Dietary fibers for treatment of patients suffering from methylmalonic and propionemia

Abstract

The present invention relates to a composition comprising dietary fibers for dietary management of methylmalonatemia (MMA) and / or propionatemia (PA), and / or for treating and / or alleviating MMA and / or PA, and / or for treating, alleviating and / or preventing symptoms associated therewith.

Description

[0001] This application is a divisional application of an invention patent application with an application date of October 1, 2019, application number 201980065752.7, and invention name “Dietary fiber for treating patients with methylmalonic acidemia and propionic acidemia”. Technical Field

[0002] The present invention relates to the field of dietary management of methylmalonic acidemia (MMA) and propionic acidemia (PA), and to the field of treatments for symptoms associated therewith. Background Art

[0003] People with organic aciduria (OA) have rare inborn errors of metabolism. The largest disorders in OA are methylmalonic acidemia (MMA) and propionic acidemia (PA). Both disorders share common biochemical and clinical features: a deficiency of the enzymes propionyl-CoA carboxylase or methylmalonyl-CoA mutase, respectively, leading to the accumulation of propionyl-CoA and / or methylmalonic acid (MMA) and other metabolites. Initial symptoms of PA and MMA include poor feeding, vomiting, loss of appetite, weak muscle tone (hypotonia), and lack of energy (lethargy). These symptoms can sometimes progress to more serious medical problems, including heart abnormalities (cardiomyopathy), pancreatitis, seizures (seizures), coma, and possibly death.

[0004] Propionate is a precursor of propionyl-CoA. Propionate production in humans results from amino acid metabolism of dietary fiber, odd-chain fatty acid metabolism, and anaerobic bacterial fermentation in the intestine. In addition to acetate and butyrate, propionate is one of the main short-chain fatty acids (SCFA) produced by the microbiota in the intestine. Most intestinal commensal from healthy adults carry genes for at least one of the three known metabolic pathways for producing propionate. Even if the factors that determine which pathways are effective in any given human intestine are unclear, the activity of differential pathways may have an impact on the function of the intestinal flora. In other words, any change in the production of any major SCFA (such as propionate) may have an impact on the substrates used by the microbiota and the metabolites produced by the microbiota as a collective entity. Different propionate production (or synthesis) pathways will have different effects on the overall SCFA production potential (not just the production potential of propionate itself). It is estimated that at least 25% of the total propionate in MMA and PA patients is derived from intestinal bacteria, although this may be underestimated because the microbiota of MMA and PA patients is currently barely characterized.

[0005] Fiber is a component of a normal diet and is widely recognized as an important component of healthy nutrition. There are many different types of fiber, which are generally classified as soluble or insoluble, and can be further classified as fermentable, non-fermentable, or poorly fermentable. Fiber has been shown to have many beneficial effects on intestinal health, including improving stool consistency, normalizing intestinal transit time, producing short-chain fatty acids, and restoring a balanced intestinal flora composition. Not all types of fiber have the same qualitative or quantitative effects. The full range of fiber's health benefits can best be obtained by consuming a variety of fiber sources. Fermentable fiber is important for the production of short-chain fatty acids and restoring a balanced microbiota. Poorly fermentable fiber increases stool bulk, consistency, and viscosity and may help reduce bacterial translocation.

[0006] Although fermentable fibers are considered beneficial because they increase the levels of short-chain fatty acids in the large intestine, this increase may be detrimental in patients with MMA and PA because propionate levels may be increased as a result.

[0007] Currently used prior art nutritional products for MMA and PA patients typically contain dietary fiber that is not optimized for use in treating MMA and PA patients because when the fiber present is fermented by the intestinal flora, large amounts of propionate are still produced. Next and MMA / PA Junior contains a digestive fiber blend to promote digestive health; the fiber blend includes oligofructose, inulin, gum arabic, cellulose, soy polysaccharides, and resistant starch. The product contains an amino acid composition that is methionine-free, threonine-free, and valine-free and low in isoleucine. Both MMA / PA Anamix products are marketed to MMA / PA patients.

[0008] Knol et al. (J. Pediatr. Gastroenteral Nutr., vol 40(1), January 2005) demonstrated that an infant formula containing GOS / FOS in a 9:1 ratio was able to reduce the ratio of propionate to short-chain fatty acids in the feces of 7- to 8-week-old infants. The publication does not mention the total amount of SCFA produced. In general, the results of dietary fiber digestion cannot be extrapolated from infants to older subjects. Older subjects have a completely different microbiome compared to infants (Edwards and Parrett; Brit. J. Nutr. 2002, 88: Suppl. 1, S11-S18). This difference is generally attributed to the natural development of the intestine, changing nutritional patterns, and in some cases events such as illness and antibiotic use. Hormonal changes during adolescence may also further affect the microbiome. It is believed that the greatest changes in the microbiome occur between 0 and 3 years of age.

[0009] Venkatamaran et al. (Microbiome (2016), 4:33) demonstrated that resistant starch (type 2) had no significant effect on propionate in the stool of young people.

[0010] The aim of the present invention is to improve known fiber compositions for MMA and PA patients to optimize the overall health effects of fiber through fermentation products such as lactic acid and butyric acid and at the same time limit the production of propionic acid when fermented by the intestinal flora. Summary of the invention

[0011] The inventors have found that certain fibers and fiber mixtures are able to modulate the production of propionic acid, which plays an important role in the clinical features of MMA and PA patients, thereby also improving the gastrointestinal complications of these patients. The inventors have found that even when the total amount of short-chain fatty acids is increased, the production of propionic acid can be reduced. Therefore, MMA and PA patients can benefit from the benefits of the dietary fiber mixture of the present invention while reducing the level of propionic acid and thus improving their condition. The inventors have also unexpectedly demonstrated that these benefits also occur in the adult population.

[0012] The examples show that galacto-oligosaccharides (GOS) or fiber mixtures containing GOS lead to lower propionate production by the microbiome than expected. The total amount of SCFAs of these fibers is also increased. In addition, the inventors unexpectedly found that when GOS is combined with resistant starch, the level of propionate can be further reduced, while the prior art reports that resistant starch has no effect on propionate formation.

[0013] List of Preferred Implementation Options

[0014] 1. A composition comprising galacto-oligosaccharides for use in:

[0015] - Treating and / or alleviating methylmalonic acidemia (MMA) and / or propionic acidemia (PA), and / or treating, alleviating and / or preventing symptoms associated therewith;

[0016] -Dietary management of MMA and / or PA; and / or

[0017] - Reduces propionic acid production caused by intestinal flora.

[0018] 2. The composition for use according to embodiment 1, wherein the subject is at least 12 years old, preferably at least 18 years old.

[0019] 3. The composition for use according to any one of the preceding embodiments, wherein the composition further comprises resistant starch.

[0020] 4. The composition for use according to any one of the preceding embodiments, wherein the composition further comprises gum arabic, soybean polysaccharide, and at least one of oligofructose and inulin.

[0021] 5. A composition comprising galacto-oligosaccharides, resistant starch, gum arabic, soy polysaccharides, and at least one of oligofructose and inulin for use in patients with MMA or PA:

[0022] - Treating and / or alleviating methylmalonic acidemia (MMA) and / or propionic acidemia (PA), and / or treating, alleviating and / or preventing symptoms associated therewith;

[0023] -Dietary management of MMA and / or PA; and / or

[0024] - Reduces propionic acid production caused by intestinal flora.

[0025] 6. A composition for use according to any one of embodiments 1 to 5, wherein the composition comprises at least 10 wt%, preferably at least 20 wt%, most preferably at least 30 wt% resistant starch, based on the total weight of dietary fiber.

[0026] 7. A composition for use according to any one of embodiments 1 to 6, wherein the composition comprises at least 20% by weight, preferably at least 30% by weight, most preferably at least 50% by weight of a combination of resistant starch and galacto-oligosaccharides, based on the total weight of dietary fiber.

[0027] 8. The composition for use according to any one of embodiments 1 to 7, wherein the composition further comprises lactic acid producing bacteria, preferably selected from the genus Bifidobacteria and Lactobacilli.

[0028] 9. The composition for use according to any one of embodiments 1 to 8, wherein the composition further comprises guar gum.

[0029] 10. The composition for use according to any one of embodiments 1 to 9, wherein the composition comprises less than 5 wt% cellulose, based on the total weight of dietary fiber, preferably the composition does not comprise cellulose.

[0030] 11. The composition for use according to any one of embodiments 1-10, wherein the composition is in the following form:

[0031] (i) a nutritional supplement, preferably wherein the supplement also comprises amino acids; or

[0032] (ii) A complete nutritional composition, wherein the nutritional composition further comprises a protein fraction, preferably in the form of amino acids, digestible carbohydrates, vitamins and minerals.

[0033] 12. A composition for use according to any one of embodiments 1-11, wherein the composition further comprises a protein fraction consisting essentially of free amino acids and dipeptides, preferably wherein the protein fraction is essentially free of valine, isoleucine, methionine and threonine.

[0034] 13. The composition for use according to any one of embodiments 1-12, wherein the composition comprises DHA.

[0035] 14. The composition for use according to any one of embodiments 1 to 13, wherein the composition comprises vitamin D and / or calcium, preferably vitamin D.

[0036] 16. A composition comprising galacto-oligosaccharide, resistant starch, gum arabic, soybean polysaccharide, and at least one of fructo-oligosaccharide and inulin.

[0037] 17. A composition according to embodiment 16, wherein the amount of GOS is at least 5 wt% of the dietary fiber in the composition, and the resistant starch is at least 10 wt%, preferably at least 20 wt%, most preferably at least 30 wt% of the dietary fiber in the composition.

[0038] 18. A composition according to embodiment 16 or 17, wherein the composition comprises less than 5 wt% cellulose, based on the total weight of dietary fiber, preferably wherein the composition does not comprise cellulose. DETAILED DESCRIPTION

[0039] The present invention relates to a composition comprising dietary fiber, which is suitable for the dietary management of patients suffering from methylmalonic acidemia (MMA) and / or propionic acidemia (PA), and for treating and / or alleviating methylmalonic acidemia (MMA) or propionic acidemia (PA) and / or treating, alleviating and / or preventing symptoms associated therewith, and for reducing the production of propionic acid caused by intestinal flora while maintaining / increasing the production of other short-chain fatty acids. The composition to be used in this regard is referred to as the composition of the present invention and is defined in detail below.

[0040] Composition

[0041] The composition of the present invention comprises at least one dietary fiber and may comprise other components as defined below. In a preferred embodiment, the composition further comprises a protein source consisting of a specially designed blend of free amino acids or dipeptides. The amino acid composition is a mixture of specifically selected amino acids that can support the growth of MMA / PA patients and at the same time support the effect of the selected dietary fiber in reducing propionic acid production.

[0042] The composition of the present invention may also be referred to as a nutritional composition. The composition may be in the form of a supplement providing dietary fiber, which may be administered to the patient in addition to a regular diet. If the composition of the present invention is in the form of a supplement, it comprises dietary fiber, and preferably comprises a blend of amino acids. Supplements may also be referred to as dietary supplements or nutritional supplements, and may be in any form known in the art, including tablets, capsules, (reconstructable) powders, liquids, etc. The composition may also be in the form of a complete nutritional composition, which may be administered to the patient in place of one or more meals. If the composition of the present invention is in the form of a complete nutritional composition, it comprises dietary fiber, proteinaceous matter, digestible carbohydrates, vitamins, and minerals. Preferably, the complete nutritional composition is in the form of a liquid or a powder intended to be reconstituted with a liquid. In one embodiment, the composition is a supplement. In one embodiment, the composition is a complete nutritional composition. In one embodiment, the composition is in liquid form. The composition of the present invention is intended for patients with MMA and / or PA, and since these patients are accustomed to a special diet to cope with their disease, the administration of the composition of the present invention is easy to carry out in their daily eating habits.

[0043] The compositions are further defined below. As used herein, the term "about" means a range of + / - 10%.

[0044] Subjects

[0045] When referring to a patient or subject, it refers to a human patient or subject.

[0046] In the context of the present invention, an infant is a subject between 0 and 1 years old, a toddler is a subject between 1 and 3 years old, a child is a subject between 3 and 12 years old, a teenager is a subject between 12 and 18 years old, and an adult is a subject older than 18 years old. Preferably, the patient is older than 1 year old, more preferably 3 years old, even more preferably 12 years old, even more preferably 14 years old, and most preferably 18 years old. Preferably, the patient is an infant, toddler, child, teenager or adult.

[0047] At the end of the first year of life, infants have their own unique microbial characteristics, which tend to be typical of adult microbiota, so that at the age of 2-5 years, their microbiota is completely similar to that of adults in terms of composition and diversity. Therefore, the first 3 years of life are the most critical period for dietary intervention to improve growth and development. This is a period of establishing intestinal flora (an asset that is essential for health and neurodevelopment), during which changes in intestinal flora are likely to have a profound impact on the health and development of the host. Reference Rodriguez et al. "The composition of the gutmicrobiota throughout life, with an emphasis on early life" Microb.Ecol.HealthDis. (2015); 26. These findings are particularly relevant to children, adolescents or adults; even more preferably, the patient is an adolescent or adult, and most preferably, the patient is an adult.

[0048] Dietary fiber

[0049] Compositions of the present invention include dietary fiber, which term also includes a mixture of dietary fiber. In one embodiment of the present invention, dietary fiber includes galacto-oligosaccharides. In another embodiment of the present invention, dietary fiber includes a mixture of galacto-oligosaccharides and resistant starch. In another embodiment, dietary fiber is a mixture of galacto-oligosaccharides, resistant starch and other fibers. The inventors unexpectedly found that dietary fiber of the present invention or a mixture of dietary fiber reduced the amount of propionic acid formed during the anaerobic fermentation process that occurs in the intestinal tract.

[0050] In the context of the present invention, "fiber" and "dietary fiber" are used interchangeably. According to the present invention, the term dietary fiber means the edible part of a plant or similar carbohydrates, which are resistant to digestion and absorption in the human small intestine, and fully fermented, partially fermented or not fermented in the large intestine. This includes polysaccharides, oligosaccharides, lignin and related plant matter. Preferably, the dietary fiber used in the composition of the present invention is selected from fermentable fibers and poorly fermentable fibers and non-fermentable fibers. Preferably, the fiber of the mixture of dietary fibers used in the composition of the present invention is selected from fermentable fibers and poorly fermentable fibers, or non-fermentable fibers, and more preferably a mixture of two types is used. Without being bound by theory, the inventors believe that constipation and defecation problems in patients with methylmalonic acidemia (MMA) and propionic acidemia (PA) are improved by using these poorly fermentable fibers or non-fermentable fibers. In one embodiment, one or more poorly fermentable fibers or non-fermentable dietary fibers are selected from hemicellulose, lignin, alpha cellulose and resistant starch and mixtures thereof. In one embodiment, the one or more fermentable dietary fibers are selected from oligofructose, inulin, wheat bran, gum arabic, soybean polysaccharides, oat fiber, galacto-oligosaccharides, locust bean gum, guar gum, pectin, hydrolyzed pectin and mixtures thereof. In a preferred embodiment, the one or more dietary fibers are selected from oligofructose, inulin, resistant starch, cellulose, methylcellulose (preferably hydroxypropyl methylcellulose), wheat bran, gum arabic, soybean polysaccharides, oat fiber, galacto-oligosaccharides, locust bean gum, guar gum, pectin, hydrolyzed pectin and mixtures thereof. The terms "gum Arabic" and "arabic gum" are used interchangeably.

[0051] In one embodiment, a kind of fiber is used, it is galacto-oligosaccharide.Or, use the mixture of different dietary fibers, for example, use the mixture of at least 2 kinds, at least 3 kinds, at least 4 kinds, at least 5 kinds, at least 6 kinds or even at least 7 kinds of different dietary fibers, preferably selected from the preferred dietary fibers of above list.Preferably, the mixture of fiber comprises galacto-oligosaccharide at least.Although there is no particular restriction on the amount of the different dietary fibers used in the context of the present invention, for practical reasons, can use up to 10 kinds, up to 9 kinds or even up to 8 kinds of different dietary fibers.Preferred fiber (mixture) is as follows:

[0052] (i) Fiber is galacto-oligosaccharide.

[0053] (ii) The fiber blend comprises two fibers, one of which is galacto-oligosaccharide.

[0054] (iii) The fiber blend comprises two fibers, one of which is galacto-oligosaccharide and the other is resistant starch.

[0055] (iv) The fibre mixture comprises at least three, preferably at least four, at least five or at least six fibres, one of which is galacto-oligosaccharide and one of which is resistant starch.

[0056] (v) the fiber mixture (ii), further comprising oligofructose and / or inulin, gum arabic and soy polysaccharide.

[0057] (vi) the fiber mixture (iv) further comprising oligofructose and / or inulin, gum arabic and soy polysaccharide.

[0058] (vii) The fiber mixture (ii), (iii), (iv), (v) or (vi), further comprising guar gum and / or partially hydrolyzed guar gum.

[0059] (viii) a fiber blend comprising at least two, at least three, at least four, at least five, at least six or all seven fibers selected from the group consisting of fructooligosaccharides, inulin, resistant starch, gum arabic, locust bean gum, galacto-oligosaccharides and soy polysaccharides.

[0060] (ix) The fibre mixture (ii), (iv), (v), (vi), (vii) or (viii) does not contain cellulose.

[0061] (x) a fiber mixture comprising at least two, at least three, at least four, at least five, at least six, at least seven or all eight fibers selected from the group consisting of fructooligosaccharides, inulin, resistant starch, cellulose, gum arabic, locust bean gum, galacto-oligosaccharides and soy polysaccharides.

[0062] A particularly preferred dietary fiber for use in the composition of the present invention is GOS. GOS helps to achieve a balance between the different SCFAs produced along the length of the colon and helps to improve the looseness of the stool while reducing the formation of propionic acid. Preferably, GOS is combined with resistant starch. This combination combines the benefits of non-fermentable dietary fiber and fermentable dietary fiber.

[0063] Preferably, GOS or a mixture of GOS and resistant starch is supplemented with other dietary fibers, preferably a combination of gum arabic, soy polysaccharides and oligofructose and / or inulin. Compared to GOS or a mixture of GOS and resistant starch, the fiber mixture closely reflects the range and type of fibers habitually consumed in a normal diet and further reduces the formation of propionic acid. In a preferred embodiment, the amount of resistant starch is at least 10% by weight of the dietary fiber in the composition, more preferably at least 20% by weight, most preferably at least 30%. In a preferred embodiment, when two GOS are present as resistant starch in a fiber mixture comprising more than two fibers, the sum of the amounts of resistant starch and oligofructose is at least 20% by weight, preferably at least 30% by weight, most preferably at least 50% by weight of the dietary fiber in the composition.

[0064] Preferably, GOS supplemented with acacia gum, soy polysaccharides and a combination of oligofructose and / or inulin, a mixture of GOS and resistant starch or these fibers are supplemented with guar gum and / or partially hydrolyzed guar gum. Guar gum and / or partially hydrolyzed guar gum are fermentable fibers and may further act as a taste masking agent and may therefore support masking of any taste, e.g. bitterness of the fibers and amino acids that may be contained in the composition.

[0065] Preferably, the composition of the present invention comprises 0.4-50g dietary fiber / 100kcal, more preferably 0.6-30g / 100kcal, most preferably 1-20g / 100kcal, based on the total energy content of the composition (including fiber). If the composition of the present invention is a complete nutritional composition, the dietary fiber content is preferably a composition of 0.4-9g dietary fiber / 100kcal, even more preferably a composition of 0.6-7g / 100kcal and most preferably a composition of 0.8-3g / 100kcal. If the composition of the present invention is a supplement, the dietary fiber content is preferably a composition of 2-50g dietary fiber / 100kcal, even more preferably a composition of 4-30g / 100kcal and most preferably a composition of 5-20g / 100kcal. The composition of the present invention preferably comprises 1.5-5g dietary fiber / 10g protein, more preferably 2-4g dietary fiber / 10g protein and most preferably 2.5-3.5g dietary fiber / 10g protein. Preferably, the composition of the present invention provides 2-40g dietary fiber, preferably 10-30g dietary fiber, in a daily dose. The actual dosage depends on the age of the patient. For infants and children up to 12 years old, the preferred daily dose is 2-10g dietary fiber, and for adults, the preferred dose is 7-30g dietary fiber. Even if the patient is also eating low-protein foods (such as fruits and vegetables), it is recommended not to modify the daily dose of the fiber composition of the present invention described above to limit the propionic acid produced by the intestinal flora.

[0066] The preferred nutritional composition of the present invention comprises 70-250 kcal / 100 ml of the nutritional composition, and 1-5 g of dietary fiber / 100 kcal of the nutritional composition, more preferably 1.5-4.5 g of dietary fiber / 100 kcal of the nutritional composition, and even more preferably 2.0-4.0 g of dietary fiber / 100 kcal of the nutritional composition. Such a composition is found to be particularly suitable for long-term dietary management of MMA and PA patients.

[0067] Galactooligosaccharides (GOS), also known as oligogalactosyllactose, oligogalactose, oligogalactose or transgalactooligosaccharides (TOS), belong to prebiotics. GOS generally comprises a chain of galactose units produced by continuous transgalactosylation reactions with terminal glucose units. The degree of polymerization of GOS can vary very significantly, for example, in the range of 2-8 monomer units. In a preferred embodiment, the fiber mixture comprises galacto-oligosaccharides. GOS can be present in the composition in an amount of up to 100% by weight of the total weight of the fiber, for example 0.5-100% by weight, preferably 1-100% by weight or even 5-100% by weight. Alternatively, other fibers are present and GOS is preferably included in the composition in an amount of 0.5-90% by weight, preferably 0.5-70% by weight, and most preferably 1-30% by weight, based on the total weight of the fiber.

[0068] Resistant starch (RS) is any starch or starch digestion product that is not digested and absorbed in the stomach or small intestine and passed to the large intestine. RS has been classified into four types. Any of these types is suitable for the present invention. RS1 refers to physically inaccessible or indigestible resistant starch, such as those present in seeds or beans and unprocessed whole grains. RS2 refers to resistant starch that cannot be contacted with enzymes due to starch conformation (such as high-amylose corn starch). RS3 refers to resistant starch formed when starch-containing foods (such as pasta) are cooked and cooled. RS3 is produced due to retrogradation, which refers to the aggregation process in which dissolved starch becomes insoluble after being heated and dissolved in water and then cooled. RS4 refers to starch that is chemically modified to resist digestion. In a preferred embodiment, the fiber mixture contains resistant starch. If present, preferably resistant starch is included in the composition at 0.5-75% by weight, preferably 3-50% by weight, more preferably 10-40% by weight, and most preferably 15-30% by weight, based on the total weight of the fiber.

[0069] Inulin is a heterogeneous collection of fructose polymers or oligofructose (FOS). Inulin generally refers to material obtained from plant materials and is commercially available itself. It consists of chain-terminated glucosyl moieties and repeating fructosyl moieties, which are linked by β(2,1) bonds. The degree of polymerization (DP) of standard inulin ranges from 2 to 60. After removing the portion with a DP below 10 during the preparation process, the remaining product is called long-chain FOS (lcFOS). The portion with a DP below 10 may be called short-chain oligofructose or scFOS. In a preferred embodiment, the fiber mixture comprises inulin. If present, inulin is preferably included in the composition at 0.5-40% by weight, more preferably 5-30% by weight, and most preferably 10-25.5% by weight, based on the total weight of the fiber.

[0070] In addition to inulin, oligofructose is preferably present in the fiber mixture of the present invention. Oligofructose is an oligofructose having a DP generally below 10 and is a commercially available product, such as Orafti Oligofructose. In a preferred embodiment, the fiber mixture comprises oligofructose. If present, oligofructose is preferably included in the composition at 0.5-50 wt%, preferably 5-50 wt%, most preferably 5-28.4 wt%, based on the total weight of the fiber.

[0071] Pectin, also known as pectin polysaccharide, is rich in galacturonic acid. Several different polysaccharides have been identified and characterized in the pectin group. Galacturonan polysaccharides are linear α-(1-4)-linked D-galacturonic acid. In nature, about 80% of the carboxyl groups of galacturonic acid are esterified with methanol. During the pectin extraction process, this ratio is reduced to varying degrees. The ratio of esterified to non-esterified galacturonic acid determines the behavior of pectin in food applications. This is why pectin is classified as high-ester pectin versus low-ester pectin (HM pectin versus LM pectin), in which more or less than half of all galacturonic acid is esterified. Pectin can be hydrolyzed to reduce the molecular weight. For the present application, hydrolyzed pectin is preferred to prevent undesirable viscosity increases. In a preferred embodiment, the fiber mixture comprises pectin. If present, preferably pectin is included in the composition at 0.1-45% by weight, preferably 0.2-27% by weight, preferably 0.5-25% by weight, based on the total weight of the fiber.

[0072] Cellulose is a chemical with the molecular formula (C 6 H 10 O 5 ) nAn organic compound, a polysaccharide consisting of a linear chain of hundreds to thousands of β (1→4) linked D-glucose units. Cellulose is not digested or fermented in the human intestine, so cellulose is a fiber excreted in feces, and therefore contributes to the consistency of feces. The fiber mixture may contain cellulose. In a preferred embodiment, the fiber mixture contains less than 5% by weight of cellulose relative to the dietary fiber in the composition, preferably no cellulose. If present, cellulose may be present in the composition at 0.5-5% by weight, preferably 1-3% by weight, based on the total weight of the fiber. Alternatively, cellulose may be present at 0.5-50% by weight, preferably 6-19.6% by weight, based on the total weight of the fiber.

[0073] Gum Arabic, also known as acacia gum, is a natural gum composed of the hardened sap of various species of acacia trees. Arabinogalactan is a biopolymer composed of arabinose and galactose monosaccharides. It is the main component of many plant gums, including gum Arabic. In a preferred embodiment, the fiber mixture comprises gum Arabic. If present, preferably gum Arabic is included in the composition at 0.1-40% by weight, preferably 1-15% by weight, based on the total weight of the fiber.

[0074] Locust bean gum is a galactomannan plant gum extracted from the seeds of the carob tree. It can be used in hydrolyzed or unhydrolyzed form. In a preferred embodiment, the fiber mixture comprises locust bean gum. If present, preferably locust bean gum is included in the composition at 0.1-10% by weight, preferably 0.5-3% by weight, based on the total weight of the fiber.

[0075] Soy polysaccharides, also known as soy fiber, generally refer to non-starch, highly insoluble polysaccharides isolated from soybeans. When soy polysaccharides are mentioned in the present invention, their DP is generally greater than 10, preferably greater than 20, more preferably greater than 50, and even more preferably greater than 100. A suitable source of soy fiber is Fibrim (Solae). In a preferred embodiment, the fiber mixture comprises soy polysaccharides. If present, preferably soy polysaccharides are included in the composition at 0.01-10% by weight, preferably 0.05-0.5% by weight, based on the total weight of the fiber.

[0076] Guar gum is a galactomannan plant gum extracted from the seeds of guar beans. It can be used in (partially) hydrolyzed or unhydrolyzed form. In the context of the present invention, partially hydrolyzed guar gum is most preferably used. In a preferred embodiment, the fiber mixture comprises partially hydrolyzed guar gum. In an alternative embodiment, the fiber mixture does not comprise partially hydrolyzed guar gum as the only dietary fiber. If present, preferably guar gum is included in the composition in 0.01-10% by weight, preferably 0.05-3% by weight, based on the total weight of the fiber.

[0077] Lactic acid producing bacteria

[0078] Preferably, the composition further comprises lactic acid producing bacteria. Alternatively, the dietary fiber composition is administered together with a composition comprising lactic acid producing bacteria. The inventors believe that the use of supplemented lactic acid producing bacteria can synergistically restore and balance the intestinal flora microbiota of MMA and PA patients, especially if the presence of propionic acid producing bacteria is avoided, thereby providing a synergistic effect with dietary fiber. Therefore, in one embodiment, the composition is substantially free of propionic acid producing bacteria. Preferably, the composition is administered at 10 8 CFU to 10 12 The daily dose of colony forming units provides the lactic acid producing bacteria comprised in the composition of the present invention. Preferably, the lactic acid producing bacteria are selected from low propionic acid producing bacteria. Preferably, the composition of the present invention comprises bifidobacteria and / or lactobacilli. Preferred strains comprised in the composition of the present invention include Latobacillus plantarum (preferably WCFS1) and / or Bifidobacterium adolescentis (preferably DSM 18350).

[0079] protein

[0080] Preferably, the composition of the present invention also comprises a protein fraction. Preferably, the composition is free of intact proteins and partially hydrolyzed proteins, and the protein fraction consists essentially of free amino acids and dipeptides. Therefore, the protein levels defined hereinafter preferably apply only to amino acids. The term "protein equivalent" is well known in the art and refers to the amount of free amino acids, as if they were part of a protein, i.e. the weight values ​​of amino acids are understood as protein equivalent weight values. Typically, the contribution of amino acids to protein represents about 81% of the weight of the individual amino groups.

[0081] Amino acids are necessary for maintaining body cell mass and nearly all major body functions. Protein in the diet serves as a source of essential amino acids and provides nitrogen for the synthesis of other amino acids and nitrogenous compounds of physiological importance. Organic aciduria is caused by the body's inability to break down certain precursor amino acids in protein (valine, isoleucine, methionine and threonine). Therefore, it is preferred that these amino acids are limited or even completely excluded from the composition of the present invention. In other words, in a preferred embodiment, the protein fraction is substantially free of at least two, more preferably at least three, and most preferably at least four of valine, isoleucine, methionine and threonine.

[0082] The following table shows a summary of the preferred amino acid profiles of the present invention, in g / 10 g protein equivalent.

[0083] Preferred More preferred Examples L-Alanine 0.5-2.2 1.0-2.0 1.03 L-Arginine 0.4-1.8 0.5-1.5 0.90 L-Aspartic Acid 0.3-1.8 0.5-1.5 0.82 L-Cystine 0.2-1.0 0.25--0.75 0.46 Glycine 0.2-1.0 0.25--0.75 0.41 L-Glutamine 0.5-2.2 1.0-2.0 1.08 L-Histidine 0.3-1.8 0.5-1.5 0.61 L-Isoleucine 0.0-0.1 0.0-0.05 0.0 L-Leucine 0.8-2.5 1.0-2.0 1.36 L-Lysine 0.4-2.2 0.7-2.0 0.91 L-Methionine 0.0-0.1 0.0-0.05 0.0 L-Phenylalanine 0.3-1.8 0.5-1.5 0.60 L-Proline 0.2-1.0 0.25--0.75 0.41 L-Serine 0.3-1.8 0.5-1.5 0.59 L-Threonine 0.0-0.1 0.0-0.05 0.0 L-Tryptophan 0.05-0.8 0.1-0.5 0.21 L-Tyrosine 0.3-1.8 0.5-1.5 0.60 L-Valine 0.0-0.1 0.0-0.05 0.0 L-Carnitine 0.0-0.8 0.005-0.5 0.01 Taurine 0.0-0.8 0.005-0.5 0.02

[0084] The preferred content of amino acids in the above table applies to each amino acid individually as well as to the entire amino acid spectrum. It is worth noting that the contribution of each single amino acid weight to the total protein equivalent weight is about 80%.

[0085] Preferably, the composition of the present invention comprises 0-50 wt% protein equivalents, based on the dry weight of the composition, even more preferably 0-40 wt% protein equivalents and most preferably 20-35 wt% protein equivalents, based on the dry weight of the composition. If the composition of the present invention is a nutritional composition, it may preferably comprise 10-60 wt%, preferably 20-50 wt%, more preferably 25-35 wt%, most preferably about 28 wt% protein equivalents (preferably amino acids), based on dry weight. Per energy unit, the composition of the present invention preferably comprises 2.5-10 g amino acids / 100 kcal of the composition, preferably 4-9.5 g amino acids / 100 kcal of the composition, most preferably 5-8.0 g amino acids / 100 kcal of the composition. Preferably, the composition of the present invention comprises less than 1.0 wt% of each amino acid, more preferably less than 0.5 wt% of each amino acid, even more preferably less than 0.1 wt% of each amino acid and most preferably 0.0-0.05 wt% of each amino acid, based on the total weight of amino acids in the composition; the amino acids are selected from isoleucine, valine, threonine and methionine. In a preferred embodiment, the composition of the present invention further comprises carnitine, preferably at least 0.01 wt% carnitine, more preferably 0.05-7.5 wt% carnitine, more preferably 0.05-5 wt% carnitine, based on the total weight of amino acids in the composition.

[0086] The optimal protein content provided to the patient generally depends on the amount of the composition prescribed by the doctor or nutritionist according to the calculated needs of the individual patient. Depending on age and clinical condition, the average protein requirement may vary from 1-3 g / kg body weight per day. In one embodiment, the composition of the present invention comprises sufficient protein to provide 60-100% by weight of the recommended daily intake, and the recommended daily intake is as recommended by the Medical Research Council (MRC) in the Recommendations on the dietary management of phenylketonuria. Report of Medical Research Council Working Party on Phenylketonuria. Arch Dis Child, 1993 Mar. 63 (3): p. 426-427. In an alternative embodiment, the composition of the present invention comprises sufficient protein to provide up to 60% by weight of the recommended daily intake as listed by the MRC, which is particularly preferred if the composition of the present invention is in the form of a supplement.

[0087] Lipids

[0088] Compositions of the present invention preferably also comprise lipid part.Lipid is the important energy source of children, and can utilize amino acid.Some fatty acid (such as long-chain polyunsaturated fatty acid (LCPUFA)) is considered to be beneficial to the diet of protein restriction.The intake of LCPUFA of the children suffering from congenital amino acid metabolism defect is usually limited, because LCPUFA is mainly present in animal source food, and dietary therapy requires to exclude this natural abundant protein source from diet.Lipid also stores fat-soluble vitamins, and is the source of essential fatty acids.The total lipid content of preferred embodiment is preferably 2.5-9g lipid / 100kcal, more preferably 3-7.5g lipid / 100kcal, even more preferably 3.5-6g lipid / 100kcal and most preferably about 4.5g lipid / 100kcal or about 12.5-25g lipid / 100g composition dry weight. Preferably, the lipid source is a blend of vegetable oils (e.g., a rapeseed-sunflower-palm kernel-coconut blend) that provides percentages of saturated fatty acids (16.6% fat by weight), polyunsaturated fatty acids (15.0% fat by weight), and monounsaturated fatty acids (68.4% fat by weight). Preferably, the nutritional composition of the present invention comprises the essential fatty acids, linoleic acid (C18:2 (n-6)) and alpha-linolenic acid (C18:3 (n-3), and is preferably present in amounts in accordance with current recommendations (3-10 wt% and 0.5-4.5 wt% of the total lipid weight). The ratio of n-6 to n-3 fatty acids is preferably 6:1-1:1, more preferably 3:1-2:1, and most preferably about 2.6:1. Docosahexaenoic acid (22:6n-3, DHA) is an important omega-3 long chain polyunsaturated (LCP) fatty acid because it is the most predominant fatty acid in neural tissues. It accounts for about 20% of all fatty acids in the brain and up to 60% of all fatty acids in the retina (eye). DHA is essential for the formation of neural membranes. , membrane integrity, electrical insulation, vesicle transport and synaptic transmission. Studies have shown that the efficiency of conversion of DHA from its precursor essential fatty acid ALA is lower than commonly assumed. Since it has been found that DHA is lacking in the diet and plasma of PKU subjects after a restricted diet, and also in subjects with other inborn errors of metabolism, the level of DHA contained in the composition of the present invention is 20-120 mg / 100 kcal, preferably 30-90 mg / 100 kcal, even more preferably 35-85 mg / 100 kcal, and most preferably about 65 mg / 100 kcal. The source of DHA is preferably seaweed, which has the least effect on the taste of the final product compared to sources from fish oil.

[0089] Digestible carbohydrates

[0090] Preferably, the composition of the present invention also comprises a digestible carbohydrate portion. Carbohydrates are classified as monosaccharides, disaccharides, oligosaccharides and polysaccharides. Digestible carbohydrates include important biomolecules that are important energy sources. Preferably, the total carbohydrate content of the composition of the present invention is 0-50g / 100kcal, preferably 20-40g / 100kcal, most preferably about 30g / 100kcal. Preferably, the source of carbohydrates in the composition of the present invention includes, preferably maltodextrin. Compared with, for example, glucose or sucrose, the use of maltodextrin increases solubility and reduces the contribution to the weight molar osmotic pressure concentration of the formula.

[0091] Micronutrients

[0092] Preferably, the composition of the present invention also contains micronutrients. Preferably, the composition of the present invention contains vitamins, minerals and trace elements in amounts that meet the RDA / DRI and DRV for 1-3 years old based on typical product usage (e.g., see Institute of Medicine, Dietary Reference Intakes for Calcium and Vitamin D, National Academy Press, Editor 2010: Washington DC). Specifically, vitamin D and calcium are increased according to the new recommended intakes, as discussed below. Sodium and potassium are intentionally reduced to optimize taste.

[0093] In a preferred embodiment, the composition of the invention comprises vitamin D and / or calcium, preferably vitamin D.

[0094] The main source of vitamin D in the human body is exposure to sunlight, and any condition that blocks sunlight or interferes with the penetration of UVB into the skin will affect the synthesis of vitamin D. There are few dietary sources of vitamin D. The main sources are fatty fish, fish oil, liver and other organ meats, and egg yolks from chickens fed vitamin D, which are often excluded from the restricted diets of patients with inborn errors of metabolism. Vitamin D deficiency in children can lead to growth retardation and the classic signs and symptoms of rickets. Vitamin D is essential for bone health, and since the foundation of adult bone health is laid in the early years, appropriate intake of vitamin D in childhood is critical. Suboptimal vitamin D status and / or suboptimal exposure to sunlight are also associated with muscle weakness, functional deficits, cardiovascular disease, cancer mortality, and potentially longer hospital stays in hospitalized patients. In addition, vitamin D has a critical role in supporting serum calcium concentrations within a narrow range and is essential for maximizing calcium absorption in the small intestine. It is estimated that adequate vitamin D status increases calcium absorption to 30-40% compared to 10-15% when vitamin D status is inadequate. Factors that affect vitamin D status include race, malnutrition, advanced age, use of multivitamins, and ultraviolet radiation. It is expected that patients with inborn errors of metabolism will have very limited vitamin D intake from their normal diet. Therefore, the composition of the present invention preferably comprises 2-20 μg / 100 kcal, more preferably 4-17 μg / 100 kcal, and most preferably 5-14 μg / 100 kcal (200-560 IU / 100 kcal) of vitamin D.

[0095] Calcium is an essential nutrient for bone and tooth mineralization. In addition, calcium is used as a signal for many cellular processes (e.g., secretion of hormones, enzymes, and nervous systems). Calcium and vitamin D are closely linked to each other. The main physiological function of vitamin D is to maintain serum calcium and phosphorus levels within a normal range to support, for example, metabolic functions and bone mineralization. If calcium intake is insufficient, vitamin D helps to maintain calcium homeostasis. However, when vitamin D is deficient, this can prevent the effective absorption of calcium. Preferably, the level of calcium included in the composition of the present invention is 200-600mg / 100kcal, more preferably 250-500mg / 100kcal, and most preferably about 375mg / 100kcal. Per 100g of composition dry weight, calcium content is preferably 500-1500mg, more preferably 800-1200mg, and most preferably about 980mg.

[0096] Caloric density

[0097] In a preferred embodiment, the composition of the present invention is a supplement comprising only dietary fiber. Therefore, fiber constitutes about 90-100% energy of the composition. In another preferred embodiment, the composition of the present invention is a supplement comprising only dietary fiber and protein. In the latter embodiment, the energy density of protein is preferably 4-98 energy%, and the energy density of dietary fiber is preferably 2-96 energy%. In another preferred embodiment, the composition of the present invention is a complete nutritional composition comprising dietary fiber, protein, digestible carbohydrates and lipid, wherein the energy density is preferably as follows: 10-60 energy% lipid, 10-65 energy% digestible carbohydrates, 2.0-15 energy% dietary fiber and 10-40 energy% protein. The energy density of the complete nutritional composition is preferably 0.4-3.5kcal / ml, more preferably 0.7-3.0kcal / ml, even more preferably 0.8-2.6kcal / ml and most preferably 0.9-2.4kcal / ml. In this article, "only comprising" means that there are substantially no other components, and all energy densities of components are given with the percentage of the total energy content of the composition.

[0098] Particularly preferred compositions

[0099] In one aspect of the invention, the present invention relates to the composition itself as defined above. In the context of this aspect, the composition of the present invention preferably comprises dietary fiber and a protein fraction consisting of free amino acids. Particularly preferred compositions of the present invention comprise galacto-oligosaccharides, resistant starch, gum arabic, soy polysaccharides, and at least one of oligofructose and inulin, preferably in combination with a protein fraction consisting of free amino acids, more preferably wherein the free amino acids are substantially free of valine, isoleucine, methionine and threonine. Another preferred composition comprises at least one dietary fiber selected from oligofructose, inulin, resistant starch, cellulose, methylcellulose, wheat bran, gum arabic, soy polysaccharides, oat fiber, galacto-oligosaccharides, locust bean gum, pectin, guar gum and mixtures thereof, and the free amino acids are substantially free of valine, isoleucine, methionine and threonine. Preferably, the dietary fiber comprises at least GOS. Preferably, the composition also comprises lactic acid bacteria. Particularly preferably, the composition of the present invention further comprises 10-60 energy % lipids and 10-65 energy % digestible carbohydrates, wherein dietary fiber is present in 2.0-25 energy % of the total composition and protein is present in 10-40 energy % of the total composition, wherein the energy density of the composition is 0.7-3.5 kcal / ml.

[0100] Application

[0101] In a first aspect, a composition of the invention comprising dietary fiber is used for the dietary management of methylmalonic acidemia (MMA) and / or propionic acidemia (PA). In other words, the invention relates to the use of dietary fiber in the preparation of a composition for the dietary management of methylmalonic acidemia (MMA) and / or propionic acidemia (PA). In other words, the invention relates to a method for the dietary management of methylmalonic acidemia (MMA) and / or propionic acidemia (PA), comprising administering a composition of the invention comprising a therapeutic amount of dietary fiber to a subject in need thereof.

[0102] In addition, the composition of the present invention comprising dietary fiber is used to treat and / or reduce methylmalonic acidemia (MMA) and / or propionic acidemia (PA), and / or treat, reduce and / or prevent symptoms associated therewith. In other words, the present invention relates to the use of dietary fiber in the preparation of a composition for treating and / or reducing methylmalonic acidemia (MMA) and / or propionic acidemia (PA), and / or treating, reducing and / or preventing symptoms associated therewith. In other words, the present invention relates to a method for treating and / or reducing methylmalonic acidemia (MMA) and / or propionic acidemia (PA), and / or treating, reducing and / or preventing symptoms associated therewith, comprising administering a composition of the present invention comprising a therapeutic amount of dietary fiber to a subject in need thereof.

[0103] In addition, the composition of the present invention comprising dietary fiber is used to reduce the production of propionic acid caused by intestinal flora. In other words, the present invention relates to the use of dietary fiber in the preparation of a composition for reducing the production of propionic acid caused by intestinal flora. In other words, the present invention relates to a method for reducing the production of propionic acid caused by intestinal flora, which comprises administering a composition of the present invention comprising a therapeutic amount of dietary fiber to a subject in need thereof.

[0104] The uses described herein with respect to the invention also apply to the methods according to the invention and to the compositions used according to the invention. These uses are medical in nature. The target population for these uses is patients suffering from MMA and / or PA. The uses according to the invention generally relate to reducing the propionic acid produced by the intestinal flora as measured in the feces of the patient.

[0105] The use according to the first aspect may also be used to treat and / or alleviate MMA or PA, and / or treat, alleviate and / or prevent symptoms associated therewith. In one embodiment, the use according to the first aspect is also used to treat and / or alleviate MMA or PA. In one embodiment, the use according to the first aspect is also used to treat, alleviate and / or prevent symptoms associated with MMA and / or PA.

[0106] In one embodiment, the use according to the second aspect is for treating and / or alleviating MMA and / or PA. In one embodiment, the use according to the second aspect is for treating, alleviating and / or preventing symptoms associated with MMA and / or PA. The use according to the second aspect may also be used for dietary management of MMA and / or PA. Treating, alleviating and / or preventing symptoms may also be referred to as alleviating symptoms.

[0107] Symptoms associated with MMA and / or PA may also be referred to as symptoms associated with excessive propionic acid production in the intestine, and generally include intestinal diseases, diseases associated with vitamin D deficiency, and diseases associated with LC-PUFA deficiency. Intestinal diseases in patients with MMA and / or PA generally include one or more of the following: imbalance of microbiota, bacterial translocation, impaired stool looseness, impaired intestinal transit time, imbalance in SCFA production, and constipation. In one embodiment, intestinal diseases are selected from impaired stool looseness, imbalance in SCFA production, and constipation. Stool loose products include volume, consistency, and viscosity. Reducing the production of unbalanced SCFA preferably includes balancing the production of SCFA along the length of the colon. Diseases associated with vitamin D deficiency in patients with MMA and / or PA generally include one or more of the following: growth retardation, rickets, impaired bone health, muscle weakness, functional defects, cardiovascular disease, cancer mortality, and impaired calcium intake. Diseases associated with LC-PUFA deficiency (especially DHA deficiency) include brain diseases, such as impaired neural membrane integrity, impaired electrical insulation, impaired vesicle transport, and impaired synaptic transmission. These symptoms associated with MMA and / or PA are treated, alleviated and / or prevented by administering the composition of the present invention. In a preferred embodiment, intestinal diseases associated with MMA and / or PA are treated, alleviated and / or prevented.

[0108] Example 1

[0109] Fermentation

[0110] In a high-throughput anaerobic colon model (I-screen TM After 24 h of incubation in a 100 μl (10 μl) flask (TNO, Zeist, The Netherlands), the effects of the fiber mixtures in Table 1 on SCFA production were measured. This platform simulates intestinal flora conditions and allows the determination of the effects of compounds on microbiota composition over time under strictly anaerobic conditions. The I-screen was inoculated with standard healthy human adult intestinal flora. TMModel. The intestinal flora was obtained by pooling stool samples from 6 healthy adult volunteers and incubating the pooled stool samples in a fed-batch fermenter for 40 h to produce a standardized microbiota. The pooled stool samples were then cultured in vitro in a modified standard ileal efflux medium (SIEM) and the pH was adjusted to 5.8. The standardized adult intestinal flora was stored in 12% glycerol at -80°C until further analysis. This pooling approach was intended to limit inter-individual variation and increase the likelihood of having a greater representation of potential bacterial species in the human colon.

[0111] Before testing the fiber mixture, the standard adult microbiome was activated by incubating overnight in modified SIEM medium under anaerobic conditions at 37°C and shaking at 300rpm. Four conditions were tested at a concentration of 6mg / ml (fiber level concentration), corresponding to different combinations of fiber mixtures and components (Table 1). Negative controls (microbiome not exposed to SIEM medium) and blanks (SIEM medium without microbiome) were included. Each condition (including controls) was tested in triplicate. Table 1 summarizes the experimental setup. After adding the test compound (combination), negative control or blank, the microbiome was incubated anaerobically at 37°C for 24 hours. Samples were then collected and further analyzed.

[0112] Short-chain fatty acids (SCFA) measurement

[0113] To analyze short-chain fatty acids, TM The material produced by the incubation was sampled and centrifuged at 4,000g for 5 minutes. The supernatant was sterilized by filtration with a 0.45pm filter. A mixture of formic acid (20%), methanol and 2-ethylbutyric acid (internal standard, 2mg / ml methanol solution) was added. In a Shimadzu GC-2014 gas chromatograph, 3 picoliters (pl) of sample with a split ratio of 75.0 was injected into a GC column (ZB-5HT inferno, ID 0.52mm, film thickness 0.10um; Zebron; phenomenex, USA). The SCFA analyzed were acetic acid, propionic acid, isobutyric acid, n-butyric acid and isovaleric acid.

[0114] result

[0115] The amount of propionate produced by the fiber mixtures and the percentage of propionate relative to total SCFA after 24 hours of anaerobic in vitro fermentation with adult human microbiota are shown in Table 2. Compared with the control, mixtures A, B, D, E and F reduced the formation of propionate and increased the total amount of SCFA formed, while mixture C caused an increase in propionate formation. Moreover, mixture B (GOS) showed the greatest effect relative to mixtures A and C in terms of both propionate formation and SCFA formation. Next was mixture D, which had an increased level of resistant starch (at the expense of cellulose) compared to mixture A, indicating a decrease in propionate relative to mixture A. The total amount of SCFA was also higher in mixture D compared to mixture A. The addition of 10 wt% GOS to mixture D further reduced the amount of propionate in the resulting mixture F.

[0116] The effect of GOS on propionic acid appears to be higher when relatively high amounts of resistant starch are present. Mixture F vs. Mixture D showed an improved effect compared to Mixture E vs. Mixture A.

[0117] in conclusion

[0118] The inventors have found that the fiber mixtures of the present invention lead to lower levels of propionate production in the microbiome of adults. Specifically, the propionate production of mixtures B, D and F was unexpectedly low, while maintaining high production of other SCFAs. This suggests that the fiber composition of the present invention comprising fiber can play an important role in the clinical characteristics of patients with methylmalonic acidemia (MMA) and propionic acidemia (PA).

[0119] Table 1: Composition of the tested fiber mixtures (weight percentage of each fiber relative to the total fibers).

[0120]

[0121] Table 2: Propionic acid produced during in vitro fermentation (average of 3 measurements).

[0122]

[0123] Example 2: Composition of the present invention

[0124] The following composition of the present invention is a composition suitable for treating MMA and PA by regulating the intestinal flora so that the production of propionic acid is reduced. Based on the total weight of the composition, the supplement contains the following ingredients in weight %:

[0125] 1.5-28.4% fructooligosaccharides

[0126] 1.5-25.5% inulin

[0127] 1.5-50% resistant starch

[0128] 1-15% gum arabic

[0129] 0-0.5% soybean polysaccharide

[0130] 0-3% guar gum

[0131] 5-79.5% galacto-oligosaccharide

[0132] Optionally supplemented with lactic acid producing bacteria, preferably Bifidobacteria and / or Lactobacilli.

[0133] Example 3: Composition of the present invention

[0134] The following composition of the present invention is a composition suitable for treating MMA and PA by regulating the intestinal flora so that the production of propionic acid is reduced. Based on the total weight of the composition, the supplement contains the following ingredients in weight %:

[0135] 5-100% galacto-oligosaccharide

[0136] 0-70% resistant starch

[0137] Optionally supplemented with lactic acid producing bacteria, preferably Bifidobacteria and / or Lactobacilli.

[0138] - Optionally a lipid source and a digestible carbohydrate source.

[0139] Example 4: Composition of the present invention

[0140] The following composition of the present invention is a composition that is used for the treatment and / or dietary management of MMA or PA patients by regulating intestinal flora and supplementing protein to reduce the level of toxic metabolites in the blood. The composition comprises the fiber blend of Example 2 and an amino acid blend, wherein the amino acid blend comprises the following amino acids in g / per 10 grams of protein equivalent:

[0141]

[0142]

[0143] Example 5: Composition of the present invention

[0144] The following composition of the present invention is a complete nutritional composition for the treatment and / or dietary management of MMA or PA patients by regulating intestinal flora and supplementing protein so that the level of toxic metabolites in the blood is reduced. The composition can be used as an exclusive diet. The supplement comprises the fiber and protein blend of Example 3, lipids, digestible carbohydrates and micronutrients.

[0145]

[0146]

[0147]

[0148] Notes

[0149] * The term "protein equivalent" is well known in the art and refers to the amount of free amino acids as if they were part of protein, i.e. the weight values ​​of amino acids should be understood as protein equivalent weight values. The contribution of amino acids to protein represents about 81% of the weight of the individual amino groups.

Claims

1. Use of a composition comprising galacto-oligosaccharides in the preparation of a product for use in a human subject aged at least 3 years: - Treating and / or alleviating methylmalonic acidemia (MMA) and / or propionic acidemia (PA), and / or treating, alleviating and / or preventing symptoms associated therewith; -Dietary management of MMA and / or PA; and / or - Reduces propionic acid production caused by intestinal flora.

2. The method according to claim 1, wherein the subject is at least 12 years old, preferably at least 18 years old.

3. Use according to any one of the preceding claims, wherein the composition further comprises resistant starch.

4. The use according to any one of the preceding claims, wherein the composition further comprises gum arabic, soy polysaccharides, and at least one of oligofructose and inulin.

5. Use of a composition comprising galacto-oligosaccharides, resistant starch, gum arabic, soy polysaccharides, and at least one of oligofructose and inulin in the preparation of a product for use in patients with MMA or PA: - Treating and / or alleviating methylmalonic acidemia (MMA) and / or propionic acidemia (PA), and / or treating, alleviating and / or preventing symptoms associated therewith; -Dietary management of MMA and / or PA; and / or - Reduces propionic acid production caused by intestinal flora.

6. Use according to any one of claims 1 to 5, wherein the composition comprises at least 10 wt%, preferably at least 20 wt%, most preferably at least 30 wt% resistant starch, based on the total weight of dietary fiber.

7. Use according to any one of claims 1 to 6, wherein the composition comprises at least 20 wt%, preferably at least 30 wt%, most preferably at least 50 wt% of the combination of resistant starch and galacto-oligosaccharide, based on the total weight of dietary fiber.

8. Use according to any one of claims 1 to 7, wherein the composition further comprises lactic acid producing bacteria, preferably selected from the genera Bifidobacterium and Lactobacillus.

9. Use according to any one of claims 1 to 8, wherein the composition further comprises guar gum.

10. Use according to any one of claims 1 to 9, wherein the composition comprises less than 5 wt% cellulose, based on the total weight of dietary fiber, preferably the composition comprises no cellulose.

11. The use according to any one of claims 1 to 10, wherein the composition is in the form of: (i) a nutritional supplement, wherein the supplement preferably further comprises amino acids; or (ii) A complete nutritional composition, wherein the nutritional composition further comprises a protein fraction, preferably in the form of amino acids, digestible carbohydrates, vitamins and minerals.

12. Use according to any one of claims 1 to 11, wherein the composition further comprises a protein fraction consisting essentially of free amino acids and dipeptides, preferably wherein the protein fraction is essentially free of valine, isoleucine, methionine and threonine.

13. Use according to any one of claims 1 to 12, wherein the composition comprises DHA.

14. Use according to any one of claims 1 to 13, wherein the composition comprises vitamin D and / or calcium, preferably vitamin D.

15. A composition comprising galacto-oligosaccharide, resistant starch, gum arabic, soybean polysaccharide, and at least one of fructo-oligosaccharide and inulin.

16. A composition according to claim 15, wherein the amount of GOS is at least 5 wt% of the dietary fiber in the composition and the resistant starch is at least 10 wt%, preferably at least 20 wt%, most preferably at least 30 wt% of the dietary fiber in the composition.

17. A composition according to claim 15 or 16, wherein the composition comprises less than 5 wt% cellulose, based on the total weight of dietary fibre, preferably wherein the composition comprises no cellulose.

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