WO2020105051A1 - Compositions orales affectant le microbiome et procédés correspondants - Google Patents

Compositions orales affectant le microbiome et procédés correspondants

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Publication number
WO2020105051A1
WO2020105051A1 PCT/IL2019/051274 IL2019051274W WO2020105051A1 WO 2020105051 A1 WO2020105051 A1 WO 2020105051A1 IL 2019051274 W IL2019051274 W IL 2019051274W WO 2020105051 A1 WO2020105051 A1 WO 2020105051A1
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WO
WIPO (PCT)
Prior art keywords
composition
group
subject
intestinal
useful
Prior art date
Application number
PCT/IL2019/051274
Other languages
English (en)
Inventor
Alon Rosenberg
Abraham MILSTEIN
Ava Marie FIRTH
Simon Van Dalsem
Arie HALPERN
Original Assignee
Kalmarna Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kalmarna Limited filed Critical Kalmarna Limited
Publication of WO2020105051A1 publication Critical patent/WO2020105051A1/fr

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Classifications

    • 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
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/142—Amino acids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/30—Feeding-stuffs specially adapted for particular animals for swines
    • 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
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/175—Amino acids
    • 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
    • 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

Definitions

  • the present disclosure relates to compositions and methods for affecting and modulating the gut microbiome of subjects.
  • Gut microbiota influences host physiology in multiple ways, such as digestion and fomentation of carbohydrates, production of vitamins, maintenance of normal functions of the intestinal villi, regulation of the immune responses, and protection from pathogenic bacteria.
  • GI gastro-intestinal
  • gut microbiota disruption is likely to be recognized as one of the keys leading to post-weaning diarrhea.
  • the pig gut microbiota is a very complex ecosystem showing dynamic composition and diversity which shifts over time and along the entire GI tract. Colonization is initiated at birth and is shaped by consumption of the sow’s milk, which provides nutritional advantages to the population of lactic acid bacteria, building a milk-oriented microbiome.
  • probiotics live bacteria
  • prebiotics which are nutritional products that stimulate or support the growth of these bacteria and defined by the WHO as non- viable food component that confer health benefits
  • a significant body of studies has demonstrated the favourable effects of consuming probiotics and prebiotics (see“Using probiotics in clinical practice: Where are we now? A review of existing meta-analyses”, Rondanelli, M. et al, Gut Microbes, 8(6): 521-543, 2017, and“Probiotics, prebiotics and synbiotics- a review”, Pandey.
  • prebiotic supplements seem to be advantageous as they are not as sensitive as bacteria to temperature, stomach acidity, or time and they are less likely to trigger allergic reactions, adverse effects or to pose health risks for immune-compromised and susceptible patients, such as bacteremia (see www.healthline.com/nutrition/probiotics-side-effects#section3 and “Genomic and epidemiological evidence of bacterial transmission from probiotic capsule to blood in ICU patients”, Yelin. I., et al, Nat Med 25, 1728-1732, 2019).
  • US patent 20190261651 to Yessinergy Holding discloses a composition for additives which can be employed in animal feeds, for the control, modulation and prophylaxis of pathogenic bacteria in the intestinal tract of animals or farm animals.
  • the composition comprises sugars (Fructooligosaccharides, Galacto-oligosaccharides, Mannan- oligosaccharides and 1,3 and l,6 Beta-glucans).
  • US patent 20180028490 to Jaguar Health discloses methods of treating neonatal and young non-human animals suffering from diarrhea by administering to an animal in need a proanthocyanidin polymer composition isolated from a Croton spp. or a Calophyllum spp.
  • EP patent 2672980 to LAVIVO discloses synbiotic compositions comprising probiotic bacterial strains and prebiotic substances (di saccharides, oligosaccharides, and/or polysaccharides) that, when combined exhibit synergistic behavior.
  • the synergetic compositions stimulate the indigenous microflora to restore and reconstitute in vivo gut like conditions after antibiotic associated diarrhea and/or other gut infections caused by gastrointestinal pathogens, and relapses thereof, as well as the prevention of these disorders.
  • compositions for increasing beneficial gut bacterial populations in a subject are characterized by at least three members of a group consisting of steviol glycoside, citric acid monohydrate, monosodium glutamate, glycine, mixtures and derivatives thereof.
  • compositions as defined above, wherein the composition is in the form selected from the group consisting of a tablet, a capsule, a pill, lyophilized, powder, emulsion, powder, cream, ointment, enema, food additive, food ingredient, beverage, drink, paste, lotion, gel, liquid, a solution, a patch, suspension, granulated powder, liquid, syrup, cream, foam, capsule, suppository, enema, infusion, enteric-coated pill, enteric-coated capsule, mouth wash, toothpaste and any combination thereof.
  • Fig. 1 depicts relative abundance of iMctobacillus in pigs receiving Tonisity Px between days 2 and 8 of life;
  • Fig. 2 depicts relative abundance of Bacteroides in pigs receiving Tonisity Px between days 2 and 8 of life;
  • microbiome refers hereinafter in a non-limiting manner to a community of microorganisms, such as bacteria, fungi, and viruses that inhabit a particular environment and especially the collection of microorganisms living in or on the host’s body; or to the collective genomes of microorganisms inhabiting a particular environment and especially the mammalian and avian body.
  • the microbiota includes inter alia bacteria, fungi, archaea and viruses.
  • beneficial gut bacterial populations refers hereinafter to bacteria inhabiting the intestines of a subject and providing health-related benefits for the host, such as physically occupying niches to avoid pathogen colonization, vitamin production, and dietary fibers fermentation resulting in improved digestion.
  • the subject has any type of digestive system: Monogastric (simple); Avian; Auminants (polygastric) and Pseudo-ruminants.
  • VFAs volatile fatty acids
  • acetic add, propionic add and butyric add are the most abundant VFAs in the colon.
  • VFAs are produced by gut microbiota in the large bowel upon fermentation of unabsorbed or undigested carbohydrates and therefore, they serve as an indicator of beneficial gut bacteria activity.
  • dysbiosis or dysbacteriosis refer hereinafter in a non-limiting manner to microbial imbalance, or maladaptation on or inside the body, such as impaired microbiota.
  • a part of the human microbiota e.g., skin flora, gut flora, or vaginal flora
  • Dysbiosis is most commonly reported as a condition in the gastrointestinal tract.
  • steviol refers hereinafter in a non-limiting manner to steviol glycoside, and/or rebaudioside A extract.
  • Tonisity PxTM, PxTM or TPX interchangeably refer hereinafter in a non-limiting manner to the commercially available isotonic composition by Tonisity International Ltd, see currently available site www.tonisity.com. Typical Px composition is described in Table 1 bellow.
  • the Px solution additional comprises cereals as a protein source; enzyme co-factors; and a monosaccharide.
  • the current invention further discloses compositions and methods for affecting gut microbiota in subjects.
  • the current invention pertains to dietary manipulation of Px on porcine gut microbiota.
  • Administration of Tonisity Px in the form of peri-weaning (pre- and post-weaning) application modulates the intestinal microbial profile in piglets, by increasing the abundance of beneficial bacterial populations, including inter alia Lactobacillus, Bacteroides, Veilonella, Oscillospira and Ruminococcus, as compared to the total number of sampled gut bacteria.
  • Px improves gut health, assists with gut development, digestion and post-weaning feed intake while maintaining GI microbial homeostasis, preventing dysbiosis and modulating the host gut’s microbiota.
  • compositions of the present invention comprise at least two members of a group consisting of inter alia, steviol glycoside, citric acid monohydrate, monosodium glutamate and glycine.
  • this composition is characterized by a composition which inter alia comprises at least three members of a group consisting of steviol glycoside, citric acid monohydrate, monosodium glutamate and glycine.
  • this composition is characterized by a composition comprising, inter alia, steviol glycoside, citric acid monohydrate, monosodium glutamate and glycine.
  • the two mammals are very similar in terms of metabolic processes, digesta transit times, compositions of enteric microbiota and villus structure and epithelial cell types.
  • intestinal length pigs have undoubtedly longer organs, but when bodyweight is factored in and accounted for, the end result is a value of around 0.1 meters of intestine per kilogram bodyweight for humans and pigs alike (see“The Pig as an Experimental Model for Elucidating the Mechanisms Governing Dietary Influence on Mineral Absorption”, PATTERSON, J.K. et al, Exp Biol Med 233:651-664, 2008 and“Swine as Models in Biomedical Research and Toxicology Testing”, Swindle M. M.
  • compositions and methods for affecting and modulating the gut microbiome of subjects relate to compositions and methods for affecting and modulating the gut microbiome of subjects.
  • the beneficial effect of the composition administration can be observed in all types of digestive systems of the subjects: mono-gastric (simple), avian, ruminants (poly-gastric) and pseudo-ruminants.
  • 'about* refers hereinafter to a value being 25% lower or greater than the defined measure.
  • the tested material comprised of an isotonic protein solution (namely Tonisity PxTM), which provides easily-absorbable nutrients, e.g., glucose, amino acids, peptides and electrolytes that can be utilized and metabolized directly by the enterocytes.
  • Tonisity PxTM an isotonic protein solution
  • nutrients e.g., glucose, amino acids, peptides and electrolytes that can be utilized and metabolized directly by the enterocytes.
  • TPX litters also received the 3% solution 3 and 2 days before weaning followed by a gruel mixture of creep feed and the 3% protein solution from 1 day before weaning up until 2 days after weaning. Both groups had ad lib access to normal feed after weaning. Weaning was at about 21 days. A total of 56 piglets was randomly selected from each litter for euthanasia at 9 and 17 days of age and a further 20 piglets were randomly selected from each treatment group at 30 days of age.
  • Resident intestinal streptococci do not seem to be associated with pathology, as it is known that the streptococci from the respiratory tract and tonsils are the strains most likely to cause pathologies. Since the microbiota sequencing only classified the bacteria to genus level, there was no information as to the identity at a species level. However, differences observed in this study did not translate to any pathology present in these pigs, either respiratory or intestinal.
  • Tonisity Px has been shown to promote a more beneficial microbial profile in the intestine of the treated pigs.
  • the isotonic protein drink“Tonisity Px” has the ability to influence some of the major intestinal beneficial genera in the pig intestine.
  • the protection provided by the Lactobacillus and Bacteroides at days 9 and 17 of life, respectively, is likely to provide a better gut environment for weaning, which is a maj or stressor in a pig’ s life.
  • the changes observed at days 9 and 17 of life could be linked to nutritional effects of the Tonisity Px and occur in well-known beneficial populations
  • the post-weaning changes, at a time of great restructuring for the gut microbiota are also worth noting.
  • Increase and recovery of fiber-fermenting populations, along with an increase in the Veillonella, a potential immune modulator, is provided useful for long-term health of the intestine.
  • Tonisity Px had a probiotic effect. Increases were observed in bacteria considered to support GI health. Table 3 summarizes the different genera affected by the administration of Tonisity Px as assayed by 16s RNA sequencing.
  • the experiment included 120 litters of the same commercial origin with high genetic potential based on the age and farrow numbers of sows and the initial weight of her litter.
  • the litters were identified by sow cards in the pens and the piglets were individually identified by numbered ear tags and with different colors so that after the treatments were established the piglets were no longer transferred between pens and treatments.
  • mice The experimental design was by randomized blocks, with 4 treatments with 30 replicates (litters). The block was performed according to the order of delivery and the experimental unit was the litter. The trial included the following groups:
  • T2 - Tonisity Px from 2 to 8 days of life (500 ml of the 3% solution per litter);
  • Microbiological and morphometric information Only animals that were selected for slaughter were evaluated. Microbiological variables were submitted to analysis of variance, using treatments as variables. When there was a significant difference by the F test (p ⁇ 0.05), the Tukey-Kramer test was used to compare the means.
  • mice remained in farrowing pens in the presence of the mother and were submitted to the standard procedures of the farm, where the navel cure, anticoccidial application, tail cutting, castration performed at seven days of age and animals that presented diseases were treated with antibiotics specific for the disease.
  • Penicillin was used for the treatment of arthritis and, for diarrhoea, fosfomycin or tylosin was used. All the animals that underwent some therapeutic treatment were listed in a specific file.
  • weighing was carried out at the second day of life of the animals after standardization, another weighing on the eighth day and the day before weaning.
  • the animals were selected for the nursery phase according to the housing shed and the number of animals per litter, and 106 animals w r ere selected per treatment.
  • the slides were photographed through the trinocular microscope (CX31, Olympus Optical do Brasil Ltda., Sao Paulo, SP) and digital image capture camera (SC30, Olympus Optical do Brasil Ltda., S&o Paulo, SP).
  • CX31 Olympus Optical do Brasil Ltda., Sao Paulo, SP
  • SC30 Olympus Optical do Brasil Ltda., S&o Paulo, SP
  • the villi height and crypt depth were measured using the ImajeJ program using ten villi and well- directed crypts.
  • the villi/crypt ratio was calculated, and the analyses were performed by a single person. Histology analyses were performed at the Laboratory of Histology and Immunohistochemi stry of the Department of Zootechnics of the Federal University of Lavras. For the microbiological analysis samples of cecal content were collected shortly after slaughter.
  • VFAs volatile fatty acids
  • acetic, propionic and butyric acids volatile fatty acids
  • Volatile fatty acids are saturated aliphatic organic acids that consist of one to six carbons of which acetic acid (C2), propionic (C3), and butyric acid (C4) are the most abundant, representing 90-95% of the VFAs in the colon.
  • VFAs are produced by gut microbiota in the large bowel upon fermentation of unabsorbed or undigested carbohydrates.
  • the Bacteroidetes phylum mainly produces acetate and propionate, whereas other genera produce butyrate as their primary metabolic end product.
  • VFAs have multiple benefits for the host, as they might be associated with the prevention and treatment of the metabolic syndrome, bowel disorders, and certain types of cancer.
  • VFAs administration positively influenced the treatment of ulcerative colitis, Crohn’s disease, and antibiotic-associated diarrhea.
  • VFAs have been demonstrated to contribute to shaping the gut environment, influence the physiology of the colon, they can be used as energy sources by host cells and the intestinal microbiota, induce the expansion of colonic T-reg cells and they also participate in different host-signaling mechanisms (see“Intestinal Short Chain Fatty Acids and their Link with Diet and Human Health”, Rios-Covia, D. et al. Front.

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  • Life Sciences & Earth Sciences (AREA)
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  • Engineering & Computer Science (AREA)
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  • Health & Medical Sciences (AREA)
  • Animal Husbandry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
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Abstract

La présente invention concerne une composition isotonique destinée à augmenter les populations bactériennes intestinales bénéfiques chez un sujet, caractérisée par au moins trois membres d'un groupe constitué du glycoside de stéviol, de l'acide citrique monohydrate, du glutamate monosodique, de la glycine, des mélanges et des dérivés de ceux-ci. La présente invention concerne plus particulièrement une composition isotonique administrée par voie orale exempte d'antibiotique pour augmenter le microbiote bénéfique chez des sujets, sans goût de chlore.
PCT/IL2019/051274 2018-11-21 2019-11-21 Compositions orales affectant le microbiome et procédés correspondants WO2020105051A1 (fr)

Applications Claiming Priority (2)

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US201862770215P 2018-11-21 2018-11-21
US62/770,215 2018-11-21

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023288279A3 (fr) * 2021-07-14 2023-02-23 Basepaws Test basé sur un écouvillon oral pour la détection de divers états pathologiques chez les chats domestiques

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070116826A1 (en) * 2005-11-23 2007-05-24 The Coca-Cola Company High-Potency Sweetener Composition with Probiotics/Prebiotics and Compositions Sweetened Therewith
US20160058052A1 (en) * 2014-09-02 2016-03-03 Purecircle Usa Inc. Stevia extracts
AU2018101362A4 (en) * 2018-04-29 2018-10-18 Kalmarna Limited Oral compositions and methods for affecting mammalian offspring
AU2018101364A4 (en) * 2018-04-29 2018-10-18 Kalmarna Limited Compositions and methods for nourishing mammals

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070116826A1 (en) * 2005-11-23 2007-05-24 The Coca-Cola Company High-Potency Sweetener Composition with Probiotics/Prebiotics and Compositions Sweetened Therewith
US20160058052A1 (en) * 2014-09-02 2016-03-03 Purecircle Usa Inc. Stevia extracts
AU2018101362A4 (en) * 2018-04-29 2018-10-18 Kalmarna Limited Oral compositions and methods for affecting mammalian offspring
AU2018101364A4 (en) * 2018-04-29 2018-10-18 Kalmarna Limited Compositions and methods for nourishing mammals

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023288279A3 (fr) * 2021-07-14 2023-02-23 Basepaws Test basé sur un écouvillon oral pour la détection de divers états pathologiques chez les chats domestiques

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