyceryl monobutyrate in an amount from 10 to 80 g / L. According to a further preferred embodiment, the present invention comprises 100 g / L of agave fructan and 30 g / L of glyceryl monobutyrate or a mixture of glyceryl monobutyrate, glyceryl dibutyrate, and glyceryl tributyrate, of which monobutyrate is the principal component. According to a further preferred embodiment, the present invention is administered, generally, at a dose ranging from 5 to 100 ml per day.

[0078] The compositions of the present invention can be administered as monotherapy or in combination with one or more other drugs for the use described. The active ingredients according to the invention can, for example, be combined with prebiotics, antibiotics, probiotics, vitamins, and nutrients.

[0079] The compositions according to the invention and the other active ingredients can be administered at the maximum recommended dose or at a lower dose. The dose levels of the active ingredients in the compositions according to the invention can be modified to obtain a desired effect, depending on the route of administration, the severity of the condition, and the patient's response to treatment. The drug combination can be administered as individual compositions or as a single dosage form containing both drugs. When administered In combination, therapeutic agents can be formulated as individual compositions that can be administered simultaneously or at different times, or the therapeutic agents can also be administered as a single composition. EXAMPLES Analytical testing methods Preparation of stool samples

[0080] Approximately 200 mg of the stool sample was weighed into a tube and then dissolved in 2 ml of deionized water. The samples were homogenized by mechanical stirring using a vortex mixer. The dry matter fraction of the stool sample was determined by drying an aliquot of the homogenized mixture overnight in an oven at 60 °C. Analysis of the AGCCs

[0081] Short-chain fatty acids (SCFAs: acetate, propionate, and butyrate) and branched-chain short-chain fatty acids (BCFAs: isobutyrate, isovalerate, and isocaproate) were extracted from stool samples using an extraction mixture. The extraction mixture was prepared with 0.5% formic acid and 0.3% 2-methylhexanoic acid in acetonitrile (ACN). 2-Methylhexanoic acid was used as an internal standard.

[0082] The extracts were then analyzed using a GC-2030 gas chromatograph (Shimadzu, 's-Hertogenbosch, The Netherlands), equipped with a GC SH-polarD capillary column (30 mm x 0.32 mm ID-BP 21 x 0.25 pm, Shimadzu, Hertogenbosch, The Netherlands), a flame ionization detector, and a split injector. The injection volume was 1 µL, and the temperature profile was set from 110 °C to 160 °C with a temperature increase of 6 °C min⁻¹. The carrier gas was nitrogen, and the injector and detector temperatures were 100 °C and 220 °C, respectively. Calibration standards

[0083] Calibration standards were established by diluting a stock solution of AGCC and AGCCr in deionized water. Each stock solution contained 10 mM of acetate, propionate, isobutyrate, butyrate, isovalerate, valerate, isocaproate, and caproate. The calibration curve was constructed using ten calibration standards that cover the concentration range.

[0084] Example 1: Increase in SCFA levels in the intestinal tract of a horse upon administration of an agave butyric acid and fructan derivative

[0085] The effect of glycerol monobutyrate administered alone, of agave fructan administered alone, and of the simultaneous administration of Glycerol monobutyrate and agave fructan on the concentration of SCFAs in the colon of a horse was studied based on stool analysis.

[0086] The study was conducted on a healthy 6-year-old mare, which was kept in a stall with straw bedding. The mare was fed ad libitum with good-quality hay and received, morning and evening, a supplement of 1.5 kg of Pavo maintenance pellets. Every day at 4 p.m., the majority of the feces were eliminated from the mare's rectum, and then a fecal sample was taken as far back in the rectum as possible. The fecal sample was then placed in a 5 ml tube and immediately immersed in liquid nitrogen (-80 °C). The samples were thawed only at the time of analysis.

[0087] In the study, the following compositions were evaluated: composition A (1.5 g of glycerol monobutyrate in 50 ml of water); composition B (5.0 g of agave fructan in 50 ml of water); and composition C (a mixture of 1.5 g of glycerol monobutyrate and 5.0 g of agave fructan in 50 ml of water). Each composition was administered to the mare in the evening, mixed with maintenance pellets. It was verified each time that all of the liquid in the composition was consumed by the mare. From Day 1 to Day 3 of the study, a baseline fecal sample was collected daily. From Day 3 to Day 9, the mare received composition A, and from Day 8 to Day 10, fecal samples of composition A were collected. From Day 10 to Day 16, the mare received composition B and from Day 15 to Day 17, stool samples of B were collected.From Day 17 to Day 23, the mare received composition C, and from Day 22 to Day 24, C stool samples were collected. The corresponding stool samples, which were collected on three different days (reference samples, A samples, B samples, and C samples), were systematically thawed, added together, and analyzed as a mixture.

[0088] The standardized results in Table 1 and Fig. 1 show that the concentration of SCFAs in feces increases significantly with the simultaneous administration of glycerol monobutyrate and agave fructan, but not with the isolated administration of each substance. As indicated in Table 1 and Figures 2-3, this increase in SCFA levels is primarily due to the increase in propionic and butyric acid levels. Therefore, simultaneous administration of glycerol monobutyrate and agave fructan has a remarkable synergistic effect on the SCFA concentration in the intestinal tract. A high SCFA concentration, in turn, has a beneficial effect on the animal's overall health and gastrointestinal health, particularly on the gut microbiome and intestinal wall function.

[0089] Table 1: Variation in the concentration of SCFAs in the stool sample of a horse related to the administration of glycerol monobutyrate and / or agave fructan.

[0090] [Tables 1] Variation in SCFA concentration Propionic acid Butyric acid Total SCFA Initial value 100 100 100 γ-Lycerol monobutyrate 117 121 98 Agave fructan 114 103 84 γ-Lycerol monobutyrate + agave fructan 161 167 130

[0091] Example 2: Increase in short-chain fatty acid levels in the intestinal tract of a dog upon administration of a butyric acid and agave fructan derivative

[0092] The effect of glycerol monobutyrate administered alone, of agave fructan administered alone, and of the simultaneous administration of glycerol monobutyrate and agave fructan on the concentration of SCFAs in the colon of a dog was studied based on stool analysis.

[0093] The study was conducted on a healthy 10-year-old female Jack Russell Terrier. The dog was fed 150 g / day of Sanimed Preventive Adult kibble. Each day, at the same time, a fecal sample was collected from the anus by the veterinarian. The fecal sample was then placed in a 5 ml tube and immediately immersed in liquid nitrogen (-80 °C). The samples were thawed only at the time of analysis.

[0094] In the study, the following compositions were evaluated: composition A (0.3 g of glycerol monobutyrate in 10 ml of water); composition B (1.0 g of agave fructan in 10 ml of water); composition C (a mixture of 0.3 g of glycerol monobutyrate and 1.0 g of agave fructan in 10 ml of water). Each composition was administered in the evening, using a syringe, into the dog's mouth with chopped food. It was verified each time that the entire contents of the composition were consumed by the dog. From Day 1 to Day 3 of In the study, a baseline stool sample was collected daily. From Day 3 to Day 9, the female dog received composition A, and from Day 8 to Day 10, samples of stool A were collected. From Day 10 to Day 16, the female dog received composition B, and from Day 15 to Day 17, samples of stool B were collected. From Day 17 to Day 23, the female dog received composition C, and from Day 22 to Day 24, samples of stool C were collected. The corresponding stool samples, collected on three different days (baseline samples, samples A, samples B, and samples C), were systematically thawed, pooled, and analyzed together.

[0095] The standardized results in Table 2 and Figure 4 show that the concentration of SCFAs in stool increased only slightly or remained virtually unchanged when glycerol monobutyrate and agave fructan were administered alone. In contrast, the concentration of SCFAs increased significantly when glycerol monobutyrate and agave fructan were administered together. As shown in Table 2 and Figures 5-8, this increase in SCFA levels is primarily due to increased levels of acetic acid, propionic acid, isobutyric acid, and isovaleric acid. Therefore, the simultaneous administration of glycerol monobutyrate and agave fructan has a striking synergistic effect on the concentration of SCFAs in the intestinal tract.A high concentration of SCFAs, in turn, has a beneficial effect on the animal's gastrointestinal health, particularly on the gut microbiome and intestinal wall function.

[0096] Table 2: Variation in SCFA concentration in a dog's stool sample related to the administration of glycerol monobutyrate and / or agave fructan.

[0097] [Tables2] Variation in SCFA concentration Acetic acid Propionic acid Isobutyric acid Isovaleric acid Total SCFA Initial value 100 100 100 100 100 Glyceryl monobutyrate 104 116 125 105 108 Agave fructan 128 124 98 126 118 Glyceryl monobutyrate 167 214 175 192 161 + agave fructan

Claims

Demands

1. Composition comprising butyric acid or a derivative thereof and agave fructan as active ingredients, wherein the butyric acid derivative is selected from the group consisting of a salt, an ester and an amide of butyric acid; the composition comprising agave fructan in an amount from 20 to 500 g / l and butyric acid or a derivative thereof in an amount from 5 to 100 g / l.

2. Composition according to claim 1, wherein the butyric acid derivative is glycerol monobutyrate.

3. Composition according to any one of the preceding claims comprising agave fructan in an amount from 50 to 200 g / l and butyric acid or a derivative thereof in an amount from 10 to 80 g / l.

4. Foodstuff comprising the composition according to any one of the preceding claims.

5. Food supplement comprising the composition according to any one of claims 1-3.

6. Pharmaceutical composition comprising the composition according to any one of claims 1-3 and an acceptable pharmaceutical vehicle.

7. Composition according to any one of claims 1-3, foodstuff according to claim 4, food supplement according to claim 5 or pharmaceutical composition according to claim 6 for its use in maintaining and / or strengthening gastrointestinal health.

8. Composition according to any one of claims 1-3, food according to claim 4, food supplement according to claim 5 or pharmaceutical composition according to claim 6 for its use according to claim 7, wherein the maintenance and enhancement of proper gastrointestinal function includes the treatment and / or prevention of a disturbed gut microbiome.

9. Composition according to any one of claims 1-3, foodstuff according to claim 4, food supplement according to claim 5 or pharmaceutical composition according to claim 6 for its use according to claim 7, in which includes maintaining and strengthening gastrointestinal health by improving the function of the intestinal wall.

10. Composition, foodstuff, food supplement or pharmaceutical composition for use according to any one of claims 7-9, wherein the use includes oral administration of the composition.

11. Composition, foodstuff, food supplement or pharmaceutical composition for use according to any one of claims 7-9, wherein the composition is an aqueous solution containing 50 to 200 g / l of agave fructan and 10 to 80 g / l of glycerol monobutyrate, and wherein the use includes the oral administration of the composition to a horse or dog.

12. Composition for its use according to claim 11, wherein the composition contains 100 g / l of agave fructan and 30 g / l of glycerol monobutyrate.

13. Composition for its use according to claim 12, wherein the composition is administered at a dose of 2 to 200 ml per day or wherein the composition is administered at a dose which contains 1 to 500 mg / kg body weight of agave fructan and 0.5 to 150 mg / kg body weight of glycerol monobutyrate.