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    • 专利摘要:
    use of a composition comprising microorganisms to increase intestinal production of butyric acid, folic acid or niacin and/or decrease intestinal production of succinic acid The present invention relates to the use of a composition comprising bacteria to increase intestinal production of butyric acid, folic acid or niacin and/or to decrease intestinal production of succinic acid. further, the present invention relates to the use of said composition for treating and/or preventing a pathological condition dependent on butyrate and/or succinate. in particular, for the treatment and/or prevention of intestinal inflammation, diarrhea, ulcerative colitis or intestinal colopathies.
    公开号:BR112016005059B1
    申请号:R112016005059-2
    申请日:2014-09-05
    公开日:2022-01-04
    发明作者:Ruggero ROSSI；Simone Domenico Guglielmetti；Andrea BIFFI；Walter FIORE
    申请人:Sofar S.P.A.；
    IPC主号:
    专利说明:

    [0001] The present invention relates to the use of a composition comprising bacteria in order to increase intestinal production of butyric acid, folic acid or niacin and/or to decrease intestinal production of succinic acid. Furthermore, the present invention relates to the use of said composition for the treatment and/or prevention of an intestinal pathological condition dependent on butyrate and/or succinate, in particular, for the treatment and/or prevention of intestinal inflammation, diarrhea, colitis ulcerative disease or intestinal colopatitis.
    [0002] Gut microbiota, also known by the now obsolete term gut flora, is the totality of microorganisms, consisting predominantly of bacteria, residing in the gut and in symbiosis with the host body.
    [0003] The intestinal microbiota is an extremely complex ecosystem and the condition of balance between the different microorganisms that make up the intestine is fundamental in order to ensure the well-being and health of the body, since the microbial flora significantly conditions the development and homeostasis of the host individual's intestinal mucosa.
    [0004] In other words, the gut microbiota represents a true organ. In fact, qualitative and/or quantitative changes in the intestinal microbiota of an individual, or the so-called dysbiosis or dysmicrobism, can result in the loss of intestinal homeostasis, which in turn can condition the etiopathogenesis of a large number of pathologies.
    [0005] For the purpose of treating a condition of intestinal dysbiosis, or, in any case, for the purpose of maintaining the homeostasis of the intestinal microbiota, people often take substances that are defined as probiotics, or, according to the definition from the FAO/WHO, "live microorganisms which, when administered in adequate amounts, confer a health benefit on the host". Likewise, the effectiveness of paraprobiotics for health has also been demonstrated; these are defined as "non-viable (intact or broken) microbial cells or crude cell extracts that, when administered in adequate amounts (orally or topically), confer a health benefit on the host" (Taverniti and Guglielmetti, 2011).
    [0006] It is clear that the beneficial activities of a microorganism will vary depending on its composition and, in fact, these are usually strain-specific activities.
    [0007] Based on the above considerations, there continues to be a felt need to determine new health promoting and/or therapeutic effects of microorganisms, in particular those included in a probiotic or a paraprobiotic, in order to broaden the applications of use.
    [0008] For example, a need continues to be felt in the art to identify microorganisms capable of modulating the intestinal amount of substances that are particularly beneficial and therapeutic for the body, such as butyric acid, folic acid and nicotinic acid.
    [0009] Butyric acid is a short-chain fatty acid that is physiologically formed in the colon of humans as a result of the fermentation of dietary fiber by microbiota.
    [0010] Butyric acid is the main source of energy for colon cells (colonocytes) and is therefore a nutrient that is essential for the human body.
    [0011] At the intestinal level, butyric acid performs several important functions, eg: it stimulates the volume and physiological maturation of colonocytes; it plays a fundamental role in the maintenance of mucosal integrity and in the repair processes of intestinal lesions; stimulates the reabsorption of water and sodium in the colon; and contributes to the reduction of intestinal pH, creating an environment that is unfavorable for the development of pathogenic bacteria.
    [0012] Butyric acid deficiency can cause inflammatory colitis in humans.
    [0013] Succinic acid is also a short-chain organic acid of the dicarboxylic type. It is considered ulcerogenic and can cause serious damage to the mucosa. Consequently, an increase in the amount of succinic acid (succinate) is harmful to human health.
    [0014] Folic acid (vitamin B9, or H or folacin) is an important vitamin for the entire population, especially in adults over 50 years of age and in women of childbearing age, because it intervenes (directly or, in the most often, by decreasing plasma homocysteine levels) in many vital processes, such as DNA synthesis, repair and methylation.
    [0015] Folic acid deficiency can lead to macrocytic anemia, which can be accompanied by leukopenia and thrombocytopenia, skin and mucosal changes, and gastrointestinal disturbances (malabsorption and diarrhea). Niacin (vitamin PP or vitamin B3), nicotinic acid and nicotinamide is important because, among other things, it is the essential component of the NAD and NADH coenzymes and a deficiency of the same causes a pathology known as pellagra. Usually, this pathology starts with problems in the gastrointestinal system, which are then compounded by photosensitizing dermatitis, mental disorders with fatigue, depression and memory disorders.
    [0016] The present invention responds to the needs of the state of the art described above, with a composition that comprises microorganisms, preferably bacteria of the genus Lactobacillus species paracasei, capable of (directly and/or indirectly) increasing, in an individual that takes, the production intestinal tract of butyric acid, folic acid, niacin and/or their salts.
    [0017] Furthermore, the Applicant found, quite unexpectedly, that a composition comprising microorganisms, preferably of the genus Lactobacillus species paracasei, is capable of (directly and/or indirectly) decreasing the intestinal production of succinic acid and/or the your salts. Therefore, the composition of the present invention is particularly advantageous for the treatment and/or prevention of intestinal succinate and/or butyrate dependent pathological conditions.
    [0018] Other advantages of the present invention will be more apparent from the detailed description which follows and from the examples which, however, are for demonstrative, not limiting purposes only.
    [0019] To allow a better understanding of the detailed description, Figures 1-4 have been attached:
    [0020] - Figure 1.1 shows the result of the statistical analysis that demonstrates the increase in the population of bacteria of the genus Coprococcus before and after treatment with the composition of the present invention (A) and the decrease of the same, in contrast, before and after placebo treatment (B);
    [0021] - Figure 1.2 shows the result of the statistical analysis demonstrating the decrease in the population of bacteria of the genus Blautia before and after treatment with the composition of the present invention (A) and the increase of the same, in contrast, before and after the treatment. placebo treatment (B);
    [0022] - Figure 2.1 shows the increase in the population of bacteria of the genus Coprococcus (dark gray) and the decrease in the population of bacteria of the genus Blautia (light gray) before and after treatment with the composition of the present invention;
    [0023] - Figure 2.2 shows the percentage increase in the population of bacteria of the genus Coprococcus (dark gray) and the percentage decrease in the population of bacteria of the genus Blautia (light gray) before and after treatment with the composition of the present invention ( A) and the percentage decrease in the population of bacteria of the genus Coprococcus (dark gray) and the percentage increase in the population of bacteria of the genus Blautia (light gray) before and after treatment with the placebo (B);
    [0024] - Figure 3 shows the result of the statistical analysis demonstrating the increase in nicotinic acid metabolism, before and after treatment with the composition of the present invention and the reduction of the same before and after treatment with placebo;
    [0025] - Figure 4 shows the result of the statistical analysis demonstrating the increase in folic acid biosynthesis before and after treatment with the composition of the present invention and an absence of any modifications, in contrast, before and after treatment with the placebo .
    [0026] The present invention relates to the use of a composition comprising microorganisms, preferably at least one bacterium of the genus Lactobacillus species paracasei, to increase the direct and/or indirect intestinal production of butyric acid and/or the its salts, and/or folic acid and/or its salts, and/or niacin and/or its salts and/or to decrease the direct and/or indirect intestinal production of succinic acid and/or its salts.
    [0027] In the context of the present invention, intestinal production releases, to the environment, any molecule produced by primary or secondary metabolism, any intestinal microorganism in any region of the intestine.
    [0028] In addition, the composition of the present invention can also be used to reduce the intestinal proliferation of pathogenic microorganisms, and/or to promote the integrity of the intestinal mucosa, and/or to promote the processes of repair of intestinal lesions, preferably , by increasing direct and/or indirect intestinal production of butyric acid and/or its salts and/or by decreasing direct and/or indirect intestinal production of succinic acid and/or its salts.
    [0029] Some pathogenic microorganisms particularly sensitive to the composition of the present invention are, for example, enterohemorrhagic Escherichia coli, Listeria monocytogenes, Clostridium difficile, Pseudomonas aeruginosa and Salmonella spp.
    [0030] The above-described uses of the composition of the present invention are intended for both a healthy individual and an individual with a pathological intestinal condition. In particular, in the case of a healthy individual, the composition of the invention exerts in that individual, after ingestion, an action of maintaining the homeostasis of the microbiota and/or preventing its alteration, and is therefore also defined as a composition probiotic (or probiotic).
    [0031] A further aspect of the present invention relates to the medical use of the composition comprising microorganisms, preferably at least one bacterium of the genus Lactobacillus species paracasei, for the treatment and/or prevention of a butyrate-dependent intestinal disease state. and/or succinate.
    [0032] In the context of the present invention, a butyrate and/or succinate-dependent intestinal pathological condition means a pathological condition that is sensitive to treatment with butyric acid and/or its salts and/or treatment with succinic acid and/or its salts. Examples of said pathologies are: diarrhea, intestinal inflammation, ulcerative colitis, gastric atrophy, intestinal diverticula, stenosis, obstructions and diabetic neuropathy.
    [0033] In a particularly preferred embodiment of the present invention, the composition comprises the bacterial strain of Lactobacillus paracasei DG. The bacterial strain Lactobacillus paracasei DG was deposited by SOFAR S.p.A. with the National Collection of Microorganism Cultures of the Pasteur Institute in Paris, on 05/05/1995, with the deposit number CNCM I-1572. Initially, the name of the deposited strain was Lactobacillus casei DG sub.casei.
    [0034] In another embodiment of the invention, the direct and/or indirect increase in intestinal production of butyric acid and/or its salts, and/or folic acid and/or its salts, and/or niacin and/or or its salts and/or the direct and/or indirect reduction in the intestinal production of succinic acid is attributable to the intestinal microbiota, preferably bacteria of the genus Coprococcus and/or Blautia.
    [0035] In the particularly preferred embodiment of the invention, the direct and/or indirect increase in intestinal production of butyric acid and/or its salts is attributable to bacteria of the genus Coprococcus, and/or the direct and/or indirect reduction in intestinal production of succinic acid is attributable to bacteria of the genus Blautia.
    [0036] Therefore, the composition comprising microorganisms, preferably at least one bacterium of the genus Lactobacillus species paracasei, more preferably the bacterial strain of Lactobacillus paracasei DG, can also be used to modify the density of the bacterial population of the genus Coprococcus and/or Blautia in the intestinal microbiota, preferably so as to induce an increase in the bacterial population of the genus Coprococcus and/or a decrease in the bacterial population of the genus Blautia. In other words, ingestion of the composition of the present invention modifies the amount of bacteria of the genus Coprococcus and/or Blautia within the intestinal microbiota. In particular, bacteria of the genus Coprococcus increase and/or bacteria of the genus Blautia decrease after ingestion of said composition.
    [0037] The composition used in the present invention comprises said microorganism, preferably said at least one bacterium of the genus Lactobacillus species paracasei, in live or dead form, as a lysate or extract.
    [0038] In one embodiment of the invention, the composition comprises about 15-30 billion bacterial colony forming units (CFU), preferably 20-25 billion bacterial CFU.
    [0039] Preferably, the composition is formulated for oral administration. In particular, the composition is formulated in solid form, preferably in the form of tablets, capsules, tablets, granulated powder, hard capsules, water-soluble granules, sachets or lozenges.
    [0040] Alternatively, the composition of the invention is formulated in liquid form, for example as a syrup or beverage, or is added to a food, for example, to a yogurt, cheese or fruit.
    [0041] Alternatively, the composition of the invention is formulated in a form capable of exerting an action topically, for example, as an enema.
    [0042] In one embodiment of the invention, the composition additionally comprises excipients generally accepted for the production of probiotic and/or pharmaceutical products.
    [0043] In another embodiment of the invention, the composition of the invention can be enriched with vitamins, trace elements such as zinc and selenium, enzymes, prebiotic substances such as fructooligosaccharides (FOS), galactooligosaccharides (GOS), inulin, guar gum or combinations thereof. Preferably, for the purposes of the uses of the present invention, the composition is taken once a day, more preferably upon waking.
    [0044] Alternatively, they can also be taken overnight, preferably after meals. EXAMPLE Treatment.
    [0045] A double-blind, randomized, placebo-controlled crossover study of dietary intervention was performed in healthy subjects.
    [0046] Volunteers were recruited according to the following criteria:
    [0047] - inclusion criteria: healthy men and women, aged between 18 and 55 years; signing the informed consent form;
    [0048] - exclusion criteria: treatment with antibiotics in the month prior to the examination; episodes of viral or bacterial enteritis in the 2 months prior to the first examination; gastric or duodenal ulcers in the 5 years prior to the first examination; pregnancy or breastfeeding; recent or suspected cases of alcoholism and drug use; other conditions of non-compliance with the study protocol.
    [0049] The probiotic dietary intervention was performed according to a crossover design, as outlined in Table I below. Table I

    [0050] In the pre-registration stage (4 weeks) the volunteers followed their usual diet, without consuming probiotic fermented dairy products (traditional yogurt was thus allowed), probiotic food supplements, or prebiotic food supplements.
    [0051] At the end of the pre-enrollment period, volunteers were randomly assigned to receive one capsule per day of a probiotic or placebo for 4 weeks.
    [0052] By way of example, Enterolactis Plus was used as a probiotic being administered; It consists of 420 mg capsules that contain 24 billion CFU (colony forming units) of Lactobacillus paracasei, the DG strain.
    [0053] The placebo consisted of capsules identical in appearance to the probiotics, obviously devoid of the probiotic agent.
    [0054] The taste and color of the active substance (ie the probiotic) and the placebo were identical.
    [0055] The product was taken in the morning on an empty stomach, at least ten minutes before breakfast, or, in case of forgetfulness, in the evening before going to bed and, in any case, at least two hours after the last meal.
    [0056] After the first four weeks of treatment, volunteers underwent a four-week washout period identical to the pre-enrollment period.
    [0057] At the end of the washout period, volunteers took either one capsule daily of Enterolactis Plus or placebo for four weeks, according to the crossover design described above.
    [0058] In summary, the study involved 4 phases, each of which lasted 4 weeks:
    [0059] • Pre-recruitment phase: Subjects underwent neither treatment A nor treatment B.
    [0060] • Treatment 1: Subjects underwent treatment A or treatment B.
    [0061] • Elimination: Subjects underwent neither treatment A nor treatment B
    [0062] • Treatment 2: subjects undergoing treatment B or treatment A. Treatments A and B can be the composition of the present invention, in the specific example Enterolactis plus, or else the placebo. At the beginning of treatment, it was not known what the individual was taking; only at the end of treatment, when the blind was broken, was the sequence of ingestion known.
    [0063] Examinations and sample collection.
    [0064] Each volunteer was initially instructed on the entire procedure to be followed, which involved a total of 5 meetings per volunteer.
    [0065] During the first meeting, informed consent was obtained along with the volunteer's personal data. The volunteer also received general information about how the study was being carried out and was instructed on the dietary changes to be applied in the following 4 weeks of pre-registration (prohibition of consuming the previously specified products). After 4 weeks, the volunteer went to the second meeting with a fecal sample (sample A), collected during the last 24 hours in a special container delivered during the first meeting.
    [0066] To ensure optimal preservation, stool samples were stored at room temperature and delivered to the laboratory within 24 hours.
    [0067] During the second meeting, in addition, the volunteer was given the probiotic product (or placebo) to be taken over the next 4 weeks.
    [0068] In addition, the volunteer was instructed on how to take the product.
    [0069] At the end of the 4 weeks taking the product (or placebo), the volunteer went to the third meeting with another fecal sample (T1 sample) collected during the previous 24 hours.
    [0070] During the third meeting, the volunteer completed a questionnaire about the possible effects, both positive and undesirable, arising from the consumption of the product.
    [0071] The volunteer was then instructed about the next 4 weeks, during which he or she again did not take the aforementioned products.
    [0072] At the end of these 4 weeks, the volunteer went to the fourth meeting with a fecal sample (sample T2) and received the probiotic product (or placebo) to be taken over the next 4 weeks.
    [0073] Finally, after 4 weeks of treatment with the product (or placebo), the volunteer went to the fifth meeting to deliver the last fecal sample (sample T3).
    [0074] During this last meeting, the volunteer completed a questionnaire similar to the one received during the third meeting.
    [0075] All collected stool samples were stored at -20°C for no longer than 7 days before being subjected to microbiota analysis.
    [0076] Analysis of the fecal microbiota
    [0077] Fecal microflora was evaluated by analyzing the nucleotide sequence of portions of the gene encoding the 16S ribosomal subunit of bacterial rRNA. More specifically, a metagenomics strategy was adopted; it consists of shorting the following steps:
    [0078] 1. extraction, quantification and normalization of metagenomic DNA from stool samples;
    [0079] 2. amplification of the V3 hypervariable region of the bacterial gene encoding 16S rRNA by PCR;
    [0080] 3. quantification of PCR products;
    [0081] 4. sequencing of amplification products;
    [0082] 5. Bioinformatically analyze the sequences.
    [0083] The procedures according to steps 1 and 3 are techniques that are well known in the art and are therefore performed with the protocols commonly used in this field. For example, methods described in laboratory manuals such as those by Sambrook et al. 2001, or Ausubel et al. 1994. Step 2 of amplifying the V3 region of the 16S ribosomal RNA genes was performed using the DNA amplification technique known as PCR, using Probio_Uni 5'-CCTACGGGRSGCAGCAG-3' (SEQ ID NO: 1) and 5'-Probio_Rev ATTACCGCGGCTGCT-3' (SEQ ID NO: 2) as oligonucleotides (primers).
    [0084] In particular, the primer pair of SEQ ID NOs: 1 and 2 amplifies the V3 region of the 16S rRNA gene.
    [0085] Step 4 can be carried out with the techniques known in the art for this purpose, for example techniques based on the Sanger method, pyrosequencing or the Ion Torrent sequencing method of Fusion primers used in the specific example of the present invention, in accordance with with the protocol described in the materials and methods section of the scientific article by Milani et al. (2013).
    [0086] In the case of the Ion Torrent technique, the primers are designed and synthesized so as to include, at the 5' end, one of the two adapter sequences used in this specific DNA sequencing technique. In this case, the adapter sequences were SEQ ID NOs: 1 and 2.
    [0087] The conditions under which the PCR was performed are as follows:
    [0088] • 5 minutes at 95 °C;
    [0089• 30 seconds at 94°C, 30 seconds at 55°C and 90 seconds at 72°C for 35 cycles;
    [0090] • 10 minutes at 72°C.
    [0091] At the end of the PCR, the integrity of the amplified was verified by electrophoresis.
    [0092] Step 5 of the method, necessary for the characterization of microbial communities, can be carried out with numerous techniques presently known for this purpose. More specifically, use was made of: hierarchical grouping, taxonomic analysis and construction of phylogenetic trees with heat maps according to the protocol described in the materials and methods section of the scientific article by Milani et al. (2013); more specifically, sequence data analysis was performed using QIIME software. Statistical analysis of data
    [0093] Statistical analysis was performed using Statistica software (Statsoft Inc., Tulsa, OK, USA).
    [0094] In order to reveal significant differences, data were analyzed using both parametric (multivariate and repeated measures univariate ANOVA) and nonparametric (Wald-Wolfowitz and Mann-Whitney) statistical methods.
    [0095] The normality of the data series (important assumption for ANOVA) was evaluated using the Shapiro-Wilk and Kolmogorov-Smirnov tests. treatment results
    [0096] The study was completed by a total of 22 subjects (11 women and 11 men).
    [0097] Thirty-three subjects were initially enrolled, but 11 of them dropped out early, for various reasons: taking antibiotics (4), refusal to continue the study (1), frequent episodes of diarrhea (1), ingestion of other probiotics during the study period (3), drastic change in eating habits (1), and seasonal flu, with episodes of diarrhea (1).
    [0098] After the conclusion of the study and the conclusion of the analysis of the results of the two treatments, the protocol was revealed and it was found that: A is the active treatment, containing Lactobacillus paracasei DG; Treatment B is the placebo, identical on the outside to the active treatment, but devoid of lactobacilli.
    [0099] When the data obtained from the study were analyzed, a high stability, from a taxonomic point of view, of the intestinal microbiota of the study participants was observed.
    [0100] In fact, it was found that:
    [0101] . two bacterial divisions of the 15 identified, ie Bacteroides and Firmicutes, constitute more than 90% of the sequences;
    [0102] . 11 families of the 131 identified constitute more than 90% of the sequences; and
    [0103] . 20 out of 262 genera identified constitute more than 90% of the sequences.
    [0104] Furthermore, this study confirmed that the human gut microbiota at lower taxonomic levels (ie at the family and gender level) is highly variable from one individual to another.
    [0105] Therefore, experimental evidence has demonstrated the need to carry out, in a healthy population, cross-intervention studies, in order to avoid that inter-individual variability hides the possible effects of probiotic treatment or lead to false positive statistics. When the changes induced in the gut microbiota by two treatments were evaluated, a statistically significant difference emerged in terms of genders only in the group that received the Lactobacillus paracasei DG treatment (active treatment). More specifically, an increase was observed in the genus Coprococcus. In fact, as can be seen in figures 1.1, 2.1 and 2.2, before and after treatment with Lactobacillus paracasei DG a statistically significant increase in Coprococcus was observed. In contrast, a moderate reduction was seen in the group that received the placebo treatment.
    [0106] In addition, a statistically significant reduction in bacteria of the genus Blautia was observed after treatment with Lactobacillus paracasei DG. In contrast, a slight increase in the same was observed in the group that received the placebo treatment (Figures 1.2, 2.1 and 2.2).
    [0107] Coprococci is among the main producers of butyrate at the intestinal level.
    [0108] Butyrate is an essential compound at the intestinal level, since, on the one hand, it contributes to the restoration of the functional integrity of the intestinal mucosa and maintain it over time, and, on the other hand, it has anti-inflammatory effects. important, so much so that it is used as an adjunct to dietary treatments for intestinal colopathies (eg, chronic inflammatory bowel disease).
    [0109] Furthermore, an analysis of their genome reveals that these bacteria can utilize succinate as a fermentation substrate.
    [0110] This information is critical, given the fact that members of the genus Blautia generate ethyl and succinate as the main end products of glucose fermentation.
    [0111] Succinate is considered an ulcerogenic factor, capable, therefore, of exacerbating the condition of individuals with ulcerative colitis, since it is probably the culprit for the mucosal damage present especially in the active phases of the disease.
    [0112] In conclusion, following treatment with a probiotic, in this case, after the administration of Lactobacillus paracasei DG, an increase in bacteria belonging to the genus Coprococcus and, consequently, an increase in the concentration of intestinal butyrate is observed.
    [0113] At the same time, a reduction in the concentration of succinate is observed, which may be responsible for mucosal damage in individuals with ulcerative colitis, in a direct way, once following the treatment with the probiotic, in this case, after the administration of Lactobacillus paracasei DG, there is a reduction in bacteria belonging to the genus Blautia, and, in an indirect way, because the increase in the population of coprococci is still able to decrease the concentration of succinate, using it as a substrate in its process. of fermentation.
    [0114] In conclusion, following treatment with the probiotic, in the specific example after the administration of Lactobacillus paracasei DG, there is an increase in the concentration of butyric acid in the feces of the subjects, with a simultaneous reduction in other organic acids, such as acid succinct.
    [0115] Data concerning the composition of the fecal microbiota were used, finally, in a bioinformatics analysis that aims at a virtual reconstruction of the metagenome based on the knowledge of bacterial genomes (Okuda S, Tsuchiya Y, Kiriyama C, Itoh M, Morisaki H. Virtual metagenome reconstruction of 16S rRNA gene sequences Nat Commun 2012; 3:1203); in other words, it has been established in silico which potential genes are present and how abundantly in a given microbiota. This analysis allowed us to verify a putative increase in genes encoding folic acid synthesis and nicotinic acid metabolism (Figures 3 and 4). These two molecules represent important vitamins for the human host (respectively called vitamin B9 and B3). Vitamin B9, in particular, represents a factor of primary nutritional importance, a deficiency of which, especially in specific physiological conditions such as pregnancy, can lead to serious health consequences. Treatment with the probiotic used in this study could, therefore, favor the ability of the intestinal microbiota to produce folic acid (vitamin B9), with a consequent nutritional benefit for the human host.
    权利要求:
    Claims (8)
    [0001]
    1. Use of a composition comprising a bacterial strain of Lactobacillus paracasei DG deposited in the National Collection of Microorganism Cultures of the Pasteur Institute in Paris, on May 5, 1995, under the deposit number CNCM I-1572, characterized by the fact that it is for the manufacture of a medicament for the treatment and/or prevention of intestinal pathological conditions dependent on butyrate and/or succinate.
    [0002]
    2. Use according to claim 1, characterized in that said intestinal pathological condition is selected from: diarrhea, stenosis, obstructions and diabetic neuropathy.
    [0003]
    3. Use according to claim 1 or 2, characterized in that the bacterial strain of Lactobacillus paracasei DG is a live or dead bacterium, or a bacterial lysate or extract.
    [0004]
    4. Use according to claim 1, characterized in that it comprises 15 to 30 billion CFU, preferably 20 to 25 billion CFU of the bacterial strain of Lactobacillus paracasei DG.
    [0005]
    5. Use according to claim 1, characterized in that it is in the form of pills, capsules, tablets, granulated powder, hard capsules, water-soluble granules, sachets or pellets.
    [0006]
    6. Use according to claim 1, characterized in that it is formulated in liquid form, preferably as a syrup or drink, or added to a food, preferably to a yogurt, cheese or fruit juice.
    [0007]
    7. Use according to claim 1, characterized in that it is in a form capable of exerting a topical action, preferably as an enema.
    [0008]
    8. Use according to claim 1, characterized in that it also comprises dietary fibers with prebiotic activity, preferably FOS, inulin or guar gum, or comprises other substances, such as vitamins, trace elements and/or enzymes.
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    SI3041489T1|2020-10-30|
    RS60518B1|2020-08-31|
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    HUE050146T2|2020-11-30|
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    法律状态:
    2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2018-02-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-05-21| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |
    2019-11-05| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2021-07-20| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|
    2021-10-26| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2022-01-04| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 05/09/2014, OBSERVADAS AS CONDICOES LEGAIS. |
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    ITMI2013A001467|2013-09-06|
    PCT/IB2014/064285|WO2015033305A1|2013-09-06|2014-09-05|Use of a composition comprising microorganisms to increase the intestinal production of butyric acid, folic acid or niacin and/or decrease the intestinal production of succinic acid|
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