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    • 专利摘要:
    Bifidobacterium longum sub strain. infantis and use of it. The present invention relates to the Bifidobacterium longum sub strain. infantis CECT 9720, its cellular components, metabolites, and secreted molecules, and compositions comprising the above products, as well as the use of said strain for the prevention and/or treatment of inflammatory bowel diseases and liver inflammation, as well as derived pathologies, such as liver cirrhosis. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2752798A1
    申请号:ES201830961
    申请日:2018-10-05
    公开日:2020-04-06
    发明作者:Herranz Yolanda Sanz；Alfonso Benitez-Páez；DEL PULGAR VILLANUEVA EVA Mª GÓMEZ；Guarinos Rubén Francés；Cubillana Isabel Gómez-Hurtado；Romero Paula Piñero；Juárez Oriol Juanola
    申请人:Consorcio Centro De Investig Biomedica En Red Ciber；Fundacion de la C V Para La Gestion De Instituto De Investig Sanitaria Y Biomedica De Alicante；Consejo Superior de Investigaciones Cientificas CSIC；Universidad Miguel Hernandez de Elche；
    IPC主号:
    专利说明:

    [0001]
    [0002] Bifidobacterium longum sub strain . infantis and use of it
    [0003]
    [0004] The present invention relates to the Bifidobacterium longum sub strain . infantis CECT 9720, its cellular components, metabolites, and secreted molecules, and compositions comprising the above products, as well as the use of said strain for the prevention and / or treatment of diseases that cause intestinal and / or hepatic inflammation, as well as pathologies derived from them, such as, for example, liver cirrhosis. The present invention falls within the field of therapeutic activity of pharmaceutical compositions or preparations, as well as within the field of food.
    [0005]
    [0006] BACKGROUND OF THE INVENTION
    [0007]
    [0008] The human being is home to around 10 trillion intestinal bacteria, and its genome has a coding capacity much higher than that of the human (about 100-150 times higher). The gastrointestinal tract is the largest surface area of the body with an epithelial surface of approximately 400 m2, constantly exposed to these live microorganisms. The existing symbiosis, demonstrated by the lack of a pro-inflammatory response against commensal bacteria (Littman DR et al. Role of the commensal microbiota in normal and pathogenic host immune responses. Cell host & microbe 2011; 10 (4): 311-23; Hooper LV et al J. Interactions between the microbiota and the immune system. Science 2012; 336 (6086): 1268-73) implies the presence of clearly defined lines of communication. Recent literature suggests that organisms in the gastrointestinal tract play an indispensable role in maintaining host homeostasis (Wu GD et al. Analysis of the human gut microbiome and association with disease. Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 2013; 11 (7): 774-7). Alterations in the intestinal microbiota appear to have a role in the pathogenesis and progression of various diseases, including, for example, liver and gastrointestinal diseases.
    [0009]
    [0010] More specifically, the intestinal microbiota has been shown to have a direct role in the progression and development of complications in liver disease (Bajaj.
    [0011] JS et al. Linkage of gut microbiome with cognition in hepatic encephalopathy. American journal of physiology Gastrointestinal and liver physiology 2012; 302 (1): G168-75; Bajaj JS et al. Colonic mucosal microbiome differs from stool microbiome in cirrhosis and hepatic encephalopathy and is linked to cognition and inflammation. American journal of physiology Gastrointestinal and liver physiology 2012; 303 (6): G675-85; Chen Y. et al. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 2011; 54 (2): 562-72).
    [0012]
    [0013] Cirrhosis is the common final stage of different liver diseases characterized by a histological distortion of the liver with the presence of regenerative nodules causing portal hypertension (Bosch J. et al Pathophysiology of portal hypertension. Gastroenterology clinics of North America 1992; 21 (1): 1-14). This fact, in turn, alters intestinal motility by inducing intestinal bacterial overgrowth (SBI) (Morencos FC et al. Small bowel bacterial overgrowth in patients with alcoholic cirrhosis. Digestive diseases and sciences 1995; 40 (6): 1252-6; Pande C. Small-intestinal bacterial overgrowth in cirrhosis is related to the severity of liver disease. Alimentary pharmacology & therapeutics 2009; 29 (12): 1273-81; Bauer TM et al. Small intestinal bacterial overgrowth in patients with cirrhosis: prevalence and relation with spontaneous bacterial peritonitis. Am J Gastroenterol 2001; 96 (10): 2962 67). Specifically, in patients with cirrhosis there is an overgrowth of potentially pathogenic bacteria (eg Gram negative species), and a decrease in native bacterial families. The close relationship between the most frequent complications that arise in patients with cirrhosis and the intestinal microbiota (edesma F. Small bowel bacterial overgrowth in patients with alcoholic cirrhosis. Digestive diseases and sciences 1995; 40 (6): 1252-6; Pande C . et al. Small-intestinal bacterial overgrowth in cirrhosis is related to the severity of liver disease. Alimentary pharmacology & therapeutics 2009; 29 (12): 1273-81; Bauer TM et al. Small intestinal bacterial overgrowth in patients with cirrhosis: prevalence and relation with spontaneous bacterial peritonitis. Am J Gastroenterol 2001; 96 (10): 2962-67; Chang CS et al. Small intestine dysmotility and bacterial overgrowth in cirrhotic patients with spontaneous bacterial peritonitis. Hepatology 1998; 28 (5): 1187- 90) has been studied intensively in recent years and has highlighted the importance of constant communication between the intestine and the liver during the management of patients with cirrhosis (Garcia-Tsao G. et al . Gut microflora in the pathogenesis of the complications of cirrhosis. Best Pract Res Clin Gastroenterol 2004; 18 (2): 353-72). Complications such as hepatic encephalopathy (HD), spontaneous bacterial peritonitis (PBE), and variceal bleeding in cirrhotic patients are directly caused or aggravated by the translocation of enteric microbiota or its products to extra-intestinal territories.
    [0014]
    [0015] Going further, the direct communication between the liver and the intestine through the portal circulation called the "liver-intestine axis", plays an important role in the progression of complications of cirrhosis, the intestinal microbiota being a key regulator of inflammation and bacterial translocation in this context (Garcia-Tsao G. et al. Gut microflora in the pathogenesis of the complications of cirrhosis. Best Pract Res Clin Gastroenterol 2004; 18 (2): 353-72).
    [0016]
    [0017] On the other hand and in relation to intestinal disease, it is also widely known that the intestinal microbiota has a direct role in the progression and development of complications in this pathology. Thus, for example, endotoxins are immunogenic molecules derived from the cell walls of Gram-negative bacteria present in the gut microbiota, which can over-activate the innate immune system and break immune homeostasis and gut barrier function. (Rodes L. et al. Microencapsulated Bifidobacterium longum subsp. Infantis ATCC 15697 Favorably Modulates Gut Microbiota and Reduces Circulating Endotoxins in F344 Rats. BioMed Research International. Volume 2014, Article ID 602832, 11 pages).
    [0018]
    [0019] In routine medical practice, as an alternative or complementary to pharmacological treatments, the use of a wide range of probiotic strains has become widespread in recent years, as there is evidence of their contribution to the restoration of alterations in intestinal permeability. , the intestinal microbial composition and the inflammatory response. In this sense, probiotic strains of species belonging to the genus Bifidobacterium and Lactobacillus have been specially used for the treatment and / or prevention of various pathologies so that they naturally restore a situation of intestinal homeostasis, improving the symbiotic interaction between the microbiota and the Patients' immune system, while avoiding the non-selective eradication of microbiota associated with the use of antibiotics and the appearance of resistance, the main problems that occur with the use of antibiotics.
    [0020] Specifically, the use of strains of Bifidobacterium longum subp has been related . infantis with the treatment of intestinal pathologies, for example:
    [0021] WO2009134948A1 discloses the treatment of inflammatory bowel disorders including irritable bowel syndrome, lymphocytic colitis, collagen colitis, and undetermined colitis, by administering a composition comprising an anti-inflammatory active agent and a probiotic such as Bifidobacterium infantis diseases, as an adjuvant,
    [0022] WO2010105207A1 refers to a composition useful for stimulating the growth of the beneficial microbiota, including species of the genus Bifidobacterium, in order to regulate bacterial dysbiosis in an animal. The composition comprises galactooligosaccharides and a Bifidobacterium longum subps strain . infantis and as indicated may be used to treat, among other diseases, colitis, Crohn's disease, irritable bowel syndrome and inflammatory bowel disease,
    [0023] - The publication: Elian, SDA et al. "Bifidobacterium longum subsp infantis BB-02 attenuates acute murine experimental model of inflammatory bowel disease" Beneficial Microbes. 2015, 6 (3), 277 - 286 refers to the use of the bacterium Bifidobacterium longum subsp infantis BB-02 as a probiotic that attenuates an acute murine experimental model of inflammatory bowel disease,
    [0024] -Finally, the publication: Rodes, L. et al. “ Microencapsulated Bifidobacterium longum subsp infantis ATCC 15697 Favorably Modulates Gut Microbiota and Reduces Circulating Endotoxins in F344 Rats” BioMed Research International 2014; 2014: 602832., Describes the application of the Bifidobacterium longum subsp infantis ATCC 15697 strain in a microencapsulated form, which modulates the intestinal microbiota and reduces circulating endotoxins in an animal mouse model used in aging, oncology and nutrition.
    [0025]
    [0026] The identification of new probiotic bacterial strains that have the capacity to treat and / or prevent pathologies that cause inflammation, preferably intestinal and hepatic, as well as derived pathologies such as cirrhosis, and that are preferably effective, are considered of interest. simultaneously against more than one of them.
    [0027]
    [0028] DESCRIPTION OF THE INVENTION
    [0029] The present invention relates to the strain Bifidobacterium longum subsp. infantis CECT 9720, to the cellular components, metabolites, secreted molecules of said strain, and to the compositions comprising the above products, as well as to their use for the prevention and / or treatment of intestinal and / or hepatic inflammation, and derived pathologies such as liver cirrhosis. Preferably the strain of the invention exhibits activity simultaneously in more than one of the indicated diseases.
    [0030]
    [0031] The CECT 9720 strain, which belongs to the species Bifidobacterium longum subsp. Infantis reduces peripheral levels of proinflammatory cytokine TNF-a and IL-6 in vivo in a model of liver damage and also reduces peripheral levels of proinflammatory cytokine TNF-a, IL-6 and MCP-1 in vivo in a intestinal inflammation model. Furthermore, this strain exerts its effect without inducing a proinflammatory response in vitro in Kupfer cells isolated from the liver or in isolated macrophages from the intestinal wall, which is indispensable in any strain with potential use as a probiotic. All this makes the strain of the present invention a bacterial strain of potential interest for probiotic use by reducing liver and intestinal inflammation.
    [0032]
    [0033] Therefore, the present invention contributes to the state of the art a strain of the species Bifidobacterium longum subsp. infantis for the treatment of intestinal inflammation, liver inflammation and derived pathologies such as, for example, liver cirrhosis.
    [0034]
    [0035] Then, an aspect of the present invention relates to a strain of Bifidobacterium longum subsp. infantis with deposit number CECT 9720. This strain was deposited in the Spanish collection of type cultures (CECT) on September 18, 2018 and the deposit number CECT 9720 corresponded to it. The address of said International Deposit Authority is: Spanish Type Culture Collection (CECT), Building 3 CUE, Parc Científic Universitat de Valencia, Catedrático Agustín Escardino 9, 46980 Paterna (Valencia) Spain.
    [0036]
    [0037] In the scope of this document, the reference to the strain of the invention will be made interchangeably as: Bifidobacterium longum subsp. infantis with deposit number CECT 9720, strain CECT 9720, strain Bifidobacterium longum subsp infantis 16p1 or 16p1.
    [0038] The CECT 9720 strain can be in the form of viable cells or in the form of non-viable cells.
    [0039]
    [0040] The present invention also contemplates a strain derived from the CECT 9720 strain, where said strain maintains or enhances the capabilities described throughout the present invention. The derived microorganism can be produced naturally or intentionally, by mutagenesis methods known in the state of the art, such as, but not limited to, the growth of the original microorganism in the presence of mutagenic or stress causing agents, or by engineering. genetics aimed at modifying specific genes. According to a preferred embodiment, the strain derived from the CECT 9720 strain is a genetically modified mutant. The terms mutant strain or derived strain can be used interchangeably.
    [0041]
    [0042] The combination of cellular components, metabolites, secreted molecules or any of their combinations, obtained from the CECT 9720 strain, is also contemplated in the present invention.
    [0043]
    [0044] The cellular components of the bacterium could include components of the cell wall (such as, but not limited to, peptidoglycan), nucleic acids, membrane components, or others such as proteins, lipids, and carbohydrates and their combinations , such as lipoproteins, glycolipids, or glycoproteins. Metabolites include any molecule produced or modified by the bacterium as a consequence of its metabolic activity during its growth, its use in technological processes (for example, but not limited to, food or drug manufacturing processes), during product storage or during gastrointestinal transit. Examples of these metabolites are, but are not limited to, organic and inorganic acids, proteins, peptides, amino acids, enzymes, lipids, carbohydrates, lipoproteins, glycolipids, glycoproteins, vitamins, salts, metals, or nucleic acids. Secreted molecules include any molecule exported or released abroad by the bacterium during its growth, its use in technological processes (for example, food or drug manufacturing), product storage, or gastrointestinal transit. Examples of these molecules are, but are not limited to, organic and inorganic acids, proteins, peptides, amino acids, enzymes, lipids, carbohydrates, lipoproteins, glycolipids, glycoproteins, vitamins, salts, metals or nucleic acids.
    [0045]
    [0046] Another aspect of the present invention relates to a composition comprising the strain of the invention and / or the cellular components, metabolites, secreted molecules of the strain of the invention or any combination thereof.
    [0047]
    [0048] In a preferred embodiment, the composition has a strain concentration of between 105 and 1014 colony forming units (cfu) per gram or milliliter of final composition.
    [0049]
    [0050] The composition can also include at least one bioactive component (active substance, active ingredient or therapeutic agent).
    [0051]
    [0052] The term "bioactive component" refers to a compound with biological activity in the scope of the patent that can improve or complement the activity of the CECT 9720 strain, including ingredients or components of food (for example and without limitation: acids polyunsaturated fats, conjugated linoleic acid, prebiotics, fiber, Guar gum, glucomannan, chitosan, copper picolinate, calcium, etc.), other probiotics, plants, extracts or components of plants and drugs.
    [0053]
    [0054] The composition may be a pharmaceutical composition, in which case it will preferably comprise at least one pharmaceutically acceptable carrier and / or excipient.
    [0055]
    [0056] The pharmaceutical composition or medicament can be presented under any clinically permitted administration form and in a therapeutically effective amount. For example, a form adapted for oral, sublingual, nasal, intracathecal, bronchial, lymphatic, rectal, transdermal, inhaled, or parenteral administration may be in form, preferably in a form adapted for oral administration. The pharmaceutical composition of the invention can be formulated in solid, semi-solid, liquid or gaseous forms, such as tablet, capsule, powder, granule, ointment, solution, suppository, injection, inhalant, gel, microsphere or aerosol. The form adapted for oral administration is selected from the list comprising, but not limited to, drops, syrup, herbal tea, elixir, suspension, extemporaneous suspension, vial drinkable, tablet, capsule, granule, seal, pill, tablet, pill, troche or lyophilisate.
    [0057]
    [0058] The term "excipient" refers to a substance that assists in the absorption of any of the components of the composition of the present invention, stabilizes said components or helps the preparation of the pharmaceutical composition in the sense of giving it consistency or providing flavors that make it more enjoyable. Thus, the excipients could have the function of keeping the components together, such as starches, sugars or cellulose, function of sweetening, function of dye, function of protection of the medicine, for example, to isolate it from air and / or humidity, function for filling a pill, capsule or any other form of presentation, such as, for example, dibasic calcium phosphate, a disintegrating function to facilitate the dissolution of the components and their absorption in the intestine, without excluding other types of excipients not mentioned in this paragraph. Therefore, the term "excipient" is defined as that matter that, included in the galenical forms, is added to the active ingredients or to their associations to enable their preparation and stability, modify their organoleptic properties or determine the physico-chemical properties of the pharmaceutical composition and its bioavailability. The "pharmaceutically acceptable" excipient must allow the activity of the compounds of the pharmaceutical composition, that is, to be compatible with said components.
    [0059]
    [0060] The "pharmaceutical form" or "pharmaceutical form" is the arrangement to which the active ingredients and excipients are adapted to constitute a medicine. It is defined by the combination of the way in which the pharmaceutical composition is presented by the manufacturer and the way in which it is administered.
    [0061]
    [0062] The "vehicle" or carrier, is preferably an inert substance. The function of the vehicle is to facilitate the incorporation of other compounds, to allow a better dosage and administration or to give consistency and shape to the pharmaceutical composition. Therefore, the vehicle is a substance that is used in the medicine to dilute any of the components of the pharmaceutical composition of the present invention to a determined volume or weight; or that even without diluting said components it is capable of allowing a better dosage and administration or giving consistency and shape to the medicine. When the way Presentation is liquid, the pharmaceutically acceptable vehicle is the diluent.
    [0063]
    [0064] In addition, the excipient and vehicle must be pharmacologically acceptable, that is, that the excipient and vehicle are allowed and evaluated so as not to cause harm to the organisms to which it is administered.
    [0065]
    [0066] In the present invention, the term "therapeutically effective amount" refers to that amount of the component of the pharmaceutical composition that when administered to a mammal, preferably a human, is sufficient to produce prevention and / or treatment, such as defined below, of a disease or pathological condition of interest in the mammal, preferably a human The therapeutically effective amount will vary, for example, according to the activity of the strain of the invention; of the cellular components, metabolites, secreted molecules or any of its combinations, in any form of presentation; the therapeutically effective amount will also vary according to the metabolic stability and duration of action of the compound; the patient's age, body weight, general state of health, sex and diet ; mode and time of administration; rate of excretion, drug combination; severity of the particular disorder or pathological condition; and the subject undergoing therapy, but may be determined by a specialist in the art based on his or her own knowledge and description.
    [0067]
    [0068] The composition can also be a nutritional composition such as a food, a supplement, a nutraceutical, a probiotic, or a symbiotic.
    [0069]
    [0070] The term "nutritional composition" of the present invention refers to that food that, independently of providing nutrients to the subject who takes it, beneficially affects one or more functions of the organism, so as to provide a better state of health and well-being. As a consequence, said nutritional composition can be used for the prevention and / or treatment of a disease or the factor causing a disease. Therefore, the term "nutritional composition" of the present invention can be used as a synonym for functional food or food for specific nutritional purposes or medicinal food.
    [0071]
    [0072] The term "nutraceutical" as used in the present invention refers to substances isolated from a food and used in dosages that have a beneficial effect on health.
    [0073]
    [0074] The term "probiotic" as used in the present invention refers to live microorganisms that when supplied in adequate amounts promote health benefits of the host organism.
    [0075]
    [0076] The term "symbiotic" as used in the present invention refers to those foods that contain a mixture of prebiotics and probiotics. As a general rule, they contain a prebiotic component that favors growth and / or metabolic activity and, ultimately, the effect of the probiotic with which it is combined, as for example and without limitation, may be the association of fructooligosaccharides or galactooligosaccharides with bifidobacteria.
    [0077]
    [0078] The term "supplement", synonymous with any of the terms "dietary supplement", "nutritional supplements"; or "food supplement" is a "food ingredient" intended to supplement food. Some examples of dietary supplements include, but are not limited to, vitamins, minerals, botanicals, amino acids, and food components such as enzymes and glandular extracts. They are not presented as substitutes for a conventional food or as a single component of a meal or diet but rather as a supplement to the diet.
    [0079]
    [0080] Another aspect of the present invention relates to the use of a strain Bifidobacterium longum subsp. infantis CECT 9720 for the manufacture of a medicinal product with a nutritional composition or a food.
    [0081]
    [0082] Another aspect of the present invention relates to the Bifidobacterium longum subsp. infantis CECT 9720 for use as a medicine.
    [0083]
    [0084] The medicine to which the present invention refers can be for human or veterinary use. The "medicine for human use" is any substance or combination of substances that is presented as possessing properties for the treatment or prevention of diseases in humans or that can be used in humans or administered to humans in order to restore, correct or modify physiological functions exerting a pharmacological, immunological or metabolic action, or establishing a medical diagnosis. "Veterinary medicine" is any substance or combination of substances that is presented as having curative or preventive properties with respect to animal diseases or that can be administered to the animal in order to restore, correct or modify its physiological functions by exercising a pharmacological, immunological or metabolic action, or to establish a veterinary diagnosis. "Veterinary drugs" are also considered to be "veterinary drugs" prepared to be incorporated into a feed.
    [0085]
    [0086] Another preferred embodiment of the present invention relates to the use of a CECT 9720 strain, or of the cellular components, metabolites, secreted molecules, or any of their combinations; or of the composition of the invention; for the manufacture of a medicament for the prevention and / or treatment of inflammatory bowel disease, liver inflammation and / or derived pathologies such as, for example, liver cirrhosis.
    [0087]
    [0088] Another preferred embodiment of the present invention relates to the CECT 9720 strain, or of the cellular components, metabolites, secreted molecules, or any of their combinations for use in the prevention and / or treatment of inflammatory bowel disease, liver inflammation and / or derived pathologies such as, for example, liver cirrhosis.
    [0089]
    [0090] Another preferred embodiment of the present invention relates to the CECT 9720 strain, or of cellular components, metabolites, secreted molecules, or any of their combinations for use in the simultaneous prevention and / or treatment of inflammatory bowel disease and inflammation liver.
    [0091] In a preferred embodiment, inflammatory bowel disease or intestinal inflammation is selected from the list comprising: Crohn's disease, ulcerative colitis, indeterminate colitis, collagen colitis, and lymphocytic colitis.
    [0092]
    [0093] The term "treatment" as understood in the present invention refers to combating the effects caused as a consequence of a disease or pathological condition of interest in a subject (preferably mammal, and more preferably a human) that includes:
    [0094] (i) inhibit the disease or pathological condition, that is, stop its development;
    [0095] (ii) alleviating the disease or pathological condition, that is, causing regression of the disease or pathological condition or its symptoms;
    [0096] (iii) stabilize the disease or pathological condition.
    [0097]
    [0098] The term "prevention" as understood in the present invention consists in preventing the appearance of the disease, that is, preventing the disease or pathological condition from occurring in a subject (preferably a mammal, and more preferably a human), in particularly, when said subject has a predisposition for the pathological condition.
    [0099]
    [0100] In the scope of the invention, preferably treatment and / or prevention is effective against more than one disease, preferably inflammatory bowel disease and liver cirrhosis.
    [0101]
    [0102] The term "liver inflammation" or "liver inflammation" refers to an inflammatory response of the liver that can be initiated by physical injury, infection, or a local immune response and may include local accumulation of fluid, plasma proteins, and white blood cells, as well as migration and infiltration of neutrophils, lymphocytes and other cells of the immune system in the regions of the damaged liver.
    [0103]
    [0104] The term "inflammatory bowel disease" or "intestinal inflammation" refers to an inflammatory response of the intestine that can be initiated by physical injury, infection, or a local immune response and may include local accumulation of fluid, plasma proteins, and white blood cells, as well as migration and infiltration of neutrophils, lymphocytes and other cells of the immune system in the regions of the damaged intestine.
    [0105]
    [0106] The term "liver cirrhosis", "liver cirrhosis", or simply "cirrhosis" is the end stage inflammatory liver disease and refers to a condition in which the liver slowly deteriorates and malfunctions because the liver tissue is changed by fibrous scar tissue and regenerative nodules. This produces a partial blockage in the blood flow through the liver as well as a deterioration of the liver's ability to control infections, eliminate bacteria and toxins from the blood, process nutrients, hormones and drugs, make proteins that regulate the clotting of the blood and produce bile to help absorb fats, including cholesterol, and fat-soluble vitamins. The strain of the present invention is suitable for the treatment of cirrhosis of different causes, including alcohol-related cirrhosis, chronic hepatitis B, C or D, non-alcoholic liver steatosis (NASH), autoimmune hepatitis, primary or secondary biliary cirrhosis, sclerosing cholangitis Primary, inherited diseases such as cystic fibrosis, alpha-1 antitrypsin deficiency, hemochromatosis, Wilson's disease, galactosemia, and glycogen storage diseases. The present invention can be used to prevent or treat liver cirrhosis regardless of its etiology.
    [0107]
    [0108] Throughout the description and claims, the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and characteristics of the invention will emerge in part from the description and in part from the practice of the invention. The following examples and figures are provided by way of illustration, and are not intended to be limiting of the present invention.
    [0109]
    [0110] BRIEF DESCRIPTION OF THE FIGURES
    [0111]
    [0112] FIG. 1: Serum cytokine levels (IL-6, IL-10, MCP-1, TNF-a) in animals with BDL-induced cirrhosis, distributed by study groups: Untreated (0), Bifidobacterium bifidum MT7 (MT7) , Bifidobacterium bifidum G1 (G1), Bifidobacterium longum subsp infantis 16p1 according to the example of the invention.
    [0113]
    [0114] FIG. 2: Secreted levels of cytokines (IL-6, IL-10, MCP-1, TNF-a) in cultures of liver macrophages from animals with BDL-induced cirrhosis: Untreated macrophages (MCF), Macrophages with Bifidobacterium bifidum MT7 (MCF + MT7), Macrophages with Bifidobacterium bifidum G1 (MCF + G1), Macrophages with Bifidobacterium longum subsp infantis 16p1, (MCF + 16p1) according to the example of the invention.
    [0115]
    [0116] FIG. 3: Shows a direct comparison of the use of the Bifidobacterium longum subsp infantis 16p1 strain in Kupffer cells from animals with BDL-induced cirrhosis, against lipopolysaccharide (LPS) and cells not stimulated in the production of cytokines (IL-6, IL- 10, MCP-1, TNF-a) in the culture supernatants, discarding the strains MT7 and G1, according to the example of the invention.
    [0117]
    [0118] FIG. 4: Secreted levels of cytokines (IL-6, IL-10, MCP-1, TNF-a) in cultures of intestinal wall macrophages from animals treated with DSS: Untreated macrophages (MCF), Macrophages with Bifidobacterium bifidum MT7 ( MCF + MT7), Macrophages with Bifidobacterium bifidum G1 (MCF + G1), Macrophages with Bifidobacterium longum subsp infantis 16p1, (MCF + 16p1) according to the example of the invention
    [0119]
    [0120] FIG. 5: Shows a direct comparison of the use of the Bifidobacterium longum subsp infantis 16p1 strain in intestinal wall macrophages from animals treated with DSS, against lipopolysaccharide (LPS) and cells not stimulated in the production of cytokines (IL-6, IL-10 , MCP-1, TNF-a) in the culture supernatants, discarding the MT7 and G1 strains, according to the example of the invention.
    [0121]
    [0122] FIG. 6: Serum cytokine levels (IL-6, IL-10, MCP-1, TNF-a) in animals with intestinal inflammation induced by DSS treatment, distributed by study groups: Untreated (0), Bifidobacterium bifidum MT7 (MT7), Bifidobacterium bifidum G1 (G1), Bifidobacterium longum subsp infantis 16p1, (16p1) according to the example of the invention.
    [0123]
    [0124] EXAMPLES
    [0125]
    [0126] The invention will now be illustrated by tests carried out by the inventors, which shows the effectiveness of the product of the invention.
    [0127]
    [0128] Example 1: Treatment of mice with cirrhosis
    [0129]
    [0130] Isolation and identification of the strains:
    [0131] Strains of the genus Bifidobacterium were isolated from the faeces of healthy infants who had not eaten food containing bifidobacteria for at least the month prior to analysis and who had not been subjected to antibiotic treatments. The samples were kept at 4 ° C and analyzed without more than two hours after collection. Two grams of each of them were diluted in 10 mM phosphate buffer with a content of 130 mM NaCl (PBS) and homogenized in a Lab-Blender 400 digester (Seward Medical, London, UK) for 3 min and then diluted in peptone water. 0.1 ml aliquots of various decimal dilutions were inoculated into MRS agar (from Man Rogosa and Sharpe; Scharlau, Barcelona) with a content of 0.05% cysteine (Sigma, St. Louis, MO; MRS-C) , and 80 pg / ml mupirocin. After an incubation of 48 h at 37 ° C under anaerobic conditions (AnaeroGen, Oxoid, United Kingdom), isolated colonies were selected and their identity confirmed by a study of their morphology under Gram stain. The identity of the isolates was confirmed by gender-specific PCR, according to the methodology described by Kaufman et al. (1997, Identification and quantification of Bifidobacterium species isolated from food with genus-specific 16S rRNA-targeted probes by colony hybridization and PCR. Appl. Environ. Microbiol. 63: 1268-1273), using the primers (LM26 and LM3) that amplify a 1.35 kb fragment of the 16S ribosomal RNA gene. Its identification at the species level was performed by sequencing the 16S rRNA gene (1.26 Kb) using primers 27f (5'-AGAGTTTGATCCTGGCTCAG-3 '(SEQ ID NO: 1) and 1401r (5'-CGGTGTGTACAAGACCC-3' (SEQ ID NO: 2) by Sanger technology on an ABI 3730XL sequencer, by comparing the sequences obtained with those of the NCBI database and the BLASTn algorithm, the identification of the isolated strains and in particular the one that constitutes the object was obtained. of the present patent, obtaining a 100% degree of identity with Bifidobacterium longum subsp infantis.
    [0132]
    [0133] Sequence of the 16S rRNA of the Bifidobacterium longum subsp infantis CECT9720 (SEQ ID NO: 3):
    [0134]
    [0135] TAGCGACTCCGCCTTCACGCAGTCGAGTTGCAGACTGCGATCCGAACTGAGACCGGTTTT CAGGGATCCGCTCCGCGTCGCCGCGTCGCATCCCGTTGTACCGGCCATTGTAGCATGCGT GAAGCCCTGGACGTAAGGGGCATGATGATCTGACGTCATCCCCACCTTCCTCCGAGTTAA CCCCGGCGGTCCCCCGTGAGTTCCCGGCATAATCCGCTGGCAACACGGGGCGAGGGTTGC GCTCGTTGCGGGACTTAACCCAACATCTCACGACACGAGCTGACGACGACCATGCACCAC CTGTGAACCCGCCCCGAAGGGAAGCCGTATCTCTACGACCGTCGGGAACATGTCAAGCCC AGGTAAGGTTCTTCGCGTTGCATCGAATTAATCCGCATGCTCCGCCGCTTGTGCGGGCCC CCGTCAATTTCTTTGAGTTTTAGCCTTGCGGCCGTACTCCCCAGGCGGGATGCTTAACGC GTTAGCTCCGACACGGAACCCGTGGAACGGGCCCCACATCCAGCATCCACCGTTTACGGC GTGGACTACCAGGGTATCTAATCCTGTTCGCTCCCCACGCTTTCGCTCCTCAGCGTCAGT AACGGCCCAGAGACCTGCCTTCGCCATTGGTGTTCTTCCCGATATCTACACATTCCACCG TTACACCGGGAATTCCAGTCTCCCCTACCGCACTCAAGCCCGCCCGTACCCGGCGCGGAT CCACCGTTAAGCGATGGACTTTCACACCGGACGCGACGAACCGCCTACGAGCCCTTTACG CCCAATAATTCCGGATAACGCTTGCACCCTACGTATTACCGCGGCTGCTGGCACGTAGTT AGCCGGTGCTTATTCAACGGGTAAACTCACTCACGCTTGCTCCCCGATAAAAGAGGTTTA CAACCCGAAGGCCTCCATCCCTCACGCGGCGTCGCTGCATCAGGCTTGCGCCCATTGTGC AATATTCCCCACTGCTGCCTCCCG TAGGAGTCTGGGCCGTATCTCAGTCCCAATGTGGCC GGTCGCCCTCTCAGGCCGGCTACCCGTCGAAGCCACGGTGGGCCGTTACCCCGCCGTCAA
    [0136] GCTGATAGGACGCGACCCCATCCCATACCGCGAAAGCTTTCCCAGCAAACCATGCGGAAA GTTGGAGCATCCGGCATTACCACCCGTTTCCAGGAGCTATTCCGGTGTATGGGGGCAGGTC GGTCACGCATTACTCACCACCGTTCGCCCATC
    [0137]
    [0138] Animals and Methods:
    [0139] Study design:
    [0140] Male Sprague-Dawley rats (Harían, Barcelona, Spain) weighing 100-150 g were included in this study. Rats were individually housed at a constant room temperature of 21 ° C and exposed to a 12:12 light / dark cycle. Animals were fed standard food throughout the study protocol. The protocol spanned a total of 6 weeks. After one week of quarantine, the animals were subjected to induction of experimental cirrhosis by double ligation of the common bile duct (Bile Duct Ligation, BDL). Briefly, the rats were anesthetized with ketamine and xylazine. After laparotomy through the midline, the common bile duct was ligated at two different levels with 5-0 silk sutures, and the duct was sectioned between the ligatures. The abdominal wall was closed with 5-0 silk sutures. A subgroup of animals acted as controls and was simulated.
    [0141]
    [0142] a) In vivo study :
    [0143] One week prior to laparotomy, the animals were randomly divided into 4 groups:
    [0144] - Without treating
    [0145] - Treated with Bifidobacterium bifidum MT7
    [0146] - Treated with Bifidobacterium bifidum G1
    [0147] - Treated with Bifidobacterium longum subsp infantis 16p1
    [0148]
    [0149] Each animal included in the different groups received a set amount (109 CFU) of the strains included in the study daily. The administration was made by intragastric probing and lasted for 7 days.
    [0150]
    [0151] After finishing the treatment, all the animals were sacrificed and blood samples were collected from the lower cava in heparin tubes. The blood was centrifuged (10 min at 3500 FCR (relative centrifugal force)) to obtain the serum, which was aliquoted and stored at -20 ° C until use.
    [0152] b) In vitro study :
    [0153] Animals subjected to experimental cirrhosis induction by double ligation of the common bile duct (Bile Duct Ligation, BDL) were anesthetized with a mixture of ketamine (75mg / kg) and xylazine (10mg / kg) for the development of laparotomies. Once the liver was located, it was perfused in situ with 50 mL of perfusion buffer (HBSS 10% FBS, 1mg / mL collagenase I, 0.2mg / mL collagenase IV, 20 pg / mL DNase I and 5 mM MgCl2) previously tempered at 37 ° C. The liver was then removed and placed in a tube with RPMI 1640 10% FBS, cut into small pieces and centrifuged at 1300 rpm for 10 min at 4 ° C. The supernatant was carefully removed, the tissue was resuspended in 50 mL of digestion buffer (RPMI 1640, 1mg / mL of collagenase I, 0.2mg / mL of collagenase IV, 20 pg / mL of DNase I and 5mM of MgCl2) and incubated for 1 h at 37 ° C with shaking (400 rpms).
    [0154]
    [0155] The mixture resulting from the digestion was passed through a sieve column after being completely mechanically disaggregated, washing everything with RPMI 1640 to recover as many cells as possible. Subsequently, a very gentle centrifugation (3 min at 30 FCR (relative centrifugal force) and 4 oC) was carried out to remove the hepatocytes. The pellet was discarded and the collected supernatant was centrifuged 10 min at 1300 rpm and 4 ° C. The resulting pellet was separated by means of a Percoll gradient, which was centrifuged for 10 min at 1500 rpms and without brakes. After collecting the cells from the percoll, they were resuspended in Red Blood Cell Lysing Buffer (Sigma Aldrich) and lysed for 10min at 4 ° C to remove the remaining red blood cells. At the end of the lysing time, the cells were washed with RPMI 1640 and the total cells were counted.
    [0156]
    [0157] Isolation of kupffer cells was carried out by magnetic separation, according to their expression of the monocyte differentiation marker CD68. Firstly, labeling (20min at 4oC) with PE-bound CD68 antibody (Miltenyi Biotec) was performed using 5 pL per million cells, followed by a 5min wash at 300gx to remove the rest of the antibody not bound to the cells. Subsequently, a second labeling (15min at 4oC) was carried out with anti-PE beads (Miltenyi Biotec) at a rate of 2 pL per million cells. After subsequent washing to remove excess magnetic beads, a positive selection of the sample was made, passing the suspension of labeled cells through an LS column (Miltenyi Biotec) to obtain a pure population of kupffer cells. The cells obtained were resuspended in RPMI 1640 culture medium (Gibco BRL, Life Technologies) supplemented with 10% fetal bovine serum FBS. Cell viability was checked by staining with "trypan blue" and counted. Viable cells were plated at the rate of (106 cell / mL) in 5 wells under the following conditions:
    [0158]
    [0159] - Without stimulating
    [0160] - Stimulated with LPS
    [0161] - In co-culture with Bifidobacterium bifidum MT7 (5x105 CFUs / well)
    [0162] - In co-culture with Bifidobacterium bifidum G1 (5x105 CFUs / well)
    [0163] - In co-culture with Bifidobacterium longum subsp infantis 16p1 (5x105 CFUs / well)
    [0164]
    [0165] After 48 hours of culture, the supernatants were collected and stored at -20 ° C for the subsequent analysis of the inflammatory response. The study was approved by the Animal Research Committee of the Miguel Hernández University (Alicante, Spain) with the code HA-RFG-001-15.
    [0166]
    [0167] Culture conditions of the strains.
    [0168] Strains were grown in MRS broth (Scharlau, Barcelona, Spain) supplemented with 0.05% (w / v) cysteine (MRS-C Sigma, St. Louis, MO, USA) and incubated at 37 ° C for 22 h (in stationary growth phase) under anaerobic conditions (AnaeroGen, Oxoid, Basingstoke, UK). Cells were harvested by centrifugation (6,000 g for 15 min), washed twice in phosphate buffered saline (PBS, 130 mM sodium chloride, 10 mM sodium phosphate, pH 7.4) and resuspended in skim milk. 10% for oral administration to rats. Aliquots of these suspensions were frozen in liquid nitrogen and stored at -80 ° C until use. The number of living cells was determined by the Colony Forming Unit (CFU) that has MRS-C agar (Biomerieux) after an incubation of 48 h at 37 ° C. For the tested strains, more than 90% of the cells they were alive upon thawing and no significant differences were found during storage time (2 months). A fresh aliquot was thawed for each new experiment to avoid variability in the viability of the cultures.
    [0169] ELISAs
    [0170] Inflammatory responses in serum and culture supernatants were carried out using ELISA kits according to the manufacturer's instructions (R&D Systems, Minneapolis, MN). All samples were measured in triplicate on a Sunrise Microplate Reader (Tecan) and standard curves were generated for each of the plates, establishing a standard zero value that was subtracted from the results of the standards as well as the samples to obtain corrected values.
    [0171]
    [0172] Statistic analysis
    [0173] The U-Mann-Whitney test was used for paired comparisons between treatment groups, with the Bonferroni correction for multiple comparisons. The level of significance was 0.05. Statistical analyzes were performed using the SPSS program (version 22.0).
    [0174]
    [0175] Results:
    [0176] A total of 28 animals were initially included in the study. Mortality in the BDL group was 23.1% (6 of the 24 animals operated on initially). None of the control rats (n = 4) died during the study protocol. Rats undergoing BDL surgery were randomized to study in vivo (n = 12) or in vitro (n = 6). Within the in vivo study , they were also randomized to belong to any of the treatment groups with the different strains of bifidobacteria (n = 4 / group) the week prior to laparotomy. The expression of soluble inflammatory mediators such as IL-6, IL-10, MCP-1 and TNF-a in the serum and the supernatant of the cultures performed was quantified.
    [0177]
    [0178] a) In vivo :
    [0179] The results of the measurements made in serum (Figure 1) reflected a clear decrease in the pro-inflammatory response. It should be noted that TNF-a levels were ten times lower in the group of animals treated orally with Bifidobacterium longum subsp infantis 16p1 compared to untreated animals. Likewise, a significant decrease was observed in both IL-6 and MCP-1 levels.
    [0180]
    [0181] In contrast, levels of IL-10, a cytokine that regulates the immune response and inhibits pro-inflammatory molecules (including TNF-a), were maintained. elevated with Bifidobacterium longum subsp infantis 16p1 as it occurred in the basal situation.
    [0182]
    [0183] b) In vitro:
    [0184] Figure 2 shows the in vitro production of cytokines measured in the culture supernatant. When evaluating the direct response of the kupffer cells against each of the strains studied, we observed that the expression of the mediators MCP-1, and IL-6 was increased in all cases with respect to the cells that were not stimulated, however, this increase was only similar to that of the LPS-stimulated macrophages in the cultures treated with the MT7 and G1 strains. The cells treated with Bifidobacterium longum subsp infantis 16p1 hardly increased IL-6 production, unlike what happened with LPS or the rest of the studied strains. Similarly, in the presence of this strain, TNF-a levels were also not increased with respect to baseline conditions. Furthermore, these results were accompanied by a decrease in the production of the chemotactic protein MCP-1, implicated in the recruitment of monocytes and basophils to areas of inflammation.
    [0185]
    [0186] Figure 3 shows the direct comparison of the use of the Bifidobacterium longum subsp infantis 16p1 strain in Kupffer cells versus LPS and cells not stimulated in the production of cytokines in the culture supernatants, ruling out the MT7 and G1 strains. As can be clearly seen, the use of the strain of the invention maintained cytokine levels at concentrations similar to those of unstimulated cells. That is, the Bifidobacterium longum subsp infantis 16p1 strain does not induce the secretion of inflammatory mediators in Kupffer cells.
    [0187]
    [0188] Conclusion:
    [0189] With these results it can be concluded that the Bifidobacterium longum subsp infantis 16p1 strain reduces peripheral levels in vivo of the proinflammatory cytokine TNF-a and IL-6 in a model of liver damage. Furthermore, this strain exerts its effect without inducing a proinflammatory response in vitro in Kupfer cells isolated from the liver, which is indispensable in any strain with potential use as a probiotic. All this makes the Bifidobacterium longum subsp infantis 16p1 strain a bacterial strain of potential interest for probiotic use by reducing inflammation induced in an experimental model of cholestasis liver damage.
    [0190] Example 2: Treatment of mice with intestinal inflammation Animals and Methods:
    [0191] Study design:
    [0192] Male Sprague-Dawley rats (Harían, Barcelona, Spain) weighing 100-150 g were included. Rats were individually housed at a constant room temperature of 21 ° C and exposed to a 12:12 light / dark cycle. Animals were fed standard food throughout the study protocol. The protocol spanned a total of 6 weeks. After one week of quarantine, animals were subjected to inflammatory bowel disease by treatment with 3% DSS in drinking water. Laparotomy and sampling was performed under Isofluorane anesthesia one week after the start of treatment.
    [0193]
    [0194] A) In vitro study : The intestine was isolated and cut into 1.5cm pieces, which were placed in a 50mL tube preheated with HBSS / FBS and 2mM EDTA, and stirred twice at 250rpm for 20 minutes at 37 ° C. The intestinal pieces were then transferred to a collagenase solution (1.5mg / mL collagenase VIII in HBSS / FBS with 40pg / mL DNAse I), and stirred at 200rpm for 15 minutes at 37 ° C. Tissue debris was filtered (100pm) into another 50mL tube. The resulting solution was centrifuged again at 1500rpm for 5 minutes at 4 ° C until a cell pellet was obtained and the supernatant was removed.
    [0195]
    [0196] Isolation of intestinal macrophages was carried out by magnetic separation, according to their expression of the macrophage differentiation marker CD45, F4 / 80 + and CD11c.
    [0197]
    [0198] The extracted macrophages were cultured for 48 hours alone (106 cells / mL RPMI), with LPS, or with each of the three strains to be analyzed:
    [0199] + Bifidobacterium bifidum MT7 (5x105 CFUs / well),
    [0200] + Bifidobacterium bifidum G1 (5105 CFUs / well)
    [0201] + Bifidobacterium longum subsp infantis 16p1 (5105 CFUs / well).
    [0202]
    [0203] After 48 hours of culture, the supernatants were stored at -20 ° C until the inflammatory response was evaluated using ELISA kits (IL-6, IL-10, MCP-1,
    [0204] TNF-a).
    [0205] B) In vivo study: One week prior to laparotomy, coinciding with DSS treatment, the animals were divided into groups and randomly received one of the strains included in the study (109 CFU / oral / day / 7 days). .
    [0206]
    [0207] Animals were divided into 4 groups: 1) untreated, 2) B. bifidum MT7, 3) B. bifidum G1 and 4) B. longum subsp infantis16p1. All the animals were sacrificed at the end of the treatment and were taken
    [0208] serum samples that were stored at -20 ° C until measurements were made to assess the inflammatory response using ELISA kits (IL-6, IL-10, MCP-1, TNF-a).
    [0209]
    [0210] The culture conditions of the strains, the realization of the different ELISA kits and the statistical analysis were carried out in the same way as in Example 1.
    [0211]
    [0212] Results:
    [0213] A total of 22 animals were initially included in the study. None of the DSS-treated rats (n = 18) or any of the control rats (n = 4) died during the study protocol. Rats were randomized to study in vivo (n = 12) or in vitro (n = 6). Within the in vivo study , they were also randomized to belong to any of the treatment groups with the different strains of bifidobacteria (n = 4 / group) the week prior to laparotomy. The expression of soluble inflammatory mediators such as IL-6, IL-10, MCP-1 and TNF-a in the serum and the supernatant of the cultures performed was quantified.
    [0214]
    [0215] a) In vitro:
    [0216] Figure 4 shows the in vitro production of cytokines measured in the culture supernatant. When evaluating the direct response of the intestinal macrophages against each of the studied strains, we observed that the expression of the mediators MCP-1, IL-6 and TNF-a was increased in all cases with respect to the cells that were not However, this increase was only similar to that of the LPS-stimulated macrophages in the cultures treated with the MT7 and G1 strains. The cells treated with Bifidobacterium longum subsp infantis 16p1 hardly increased IL-6 production, unlike what happened with LPS or the rest of the studied strains. Similarly, in In the presence of this strain, TNF-a levels were also not increased with respect to baseline conditions.
    [0217]
    [0218] Figure 5 shows the direct comparison of the use of the Bifidobacterium longum subsp infantis 16p1 strain in Kupffer cells against LPS and cells not stimulated in the production of cytokines in culture supernatants, ruling out the MT7 and G1 strains. The use of the strain of the invention maintained cytokine levels at concentrations similar to those of unstimulated cells. That is, the Bifidobacterium longum subsp infantis 16p1 strain does not induce the secretion of inflammatory mediators in intestinal macrophages.
    [0219]
    [0220] b) In vivo:
    [0221]
    [0222] The results of the measurements made in serum (Figure 6) reflected a clear decrease in the pro-inflammatory response. Both TNF-a levels and Il-6 and MCP-1 levels were lower in the group of animals treated orally with Bifidobacterium longum subsp infantis 16p1 compared to untreated animals.
    [0223] In contrast, IL-10 levels were maintained elevated with Bifidobacterium longum subsp infantis 16p1 as occurred in the baseline situation.
    [0224]
    [0225] Conclusion:
    [0226] With these results it can be concluded that the Bifidobacterium longum subsp infantis 16p1 strain reduces peripheral levels in vivo of the proinflammatory cytokine TNF-a, IL-6 and MCP-1 in a model of intestinal inflammation. Furthermore, this strain exerts its effect without inducing a proinflammatory response in vitro in isolated macrophages from the intestinal wall, which is indispensable in any strain with potential use as a probiotic. All this makes the Bifidobacterium longum subsp infantis 16p1 strain a bacterial strain of potential interest for probiotic use by reducing the inflammation induced in an experimental model of intestinal inflammation.
    权利要求:
    Claims (19)
    [1]
    1. Bifidobacterium longum sub strain . infantis with deposit number CECT 9720.
    [2]
    2. Strain according to claim 1, wherein said strain is in the form of viable cells or in the form of non-viable cells.
    [3]
    3. Cellular components, metabolites, secreted molecules or any of their combinations obtained from the strain according to any of claims 1 to 2.
    [4]
    4. Composition comprising the strain according to any of claims 1 to 2 or the cellular components, metabolites, secreted molecules, or any of their combinations, according to claim 3.
    [5]
    5. Composition according to claim 4, additionally comprising at least one bioactive component.
    [6]
    6. Composition according to any of claims 4 to 5, wherein said composition is a pharmaceutical composition.
    [7]
    7. Composition according to claim 6, additionally comprising at least one pharmaceutically acceptable vehicle and / or excipient.
    [8]
    Composition according to any one of Claims 6 to 7, wherein said composition is presented in a form adapted for oral, sublingual, nasal, intracathecal, bronchial, lymphatic, rectal, transdermal, inhaled or parenteral administration.
    [9]
    9. Composition according to claim 8, wherein said composition is presented in a form adapted for oral administration.
    [10]
    10. Composition according to any of claims 4 to 5, wherein said composition is a nutritional composition.
    [11]
    11. Composition according to claim 10, wherein the composition is selected from a food, a supplement, a nutraceutical, a probiotic or a symbiotic.
    [12]
    12. Strain according to any of claims 1 to 2, or of the composition according to any of claims 3 to 5, for use as a medicine.
    [13]
    13. Strain or composition for use according to claim 12 for the prevention and / or treatment of liver inflammation.
    [14]
    14. Strain or composition for use according to claim 12 for prevention and / or treatment of liver cirrhosis.
    [15]
    15. Strain or composition for use according to claim 12 for the prevention and / or treatment of inflammatory bowel disease.
    [16]
    16. Strain or composition for use according to claim 12 for the prevention and / or simultaneous treatment of inflammatory bowel disease and liver inflammation.
    [17]
    17. Strain or composition for use according to claim 12 for the prevention and / or simultaneous treatment of inflammatory bowel disease and liver cirrhosis.
    [18]
    18. Strain or composition for use according to any of claims 15 to 17 wherein the inflammatory bowel disease is selected from the list comprising: Crohn's disease, ulcerative colitis, undetermined colitis, collagen colitis, lymphocytic colitis.
    [19]
    19. Use of the strain according to any of claims 1 to 2, or of the composition according to any of claims 4 to 5 for the preparation of a food.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    WO2000042429A2|1999-01-15|2000-07-20|Enterprise Ireland|In vitro model for gastrointestinal inflammation|
    WO2004069156A2|2003-01-30|2004-08-19|The Regents Of The University Of California|Inactivated probiotic bacteria and methods of use thereof|
    WO2005077391A1|2004-02-17|2005-08-25|Synbiotics Ab|New synbiotic use|
    WO2009134948A1|2008-05-01|2009-11-05|The Procter & Gamble Company|Methods and kits for the treatment of inflammatory bowel disorder conditions|
    WO2018180728A1|2017-03-30|2018-10-04|森永乳業株式会社|Composition for promoting expression of antiinflammatory gene|
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