MXPA97001816A - Bacterials and pharmaceutical composition containing such strains and using the same to prevent and treat diseases associated with metabolism altered biliary deactives or caused by my - Google Patents

Abstract

The present invention relates to strains of bacteria characterized in that they exhibit: (a) an activity of 7alpha-dehydroxylase less than 50%, and (b) a deconjugation activity of bile acids less than 50%, and descendants, mutants and derivatives of the same that preserve activities (a) and (b), and a pharmaceutical composition comprising one or more said strains and use thereof to prevent and treat diseases associated with a metabolism of bile acids or caused by the same.

Description

BACTERIAL SCAPS AND PHARMACEUTICAL COMPOSITION CONTAINING CEPOSED LICKS AND USING THE SAME TO PREVENT AND TREAT DISEASES ASSOCIATED WITH THE ALTERED BILIARY ACID METABOLISM OR CAUSED BY THE SAME DESCRIPTIVE MEMORY The present invention relates to strains of bacteria and pharmaceutical compositions containing one or more of said strains and the use thereof for preventing and / or treating diseases associated with or caused by an altered metabolism of bile acids. Hepatic bile is a pigmented isotonic fluid with an electrolyte composition that resembles blood plasma. The main components of bile include water (80%), bile acids (12%), lecithin and other phospholipids (4%), and non-estepficated cholesterol (0.7%). Other constituents include conjugated bilirubin, proteins, electrolytes, mucus and final products of hepatic transformations of drugs, hormones, etc. The production of bile in the liver, in conditions b salts, is approximately 500-1000 ml / day. The primary bile acids, cholic acid (CA) and chenodeoxycholic acid (CUCA), are synthesized from cholesterol in the liver, conjugated with glycine or taurine, and excreted in the bile. Secondary bile acids, including deoxycoccal acid (DCO) and lithocholic acid (LA), are formed in the colon as bacterial etaboiites of primary bile acids. Other bile acids, called tertiary bile acids (e.g., ursodeoxycholic acid-UCHA), are formed in the intestine after enzymatic epithelialization of -OH groups on sterol rings by the intestinal flora. In normal bile, the ratio of glycine to taurine conjugates is 2: 1, while in patients with coleostasis, there are often increased concentrations of bile acid sulfate and glucuronide conjugates. The intestinal microflora transforms bile acids into different metabolites. These biotransfor- mations include the hydrolysis of the bond between bile acid and taurine or glycine, with the formation of unconjugated or free bile acids and taurine or glycine. The unconjugated bile acids are therefore available for the oxidation of the hydroxyl groups in positions C3, C7, and C12 and for dehydroxylation in positions 76 and 7β. This latter transformation leads to the formation of secondary bile acids DCA and LA. The primary bile acids, deconjugated but not transformed, and the secondary bile acids are reabsorbed from the lumen of the intestine and enter the portal bloodstream, after which they are taken up by the hepatocytes, conjugated with glycine or taurine and are again secreted into the bile. (enterohepatic circulation).

Normally, the common supply of circular bile acid 5 to 10 times daily. The intestinal absorption of the common supply is approximately 95% efficient, so the fecal loss of bile acids is in the range of 0.3 to 0.6 g / day. The fecal loss is compensated for by an individual daily synthesis. For this reason, the composition of the common supply of bile acids present in the bile is the result of complex interactions that occur between the liver and the enzymes of the rnicroflora. Deconditioning activity is a characteristic shared by many bacteria, aerobic and anaerobic, but is particularly common among obligate anaerobic bacteria, ie, Bacteroides, Eubacteria, Clostridia, Bi Ibacteria, etc. Most bacteria are active against conjugates of glycine and taurine; however, some of them have a certain degree of specificity, depending on the amino acid bound, and the number of hydroxides bound to the steroid nucleus. The free bile acids obtained following the action of the bacterial hydrolases can undergo oxidation of the hydroxide groups present at positions C3, C7 and C12 by the hydroxysteroidodehydrogenase. The importance of rnetabolic disorders of bile acids comes from the hypothesis that bile acids and / or metabolites thereof are involved in the pathogenesis of some hepatobiliary and gastroenterological diseases: biliary dyspepsia., cholelithiasis, acute and chronic hepatopathies, inflmatory diseases of the colon, etc. Very often, in the literature the hydrophobic character of bile acid correlates with detergency. Secondary biliary acids are more hydrophobic than primary bile acids, deoxycholic acid (DCI) being actually more detergent than cholic acid (CO). Therefore, an increased concentration <Je DCA in the bile may imply: a) an increase in cholesterol secretion, with an increased saturation index; b) a cytotoxic effect on hepatic cells. For this reason, a qualitative modification of the bile acid pattern could be a decisive factor, especially to treat the aforementioned pathologies. Therefore, the need still exists for effective bacterial strains or compositions which, by reducing the activity of 7d-dehydroxine and at the same time deconjugation, can be used and / or prevented from diseases associated with bile acid etabolic disorders. No bacterial strains have been found that are capable of qualitatively modifying the bil acid pattern in that manner. Accordingly, an object of the present invention is to provide a new strain of bacteria, in particular germ-positive bacteria, that are useful for treating and / or preventing diseases associated with or caused by a metabolic disorder of bile acids. Another object of the present invention is to provide pharmaceutical compositions containing one or more strains of said bacteria and are useful for treating and / or preventing diseases associated with or caused by a metabolic disorder of bile acids. The above and other objects, which will be more apparent during the following detailed description, have been achieved by the inventors, who have found bacterial strains having a reduced or zero 7d-dehydroxylase activity and a reduced or reduced capacity. zero to deconjugate bile acids. This contrasts with the prior art technique. Accordingly, the present invention provides the use of said strains for modifying the metabolism of bile acids in a useful manner to prevent or reduce diseases caused by or associated with metabolic disorders of bile acids. Therefore, in a first embodiment, the present invention provides novel strains of bacteria having a 70-dehydroxylase activity of less than 50%, preferably less than 25%, and a conjugated bile acid deconjugation activity of less than 50%, preferably less than 25%. The essential characteristics of the strains according to the present invention are defined in claim 1; the specific strains having said characteristics are defined in the dependent claims 2 to 2. The present invention also provides a pharmaceutical composition for treating and / or preventing diseases associated with or caused by an altered metabolism of bile acids, said composition comprising at least one bacterial strain according to the present invention. The essential aspects of the composition according to the present invention are defined in claim 12; Specific embodiments of said composition are defined in dependent claims 13 to 25. Still, the present invention provides for the use of at least one bacterial strain according to the present invention for preparing said pharmaceutical composition. The essential aspects of such use are defined in claim 26; Specific embodiments are defined in dependent claims 27 to 36. In the context of the present invention, diseases associated with or caused by a metabolic disorder of bile acids include liver diseases and diseases of the digestive system, such as blind loop syndrome, gallstones, cirrhosis, chronic liver disease, acute liver disease, cystic fibrosis, cholestasis mterhepatica, inflammatory bowel disease, colonies, poor bsorption. The present pharmaceutical compositions can also be used to prevent the onset of gallstones in women during pregnancy or subsequent periods and in subjects who are carrying out programs or diets for weight loss. The 7d-dehydroxase activity of the bacterial strain must be less than 50%, preferably less than 25%. The activity values of 76-dehydroxyslase are those measured by the method described in example 1 below. Specifically, the 107 cells of the strain in question are incubated at 37 ° C for 48 hours, in 15 ml of the specific culture medium with the addition of 2 mg / ml glycocholic acid (GCO) or 2 mg / ml taurocolic acid (TCO), and then the product quantity of 7d-deh? Drox? Lado is measured. The percent value for 7S-dehydroxylase activity is calculated by the following formula: Product mass 76 ~ dex? Drox? Side Activity after 48 hours of incubation 76-dex? Drox? Lasa = X 100 Mass of GCO or TCO at the start of incubation Based on the foregoing, the bacterial strain to be administered must also have a conjugate biliary acid cleavage activity of less than 50%, preferably less than 25%. The ability to deconjugate bile acids is determined by the use of the same incubation procedure described to measure the activity of 7d-dex? Drox? Lasa followed by measurement of the amount of deconjugated pr-oduct formed. The deconjugation activity is calculated using the following formula: mass of GCO or deconjugated TCO Activity after 48 hours of incubation deconjugation = X 100 mass of GCA or TCO at the start of incubation The bacterial strains of the present invention can be administered enterically Preferably, the bacterial strains of the present invention are administered orally. Although a single bacterial strain can be administered, it is also possible to administer a mixture of two or more bacteria according to the present invention. Although the exact dose of bacteria that will be adhered to will vary with the condition and size of the patient, the exact disease being treated, and the identity of the strains that are being administered, good results have been achieved by administering 103 to 1013 bactepa / g cells preferably 108 to 10 * 2 cells of the bactepana strain / g. In order to achieve the good effects of the present invention, it is preferred that the strain be administered in a sufficient amount and concentration to result in the patient's intestines being populated with a significant amount thereof. Thus, it is preferred that the strain be administered in a composition containing 103 to 1013 cells of the strain / g preferably 108 to 1012 cells of the strain / g and that the composition be administered in such a regimen that the patient receives 100 mg a 100 g of the strain / day, preferably 1 g to 20 g of the strain / day, for a period of 1 to 365 days, preferably 3 to 60 days in case of therapy, or according to periodic cycles in the case of prophylaxis . The bacterial strain can be administered in any form suitable for enteral administration, such as capsules, tablets or liquids for oral administration or liquids for enteral administration. Typically, administration of the bacterial strain according to the present invention can occur after the diagnosis of bile acid etabolic disorders. However, in the case of prophylaxis of gallstones, the strain can be administered when it is determined that the subject belongs to a population at risk, such as a pregnant woman or a person who starts a program or diet to lose weight. In addition, the present strain of bacteria can be administered after the gallbladder has been removed to a patient. In a preferred embodiment, the co-administration of lactulose is provided when the disease being treated is cirrhosis. Suitably, lactulose is administered in an amount of 100 g to 100 g / day, preferably 1 g to 20 g / day. In another preferred embodiment, the coadministering preparation is based on bile acid, such as ursodeoxycholic acid or tauroursodeoxycholic acid. Odequately, the ursodeoxycholic acid or tauroursodeoxycholic acid is administered in an amount of 10 to 3,000 mg / day, preferably 50 to 800 mg / day. Preferably, the present pharmaceutical compositions contain the strain (s) of bacteria at a concentration of 103 to 1013 cells / g., preferably from 108 to 1012 cells / g. The pharmaceutically acceptable carrier can be any which is suitable for enteral administration and which is compatible with the strain of bacteria, such as dextrose, calcium carbonate together with different additional substances such as starch, gelatin, vitamins, anti-oxidants, dyes or substances rne speakers of flavor. As an optional component, the compositions of the invention may possibly contain a drug compatible with the bacterium employed and capable of enhancing the activity of the active ingredients present. Anticholinergic drugs, antihistammas, adrenergic, antiulcer, antacid, antidiarrheal and antiinflammatory, sedatives, antipyretics, coleretics, antiredectic agents, analgesic drugs, diuretics, antiseptic agents, antilipérníos, hepatoprotective drugs and active drugs on gastrointes mobility inal (ie, tpmebutine) may be mentioned herein. When treating cirrhosis, it is preferred that the pharmaceutical composition also comprises lactulose. Odequately, the composition will contain from 100 rng to 100 g / day, preferably 1 g to 20 g / day of lactulose. When treating biliary cirrhosis and chronic hepatitis, it is preferred that the pharmaceutical composition comprises preparations based on bile acid, such as ursodeoxycholic acid or tauroursodeoxycholic acid. Suitably, the composition will contain from 10 to 3,000 mg / day of said bile acid preparations, preferably from 50 to 800 mg / day of ursodeoxycholic acid and tauroursodeoxycholic acid. Other aspects of the invention will become apparent in the course of the following descriptions of illustrative embodiments that are given to illustrate the invention and are not intended to be limited thereto.

EXAMPLES EXAMPLE 1 Strains of the following species have been tested: Streptococcus ther ophilus, Streptococcus faeci, Lactobacillus acidophilus, Lactobacillus bul aricus, Lactobacillus plantaru, Bifi obacteriurn infantis. Each strain (.107 CFU) was cultured in duplicate in specific nutrient broths (15 ml); "CFU" means "colony forming units".

List of the culture medium used depending on the different species Bit "i dobacteriurn mfantis: MRS * 0.5% glucose (added after sterilization by diluting a sterile 20% solution) Streptococcus thermophilus: M17 All the remaining strains MRS Composition of the MRS broth : g / 1itro universal peptone 10.0 g meat extract 5.0 g yeast extract 5.0 g D (+) -glucose 20.0 g phosphate acid potassium 2.0 gt? een 80 1.0 g ex ammonium treatment dibasic 2.0 g sodium acetate 5.0 g sulfate magnesium 0.1 g manganese sulfate 0.05 g Preparation: 50 g / l are dissolved in distilled water, sterilized at 121 ° C for 15 minutes - pH 6.5 + -0.1 at 25 ° C Composition of broth 1117 (Merck): g / 1 stippton of soybean meal 5.0 < j meat peptone 2.5 g casein peptone 2.5 g yeast extract 2.5 g meat extract 5.0 g D (+) - lactose 5. 0 g ascorbic acid 0 .5 g (3-gl Sodium Caphosphate 19. 5 g Magnesium Phosphate 0.25 g Preparation: dissolve 42.5 g / 1 in distilled water, sterilized at 121 ° C for 15 minutes -pH 7.2 + -0.1 to 25 ° Bifidobacteriurn mntis was cultivated under anaerobic conditions as it is known to be anaerobic bacteria. After a 24-hour incubation at 37 ° C for each tube an equivalent amount of bile salts was added at 30 rng to obtain a final concentration of 2 mg / ml. The bile acids used are: glycolic acid (GCO) and taurocolic acid (TCO), obtained from Signa Chemicals. Each bile acid was added separately to each series of bacterial cultures. After 48 hours of incubation, isopropanol, 3 ml, was added for 2 minutes. It was then centrifuged at 400 rprn for 15 minutes and the supernatant was collected (5 rnl). The supernatant was kept refrigerated at -30 ° C until it was analyzed. The percentage of conjugated bile salts present was determined by CLOR (High Performance Liquid Chromatography) using a Gilson apparatus equipped with a detector diode arrangement model 1000 and a reverse phase column Spherisobr 5 μrn ODS 2 C18, a composite mobile phase by methanol / osphate regulated in its pH (20 Mol), pH 2.5 in water / acetonitle / water (150: 60: 20: 20 in volume), a fluid velocity of 0.85 ml / mm, at a sling length of 205 nm; 100 μi of the sample to be tested, dried ba or nitrogen, were extracted with 100 μl of the phase that contained as internal standard 7d-OH-12d-OH-dihydroxα-58-collagen (Calbiochem EUO) acid at a concentration of 2 rng / rnl. The percentage recovery of bile acid incubated with bacterial cultures was clated by the ratio of the area of the bile acid to be detected (GCO or TCO) to the area of the internal standard. When the amount of the conjugated bile acid found in the bacterial cultures after 48 hours of incubation was less than 50%, thin layer chromatography (BCC) was performed on silica gel plates 60 to detect the presence of CO and DCO, using a mobile phase of cyclohexane / isopropanol / acetic acid (30: 10: 1 by volume). In each plate, stains of 20rnμl of the holic extract of the sample, 20 μl of a solution of CO and DCO, and 20 μl of CO, 20 μl of DCO were placed. The plates, after being grown at room temperature, were treated with sulfuric acid and heated at 145 ° C until the appearance of the colored spots. The results of the deconjugation experiments (Table I) show that 5 of the 15 strains tested with GCO could completely deconjugate bile acid added to the culture, as previously reported in the literature and as well known to all researchers. In a surprising way, 10 strains could deconjugate GCO but not completely, varying from 9 to 90% (Table I). There was no difference between aerobic and anaerobic bacteria. Two strains Streptococcus thermophilus YS 52 and Bi idobacterium infantis Bi 6 do not have any deconjugation activity for GCO. Strain YS 52 also does not attack the bile acid-taurine linkage. Only one of the 16 strains tested could completely deconjugate TCO: the Bifi obacterium infantis B.i. 6. The result of the dehydroxylation experiments (Table II) shows that only one (Bi 4) of the 16 strains can completely dehydroxylate GCO. 6 strains did not deehydroxylate at all: YS 52; SF 2; SF 4; Lfl 3; LO 10; Bi 6. The other strains could be hydrocoiling GCO but not completely varying from 9% to 90%. As for GCO, 7 strains did not dehydroxylate at all: YS 52; SF 3; LO 3; LO 10 :: LB 1; LB 7; LB 77. A Bi 6 strain dehydroxylated TCO completely; the other strains dehydroxylated TCO according to varying percentages.

TABLE I GCO and TCA deconjugation percentage for bacterial cultures after 48 hours of incubation.

OCCASIONAL BACTERY No.% GCO% TCO Streptococcus thermophilus YS 46 1-1668 9 9 Streptococcus therrnophilus YS 48 1-1669 17 11 Streptococcus therrnophillus YS 52 1-1670 0 0 Streptococcus faeciu SF 2 100 3 Streptococcus faeci? N SF 3 1-1671 27 0 Streptococcus faeciurn SF 4 100 12 Lactobacillus acidophilus LA 3 100 80 Lactobacillus aci ophilus LA 10 100 95 Lactobacillus bulgaricus LB 1 T-1664 9 0 Lactobacillus bulgaricus LB 3 1-1665 20 12 Lactobacillus bulgaricus LB 7 1-1666 14 0 Lactobacillus bulgaricus LB 77 1-1667 20 0 Bifidobacterium infantis Bi 2 80 15 Bi fi dobacterium infantis Bi 3 90 10 Bi fidobacterium infantis Bi 4 100 26 Bi f i dobacteriurn infantis Bi 6 0 100 TABLE II Percentage of dehydroxylation of GCA and TCA by bacteria culture after 48 hours of incubation.

BACTERY ACCESS NO.% GCA% TCA Streptococcus thermophilue YS 46 1-1668 9 9 Streptococcus thermophilus YS 48 1-1669 17 11 Streptococcus thermophilus YS 52 1-1670 0 0 Streptococcus faeciu SF 2 0 3 Streptococcus faeciurn S 3 I-1671 27 0 Streptococcus faeciurn SF 4 0 12 Lactobacillus acidophilus LA 3 0 80 Lactobacill's acidophilus LO 10 0 95 Lactobacillus bul apcus LB 1 1 -1664 9 0 Lactobacillus bulgapcus LB 3 1-1665 20 12 Lactobacillus bulgaricus LB 7 1-1666 14 0 Lactobacillus bulgaricus LB 77 1-1667 20 0 Bifi dobacteriurn mfantis Bi 2 80 15 Bifidobacterium mf nis Bl 3 90 10 Bifi dobacteriurn infantis Bl 4 100 26 Bifidobacteriurn mfantis Bl 6 0 100 These strains have been deposited in the CNCM-Collection Nationale de Cultures of Microorganis es- Institut Pasteur, (National Deposit of Cultures of Microorganisms, Institute 15 Pasteur) under the following access numbers: Streptococcus therrnophilus YS 46: 1-1668 Streptococcus thermophilus YS 48: 1-1669 Streptococcus thermophilus YS 52: 1-1670 20 Streptococcus faeciurn SF 3: 1-1671 Lactobacillus bulga icus LB 1: 1-1664 Lactobacillus bulgaricus LB 3: 1-1665 Lactobacillus bulgapcus LB 7: 1-1666 Lactobacillus bulgaricus LB 77: 1-1667: > The following strains are maintained and are available in the Centro Ricerche Sitia-Yo or S.p.O.- Strada per Merlino, 3- ZELO BUON PÉRSICO (Milan) -Italia, which are distinguished by the following identification numbers: Streptococcus faecium SF 2: SF 2 Streptococcus faeci? Rn SF 4: SF 4 Lactobacillus acidophilus LO 3: LO 3 Lactobacillus acidophilus LO 10: LO 10 Bifido acteriurn infan is Bi 2: Bi 2 Bifidobacteriurn infantis Bi 3: Bl 3 Bifidobacteriurn infantis Bi 4 : Bi 4 Bifidobacterium in fantis Bl 6: Bi 6 The results show that most of the strains tested by the present inventors have a capacity to deconjugate bile acids and that there are strains that do not deconjugate at all. This observation is surprising since it has not been known that lactic acid bacteria deconjugate bile salts. In addition, it is evident that the enzymes of the strains are eelective for specific bile acid binding in the side chain. In this study, the clearest example is offered by Bifidobact riurn infantis Bi 6.

This know can not deconjugate bile acid conjugated with glycine but can completely deconjugate bile acid conjugated with taurine. Some other strains (LB 1, LB 7, LB 77, SF 3) can deconjugate TCA but can deconjugate GCO only to a certain degree. To conclude, strains that have a weak or zero capacity to deconjugate and dehydroxylate have been discovered.

EXAMPLE 2 Healthy tree volunteers were tested for their biliary acid content after treatment with a lactobacillus preparation containing lxion Streptococcus therrnophil cells and YS 52 per gram for a daily total of 6 grams per 28 days. Before starting the treatment and after 12 hours of fasting, the subjects were intubated and bile was obtained from the vesicle, after stimulation with ceruletido, and the bile was frozen at -80 ° C. The contraction of the gallbladder was evaluated by ultrasound and the position of the tube, in the second portion of the dodene was verified by Rx (floroscopy). After a 4-week treatment, the subjects underwent a second intubation and bilie. The bile samples were then tested for their content of some bile acids as described above. The results are shown in table III.

TABLE III PATIENT ACID PATIENT PATIENT BILIAR # 1 # 2 # 3 before after before after before after Glycerodeoxycholic 32 15 22 15 28 12 Glycodeoxycholic 6 5 9 4 3 Glicoursodeocicólico 1 5 1 7 1 4 Taurocolico 9 26 15 25 12 21 Taurodeoxycholic 1 3 5 8 3 9 NOTO: (The bile acids are listed following the order of idrophilic capacity, that is, in inverse relation to detergency) Taurocolico Taurodeoxy colic Glicoursodeoxycholic Glycerodeodeoxycolico This experiment is a confirmation of what is shown in example No. 1, ie , a lower deconjugation in one of the primary bile acids if the bacteria which are the object of the present invention are administered. The result achieved is a longer maintenance of the primary bile acids in the enterohepatic circulation. The properties of biliary acidoe are reported in the note to Table III. Therefore, according to these results, the administration of selected strains of bacteria can reduce the property of detergency and therefore the cytolytic activity of bile acids.

EXAMPLE 3 Fourteen patients with chronic hepatitis were treated with a bacterial preparation containing Streptococcus therrnophilus YS 46 and YS 48 (two strains), Lactobacillus bulgaricus LB1, LB7 and LB 77 (three strains). Each strain has been brought to a concentration of 150xl09 cells per gram before being mixed with the others, to prepare a mixture containing the same parts by weight of each strain. 6 grams per day of said mixture were administered for 28 days. Liver enzymes were measured before and after the attachment, and the results are shown in Table IV.

TABLE IV Influence of the treatment with a mixture of bacteria on the hepatic enzymes aepartate araneammase (OST, SGOT) and alanine transarninase (OLT; SGPT) Patient AST (SGOT) ALT (SGPT) before after before after # 1 92 59 102 46 # 2 89 67 96 42 # 3 174 86 97 39 # 4 121 91 102 66 # 5 116 81 lll 55 # 6 156 87 94 76 # 7 163 66 69 37 # 8 78 64 122 57 # 9 109 39 87 86 # 10 166 70 102 48 # 11 56 24 118 62 # 12 131 83 96 79 # 13 137 86 94 74 # 14 84 87 144 114 Medium 119 71 102 63 Deeviacion Eet. 36 19 17 21 Test t of Student's significance for paired data P < 0, 001 P < 0.001

Claims (36)

NOVELTY OF THE INVENTION CLAIMS

1. - A strain of bacteria characterized in that it exhibits: (a) a 7d-dehydroxase activity less than 50%, and (b) a bile acid deeconjugation activity of less than 50%, and descendants, mutants and derivatives thereof. same that preserve activities (a) and (b).

2. The strain of claim 1, which is a strain of gram-positive bacteria.

3. The strain of claim 1 and / or 2, which belongs to a selected species of Streptococcus therrnophilus, Streptococcus faecium and Lactobacillus bul aricus.

4. The strain of claim 3, characterized in that the strain of bacteria is Streptococcus ther ophilus YS 52 deposited in the CNCM -Collection Nationale de Cultures de Microorganisnee - Institut Pasteur- (National Deposit of Cultures of microorganisms, Pasteur Institute), under the access number 1-1670.

5. The strain of claim 3, characterized in that the strain of bacteria is Streptococcus thermophilus YS 46 deposited in the CNCM -Collection Nationale de Cultures de Microorgamemes - Institut Pasteur- (National Deposit of Cultures of microorganisms, Pasteur Institute), ba or the access number 1-1668.

6. The strain of claim 3, characterized in that the strain of bacteria is Streptococcus thermophilus YS 48 deposited in the CNCM -Collection Nationale of Cultures of Microorganisms - Institut Pasteur (National Deposit of Cultures of microorganisms, Pasteur Institute), under the number of access 1 - 166.

7. The strain of claim 3, characterized in that the strain of bacteria is Streptococcus faeciurn SF 3 deposited in the CNCM -Collection Nationale de Cultures de Microorgamsmes - Institut Pasteur (National Deposit of Crops of microorganisms, Tns-tituto Paeteur), under the access number 1-1671.

8. The strain of claim 3, characterized in that the strain of bacteria is Lactobacil lus bul apcus LB 1 deposited at the CNCM -Collec ion Nationale < le, ulturos de Microorgamsmes - Institut Pasteur (National Deposit of Microorganism Crops, Instituto Paeteur), under accession number 1-1664.

9. The strain of claim 3, characterized in that the strain of bacteria is Lactobacillus bulgaricus LB 3 deposited in the CNCM -Collection Nationale de Cultures de Microorganismes - Institut Pasteur (National Deposit of Cultures of microorganisms, Pasteur Institute), under the number of access 1-1665.

10. The strain of claim 3, characterized in that the bacterial strain is Lactobacillus bulgaricus LB 7 deposited in the CNCM -Col lec ion Nationale de Culturec de Microorganis en - Institut Pasteur (National Deposit of Cultures of microorganisms, Pasteur Institute) , under the access number t-1666.

11. The strain of claim 3, characterized in that the strain of bacteria is Lactobacil lus bulgar cus LB 77 deposited in the CNCM -Collection Nationale de Cultures of Microorganisn.es - Institut Pasteur (National Deposit of Cultures of microorganisms, Pasteur Institute) , under accession number 1-1667.

12. A bacterial composition for preventing and / or treating diseases associated with or caused by bile acid metabolism, characterized in that it comprises an effective amount capable of producing a normalizing effect on said altered metabolism in a patient suffering from the same , of (1) at least one strain of bacteria provided with: (a) a 7d-dehydroxine activity less than 50%, and (b) a bile acid deconjugation activity of less than 50%, and descendants, mutants and derivatives thereof which retain activities (a) and (b), and (2) a pharmaceutically acceptable vehicle of the ism.

13. The pharmaceutical composition according to claim 12, further characterized in that at least one strain of bacteria is a strain of gram-positive bacteria.

14. The pharmaceutical composition according to claim 12 and / or 13, further characterized in that at least one strain of bacteria belongs to a species selected from the group consisting of Streptococcus therrnophilus, Streptococcus faecium and Lactobacillus bul apcus.

15. The composition according to claim 14, characterized in that the strain of bacteria is Streptococcus thernophi lus YS 52 deposited in the CNCM -Collection Nationale de Cultures de Microorgam srnes -Ins 3 ut Pasteur (National Deposit of Cul 3vos de microorganismos, Instituto Pasteur), under accession number 1-1670.

16. The composition according to claim 14 further characterized in that the bacterial strain is Streptococcus therrnophi lus YS 46 deposited in the CNCM -Collection Nationale de CuHures de Microorganismes -Instit? T Pasteur (National Deposit of Cultures of microorganisms, Pasteur Institute ), under access number 1-1668.

17. The composition according to claim 14, further characterized in that the bacterial strain is Streptococcus thepnop i lus YS 48 deposited in the CNCM -Collection Na ionale de Cultures de Microorgam srnes -Institut Pasteur- (National Deposit of Cultures of microorganisms , Pasteur Institute), under accession number 1-1669.

18. - The composition according to claim 14, further characterized in that the strain of bacteria is Streptococcus faecium SF 3 deposited in the CNCM -Collection Nationale de Cultures de Microorganis en - Institut Pasteur (National Deposit of Cultivoe of microorganisms, Pasteur Institute), under the access number 1-1671.

19. The composition according to claim 14, further characterized in that the strain of bacteria is Lactobacillus bulgapcus LB 1 deposited in the CNCM -Collection Nationale de Cultures de Microorganisrnes -Institut Pasteur (National Deposit of Cultures of microorganisms, Paeteur Institute), under the access number 1-1664.

20. The composition according to claim 14, further characterized in that the strain of bacteria is Lactobacillus bulgaricus LB 3 deposited in the CNCM -Collection Nationale de Cultures de Microorganisrnee -Inetit? T Pasteur- (National Deposit of Cul ivos de microorganismos, Instituto Pasteur), under the number of acceeo 1-1665.

21. The composition according to claim 14, further characterized in that the bacterial strain is Lactobacillus bulgaricus LB 7 deposited in the CNCM -Collection Nationale de Cultures de Microorganisrnee -Inetitut Pasteur (National Repository of Crops of rnicroorganismoe, Inetituto Pasteur), under the access number 1-1666.

22. The composition according to claim 14, further characterized in that the strain of bacteria is Lactobacillus b? Lgaricus LB 77 deposited in the CNCM -Collection Nationale de Cultures de Microorganis is -Tnstitut Pasteur (National Deposit of Cultures of microorganisms, Institute Pasteur), under access number 1-1667.

23. The composition according to claim 12, further characterized in that it comprises from 103 to 1013 cells of the bactepae strain per gram of composition.

24. The composition according to claim 12, further characterized in that it also comprises lactulose.

25. The composition according to claim 12, further characterized in that it also comprises preparations based on selected bile acids of ursodeoxycholic acid and tauroursodeoxycholic acid.

26. The use of at least one strain of bacteria characterized in that it exhibits: (a) a 76-dehydroxylase activity of less than 50%, and (b) a bile acid deconjugation activity of less than 50%, and descendants, rnutants and derivatives thereof which retain activities (a) and (b), for preparing a pharmaceutical composition for preventing and treating diseases caused by an altered or associated metabolism of bile acids.

27. The use according to claim 26, further characterized in that at least one strain of bacteria is a strain of germinating bacteria.

28. The use according to claim 12 and / or 13, further characterized in that at least one strain of bacteria belongs to a species selected from the group consisting of Streptococcus thernophi lus, Streptococcus faeciurn and Lactobacillus bulgaricus.

29. The use according to claim 28, further characterized in that the bacterial strain is Streptococcus therrnophilus YS 52 deposited in the CNCM - Collection Nationale de Cultures de Microorganisrnee - Tnstitut Pasteur (National Deposit of Cultivoe of microorganisms, Pasteur Institute), under accession number 1-1670.

30. The use according to claim 28, further characterized in that the composition according to claim 14, further characterized in that the bacterial strain is Streptococcus thermophilus YS 46 deposited in the CNCM -Collection Nationale de Cultures de Microorganis is -Institut Pasteur (National Deposit of Cultures of Microorganisms, Pasteur Institute), under accession number 1-1668.

31. The use according to claim 28, further characterized in that the bacterial strain is Streptococcus herrnophilue YS 48 deposited in the CNCM -Collection Nationale de Cultures de Microorganis en - Institut Paeteur (National Deposit of Cultures of microorganisms, Pasteur Institute) , under access number 1-1669. 32.- The use according to the rei indication 28, also characterized because the bacterial strain is Streptococcus faeciurn SF 3 deposited in the CNCM -Collegetion National de Cultures de Microorgamsmes - Institut Pasteur (National Deposit of Cultures of microorganisms, Pasteur Institute) , under the access number 1-1671. 33. The use according to claim 28, further characterized in that the bacterial strain is Lactobacillus bulgaricus LB 1 deposited in the CNCM -Collection Nationale de Cultures de Microorgamsrnes - Institut Pasteur (National Deposit of Cultures of Microorganisms, Institute Pasteur), ba or access number 1-1664. 34. The use according to claim 28, further characterized because the strain of bacteria is Lactobacillus bulgapcus LB 3 deposited in the CNCM -Collect ion Nationale de Cultures de Microorganismos - Institut Pasteur (National Deposit of Microorganism Crops, Institute Pasteur), under the number of acceeo 1-1665. 35.- The use according to claim 28, further characterized in that the bacterium strain is Lactobacillus bulgapcus LB 7 deposited in the CNCM -Collection National de Cultures de Microorgams is - Institut Paeteur (National Deposit of Microorganism Crops, Pasteur Institute), under accession number I-I666. 36.- The use according to claim 28, further characterized in that the strain of bacteria is Lactobacillus bulgaricue LB 77 deposited in the CNCM National Collection of Cultures of Microorganisms - Institut Pasteur (National Deposit of Cultures of microorganisms, Pasteur Institute), under accession number 1-1667.