WO2011107960A1 - Compositions comprenant l'espèce lactobacillus mucosae pour une utilisation médicale - Google Patents

Compositions comprenant l'espèce lactobacillus mucosae pour une utilisation médicale Download PDF

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WO2011107960A1
WO2011107960A1 PCT/IB2011/050913 IB2011050913W WO2011107960A1 WO 2011107960 A1 WO2011107960 A1 WO 2011107960A1 IB 2011050913 W IB2011050913 W IB 2011050913W WO 2011107960 A1 WO2011107960 A1 WO 2011107960A1
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strains
coli
species
probiotic
strain
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PCT/IB2011/050913
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English (en)
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Corrado Fogher
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Italstarter S.R.L.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • C12N1/205—Bacterial isolates
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
    • C12R2001/225—Lactobacillus

Definitions

  • the present description refers to the use of one or more strain of the species Lactobacillus mucosae in the treatment and/or prevention of gastroenteritis from £ coli in animals including humans and pharmaceutical or veterinary compositions, probiotics food, additives and food supplements containing the same.
  • Escherichia coli is a commensal bacterium making up the microflora of the gastrointestinal track of many animals, including humans. However, there are many £ coli strains with high pathogenicity that are responsible of enteritis, toxemia and septicemia.
  • £. coli infection is, in fact, described as one of the major causes of enteritis.
  • £ coli strain 0157:H7 has been for the first time identified as a pathogenic agent in 1982 following an enteric epidemic in the United States, associated with the consumption of contaminated hamburgers, having even fatal implications.
  • £ coli Although it represents a common intestine inhabitant and plays a key role in the digestive process, there are situations in which £ coli can cause diseases in humans and animals. Some £ coli strains are the causative agent of intestinal and extra intestinal diseases such as urinary tract infections, meningitis, peritonitis, septicaemia and pneumonia.
  • £ coli strains are toxigenic, i.e. producing toxins that can cause diarrhoea.
  • Dysentery from £ coli is a common food-borne poisoning, because is mainly contracted by contaminated food. The contamination can take place from poorly cooked infected meat, from unpasteurized milk and cheese products, and from other food contaminated with faeces.
  • £ coli produces four types of toxins that are differentiated by their different sensitivity to heat treatment, in heat-labile and thermostable, and for the toxigenic action (shiga toxin and haemolytic toxin, HlyA).
  • the heat-labile toxin is very similar in its structure and function to cholera toxin. It contains one 'A' subunit and five 'B' subunits in an olotoxin. The B subunits contribute to the adhesion and to the entry of the toxin into the host intestinal cells, whereas the A subunit stimulates the cells to release water causing diarrhoea.
  • ETEC enterotoxigenic £ coli
  • HUS haemolytic uremic syndrome
  • Stx-2 is able to bind with higher affinity to Gb3 expressed by renal cells, causing their destruction.
  • Stx toxins are also capable of stimulating the TNF-a ad interleuchina-6 production that while supporting the inflammatory situation, promote the exposure of Gb3.
  • £ coli 0157:H7 in contrast to other serotypes, does not ferment sorbitol, this allows its identification in Mac Conkey agar containing sorbitol (evaluating the colonies that lack the fermentation activity).
  • the bacterial culture analysis must be accompanied by the identification of toxins by commercial immunoassay.
  • the 0124, 0143 and 0164 strains can cause bloody diarrhoea (are also white blood cells are present), abdominal cramps and fever.
  • Enteroaggregant £. coli Pathogenic strains EAEC are involved in a persistent watery diarrhoea in travellers and infants in developing countries. These strains express both Bfp and AAF/1 , AAF/2 and AAF/3 (all encoded by a plasmid), that are adhesion factors promoting colonization of the small intestine, with stimulation of mucus production. This forms a bio film that is able to isolate and aggregate bacteria. The aggregation is followed by a reduction of the microvilli length, mononucleata infiltration and haemorrhage.
  • VTEC verocytotoxic
  • the clinical picture shows a lengthening of the microvilli of the enterocytes of the small intestine, with incorporation of bacteria in the enterocytes.
  • £ coli infections in humans are mainly caused by the consumption of contaminated food (ground beef, unpasteurized milk, cured sausages, and cheese from raw milk).
  • the highest contamination risk is relative to undercooked meat and unpasteurized milk.
  • a significant risk is due to the contamination of acid foods, as pathogenic £ coli strains are known that have a marked acid tolerance which allows them to survive for long periods in the foods.
  • £ coli contamination of foods is mainly due to the fact that livestock is the major reservoir of the £ coli bacterium.
  • cattle such as calves are the most susceptible to infections caused by this bacterium.
  • This infection in young individuals is characterized by high mortality due to enteritis during the first months of life, resulting in considerable economic losses for the farmer.
  • the therapy against £ coli infections by consists in the administration of electrolyte solutions to restore the proper water and salt balance made preca riou s by dehyd ration with concom itant use of active anti biotics or, alternatively, in carrying out a prophylactic vaccination.
  • US 5,965,128 patent describes a method for the treatment and prevention of £ coli 0157:1-17 infection in ruminants by using probiotics.
  • the inventors isolate a number of bacterial strains from the gastrointestinal tract and faeces of adult bovines and report as a probiotic against £. coli 0157:1-17 infections at least one strain of £ coli selected from: £ coli 271 ATCC 20220, £ coli 786 ATCC 202018 and £ coli 797 ATCC 202019.
  • Such strains, belonging to the same pathogenic species are, according to the inventors among those isolated, the only ones that are capable to significantly inhibit the growth of £ coli 0157:H7.
  • the patent application US 2006/0134082 describes a specific probiotic for the treatment and prevention of £. coli infection in calves. It is recalled here that in the state of the are, the calves appear to be particularly susceptible to £. coli gastrointestinal infections.
  • the inventors selected strains to be used, among those present in the faeces of adult cattle, and show the combination of strains of Streptococcus bovis and Lactobacillus gallinarum as the one effective for reducing the presence of £ coli bacteria in the gastrointestinal tract of calves.
  • the patent application WO2009/15571 1 claims a probiotic for the treatment and/or prevention of enteritis caused by £ coli in mammals, consisting of bacteria selected from Lactobacillus, Streptococcus, Lactococcus, Bifidobacterium In particular among the lactobacilli the £ coli species L. acidophilus, L. fermentum, L. rhamnosus are shown to be effective in infections.
  • the present invention relates to one or more strain belonging to the Lactobacillus mucosae species to be used in the treatment and/or prevention in animals including humans of pathogenic £. coli bacillosis , pharmaceutical and/or veterinary compositions comprising one or more strain of the Lactobacillus mucosae species for use in the treatment and/or prevention of gastroenteritis caused by pathogenic £ coli in animals including humans, methods of preparing such compositions, probiotics foods or food supplements comprising one or more strain of the Lactobacillus mucosae species and methods of preparation of such foods or food supplements.
  • the invention relates to: - one or more strain of the Lactobacillus mucosae species for use in the treatment and/or prevention in animals including humans of pathogenic E. coli bacillosis ;
  • composition comprising at least one strain belonging to the Lactobacillus mucosae s peci es a n d o n e or m ore pharmaceutically acceptable excipient for use in the treatment and/or prevention in animals including humans of pathogenic £ coli bacillosis;
  • probiotic food or a probiotic food supplement comprising at least one strain belonging to the L. mucosae species and suitable food ingredients and/or preservatives and/or acidifying and/or antioxidants and/or colouring agents and/or substance stimulating the immune response and/or further probiotic bacteria and/or dietary supplements and/or excipients;
  • any one of claims from 14 to 16 comprising the step of mixing at least one strain belonging to the Lactobacillus mucosae species with preservatives and/or acidifying agents and/or antioxidant agents and/or further probiotic bacterial strains and/or dietary supplements and/or excipients suitable and the storage thereof in frozen or freeze-dried form.
  • Table 1 shows the efficacy results of L. mucosae CCCF 3706 in preventing infections from pathogenic £. coli in calves to which L. mucosae was administered within the first 30 min after birth, after mixing with colostrum that can be maternal or artificial colostrum, (e.g., whole colostrum by Sloten).
  • Table 2 shows the efficacy results of L. mucosae CCCF 3706 in gastroenteritis caused by pathogenic £ coli in calves to which freeze-dried L. mucosae was mixed with the artificial milk and administered for 20 days at the indicated dose.
  • Table 3 L. mucosae effect in gastroenteritis caused by pathogenic £ coli in calves treated with probiotic for 60 days.
  • Table 3 shows the efficacy results of L. mucosae CCCF 3706 in gastroenteritis caused by pathogenic E. coli in calves to which freeze-dried L. mucosae was mixed with the artificial milk and administered for 60 days at the indicated dose.
  • Lactobacillus mucosae spp. L. mucosae spp.
  • species of Lactobacillus mucosae L. mucosae are intended all the strains belonging to the L. mucosae specie.
  • adult animal animals that are in a developmental stage corresponding to the paediatric age for men, a cow, for example, is defined not adult if aged between 0 and about 8 months of age.
  • Probiotic bacteria bacteria that positively influence the health of the host, improving his intestinal microbial balance.
  • E. coli strains that are causative agents of intestinal and extra intestinal diseases such as urinary tract infections, meningitis, peritonitis, septicaemia and pneumonia.
  • pathogenic £ coli Included in the definition of pathogenic £ coli are:
  • EHEC Enterohemorrhagic £ coli
  • VTEC Verocytotoxic £ coli
  • probiotic food/feed or probiotic dietary supplement it is meant a food/feed product containing living micro-organisms capable of producing a beneficial effect to the person who ingests it.
  • fragments or biologically active derivates of lactoferrin it is meant parts of the molecule or modified forms of the molecule (such as deletion, mutation, addition of amino acids) that maintain the biological activity of lactoferrin (e.g., immunomodulating, in particular immunostimulatory).
  • the present invention reports for the first time the effectiveness of strains of the species Lactobacillus mucosae as active principles in the treatment and/or prevention of gastroenteritis caused by pathogenic £ coli such as, for example, enteropathogenic £ coli (EPEC); enterotoxigenic £ coli (ETEC); enterohaemorrhagic £. coli (EHEC); enteroaggregative £ coli (EAEC); diffusely adherent £ coli (DAEC); enteroinvasive £ coli (EIEC); avian pathogenic £ coli (APEC); verocytotoxic £ coli (VTEC).
  • pathogenic £ coli such as, for example, enteropathogenic £ coli (EPEC); enterotoxigenic £ coli (ETEC); enterohaemorrhagic £. coli (EHEC); enteroaggregative £ coli (EAEC); diffusely adherent £ coli (DAEC); enteroinvasive £ coli (EIEC); avian pathogenic £ coli (APEC);
  • the executors of the present invention have in fact highlighted how strains of the bacterial species Lactobacillus mucosae when administrated even alones experimentally to individuals, show the ability to effectively fight and prevent infection by pathogenic £ coli.
  • Lactobacillus mucosae species was firstly isolated in the gastrointestinal tract of pigs (Roos S et al. Lactobacillus mucosae sp. nov., "A new species with in vitro mucus-binding activity isolated from pig intestine.” International Journal of Systematic and Evolutionary Microbiology 2000, 50: 251 -258) and only in recent years its presence has been described among the species constituting the micro flora of the gastrointestinal tract of calves (Busconi M, Reggi S, Fogher C. "Evaluation of biodiversity of lactic acid bacteria microbiota in the calf intestine tracts.” Antonie Van Leeuwenhoek. 2008, 94:145-155).
  • the Lactobacillus mucosae species can be isolated from biological samples such as faeces, gastrointestinal tissue samples and any other suitable sample known by the skilled person, belonging to animal species for which the presence of said species in the gastrointestinal micro flora has been described, such as, e.g., calves or pigs. Alternatively, they may be isolated, where present, from samples obtained from other animals, including humans according to standard procedures as, for example, described in Busconi M, Reggi S, Fogher C. Antonie Van Leeuwenhoek. 2008. 94:145-155.
  • the starting sample is represented by gastrointestinal tissue samples obtained from calves, the averagely skilled person can isolate and identify the L.
  • mucosae species following what is described in Material and Methods section of the scientific article of Busconi et al (Busconi M, Reggi S, Fogher C. Evaluation of biodiversity of lactic acid bacteria microbiota in the calf intestine tracts. Antonie Van Leeuwenhoek. 2008. 94: 145-155).
  • the biological identification of the isolated species in the L. mucosae species can be carried out by analysis of gene sequence homology using, for example, the 16S ribosomal gene.
  • one or more strains of Lactobacillus mucosae spp. can be used in treatment and/or prevention of gastroenteritis caused by pathogenic £ coli in animals, including humans.
  • the association of two strains according to the present invention may also result in a synergistic effect of the two, i.e., the sum of the antipathogenic £ coli activity of each individual strain, is inferior to the antipathogenic activity of the strains used together.
  • the strains can be selected from any L. mucosae strain known or isolated from samples and characterized using techniques known in the literature such as, for example, the one described in the materials and methods chapter (pp 147-148) in Busconi M, Reggi S, Fogher C. Antonie Van Leeuwenhoek. 2008. 94 herein incorporated by reference, or they can be selected among the ones deposited on March, 1 st 2010 at DSMZ, according to the Budapest Treaty with deposit receipt dated March 2 2010, and identified by deposit numbers DSM 23409 and DSM 23408, depositor Italstarter Sri. with deposit receipt of DSMZ dated March 2 2010, Such strains are identified in the present description, respectively, as L. mucosae CCCF 3706 and CCCF 3464.
  • the above indicated strains can be in combination with human or animal, native or recombinant, lactoferrin or biologically active fragments thereof or biologically active derivatives thereof.
  • lactoferrin or biologically active fragments thereof or biologically active derivatives thereof.
  • an association with lactoferrin, fragments or derivatives thereof from the species in which they will perform prevention or the treatment for bacillosis from pathogenic £ coli will be made.
  • the association with natural or recombinant lactoferrin or with fragments thereof or biologically active derivatives thereof of human origin will be preferred; or the treatment, e.g., of cattle or calves the association with natural or recombinant lactoferrin or fragments thereof or biologically active derivatives thereof cattle origins will be preferred etc.
  • the mammals are selected in the group of: cattle, pigs, equines, sheep, primates (humans), canines, felines, rodents and goats.
  • cattle, pigs, equines, sheep, primates humans
  • canines felines
  • rodents and goats canines, felines, rodents and goats.
  • not adults (for humans in the paediatric age) infections from pathogenic £ coli can cause severe enteritis.
  • breeding animals as for example cattle, the mortality in young individuals, not adults (e.g.. calves) due to those gastroenteritis is really frequent.
  • one or more strain of the L. mucosae species are more effective in restoring the gastrointestinal balance in individuals affected by pathogenic £ coli enteritis when compared to commonly known probiotic bacterial strains for said use, such as, by way of example Streptococcus faecium.
  • L. mucosae strains can hence be used for the prevention and the therapy of the above reported diseases caused by £ coli in a particularly advantageous way in humans of paediatric age and in subjects having an analogous age among animals, in physically debilitated subjects, in patients undergoing special medical treatment rendering them more susceptible to pathogenic £. coli infections and in elderly subjects that are less resistant to the above mentioned bacterial infections.
  • L. mucosae strains as herein described is of particular importance as they are those most exposed to damages, even lethal, by the pathogenic microorganism.
  • Any strain or combinations of strains belonging to the Lactobacillus mucosae species can be used, in particular, in the treatment or in the prevention of pathogenic £ coli gastroenteritis in paediatric age for humans and for not adult subjects for the remaining animals.
  • strains as explained above allows avoiding, for example in animal breeding, or in epidemics, the propagation of the infection from other affected subjects or from healthy carriers of the pathogenic £ coli strain.
  • the possible strains belonging to the L. mucosae species can be one or more among those deposited (CCCF 3706 and CCCF 3464) on March the 1 st, 2010 at DSMZ, according to the Budapest Treaty, and identified by deposit numbers DSM 23409 and DSM 23408, depositor Italstarter Sri. with deposit receipt of DSMZ dated March 2 2010, Such strains are identified in this description as L. mucosae CCCF 3706 and CCCF 3464.
  • one or more strain belonging to this group optionally in combination with other L. mucosae strains can be used.
  • Th e strains are useful and effective in preventing and treating in general pathogenic E. coli infections , for example, they can be useful in the treatment of infections by pathogenic £ coli such as enteropathogenic £ coli (EPEC); enterotoxigenic £. coli (ETEC); enterohaemorrhagic £ coli (EHEC); enteroaggregative £ coli (EAEC); diffusely adherent E.
  • pathogenic £ coli such as enteropathogenic £ coli (EPEC); enterotoxigenic £. coli (ETEC); enterohaemorrhagic £ coli (EHEC); enteroaggregative £ coli (EAEC); diffusely adherent E.
  • DAEC verocytotoxic £ coli
  • VTEC verocytotoxic £ coli
  • EIEC enteroinvasive £ coli
  • APEC avian pathogenic £ coli
  • strains belonging to these groups of £ coli are, for example, £ coli 0157: H7; 01 :K1 : H7; 045:K1 :H7; O78: K80: H9; 06:K2:H1 ; 04:K54:H5; 018:K1 :H7; 02:K1 :H5; 02:K1 :H7, etc.
  • one or more strain belonging to the L. mucosae species can also be in freeze-dried and/or frozen form. Freeze-drying and freezing are to be intended as means for the temporary inactivation of the bacteria, that do not prevent the restoration of cell division, and that can be carried out in any one of the ways known to the skilled person that are reported in detail in laboratory manuals.
  • Object of the present invention are also pharmaceutical (including paediatric pharmaceutical compositions) or veterinary compositions comprising at least one strain belonging to the L. mucosae species for use in the treatment and/or prevention of gastroenteritis caused by pathogenic £ coli in animals including humans.
  • Such compositions will comprise an amount of L. mucosae bacteria in the range from 100 to 100,000 x 10 6 UFC per each single dose.
  • compositions include also paediatric pharmaceutical compositions and compositions suitable for administration to baby animals.
  • one or more pharmaceutically acceptable excipients may be present in the compositions.
  • Suitable excipients can be: culture medium, calcium carbonate, silicic acid, talc, magnesium stearate, anhydrous lactose, gelatine, trehalose.
  • a suitable stimulating substance could be the protein lactoferrin or peptides derived thereof.
  • Th e compositions may comprise, as active ingredients, solely bacterial strains belonging to the L. mucosae species or can further comprise one or more bacterial strains belonging to probiotic bacterial species, that is to say, strains belonging to probiotic bacterial species other than L. mucosae.
  • these species may be Lactobacillus acidophilus, L. rhamnosus, L. delbrueckii, L. helveticus, L. plantarum, L. gassei, L. casei, L. reuteri, Enterococcus faecium, Bifidobascterium animalis, B. breve, B. infantis, B. longum, etc.
  • the bacterial strains belonging to the L. mucosae species useful for the preparation of the pharmaceutical or veterinary compositions can be selected from any L. mucosae strain known or isolated by samples and characterized using techniques known in the literature such as, for example, the one described in the chapter material and methods (pp 147-148) in Busconi M, Reggi S, Fogher C. Antonie Van Leeuwenhoek. 2008. 94 herein incorporated by reference or selected by: the ones deposited (DSM 23409 and DSM 23408, depositor Italstarter Sri, respectively CCCF 3706 and CCCF 3464) on 1 st of March 201 0 at DSMZ, with deposit receipt of DSMZ dated March 2 2010, according to the Budapest Treaty.
  • Th e bacteria according to the present description may be suspended, freeze-dried or frozen, provided they are not killed because their vitality is essential for the preventive or therapeutic effect here disclosed bound to the probiotic activity of such bacteria.
  • compositions of the invention can be carried out by freeze-drying of bacterial cultures, by a dmixing freeze-dried cultures or by suspension of bacterial pellets or colonies with water or with further suitable excipients, preservatives, flavouring, colouring agents.
  • the bacteria can also be supplied in frozen form, stored according to standard techniques.
  • excipients can be commonly used excipient for bacterial therapeutic or preventive preparations , of veterinary or pharmaceutical grade.
  • compositions according to the invention are for use in the treatment and/or prevention of gastroenteritis caused by E. coli in animals including humans.
  • these animals are mammals such as for example: cattle, pigs, equines, sheep, primates, canines, felines, goats, rodents and farm mammals, for breeding, competition or as pets.
  • these pharmaceutical compositions comprising one or more Lactobacillus mucosae strains are used, in gastroenteritis caused by E. coli in humans of paediatric age, and their correspondent veterinary compositions can be particularly suitable for use with non adu lt animals in a development stage corresponding to the paediatric age of humans (puppies, for example calves).
  • compositions will be of considerable utility when administered to new born or in the first months of age.
  • compositions herein described can be provided in the form of powder, freeze-dried, in tablets, capsules, liquid, thick liquid, semisolid, gel, suspension, emulsion, slurry, syrup, elixir, lozenge, hard or soft gelatine capsule, granulate.
  • flavouring agents that rendering their administration to kids or puppies easier.
  • flavouring agents are obviously to be selected form the ones commonly used according to the desired patient. I n the case of children there flavouring agents having fruit flavour, honey flavour or other flavours commonly used by the skilled person can be used. For veterinary compositions, flavouring agents which make the composition more palatable for the desired animal can be used. Obviously these flavouring agents can be different if the patient is an herbivore or a carnivorous as known in the state of the art.
  • compositions do be administered to newborns or before weaning, can conveniently be tasteless and odourless so to be, administrated together with maternal milk or alone, when necessary or desirable, without being rejected by the patient.
  • Object of the present description are also probiotic foods and supplements or probiotic food additives comprising at least one strain belonging to the L. mucosae species.
  • a foodstuff containing microorganism capable of reaching the intestines, multiply and exert a beneficial effect on health of the organism.
  • That food or supplement besides containing as probiotic microorganism at least one strain of L. mucosae, will contain suitable food ingredients and/or activators of the immune response and/or preservatives and/or acidifying and/or antioxidant and/or colouring agents and/or further probiotic bacteria strains and/or food supplements (mineral salts, vitamins or others) and/or excipients.
  • the bacteria of the L. mucosae species present in the food or supplement can belong to one or more strain, selected from any L. mucosae strain known or isolated by samples and characterized following techniques known in literature, such as, for example the one described in the chapter materials and methods (pp 147-148) in Busconi M, eggi S, Fogher C. Antonie Van Leeuwenhoek. 2008. 94 herein incorporated by reference.
  • the food and supplements can contain one or more strain (for example two) belonging to the L. mucosae species as sole probiotic strains.
  • such foods or supplements can comprise also strains belonging to different probiotic species for example the species Lactobacillus acidophilus, L. rhamnosus, L. delbrueckii, L. helveticus, L. plantarum, L. gassei, L.casei, L. reuteri, Enterococcus faecium, Bifidobascterium animalis, B. breve, B. infantis, B. longum.
  • the foodstuff, the supplement or the additive can conveniently be, as of example and not as a limitation, in the form of liquid, thickened liquid, semisolid, solid, freeze-dried, powder, granules, paste, emu lsion , suspension, slurry, croquettes, chewable bars, yoghurt, cheese, juice or fruit compote, drink or dairy- food or non dairy food, gelatine, syrup, elixir, natural colostrum, artificial colostrum, condensed milk, powdered milk, flavoured powder, infant milk formula.
  • Probiotic foods of particular interest can be foods intended for paediatric patients such as, for example, natural colostrum, artificial colostrum, condensed milk, powdered milk, flavoured powder, infant milk formula and homogenized food.
  • the foodstuff is probiotic foods for use with animals, for example, croquettes.
  • the foods of the invention can be prepared according to any of the methods known by the skilled person mixing at least one of the bacterial strains of L. mucosae in fresh, freeze-dried or frozen from, with suitable food ingredients and optionally preservatives and/or acidifying and/or antioxidant agents.
  • probiotic bacterial strains not belonging to the L. mucosae species and/or supplements such as for example, vitamins, food salts, amino acids, immunostimulants and/or suitable excipients.
  • one or more substance stimulating the immune response or capable of chelating iron may be present in the compositions or in the probiotic foods comprising as unique active ingredients or probiotic strains one or more L. mucosae strains as indicated above (optionally in combination with one or more further probiotic strain indicated above).
  • lactoferrin a known immunostimulant
  • This lactoferrin can be human lactoferrin, recombinant human lactoferrin (in the art many ways of producing recombinant human lactoferrin are known such as, for example, in plant seeds), fragments or derivatives thereof that retain the biologic immunostimulating activity of lactoferrin.
  • the fragments can be part of the immunostimulating protein, and the derivatives can be forms of the protein, in which one or more amino acids can be deleted, added or mutated, that retain the immunostimulating characteristics of the lactoferrin .
  • Derivatives in which the mutations are neutral, in which one or more amino acid is replaced by amino acids with the same characteristics (for example basic, acids etc.) are preferred.
  • the lactoferrin can be human or animal lactoferrin, even if not necessary, a species-specific use of the lactoferrin is preferred, hence human lactoferrin (or derivatives or fragments thereof as described above) for pharmaceutical compositions and an imal lactoferrin (or derivatives or fragments thereof as described above) for veterinary compositions.
  • the veterinary compositions can comprise lactoferrin (or derivatives or fragments thereof as described above) of the species to which they are designed.
  • the amount of bacteria to be inserted in the foodstuffs can be any amount considered suitable by the skilled person.
  • foods and probiotic supplements can comprise from 100 to 100,000 x 10 6 CFU per gram. These can be grown directly in the foodstuff or added in any preparation stage of the foodstuff.
  • L. mucosae The marked effect of L. mucosae, at very high doses, on the intestine physiology worth consideration.
  • the skilled person can easily distinguish a diarrhoea due to a pathogenic from an alimentary diarrhoea due to high doses of L. mucosae that resolves in few days, without any antibiotic therapy and without consequences for the animal. It is the first time that a phenomenon of this kind is observed after the administration of a probiotic and this testifies the physiological relevance of this bacterial species (L. mucosae) in the intestinal balance of the animal.
  • the quantity to be administered can be calibrated, for each animal species, to avoid episodes of physiological imbalance that however have no consequences on the animal, as they resolve spontaneously in a few days and are not evidenced with adequate dosages (100 x 10 6 ).
  • CCCF 3706 deposit number DSM 23409 deposited at DSMZ
  • Italstarter Sri according to the Budapest Treaty on th e 1 st of March 2010 with deposit receipt of DSMZ dated March 2 2010
  • Formulated in a blended frozen product mixing the bacterial biomass harvested after centrifugation of the fermented in a suitable cryoprotectant. The preparation thus obtained in administrated within the first 30 minutes from birth to the calves. Different concentrations of L.
  • mucosae where tested and the effectiveness of the treatment has been evaluated (i) in terms of reduced percent of diarrhoea episodes in early life period (1 st-10th day), (ii) as reduction of coliform bacterial load in the faeces of the treated animals, (iii) with assessment of the health status of the animal after 30 days from the treatment. As shown in table 1 it is possible to highlight that L.
  • mucosae when administered in a dose comprised between 100 and 100,000 X 10 6 CFU) within 30 minutes from birth can (i) completely contrast the onset of diarrhoea phenomena due to colibacillosis, (ii) induce a significant decrease of the presence of coliform in faeces, (iii) determine a good state of health after 30 days from the treatment with higher weight gain than the one of non treated animals or of animals treated with antibiotics. For the control animals, for which diarrhoea and an high bacterial load were observed, it has been necessary take action with a antibiotic therapy (gentamicin) on the 10th day after birth to remove the infection.
  • gentamicin antibiotic therapy
  • composition has been formulated as frozen 8 ml single dose bacterial product of the strain of the L. mucosae stored at -20°C and administered, after defrost at 30°C, in the first minutes from birth mixing it with 50/100 ml of colostrum.
  • Cells of L mucosae strain CCCF 3706 (number of deposit DSM 23409) deposited on 1 st of March 2010 at DSMZ, with DSMZ deposit receipt on March 2 2010 depositor Italstarter Sri according to the Budapest Treaty has been lyophilized and diluted, using suitable inert substances, at a CFU concentration desired for the administration at the dose of 1 0 g for each animal per day, after mixing in milk.
  • suitable inert substances were suitable, at the dosage of 10 g day/animal, for the administration of several bacterial concentrations between 100 and 100,000 x 1 0 6 CFU.
  • the administration to the calves has been continued for 20 days or 60 days starting from the first day after birth without preliminary administration of the colostrum containing L.
  • L. mucosae in the frozen form As highlighted from the obtained results reported in table 2 and table 3 the administration of L. mucosae is effective at the different concentrations used against the pathogenic E. coli infections.
  • concentrations of L. mucosae have been tested and the efficacy of the treatment has been evaluated (i) in terms of reduced percent of diarrhoea episodes in early life (1 st-10th day), (ii) as reduction of coliform bacteria in the faeces of the treated animals, (iii) with assessment of the health status of the animal after 30 days from the treatment. As shown in table 2 and 3 it is possible to highlight that L.
  • mucosae when administered in a dose between 100 and 100,000 X 10 6 CFU) for 20 or 60 days after birth can (i) completely contrast the onset of diarrhoea phenomena due to colibacillosis, (ii) induce a significant decrease of the presence of coliform in faeces, (iii) determine a good state of health at 30 and 60 days from the treatment with higher weight gain than with respect to non treated animals or to animals treated with antibiotics. For the control animals, for which diarrhoea and high bacterial load were observed, it has been necessary take action with an antibiotic therapy (gentamicin) on the 10th day after birth to remove the infection. The evaluation of the effectiveness of L. mucosae in the treatment of pathogenic E.
  • the L. mucosae strains used in the experiment reported above have been isolated from sample coming from different breeding farms.

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Abstract

La présente invention porte sur l'utilisation d'une ou plusieurs souches appartenant à l'espèce Lactobacillus mucosae pour le traitement et/ou la prévention de gastroentérite provoquée par Escherichia coli chez des animaux, incluant l'humain, et des compositions pharmaceutiques ou vétérinaires, des aliments probiotiques et des compléments alimentaires comprenant celles-ci.
PCT/IB2011/050913 2010-03-03 2011-03-03 Compositions comprenant l'espèce lactobacillus mucosae pour une utilisation médicale WO2011107960A1 (fr)

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EP2552230A2 (fr) * 2010-03-29 2013-02-06 Technische Universität München Aliment pour animaux destiné aux veaux visant à un conditionnement de la flore intestinale
WO2013093561A1 (fr) 2011-12-21 2013-06-27 Compagnie Gervais Danone Nouvelle souche de lactobacillus mucosae
CN105505815A (zh) * 2015-11-30 2016-04-20 南昌大学 一株抗衰老功能的粘膜乳杆菌
CN112877231A (zh) * 2019-11-29 2021-06-01 中国农业科学院哈尔滨兽医研究所（中国动物卫生与流行病学中心哈尔滨分中心） 具有抑菌和抗氧化活性的乳酸菌及其应用

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AU2022294135A1 (en) * 2021-06-18 2023-12-14 Chr. Hansen A/S Compositions for increasing resilience towards bacterial infections

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2552230A2 (fr) * 2010-03-29 2013-02-06 Technische Universität München Aliment pour animaux destiné aux veaux visant à un conditionnement de la flore intestinale
WO2013093561A1 (fr) 2011-12-21 2013-06-27 Compagnie Gervais Danone Nouvelle souche de lactobacillus mucosae
CN104053767A (zh) * 2011-12-21 2014-09-17 热尔韦·达诺尼公司 新的粘膜乳杆菌菌株
US9297049B2 (en) 2011-12-21 2016-03-29 Compagnie Gervais Danone Strain of Lactobacillus mucosae
RU2606770C2 (ru) * 2011-12-21 2017-01-10 Компани Жервэ Данон Штамм lactobacillus mucosae для получения ферментированных пищевых продуктов
CN105505815A (zh) * 2015-11-30 2016-04-20 南昌大学 一株抗衰老功能的粘膜乳杆菌
CN105505815B (zh) * 2015-11-30 2019-04-12 南昌大学 一株抗衰老功能的粘膜乳杆菌
CN112877231A (zh) * 2019-11-29 2021-06-01 中国农业科学院哈尔滨兽医研究所（中国动物卫生与流行病学中心哈尔滨分中心） 具有抑菌和抗氧化活性的乳酸菌及其应用
CN112877231B (zh) * 2019-11-29 2023-06-23 中国农业科学院哈尔滨兽医研究所（中国动物卫生与流行病学中心哈尔滨分中心） 具有抑菌和抗氧化活性的乳酸菌及其应用

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