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    • 专利摘要:
    A pharmaceutical or nutraceutical composition for the prevention or treatment of chronic inflammation and accompanying bio films in the gastrointestinal (MD) tract. The multidimensional clinically tested composition accelerates intestinal epithelium regeneration and destabilizes Gram-negative bacteria in their habitat, but it also eliminates their LPS molecules, which are highly allergenic. The synergistic composition contains a pharmaceutically effective amount of at least L-glutamine with zinc and vitamin A for the repair of the epithelial cells of the gastrointestinal tract, at least enzymes selected from the group of polysaccharidases, proteases, lipases and / or antioxidants, for the degradation of a biofilm present in the intestine, at least one chelator for inorganic components such as iron and at least one binder for organic components resulting from the breakdown of the biofilm and / or bacteria.
    公开号:BE1022759B1
    申请号:E2015/5221
    申请日:2015-04-03
    公开日:2016-08-30
    发明作者:Seyed Saied Bathaei
    申请人:Biotechnobel；
    IPC主号:
    专利说明:

    Composition for prevention and / or treatment of chronic inflammation and associated biofilms in the gastrointestinal tract
    The present invention relates to a pharmaceutical or nutraceutical composition for the prevention and / or treatment of chronic inflammations in the presence of the associated biofilms in the gastrointestinal tract (MD channel). There is often a mutual relationship between biofilms, chronic inflammation of the MD channel and / or dysbiosis in the MD channel.
    Dysbiosis refers to a state of imbalance in the intestinal flora of the human body. The intestinal flora, also called intestinal microflora, consists of a complex of all kinds of microorganisms, including bacteria, yeasts, fungi, viruses and parasites that live in the digestive tract. In contrast to dysbiosis, eubiosis refers to a healthy balance of the microflora in the gastrointestinal tract.
    The intestinal flora is essential for basic biological mechanisms for humans and animals such as digestion, energy production and detoxification.
    Bacteria make up most of the flora in the colon and up to 60% of the dry mass of the stool. There are around 300 to 1000 different species in the intestinal tract, of which around 30 to 40 different species probably represent 99% of the bacterial population.
    Many chronic conditions result from digestive problems and inadequate absorption of nutrients. Good gastrointestinal function is needed to eliminate toxins, pathogenic microbes and undigested food particles from the body to prevent health problems. Nutrients need a specific internal environment in order to be properly digested and transported through the body.
    It is well known that abnormal intestinal microorganisms in the MD channel cause diseases. Research shows that there is a relationship between the MD channel and the neurological, liver and immune systems.
    Eubiosis can vary from person to person. Table 1 shows an example of flora with typical reference values for a condition of eubiosis measured and analyzed in stool. Table 1 shows a typical population of normal bacteria in the stool. Table 2 further shows typical reference values of other factors that can be measured in the stool for a condition of eubiosis, namely intestinal immune function, general intestinal health and inflammatory markers.
    Table 1: Typical reference values of microorganisms that can be measured in stool in a state of eubiosis Aerobic bacterial microflora CFU / g *
    * CFU / g, stool samples were collected and plated on selective media to determine the amount of colony forming units (CFU) per gram of stool; the method and type of selective media are well known.
    To restore and / or maintain a condition of eubiosis, it is usually suggested to administer probiotics and / or prebiotics. International patent application WO 2013/037068 A1 further suggests the use of a synthetic stool preparation containing a mix of bacterial strains for treating disorders of the MD channel, i.e., dysbiosis.
    In the case of dysbiosis, when the intestinal flora is out of balance, the metabolic activity of the intestinal flora changes and the presence of potential pathogenic microorganisms increases.
    This leads to the release of metabolites that are potentially toxic, e.g. endotoxins. For example, lipopolysaccharides (LPS) form part of the cell wall of Gram-negative bacteria, which also play a role in the construction of biofilms (1-2). These metabolites or endotoxins are extremely virulent and lead to a wide range of disorders, the so-called degenerative chronic diseases. Examples are irritable bowel syndrome, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, multiple sclerosis, Parkinson's disease, chronic fatigue, eczema, food allergy, certain cancers, metabolic syndrome, arteriosclerosis, etc. (3).
    Table 2: Typical reference values of a number of immunity markers that can be measured in stool in a state of eubiosis *
    * Pancreatic elastase 1, Calprotectin and slgA are determined by Enzyme-Linked Immuno Sorbent Assay (ELISA) which are well known.
    Intestinal dysbiosis can lead to changes in the intestinal mucosa which increases the permeability of the intestine, resulting in leaky gut syndrome and chronic inflammation of the MD channel. The intestinal mucosa is a barrier that normally only allows well-digested fats, proteins and carbohydrates to be absorbed into the bloodstream. When the intestinal mucosa is damaged, for example by bacterial toxins, it is no longer in good condition. This opens the way for bacteria, viruses, parasites and even undigested food macromolecules. These activate the immune system and often also stimulate it, causing it to secrete inflammatory substances, the so-called cytokines, and the intestinal wall to weaken. This leads to chronic inflammation and hence to a whole series of disorders. The stimulated immune system can also become so unstable that it results in autoimmune diseases.
    Bowel dysbiosis often leads to the formation of biofilms by pathogenic bacteria. These biofilms protect the pathogenic bacteria, resulting in chronic infections that are difficult to eradicate. Gram-negative bacteria in particular have a strong tendency to make bio films.
    With its wide range of moist surfaces and mucosal tissue, the human body is a place where bio films thrive. The bacteria present in a biofilm are considerably more likely to evade the battery cells of the immune system, which will more easily attack free-living microbial cells. The bacterial biofilms seem to have a lot of potential to cause human diseases such as common infections, including urinary tract infections caused by E. coli and other pathogens, catheter infections caused by Staphylococcus aureus and other Gram-positive pathogens, common dental plaque formation and gum disease ( 4-6).
    There is a 'biofilm cycle' that starts with the attachment of the bacteria over colony formation to the formation of the biofilm, maturation and release of the bacteria. This cycle can take weeks or months. The acute inflammatory phase makes it impossible for the immune system to correct the problem and eliminate the infection.
    In an attempt to tackle the bacterial biofilms, high and constant doses of antibiotics are administered to patients. Unfortunately, even when administered in high doses, the antibiotics can only temporarily weaken the biofilm and are generally unable to completely destroy it. Inevitably, a number of bacterial cells continue to survive in the remaining biofilm, allowing the biofilm to regain strength. Often the regenerated biofilm contains bacteria with an increased resistance.
    International patent application WO 2011/063394 A1 proposes an interesting composition for eliminating biofilms in, for example, the gastrointestinal tract. The proposed composition contains predominantly enzymes to degrade the biofilm. However, it does not offer a solution to prevent subsequent rapid regeneration of a new biofilm, which is likely to occur after the degradation of the biofilm.
    According to the gut dysbiosis hypothesis, a number of factors associated with a modern lifestyle have an adverse effect on the microflora in the gastrointestinal tract. Factors such as antibiotics, psychological and physical stress, certain food ingredients such as food additives (such as 'azo' colorants or certain flavorings), and chemical products such as pesticides, herbicides, fungicides or insecticides have been found to contribute to intestinal dysbiosis (7-8).
    The longer we live, the greater the likelihood that such an accident will occur, leading to a permanent condition of dysbiosis.
    It is an object of the present invention to provide a pharmaceutical or nutraceutical composition for the prevention and / or treatment of chronic inflammation of the gastrointestinal tract (MD channel) and / or bio films in the MD channel, often associated with e.g. dysbiosis. The treatment of biofilms involves disrupting and removing the biofilm from the MD channel and further preventing the biofilm from recovering. It is a further object of the invention to restore eubiosis in addition to a healthy intestinal epithelium (enterocyte) with normal permeability.
    To this end, the present invention provides a pharmaceutical composition for preventing and / or treating biofilms in the gastrointestinal tract, for eliminating pathogenic bacteria and their allergenic bodies, ie debris, as well as their endotoxins, and further for recovering the gastrointestinal epithelium. (enterocyte) and repopulating the MD channel with healthy flora, what we call eubiosis, as set out in the appended claims.
    As such, the composition of the invention comprises (z) enzymes selected from the group of polysaccharidases, proteases, lipases and / or antioxidant enzymes for the degradation of a biofilm present in the gut; (; ii) at least one chelator, comprising lactoferrin, for binding inorganic components such as iron; and (iii) at least one binder, for binding organic components derived from the degradation of the biofilm and / or bacteria; (zv) glutamine, vitamin A, vitamin D and zinc, to promote the recovery of the mucosal cells in the intestines.
    According to an interesting embodiment, the composition further comprises chitosan, for an antibacterial action against Gram-negative bacteria.
    According to another interesting embodiment, the composition further comprises Rosmarinus officinalis extract to decrease the action and adhesion of the biofilm.
    According to a further interesting embodiment, the composition comprises at least one binder for binding organic components originating from the degradation of the biofilm and at least one binder for binding organic components originating from the degradation of bacteria from the biofilm.
    According to a preferred further interesting embodiment, the composition comprises - at least one binder for binding organic components from the degradation of the biofilm selected from the group of inositol and / or rice bran or a combination thereof; - at least one binder for binding organic components from the degradation of bacteria of the biofilm selected from the group of Punica granatum extract, Citrus aurantium extract, Quercus rubra extract and / or Quercus petraea extract, or a combination thereof; and - at least one binder for binding organic components derived from the degradation of bacteria of the biofilm selected from the group of phosphatidylcholine and / or magnesium or a combination thereof;
    The composition may further also contain interesting compounds such as anti-inflammatory ingredients, even more vitamins, active carbon and / or Pistacia lentiscus resin.
    According to the invention, the ingredients of the composition may be presented as a food supplement, functional food ingredients or as pharmaceutical ingredients to prepare a composition for oral administration for the prevention and / or treatment of biofilms in the MD channel and / or chronic inflammation of the MD. channel.
    Details and advantages of the invention will become apparent from the following description and practical embodiments of the composition according to the invention; the description and practical embodiments are given by way of example only and in no way limit the scope of the claimed invention.
    The present invention provides a synergistic composition for oral administration to treat chronic inflammation of the gastrointestinal tract and to destabilize biofilms containing and protecting harmful microorganisms in the intestinal tract, and subsequently also the normal intestinal flora and the epithelium (enterocytes) ) to recover. In addition to destabilizing and disrupting the biofilm, in order to reduce the chronic inflammation of the gastrointestinal tract, the composition according to the invention also enables the recovery of the immune system (such as secretory immunoglobulin A: slgA and intestinal alkaline phosphatase) and thus makes it possible to control the bacterial flora.
    Due to the complexity of the composition, it may be necessary to administer the components via separate mixtures or capsules. Polysaccharidases, for example, are preferably not mixed with their substrate, e.g. rice bran. The possible incompatibility of different ingredients of the composition is known per se to those skilled in the art.
    The composition according to the invention is a multidimensional and therefore synergistic composition for destabilizing and disrupting biofilms and restoring a state of eubiosis that acts in three different areas: I. disrupting the biofilm; II. decrease pathogenic bacteria by destroying the cell wall, in particular Gram-negative bacteria; and III. accelerate the recovery of the intestinal epithelium.
    Once the biofilm has been eliminated, it is useful to further create the necessary conditions for a balanced intestinal flora in the MD channel to achieve a stable state of eubiosis. Conditions for the recovery of the colon epithelium and the promotion of a balanced flora are known, for example, from European patent application EP 2 478 779 A1. However, creating optimum conditions for a condition of eubiosis to restore balance in the bacterial gut flora is not sufficient to maintain a stable condition of eubiosis when a biofilm is present. I. disrupting the biofilm
    Creating the right conditions for a healthy bacterial flora is sometimes not sufficient if pathogenic bacteria, in particular Gram-negative bacteria, are hidden in a biofilm. With an abundance of pathogenic bacteria, the chance of forming a biofilm is high, since many of these pathogenic bacteria tend to produce biofilms. According to the present invention, a series of natural ingredients are used to destabilize and disrupt these bio films.
    The biofilm is predominantly composed of exopolysaccharide, i.e. polysaccharides, homopolysaccharides and heteropolysaccharides, organic substituents such as acyl, and inorganic substituents such as phosphate or sulfate. It was recently discovered that proteins associated with biofilms also exist.
    The biofilm is preferably at least partially detached from the intestinal wall thanks to an anti-adhesive effect of Rosmarinus officinalis extract.
    Rosmarinus officinalis extmct also prevents the formation of a new biofilm with Gram-negative bacteria that have escaped from the biofilm.
    The biofilm is then attacked by a series of enzymes and by taking away food that is essential for the construction of biofilms. Hence, enzymes and chelators are used in the composition to destabilize the biofilm. The destabilization of the biofilm leads to the release of pathogenic bacteria, in particular Gram-negative bacteria, which are present in the biofilm. After the release of Gram-negative bacteria from the biofilm, it becomes easier to attack and destroy these potentially pathogenic bacteria.
    The exopolysaccharides are attacked and disrupted with polysaccharidase enzymes such as, for example, alpha-amylase, beta-amylase, glucosamylase, alpha-galactosidase, invertase, maltase, cellulose, hemicellulose, xylanase, pectinase, pectinesterase or pull dextranase.
    The protein component is hydrolyzed by proteases such as e.g. bromelain, papain, ficin and / or other proteases, preferably of vegetable origin.
    The bound esters and acyl groups are hydrolyzed by lipolytic enzymes such as, for example, lipases and phospholipases.
    The inorganic Substituents required for the production of biofilms are neutralized by complexation with chelators and binders such as, for example, inositol, rice bran and / or lactoferrin. Iron is essential for the activity of microorganisms, especially Gram-negative bacteria, which produce biofilms. Iron can be neutralized by, for example, lactoferrin. II. decrease pathogenic bacteria and immunogenic substances
    Potentially pathogenic bacteria and also immunogenic substances from these bacteria, which are released from the disturbed biofilm, must be neutralized to prevent the intestinal flora from being exposed to large amounts of potentially pathogenic bacteria and / or to prevent an excessive immune response.
    Breaking down the biofilm will inevitably lead to a high risk of, for example, life-threatening inflammatory reactions, an exaggerated immune reaction, diarrhea, endotoxemia and / or septic shock due to the release of endotoxins.
    The organic components resulting from the degradation of the biofilm are neutralized with a view to their evacuation by complexing with binders such as inositol and rice bran.
    The release of bacteria from the biofilm will then lead to an intestinal microflora that is susceptible to a transition to a state of dysbiosis. The condition of dysbiosis once again increases the risk of the formation of a biofilm.
    Antibiotics could be used to decrease the presence of pathogenic bacteria, but they also do a lot of damage to the good bacterial flora, making the recovery of the good bacterial flora more difficult.
    Lipopolysaccharide (LPS), the major component of endotoxin, is present in the outer membrane of Gram-negative bacteria and triggers an immune response through interaction with LPS receptors on the surface of immune cells (5). If too much endotoxin is released in the presence of an overwhelming Gram-negative bacterial infection, it can contribute to life-threatening inflammatory reactions, exaggerated immune reactions, diarrhea, endotoxemia and / or septic shock. LPS can also play an important role in suppressing the activity of lipoprotein lipase (LPL). This leads to hypertriglyceridemia. Cell wall LPS of Gram-negative bacteria is preferably attacked systematically by one or more components selected from the group of, for example: polysaccharidase enzymes, proteolytic enzymes, lipolytic enzymes, magnesium, polyphenols, tannins, chitosan, lactoferrin, EDTA and / or activated carbon.
    Polysaccharidase enzymes attack and hydrolyze the polysaccharide particles of the LPS formed from the O-antigen, the outer core and the inner core. Suitable polysaccharidases are alpha amylase, beta amylase, amyloglucosidase, alpha galactosidase, invertase, maltase, cellulase, lactase, hemicellulase, pectinase, xylanase, dextranase and / or pullulanase.
    Proteolytic enzymes hydrolyze the protein part of the bacterial cell wall. Various types of proteases such as plant proteases / cysteine proteases, e.g. bromelain, papain and / or ficin are suitable.
    Lipolytic enzymes hydrolyze the lipid A of the LPS. Lipid A is responsible for the toxicity of Gram-negative bacteria and is a very powerful stimulant for the immune system. According to the present invention, it is recommended to eliminate lipid A for the protection of the immune system and to prevent an exaggerated immune response. In the composition according to the invention, proteases are preferably always combined with lipase to attack the cell wall LPS of the Gram-negative bacteria.
    Magnesium connects with the phosphate part of the inner core (phospholipid) and thereby neutralizes it.
    Polyphenols present in plant extracts such as, for example, Punica granatum extract (pomegranate), Rosmarinus officinalis extract (rosemary), Citrus aurantium extract, Quercus rubra extract, and / or Quercus petraea extract connect the above polysaccharide particles and thus make them ready for evacuation through the stool. These components are also known for their anti-inflammatory and / or antioxidant effects. In the case of dysbiosis, when the intestine is chronically inflamed, the anti-inflammatory and / or antioxidant effects of the polyphenols in plant extracts form interesting properties. In addition, these effects are also obtained by superoxide dismutase and catalase in the composition.
    Rosmarinus officinalis extract can inhibit the formation of the bacterial biofilm by limiting its activity and its adhesion to the intestinal wall. Rosmarinus officinalis extract is also known as an antioxidant. Numerous studies have shown that Rosmarinus officinalis extract cleans up free radicals to a large extent and also has a positive effect on maintaining the stability of the lipid membrane. It has also been shown to be an effective antibiotic against a large number of bacterial strains.
    Tannins present in plant extracts such as, for example, Quercus rubra extract, Quercus petraea extract and / or ellagitannin from Punica granatum, form complexes with proteins, starch, cellulose, polysaccharides and / or minerals. Tannin compounds were found to interfere with bacterial adhesion by blocking LPS receptors. Tannins are naturally occurring plant polyphenols such as, for example, ellagitinin from Punica granatum, Quercus petraea and Quercus rubra. Their main characteristic is that they bind to proteins and precipitate them or that they form complexes with polysaccharides. After precipitation, these components are discharged via the stool. Ellagitannin from Punica granatum also has an inhibitory effect on the LPS-induced inflammatory response (9). Punica granatum bark extracts have been shown to exhibit significant antibacterial activity for Gram-positive and Gram-negative bacteria (11). Horvath (10) gave one of the most satisfactory definitions of tannins: "Any phenolic compound of sufficient molecular weight that contains sufficient hydroxyls and other suitable groups, especially carboxyls, to form sufficiently strong complexes with proteins and other macromolecules among the specific studied environmental conditions ".
    Chitosan has an antibacterial effect against Gram-negative bacteria in particular. As such, chitosan is an interesting optional ingredient in the composition for selectively suppressing Gram-negative bacteria. In comparison with Gram-positive bacteria, Gram-negative bacteria are more hydrophilic and have more negatively charged cell surfaces that show a greater interaction with chitosan. Consequently, chitosan has a preferred antibacterial activity against Gram-negative bacteria. Chitosan increases the permeability of the outer membrane and ultimately disrupts the bacterial cell membranes. The damage is probably caused by the electrostatic interaction between NH3 + groups of chitosan and carbonyl or phosphoryl groups of phospholipid components of cell membranes (12-13).
    Lactoferrin binds free iron and has an influence on the bacterial membranes. The main role of lactoferrin is to sequester free iron and thereby remove an essential substrate required for bacterial growth and the formation of biofilms. The antibacterial effect of lactoferrin is also explained by the presence of specific receptors on the cell surface of microorganisms. Lactoferrin binds to the lipopolysaccharides (LPS) of bacterial cell walls, and the oxidized iron portion of the lactoferrin oxidizes bacteria via the formation of peroxides. This influences the membrane permeability and results in cell lysis. Lactoferrin is therefore an interesting component in the composition because of its selective antibacterial effect and its approach to the biofilm.
    After the degradation of the LPS and the release of the abundant anionic groups, lipid A and oligosaccharides, these fragments can be closely linked by electrostatic interactions with divalent cations such as Mg 2+. The negatively charged groups are selective targets for cationic Mg2 + and also for antimicrobial peptides.
    Activated carbon absorbs harmful substances, eg toxins from the debris of Gram-negative bacteria, in the gastrointestinal tract to eliminate them and evacuate them through bowel movements.
    Therefore, various components of the LPS are broken down, collected and discharged through the bowel movements.
    Addition of Pistacia lentiscus resin lowers the pH of the colon due to the production of organic acids through bacterial fermentation. The decreased pH creates an environment that is both hostile to the survival of urease-producing intestinal flora, such as the Klebsiella species (spp) and Proteus spp, and promotes the growth of acid-resistant, non-urease-producing species such as lactobacilli and bifidobacteria, resulting in a reduced production of ammonia in the lumen of the colon. The acidification of the colon secretion also reduces the absorption of ammonia through non-ionic diffusion.
    Furthermore, the optional provision of prebiotic fibers, which are preferably digested and used by the good gut flora and which are known per se, helps to recolonize the gut with a balanced gut flora in order to achieve a state of eubiosis in the MD channel. Moreover, the provision of prebiotic fibers and nutrients, which are preferably digested and used by both humans and the beneficial flora in the intestinal tract and which are known per se, stimulates the beneficial flora in the intestinal tract. III. restore intestinal epithelium to restore immune defense
    The immune system is undermined by the presence of harmful microorganisms in the biofilm and the resulting leaks in the intestine. Tight seams are no longer intact, causing intestinal contents to leak into the body and the immune system to become overloaded.
    The composition according to the invention therefore treats intestinal permeability with ingredients such as vitamin A, glutamine, zinc, Punica granatum extract, Curcuma longa extract, catalase, superoxide dismutase and vitamin B6. Another support for the immune system is the administration of antioxidants such as catalase, Punica granatum extract, Citrus aurantium-cx tract, Rosmarinus officinalis extiact, Superoxide dismutase. Inflammation is the result of an immune response and causes the immune system to react to itself. It is important to break this vicious circle.
    When looking for ways to prevent excessive growth of bacteria, the key lies in the natural allies of the immune system. Immune protection goes together with a healthy intestinal wall.
    An excessive growth of bacteria can even lead to even more damage to the protective endothelial lining of the intestine. Bacteria produce their own enzymes, which destroy the protective mucus of the intestinal mucosa. Increased intestinal permeability is observed in various autoimmune diseases. Recovery of the intestinal epithelium is important for the immune system to function normally again, in particular the recovery of the intestinal alkaline phosphatase and the secretory immunoglobulin A (slgA). Several studies have shown that the intestinal alkaline phosphatase enzyme can dephosphorylate and neutralize the endotoxin component of LPS, presumably through dephosphorylation of the lipid A moiety, the major source of endotoxic effects.
    Intestinal alkaline phosphatase (IAP) is an intestinal brush boryme enzyme that has been shown to act as a defensive factor for the intestinal mucosa.
    Inflammatory bowel disease is characterized by chronic inflammation of the gut and is accompanied by damage to the epithelial lining and undesirable immune responses to enteric bacteria. Intestinal alkaline phosphatase (IAP) has been shown to protect against the induction of inflammation, possibly through dephosphorylation of lipopolysaccharides (LPS). Consequently, the intestinal alkaline phosphatase contributes to the reduction of severe inflammation and maintains the normal homeostasis of the intestinal flora.
    It has already been shown that intestinal alkaline phosphatase (IAP), a small intestinal brush borzyme enzyme, acts as a defense factor for the intestinal mucosa that limits the transfer of bacteria from the intestine to mesenteric lymph nodes.
    Secretory IgA (slgA) is the main category of antibodies found in intestinal juices, although slgA acts as the first line of defense in protecting the intestinal epithelium against enteric toxins and pathogenic microorganisms.
    Intestinal permeability lowers the effect of the mucosal epithelial barrier as well as the activity of the intestinal alkaline phosphatase (IAP) and secretory IgA (slgA).
    New epithelium is created every 2 to 5 days. Providing proper nutrition to the small intestine cells is therefore useful to help heal the lining of the intestine. Restoring the intestinal epithelium also restores the initial antibacterial effect of slgA and IAP.
    Regeneration of the intestinal epithelium, including enterocytes, is preferably achieved by providing a combination of components selected from the group of, for example: glutamine, Curcuma longa, Punica granatum extract, phosphatidylcholine, vitamin B9, vitamin A, vitamin C, vitamin D, vitamin B6, vitamin B12, zinc, magnesium, superoxide dismutase (SOD) and / or catalase.
    Glutamine, in particular L-glutamine, is the most important nutrient to support the recovery of the intestinal mucosa. It is the preferred fuel and source of nitrogen for the small intestine. Glutamine improves intestinal epithelial cell functions, intestinal flora proliferation and cellular differentiation and helps further reduce infections. Glutamine is an important source of energy for enterocytes, but also for other cells that renew rapidly, in particular immune cells such as lymphocytes and macrophages. Glutamine controls the stimulation and proliferation of the intestinal epithelial cells via their specific growth factor, the Epidermal Growth Factor I (EGF). It increases the effects of the growth factors responsible for the repair and proliferation of the cells.
    Curcuma longa turmeric has powerful anti-inflammatory effects. Turmeric has an antioxidant, antiviral and antifungal effect. Turmeric is also a powerful immunomodulator. A combination of glutamine and turmeric is interesting in view of their complementary mechanical properties, which correspond well with the pathological disorders that characterize intestinal epithelial cell damage.
    Punica granatum extract is rich in punicalagine and has powerful anti-inflammatory effects on the human gut epithelium. It could also be an interesting natural source to help prevent chronic inflammation of the gut.
    Phosphatidylcholine is an anti-inflammatory and surface hydrophobicity enhancing compound with promising therapeutic potential for the treatment of inflammatory bowel diseases.
    Vitamin B9, also known as folic acid, folacin and / or folate, contributes to the proper functioning of the intestinal mucosa.
    Vitamin A supplements temper the intestinal inflammation. Two important mechanisms that appear to play a role in preventing bowel inflammation are the effect of vitamin A on the immune system and the effect of vitamin A on safeguarding the intact condition of the intestinal epithelium. Retinol appears to be important for the renewal of the epithelium and contributes to its maintenance. Together with zinc, it improves intestinal permeability.
    The inhibitory effects of vitamin D on colitis are known. Epidemiological studies have shown that low levels of vitamin D are common in inflammatory bowel diseases (IBD - Inflamatory Bowl Disease).
    Vitamin C reacts with free radicals and can act as an antioxidant. It regenerates vitamin E, a protective antioxidant present in the cell membrane.
    Vitamin B6 plays a role in the metabolism of proteins, carbohydrates and lipids. It is a cofactor of various metabolic enzymes. Vitamin B6 is important for the assimilation of magnesium and the absorption of amino acids. It stimulates the immune system, is important for the regulation of tissue production and has an antioxidant effect. Vitamin B6 and zinc are needed to keep the intestinal wall intact.
    Zinc is a crucial nutrient for the intestinal mucosa. A shortage of zinc disrupts the full growth of the body and is the cause of considerable reductions in the protein content in the intestinal mucosa. Zinc plays an important role in the healing of tissues. It is a cofactor in many enzymatic systems, essential for protein synthesis, cell proliferation, genetic expression of growth factors and steroid receptors. Zinc forms the last line of defense against oxidation of the sulfhydryl groups of the cell membrane. In addition, it inhibits bacterial lipase, reduces intestinal hyperpermeability and increases the rate of prostaglandin E1 (PGE1) in the gut, which is beneficial for immune function.
    Superoxide dismutase (SOD) and catalase are examples of suitable antioxidant enzymes that can be used in the composition of the invention. The use of superoxide dismutase (SOD) and catalase has beneficial effects on the chronic inflammation of the colon. SOD supplements also reduce the intestinal inflammation induced by pathogenic bacteria. The role of free radicals in certain gastrointestinal disorders and inflammatory bowel diseases emerged from a number of studies. Crohn's disease is characterized by the chronic inflammation of the gastrointestinal mucosa. Several studies show the importance of the anti-inflammatory effect of SOD on intestinal inflammation.
    The composition according to the invention can vary. Preferably the amount of enzymes, including catalase and SOD, is at least 10% to about 40% by weight of the composition.
    The composition is optimal if a number of different types of enzymes are present. Preferably, polysaccharidases are present in the composition in an amount of 5 to 25% by weight, proteases typically represent 5 to 25% by weight in the composition, and lipases represent between 3 and 15% by weight in the composition. Finally, antioxidant enzymes preferably represent a maximum of 15% by weight in the composition.
    Vitamins and minerals are preferably present in an amount between 3 and 15% by weight of the composition. Glutamine is preferably present in an amount of up to 20% by weight of the composition.
    Complexing substances and chelators can represent up to 40% by weight of the composition.
    Furthermore, other excipients such as dietary fibers, prebiotic fibers can be used as bulk material in the composition.
    Despite their main function in the composition, the various components of the composition can perform multiple activities such as, for example, chelating, binding, an antioxidant, antibacterial and / or anti-inflammatory effect.
    A preferred composition according to the invention contains at least - polysaccharidases, proteases, lipases and / or antioxidant enzymes for degrading a biofilm present in the MD channel, - lactoferrin as a chelator for binding inorganic components such as iron, - Rosmarinus officinalis - extract for its anti-adhesive effect on the biofilm, - glutamine, vitamin A, vitamin D and zinc to promote the recovery of the intestinal mucosal cells, and - chitosan for an antibacterial effect against Gram-negative bacteria.
    Preferably a composition according to the invention is administered twice a day between meals in an amount of about 2.5 to 3.0 grams.
    The composition can be administered in powder form, capsules, tablets and / or liquid or solid form. It can be used in, for example, cookies, a cookie filling or soup.
    Table 4a is an example of a typical composition according to a first embodiment of the invention. Tables 4b, 4c and 4d are examples of different compositions according to further embodiments of the invention.
    Table 5 shows a specific test composition according to a fifth embodiment of the invention wherein the composition contains four groups of ingredients (a), (b), (c) and (d). Ingredients of group (a) are intended to stimulate the recovery of the intestinal epithelium and they could be administered for that purpose. to patients, regardless of the other groups of ingredients.
    The test composition according to Table 5 was administered twice a day between meals in an amount of 3.0 grams for a test treatment of 135 patients over a 90-day period. All patients suffered from dysbiosis.
    For practical and stability reasons, the different ingredients were spread over different capsules.
    Table 6 shows the results of the bacterial analysis of the stool of the test patient group before and after the 90-day test treatment. The values are average values for the 135 patients with a standard deviation as indicated in Table 6.
    Table 4a: Example of a typical composition according to a first embodiment of the invention.
    Initially, prior to treatment, the flora exhibits a change in the balance of the intestinal flora that indicates a condition of dysbiosis. The resident flora, including e.g. Escherichia coli, Enterococcus spp., Bacteroides spp., Lactobacillus, Bifidobacterium, were underrepresented in all patients suffering from dysbiosis.
    Table 4b: Example of a typical composition according to a second embodiment of the invention.
    Table 4c: Example of a typical composition according to a third embodiment of the invention.
    Table 4d: Example of a typical composition according to a fourth embodiment of the invention.
    Table 5: Example of a specific test composition according to a fifth embodiment of the invention, wherein the composition contains four groups of ingredients (a), (b), (c) and (d).
    Table 6: Bacterial analysis of stool during test treatment in a group of 135 patients.
    P <0.01; * N is the number of patients out of 135 tested; ** CFU / g, stool samples collected and plated on selective media to determine the amount of colony forming units (CFU) per gram of stool; the method and type of selective media are well known.
    Prior to treatment, a significant colonization of potentially pathogenic microorganisms, including Gram-negative and optional anaerobic bacteria, was observed in the colon.
    After 90 days of treatment, the results were as follows: - a sharp decrease in pathogenic microorganisms in the composition of the colon flora; - an increase in resident beneficial microorganisms; - a balance in the transit flora and the resident flora; the transit flora contains, for example, Enterobacteriaceae, Enterococcus, Pseudomonas, Yersinia pestis, Klebsiella oxytoca, Proteus spp, Citrobacter spp ,.
    We can therefore conclude that after 90 days of treatment, the condition of eubiosis was restored in all patients.
    The presence of virulence factors in the stool of the 135 patients was also analyzed before and after the test treatment. The results are shown in Tables 7 and 8. These virulence factors are molecules that have been expressed and secreted by pathogens, including bacteria, viruses, fungi and protozoa, with which they can achieve the following (14-15): - immuno- evasion, ie evasion of the host's immune response; immunosuppression, i.e. inhibition of the host's immune response; - entering and leaving the cells in case the pathogen is intracellular; - receive food from the host.
    Table 7: Analysis of virulence factors (extracellular enzymes) during a test treatment in a group of 135 patients, before the start of the test treatment.
    * N is the number of 135 patients tested; +, present, detected; -, absent, not detected.
    Table 8: Analysis of virulence factors (extracellular enzymes) during test treatment in a group of 135 patients, after 90 days of test treatment.
    * N is the number of 135 patients tested; +, present, detected; -, absent, not detected.
    Extracellular enzymes secreted by pathogenic bacteria are considered to be one of the most important types of virulence factors (16).
    An increase in one or more virulent factors, produced by pathogenic bacteria, is therefore an indication of intestinal dysbiosis.
    Based on the results, patients are classified into 8 categories depending on the presence and combination of indications of virulence. After 90 days of treatment, the results of the analyzes with regard to the virulence factors are negative for almost all patients. The results indicate an equilibrium in the gut microbiota, i.e. a state of eubiosis and consequently a decrease in dysbiosis.
    Immunological markers in the stool of the 135 patients were also analyzed before and after the test treatment. The results are shown in Table 9. Prior to the test treatment, there were very few gut immunity markers, confirming that gut immunity was weak due to gut permeability and dysbiosis.
    Table 9: Analysis of immunological markers in stool before and after test treatment in a group of 135 patients.
    P <0.01; * N is the number of 135 patients tested.
    After the 90-day test treatment with the test composition, the results are as follows: - increase in secretory IgA (slgA); - increase in beta-defensin; - decreased activity of alpha antitrypsin; - decreased activity of calprotectin.
    The increase in secretory IgA (slgA) is due to: - decreased infection by antigens, endotoxins and certain proteins; - recovery of the intestinal mucosa; - reduced intestinal permeability; - reduced dysbiosis; - Increased performance of the intestinal mucosa. Human beta defensins are an essential part of the intestinal lumen in the innate immunity. Increased human beta-defensin-2 levels indicate activation of the innate immune system, especially in patients suffering from irritable bowel syndrome.
    The decrease in beta-defensin-2 is due to: - reduced infection by pathogenic bacteria; - reduced inflammation in the intestinal epithelium; - decreased response to IL-1 or lipopolysaccharide (LPS); - increase in innate immunity; equilibrium of the gut microbiota, i.e. eubiosis; - reduced intestinal permeability; - reduced dysbiosis.
    Increased alpha-1-antitrypsin clearance suggests an excessive gastrointestinal protein loss.
    The fecal decrease in alpha antitrypsin 1 is due to: - decreased intestinal permeability; - reduced inflammation in the intestinal epithelium; equilibrium of the gut microbiota, i.e. eubiosis; - reduced dysbiosis.
    The faecal calprotectin test is a powerful marker of intestinal inflammation. It is considerably higher in patients with inflammatory bowel disease (IBD). The decrease in faecal calprotectin is due to: - greatly reduced inflammation of the intestinal epithelium; - reduced intestinal hyperpermeability; equilibrium of the gut microbiota, i.e. eubiosis; - reduced dysbiosis.
    The initially elevated pH, i.e. before the test treatment, indicates an alkalization of the colon. This is the result of a significant decrease in bacteria such as Lactobacillus and Bifidobacterium and a low production content of short-chain fatty acids (SCFA). An increased pH allows the proliferation of pathogenic bacteria such as E. coli and Clostridium, etc. The decrease in faecal pH after the 90-day test treatment indicates: - proliferation of bacteria such as Lactobacillus and Bifidobacterium ·, - production of short-chain fatty acids by fermenting bacteria responsible for a decrease in intestinal pH; - slowing down the proliferation of pathogenic micro-organisms, reduced production of ammonia, phenols and indoles and the number of sulfur compounds that are considered to be harmful to health.
    The purpose of determining fecal elastase E1, commonly known as fecal elastase, is to evaluate the proteolytic activity of fecal pancreatic origin. In contrast to the chymotrypsin test, it is not an immune test and a measure of proteolytic activity.
    Hence, only if the immune system is massively supported will the disruption of the biofilm have a lasting effect.
    The combination of supporting the immune system, breaking down the biofilms and putting harmful bacteria under pressure makes the immune system strong again, as the test results show. Measurements in the relief of slgA, beta-defensin and fecal calprotectin prove that the bacterial flora returns to the reference value and that the intestinal inflammation decreases to a normal state.
    The present invention is not limited to the compositions of the embodiments according to the invention as described above. The synergistic function of different ingredients has been made clear on the basis of the description. Therefore, according to the invention, various ingredients included in the compositions of the described embodiments can be combined into further compositions that fall within the scope of the present invention. As such, for example, Pistacia lentiscus-h &amp; rs included in the composition of the second embodiment can be added to the compositions of the other embodiments; active carbon can be added to the second embodiment.
    REFERENCES 1. Caroline Roper et al. (2010) "The role of lipopolysaccharides in virulence, biofilm, formation, and host specificity of Xylella Fastidiosa". Dept. or Plant Pathol. &amp; Microbiol. University of California Riverside. 2. Ce'cilia De Araujo et al. "Quorum sensing affects biofilm formation through lipopolysaccharide synthesis in Klebsiella pneumoniae". Research in Microhiology. Volume 161, Issue 7, September 2010, Pages 595-603 3. Jason A. Hawrelak, BNat (Hons), PhD Candidate and Stephen P. Myers, PhD, BMed, ND, (2004) "The causes of Intestinal Dysbiosis: a Review ", Alternative Medicine Review. Volume 9, Number 2. 4. Ian W. Sutherland. (2001). "Biofilm exopolysaccharides: a strong and sticky frame fork", A // croo / o / og)>, 147.3-9 5. Tamilvanan Shunmugaperumal. (2010). "Biofilm accreditation and prevention, Pharmaceutical Approach to Medical Device Infections"., A JOHN WILEY &amp; SONS, INC. PUBLICATION., 2010. 6. Medical Microbiology, 4th Edition, Edited by Samuel Baron. Adapter 7 Bacterial Pathogenesis Johnny W. Peterson University of Texas Medical Branch at Galveston, Galveston, Texas Galveston (TX): University of Texas Medical Branch at Galveston; 1996. ISBN-10: 0-9631172-1-1. 7. Jason A. Hawrelak, BNat (Hons), PhD Candidate and Stephen P. Myers, PhD, BMed, ND, "The Causes of Intestinal Dysbiosis: a Review", Alternative Medicine Review _ Volume 9, Number 2 _ 2004 8. Lewis, K. (2001). Riddle or biofilm resistance. Antimicrobial agents and chemotherapy, 45 (4), 9991007. 9. Shanmugam K. et al. (2008) "Plant-derived polyphenols attenuate lipopolysaccharide-induced nitric oxide and tumor necrosis factor production in murine microglia and macrophages". Biochemistry and Molecular Biology, Apr; 52 (4): 427-38. 10. Horvath P J. 1981. The nutritional and ecological significance of acute tannins and related polyphenols. MSc thesis, Comell University, Ithaca, New York, USA. 11. H. Kadi, A. et al. (2011) "Antibacterial activity of ethanolic and aqueous extracts or Punica Granatum L. Bark", Journal of applied Pharmaceutical Science, 01 (10); 2011: 180-182. 12. Chitosan as an antimicrobial compound: Modes of action and resistance mechanisms Dissertation of Erlangung des Doktorgrades (Dr. rer. Nat.) Der MathematischNaturwissenschaftlichen Fakultät der
    Rheinischen FriedrichWilhelmsUniversität Bonnvorgelegt von Dina Raafat Gouda Fouad aus Alexandria / Ägypten; Bonn 2008. 13. Liu Hong-tao, et al. (2011) "Chitosan oligosaccharides suppress LPS-induced IL-8 expression in human umbilical vein endothelial cells through blockade of p38 and Akt protein kinases" Acta Pharmacol Sin. 2011 Apr; 32 (4): 478-86. 14. Arturo Casadeval and Liise-anne Pirofski, "Virulence factors and their mechanisms of action: the view of a damage-response framework", Journal of Water and Health, 07.51, 2009. 15. Medical Microbiology, 4th edition, Edited by Samuel Baron.Chapter 7 Bacterial Pathogenesis Johnny W. Peterson University of Texas Medical Branch at Galveston, Galveston, Texas Galveston (TX): University of Texas Medical Branch at Galveston; 1996. 16. Salmond G. P. (1994). "Seclusion of Extracellular Virulence Factors by Plant Pathogenic Bacteria". Annual Review of Phytopathology Vol. 32: 181-200.
    权利要求:
    Claims (23)
    [1]
    CONCLUSIONS
    A pharmaceutical composition for use in the treatment of chronic inflammation of the gastrointestinal tract containing a pharmaceutically effective amount of at least (i) enzymes selected from the group of polysaccharidases, proteases, lipases and / or antioxidant enzymes capable of to break down a biofilm present in the gut; (ii) at least one chelator, containing lactoferrin, for binding inorganic components such as iron; and (iii) at least one binder capable of binding organic components from the degradation of the biofilm and / or bacteria; (iv) glutamine, vitamin A, vitamin D and zinc to promote the recovery of the intestinal mucosa cells.
    [2]
    The composition for use according to claim 1, wherein it further contains chitosan for an antibacterial action against Gram-negative bacteria.
    [3]
    The composition for use according to claim 1 or 2, wherein it further contains Rosmarinus officinalis extract to decrease the activity and adhesion of the biofilm.
    [4]
    The composition for use according to any of claims 1 to 3, wherein the binder comprises at least one binder capable of binding organic components derived from the degradation of the biofilm and at least one binder capable of binding organic components from the degradation of bacteria from the biofilm.
    [5]
    The composition for use according to any of claims 1 to 4, wherein the binder comprises at least one binder for binding organic components derived from the degradation of the biofilm selected from the group of inositol and / or rice bran or a combination thereof.
    [6]
    The composition for use according to any of claims 1 to 5, wherein the binder comprises at least one binder for binding organic components derived from the degradation of bacteria from the biofilm selected from the group of Punica granatum extract, Rosmarinus officinalis extract, Quercus rubra extract, Quercus petraea extract, phosphatidylcholine and / or magnesium or a combination thereof.
    [7]
    A composition for use according to claim 6, wherein a first binder is selected from the group of Punica granatum extract, Quercus rubra extract and / or Quercus petraea extract or a combination thereof and a second binder is selected from the group of phosphatidylcholine and / or magnesium or a combination thereof.
    [8]
    A composition for use according to any of claims 1 to 7, wherein it comprises at least one anti-inflammatory ingredient selected from the group of Curcuma longa extract, Punica granatum extract, Citrus aurantium extract, Quercus extract, superoxide dismutase and / or catalase or a combination thereof.
    [9]
    The composition for use according to any of claims 1 to 8, wherein it further comprises vitamin B9, vitamin B6, vitamin C, vitamin B12 and / or magnesium to promote the recovery of the intestinal mucosa cells.
    [10]
    The composition for use according to any of claims 1 to 9, wherein it further comprises active carbon for absorbing and eliminating toxins from the stool.
    [11]
    The composition for use according to any of claims 1 to 10, wherein it further contains Pistacia lentiscus resin.
    [12]
    The composition for use according to any of claims 1 to 11, wherein said polysaccharidases are selected from the group of alpha-ylase, beta-amylase, glucosamylase, alpha-galactosidase, invertase, maltase, cellulase, hemicellulase, xylanase, pectinase, pectinasease, pullulan and / or dextranase or a combination thereof.
    [13]
    The composition for use according to any of claims 1 to 12, wherein said proteases are selected from the group of bromelain, papain and / or ficin or a combination thereof.
    [14]
    The composition for use according to any of claims 1 to 13, wherein said lipases comprise phospholipase.
    [15]
    The composition for use according to any of claims 1 to 14, wherein it contains at least 10-40% by weight of enzymes, 3-15% by weight of vitamins and nutritional minerals, 1-20% by weight of glutamine, 1-40% by weight of complexing substances and chelators , 0-50% by weight of a bulk material, the total composition representing 100% by weight.
    [16]
    The composition of any one of claims 1 to 15, wherein it comprises at least polysaccharidase, protease and lipase.
    [17]
    The composition for use according to any of claims 1 to 16, wherein it contains said enzymes in an amount of 5-25% by weight of polysaccharidases, 5-25% by weight of proteases, 3-15% by weight of lipases, 0-15% by weight of antioxidant enzymes wherein the total composition represents 100% by weight.
    [18]
    A food supplement for use in the treatment of chronic inflammation of the gastrointestinal tract, which contains a composition according to any one of the preceding claims.
    [19]
    A functional food for use in the treatment of chronic inflammation of the gastrointestinal tract, which contains a composition according to any one of the preceding claims.
    [20]
    A pharmaceutical composition according to any of claims 1 to 19, for use for prevention and / or treatment of a biofilm in the gastrointestinal tract.
    [21]
    A food supplement for use in the prevention and / or treatment of a biofilm in the gastrointestinal tract containing a composition according to any one of the preceding claims.
    [22]
    A functional food for use in the prevention and / or treatment of a biofilm in the gastrointestinal tract, which contains a composition according to any one of the preceding claims.
    [23]
    The composition of any one of claims 1 to 22 for use for prevention and / or treatment of dysbiosis in the gastrointestinal tract.
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    US20170020999A1|2017-01-26|
    WO2015150590A1|2015-10-08|
    EP3125913A1|2017-02-08|
    BE1022759A1|2016-08-30|
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    法律状态:
    2021-02-03| MM| Lapsed because of non-payment of the annual fee|Effective date: 20200430 |
    优先权:
    申请号 | 申请日 | 专利标题
    EP14163644.9|2014-04-04|
    EP14163644|2014-04-04|
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