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  • 专利说明
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    • 专利摘要:
    LACTOBACILLUS PLANTARUM STRAPS AS HYPOCOLESTEROLEMIC AGENTS. The invention relates to a composition comprising an effective amount of at least one of the strains selected from the group consisting of Lactobacillus plantarum CECT 7527, Lactobacillus plantarum CECT 7528, and Lactobacillus plantarum CECT 7529. These new strains have good probiotic characteristics and are useful for the prevention and / or treatment of cardiovascular disorders.
    公开号:BR112012008005B1
    申请号:R112012008005-9
    申请日:2010-09-28
    公开日:2021-01-26
    发明作者:Jordi Cune Castelana
    申请人:Ab-Biotics S.A.；
    IPC主号:
    专利说明:

    [0001] [0001] This application claims the benefit of European Patent Application 09172613.3, filed on October 9, 2009 and US Provisional Patent Application No. 61 / 265,095 filed on November 30, 2009. Field of the Invention
    [0002] [0002] The present invention relates to the fields of medicine, microbiology and nutrition, and particularly to new probiotic strains of Lactobacillus plantarum for use in reducing cholesterol. Background of the Invention
    [0003] [0003] Extremely high cholesterol levels (hypercholesterolemia) are strongly associated with cardiovascular disease because they promote the development of atheroma in the arteries.
    [0004] [0004] Potential hypocholesterolemic food products and pharmaceuticals are continually being developed to control serum cholesterol in people with extremely high levels. These pharmaceutical products can be based on the interruption of the enterohepatic circulation (EHC) of bile salts. The metabolism of bile salts and the metabolism of cholesterol are closely linked. Bile salts are the final products excreted (water soluble) of cholesterol and are essential for the emulsification of fats in the digestive tract. They are synthesized in the liver mainly as glyco or tauroconjugates. Bile salts are secreted several times a day (six on average) in the duodenum, and pass through the jejunum into the ileum. During intestinal transit, most bile salts are reabsorbed to return to the liver via the portal vein. A small proportion is lost within the stool and this loss is again synthesized from endogenous cholesterol in the liver. An increase in the amount of bile salts that are lost within the stool results in increased cholesterol neosynthesis, thereby effectively reducing the pool of endogenous cholesterol. A group of currently used hypocholesterolemic drugs, called resins (Colestyramine, Colestipol, Colesevelam), is active through this mechanism of action.
    [0005] [0005] Apart from pharmaceutical or surgical attempts to decrease serum cholesterol levels by stopping EHC, it has been suggested that the ingestion of certain bacterial cells should also influence cholesterol levels. Intestinal bacteria can influence cholesterol levels through the assimilation of exogenous cholesterol from the diet in the bacterial membrane or through the breakdown of bile salts. During intestinal transit, bile salts undergo a number of bacterial transformations, one of the most important of which is the breakdown of bile salts. The ability to decouple (or hydrolyze) bile salts is found in some species of intestinal lactic acid (LAB) bacteria, but also in other genera. Upon disjugation of the bile salts, glycine or taurine is released from the steroidal portion of the molecule, resulting in the formation of free (unconjugated) bile salts. Free bile salts are more easily precipitated at low pH. They are also less effectively reabsorbed than their combined counterparts. Therefore, unconjugated bile salts are more readily excreted into the faeces than conjugated bile salts. The disjugation of bile salts influences EHC by increasing the excretion of bile salts and is believed to be more effective in lowering blood cholesterol levels than merely retaining exogenous cholesterol.
    [0006] [0006] Bile salt hydrolase (BSH), the enzyme responsible for the breakdown of bile salts during EHC, has been detected in several LAB species native to the gastrointestinal tract. Tanaka et al. (See "Screening of Lactic Acid Bacteria for Bile Salt Hydrolase Activity", Journal of Dairy Science 1999, vol. 82, pages 2530 to 2535) examined more than 300 strains of LAB from the genera Bifidobacterium and Lactobacillus and the species Lactococcus lactis, Leuconostoc mesenteroides, and Streptococcus thermophilus. The results obtained for 273 strains showed that the BSH activity is heterogeneously distributed among the different species. According to this study, almost all bifidobacterial strains have BSH activity, and this activity can only be found in selected strains of lactobacilli.
    [0007] [0007] Lactobacillus plantarum is a Gram-positive air-tolerant LAB generally found in many fermented food products as well as anaerobic plant material. It is also present in the saliva (from which it was first isolated). L. plantarum strains are especially suitable for the industrial preparation of fermented food products thanks to their good survival rate through the industrial process and the conservation period, as well as their high acidification profile and good organoleptic properties. Some strains of L. plantarum are also considered to be probiotics. Probiotics are live microorganisms that, when administered in adequate amounts, confer a benefit to the health of the host. To be called a probiotic, the bacterium must fulfill several requirements related to its absence of toxicity, viability in reaching the lower gastrointestinal tract (GIT) and adherence to the intestinal mucosa, among others. Most probiotic bacteria belong to the LAB group, but, nevertheless, it is known that the probiotic characteristics and benefits are extremely dependent on the strain, even among LAB of the same species.
    [0008] [0008] The commercial strain of L. plantarum 299v is generally considered to be probiotic and has been described as decreasing serum fibrinogen and cholesterol levels when ingested as a probiotic drink (see Bukowska et al., "Decrease in fibrinogen and LDL- cholesterol levels upon supplementation of diet with Lactobacillus plantarum in subjects with moderately elevated cholesterol "Atherosclerosis 1998, vol. 137, pages 437 to 438). However, the reduction in LDL cholesterol was very moderate in these studies and was accompanied by a similar mild reduction in HDL cholesterol. No BSHA-related data for L. plantarum 299v has been published.
    [0009] [0009] It is therefore desirable to provide new improved probiotic strains to be used as hypocholesterolemic agents. Summary of the Invention
    [0010] [00010] The present invention provides new improved probiotic strains for the reduction of blood cholesterol and, consequently, for the prevention and treatment of cardiovascular disorders.
    [0011] [00011] Three new probiotic strains of Lactobacillus plantarum isolated from human feces are provided by the present inventors. The strains were found to have surprisingly high BSH activity. As mentioned above, the close relationship between high bacterial BSH activity and cholesterol reduction makes the present strains useful as hypocholesterolemic agents. The working examples below demonstrate that these strains have significantly higher BSH activity compared to relevant commercially available L. plantarum strains, such as L. plantarum 299v or the L. plantarum strain that is present in the commercial probiotic mixture VSL # 3. It is also shown that the strains of the invention are effective in reducing cholesterol in culture from medium containing soluble cholesterol. Even though each of the new strains demonstrates advantages over the known strains, these advantages are increased when the three strains are used together, thus showing a synergistic behavior.
    [0012] [00012] The cholesterol-lowering activity of the strains of the invention has also been demonstrated in vivo. The example below demonstrates that a product containing the probiotic strains of the invention is particularly effective in reducing cholesterol when administered to hypercholesterolemic individuals.
    [0013] [00013] Consequently, a first aspect of the invention relates to a composition comprising an effective amount of at least one of the strains selected from the group consisting of Lactobacillus plantarum CECT 7527, Lactobacillus plantarum CECT 7528, and Lactobacillus plantarum CECT 7529, or mutant strains thereof, the mutant strains being obtained using the deposited strains as starting material and the mutant strains retain or further enhance the cholesterol-lowering activity of the original strains. In a particular embodiment, the invention relates to a composition that comprises an effective amount of at least one of the strains selected from the group consisting of Lactobacillus plantarum CECT 7527, Lactobacillus plantarum CECT 7528, and Lactobacillus plantarum CECT 7529, mutant strains are obtained using the deposited strains as starting material and the mutant strains retain or further enhance the cholesterol-lowering activity of the original strains. In a particular embodiment, the invention relates to a composition that comprises an effective amount of at least one of the strains selected from the group consisting of Lactobacillus plantarum CECT 7527, Lactobacillus plantarum CECT 7528, and Lactobacillus plantarum CECT 7529.
    [0014] [00014] The term "effective amount", as used here, means an amount of an active agent high enough to deliver the desired benefit, but low enough to avoid serious side effects within the scope of medical judgment.
    [0015] [00015] Another embodiment of the present invention relates to a composition comprising an effective amount of Lactobacillus plantarum CECT 7527, Lactobacillus plantarum CECT 7528, and Lactobacillus plantarum CECT 7529 or mutant strains thereof, the mutant strains being obtained using the deposited strains as starting material, and the mutant strains retain or even enhance the cholesterol-lowering activity of the original strains. In a particular embodiment, the composition of the invention comprises an effective amount of Lactobacillus plantarum CECT 7527, Lactobacillus plantarum CECT 7528, and Lactobacillus plantarum CECT 7529.
    [0016] [00016] It is clear that using the strains deposited as starting material, the person skilled in the art can repeatedly, by conventional mutagenesis or re-isolation techniques, obtain more mutants or derivatives of them that retain the characteristics and advantages described here. Consequently, the term "such a mutant" refers to mutant strains obtained using the deposited strains as starting material, said mutant strains retaining or improving the cholesterol-lowering properties of the original strains. The person skilled in the art will decide using the appropriate method to be employed to determine the cholesterol-lowering activity of the strains. Examples of possible methods for measuring this activity are shown in the examples below.
    [0017] [00017] The strains of this invention have the advantage that they are particularly useful as probiotics. As mentioned above, probiotic bacteria must fulfill several requirements related to the absence of toxicity, viability, adhesion and beneficial effects. These probiotic characteristics are dependent on the strain, even among bacteria of the same species. So, it is important to find those strains that perform best in all probiotic requirements. The examples below demonstrate that the present strains have excellent probiotic characteristics.
    [0018] [00018] The strains of the invention demonstrated that they are highly resistant to the conditions of the mammalian gastrointestinal environment (acidic environment, high concentrations of lysozymes, bile salts and oxygen peroxide), thus being able to survive the passage through the GIT. Strains also have good adhesion to the intestinal epithelium, which allows them to remain in the intestinal tract and exert their probiotic effects. When compared to other commercial strains, the strains of the invention show better resistance to GIT conditions and greater adherence capacity. In addition, they have also been shown to be safe, since they have no toxic effects, they do not lead to an increase in LAB translocation, nor do they facilitate enterobacterial translocation in host mammals.
    [0019] [00019] Furthermore, the present strains have several beneficial effects on the host. In addition to their cholesterol-lowering activity, they benefit the balance of the intestinal microbiota due to their antagonistic activity. The term "antagonistic activity" refers to the inhibition of the growth of non-beneficial gastrointestinal bacteria by the activity of probiotic bacteria. The condition of having inadequate gastrointestinal microbial balance is known as dysbiosis and has many negative consequences for humans. It is shown below that the strains have a greater capacity to inhibit the growth of pathogenic strains when compared to other commercial strains of L. plantarum.
    [0020] [00020] Strains also produce large amounts of short-chain fatty acids (SCFA). The production of SCFA from non-digestible fibers is an interesting probiotic capacity. This ability is desirable in a probiotic because the SCFA produced shows several beneficial properties in the host (see Wong J., "Colonic health: fermentation and short chain fatty acids", J Clin Gastroenterol 2006, vol. 40, pages 235 to 243). Among SCFA, the production of propionic and butyric acid is of greatest interest for the scope of the present invention. The first has a useful anti-inflammatory effect in order to reduce systemic inflammation. Global inflammation has an incidence in atherogenesis, which is one of the most important cardiovascular risk factors (see Naruszewicz M., "Potential parapharmaceuticals in the traditional Polish diet" 2005, Journal of Physiology and Pharmacology, vol. 56, suppl 1, p. 69 to 78). Butyric acid is generally known to be beneficial for the colonic epithelium, since it is the main source of energy for colonic cells.
    [0021] [00021] By exerting several beneficial effects on the human host, these probiotic bacteria are useful as therapeutic or prophylactic agents. In particular, the strains of the present invention are effective in reducing blood cholesterol levels. As explained above, high cholesterol levels are strongly associated with cardiovascular disease because they promote the development of atheroma in the arteries. Thus, strains of the invention are useful for the prevention or treatment of cardiovascular disorders.
    [0022] [00022] Accordingly, another aspect of the invention relates to a composition comprising an effective amount of at least one of the strains of this invention, or mutant strains thereof, for use as a preventive and / or therapeutic agent. In a preferred embodiment, the composition of the invention is for use in preventing or treating cardiovascular disorders in an animal, including a human. In another preferred embodiment, the invention provides the use of the composition as described above for the manufacture of a medicament for the prevention and / or treatment of cardiovascular disorders. It can alternatively be formulated as a method for the prevention and / or treatment of cardiovascular disorders in an animal, including a human, comprising administering to said animal in need of treatment an effective amount of the composition of the invention.
    [0023] [00023] In another embodiment, the composition of the invention is used as a hypocholesterolemic agent. In a further embodiment, the invention provides the use of the composition as described above for the manufacture of a cholesterol-lowering medicament. It can alternatively be formulated as a method for reducing cholesterol in an animal, including a human, comprising administering to said animal in need of treatment an effective amount of the composition of the invention.
    [0024] [00024] The composition of the invention can be administered to healthy individuals as well as to patients suffering from a coronary disorder. In a particular embodiment, the individual receiving the composition of the invention suffers from hypercholesterolemia.
    [0025] [00025] The probiotic compositions of the invention have the additional advantage of being free of side effects presented by plant sterols, which have been described as being contraindicated in combination with statin in sterol hyperabsorbent individuals. Recent evidence suggests that the residual coronary risk seen with statin monotherapy is a consequence of statins actually increasing coronary risk in patients who are steroidal hyperabsorbents, including plant sterols. The amount of hyperabsorptive sterol individuals is around 25% of the population and most of them have been shown to contain polymorphisms in the ABCG8 binding medium (ABC) medium to adenosine-5'-triphosphate (ATP) (Goldstein M et al. , "Statins, plant sterol absorption, and increased coronary risk." Journal of Clinical Lipidology, 2008, vol. 2, pages 304 to 305). In addition, it has been suggested that the effects of enriching dietary plant sterol and statin therapy are additive in raising plant sterol levels in tissues and blood, and that these are particularly evident in sterol hyperabsorbents. The probiotic composition of the invention does not have these disadvantages and can be administered to any population and in combination with strains or any other cholesterol-lowering drug.
    [0026] [00026] Thus, in a particular embodiment, the composition of the invention is administered to individuals sterol hyperabsorbents. In another particular embodiment, the composition of the invention is administered in combination with a statin.
    [0027] [00027] Strains of the invention also promote immunomodulatory effects on the host, since they induce an enhanced cytokine pattern from the intestinal mucosa. These immunomodulatory effects are beneficial to the host because they help to achieve increased resistance to disease and decreased risk of allergies. Gram-positive bacteria that live in the GIT are known to show the LPS (lipo-polysaccharide) molecule on their cell surface, which induces the production of inflammatory markers from the cells of the intestinal mucosa. Probiotic supplementation can change this situation to favor a greater presence of Gram-positive bacteria in the GIT (grouped in the group of lactic acid bacteria), with better ecological adaptation or with antagonistic properties against some Gram-negative microorganisms, thus reducing the presence of LPS in the intestinal mucosa. However, some probiotic microorganisms show the ability to modulate the production of cytokines themselves, which are messenger molecules that regulate the inflammatory and immune responses in the body. In particular, some probiotic bacteria induce a better balanced pattern between pro / anti-inflammatory signaling in the intestinal mucosa (without reducing the number of Gram-negative bacteria). As mentioned above, this bacterially stimulated immunomodulation also has an anti-atherosclerotic effect.
    [0028] [00028] As will be illustrated below, it was concluded that the strains of the invention on their own promote a reduction in inflammatory levels of tumor necrosis factor α (TNF-α) and an increase in levels of interleukin-10 (IL-10) anti-inflammatory cells produced by intestinal mucosa cells, thus inducing an enhanced cytokine pattern from the intestinal mucosa. This immunomodulatory effect is complemented by the antagonistic properties of the strain in reducing the presence of pathogenic Gram-negative bacteria in the GIT and decreasing the amount of LPS in the intestinal mucosa.
    [0029] [00029] The compositions according to the invention that comprise an effective amount of at least one of the deposited strains or their mutants can be formulated as edible pharmaceutical or veterinary products, in which said strains are the only active agents or are mixed with one or more other active agents and / or are mixed with veterinary or pharmaceutically acceptable excipients (in the case of a pharmaceutical or veterinary product) or suitable additives (in the case of an edible product). In a particular embodiment of the invention, the products additionally contain one or more additional active agents. Preferably, the additional active agent or agents are other probiotic bacteria. Depending on the formulation, strains can be added as purified bacteria, as a bacterial culture, as part of a bacterial culture, as a bacterial culture that has been post-treated, and alone or together with suitable carriers or ingredients. Prebiotics could also be added, giving rise to a symbiotic composition. In a particular embodiment, the compositions of the invention additionally contain a prebiotic selected from the group consisting of fructooligosaccharides and galactooligosaccharides.
    [0030] [00030] In another aspect, the invention provides a pharmaceutical and / or veterinary product that contains an effective amount of a composition comprising at least one of the deposited strains or mutant strains thereof, together with suitable amounts of veterinary or pharmaceutically acceptable excipients. In this respect, the pharmaceutical product can be prepared to be administered orally in the form of tablets, pills, capsules, microcapsules, granules, suspensions, syrups, post-lyophilized, liquid preparations, etc. The selection of excipients and the most appropriate methods for formulation in view of the particular purpose of the composition are within the scope of those skilled in the art of pharmaceutical technology. Although oral administration is preferred, other forms are possible, such as the injectable, rectal or topical form.
    [0031] [00031] The term "pharmaceutically acceptable", as used here, belongs to compounds, materials, compositions and / or dosage forms that are, within the scope of medical judgment, suitable for use in contact with an individual's tissues (eg example, a human being) without toxicity, irritation, excessive allergic response, or other problem or complication, proportional to a reasonable risk / benefit ratio. Each carrier, excipient, etc. it must also be "acceptable" in the sense of being compatible with the other ingredients in the formulation. Carriers, excipients, etc. suitable pharmaceuticals can be found in standard pharmaceutical texts. Also, the term "veterinarily acceptable" means suitable for use in contact with the tissues of a non-human animal.
    [0032] [00032] Strains of the invention can also be included in a variety of edible products, such as dairy products, yogurts, curds, cheeses (for example, curd, cream, processed, soft or hard), fermented milk, dairy powder, product fermented milk-based, ice cream, fermented cereal-based product, milk-based powder, drink, seasoning and feed. The term "edible product" is used here in its broadest sense, including any type of product, in any form of presentation, which can be ingested by an animal, but excluding pharmaceutical and veterinary products. Examples of other edible products are meat products (eg liver paste, sausage and sausage or meat pastes), chocolate pastes, fillings (eg truffle, cream) and toppings, chocolate, sweets (eg , caramel, fondants or caramel candies), baked goods (cakes, pasta), sauces and soups, fruit juices and coffee bleaches. Particularly interesting edible products are dietary supplements and infant formulas. In the sense of the present invention, dietary supplements also include nutraceuticals, which are known to be extracts from foods that have a medicinal effect on human health. Forages for animal feed are also included in the scope of the invention. The compositions of the invention could also be used as an ingredient in other food products.
    [0033] [00033] Consequently, in another aspect of the invention, a
    权利要求:
    Claims (2)
    [0001]
    Composition, characterized by the fact that it comprises an effective amount of at least one of the strains selected from the group consisting of Lactobacillus plantarum CECT 7527, Lactobacillus plantarum CECT 7528, and Lactobacillus plantarum CECT 7529 for use as a preventive and / or therapeutic agent.
    [0002]
    Composition, characterized by the fact that it comprises an effective amount of the strains Lactobacillus plantarum CECT 7527, Lactobacillus plantarum CECT 7528, and Lactobacillus plantarum CECT 7529.
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    法律状态:
    2017-12-12| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |
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