Dietary Fibre for Use in the Treatment of a Gastro-Intestinal Side-Effect of a Nutrition or Medicament
The invention relates to a dietary fibre for use in delaying or otherwise reducing a sating effect of a medical nutrition or of a medicament, wherein the medical nutrition or medicament is for oral or gastro-enteric administration by a human. The invention further relates to a method for prophylactically or therapeutically treating a human in need thereof, the treatment comprising administering an effective amount of a dietary fibre, in combination with a pharmaceutical composition or a nutrition as defined in any of the preceding claims, thereby reducing a sating effect of the pharmaceutical composition or the nutrition. The invention further relates to products suitable for use in such a method.
The invention relates to dietary fibre for use in a treatment of a subject that suffers from an undesired side-effect of a nutrition, a nutritional product or a medicament. Further, the invention relates to a nutrition, a nutritional product and to a medicament. Further, the invention relates to a product for use in the treatment of malnourishment.
Various medicaments are known to cause negative gastro-intestinal side-effects, such as nausea, loss of appetite, vomiting, excessive satiety, inactive action and peristalsis of the gut or abdominal cramps. Examples of such medicaments are opiates, selective serotonine re-uptake inhibitors (SSRI's) and chemotherapeutics. Apart from being discomforting to the subject, such effects may impair consumer compliance.
In addition, medical nutrition, when designed inappropriately or when comprising high amounts of otherwise healthy nutrients, may give rise to similar undesired gastro-intestinal side-effects, whereby consumer compliance is relatively poor. As a result thereof (voluntary) intake is impaired, which decreases the overall benefit of administration of the food product. In particular highly concentrated liquid formulae (or solid nutrition or tube feeding which is administered at too high rate may cause nausea or be experienced by consumers as too filling (heavy), whereby less of the nutrition is consumed than is desired in order to provide sufficient nourishment.
In WO 2005/002588 it is observed that a pharmaceutical provided with an enteric coating can provide improved pharmaceutical activity with reduced adverse side effect such as nausea. For example, the bicyclic 13,14-dihydro-16,16-difluoro-prostaglandin E1 had less side effect of nausea when delivered by enteric coated capsules produced by spraying hydroxypropyl Me cellulose phthalate as enteric coating. It is apparent that the cellulose derivative is used herein to control release of the pharmaceutically active compound.
It is a drawback that the product needs to be coated in order to reduce a side effect, as the process of coating makes the process of making the product more complex. In addition, although enteric coatings are often used for pharmaceuticals, it is not an approach that would generally be considered to be useful for nutrition; a dosage of nutrition is generally much bulkier than a pharmaceutical dosage. Moreover, at least for orally ingested nutrition, coating the nutrition may affect organoleptic properties (such as loss of taste, change in mouth feel), which may have a detrimental effect on the liking of the product and impair food compliance. In addition coated nutrients typically loose coating integrity under the conditions used for manufacture of heat-treated homogeneous liquid formula
WO 97/28700 relates to a nutrient composition for use during exercise and aims to overcome problems associated with the ingestion of carbohydrates resulting in a blood glucose peak shortly after ingestion; along with a concomitant peak in blood insulin. It is observed in WO 97/28700 that this is then followed by an equally rapid drop in blood glucose levels, even to levels below normal range. Such reactive hypoglycaemia causes unpleasant symptoms, like fatigue and reduce exercise performance.
Further, fatigue may rapidly set in; greatly reducing exercise performance. A nutrient composition designed to avoid these problems whilst maintaining raised blood glucose levels is disclosed, which contains carbohydrate and a source of soluble fibre, especially a fibre-rich cereal. This document does not relate to increasing satiety or decreasing nausea as caused by medicaments or medical nutrition.
It is an objective of the present invention to provide a product for use in a prophylactic or therapeutic treatment of a negative gastro-intestinal side-effect a medicament or of medical nutrition, wherein preferably consumer compliance is increased.
It is another objective of the invention to increase voluntary food intake, shorten the period between surgery and the moment that voluntarily oral food intake can be started, prevent the need to change over from sip feed to oral feeding of enteral or parenteral tube feeding, improve recovery after trauma, decrease length of stay in hospitals, decrease secondary complications after trauma, and/or decrease low appetite, nausea, after medication.
The inventors found that one or more of these objectives is realised by providing a specific component, to a subject using medical nutrition or a medicament.
Accordingly, the present invention relates to dietary fibre, for use in prophylactically or therapeutically treating a negative gastro-enteric side-effect of a composition, preferably a medical nutrition or a medicament, wherein the medical nutrition or medicament is for oral or gastro-enteric administration by a human. An example of the latter way of administration is a drink feed or tube feeding into the stomach.
The inventors realised in particular that administration of specific medical nutrition or a medicament such as an SSRI, a monoamine oxidase (MAO) inhibitor, an opiate or a chemotherapeutic agent, can give rise to a undesired side-effect as a result of an interaction between the nutrition or medicament in the stomach or the proximal part of the intestines, more in particular in the stomach, duodenum, jejunum, and/or the proximal part of the ileum.
Without being bound by theory, the inventors consider that medical nutrition or a specific medicament can give rise to an undesired side-effect as a result of overstimulation of sensing cells in the intestines. These sensing cells induce a neuro-endocrine response to (changes in) the luminal contents of stomach or intestine. This response when proper is useful to aid digestion, prepare for the microbial condition in the lumen, to prevent damage to the gut tissue and allow efficient absorption of nutrients. However, overstimulation induces cramps, diarrhea and other gastrointestinal discomfort. For instance sensing cells may release a pattern of neurotransmitters and neuropeptides dependent on the intraluminal circumstances. In particular enteral administration of nutrition or a medicament into the gastro-intestinal tract can invoke a response by the sensing cells as a consequence of intraluminal circumstances, such as stretch, ‘physical’ pressure (stretch due to changes in internal volume), acidity, osmotic value (e.g. high ionic strength of the contents of the intestine), distortion and shearing forces and the presence of pungent components or activating substances, such as receptor agonists, specific proteins or peptides, specific lipids and fatty acids. Entero-endocrine cells (EE cells) and enterochromaffin cells (EC cells) are particularly sensitive in this respect and are widely expressed in the gut and especially in the proximal parts of the small intestine. EC cells are capable of releasing serotonin as an important member of the total neuro-endocrine response and this released serotonin is thought to be of particular importance in themodulation of the response of the gastrointestinal system and the systemic serotonin concentrations by consumption of a nutritional product or medicament. The enteric nervous system (ENS) is an important modulator of the neuroendocrine response. A part of this is the nervus vagus. It is the inventors understanding that a medical nutrition may in particular give rise to overstimulation of sensing cells, due to a ‘highly filling property’, a high energy density, its rheological consistency, a high dry matter content, a high acidity and/or a high buffer strength or capacity.
For a medicament, it is contemplated that it is in the nature of certain active components, such SSRI's and others mentioned herein, that sensing cells In the gastrointestinal tract become stimulated after oral intake of these medicaments and trigger a sating neuro-endocrine response.
Accordingly, the invention in particular relates to a dietary fibre for use in avoiding or reducing an overstimulation of the proximal parts of the small intestine, preferably of the duodenum and/or jejunum, in particular an overstimulation of sensing cells, preferably EC cells in the small intestine, preferably in the duodenum and/or jejunum. An effect of such use is in particular reducing, optionally to the extent that its occurrence is avoided, a gastro-intestinal side-effect, as mentioned elsewhere in the present disclosure.
It is noted that a role of dietary fibre in the functioning of the gastro-intestinal tract has been a topic of major scientific interest for a considerable period of time. However, the attention is generally drawn to a role of dietary fibre in the colon by modulating the growth of colonic bacteria. Dietary fibre is generally not considered to be biologically active in the smaller intestine other than potentially affecting local viscosity and rate of absorption of nutrients. A significant effect on EC cells in the proximal part of the intestines is thus unexpected.
In a particularly preferred embodiment, the invention relates to a dietary fibre for use in delaying or otherwise reducing nausea or a sating effect of a composition, preferably a medical nutrition or of a medicament, wherein the composition, such as the medical nutrition or medicament, is for oral or gastro-enteric administration by a human.
The sating effect of a medicament or medical food can be established by applying the guidelines as described in Blundell et al, Obesity Rev 2010, 11, 251-270. It can be determined in various ways, e.g. by interviewing and individual or measuring ad libitum food consumption of the experimental food. A method is selected which is capable of measuring that the inclusion of the fibre component in a product decreases the sating properties of the original product. It is important to notice that the sating properties of a product become evident briefly after consumption and last for a period of 1 to 5 hours. The time of measurement is important. For measuring sating properties on shorter term, i.e. within 1.5 hours after consumption, measurement of neuro-endocrine response is preferred, while for measurement of longer term effects, interviews are preferred by the inventors. Examples of suitable biomarkers for the neuro-endocrine response are the concentration of one or more peptides, like CCK, PYY 3-36), GLP-1, amylin or ghrelin, or of neurotransmitters, like serotonin and/or its metabolites. Alternatively the activity of the gut tissue (motility) or ENS can be measured.
Alternatively one can measure the amount of a standard food that is consumed on a voluntary base in the period 15 minutes to 3 hours after having consumed the first product. The latter amount is preferably expressed as the amount of energy (kJ) that is consumed.
The inventors consider that the invention is in particular suitable for reducing a sating effect, as a side effect of an overstimulation of sensing cells, preferably EC cells, in the small intestine. It is in particular surprising that a dietary fibre is suitable for reducing a satiety effect of a composition such as a medical nutrition or of a medicament. Dietary fibre has been reported in the art as having a sating effect. For example WO2008/066308 discloses a nutritional product comprising glucomannans, whey proteins and soy protein isolate to induce satiety. The anorexic effect is suitable for letting people lose weight. This is contrary to what is desirable for many patients which suffer from malnourishment, like many hospital patients and elderly.
In a further preferred embodiment, the invention relates to a dietary fibre for use in alleviating or avoiding nausea, reducing loss of appetite (optionally to the extent that the loss is avoided), or reducing vomiting urges (optionally to the extent that such urges are avoided), experienced after oral or gastro-enteric intake of a composition, preferably a medicament or medical nutrition.
In a further preferred embodiment, the invention relates to the use of dietary fibre for increasing consumer's compliance to consuming the prescribed dose, in particular to consuming the ready to use dose unit of a composition, preferably being a medical nutrition or a medicament. In a further embodiment the invention relates to increasing overall food intake, by increasing the intake of the product, and/or by increasing net intake of food over the same day.
In a preferred embodiment, an individual who is malnourished or is at risk of becoming malnourished and experiences adverse effects when consuming normal or inappropriately designed nutritional products is treated with a nutritional product according to the invention. In a preferred embodiment a product according the invention is used for (improving the) treatment of malnourishment.
Malnourishment in one or more nutritional components is a frequent and internationally recognized problem, especially in aged and diseased individuals, despite the availability of many kinds of food products. This has a major impact on the persons health, recovery rate and on costs of the society (Freijer, 2012, 2013 and http://www.guardian.co.uk/social-care-network/2013/may/29/malnutrition-older-people-lack-of-food. and http://www.nutraingredients.com/Research/Malnutrition-in-hospital-Avoidable-but-not-a-priority
Malnourishment is especially prevented or treated and health is in particular improved when the individual is compliant to food protocols and is starting as soon as possible after discovery of malnourishment or trauma (like surgery).
Malnourishment is especially in issue when absorption from gut lumen is impaired or when the individual experiences a cancer or inflammation
In a specific embodiment, the dietary fibre is used for increasing early intake of food after surgery.
The dietary fibre—when administered to a human subject—may in particular be a dietary fibre that has an ameliorating effect on the neuro-endocrine response and/or the amount of serotonin that is released by the enterochromaffin cells and/or enteric nervous system in the small intestine as a reaction to the postprandial luminal contents.
The dietary fibre may modulate the human microbiota as occurs in the small intestine, which may include bacteria, archae, moulds and yeasts. In particular after oral or gastro-enterical administration of appropriate amounts of the dietary fibre or the product wherein the dietary fibre for use as an active ingredient in accordance with the present invention (the ‘active fibre’) is included, the type and activity of bacteria and archaea change, which inhabit the proximal part, more in particular those that inhabit the mucosa of duodenum, jejunum and proximal parts of the ileum. The changed microbiota in the small intestine may also induce a better symbiosis between genera in the small intestine, and between host epithelial cells and mucosal microbial species. This may be reflected by a higher rate of synthesis or release of zwitter-ionic polysaccharides from locally present bacteria. An example of such polysaccharide is the polysaccharides that are synthesized by Bacteroidetes genera, in particular Polysaccharide A2. In a specific embodiment the product increases or normalizes the presence or activity of Bacteroides fragilis. In one embodiment the product increases the presence of Bacteroidetes in or near the mucosa of the small intestine, in particular that of Bacteroides fragilis. It is observed that the polysaccharide as synthesized by the bacteria in the gut differs in chemical structure and identity from the polysaccharides that can be isolated from herbs like Echinacea, as disclosed in U.S. Pat. No. 4,857,512, though these polysaccharides may be included in certain embodiments of the invention.
In an embodiment the amount or activity of Sutterella genera as present in or near the ileal mucosa may decrease, as can be measured by determining species-specific RNA (e.g. the 16S rRNA) in a representative sample.
In an embodiment, the dietary fibre supports the development of those archaeon genera, which facilitate the colonisation of useful bacteria in the mucosa of the duodenum and proximal parts of the ileum. These archaea in the duodenum and ileum, and in the mucosa in these parts of the small intestine may differ from known colonic archeae, and from methanobrevibacter genera, as disclosed in e.g. WO2006102350. The symbiosis between archaea and mucosal bacteria is thought to be mediated by the secretion of adhesion modulating substances, glycolipids and polysaccharides that are released by archaea. The net effect of these changes may be the lower release of serotonin of locally present neurons and enterochromaffin cells, a decreased activation of the local enteric nervous system and/or a decreased degree of activation by the vagus nerve.
The presence of a more diverse and adapted community of microbiota in the proximal parts of the small intestine facilitates efficient fermentation of dietetic fibres in more distal parts of the gut. The presence of a greater variety in metabolic capacity e.g. by the presence of specific E. coli or Bifidobacteria variants may result in an early though partial hydrolysis of dietetic polysaccharides into (smaller) oligosaccharides. The smaller sized oligosaccharides are easier to access by other microbial enzymes, e.g. by hydrolases or feruloyl esterases, for example those originating from or present in symbiotic microorganisms. This allows generation of a different profile and wide diversity of fermentation products. These fermentation products may include for example ferulic acid, monosaccharides and small organic molecules which can interact with receptors on the membranes of epithelial cells or microbes. The active community of microbes in the mucosa also induces a higher expression of epithelial “brush border” di-saccharidases and hexose transporters, which facilitates absorption and use of nutrients from the intestinal lumen. The changed microbiome in the small intestine also decreases the amount of interferon-gamma that will be released as a result of luminal contents, which is thought to contribute to the lower activation of EC cells after administration of the product of the invention.
It is thought that after consumption of a product in accordance with the invention, a more stable mucous layer is produced, which remains at the same location due to the lower degree of stimulation of the sensing cells, and which is not degraded by intestinal excess serotonergic activity or due to diarrhoea, and which is not degraded excessively by intestinal microbes, like Akkermansia muciniphila, as is the case with prior art products which are used to promote central serotonergic systems.
The fibre fraction may serve, at least for a part, as a nutrient for microflora in the small intestine. To the extent that the fibre fraction reaches a specific part of the intestine, the fibre fraction will typically induce a change in the microflora in that part of the intestines. This change can be measured by proper sampling and analyzing of representative samples of mucosa or luminal contents of that part of the intestines, including the proximal parts of the small intestine.
When referring herein to a treatment, this generally includes prophylactic treatments and therapeutic treatments, unless specified otherwise. A prophylactic (preventive) treatment generally is aimed at reducing the chance that the treated subject develops a trait, impairment, symptom, disease, syndrome or disorder. The effectiveness of a prophylactic treatment can e.g. be determined by comparing the probability that a specific trait, impairment, symptom, disease, syndrome or disorder develops in a sufficiently large and representative group of subjects or animals and in a double blind placebo controlled study, designed according the principles of Good Clinical practices, wherein one part of the group is treated according to the invention and another part is treated with a placebo for a relevant period of time. The skilled person will be able to define suitable conditions for the study, depending on the intended effect.
The term “a” or “an” as used herein is defined as “at least one” unless specified otherwise.
When referring to a noun (e.g. a compound, an additive etc.) in the singular, the plural is meant to be included.
The term “or” as used herein is to be understood as “and/or” unless specified otherwise.
When referred herein to a product in relation to the invention, this generally refers to a nutritional composition, a medicament, a combination of dietary fibre claimed as such or claimed for a use in accordance with the invention.
When referred herein to the ‘total fibre fraction’ (TFF) this generally means the total of matter formed by dietary fibre. This includes the dietary fibre that is present as an active ingredient in the product, and that it is effective in contributing to an intended use of the invention (the ‘active fibre’) and other dietary fibre which does not have an effect on a claimed use, but may still have a dietary role. For instance additional fibres having no significant role in the small intestine can be included for technological or organoleptic reasons or to modulate colonic events. e.g. it can serve as a bulking fibre (e.g cellulose)) or may induce envisaged colonic events. The inclusion of dietary fibre can be derived from the label of a commercial product or can be analyzed by selecting an accepted method as known in the art as for example has been disclosed in US 2010/0317573.
In the present disclosure, indigestible carbohydrates having a degree of polymerisation of 3 or more mono-saccharides are considered to be part of the dietary fibre fraction, independent whether they are soluble or not or fermentable or not.
When the total fibre fraction comprises at least three, preferably at least four different fibre ingredients, the fibre blend is called a multifibre blend (MF). Multifibre blends can comprise natural fibre ingredients which are commonly consumed in the diet of a healthy person.
With respect to the active fibre, these may in particular be selected from hemicelluloses, xylans, arabinoxylans and derivatized xylans, which may be synthetic or substituted (arabino) xylans from natural sources.
The ‘fibre ingredient’ is the ingredient that is used to include the active dietary fibre in the manufactured nutrition, nutritional product or ready to use medicament. It does not need to be a chemically pure compound. A much preferred fibre ingredient is cereal bran, in particular rice bran, either in raw form after physical separation of the starchy endosperm, or in more purified or processed forms, as explained later in this document.
Mode of Action, Clinical EffectsThe mode of action (MOA) can be multiple and depend on conditions and timing and patient as well. Apart from an effect on 5HT release of EC cells the inventors consider in particular to be important: 1/ modulation of expression patterns of serotonergic receptors over tissues, neurons and microbiota, 2/ modulation of expression and distribution over the same type of cells, 3/ decrease of degree of postprandial stimulation of pre-synaptic 5HT1B receptors, 4/ decrease of activation of the neurons in the myenteric plexus, 5/ decrease of number of sensing cells in the lamina propria, 6/ increase of orexigenic pathways by a decrease of postprandial release of corticotrophin-releasing hormone in the paraventricular nucleus of the hypothalamus or an increase and activation of the brain-reward system by activation of the relevant neurons in the nucleus accumbens and striatum, 7/ stimulation of co-release of dopamine and serotonin from the medial and lateral hypothalamus or 8/ by other mechanisms.
In an embodiment, the invention is in particular suitable to induce a selective way of modulating serotonin signalling, but without inducing excessive serotonin—induced signalling of the enteric nervous system (ENS). In particular excessive serotonin release by the enterochromaffin cells and ENS neurons is prevented, especially in the proximal parts of the gastro-intestinal tracts (GIT).
It is the inventors' finding that the fibre for use in accordance with the invention in particular has an effect that can contribute to the effect on serotonin. Further, a preferred product according to the invention contributes to keeping the concentration of free serotonin in the blood plasma relatively low. In particular, in an advantageous embodiment the fibre will promote the action of the serotonin transporter (SERT) as expressed on platelets which keeps the concentration of free serotonin in blood plasma relatively low.
A fibre, combination or composition used in accordance with the invention can in particular contribute to changing the expression of serotonin receptors over tissues and/or changes the distribution and localization of the receptors per cell. A product according to the invention also changes the degranulation and serotonin release characteristics of serotonergic neurons, preferably in the enteric nervous system, and EC cells. Without wanting to be bound by theory, this change can be mediated by an effect of the product on the activity of the nervus vagus, including the activity on cholinergic transmission. Administration of the product according the invention will induce a secretion of serotonin that is sufficiently low to prevent excessive synergistic action with the cholecystokinine (CCK) that is released by consumption of the food and prevents over-activation of the sating systems in the brain, e.g. as modulated through the nervus vagus (NV). Alternatively or in addition the effect on the serotonin systems may be mediated by a decreased action of bile acids on the lining of the small intestine or a modulation of the composition of the mucosal microflora and the response of the enterocytes, EC cells, enteroendocrine cells and dendritic cells, on microorganisms. This changed response may include an increase of the response of tolerizable genes, for example those that occur in macrophages inhabiting the small intestine or microglia, and are essential for a proper response after repeated exposure to microorganisms which induce the release of pro-inflammatory cytokines like IL-6. Some of the relevant genes have been disclosed in Foster et al, 20078, Nature, 447, 972-978 and include the Hdc, Mmp13, Serpine 1, Edn1, Cspg2, Lipg and 116.
In one or more of these manners the administration of the product according the invention changes the functioning of the serotonergic systems, for example in terms of the release characteristics, the sensitivity to endogenously released 5-HT, the characteristics of the response and the desensitization characteristics. The inventors in particular contemplate, that thus, the invention is suitable to delay or otherwise delay nausea and/or satiety effects. It should be noted that serotonin plays a direct or indirect role in the satiety centre in the brains.
In principle, any male or female human may benefit from the use of a dietary fibre in accordance with the invention that is treated with medical nutrition or a medicament. In a specific embodiment, the fibre is for use in an individual that suffers from malnourishment, or a hospital patient, an institutionalized patient and elderly person, an oncology patient, a person that is subjected to chemotherapy or radiotherapy, or a person experiencing inflammatory processes. The latter can be determined by measuring blood values of cytokines as known in the art or by medical diagnosis.
Serotonin receptors are currently considered to be a group of 7 types of proteins. Each has its own distribution in the human body. Class 1 serotonin receptors are predominantly expressed in the central nervous system and not in the gastrointestinal tract (GIT), while e.g. class 2 and 3 serotonin receptors to an important extent determine the action of the serotonergic system in the gastrointestinal tract.
Fibre Fraction
The total fibre fraction in the nutritional product according the invention preferably comprises fibre selected from the groups of modified and unmodified cereal fibre.
The product according the invention comprises a dietary fibre which is preferably derived from a cereal. It can be isolated as such, or be modified by chemical means to improve technological properties. The inclusion of unmodified fibre is preferred.
In particular, the dietary fibre ingredient in the product may comprise fibre selected from the group of unmodified or modified cereal fibre. A preferred fibre ingredient is a cereal bran. In an embodiment the bran comprises parts of the germ and is preferably relatively poor in digestible carbohydrates originating from the grain's endosperm and relatively poor in the grain's husk as specified below.
In a different embodiment the ingredient comprises other parts of the grain like proteins and lipophilic substances, as they occur in the cereal grain, as explained below.
Examples of suitable cereal grains include rice, barley, wheat, rye, oats, corn, amaranth, millet, quinoa and triticale.
In a preferred embodiment the fibre ingredient is rice bran. The bran may in particular be provided in combination with rice germ.
In a further embodiment the fibre ingredient is isolated from the grains of Oryza sativa, Oryza glaberrima or Oryza nivara or cross-bred varieties of these species. It is most preferred to isolate the fibre from a Oryza sativa variety.
The dietary fibre content of the fibre ingredient, preferably is at least 10 wt. % of the fibre ingredient, in particular at least 15 wt. %. The dietary ingredient may substantially consist of dietary fibre molecules, but substantial amounts of other ingredients may be present. Thus, the dietary fibre content in the fibre ingredient can be less than 50 wt. %, in particular 40 wt. % or less, or 35 wt. % or less
In a preferred embodiment the amount of aleurone-derived fibre is low. In a specific embodiment, also the amount of endosperm that is co-isolated is low, which is reflected by a low amount of digestible carbohydrates in the fibre ingredient. The proper fibres can be isolated from the cereal grain by applying a combination of methods on the raw ingredient, which are as such known in the art and can include grinding, sieving, extraction, steam treatment, alkali treatment and fermentation. Preferably this amount is less than 36 weight % (=wt %), more preferably 20-32 wt % of the fibre ingredient. The amount of protein in the fibre ingredient may in particular be in the range of 12-22 wt. %, preferably 12-16 wt % of the fibre ingredient. Also lipids may be present in the fibre ingredient, in particular to an extent of 14-24 wt % of the fibre ingredient. These amounts assume a moisture content of about 5 wt % of the ingredient. The concentrations of all components in the ingredient drop proportionally with its moisture content, while the properties remain the same when used in the manufacture of a liquid formula as those according the invention. The man skilled in the art can recalculate the amount of components to a moisture degree of 5% in order to establish whether a third party operates within the scope of this invention. Part of these cereal derived lipids, nitrogenous compounds and digestible carbohydrates are caught in the fibre structures as isolated from the grain and remain there to a characteristic and relevant extent during the manufacturing process of products according the invention. The lipids that can be extracted from the fibre ingredient can comprise lipophilic substances as occur naturally in the grain, e.g. isoprenoids.
A suitable fibre can be isolated from the cereal grain by applying a combination of methods to the raw ingredient, which as such are known in the art. They can include grinding, sieving, extraction, steam treatment, alkali treatment and fermentation. Several combinations of process steps have been used by different suppliers, though the final method for isolating the fibre according the invention is specific. In a preferred embodiment the active fibre constituents are isolated by applying a treatment at alkali pH or an extraction at alkali pH. This is applied to remove residual digestible carbohydrates.
Preferably the fibre ingredient as isolated from cereal grain comprises more than 45 wt % hemicelluloses, based on the total dietary fibre content in the fibre ingredient. Parts of the cellulose and lignins present in the grain can be co-isolated, though the content of the sum of both in the fibre ingredient is less than 60 wt %. Preferably the weight ratio of hemicellulose fibres to fibres that are considered as cellulose or lignin is more than 0.3, preferably 0.5 to 3, most preferably 0.6 to 2.
In a preferred embodiment at least 10 wt %, more preferably more than 40 wt %, most preferably 45-92 wt % of the dietary fibre in the fibre ingredient is soluble in pure water at 20 degrees Celsius, when dissolved in an amount of 1 wt/vol %.
In a specific embodiment, more than 18 wt % of the fibre fraction is insoluble under these conditions.
The grains can be dehusked and grinded and most of the starches removed in conventional ways to isolate a fraction that is relatively rich in fibres compared to the intact grain. The solubility of these raw cereal-derived fibres can be improved by treatment with one or more hydrolyzing enzymes that are selective for the carbohydrates, and/or other components that are present in the raw cereal fibre.
Alternatively, the cereal fibres can be obtained from a raw cereal material that is subjected to a fermentation process by exposing a slurry of the raw material comprising cereal fibres in water to one or more organisms or enzymes. A suitable fermentation process includes subjecting the fibre to the enzymes of an Aspergillus species. Fermentation processes for cereals are known in the art and help in improving solubility, by decreasing the molecular weight of the polysaccharides that form the indigestible part of the carbohydrates. A side effect is that the amount of digestible carbohydrates in the cereal fibre ingredient decreases. The half-product thus formed can be sterilized to inactivate enzymes or kill the living microorganism. After subsequent purification steps, which are known in the art, a fibre ingredient is obtained that is suitable for use in accordance with the invention.
In particular, the dietary fibre in the fibre ingredient may be composed for at least 11 wt. % of xylans, preferably about 13 to about 80 wt % of the fibre fraction.
Preferably the xylans are hetero-saccharides, which are defined as being those oligomers or polymers of xylose that are substituted for more than 4 wt % with saccharides other than xylose. These hetero-xylans include arabino-xylans (AX). In one preferred embodiment the arabino-xylans are branched, which ensures the formation of non-linear molecules. The arabinose substituents may make up 0.05 to about 1 times the amount of xylose in the fibre. Part of the xylans may be (arabino)glucuronoxylans (AGX), glucuronoxylans or (glucurono)arabinoxylans (GAX), using the terminology of Ebringerova, et al, in Adv Polym Sci, 2005, 186, 1-67. The sum of AGX and GAX may be 0.4-30 times the amount of pure arabinoxylans. In one embodiment the amount of AGX is 0.5 to 24 times the amount AX.
The xylose moieties in the non-digestible carbohydrate fraction of the fibre ingredient may also be substituted with monosaccharides other than arabinose, like uronic acids, methylated uronic acids, fucose and galactose.
One or more of the monosaccharides that are linked to the xylose oligomer may be substituted with phenolic compounds like ferulic acid. In a preferred embodiment the amount of ferulic acid in the fibre ingredient is 0.1 to about 6%. After oral administration of the product a major part of the ferulic acid will be released in the intestine, even in proximal parts of the small intestine, by the action of intestinal enzymes, e.g. those bound to or originating from microorganisms.
In an embodiment, the xylans from the grain have been partially hydrolysed prior to inclusion in the product in order to improve solubility in the ready to use product and to improve microbial use in the proximal part of the gut and increase the efficacy of the product. A suitable degree of hydrolysis (DH) is 2 to 10. This can be achieved by applying an alkali treatment, an enzymatic hydrolysis or a fermentation process to the fibres of the grain. In a preferred embodiment the enzymatic process includes a hydrolysis by a xylanase. Suitable sources of xylanase which are capable of hydrolysing cereal xylans are known in the art. In a preferred embodiment the fermentation step includes a step wherein the cereal fibre material is subjected to fermentation by a lactobacillus or a combination of a lactobacillus with yeast and optionally other microorganisms.
As already mentioned the active fibre is preferably isolated from the hemicellulose fraction of cereal grains, though parts of the cellulose and lignin fractions can be co-isolated. In an embodiment, part of the ester-bonds between lignin and hemi-cellulose will be broken by an alkali treatment and become soluble.
More preferably, the hemicelluloses fraction is more than 45, more preferably 55 to 90 wt % of the active fibre fraction. Other parts of the isolated fibre may be beta-glucans, which may amount to for example 0.5 to 10% of the fibre fraction.
The fibre ingredient may further comprise digestible carbohydrates, lipids and protein, but generally in an amount of less than 35 wt % of the amount of fibre ingredient as will be used in manufacture of the ready to use nutritional product. Preferably the amount of digestible carbohydrates in the fibre ingredient is less than 24 wt %. The amount of resistant starch in the fibre ingredient may be up to 20 wt %.
The active fibre fraction, respectively fibre ingredient, as disclosed above can in a further embodiment be combined with dietetic fibres from alternative sources like gums, mucilage, fractions from pulses or beans, oil seeds, roots or tubers, or fruit or vegetable leafs or be synthetic oligosaccharides like those based on fructose or galactose. The combination of all indigestible carbohydrates in the ready to use product makes the total fibre fraction (TFF) in the ready to use (RTU) product. However, in a preferred embodiment the amount of the cereal grain based fibre fraction will be more than 40 wt %, more preferably more than 60 wt % of the amount of TFF.
Different fibre fractions in the TFF may be included to improve other aspects of gut function. In particular this improvement is modulated by alternative mechanisms than ameliorating the activation of the enterochromaffin cells, especially those present in the proximal parts of the small intestine. These mechanisms may include improving colonic function, e.g. by increasing bulking of luminal contents, or modulating fermentation patterns in the colon.
Preferably the TFF includes soluble fibres based on mannans, like glucomannans, galactomannans, galactoglucomannans or other heterosaccharides based on a mannose oligomers or mannose polymers. These mannans can be isolated from, for example, guar gum or Konjac gum, by applying methods known in the art. It is preferred to have these mannans at least partially hydrolysed to arrive at fibre ingredient wherein more than 88 wt % of the oligosaccharides have a degree of hydrolysis between 2 and 50. Suitable sources are commercially available and include for guar gum Benefibre and Sunfibre. In a specific embodiment, the amount of mannans in TFF is, more than 10 wt %, preferably 14-40 wt %. Preferably the mannan fraction in the TFF originates from non-grain fibres.
In an embodiment, the amount of indigestible fibres in the TFF that are predominantly homo-saccharides, like inulin, fructo-oligosaccharides and galacto-oligosaccharides remains below 37 wt %, and is preferably less than 26 wt % in order to prevent over-activation of enterochromaffin cells.
In an embodiment, the total fibre fraction in the RTU product comprises 2 to 50, preferably 3 to 40, more preferably 4 to 30 wt % galactans. These galactans are derived and isolated from gums like acacia gum. Preferably these galactans are heterosaccharides comprising at least more than 7 wt % non-galactose sugar moieties and more than 88 wt % may have a degree of polymerisation of 3 to 80.
In an embodiment, the total fibre fraction in the product comprises little or no pectinic substances and/or added acidic oligosaccharides, in order to achieve the ameliorating effect on the enterochromaffin cells and prevent the release of too much acetate in the gut. Though some uronic acids will be present in the cereal fibre and natural fibres, as substituted to xylans or as minor constituents in the raw ingredient, the nature of such indigestible saccharides differs from added purified pectins as disclosed in WO2010/147472. In particular the amount of added pectins, added pectin hydrolysates and added uronic acids is less than 40, preferably less than 10 wt % of the total fibre fraction in the product. In addition the product according the invention differs from that disclosed in WO 2010/147472, because it comprises in a preferred embodiment no or relatively little D-ribose, in order to prevent undesirable colour modification of the product during heating and shelf life. The amount of added D-ribose in a product of the invention is therefore less than 10, more preferably less than 2 wt %, and most preferably it is virtually absent.
The total dietary fibre fraction (or short ‘dietary fibre’) in a product according to the invention is usually a combination of different dietary fibre molecules. The dietary fibre molecules typically are carbohydrates that are at least substantially composed of a plurality of monosaccharide units. The dietary fibre molecules may differ in molecular weight, in chemical structure (such as difference in monosaccharide unit's composition, manner in which they are arranged in the molecule, difference in linkage between the monosaccharide units). A modified fibre may in particular be an enzymatically modified fibre, in particular modified with an enzyme that alters the structure or molecular weight of the fibre components.
The total fibre fraction (TFF) is formed by the total of all indigestible carbohydrates in a product, such as a nutritional composition in accordance to the invention, which may in particular be a ready to use (RTU) product. In an embodiment, the total fibre fraction in the (ready to use dietetic or) nutritional product (for use) according the invention consists for more than 95 wt % of oligosaccharides having a degree of polymerisation of 3 or more. Indigestible or partially digestible disaccharides are therefore not calculated as fibre. In a preferred embodiment indigestible disaccharides are not added in the manufacture of the ready to use product.
In particular, a dietary fibre is provided that is effective in decreasing the release of serotonin in the gut under physiological and stressed situations. This applies to the release of 5HT after consumption of the product compared to prior art products, which intend to improve central serotonergic subsystems. It also applies to other nutritional products that are to be consumed by the patient during that same day.
In an embodiment of the invention, the TFF has a prebiotic index below 4.2. (as defined by Roberfroid 2007, J Nutrition, 137, 830S-837S). A relatively low prebiotic index of the cereal fibres of the invention and of the total fibre fraction in the ready to use product reflects that the product does not achieve its effect by maximizing its prebiotic potential as suggested by WO2010/147472 for a blend of fibre, including acidic oligosaccharides and rice bran, baker's yeast and D-ribose to inhibit virus replication and by EP-B 1383514 to decrease inflammatory processes and activate non-specific immune parameters by a blend of fructo-oligosaccharides and inulin, and by WO02/060279 which aims to induce a prebiotic effect by oral administration of alpha-lactalbumin.
In an embodiment of the invention, the fibre may also demonstrate a relatively low prebiotic effect with respect to those bacteria that are adhered to the mucosa of the small intestine.
The mucosa-associated microbial community in the small intestine can be measured by applying the ProDigest or LabMET methodologies as are known in the art (e.g. from WO2011/060123). The adhesion-related prebiotic index may be less than 8.0, preferably less than 7.2, using the calculation method as disclosed in Van den Abbeele, et al, Appl Microbiol Biotechnol 2009, in Horremans et al Helicobacter 2012, or equivalent method. The adhesion characteristics of microorganisms can be further determined in vitro by applying an in vitro gut cell model, for example the Caco-2 cell based model as disclosed by Grootaert et al J Microbiol Meth 2011, 86 (1), 33-41 al alternative methods.
In particular, a fibre for use in accordance with the invention generates a type of metabolism in the microorganism present in or near the mucosa in the small intestine that the GPR41, as for example is expressed in the sympathetic ganglia in the nervous system are not strongly activated, which decreases the signalling through the spinal sympathetic nerves to the CNS. This prevents over-activation of the sympathetic nervous system and diarrhoea.
In particular, the fibre fraction induces the reactions on enteroendocrine (EE) and enterochromaffin cells (EC) cells and on the sympathetic system. The effect of the fibre is observed in both females and males and is observed especially in persons having a body mass index of less than 25 kg/m2 and especially in the male population.
The different pattern of free fatty acids that are released by mucosal bacteria in the small intestine activate differentially the free fatty acid receptors that are present in the gut, like the chemoattractant receptor GPR43. The low degree of activation of GPR43 after oral administration of the dietary fibre—when administered to a subject-ensures a proper immune reaction during the intense communication between microorganisms, as present in the mucosa of the small intestine, and the neighbouring epithelial cells, in particular the enterochromaffin cells. The communication may include activation of serotonin receptors but also Toll-like receptors and Nucleotide-binding oligomerization domain-like receptors, like for example NOD-2, which in one embodiment all maintain an activated state after oral administration of the fibre fraction. It has to be noted that the nature of luminal bacteria can differ from mucosal bacteria.
After oral consumption of the product the need for a high activity of T-helper 17 cells is decreased, which increases the balance between the IL-10 producing regulatory T cells and the Th17 cells in the GIT of the child or adult, though it maintains a sound release of IL-12 by dendritic cells in the gut to maintain a Th1 response, when required, e.g. to combat opportunistic infections by pathogens that may have entered the gut or developed in the lumen. The new balance between immune cells in the gut, especially in the small intestine, decreases the release of interferon-gamma and maintains the concentration of tryptophan in the intestine on a properly high level and keeps the concentrations of potentially damaging tryptophan catabolites low.
Typically, the active fibre comprises fibre selected from the group of unmodified or modified cereal fibre, preferably an unmodified or modified rice fibre.
It is preferred that 10 wt % or more of the total fibre in the product is from cereal origin. Cereals in particular include plants belonging to the group of rice, wheat, rye, triticale, barley, oats, millet, amaranth and corn. Preferably the fibre in, or attached to or surrounding the grain is used for a product of the invention.
In a preferred embodiment, the amount of the cereal grain based fibre fraction will be more than 40 wt %, more preferably more than 60 wt %, based on total fibre. This is in particular preferred for an embodiment wherein the fibre is part of a food supplement.
The fibre is preferably isolated from the cereal by treatment of the cereal grains Preferably the fibre is isolated from the caryopsis and/or the nucellar epidermis, the seed coat and/or pericarb of the cereal grain. The cereal fibre ingredient in this embodiment according the invention comprises predominantly fibres derived from pericarp, tegumen, aleurone, scuttelum, epiblast and/or plumule. Preferably, the amount of fibres derived from these parts of the grain kernel are more than 85 wt % from the total fibre in the fibre ingredient.
In an advantageous embodiment the TFF comprises cereal fibre (other than resistant starch, gums, FOS, GOS and polydextrose; typically ‘active fibre’) and at least two, preferably at least three different fibres different from the cereal fibre. Such embodiment is referred to herein as a ‘multifibre blend’. The multifibre blend may be provided as a food supplement or be a part of a food supplement, or be part of a nutritional product, further comprising other nutrients, in particular one or more macronutrients, such as digestible carbohydrates, peptides (in particular protein), and lipids (in particular triglyceride), It may be used for any use according to the invention. In a specific embodiment, a multifibre blend is for use in a medical food and/or be part of a food for the treatment of malnourishment
The multifibre blend preferably comprises the cereal fibre and at least two, preferably at least three members of the group of 1/ fibres from beans or pulses, 2/ fibres from leaves, fruit skin, vegetables or fruit, 3/ fibres from tubers or roots, 4/ gums. In a particularly preferred embodiment, the multifibre blend comprises the cereal fibre and at least two or at least three members of said groups, different from resistant starch, the multifibre blend further comprising resistant starch, which may be from cereal, beans or pulses, leaves, fruit skin, vegetables or fruit, tubers roots, or from a different source. In a preferred embodiment, the multifibre blend comprises the cereal fibre and at least two, preferably at least three members of the group of 1/ fibres from beans or pulses, 2/ fibres from leaves, fruit skin, vegetables or fruit, 3/ fibres from tubers or roots, 4/ gums from Acacia, guar, Konjac or chia. In a particularly preferred embodiment, the multifibre blend comprises the cereal fibre and at least two, preferably at least three members different from resistant starch of the group of 1/ fibres from beans or pulses, 2/ fibres from leaves, fruit skin, vegetables or fruit, 3/ fibres from tubers or roots, 4/ gums from Acacia, guar, Konjac or chia. In addition, resistant starch may be present from any source, in particular from a cereal, root or tuber. In a preferred embodiment the TFF of a product in accordance with the invention comprises the cereal fibre and further fibre from at least three of the following groups, 1/ gums, 2/ fibres from beans or pulses, 3/ fibres from leaves, fruit skin, vegetables or fruit, 4/ fibres from tubers and roots, 6/ fibres from oil seeds, nuts, polydextrose (e.g. Litesse) or additional oligosaccharides e.g. fructo or galacto-oligosaccharides. In a particularly preferred embodiment, in addition to cereal fibre, at least fibres are present from three of the following groups 1/ gums, 2/ fibres from beans or pulses, 3/ fibres from leaves, fruit skin, vegetables or fruit, 4/ fibres from tubers, 5/ resistant starch. Herein, the fibres from the plant sources (cereal, beans, pulses, leaves, fruit skin, vegetables, fruit, tubers roods, oil seeds, nuts) are preferably different from the selected gum, resistant starch, polydextrose or additional oligosaccharides.
In an advantageous embodiment, the multifibre blend forms part of a nutritional product comprising one or more macronutrients selected from the group of digestible carbohydrates, lipids and peptides. In a specifically preferred embodiment, the multifibre blend forms part of a nutritionally complete food product.
Suitable sources for cereal fibre are in particular rice, oats, corn, wheat, rye, barley, triticale, amaranth, and millet/quinoa The cereal fibre is preferably selected from rice, wheat and oats. In particular, good results have been achieved with a rice fibre. The weight percentage, based on total fibres, for cereal fibre in the multifibre blend usually is at least 20 wt. %, based on total fibre, preferably, 30-80 wt. %, in particular 30-50 wt. %.
The gums are in particular selected from acacia gum, guar gum or chia gum. Preferably they are partially hydrolyzed saccharides derived from acacia gum and/or guar gum and/or chia gum. More preferably this hydrolysis is to a degree that more than 60 wt % of the gum fibre has a degree of polymerization of 3 to 20. This is in particular preferred in view of rheological considerations inside the gut, as a high content of intact gums may give rise to an undesirably high viscosity in the guts, even in the colon. This impairs digestion and increases the degree of activation of the sensing cells, when measured over the whole intestine. Preferably the amount of intact natural gum polysaccharides in the blend is therefore less than 20 wt % and more preferably less than 5 wt %, dependant on the nature of the gum. For example gum having a high degree of polymerization should be less than 5 wt % while gums that are significantly hydrolyzed to values of 15 or below, can be included in up to 20 wt % in the blend.
The weight percentage of gums based on total fibre is usually 25 wt. % or less, in particular 2 to 18 wt. %
The tuber or root starch is preferably from a tuber or root selected from the group of onion, chicories, beta vulgaris (beetroot, sugar beet), potato, more preferably from chicory and beat.
The weight percentage, based on total fibres for fibres from a tuber or root in the multifibre blend usually is 80 wt. % or less, preferably 5-60 wt. %, in particular 10-50 wt. %.
Suitable sources for fibre from pulses or beans are in particular soy beans, pea (e.g. pisu sativum) Azuki beans, Phaseolus varieties (e.g. P. vulgarus) and lupin seeds. Preferred sources are pea and soybeans. The weight percentage, based on total fibres for fibre from pulses or beans in the multifibre blend usually is 40 wt. % or less, in particular 2-30 wt. %.
Preferred sources for fibres from fruits or leaves from plants are plantain (including banana), prune, cabbage, tomato, squash, sugarcane, bagasse and citrus fruit. Particularly preferred is fibre from plantain, in particular banana. The weight percentage, based on total fibres for fibres from vegetable leaves or fruits in the multifibre blend usually is 40 wt. % or less, in particular 1-30 wt. %, more in particular 2-20 wt.
Suitable sources for resistant starch include cereals, for instance corn, wheat, rice, and tapioca. The fibre ingredients as derived from different origins can comprise some resistant starch (RS). In the context of this patent application we define the resistant starch ingredient as being an ingredient which comprises at least 80 wt % resistant starch per 100 g dry resistant starch ingredient. When resistant starch is used as such the sum of resistant starch from all fibre ingredients is meant, including the RS from the RS ingredient. An example of a RS ingredient is Novelose 300 The resistant starch is preferably resistant starch from rice. The weight percentage, based on total fibres, for resistant starch in the multifibre brend usually is 40 wt. % or less, in particular 3-35 wt. %. In particular, the resistant starch is present in a particulate form, such as resistant starches comprising more 80 wt % particles having a size of 2-15 micron.
Suitable fibres from oil seed include in particular, fibres from sun flower seeds and fibres from flax seeds. The weight percentage, based on total fibres for fibres from oil seeds, polydextrose (e.g. Litesse), oligosaccharides e.g. fructo or galacto-oligosaccharides in the multifibre blend usually is 40 wt. % or less, in particular 3-15 wt. %.
The total content of in the multifibre blend is usually . . . or less, in particular . . . or less.
Commercial preparations are currently available and include
Sugar beet fiber from Nippon Beet Sugar being about ⅓ rd soluble
Apple fiber (about ⅓rd soluble)
Chicory: raftiline
Soy fibre e.g. Fibrim
Resistant starch (Novelose)
Oat bran (about ½ soluble; Vitacel)
Commercial sources of oligosaccharide and resistant starch and RS and their way of analysis have been disclosed in US2010/0317573, which is hereby incorporated as a reference
Optionally the multifibre blend comprises hydrolyzed fibres (fructo-oligosaccharides, galacto-oligosaccharides)
The multifibre blend comprises active fibre according the invention, and typically additional fibres that are part of a normal diet. This is 1/ to change as little as possible for the consumer/patient which would consume a healthy mixed fibre pattern and 2/ induce a gradual and maximal fermentation of the blend and induce a healthy gut flora, which would a/generate an amount of gas per time unit which can be coped with by the individual, b/ synthesize vitamins, c/ facilitate absorption of nutrients and medication, d/ interact in a symbiotic way with the host, e/ decrease the amount of ammonia and sulphides that are generated in the colon. Such healthy gut microbiota may comprise increased amounts of Roseburia and eubacteria. In one embodiment this encompasses eubacterium limosum.
In a preferred embodiment, the active fibre comprises a xylan. The xylan preferably consists for more than 40 wt % of xylan-moieties, the remainder being one or more of arabinose- or glucuronic acid, or 4-methylated glucuronic acid or other monosaccharide moieties. These may originate from cereals. They can be linear or branched. In the preferred embodiment the xylans are at least branched for more than 10%, more preferably 13-60, most preferably 15-40 wt %. The branched xylans comprise more ferulic acid than linear xylans and in addition the changed structure of the xylans are thought to have different effects on diet-induced serotonin release in the gut, e.g. through a different bile acid mediated effect on the small intestine. This is especially relevant, if the medical food or medication, taken by a subject treated with a dietary fibre in accordance with the invention, raises tryptophan concentrations in the gut tissue.
In a preferred embodiment, the active fibre constituent, comprising xylan, or part thereof, is isolated by applying a treatment at alkaline pH or an extraction at such high pH. This treatment at alkaline pH may serve to solubilise digestible carbohydrates from the matrix to facilitate their removal in the preparation of the fibre isolate, but also allows breaking of the ester bond between hemicelluloses and lignin, as they occur in the raw grains. For the latter it is useful to add a reducing agent like sodium borohydride. This allows manufacture of a fibre ingredient which is relatively low in lignin and cellulose, relatively high in ferulic acid
In particular, the fibres isolated from the cereal may be enriched in hemicellulose, compared to the total fibres content of the cereal from which the fibre originates. More in particular, the fibre fraction may be enriched in arabinoxylans.
Thus, the active fibre preferably comprises hemicellulose. The hemicellulose is preferably isolated from the hemicellulose fraction of cereal grains, though parts of the cellulose and lignin fractions can be co-isolated. More preferably, the hemicelluloses content is more than 45, more preferably 55 to 90 wt % of the fibre fraction.
Preferably, the active fibre comprises fibre, isolated from the hemicellulose fraction of cereal grains, though parts of the cellulose and lignin fractions can be co-isolated.
In particular, the dietary fibre may be composed for at least 11 wt. % of xylans, preferably about 13 to about 80 wt % of the fibre fraction.
Preferably the xylans are heterosaccharides. As used herein, the term leterosaccharides' is used for at least two different monosaccharide units. It is in particular preferred that more than 4 wt % of the xylan consists of saccharides other than xylose.
These heteroxylans in particular include arabinoxylans (AX). In a preferred embodiment, the active fibre comprises an arabinoxylan, present in an effective amount for use in the prophylactic or therapeutic treatment in accordance with the invention.
In a specifically preferred embodiment, the arabinoxylans are branched, which ensures the formation of non-linear molecules. The arabinose substituents may make up from 0.05 to about 1 times the amount of xylose in the xylan. Part of the xylans may be (arabino)glucuronoxylans (AGX), glucuronoxylans or (glucurono)arabinoxylans (GAX), using the terminology of Ebringerova, et al, in Adv Polym Sci, 2005, 186, 1-67. The sum of AGX and GAX may be 0.4-30 times the amount of pure arabinoxylans. In a specific embodiment the amount of AGX is 0.5 to 24 times the amount AX.
In addition, or alternatively the xylan may comprise one or more monosaccharide units other than arabinose linked to xylose. In particular such unit may be selected from the group of uronic acid units, methylated uronic acid units, fucose units and galactose units.
One or more of the monosaccharide units in the xylan may be substituted with a phenolic compound, for instance like ferulic acid. In a preferred embodiment, the amount of ferulic acid in the fibre ingredient is 0.1 to about 6 wt. %. After (oral) administration of the product, a major part of the ferulic acid will in particular be released in the intestine, more in particular in proximal parts of the small intestine, by the action of intestinal enzymes, e.g. those originating from microorganisms.
In a specific embodiment, the xylans are partially hydrolysed prior to inclusion in the product in order to improve solubility in the ready to use product or to improve the ameliorating effect on lumical sensing cells, i.e. enterochromaffin cells and the effect of the product. In particular, a suitable degree of hydrolysis (DH) is 2 to 10. This can be achieved by applying an alkali treatment, an enzymatic hydrolysis or a fermentation process.
In particular, in the manufacture of the fibre ingredient one or more enzymatic hydrolysis steps can be applied to remove starchy material, e.g. with amylase or mixtures of enzymes that have glycolytic activity, or to break down the matrix to allow release of its constituents in the slurry of ingredient (like pullulanases, e.g. those isolated from bacteria as known in the art, cellulases or hemicellulases).
Further, an enzymatic treatment may involve the hydrolysis of polymeric fibre molecules into oligosaccharides. Examples of suitable enzymes include the xylanases (e.g. endoxylanases, e.g. derived from bacillus subtilis.
In a preferred embodiment the enzymatic process includes a hydrolysis by a xylanase. Suitable sources of xylanase which are capable of hydrolysing cereal xylans are known in the art. In a preferred embodiment the fermentation step includes a step wherein the cereal fibre material is subjected to fermentation by a lactobacillus or a combination of a lactobacillus with yeast and optionally
In a preferred embodiment the active fibre comprises arabino-xylans that have an average degree of polymerization that is at least 10% lower than in the natural grain, either by the application of the isolation process or by the enzymatic step. More preferably arabinoxylans which have a degree of polymerization between 3 to 18 make up more than 60 wt % of the arabinoxylans in the fibre ingredient. This facilitates its functionality in the small intestine.
The TFF may comprise a beta-glucan, which may in particular amount to 0.5 to 10 wt. % of the fibre fraction. The fibre does not need to be provided in a product according to the invention as a chemically pure ingredient. For example, the ingredient used for providing fibre in a product of the invention (the fibre ingredient), may still comprise other components than the fibre, that originate from the source from which the fibre ingredient is obtained, such as the germ or (minor amounts of) parts of the hull of a cereal from which the fibre ingredient is obtained. In particular, the ingredient used for providing fibre in a product of the invention may further comprise digestible carbohydrates, lipids and protein, but generally in an amount of less than 35 wt % of the fibre that is used in the nutritional product. Preferably the amount of digestible carbohydrates in the fibre ingredient is less than 24 wt %. The amount of resistant starch in the fibre ingredient may be up to 20 wt %. In a further embodiment, the fibre comprises a dietary fibre selected from the group of gums, mucilage fibres, fractions from pulses, oil seeds, roots, fruits, leafs, such as vegetable leafs, and synthetic oligosaccharides. Said fibres may be an additional source of active fibre (e.g. hemicelluloses, xylans or arabinoxylans from such a source) but may also provide another kind of fibre molecules, which may have a different purpose than the active fibre.
Synthetic oligosaccharides may in particular those comprising fructose units or galactose units. A fibre from any of said sources is preferably used with an active fibre selected from the cereal fibres, hemicelluloses, xylans and arabinoxylan, such as described herein.
One or more of these fibres in the TFF may be included to improve one or more aspects of gut function. In particular such improvement is modulated by alternative mechanisms than ameliorating the activation of the enterochromaffin cells, especially those present in the proximal parts of the small intestine. These mechanisms may include improving colonic function, e.g. by increasing bulking of luminal contents, or modulating fermentation patterns in the colon.
The fibre fraction usually comprises soluble fibre. Insoluble fibre may also be present.
In a preferred embodiment, at least 40 wt %, more preferably more than 60 wt % of the dietary fibre is soluble in water at 20 degrees Celsius.
The soluble fibre fraction preferably includes a beta-glucan or galactomannans originating from hydrolyzed or partially hydrolyzed guar gum. Preferably the soluble fraction comprises 15 wt % or more fibres selected from the group of beta-glucans, more preferably 18-90 wt %. This is thought to induce a total fermentation pattern that improves gut performance in treatment protocols meant to promote serotonin signalling in the brain.
Beta 1,3-glucans form a group of non-digestible carbohydrates which can be found in several types of ingredients. For example yeast, mushrooms, algae and several types of cereal fibres comprise them. The beta-(1,3) glucans can comprise linear chains of monosaccharides which are predominantly connected to each other by a Beta 1-3 bond, and optionally partially by beta 1,6-, as occur in some yeasts, and/or optionally by beta 1,4 linkages, as occur in cereals or grains. The glucans can be linear or be substituted with for example other saccharides, with peptides or amino acids, and/or with lipids or fatty acids and can be soluble or insoluble in natural conditions. They can have a wide range of molecular weight and occur in several special forms, which each demonstrate different properties and biological activities. Of special interest are beta 1,3 glucans which are partially substituted with saccharides which are linked by a beta 1,4 linkage to the beta 1,3 chain as occur in cereal and grain fibre. In nature they typically occur to a high extent as insoluble globules which can be recognized under microscopy as particles which can have a diameter of 10 micrometer. Disruption of these globules is useful to make them soluble and to increase biological efficacy. Sonification and high shear or high pressure homogenization are suitable techniques to achieve this. The beta1,3 glucan molecules can absorb several times their molar amounts of water and commercial dry preparations demonstrate different degrees of dehydration.
The total dietary fibre in the product preferably comprises insoluble fibre. Such fibre induces a specific fermentation pattern, due to the different types of bacteria that preferentially will start to grow. In particular, it may contribute to a favourable production of metabolites other than acetate in the colon.
If present, the insoluble fibre content, based on total fibres in the product, preferably is at least 8 wt %, more preferably 18 to 72 wt. %, in particular 22 to 58 wt %. Such high insoluble fibre contents are usually provided in a semi-solid—or solid product. The amount of insoluble fibre in the product can be selected to be higher if a more solid matrix is selected as vehicle for the active components to be administered.
In a specific embodiment, the insoluble fibres comprise resistant starch. In a preferred embodiment, the resistant starch is retrograded or RS3 starch. In a further preferred embodiment, the resistant starch fraction comprises more than 50 wt % linear polymers of alpha 1,4 glucans which have a degree of polymerization between 10 and 35. Suitable sources of such resistant starches are beans, peas, heat-treated potatoes and heat-treated cereals. Simultaneous presence in the colon of resistant starch and beta glucans, in combination with the xylans will support of growth of the right type of butyrate generating bacteria species. A preferred content of resistant starch in the fibre fraction is 3 wt % or more, more preferably 5-60 wt %, based on total fibre. Resistant starch is defined to be as those starches which remain intact after digestion during 2 hours in the system of Englyst et al Am J Clin Nutr 1999, 69, 448-454.
Preferably the TFF includes one or more soluble fibres based on mannans, like glucomannans, galactomannans, galactoglucomannans or other heterosaccharides based on a mannose oligomers or mannose polymers. These mannans can be isolated from for example guar gum or Konjac gum, by applying a specific combination of methods known in the art. It is preferred to have these mannans at least partially hydrolysed, whereby the mannan ingredient consists for more than 88 wt % of oligosaccharides having a degree of hydrolysis between 2 and 50.
Suitable sources for the mannans are commercially available and include for guar gum Benefibre and Sunfibre. The amount of mannans in TFF is in one embodiment more than 10 wt %, preferably 14-40 wt %.
In a specific embodiment, the amount of indigestible homo-saccharides, i.e. saccharides formed of a single type of monosaccharide units, like inulin, fructo-oligosaccharides and galacto-oligosaccharides is below 37 wt %. The content of indigestible homo-saccharides is preferably less than 26 wt %, in order to prevent overactivation of enterochromaffin cells.
In a specific embodiment the total fibre fraction in a (RTU) product (for use) according to the invention comprises 2 to 50, preferably 3 to 40, more preferably 4 to 30 wt % galactans. These galactans are usually derived and isolated from gums like acacia gum. Preferably these galactans are heterosaccharides comprising at least 7 wt % non-galactose sugar moieties. Preferably more than 88 wt % has a degree of polymerisation of 3 to 80.
In a specific embodiment the total fibre fraction in the product (for use) according to the invention comprises little or no pectinic substances and/or added acidic oligosaccharides, in order to achieve the effect on the enterochromaffin cells and behaviour as disclosed in this patent application and prevent the release of too much acetate in the gut. Though some uronic acids will usually be present in cereal fibre and other natural fibres, as substituted to xylans or as minor constituents in the raw ingredient, the nature of such indigestible saccharides generally differs from added purified pectins as disclosed in WO2010147472. In particular the amount of added pectins, added pectin hydrolysates and added uronic acids is less than 40 wt. %, preferably less than 10 wt % of the total fibre fraction in the product (for use) in accordance with the invention.
In addition the product (for use) according the invention comprises in a preferred embodiment no or relatively little D-ribose, in order to prevent undesirable decolourisation of the product during heating and shelf-life. The amount of added D-ribose is therefore preferably less than 10 wt. %, more preferably less than 2 wt %, and most preferably the product is essentially free of D-ribose.
The fibre may have a relatively low content of acetogenic fibres, or be free of acetogenic fibres, like inulin and fructo-oligosaccharides and of pectins or acidic homosaccharides which comprise less than 10% saccharides other than a uronic acid. The content of acetogenic fibres, if present, in the fibre fraction is usually less than 85 wt %, preferably less than 40 wt %, more preferably less than 10 wt % or the fibre fraction. This not only ensures a proper release of short chain fatty acids other than acetate, but also decreases the release of gases from the fermentation in the gut. This therefore also improves gastrointestinal comfort and decreases abdominal bloating, and flatulence. The inclusion of the claimed fibres from cereal origin, and the presence of the specific beta glucans, resistant starch and the specific xylans, also in combination with the mannans as mentioned earlier, ensure this release of fatty acids while decreasing the amount of gas released in the gut during fermentation. The fermentation gases include hydrogen, methane, nitrogen and other gases. In an advantageous embodiment, administration of the fibres according the invention prevent also a decrease of faecal pH below a value of 7.0, preferably below 7.1, and induces a stool pH most preferably between 7.15 to 7.5, as measured by determining acidity in the stool. This reflects the presence of a non-acetogenic microflora in the colon as a result of consuming the product.
In particular, the dietary fibre, combination or nutritional composition for use according to the invention, wherein under conditions existing in the colon of a subject to which the fibre (in the combination, in the nutritional composition or in another form) is administered, at least part of the fibre is fermented thereby forming propionate, butyrate or acetate, wherein the ratio of the molar amounts of the sum of the amount of formed propionate plus butyrate to the amount of formed acetate is at least 0.2 and preferably in the range 0.25 to 0.61, most preferably in the range of 0.56 to 0.61. Such fermentation pattern may be induced by a modification of the gut flora by the diet, for example by a change in the ratio of the amounts of the phylum Firmicutes to Bacteroidetes to a ratio of more than 1.5.
The cereal fibre ingredient preferably impart a relatively a low viscosity, when dispersed or dissolved. This allows a high palatability of the product and thus compliance. Preferably, the fibre will not cause a significant increase of viscosity of the luminal contents. In addition, the low viscosity allows rapid digestion of the food components and their rapid absorption. The low viscosity does not impair a proper neuro-endocrine response due to free interaction of luminal contents with the gut epithelium.
The examples in this document disclose several of the fibre blends that can have the ameliorating effect on the neuro-endocrine response as caused by oral intake of a medicine or nutritional product.
The content of dietary fibre in a nutritional composition of the invention is usually at least 2 g per 100 g of the total nutritional composition, in particular at least 5 g per 100 gram, more in particular at least 6 g per 100 g. The content, in particular in a ready-to-eat product, is usually less than 50 g per 100 g, in particular 40 g per 100 g or less.
Usually, the total content of hemicellulose, including xylans (including heteroxylans, such as arabinoxylans) is at least 0.5 g per 100 g of the total nutritional composition, in particular at least 2.5 g per 100 gram, more in particular at least 5 g per 100 g. The total content of these fibres, in particular in a ready-to-eat product, is usually less than 50 g per 100 g, in particular 45 g per 100 g or less, more in particular, 35 per 100 g or less.
For a liquid product, the fibre content is preferably in the range of 2-15 g/100 g of the composition. For a semi-solid product, the fibre content is preferably in the range of 6-24 g/100 g of the composition. For a solid product, the fibre content is preferably in the range of 6-40 g/100 g of the composition
Per day about 20 to about 1000 g of the product should preferably be consumed to induce the effect as desired. Typically the dose per day will be about 30 to about 400 g. This dose will typically be packaged in 1 to 10 portions to allow manufacture of ready to use package units. One embodiment is a liquid packed in a container of 30 to 125 ml volume.
The Protein Fraction
The protein fraction is defined to be the amount of nitrogen in the product, as determined by applying the Kjeldahl method of analyses, multiplied by 6.25. The protein fraction comprises compounds that comprise more than 66 wt % amino acid units in the molecule. Thus, it includes, free amino acids and its salts, esters of amino acids, and peptides, including intact and hydrolyzed proteins. The protein can be substituted with a lipid, carbohydrate or other components The non-amino acid part of the protein fraction can be nitrates and other nitrogeneous products.
When referred herein to amino acids, generally the proteinogenic amino acids are meant. Thus, when referring to doses of amino acids, the dose for the L-isomer is meant, except for glycine. Though the human body has a capacity to convert D-isomers to L-isomers, and racemic mixtures of amino acids could in some cases be useful in the context of the invention, the use of the L-isomers in the absence of D-isomers is preferred.
Advantageously, the protein fraction comprises a peptide having at least 7 amino acid units. Though this may induce an allergic reaction in persons suffering from an allergy for an epitope present in the protein fraction, the inclusion of such peptide is preferred, in order to decrease the need for inclusion of free amino acids and obtain a more palatable product. This allows full compliance of the product according the invention by the envisaged subjects to be treated with a product according to the invention.
The protein fraction in a medical nutrition or nutritional product can contribute to the sating or nausea-inducing properties of the nutrition or the product. Several ways of action have been identified in the art. Some proteins can release peptides after digestion in the gut which induces the release of a high amount of CCK or other neuropeptides which are known to cause nausea and satiety. Other proteins may clot in the stomach when exposed to high acidity and thus activate pressure-sensitive cells which are located in the stomach and when activated cause satiety. A third mechanism may be the activation of sensing cells in the proximal part of the small intestine while supporting serotonin biosynthesis by providing a relatively high amount of its precursor tryptophan. Though obviously a nutritional product can be designed to have a protein fraction that induces the lowest feelings of nausea and satiety, the benefits of the cereal fiber become evident when the medical food would comprise such satiety-inducing proteins.
The satiety-inducing properties of a protein become most evident when the protein is present in high concentrations. So in a preferred embodiment the fibre is present in a medical food or nutritional product wherein the protein content is more than 8 g per 100 ml. In a different embodiment the protein fraction in the product would contribute more than 18% of the energy of the product, using the Atwater values for the amount of energy that is generated by lipids, proteins and digestible carbohydrates and a value nil (zero) for non-digestible carbohydrates.
A tryptophan source is usually provided in combination with the (active) dietary fibre in a use according to the invention. Tryptophan may be administered separately or together with the dietary fibre.
In an embodiment, the tryptophan source comprises free tryptophan, a salt thereof, an ester thereof, or compound having an amide or peptide bond to tryptophan, e.g. a dipeptide comprising a tryptophan unit.
The tryptophan content (including tryptophan present in bound form in peptides and other compounds comprising a tryptophan unit, such as an tryptophan ester) in a nutritional composition of the invention is generally 2 mg/g of the total composition or more, preferably 3 mg/g of the total composition or more. Usually the content is 6 mg/g or less, at least in liquid products. The content may be higher though, in particular in case the composition is a concentrate-product that is to be diluted before administration, e.g. reconstituted in water or blended with another nutritional product.
In an embodiment, the ratio of the weight of tryptophan to that of the large neutral amino acids leucine, isoleucine and valine in the protein fraction of the product is at least 0.22, preferably 0.23 to 20 and most preferably 0.28 to 4 Preferably the ratio of the weight of the sum of leucine plus isoleucine and valine to the weight of the sum of threonine, histidine and lysine is smaller than 2.8 preferably 0.8 to 2.4.
Advantageously, in a use of the invention, the dietary fibre and tryptophan are administered together as part of a nutritional composition. To this purpose, cereal fibre; rice fibre or a fibre similar thereto are in particularly advantageous.
The use of the dietary fibre, such as cereal fibre, which may be rice fibre, in combination with tryptophan is advantageous for an ample supply of rapidly available tryptophan to the blood compartment after oral intake and a low supply of other amino acids, which hinder passage of tryptophan over the blood brain barrier. So the amino acids in the dietetic product have a relatively high weight ratio of tryptophan to the sum of large amino acids, in particular to the large neutral amino acids (LNAA), i.e. the branched chain amino acids (leucine, isoleucine and valine), tyrosine and phenylalanine.
In particular for a nutritional composition for use according to the invention it is desirable that it is rapidly digestible. This ensures a relatively low exposure of the lower parts of the GIT to several components in the food and to dietetic tryptophan, compared to administering tryptophan in the form of slowly-digestible proteins.
In order to achieve this preferably (1) a protein fraction is used which comprises a high weight ratio of tryptophan to the sum of large neutral amino acids and/or (2) the product must allow easy digestion of the protein fraction. A high ratio is in particular a higher ratio than in a protein like casein. Suitable proteins include proteins isolated from whey, from plants (beans, seed, grains tubers, etc.), from fish, krill, animals (meat, skin, organs), algae, eggs and from mushrooms. Methods are known in the art to isolate protein fractions from these sources and include grinding and milling, sieving, dissolving and solubilising, extraction, separation and purification. Partial hydrolysis may improve technological properties of these ingredients.
Especially preferred are protein blends which comprise one or preferably two, more preferably three members of the group of pea protein, soy protein, fish protein, egg protein and whey protein.
In a preferred embodiment the proteins are present in their natural state in the product that is ready for consumption. Typically during manufacture of the protein ingredients, as well as during the manufacture of blended products which include these protein ingredients, the proteins therein are at least partially oxidized. This induces intramolecular—and intermolecular disulfide formation, which increases the globular character of proteins and hinders access or activity of digestive proteases like pepsin, trypsin and chymotrypsin. Therefore in a preferred embodiment, the in the protein fraction in a composition (for use) according the invention natural sulfhydryl bonds are still present for at least 20%, preferably at least 35%, most preferably at least 80%. This can be measured by measuring the amount of protein bound sulfhydryl moieties and comparing the value with the measured value of the protein ingredients as used in the manufacture of the product and obligatory declared on the label of the same product.
The way that the proteins can be protected during manufacture of the ingredients or the ready to use product which comprises these protein ingredients are preferably selected from the group of 1/ preventing contact to oxygen by decreasing the time and extent to which these proteins can come into contact with atmospheric oxygen, 2/ preventing inclusion of oxidizing substances, 3/ decreasing the rate of reaction with oxidizing compounds, by optimizing heat treatment and avoidance of including catalyzing substances, like trace elements and redox active substances like anti-oxidants, and optionally 4/ applying a separate reducing step when needed.
A relatively low degree of heating, of the product, and in particular of the protein fraction avoids denaturation of the protein. The presence of non-denatured protein in the product is contemplated to be beneficial in the nutritional management or other treatment of individuals suffering from negative emotions or introvert behaviour. Non-denatured proteins and peptides may demonstrate a better digestibility in the proximal parts of the intestine and thus improve uptake of tryptophan in the brain.
Thus, the inventors believe that during preparation or further processing of a composition comprising protein, it is advisable that attention is paid to prevent denaturation of protein. This can be done by applying an optimization of processing conditions, preventing excessive heating and the like. The degree of heat treatment which is applied to the product can for example be assessed by measuring Maillard components and the degree of browning. For the latter reason also the inclusion of reducing sugars, like ribose or fructose, especially in their monosaccharide form is preferably avoided.
Amino acid composition of the protein ingredients can be measured by applying methods known in the art, which include acid or alkali hydrolysis of peptide bonds in the protein, purification of the extract, chemical derivatization of the amino acids, chromatographic separation and detection of the individual components.
Preferably a protein is present that induces a postprandial response which includes neurological and endocrine effects in the gut and the enteric nervous system, which modulate satiety, nausea. In addition it is preferred that the proteins will modulate the response of e.g. the pancreas to the systemic concentrations of glucose and amino acids. This induces e.g. a specific pattern of release of insulin and glucagon. These proteins are characterized by inducing a relatively high amount of glucagon compared to insulin, when compared to conventional protein blends which are used in casein-based medical food products.
The amino acid composition is preferably optimized to help such effects, in particular the effect on the response on the serotonergic systems. A relatively high amount of tryptophan to the sum of large neutral amino acids as been discussed above is therefore preferred.
In addition, it is preferred that the content of the sum of glutamate plus glutamine is preferably high in the protein fraction, in particular more than 18 g per 100 g protein fraction, more preferably 20 to 26 g per 100 g protein fraction, because this facilitates the functioning of the nervous systems in the gastrointestinal tract, in particular the serotonin—activated nervus vagus activity. In a specific embodiment glutamate or glutamine is present in a product of the invention, preferably in the range of 0.4 to 10 g per 100 g of the protein fraction.
The amount of cysteine equivalents is usually more than 1.7, preferably 1.8 to 2.8 g per 100 g of the protein fraction. This allows sufficient release of hydrogen sulphide to modulate GIT response in case the product would be used in situations for persons who experience a partially inflamed gut. Suitable cysteine equivalents are cysteine, N-acylated forms of cysteine, like N-acetylcysteine and cysteine-rich peptides, like peptides from keratin or other cysteine-rich proteins, or specific proteins from egg or whey.
The amount of branched chain amino acids is preferably low to get the highest possible ratio of tryptophan to large neutral amino acids. So preferably a composition (for use) according to the invention is essentially free of added free leucine, including a salt thereof.
Preferably a composition (for use) according to the invention is essentially free of added free proline, including a salt thereof.
The amount of threonine in the protein fraction is preferably relatively high in order to allow a proper neuro-endocrine response in malnourished or elderly patients. Without wanting to be bound on theory the effect of threonine is thought to be related to its ability to facilitate proper interaction between luminal contents and enterochromaffin and endocrine cells, either directly or through the mucosal micro-organisms. For this reason the amount of threonine in the product is preferably more than 5.2 and preferably more than 6.2 g per 100 g protein.
This can be achieved by inclusion of a proper protein source, like whey protein, or add free threonine or its salts or peptides during manufacture, or apply the combination of these measures.
The concentration of arginine in the product is preferably relatively high in order to facilitate the nitric oxide mediated activation of the nervus vagus. Preferably the amount of arginine in the protein fraction is more than 5, more preferably 5.4 to 9, most preferably 5.6 to 8 g arginine per 100 g of the protein fraction.
Proteins of plant origin, e.g. from cereals, like rye and wheat have a low weight ratio of tryptophan to the sum of large neutral amino acids. This means that the other proteins in the protein fraction of the product must comprise much tryptophan, or alternatively or additionally one or more other tryptophan sources should be used, such as free tryptophan (as acid, salt) or tryptophan-rich peptides. Preferably added free L-tryptophan as amino acid, its salt, its ester, or as an oligopeptide (i.e. a peptide having up to 10 amino acid units), in particular as dipeptide, preferably is provided in an amount of 0-12, more preferably 0.2 to 4 g L-tryptophan per 100 g of the protein fraction.
A product of the invention is usually essentially free of casein. If present, the casein content is typically less than 15 wt. %, preferably less than 2 wt % of the protein fraction.
The sum of dairy whey proteins and vegetable proteins is usually 5 to 100 wt %, preferably 22 to 98 wt % of the protein fraction.
In a specific embodiment, the ratio of the weight of vegetable protein (which is typically low in branched chain amino acids) compared to that of dairy protein, is at least 0.05 (wt/wt), preferably at least 0.2 (wt/wt).
A preferred protein fraction, in particular for use in a treatment of a person suffering from a mood—or behavioural disorder that is sensitive to food allergens meets the following features:
tryptophan is more than 1.9 g per 100 g of the protein fraction
the protein fraction comprises free L-tryptophan as amino acid, its salt, its ester, or as a peptide having 2-6 amino acid residues.
5-95 wt %, based on the total protein fraction, of peptides have 2-6 amino acid units.
The dosage of protein is preferably relatively low, in particular less than 6 g per dose, preferably less than 5.5 g per dose, more preferably less than 4.9 g per dose. However, based on the contribution to the total energy the protein content in the (ready to use product) is preferably more than 18 en %, using the Atwater constants for the calculation. The latter is because other energy-providing components, in particular lipids,—if present—are preferably in a relatively low amount of in the product. Preferably the product has the form of a liquid or semi solid.
In a specific embodiment, the protein fraction comprises lysozyme as tryptophan source. The amount of lysozyme hydrolysate having a DH of less than 10, in this embodiment is usually less than 25 wt. %, preferably less than 20 wt %, more preferably less than 10 wt %, of the amount of lysozyme hydrolysate in the product which has a DH of more than 20. Preferably the amount of tryptophan polypeptides from hydrolyzed intact protein in the protein fraction is less than 1 wt %. Preferably the protein fraction comprises 80 wt % or less, and more preferably less than 30 wt % of hydrolysed protein, due to taste reasons.
In an advantageous embodiment, the protein fraction also contributes to the supporting role of the product as claimed on the functioning of the dopaminergic system. This system includes the release of dopamine when food is observed or briefly before it has to be consumed and can be measured as an increased appetite. In addition the supporting role comprises a better functioning of dopamine receptors, in particular the increase of the effect of dopamine which is released before or during the first stages of eating.
The protein fraction is preferably rapidly digestible, which prevents that EC cells that are located in the distal parts of the ileum release serotonin to a larger extent than the blood platelets can absorb and thus induce a satiating and nausea effect by activating 5HT3 receptors in the CTZ (chemoreceptor trigger zone) of the medulla.
The protein fraction preferably also induces a relative low CCK release by the 1-cells in the duodenum after consumption, because it generally comprises a low amount of kappa casein. The whey proteins, if present, therefore preferably comprise acid whey. More preferably acid whey is more than 40, most preferably 51-100 wt % of the whey proteins.
If the nutritional product is in a liquid form, the product preferably is a homogeneous emulsion comprising at least a protein fraction, lipids carbohydrates, a fibre and a mineral fraction. After consumption and passage of the stomach the emulsion as such induces a release of cholecystokinin (CCK) which is relatively low, compared to prior art products.
The product preferably has a relatively low amount of organic acids or is essentially free thereof. In a particular preferred embodiment the amount of organic acids which are typically declared as digestible carbohydrates on the label of the product is less than 5 wt %, preferably less than 2 wt % and more preferred less than 1 wt % of the digestible carbohydrate fraction. When expressed as ratio to the protein, the amount of organic acids to the total amount of protein in the product is usually less than 8 g organic acid per g pure protein in the product, and preferably less than 6 g, more preferably less than 5 g organic acid per g protein. This criterion applies to organic acids like mono- or di- or tri-carboxylic acids, and in particular to di- and tricarboxylic acids. Most in particular it applies to citrate and its salts.
This facilitates proteolysis of dietetic proteins of the product already in the stomach, predominantly by allowing rapid acidification of the gastric contents to the pH value which is closer to the optimum value for the proteolytic enzymes in the gut, including pepsin. This rapid pre-digestion also allows more rapid passage through the stomach pylorus and allows a more rapid neutralization of the digests that enter the duodenum. This decreases the release of CCK compared to conventional foods.
These effects on dopaminergic and serotonergic systems contribute to a desired eating behaviour in individuals in need of the product as claimed, because the full desired amounts of the product according the invention are consumed; in other words the compliance to the feeding protocol with the product as claimed is excellent, preferably more than 90%. Compliance with a desired level of intake of healthy nutrients is a major problem in the individuals suffering from the serotonergic disorders, depression, behavioural disorders and other diseases as mentioned in this document.
A superior digestion rate of a preferred composition of the invention, including the protein fraction can be accomplished in various ways. It is therefore preferred to create a low buffer strength or capacity in the ready to consume product, for a superior digestion rate.
WO2012/092082 discloses low calorie infant formula which allow good digestion of dietetic proteins. By decreasing the energy density to a value of 200-500 kcal/l and by decreasing the amount of microingredients that are included to 30-80% of the amounts in normal infant formula patentee aims to reduce buffer capacity. In the present application the inventors aim to improve digestibility in different ways. The selection of the nature of the protein has been discussed above. In addition it appears that the matrix of the product is important, for example in terms of dry matter content and presence of insoluble material. In the present invention a preferred measure to reduce buffer capacity or strength is to decrease the inclusion of an organic acid in a composition of the invention. The phosphorous content in the ready to eat product is therefore preferably less than 14 mg, more preferably 3-13 mg per g protein fraction in the product. The pH of the product is in the range 3.0 to 7.4 and the osmolarity and viscosity is relatively low. The content of the protein fraction in a nutritional composition of the invention is usually at least 5 g per 100 g of the total nutritional composition, in particular at least 8 g per 100 gram, more in particular at least 14 g per 100 g. The content, in particular in a ready-to-eat product, is usually less than 50 g per 100 g, in particular 40 g per 100 g or less, more in particular 25 g per 100 g or less.
For a liquid product, the protein fraction content is preferably in the range of 5-9 g/100 g of the composition. For a semi-solid product the protein fraction content is preferably in the range of 8-20 g/100 g of the composition. For a solid product the protein fraction content is preferably in the range of 14-40 g/100 g of the composition.
The Digestible CarbohydratesIf present, the fraction of digestible carbohydrates preferably has a low glycaemic index (GI). This ensures a small and slow increase of NADH in the cells of the gut, the nervous systems, immune cells and the liver. This is considered to be beneficial for maintaining proper redox potential in the cell, while at the same time generating a sufficiently large flux of reducing equivalents to the mitochondria of cells in the gut, immune cells and cells of the nervous systems in the gastrointestinal tract, the nervus vagus and the brain, to generate energy in the form of ATP (adenosine triphosphate).
It should be noted that in the prior art, it has been proposed to consume large amounts of rapidly digestible glucose sources in order to prevent muscle catabolism and increase brain serotonin biosynthesis (Wurtman, et al, 2003, Am J Clin Nutr 77, 128-132).
The speed of release of glucose moieties in the GIT is considered to be of large interest. The way to determine the GI value is known in the art and includes measuring glucose concentration in blood during the first 2 hours after oral administration of the product to be tested and comparing the value of the area under the curve with that obtained after administration of glucose, which is assumed to have a value of 100. This can be determined by the method described in Englyst et g Am J Clin Nutr 1999, 69, 448-454.
The GI value of the digestible carbohydrate fraction is preferably less than 80, more preferably 20 to 72, most preferably 20 to 64. The GI value of the total digestible carbohydrate fraction complies with this criterion, though the various digestible carbohydrates in the total fraction may demonstrate different GI values, and some may even have a GI index above 64, or even above 80. It is desired that the amount of such individual digestible carbohydrates is also low. In particular the amount of free glucose in the total digestible carbohydrate fraction is preferably less than 10 wt %, more preferably less than 4 wt % in order to prevent a postprandial decrease of ghrelin release. The inventors consider a high ghrelin release after consumption of the product desirable, for example in order to increase digestion rate of the product.
The digestible carbohydrate fraction preferably comprises slowly—and rapidly digestible carbohydrate. The rapid digestible carbohydrates will keep rapidly the amount of systemic LNAA low in catabolic situations. More than 3 times, preferably more than 4 times as much weight of slowly digestible carbohydrates should be included compared to the weight of rapidly digestible carbohydrates. His ensures a long lasting anti-catabolic effect and a good taste of the product.
Examples of such slowly digestible carbohydrates are some starches, some types of large pullulan oligomers, trehalose, isomaltulose, chemically modified carbohydrates and several residues of digestible carbohydrates, as present in the fibre fractions used in the product, such as the cereal fibre. The speed of digestibility of the ingredients included in the product can be measured by applying the standard method known in the art for this purpose: Englyst et al Am J Clin Nutr 1999, 69, 448-454. Those carbohydrates that are digested under these standard conditions to monosaccharide in the period between 20 and 120 minutes after the start of the experiment were considered to be slowly digestible. Those that were not yet digested at 120 minutes after the start were considered to be fibres.
The amount of digestible carbohydrates in the product usually is up to 8 times, preferably up to 5 times, most preferably less than 4 times the amount of protein in order to have the largest protein effect of the product. Especially when it is used as a supplement, the digestible carbohydrates will be consumed in high amounts anyway and excess digestible carbohydrates will impair the health of insulin-resistant individuals, like diabetics, many obese persons and many elderly. Insulin-resistance is strongly associated with the behavioural problems which are aimed to be treated by the product according the invention.
It is preferred that at least part of the carbohydrates origin from the fruits of the Musa genus. Plantains and bananas can be used as source of digestible carbohydrates and fibres. The fruits comprise different amount of rapidly digestible carbohydrates like sugars, dependent on the species and the degree of ripening of the fruit at the moment of measurement or use. A typical Cavendish banana will comprise about 12.2 g sugars (=about 53 wt % of total carbohydrates), 2.6 g fibre and about 8 g oligomeric and polymeric carbohydrates. The fruit-derived ingredients which are preferably used in the manufacture of the products according the invention comprise rapidly digestible sugars in an amount of less than 45 wt %, preferably less than 36 wt %, more preferably less than 18 wt % of the total carbohydrate fraction in the ingredient. Also the amount of rapidly digestible starch is low.
In a specific embodiment, the amount of banana-derived carbohydrates is between 1 and 70-preferably 2-60 wt % of the amount of digestible carbohydrates in the total product. Suitable ingredients include a puree of selected fruits or an extract of the fruit. Dependant on the final composition of the ready to use product different amounts of banana or different qualities can be used. The banana puree can be included in a content of 0.2 to 26 wt/vol % in the ready to use product.
The amount of digestible carbohydrates in a nutritional product (for use) according to the invention preferably is at least 8 wt. %, in particular 8-70 wt % of the total composition (in particular when present in a ready-to-eat form). The type of digestible carbohydrates is preferably selected on the criterion that the amount of rapidly available glucose sources is relatively low, while still creating a pleasant taste which is appreciated by the person that is to be treated in accordance with the invention in particular a person who suffers from a mood—or behavioural disorder or person who is consuming a product in accordance with the invention as a prophylactic measure to prevent occurrence of such disorder. Thus, the abundance of maltodextrins and glucose/fructose syrup, if present at all, is preferably relatively low. In an advantageous embodiment, the nutritional composition comprises one or more slowly digestible ingredients, selected from the group of isomaltulose (or palatinose), isomaltose and trehalose.
A preferred blend of digestible carbohydrates in the treatment of a mood- or behavioural disorder complies with the following criterions:
1/ the sum of maltodextrins and glucose-fructose syrup is 2-90 wt %;
2/ lactose, galactose or banana puree>2 wt %;
3/ the sum of isomaltulose, trehalose and isomaltose>2 wt %;
4/ free fructose 1 to 8 wt %.
The type and amount of digestible carbohydrates appears to be important not only to provide a minimum amount of glucose and sweetness to the product to consume, but also to regulate the redox potential in intestinal cells, immune cells, liver cells and neurons. In an embodiment, a product according the invention aims to prevent excess formation of reducing equivalents, like NADH.
An improvement of the redox situation in the target tissue or target cells can be measured by measuring the weight ratio of NADH to NAD+, or of NADPH to NADP+ or of derived metabolites, like lactate to pyruvate, or oxidized glutathione to reduced glutathione, as known in the art. These values can be compared with values which are obtained after feeding under identical conditions the products as known in the art until now.
It is important that the amount of NADH in the cytosol of cells in the target tissue has become lower after feeding a dietary fibre, combination or nutritional composition according the invention. A lower value will result in the end in lower expression of stress proteins, like several heat shock proteins, for example of HSPA5, or alternative stress proteins like enolase 1 and GAPDH.
The content of the digestible carbohydrate fraction in a nutritional composition of the invention is usually at least 4 g per 100 g of the total nutritional composition, in particular at least 5 g per 100 gram, more in particular at least 8 g per 100 g. The content, in particular in a ready-to-eat product, is usually less than 80 g per 100 g, in particular 70 g per 100 g or less, more in particular 50 g per 100 g or less.
For a liquid product, the digestible carbohydrate content is preferably in the range of 1.5 to 9 g/100 g of the composition.
For a semi-solid product the digestible carbohydrate content is preferably in the range of 6-30 g/100 g of the composition. For a solid product the digestible carbohydrate content is preferably in the range of 16-70 g/100 g of the composition.
The Lipid Fraction
The amount of lipids in the nutritional composition is preferably relatively low in order to prevent a large post-prandial PYY- and CCK release. In a specific embodiment this amount is less than 4 g, preferably less than 3, more preferably less than 2 g, most preferably less than 1.7 g per dose.
The concentration nutritional composition will vary dependent on the intended serving size, but is typically less than 4 wt %. The contribution of the lipid fraction to the total energy as provided by the complete formula by its protein and digestible carbohydrates can be calculated, by using the Atwater calculation which assigned theoretical calculation factors of 16.7, 16.7 and 37.7 kJ per gram of respectively protein, digestible carbohydrates and lipids, and a contribution of zero to other food constituents. In the products according the invention the lipid fraction will typically be in the range of 1 to 35 en %, preferably 3 to 29 en %, more preferably 5 to 22 en %.
The lipid fraction preferably comprises more than 1, preferably 3 to 100, more preferably 6 to 60% of an oil comprising more than 2, preferably more than 20-g of the sum of eicosapentaenoic—and docosahexaenoic acid per 100 g fatty acids, in order to increase sensitivity of the receptors on EE cells, the EC cells and the central nervous system and the ENS but especially to increase dopamine release in the nucleus accumbens and striatal regions involved in reward sensation and motor neuron function. Important receptors which are sensitized by the product according the invention are G-protein coupled receptors on neurons. The effects of the product on membrane functioning result in better localization of receptors and better coupling to intracellular G proteins. This applies for example to the cannabinoid CB1 receptors.
Preferably, the lipid fraction of the nutritional composition comprises 1-10 wt % of marine oil in order to help proper processing and distribution of serotonin receptors in the body of the person that is suffering from a mood or behavioural disorder. In particular the lipid fraction contributes to the effect of the product to redistribute 5HT1A receptors over neurons and the internalization of 5HT2 receptors in neurons, the relative expression of serotonin receptors over the organs and the vesicle-mediated release of neurotransmitters, like serotonin.
In an embodiment, the nutritional composition comprises a source of docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA).
In a preferred embodiment the weight ratio of eicosapentaenoic (EPA)- and docosahexaenoic acid (DHA) in the product is larger than 0.8, more preferably 1.0 to 30, more preferably 2.0 to 20.
Instead of the pure fatty acids also equivalents can be used which are suitable for use in medical food and include salts, esters and ethers, including glyceride and phospholipid forms, as known in the art. When making calculations about amounts, one can assume the same bioavailability as the pure fatty acid and a contribution of fatty acid that is similar to the amount moles of fatty acids in the complete molecule, and correcting for the weight of the complete molecule.
One important property of the lipid fraction is its ability to contribute to the low satiating properties of the ready to use product. In an advantageous invention the nutritional composition of the invention is suitable to induce a relatively high ghrelin response after (oral) consumption of the product. In order to contribute to this characteristic the lipid fraction comprises per 100 g preferably more than 2 g octanoic acid (=C8:0) and more preferably 4 to 40, most preferably 8 to 20 g of octanoic acid or its equivalents (all based on total lipid content). Equivalents of octanoic acid are those chemical substances which when consumed by humans increase the concentration in blood of compounds which comprise octanoic acid, such as triglycerides. Examples of equivalents of octanoic acid are salts of octanoate, esters or ethers of octanoic acid like acetyl-octanoate or butyl-octanoate or triglycerides. Refined medium chain triglyceride oil was found to be a good source of endogenous octanoic acid.
The selection of amount and type of the lipids in the lipid fraction preferably contributes to the relatively low postprandial CCK- and PYY response after consumption of the product. This is achieved because the lipids are easily digestible and form the right micelles in the duodenum after release of the bile secretions. This is preferably achieved by including the lipid fraction in the product as small droplets that are homogeneously distributed over the product. It is also preferred to include an emulsifier system which interferes as little as possible with the emulsifying events in the duodenum. That is why the amount of diglycerides and especially monoglycerides is preferably relatively low. In a preferred embodiment the amount of the sum of mono and diglycerides is less than 10, preferably less than 2 wt % of the lipid fraction. The total amount of phospholipids and lyso-phospholipids usually is 0.5-12, preferably 0.7-6, more preferably 0.8 to 4, most preferably 0.8 to 3.4 g per 100 g lipid fraction.
The lipid fraction preferably facilitates modulation of the serotonergic system. It is therefore preferred to include a lipid fraction in the product according the invention which comprises a source of omega-3 long chain polyunsaturated fatty acids [(N-3) LC-PUFA's].
In order to modulate the serotonergic signalling, preferably the weight ratio of long chain polyunsaturated fatty acids (LCPUFA's) of the n-3 class to that of the n-6 class is 0.25-9.4, preferably 0.5 to 4. With long chain fatty acids is meant herein fatty acids having at least 18 carbon atoms. A preferred source of n-3 LCPUFA's is krill oil though more sources of omega 3 long chain poly-unsaturated fatty acids are known in the art, like other marine oils, algae oils, fungal oil and oils derived from or extracted from genetically modified organisms, including genetically modified plants. The way such organisms should be modified to increase the amount of n-3 LCPUFA's during their life is known in the art and can include introduction of genes with increased elongase- and/or desaturase activities in these organisms.
The content of the lipid fraction in a nutritional composition of the invention is usually at least 2 g per 100 g of the total nutritional composition, in particular at least 3 g per 100 gram, more in particular at least 5 g per 100 g. The content, in particular in a ready-to-eat product, is usually less than 50 g per 100 g, in particular 40 g per 100 g or less, more in particular 24 g per 100 g or less.
For a liquid product, the lipid content is preferably in the range of 1.2-5 g/100 g of the composition, more preferably 2 to 4 g per 100 g ready to drink product.
For a semi-solid product the lipid content is preferably in the range of 4 to 24 g/100 g of the composition. For a solid product the lipid content is preferably in the range of 8-40 g/100 g of the composition.
Mineral Composition:
Optionally, the nutritional composition comprises a mineral. The amount of minerals in the product can be measured as the amount of mineral ash. In order to provide the proper amount of the active mineral ions, allow a rapid digestion rate of the food constituents and induce the proper postprandial response the amount of ash nutritional product is usually relatively low, at least in the form in which it is intended to be administered (ready to use′). Preferably the amount of ash per 100 g of liquid nutritional composition, in particular when in a ready to drink product form, is less than 1.8, more preferably 0.7 to 1.7, most preferably 0.8 to 1.6 gram.
In a liquid nutritional composition, the ionic strength of the composition can play a role, in particular with respect to modulating the release of satiating gut hormones. A low ionic strength is thought to prevent too rapid release of such gut hormones. The ionic strength can be measured by determining the osmolarity or osmolality of the liquid product. It is preferred that the product demonstrates an osmolarity of 170 to 340 mOsm/l, more preferably 190 to 310 mOsm/l, most preferably 210 to 290 mOsm/l.
The amount of sodium and potassium in one ready to serve unit should preferably be low, in order to decrease emesis, nausea and activation of EC cells. The amount of sodium ions included in the composition preferably is less than 90 mg per 100 g, preferably 20 to 80 mg per 100 g. This allows a daily consumption of less than 1500 mg per day of total diet.
Zinc content is preferably relatively high in order to increase the amount of ghrelin that is released after consumption of the product. The amount of zinc in the product is preferably more than 2.4, more preferably 3.2 to 24, most preferably 4 to 18 mg per 100 g product. Preferably the magnesium content is higher than 26 mg/100 ml or 26 mg per 100 g of the nutritional composition, in particular in a ready to eat product, more preferably 32 to 48 mg per 100 ml or per 100 g of the nutritional composition, in particular in a ready to eat product, in order to treat deficiencies that are critical in the treatment of the diseases, while eating relatively low amounts of the product according the invention. Magnesium can be included in the product as food grade ingredient as known in the art, for example magnesium sulphate or magnesium bicarbonate.
Iron/copper ratio is preferably high to prevent deterioration in the product and increase metabolic pathways which support serotonin signalling and tryptophan metabolism. Preferably the weight ratio of iron to copper in the nutritional composition, in particular in a ready to use product, is more than 10, more preferably 12 to 40, most preferably 14 to 28. The amount of iron ion in the nutritional composition preferably is in the range 0.1 to 15 mg per 100 g product, more preferably 0.3 to 7 mg per 100 g product, most preferably 0.6 to 3 mg per 100 g product, in particular for a ready-to-drink product. The stated upper limit for the iron is in particular relevant in order to prevent instability in the product and entrance of iron salts in the colon. The iron ions preferably have the form of ferrous ions. The ions must be bound to anions which allow rapid dissolution in the gut and allow high bioavailability of iron. Suitable anions to achieve this are organic acids like sulphate, or gluconate, ascorbate and amino acids, like glycine or alanine.
One can distinguish between buffer strength and buffer capacity of a product, as is done in WO2012/092082. The buffer strength is defined as the number of millimoles of HCl (hydrogen chloride) that is needed to lower the pH of 50 ml of the ready to use liquid formula from 6.00 to 3.00. The buffer capacity of the nutritional composition can be measured by methods known in the art, which include titration of composition The buffer capacity is expressed as the increase in proton concentration (1-1+) or change in pH, following the addition of a selected amount of acid.
For dry products a solution/emulsion is made of 10% of dry product in water to a volume of 100 ml water.
In a preferred embodiment, the ready to use liquid medical food has a buffer strength of less than 8 mMoles HCL, more preferably 1-6 mMoles and most preferably less than 3 mMoles HCL.
In a preferred embodiment the buffer capacity of the product is especially low in the pH range 2 to 7.4. This is preferably achieved by selecting ingredients with a low buffer capacity. This applies to the macro-ingredients, for example the proteins, but also to the type of minerals. The type of anions is therefore not an organic acid or phosphate, which are known to have a high buffer capacity. Instead sulphate, chloride or nitrate, or to a small extent, bicarbonate is used as counter ion in the mineral salts. In a preferred embodiment of the mineral fraction of the nutritional composition according the invention is the weight amount of the sum of sulphate and nitrate 0.05 to 20, preferably 0.08 to 2 times the weight amount of phosphates. The weight amount of phosphates is the anion part of the mineral-phosphates that are included in the product. The concentration of phosphorus in the product is defined by applying the criterion that preferably is less than 14 mg per g protein fraction.
Other Components
Several other components are useful to improve the effect of the active ingredients. According the inventors in particular one ore more other components may be included to maintain or improve the action of the most relevant endogenous proteins involved in tryptophan catabolism and serotonin handling, in vivo. These proteins include aromatic L-amino acid decarboxylase, kynurenine hydroxylase, and the expression or localization of one or more serotonin receptors and proteins involved in the release of neurotransmitters, like serotonin, but also dopamine.
In a preferred embodiment, a composition (for use in accordance with the invention) comprises folate (vitamin B11). The content/dosage is preferably relatively high in order to allow rapid catabolism of tryptophan through the kynurenine pathway when needed, and subsequently stimulate neurogenesis and synaptogenesis and microglia function. The inventors believe that the latter phenomena can be explained by the improvement of nucleotide metabolism by the product according the invention. Folate can be included in the product in a form that increases systemic folate concentrations after oral administration. These forms include food grade qualities of folate monoglutamate, folinic acid and one-carbon-substituted folates and polyglutamate forms of these folates. The amount of folate in one dose of (ready to serve) product according the invention is preferably 0.05-4, preferably 0.1-3 times the recommended daily allowance values of the FDA 1989.
Vitamin B6 is preferably included in a composition (for use) according to the invention, in order to prevent accumulation of undesired metabolites of dietetic tryptophan when catabolised through the kynurenine pathway. Suitable sources of vitamin B6 include pyridoxine, pyridoxamine, pyridoxal and pyridoxal phosphate, in free form or as complex with other molecules like amino acids or peptides. The amounts to include are 0.05 to 4, preferably 0.1 to 3 times the recommended daily allowance values, as disclosed in 1989 by the RDA.
Though the kynurenine pathway is stimulated through inclusion of folate and vitamin B6, and this would result in additional synthesis of nicotinamide nucleotides (NAD+, NADH and NADPH and NADP+), for some subjects it can be advantageous to include vitamin B3 in the products. Suitable forms of vitamin B3 include niacin (nicotinic acid, NA), its salts or esters, and niacin mononucleotide. Suitable daily dosages are 0.1 to 3, preferably 0.15 to 2 times the daily dosage as recommended per day (RDA, 1989 values).
It is preferred to use niacin (NA) or its salts or esters as source of vitamin B3 above nicotinamide. Though it may induce flushes at lower doses compared to its amide form, and may induce a shorter and more transient increase of systemic NAD+ concentrations, it is preferred because the amide form can freely pass the blood brain barrier and the high concentrations of niacinamide will disturb NAD+ metabolism and choline metabolism in brain, while not being capable of potentially being converted to NAD+ (nicotinamide adenine dinucleotide). It is therefore preferred to keep the dose of vitamin B3 per serving unit below a threshold value of 2 times, preferably below 1.0 times the RDA value, when the source of vitamin B3 is niacin, in order to have an undisturbed and maximal biosynthesis rate of NAD in the brain.
Though the biochemical pathways in the brain are of paramount importance, the inventors believe that the hepatic processes also determine brain serotonin handling due to the passage of kynurenine and 3 hydroxy kynurenine, but not quinolinic acid and kynureninic acid over the blood brain barrier.
Hydroxylation of kynurenine is catalyzed by kynurenine mono-oxygenase (KMO) in rat brain and is a main step away from the KYNA pathway (which is katalyzed by the aminotransferase KAT-2) and into the biosynthesis of quinolinic acid and NAD. The inventors consider it to be advantageous that this step can occur in a sufficient amount and it is therefore preferred to include additional vitamin B2 in the formula. Suitable forms of vitamin B2 include food grade qualities of riboflavin or riboflavin which is non-covalently bound to other molecules like peptides or proteins. The amount to include is usually 0.05 to 4 times, preferably 0.1 to 3 times the recommended daily allowance as disclosed by the FDA in 1989.
In addition food grade bioavailable iron ions may be included in the composition, preferably in an amount of 0.1-10 times the recommended daily allowance as published by the Food and drug administration in the USA in 1989. The amount of iron ion in the nutritional composition preferably is in the range of 0.1 to 15, most preferably 0.3 to 7 mg, most preferably 0.6 to 3 mg per 100 g product, in particular per 100 g ready-to-use product.
The quinolinic acid (QA) pathway could result in toxic amounts of QA. The inventors have aimed to prevent this by increasing the rate of phosphoribosylation of QA by providing support to the 5-phosphoribosyl-1-pyrophosphate (PPRP) synthetase. This is achievable by supporting the generation of adenosine triphosphate (ATP) through the components in the composition, in particular through several of the trace elements (vitamins and minerals) in the composition.
The inventors find it important that digestible carbohydrate fraction in the product provide sufficient reducing equivalents in the form of NADPH+ in order to allow this selective form of the kynurenate pathway. A selective increase of the QA pathway at the cost of the biosynthesis of kynurenic acid (KYNA) may induce an enhanced release of neurotransmitters in general, including dopamine, serotonin, glutamate and gamma-aminobutyric acid, as a consequence of increased activation of nicotinic receptors in the brain. This applies in particular to the homomeric nicotinic receptors, like the homopentamer alpha-7 nicotinic receptor in brain.
The inclusion of vitamin B6 contributes to the capacity to get rid of excess quinolinic acid wherein catabolism to NAD is impossible or undesired, which may occur in impaired phospho-ribosylation as during energy deficiencies.
Choline or betaine is preferably included in the product. However, the amount should preferably remain relatively small in order to prevent trimethylamine oxide formation. This is achieved by selecting a concentration range of 12 to 120 mg per 100 g of the nutritional composition (in particular in a ready to serve product).
In addition, preferably a (rapidly available) compound is included which prevents that the microflora of the colon can come into contact with the dietetic choline or betaine. Suitable choline compounds are rapidly absorbed in the small intestine and include choline alfoscerate and citicoline. Salts of choline with organic acids are preferably avoided. However, preferably eutectic solvents of choline chloride with urea, zinc chloride, glycerol or mixtures thereof are included as choline source. These eutectic solvents can be manufactured using procedures known in the art, e.g. by combining the proper molar amounts and blending at the right temperature above the melting point of the eutectic solvent to manufacture. Using a facilitator, like a primary amount of solvent prior to addition of the new reagents is preferred.
The changes in serotonergic systems as induced by a product of the invention also increase the effects of the orally administered inositol compounds. In a particular embodiment according the invention an inositol compound is included in the nutritional composition. In a preferred embodiment the inositol is selected from scyllo-inositol, myo-inositol or chiro-inositol. Suitable sources for these active components include the free substances as isolated from natural sources or the chemically synthesized and purified food grade compounds. Suitable amounts of inositol are about 0.05 to about 1 g inositol per 20 to 120 g of the composition (in particular as ready to serve product). A preferred dosage or preferred amount inositol compound in a serving unit is 0.05-1 g.
The vitamin D content is preferably 1.3 to 40, more preferably 1.8 to 34, most preferably 2.0 to 28 microgram per 100 g of the composition (in particular as ready to eat product) in order to combat deficiencies that are critical in the treatment, while eating relatively low amounts of the product according the invention. As vitamin D ingredient the food grade synthetic compounds or isolates as known in the art can be used. It is preferred to use vitamin D3 as ingredient.
It is preferred that the amount of quinones, in particular PQQ in the ready to serve product is more than 5 mg, more preferably 10-2000, most preferably 20-1000 mg per 100 g composition (in particular as ready to use product).
Ascorbic acid or an equivalent is preferably included to ensure proper intake to ensure support of several oxidation (or hydroxylation) reactions in neurotransmitter metabolism, both in the enteric—and the central nervous system. Suitable equivalents or food grade ingredients, like ascorbyl esters, for example esters with organic acids like fatty acids, acetate, butyrate, amino acids, ethers with carbohydrates and salts or esters of ascorbate, like respectively potassium ascorbate and ethyl ascorbate respectively.
The following table provides preferred dosages of vitamins and miscellaneous ingredients. A product according the invention preferably comprises at least two ingredients of Table 1, next to folate (vitamin B11).
Advantageously, after consumption of a liquid product, the product should remain fluid once it has entered the stomach or ileum in order to allow rapid mixing with digestive juices, which include proteases, amylases lipases and buffering agents. This allows rapid digestion of components of the product and absorption of the active components by the first part of the GIT.
It is preferred to bring the product in a taste which is appreciated by the consumer and supports food consumption. This is preferably achieved by decreasing the activation of vanillin receptors. In a preferred embodiment the amount of vanillin is that low that activation does not occur in a relevant or significant degree, e.g. by avoiding the inclusion of vanilla flavours in the product according the invention.
Product Form, Energy Density, Dosing Unit Size
The fibre, combination or nutritional composition (for use) according the invention can be used as food supplement or as product for therapeutic—or pharmaceutical intervention. The nutritional composition can be also be provided in the form of a complete nutrition. The fibre, combination or nutritional composition can be provided in any product form, in particular as a ready-to-use product or as a concentrate that is diluted, e.g. with water or by blending it with a food product.
The products can have a liquid, semi solid or solid nature, depending on palatability requirements or desires of the intended user.
In accordance with the present invention, liquid products are typically products that are pourable (at 20° C.), in particular pourable from an opened container in which they are contained, or that can be withdrawn from a container by sucking (by a person consuming the liquid) through a straw or drunk directly from an opened container. In particular, a product is considered to be liquid or pourable if its viscosity, as measured using the method as described in the definitions section, lies below 200 mPa·s. Within the context of the invention, the viscosity is the viscosity as measurable using an Anton Paar Physica MCR301 rheometer with a CP50-1/PC cone (diameter 50 mm, 1° difference between middle and outside) at 20° C. at 100 s−1. In particular for a liquid product that is intended for administration by drinking, or via a straw or tube, the viscosity preferably is 100 mPa·s or less. In a particularly preferred embodiment, the viscosity is 40 mPa·s or less. In a preferred embodiment, the viscosity of a liquid product according the invention as stored before consumption is 1 to 24 mPa·s, in particular 1-20 mPa·s.
As used herein ‘semi-solids’ generally are nutritional products comprising 20 to 82 wt % dry mass, in particular 25-75 wt. %. Dry mass is defined as the amount of product that remains after drying under the conditions as recommended for that particular food product according to recognized methods as e.g. published most recently, prior to the effective filing date of the present disclosure by the American Organization of Analytical Chemists. In particular, semi-solids have a viscosity that exceeds the viscosity of a liquid product. Typical examples of semi-solids are puddings, gels, porridges, ice-cream, sandwich spreads, pastes, and products having a similar rheological consistency.
As used herein solids are products comprising less than 18 wt % of water. Typical examples of solids are powders, food-bars (such as granola bars, candy bars), and the like.
A product (for use) according the invention, in particular a nutritional composition, usually has an energy density (ED) in a specific range in order to provide the efficacy without the adverse effects on the intestinal systems. For liquid products the ED is usually more than 1.6, preferably at least 3.2 kiloJoule per gram product, in particular per gram ready to use product.
In a preferred embodiment, the nutritional composition of the invention, in particular a ready to use product or a concentrate, has an energy density of more than 1.67 kJ per gram product, in particular of 3.14 kJ per gram or more, the composition comprising
a tryptophan source providing more than 2 mg tryptophan per gram of the total composition, preferably 3-60 mg tryptophan per gram of the total composition;
a peptide comprising at least 7 amino acids, which peptide may be a tryptophan source; and
a dietary fibre fraction comprising dietary fibre molecules as mentioned herein.
In particular for a ready-to-eat liquid product, the ED may in particular be 6.7 kJ/g or less, more in particular 4.6 kJ per g or less.
If the product is semi-solid, in particular when having a dry matter content of 20-60 g per 100 g (ready to serve) product, the ED is preferably in the range of 19.2 to 52.8, preferably 26.3 to 46.1 kJ per 100 g (ready to serve) product.
The energy density of the solid product should generally be less than 20 kJ per g (ready to serve) product.
If the nutritional composition is to be used as a (significant part of the) diet by the subject to be treated with the composition, the ED should generally exceed the minimum value of 3.2 kJ/g because it should provide energy to the patient to prevent a lack of glucose or other metabolic energy substrates in blood or tissue, which would support prevalent catabolic processes and the subsequent loss of lean body mass. This overall decrease of catabolism is relevant for tryptophan and serotonin metabolism, because during muscle catabolism branched chain amino acids will be released into the blood, which may impair tryptophan passage over the blood brain barrier. Subsequent conversion of tryptophan into serotonin in the brain can become less, due to lack of substrate. This adverse effect is avoided or at least reduced by a sufficiently high ED.
The decrease of catabolic reactions is in particular achieved by a combination of technical features as claimed, so not only by energy density. It is contemplated that a product of the invention may in particular have an ability to decrease the degree of phosphorylation of PKR or eIF2-alpha, which decreases the degree of ubiquination of intracellular proteins through interaction with FOXO or NFkappaB.
The components in a product (for use according to) the invention preferably support energy metabolism and the induction of a beneficial epigenetic condition of nuclear histones to allow a sufficient rate of transcription of the genes of microglia and intestinal immune cells and of neurons that are relevant to for example immune function and the biosynthesis of enzymes involved in tryptophan metabolism and of neurotransmitter receptors.
The maximum value for the energy density (ED) is usually determined considering the volume of product that should be consumed in order to induce the efficacy as claimed, while both ED and the amount of food that is consumed determine the postprandial physiological response to the consumption activity. This response includes a volume-related response of the GIT through activation of the ENS or entero-endocrine system, which not only regulates digestion, but also satiety and food intake. Therefore values of the energy density of the product preferably are to be considered in combination with the relatively low volumes that are consumed per consumption event. By adding new consumption events with again low volume portions, the efficacy that is aimed for can be obtained.
Conventional food products are typically packed in all possible sizes in order to suit the needs of customers. In the present invention the volume is preferably restricted and coupled to the maximal energy density in order to achieve the efficacy.
Thus, in an advantageous embodiment of the invention, the amount of food and energy that is consumed per serving does not exceed a certain threshold value. This value is determined by the subject's capacity to digest the food properly, and to prevent activation of an excessive postprandial 5HT response in the lower gut, and to prevent activation of the release of a wide range of anorexic peptides, like PP, PYY and others.
In a specific embodiment the amount of the composition which is administered does not exceed 510 kJ per serving size and preferably is in the range of 65 to 9380 kJ, more preferably 75 to 294 kJ. This can be achieved by packaging a ready to use amount in a package size which is sufficiently small. In order to have a convenient package size, this should not be too small, i.e. more than 5 g, preferably 12-130 g, more preferably 18-90 g, most preferably 20-70 g for liquid and semi-solid products. Administration of the active components in a solid matrix is usually provided in a small size, so less than 10, preferably less than 5 g per serving size, in order to prevent overeating which would impair digestion rate and induce activation of the EC cells in the lower parts of the GIT. In addition the solid products have preferably been prepared such that the serving units rapidly will disintegrate once they enter the stomach. Disintegration should preferably not be achieved by using inclusion of highly buffering substances.
The components in the product determine in what form energy is provided to the organism and details will be described in the relevant clauses.
In a preferred embodiment, the nutritional composition is a ready-to-eat product, i.e. a product that is suitable for consumption without adding further ingredients or further processing (except for additional heating to a desired serving temperature). Examples of preferred embodiments are liquids and extruded dry products or bars.
In another preferred embodiment, the nutritional product is a concentrate, which is intended for reconstitution in water or another drinkable liquid or for blending with another nutritional product.
In a specific embodiment, the product is a sterilized liquid or semi-liquid product, in particular a product sterilised with UHT (so above 121 C) at pH2-7.5, preferably 2.6-7.0.
The invention further relates to a packaging, in particular a unit-dose packaging, comprising 5-300 g, preferably 12-130 g of a liquid or semi-solid nutritional composition according to the invention.
The invention further relates to a packaging, in particular a unit-dose packaging, comprising 0.5-10 g of a solid composition according to the invention.
In accordance with the present invention, liquid products are typically products that are pourable (at 20° C.), in particular pourable from an opened container in which they are contained, or that can be withdrawn from a container by sucking (by a person consuming the liquid) through a straw or drunk directly from an opened container. In particular, a product is considered to be liquid or pourable if its viscosity, as measured using the method as described in the definitions section, lies below 200 mPa·s. Within the context of the invention, the viscosity is the viscosity as measurable using an Anton Paar Physica MCR301 rheometer with a CP50-1/PC cone (diameter 50 mm, 1° difference between middle and outside) at 20° C. at 100 s−1. In particular for a liquid product that is intended for administration by drinking, or via a straw or tube, the viscosity preferably is 100 mPa·s or less. In a preferred embodiment, the viscosity of a liquid product according the invention as stored before consumption is 1 to 24 mPa·s.
As used herein ‘semi-solids’ are nutritional products comprising 32 to 82 wt % dry mass. Dry mass is defined as the amount of product that remains after drying under the conditions as recommended for that particular food product according to recognized methods as e.g. published most recently by the American Organization of Analytical Chemists. In particular, semi-solids have a viscosity that exceeds the viscosity of a liquid product. Typical examples of semi-solids are puddings, gels, porridges, ice-cream, sandwich spreads, pastes, and products having a similar rheological consistency.
As used herein solids are products comprising less than 18 wt % of water (moisture). Typical examples of solids are powders, food-bars (such as granola bars, candy bars), and the like.
In a specific embodiment, the food product is a medical food. A medical food preferably comprises at least 0.7 g fibre per 100 g product. The fibre preferably content preferably is 0.8 to 1.2 g fibre/100 g for tube feeding. The fibre content preferably is at least 1.2 g to 4.2 g per 100 g sip (or drink) feed.
The protein content of a medical food preferably is less than 10 g, more preferably less than 8.2 g, most preferably less than 6.3 g per 100 g product. Preferably, the medical food has a low glutamine content in the protein fraction, i.e. less than 10 g, preferably 3-9 g per 100 g protein fraction.
The amount of added organic acids in a medical food of the invention usually is less than 0.3 g per 100 ml, preferably less than 0.26 g, more preferably 0.02-0.18 g/100 ml (is declared as “others” in digestible carbohydrate fraction).
Method of Treatment
The invention further relates to a method for prophylactically or therapeutically treating a human in need thereof, the treatment comprising administering an effective amount of a dietary fibre, in combination with a pharmaceutical composition or a nutrition as defined in any of the preceding claims, thereby reducing or avoiding the occurrence of a negative gastro-enteric side-effect of a composition, preferably a medical nutrition or a medicament. The negative side effect preferably selected from those mentioned herein above, in particular, the negative side-effect is a premature sating effect.
In an embodiment, in the method of treatment, the dietary fibre, combination or nutritional composition is administered in a dosage providing 502 kJ or less, in particular in a dosage providing 20.9-502 kJ.
In an embodiment, in the method of treatment the subject in need thereof, is a human, preferably a human having an age of at least 1 years, in particular a human having an age of 2 to 85 years.
In particular, in a method according to the invention the dietary fibre, combination or nutritional composition is administered orally or administered into the gastrointestinal tract in another way, such as by tube-feeding.
When referring herein to a treatment, this generally includes prophylactic treatments and therapeutic treatments, unless specified otherwise. A prophylactic (preventive) treatment generally is aimed at reducing the chance that the treated subject develops a trait, impairment, symptom, disease, side-effect, syndrome or disorder. The effectiveness of a prophylactic treatment can e.g. be determined by comparing the probability that a specific trait (etc to disorder) develops in a sufficiently large in a double blind way according the principles of Good Clinical practices, wherein one part of the group is treated according to the invention and another part is treated with a placebo for a relevant period of time. The skilled person will be able to define suitable conditions for the study, depending on the intended effect.
EXAMPLES Example 1Ready to eat semi-solid product (pudding, porridge or ice cream or sandwich spread or paste or sauce). The product can in particular be used by toddlers & children in the age range of 1-12 year in amounts which are voluntarily acceptable.
Dry product (moisture content is less than 14 wt % in the ready to use product). The product can in particular be used by an adult.
Isolation of the rice bran is done by de-hulling the rice grains, grinding and sieving them. The flour is separated from the fibre fraction.
The rice bran can be further purified by washing it with an alkaline aqueous solution to remove digestible carbohydrates and part of the soluble fibre. Both fractions are of value.
The soluble parts can be subjected to an hydrolysis step using one or more enzymes to decrease molecular weight of the residual fibre, to remove part of the substituents or ferment part of the digestible carbohydrates.
The insoluble parts, when isolated can be subjected to enzymatic hydrolysis to decrease molecular weight and increase solubility.
Example 5 Method to Measure Effect on Satiety of the Dietary FibreThe satiety is measured using a method as disclosed below in a comparative product without the fibre and a product in which an effective amount of the fibre has been included but which is otherwise the same as the comparative product.
The determination of the sating properties of the product can be done by measuring the intensity of one or more sating signals during the first 2 hours after consumption. Suitable biomarkers in blood for such sating signals include of specific sating peptides like CCK, GLP-1, PYY or other parameters known in the art. Measurement of AUC or the release pattern for the first 2 hours allows justified comparison. Alternatively serotonin released in the full blood or blood platelets can be measured.
Stanley et al 2005 Physiol rev 85, 1131-1158 disclose the neuropeptides which are modulating food intake and satiety and refer to methods to measure their postprandial release. In addition the methods as applied in Blom et al, 2005, Am J Clin Nutr 83, 211-220 and in Karhunen et g, 2010 J Nutr, 140, 737-744 can be applied. Obviously the very high viscosity and unpalatability of psyllium as tested by Karhunen make the use of psycllium unsuitable in the manufacture of medical nutrition. In the latter study the choice for this fibre complicated the relation between the concentration of endogenous neuropeptides and desire to eat, hunger, satiety and related phenomena.
When a significant difference is measured between the product with and without the fibre the effect on satiety was considered to be convincing.
The duration of satiety becomes a relevant parameter 2 hours after intake. Proper questionnaires/interviews to assess desire to take new product or feelings of fullness can be applied. Alternatively the moment of voluntary start of consumption of new food can be measures as well as the amount of food that is consumed voluntarily at a fixed time 2-4 hours after intake of the first product. When the urge to eat again would come 10 minutes earlier after consumption of the product with fibre, compared to the product without fibre the fibre is defined to have a inhibiting effect on satiety
Example 6 Multifibre Blend
Cereal fibre other than resistant starch: 4-50 wt % (rice, wheat, oats, corn)
Resistant starch: 3-50 wt % (derived from rice starch)
Fibre from tubers or roots: 5-60 wt % (onion, chicorei, sugar beet, potato)
Fibre from pulses or beans 2-40 wt % (soy, pea, lupin), and
Fibre from vegetable leaves or fruits (banana, apple, citrus fruit): 2-40 wt %
Optionally hydrolyzed fibres (fructo-oligosaccharides, galacto-oligosaccharides, which may be comprised in any of the above fibres, except for ‘resistant starch’.)
In vitro model: the amount and rate of serotonin that is released by enterochromaffin cells is measured, after exposure to a physiological representative sample of the product with and without the active fibre
In an animal model (rats) serotonin release after consumption of the food is measured in blood or in the gut tissue ex-vivo. The activity of the enteric nervous system after food intake can be measured alternatively. The products according the invention will decrease overall release of serotonin and activation of the ENS. The sating properties of the product can be measured as well in animals
Example 9 Medical Nutrition Comprising Multifibreliquid suitable for use as complete medical nutrition, comprising per 100 ml
Protein: 4.0 gDigestible carbohydrates: 12.1 g,
organic acids<0.2 g
Dietary fibre=1.5 g, consisting of a rice fibre (other than resistant starch), resistant starch, inulin and soy fibre
The amounts of minerals (Na, K, Cl, Ca, P, Mg), trace elements (Fe, Zn, Cu, Mn, F, Mo, Se, Cr, I) and vitamins (A, B1, B2. B3. B5, B6, B11, B12, D, biotin) that are included comply with recommendations and FSMP rules.
Choline=37 mg, carotenoids=0.3 mg
Liquid suitable for use as a supplement
Protein: 6 gDigestible carbohydrates: 18.0 g
organic acids 0.4 g or less
Dietary fibre: 2.25 g, wherein the fibre comprises rice fibre (other than resistant starch), resistant starch, beet fibre, and banana fibre
The amounts of minerals (Na, K, Cl, Ca, P, Mg), trace elements (Fe, Zn, Cu, Mn, F, Mo, Se, Cr, I) and vitamins (A, B1, B2. B3. B5, B6, B11, B12, D, biotin) that are included comply with recommendations and FSMP rules.
Medicament comprising 2-100 mg of a serotonin-reuptake inhibitor (SSRI) and 2 g of rice fibre consumed in association with the intake of the SSRI. Examples are Citalopram and Fluoxetin.
Claims
1. Dietary fibre, for use in delaying or otherwise reducing a sating effect of a medical nutrition or of a medicament, wherein the dietary fibre is cereal dietary fibre and the medical nutrition or medicament is for oral or gastro-enteric administration by a human.
2. Dietary fibre for use according to claim 1, wherein the cereal dietary fibre comprises cereal fibre selected from unmodified and modified rice fibres.
3. Dietary fibre for use according to claim 2, wherein the cereal fibre is a rice fibre, provided as rice bran, preferably a rice bran combined with rice germ.
4. Dietary fibre for use according to any of the preceding claims, wherein the medicament is a drug having an inhibitory action on serotonin reuptake, an inhibitory action monoamino oxidation, or an opiate.
5. Dietary fibre for use according to any of the preceding claims, wherein the dietary fibre is for at least 15 wt. % composed of non-acetogenic saccharide units, preferably for at least 60 wt. % composed of non-acetogenic saccharide units, in particular for at least 90% composed of non-acetogenic saccharide units.
6. Dietary fibre for use according to any of the preceding claims, wherein the nutrition contains less than 0.3 g per 100 ml added organic acids, preferably less than 0.26 g, more preferably 0.02-0.18 g/100 ml.
7. Dietary fibre for use according to any of the preceding claims, wherein at least 8 wt. % of the dietary fibre is formed of insoluble fibre molecules, preferably 18-72 wt. %.
8. Dietary fibre for use according to any of the preceding claims, comprising a fibre selected from the group of, xylans, celluloses, hemi-celluloses, beta 1-3 glucans, and lignins.
9. Dietary fibre for use according to claim 8, wherein, the dietary fibre comprises an arabinoxylan.
10. Dietary fibre for use according to any of the preceding claims, wherein the fibre comprises beta-glucans, of which at least 40 wt. % is selected from insoluble beta-glucans and non-branched beta-glucans.
11. Dietary fibre for use according to any of the preceding claims, wherein the fibre forms part of a fluid composition having a viscosity of less than 30 mPa·s at shear rate of 20 at a temperature of 20° C.
12. Dietary fibre for use according to any of the preceding claims, wherein the dietary fibre is to be administered orally before or together with said medicament or nutrition.
13. Dietary fibre for use according to any of the preceding claims, wherein the human to be treated is selected from the group of hospital patients, oncology patients; persons that that are subjected to chemotherapy; persons that are subjected to radiotherapy; institutionalized persons; individuals who experienced stroke or cerebro- or vascular problems; demented persons; persons who experience taste or smell deviations; individuals who are physically impaired such as having a physical handicap, visual impairment, or essential tremor; individuals who have experienced a trauma; persons recovering from surgery; persons experiencing inflammatory processes, such as persons who suffer from an inflamed gut, mucositis or irritated bowel; humans depression, humans having autism, humans having Parkinson's disease, humans suffering from obsessive-compulsive disorder, malnourished people and elderly people.
14. Dietary fibre for use according to any of the preceding claims, wherein the fibre—when administered to a human—is a stimulant of a GPR43 receptor.
15. Dietary fibre blend, optionally for a use as defined in any of the preceding claims, the blend comprising cereal fibre other than resistant starch and gum, and a fibre from at least two, in particular at least three, of the following groups: gums; fibres from tubers or roots preferably other than resistant starch and gums; fibres from pulses or beans preferably other than resistant starch and gums; and fibres from vegetable leaves and fruits preferably other than resistant starch and gums.
16. Dietary fibre blend according to claim 15, further comprising resistant starch.
17. Dietary fibre blend according to claim 15 or 16, wherein—if present—the weight percentage of fibres from said groups, based on the total weight of fibres, is
- 20-80 wt % for the cereal fibre:
- 3-50 wt % for resistant starch:
- 5-60 wt % for the fibre from tubers or roots:
- 2-40 wt % for the fibre from pulses or beans;
- 3-60 wt. % for the gum; and
- 2-40 wt. % for fibre from vegetable leaves or fruits.
18. Dietary fibre blend according to claim 15, 16 or 17, comprising a fibre from an oil seed or nut, other than resistant starch and gum.
19. Dietary fibre blend according to any of the claims 15-18, comprising a fibre selected from the group of polydextrose, fructooligosaccharides and galactooligosaccharides.
20. Dietary fibre blend according to any of the claims 15-19, wherein the gum is partially hydrolysed, and at least 60 wt. % of the gum has a degree of polymerization in the range of 3-10.
21. Food product comprising a dietary fibre blend according to any of the claims 15-20.
22. A pharmaceutical composition comprising a (i) drug having an inhibitory action on serotonin reuptake, an inhibitory action monoamino oxidation, or an opiate; (ii) a dietary fibre or dietary fibre blend; and (iii) a pharmaceutically acceptable excipient, wherein the dietary fibre of dietary fibre blend is as defined in any of the claims 1-21.
23. A medical food product having an energy density of more than 1.67 kJ per gram, the composition comprising dietary fibre or dietary fibre blend as defined in any of the preceding claims in a total relative amount of at least 0.7 g/100 g dietary fibre, and less than 10 g/100 g protein.
24. Medical food product according to claim 23, wherein the product is a fluid.
25. Medical food product according to claim 23 or 24, comprising up to 4 g/100 g lipid, preferably in an amount providing 1-35 en % of the total energy density of the product.
26. Medical food product according to any of the claims 23-25, comprising a lipid fraction, said lipid fraction providing 2-70 g octanoic acid per 100 g fatty acids.
27. Medical food product according to any of the claims 23-26, comprising rice fibre, preferably rice bran, in particular rice bran combined with rice germ.
28. Medical food product according to any of the claims 23-27, wherein the product comprises a tryptophan source.
29. Medical food according to any of the claims 23-28, wherein the medical food has less than 0.3 g per 100 ml added organic acids, preferably less than 0.26 g, more preferably 0.02-0.18 g/100 ml.
30. Medical food according to any of the claims 23-29, wherein the glutamine content in the protein fraction is less than 10 g per 100 g protein, preferably—9 g per 100 g protein fraction.
31. Packaging, in particular a unit-dose packaging, comprising 5-300 g, preferably 12-130 g of a liquid or semi-solid food product according to any of the claim 18 or 20-26.
32. Packaging, in particular a unit-dose packaging, comprising 0.5-10 g of a solid food product according to any of the claim 18 or 20-26.
33. Kit of parts comprising at least two separately packaged components, wherein at least one component comprises a dietary fibre as defined in any of the claim 2-11, or 14 or a dietary fibre blend according to any of the claims 15-19, and wherein the at least one other component comprises an opiate, a drug having an inhibitory action on serotonin reuptake, a drug having an inhibitory action on monoamino oxidation in humans, or a medical food product.
34. Method for prophylactically or therapeutically treating a human in need thereof, the treatment comprising administering an effective amount of a dietary fibre or dietary fibre blend, in combination with a pharmaceutical composition or a nutrition as defined in any of the preceding claims, thereby reducing a sating effect of the pharmaceutical composition or the nutrition.
35. Method according to claim 34, wherein the human in need thereof, is a human having an age of at least 1 years, in particular a human having an age of at least 2 years.
36. Method according to any of the claim 34 or 35, wherein the dietary fibre and the pharmaceutical composition or nutrition is administered orally or administered into the gastrointestinal tract through a tube.
Type: Application
Filed: Jul 5, 2013
Publication Date: Jul 2, 2015
Inventor: Robert Johan Joseph Hageman (Wageningen)
Application Number: 14/412,796
