EP4271209A1 - Composition comprising at least one probiotic, at least one antioxidant and polysaccharides from adaptogenic plant(s) - Google Patents

Composition comprising at least one probiotic, at least one antioxidant and polysaccharides from adaptogenic plant(s)

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Publication number
EP4271209A1
EP4271209A1 EP21726953.9A EP21726953A EP4271209A1 EP 4271209 A1 EP4271209 A1 EP 4271209A1 EP 21726953 A EP21726953 A EP 21726953A EP 4271209 A1 EP4271209 A1 EP 4271209A1
Authority
EP
European Patent Office
Prior art keywords
composition according
probiotic
quercetin
composition
lactobacillus
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
EP21726953.9A
Other languages
German (de)
French (fr)
Inventor
Michel Frey
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Idec Therapeutic
Original Assignee
Idec Therapeutic
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Filing date
Publication date
Application filed by Idec Therapeutic filed Critical Idec Therapeutic
Publication of EP4271209A1 publication Critical patent/EP4271209A1/en
Pending legal-status Critical Current

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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
    • A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
    • 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
    • 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
    • A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7135—Compounds containing heavy metals
    • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/481—Astragalus (milkvetch)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/489—Sophora, e.g. necklacepod or mamani
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

Definitions

  • the invention relates to the field of compositions intended for human health.
  • a composition comprising at least one probiotic, one antioxidant compound and polysaccharides from adaptogenic plant(s) can be used for the prevention and/or treatment of infectious diseases of bacterial or viral origin and/or any disorder linked to an imbalance of the intestinal microbiota (dysbiosis) such as discomfort and functional digestive disorders and porous intestine syndrome (leaky gut) and more generally nervous, metabolic, hepatic, renal, cutaneous and/or pulmonary disorders.
  • the composition may be in the form of a food supplement.
  • Infectious diseases are disorders caused by micro-organisms such as bacteria, viruses, fungi or parasites. Many organisms live in and on our bodies. They are for some of them harmless or even useful, we then designate under the term of commensal forms. But in other cases, it is also microorganisms that cause disease. Some infectious diseases can be transmitted from person to person or transmitted by insects or other animals or by consumption of contaminated food or water or by exposure to organisms present in the environment. Signs and symptoms vary depending on the organism causing the infection, but often include fever and fatigue. Mild infections may respond to rest and home remedies while some life-threatening infections may require hospitalization.
  • infectious diseases such as influenza
  • Each infectious disease has its own specific signs and symptoms. General signs and symptoms common to a number of infectious diseases include: fever, fatigue, diarrhea, muscle aches, cough, headache.
  • the recent COVID19 is one of the infectious diseases concerned by the present invention.
  • SARS-CoV-2 infection is transmitted by microdroplets produced during coughing and sneezing in symptomatic patients, but can also occur in asymptomatic people and before the onset symptoms.
  • Studies have shown higher viral loads in the nasal cavity than in the throat, with no difference in viral load between symptomatic and asymptomatic people.
  • Patients can be infectious for as long as symptoms last and even upon clinical recovery.
  • Some people can play the role of super contaminator: a British citizen who attended a conference in Singapore infected 11 other people while staying at a resort in the French Alps and on his return to the UK.
  • Infected micro-droplets can spread from 1 to 3 m (or even more) and settle on surfaces.
  • the virus can remain viable on surfaces for days under favorable atmospheric conditions, but is destroyed in less than a minute by common disinfectants like sodium hypochlorite, hydrogen peroxide, etc.
  • the infection is acquired either by inhaling these droplets, or by contact with surfaces contaminated by them, then by touching the nose, mouth and eyes, or orally.
  • the virus is also present in feces and contamination of water supply and subsequent aerosol/fecal-oral transmission is also emitted.
  • ACE2 angiotensin 2
  • SRF severe respiratory failure
  • MAS immune dysregulation and macrophage activation syndrome
  • Severe forms of the disease are also often accompanied by a disorder of the digestive tract characteristic of leaky gut syndrome. This last element makes it possible to link an imbalance of the digestive microbiota to the severity of the disease. For the inventors, it is thus logical to conceive of the benefit of a balanced microbiota in the prevention of severe forms of COVID19.
  • the severe forms of SARS-CoV-2 infection are characterized by a storm of pro-inflammatory cytokines (cytokine storm) composed in particular of an excess of I L6, of TNF-a and of IL-10.
  • This overproduction of cytokines is one of the key characteristics of the immune imbalance associated with severe forms with the overproduction of pro-inflammatory cytokines by monocytes and the decrease in the lymphocyte population characterized by CD4+ and probably CD8+ lymphopenia.
  • the number of killer cells (NK, natural killer) is reduced, probably due to the rapid spread of the virus.
  • the unique signature of immune dysregulation in patients with severe forms of SARS-CoV-2 is characterized on the one hand by a strong capacity for the production of cytokines and their circulating forms (in particular IL-6) and on the other hand by defects in lymphoid function associated in particular with an IL-6-mediated decrease in the expression of HLA-DR on monocytes-CD14 cells.
  • prevention of COVID19, or any other viral and/or bacterial infection there is therefore a need to prevent immune deregulation, in particular by means of a composition making it possible to restore the imbalance of the intestinal microbiota (dysbiosis) without the use of drugs.
  • the present invention makes it possible to remedy this problem by rebalancing the intestinal microbiota by administering a composition according to the invention.
  • the present invention relates to a composition comprising at least one probiotic, preferably in the form of a live strain or of deactivated fragments, at least one antioxidant compound and polysaccharides in particular, derived from an adaptogenic plant. If this plant also has a prebiotic role, it complements the effects related to probiotics.
  • Immune dysfunction and cytokine storm are complex mechanisms.
  • the present invention targets at different levels these disorders and provides a more effective prophylactic treatment for humans or animals.
  • the invention relates to a composition
  • a composition comprising at least one probiotic, at least one antioxidant compound and polysaccharides from adaptogenic plants, in particular as a prebiotic; the probiotic being preferentially in the form of probiotic strains.
  • probiotic strains being chosen from the following probiotic strains, alone or in a mixture: Lactobacillus rhamnosus, Lactobacillus easel, Lactobacillus paracasei, Lactobacillus gasseri, Bifidobacterium longum, Lactobacillus plantarum, Bifidobacterium adolescentis, Lactobacillus reuteri, Bifidobacterium infantis.
  • probiotics to fight against respiratory infections in particular viral infections
  • the use of probiotics to fight against respiratory infections is linked to i) digestive symptoms with digestive viral multiplication of the infection as in the case of COVID-19, ii) the link between the digestive tract and the lung (gut-lung axis) and iii) the role of certain specific probiotic strains on the balance between pro and anti-inflammatory cytokines (i.e. the ratio between cytokines type 1 and type 2) respectively, IL6 i IL12 i IL1, TNF-alpha and IL-10 i TGF-b).
  • Probiotics are “live microorganisms” which, when administered in adequate quantities, confer a benefit on the host (FAO i WHO, 2001).
  • Products sold containing probiotics include foods (such as certain yogurts, kefir-type fermented milks, etc.), food supplements and some products that are not used orally, such as skin creams.
  • Probiotics are known to be extremely beneficial for health by rebalancing the intestinal microbiome and controlling pathogenic strains.
  • Lactobacillus plantarum is a versatile bacterium found in a variety of ecological niches, ranging from plant fermentations to the human gastrointestinal tract. Lactobacillus plantarum are rod-shaped with rounded, straight ends, usually 0.9-1.2 ⁇ m wide and 3-8 ⁇ m long, occurring singly, in pairs, or in short chains.
  • the genome of the first bacterium isolated from a human digestive tract L. plantarum strain WCFS1 was sequenced (Kleerebezem et al., PNAS 2003, vol.100 tome 4; 1990-1995) and its size of 3.3 Mb is among the most important known for bacteria living in the digestive tract (Makarova K.
  • Lactobacillus reuteri is a typical intestinal symbiotic bacterium which plays an important role in maintaining the stability of the intestinal flora and the health of the host.
  • Lactobacillus rhamnosus and in particular Lactobacillus rhamnosus GG is an extremely well-studied probiotic strain. It was discovered in 1985 and numerous studies have proven over 40 health benefits. Lactobacillus rhamnosus GG, has a very good adhesion to the intestinal wall and is therefore considered a good probiotic. This probiotic stimulates the immune system, fights allergies and provides a digestive benefit on Irritable Bowel Syndrome (IBS) and constipation.
  • IBS Irritable Bowel Syndrome
  • the benefits of Lactobacillus rhamnosus GG are numerous: diabetes management, immunity boosting effects: fights bacterial infections, inhibits H.
  • Lactobacillus rhamnosus strain 4B15 and Lactobacillus gasseri strain 4M13 isolated from infant faeces has also recently been described (Nam Su et al., PloSone, 2018 vol.13, tome 2).
  • Bifidobacteria are natural inhabitants of the gastrointestinal tract with genetic adaptations that allow the colonization of this difficult habitat and complex. Bifidobacteria interact with key elements of intestinal functioning and thus contribute to the maintenance of homeostasis.
  • Bifidobacterium adolescentis which was isolated for the 1st time in the intestine of an adult (Reuter, Current Issues Intest. Microbiol. 2001; vol.2 T. 2;43-53). Strains of B. adolescentis are frequently detected in the healthy adult human intestinal tract (healthy gut) (Turroni et al., 2009 Apply Environment Microbiol. 2009, vol.75 tome 6, pp 1534-1545).
  • B. infantis strain 35624 modulates both gastrointestinal and non-gastrointestinal cytokine milieu in inflammatory disorders and in healthy subjects.
  • Oral administration of B. infantis 35624 was sufficient to reduce both gastrointestinal and extraintestinal systemic inflammatory biomarkers in inflammatory disorders.
  • composition as described above comprises at least one probiotic strain, preferably live, in the following form: freeze-dried, liquid in suspension, or in the form of an extract and/or partial secretome or complete, of extracted and/or purified molecule.
  • the amounts of the various ingredients in the compositions according to the invention are effective or substantial amounts.
  • effective or substantial quantity it is meant a quantity for one or more given ingredients, sufficient to make it possible to observe an effect for a state at a precise time by comparison with an initial state, that is to say without taking the or target ingredients.
  • the antioxidants used are of exogenous or endogenous nature. Examples include vitamin E, lutein, vitamin G, beta-carotene, Resveratrol, flavonoids, and bioflavonoids and lycopene.
  • the invention relates to a composition in which the antioxidant compound is chosen from quercetin and/or an analogue of quercetin and/or of a plant extract(s) containing it. , alone or in a mixture.
  • quercetin is a flavonoid with antioxidant properties.
  • the ability of quercetin is claimed to exert many beneficial health effects, including protection against various diseases such as osteoporosis, lung cancer, and cardiovascular disease.
  • Quercetin (3,3',4',5,7-pentahydroxyflavone) is yellow in color and sparingly soluble in hot water, fairly soluble in alcohol and lipids, and insoluble in cold water. Quercetin is said to be one of the most widely used bioflavonoids for the treatment of metabolic and inflammatory disorders.
  • quercetin and its analogs are known to exhibit antibacterial effects against almost all strains of bacteria, particularly affecting the gastrointestinal, respiratory, urinary and cutaneous systems. Their anti-infective and anti-replicative capacity possibly contributes to their antiviral characteristics.
  • Viruses that typically respond to flavonoids are adenovirus, herpes simplex virus, Japanese encephalitis virus, and respiratory syncytial virus. Quercetin is one of the most abundant dietary flavonoids found in fruits (mainly citrus fruits) and berries like blueberries.
  • quercetin The highest concentrations of quercetin have been found in vegetables such as sorrel (Rumex sp), coriander (Coriandrum sativum), onions, asparagus (Asparagus officinalis), watercress (Nasturtium officinalis), cabbage ( Brassica oleracea), apples, cherries and berries.
  • the composition according to the invention comprises quercetin and/or a quercetin analogue.
  • Quercetin analogues are defined as natural flavonoids that exhibit a wide range of biological activities like isoquercetin (quercetin-3b-o-glucoside), quercetagetin, quercetin-3-gallate.
  • the quercetin analogue is chosen in particular from isoquercetin (quercetin-3b-o-glucoside), quercetagetin, quercetin-3-gallate.
  • Quercetin can also be a plant extract containing it is chosen from the following plant extracts: sorrel (Rumex sp), coriander (Coriandrum sativum), onions, asparagus (Asparagus officinalis), watercress (Nasturtium officinalis), okra (Abelmoschus esculentus ), cabbage (Brassica oleracea). Quercetin is also present in extracts of the pagoda tree (Sophora japonica).
  • the antioxidant is S-Adenosylmethionine (SAMe) which is involved in the activity of DNA methyltransferase or histone methyltransferases.
  • SAMe supplementation regulates DNA methylation and thus intervenes in various cardiovascular and hepatic disorders or depression and aging, and in the development of cancers through various mechanisms.
  • the invention relates in a particular embodiment to a composition as described above and comprising polysaccharides from plant(s) adaptogen(s).
  • These polysaccharides are extracted or purified from plants in the following forms: freeze-dried leaves and/or roots, complete or partial extracts.
  • the polysaccharides are extracted from an adaptogenic plant chosen from the genera Astragalus, Dioscorea, Schisandra, Panax, Eleuterococcus, Rosmarinus, Pfaffia, Morinda, Cordyceps or Lepidium genera, in particular in the form of a dry or purified extract. They can play a role of prebiotics, ie of substrate favoring the survival of probiotic strains.
  • Adaptogens are non-toxic herbs marketed to help the body resist stressors of all kinds, whether physical, chemical or biological. These herbs and roots have been used for centuries in Chinese and Ayurvedic healing traditions, but are experiencing a renaissance today. Adaptogens work to counter the effects of stress. Stress causes very real physical changes in the body, including damage to the neurological, endocrine, and immune systems. Adaptogens have stimulating properties that help counter these harmful effects. Adaptogens were first developed and really studied, during World War II. Peoples were looking for a way to help healthy pilots perform at even higher levels. Basically, they were looking for a "superhero" pill that would allow pilots to fly better, faster, and longer.
  • the group of adaptogenic plants includes in particular plants belonging to the following genera: Astragalus, Dioscorea, Withania, Ginkgo, Schisandra, Panax, Eleuterococcus, Rhodiola, Schisandra, Lepidium, Rosmarinus, Pfaffia, Morinda, Cordyceps.
  • polysaccharide extracts from plants belonging to the genus Astragalus and/or Dioscorea and/or Lepidium will preferably be chosen.
  • Such plants in particular Astragalus membranaceus (Astragalus) or Dioscorea villosa or opposita or even Lepidium meyenii (or Maca) have the effect of restoring and normalizing the various organs and functions of our body, in particular by increasing the number of stem cells. in bone marrow and lymphatic tissue.
  • These plants reactivate resting immune cells, stimulating macrophages and promoting the regeneration of T and NK lymphocytes; inhibit lipid peroxidation particularly in the myocardium; stimulate telomerase thus lengthening the shortest telomeres and protect DNA from cellular aging.
  • the compositions according to the latter comprise vitamins.
  • a vitamin we mean all the vitamins: A, B1, B2, B3, B5, B6, B8, B9, B12, C, D, E, K1, K2, their respective precursors, or a mixture of vitamins and/or or respective precursors.
  • said vitamin is a B group vitamin, in particular B6, B9, B12, vitamin C, vitamin D or a mixture thereof.
  • vitamin B6 notably promotes the absorption of magnesium and the synthesis of serotonin (an essential neurotransmitter).
  • Vitamin B9 or folic acid also has the property of acting on amino acid metabolism and protein synthesis; it participates in the renewal of immune cells, the formation of red blood cells and the supply of oxygen that the body needs.
  • Vitamin B12 is essential for the proper functioning of the central and peripheral nervous system.
  • Vitamin D is known for its role in the immune response and its anti-inflammatory activity on group 1 cytokines, that is to say IL-1 b, IL-6, TNF-alpha, in particular.
  • the composition described above comprises Astragalus polysaccharides chosen in particular from galacto-oligosaccharides or fructo-oligosaccharides for their ability to act as a prebiotic.
  • the composition described comprises a quantity of probiotic(s) to reduce: i. the release and/or production of inflammatory mediators, in particular the cytokines IL6, TNF-a and I L1b, in particular an excessive release and/or production of inflammatory mediators.
  • a release and/or a production of inflammatory mediators is considered excessive, when the release and/or the production thereof is above 2 times the amount normally observed in a subject without dysfunction; and/or he. immunological disorders responsible for a greater susceptibility to viral and/or bacterial infections and/or ill. dysbiosis, responsible for a greater susceptibility to viral and/or bacterial infections.
  • the composition comprises a quantity of probiotic strain(s) for reducing and/or preventing pathological disorders or sub-clinical conditions resulting in particular from dysbiosis of the digestive tract, whether of endogenous origin or exogenous due to infection, pollution, stress in particular.
  • the composition described is in the form of a solid or liquid nutritional supplement.
  • the latter being used for a non-therapeutic application.
  • the invention also relates to a non-therapeutic use of the composition according to the invention, described above, for correcting cutaneous dysbiosis and/or the subclinical or clinical (ie dermatological) disorders associated with these dysbiosis.
  • the experimental groups were incubated for 24 hours with the composition of example 1, in the presence of IL-6 (8ng/ml).
  • the “Stress” group received only the treatment with IL-6 (8 ng/ml) in order to mimic a “cytokine storm”, while the “Control” group was untreated.
  • Dexamethasone (1 ⁇ M) was used as a reference.
  • Figure 2 shows the carbonylation rates obtained for 2 different concentrations of the composition according to example 1 and their protective effect according to the protocol described in example 2.
  • Example 1 formulation in the form of a food supplement
  • Astragalus root extract (Astragalus membranaceus) with 20% polysaccharides, (plant from the Chinese pharmacopoeia and used in the composition for prebiotic activity): 200mg
  • Example 2 In vitro evaluation of the protective effects of the composition of Example 1, according to the invention, in a stressed cell model: The aim of this study is to evaluate, in an in vitro model of human fibroblasts derived from the dermis, the protective effect of a formula according to the invention (at 2 different concentrations) to prevent the deleterious effects of the hyper-inflammatory response. related to COVID-19 (“cytokine storm” or “cytokine storm”).
  • Protein carbonylation is one of the most harmful irreversible protein oxidative changes. It is considered a major feature of oxidative stress-related disorders and is often quantified to assess these disorders. In an acute form, this carbonylation, if massive, can lead to cell destruction. Accumulation of oxidatively damaged proteins is also a hallmark of deleterious processes such as chronic inflammation, the infectious inflammatory stage, aging, and many age-related disorders.
  • composition according to example 1 is evaluated in the model described above at 2 different concentrations.
  • composition according to Example 1 was directly dissolved in the culture medium at 2 different concentrations (50 pg/ml; 200 pg/ml). It was stored at 4°C in the dark until use.
  • the cells were fixed and the protein carbonyls were labeled in situ with a specific fluorescent probe.
  • Fluorescence emission was detected and recorded using a fluorescence plate reader (Varioskan, Thermo Scientific).
  • composition according to example 1 showed a protective effect against the oxidation of proteins induced by IL-6 of:
  • This study aims to evaluate the in vitro protective efficacy of the composition according to example 1, formulated at different concentrations against acute inflammation inducing protein damage.
  • Human dermal fibroblasts were incubated (or not) with the product for 24 hours in the presence of an inflammation inducer (inflammatory cytokine IL-6).
  • inflammation inducer inflammatory cytokine IL-6
  • a level of carbonylation was obtained for each sample after in situ labeling of carbonylated proteins with a specific fluorescent probe. Fluorescence emission was detected and recorded using a fluorescence plate reader (Varioskan, Thermo Scientific).
  • IL-6 inflammatory cytokine
  • Example 3 formulation treatment follow-up questionnaire according to example 1
  • the treatment is offered to healthy volunteers as part of the prevention of rhinoviruses (influenza, covid-19, etc.). It is oriented towards the reorganization of the microbiota in order to avoid the pathological complications linked to its imbalance, particularly in the event of invasion by a rhinovirus.
  • This test is offered to volunteers accepting a formula of food supplements using probiotic strains as well as prebiotics.
  • the protocol is based on taking 2 capsules of the food supplement whose composition is described in Example 1 per day during the two winter months.
  • the questionnaire below is given to volunteers who received the food supplement at the end of treatment. This questionnaire is essentially oriented towards taking into account intestinal discomfort (gastritis, gastroenteritis, digestive and pulmonary sensitivities) and the consequences of intestinal dysbiosis.

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Abstract

The invention relates to a composition comprising at least one probiotic, an antioxidant compound and polysaccharides from adaptogenic plants for reducing i) the release and/or production of inflammation mediators, in particular cytokines IL-6, TNF-alpha and IL-1beta and/or ii) immunological diseases and/or iii) dysbioses, responsible for disorders of the digestive tract, in particular leaky gut syndrome, which is involved in particular in higher susceptibility to viral and/or bacterial infections.

Description

COMPOSITION COMPRENANT AU MOINS UN PROBIOTIQUE, AU MOINS UN ANTIOXYDANT ET DES POLYSACCHARIDES DE PLANTE(S) ADAPTOGENE(S). COMPOSITION COMPRISING AT LEAST ONE PROBIOTIC, AT LEAST ONE ANTIOXIDANT AND POLYSACCHARIDES FROM ADAPTOGENE PLANT(S).
DOMAINE TECHNIQUE DE L’INVENTION TECHNICAL FIELD OF THE INVENTION
[0001] L’invention se rapporte au domaine des compositions destinées à la santé humaine. Une telle composition comprenant au moins un probiotique, un composé anti-oxydant et des polysaccharides de plante(s) adaptogène(s) peut être utilisée pour la prévention et/ou le traitement des maladies infectieuses d’origine bactériennes ou virales et /ou tout désordre lié à un déséquilibre du microbiote intestinal (dysbiose) tels que les inconforts et troubles digestifs fonctionnels et le syndrome de l’intestin poreux (leaky gut) et plus généralement les désordres nerveux, métaboliques, hépatiques, rénaux, cutanés et/ou pulmonaires. La composition peut se présenter sous la forme d’un complément alimentaire. The invention relates to the field of compositions intended for human health. Such a composition comprising at least one probiotic, one antioxidant compound and polysaccharides from adaptogenic plant(s) can be used for the prevention and/or treatment of infectious diseases of bacterial or viral origin and/or any disorder linked to an imbalance of the intestinal microbiota (dysbiosis) such as discomfort and functional digestive disorders and porous intestine syndrome (leaky gut) and more generally nervous, metabolic, hepatic, renal, cutaneous and/or pulmonary disorders. The composition may be in the form of a food supplement.
ETAT DE L’ART ANTERIEUR STATE OF THE PRIOR ART
[0002] Les maladies infectieuses sont des troubles causés par des micro-organismes tels que des bactéries, des virus, des champignons ou des parasites. De nombreux organismes vivent dans et sur notre corps. Ils sont pour certains d’entre eux inoffensifs ou même utiles, on désigne alors sous le terme de formes commensales. Mais dans d’autre cas, ce sont également des microorganismes qui provoquent des maladies. Certaines maladies infectieuses peuvent être transmises de personne à personne ou transmises par des insectes ou d'autres animaux ou par la consommation d'aliments ou d'eau contaminés ou encore par l'exposition à des organismes présents dans l'environnement. Les signes et symptômes varient en fonction de l'organisme responsable de l'infection, mais comprennent souvent de la fièvre et de la fatigue. Des infections légères peuvent répondre au repos et aux remèdes maison tandis que certaines infections potentiellement mortelles peuvent nécessiter une hospitalisation. [0002] Infectious diseases are disorders caused by micro-organisms such as bacteria, viruses, fungi or parasites. Many organisms live in and on our bodies. They are for some of them harmless or even useful, we then designate under the term of commensal forms. But in other cases, it is also microorganisms that cause disease. Some infectious diseases can be transmitted from person to person or transmitted by insects or other animals or by consumption of contaminated food or water or by exposure to organisms present in the environment. Signs and symptoms vary depending on the organism causing the infection, but often include fever and fatigue. Mild infections may respond to rest and home remedies while some life-threatening infections may require hospitalization.
[0003] De nombreuses maladies infectieuses, comme la grippe, peuvent être limitées dans leur propagation par des vaccins. Un lavage fréquent et complet des mains aide également à se protéger d’un grand nombre de maladies infectieuses. Chaque maladie infectieuse a ses propres signes et symptômes spécifiques. Les signes et symptômes généraux communs à un certain nombre de maladies infectieuses comprennent : la fièvre, la fatigue, les diarrhées, les douleurs musculaires, la toux, les maux de tête. [0003] Many infectious diseases, such as influenza, can be limited in their spread by vaccines. Frequent and thorough hand washing also helps protect against many infectious diseases. Each infectious disease has its own specific signs and symptoms. General signs and symptoms common to a number of infectious diseases include: fever, fatigue, diarrhea, muscle aches, cough, headache.
[0004] La COVID19 récente est l'une des maladies infectieuses concernées par la présente invention. L'infection par le SARS-CoV-2 est transmise par des microgouttelettes produites lors de la toux et des éternuements chez les patients symptomatiques, mais peut également survenir chez des personnes asymptomatiques et avant l'apparition des symptômes. Des études ont montré des charges virales plus élevées dans la cavité nasale que dans la gorge, sans différence de charge virale entre les personnes symptomatiques et asymptomatiques. Les patients peuvent être contagieux aussi longtemps que durent les symptômes et même lors de la guérison clinique. Certaines personnes peuvent jouer le rôle de super contaminateur : un citoyen britannique qui a assisté à une conférence à Singapour a infecté 11 autres personnes alors qu'il séjournait dans une station des Alpes françaises et à son retour au Royaume-Uni. Les microgouttelettes infectées peuvent se propager de 1 à 3 m (voir plus) et se déposer sur les surfaces. Le virus peut rester viable sur des surfaces pendant des jours dans des conditions atmosphériques favorables, mais est détruit en moins d'une minute par des désinfectants courants comme l'hypochlorite de sodium, le peroxyde d'hydrogène, etc. L'infection est contractée soit par inhalation de ces gouttelettes, soit par contact avec des surfaces contaminées par celles-ci, puis en touchant le nez, la bouche et les yeux, soit par voie orale. Le virus est également présent dans les selles et la contamination de l'approvisionnement en eau et la transmission ultérieure par aérosolisation / voie féco-orale est également émise. [0004] The recent COVID19 is one of the infectious diseases concerned by the present invention. SARS-CoV-2 infection is transmitted by microdroplets produced during coughing and sneezing in symptomatic patients, but can also occur in asymptomatic people and before the onset symptoms. Studies have shown higher viral loads in the nasal cavity than in the throat, with no difference in viral load between symptomatic and asymptomatic people. Patients can be infectious for as long as symptoms last and even upon clinical recovery. Some people can play the role of super contaminator: a British citizen who attended a conference in Singapore infected 11 other people while staying at a resort in the French Alps and on his return to the UK. Infected micro-droplets can spread from 1 to 3 m (or even more) and settle on surfaces. The virus can remain viable on surfaces for days under favorable atmospheric conditions, but is destroyed in less than a minute by common disinfectants like sodium hypochlorite, hydrogen peroxide, etc. The infection is acquired either by inhaling these droplets, or by contact with surfaces contaminated by them, then by touching the nose, mouth and eyes, or orally. The virus is also present in feces and contamination of water supply and subsequent aerosol/fecal-oral transmission is also emitted.
[0005] La période d'incubation varie de 2 à 14 jours [médiane à 5 jours]. Des études ont identifié l'angiotensine 2 (ACE2) comme le récepteur par lequel le virus pénètre dans les muqueuses. Tous les patients atteints de pneumonie causée par le SRAS-CoV-2 qui développent une insuffisance respiratoire sévère (SRF) présentent des réponses hyper-inflammatoires avec des caractéristiques de dérégulation immunitaire et de syndrome d'activation des macrophages (MAS). Les formes graves de la maladie sont également souvent accompagnées d’un désordre du tube digestif caractéristiques du syndrome de l’intestin poreux (leaky gut). Ce dernier élément permet de relier un déséquilibre du microbiote digestif à la gravité de la maladie. Pour les inventeurs, il est ainsi, logique de concevoir le bénéfice d’un microbiote équilibré dans la prévention des formes graves de la COVID19. [0005] The incubation period varies from 2 to 14 days [median 5 days]. Studies have identified angiotensin 2 (ACE2) as the receptor through which the virus enters mucous membranes. All patients with pneumonia caused by SARS-CoV-2 who develop severe respiratory failure (SRF) show hyper-inflammatory responses with features of immune dysregulation and macrophage activation syndrome (MAS). Severe forms of the disease are also often accompanied by a disorder of the digestive tract characteristic of leaky gut syndrome. This last element makes it possible to link an imbalance of the digestive microbiota to the severity of the disease. For the inventors, it is thus logical to conceive of the benefit of a balanced microbiota in the prevention of severe forms of COVID19.
[0006] Les formes graves de l’infection SARS-CoV-2 sont caractérisés par un orage de cytokines pro-inflammatoires (cytokine storm) composé notamment par un excès d'I L6 , de TNF-a et d’IL-10. Cette surproduction de cytokines est l’une des caractéristiques clés du déséquilibre immunitaire associé aux formes sévères avec la surproduction de cytokines pro-inflammatoires par les monocytes et la diminution de la population de lymphocytes caractérisée par une lymphopénie CD4+ et probablement CD8+. En parallèle, le nombre de cellules tueuses (NK, natural killer) est amoindri, probablement en raison de la propagation rapide du virus. Pour résumer, la signature unique de la dérégulation immunitaire chez les patients atteints des formes graves du SRAS-CoV- 2, se caractérise d'une part par une forte capacité de production de cytokines et de leurs formes circulantes (en particulier IL-6) et d'autre part par des défauts de la fonction lymphoïde associée notamment, à une diminution médiée par IL-6 de l'expression de HLA-DR sur les cellules monocytes-CD14.Dans la prévention de la COVID19, ou de toute autre infection virale et/ou bactérienne il existe donc le besoin de prévenir une dérégulation immunitaire, notamment au moyen d’une composition permettant de rétablir le déséquilibre du microbiote intestinal (dysbiose) sans utilisation de médicaments. La présente invention permet de remédier à ce problème en rééquilibrant le microbiote intestinal par l’administration d’une composition selon l’invention. En effet, la présente invention se rapporte à une composition comprenant au moins un probiotique, de préférence sous forme de souche vivante ou de fragments désactivés, au moins un composé antioxydant et des polysaccharides notamment, issus d’une plante adaptogène. Si cette plante a également un rôle prébiotique, il vient en complément des effets liés aux probiotiques. [0006] The severe forms of SARS-CoV-2 infection are characterized by a storm of pro-inflammatory cytokines (cytokine storm) composed in particular of an excess of I L6, of TNF-a and of IL-10. This overproduction of cytokines is one of the key characteristics of the immune imbalance associated with severe forms with the overproduction of pro-inflammatory cytokines by monocytes and the decrease in the lymphocyte population characterized by CD4+ and probably CD8+ lymphopenia. At the same time, the number of killer cells (NK, natural killer) is reduced, probably due to the rapid spread of the virus. To summarize, the unique signature of immune dysregulation in patients with severe forms of SARS-CoV-2 is characterized on the one hand by a strong capacity for the production of cytokines and their circulating forms (in particular IL-6) and on the other hand by defects in lymphoid function associated in particular with an IL-6-mediated decrease in the expression of HLA-DR on monocytes-CD14 cells. prevention of COVID19, or any other viral and/or bacterial infection, there is therefore a need to prevent immune deregulation, in particular by means of a composition making it possible to restore the imbalance of the intestinal microbiota (dysbiosis) without the use of drugs. The present invention makes it possible to remedy this problem by rebalancing the intestinal microbiota by administering a composition according to the invention. Indeed, the present invention relates to a composition comprising at least one probiotic, preferably in the form of a live strain or of deactivated fragments, at least one antioxidant compound and polysaccharides in particular, derived from an adaptogenic plant. If this plant also has a prebiotic role, it complements the effects related to probiotics.
[0007] Les probiotiques sont décrits pour réduire la gravité de certaines infections virales et envisagées pour avoir un effet sur d'autres souches de coronavirus (Baud et al., Front. Public Health 2020, vol. 8 :186). [0007] Probiotics are described to reduce the severity of certain viral infections and considered to have an effect on other strains of coronavirus (Baud et al., Front. Public Health 2020, vol. 8:186).
[0008] Le dysfonctionnement immunitaire et la tempête de cytokines (cytokine storm) sont des mécanismes complexes. La présente invention cible à différents niveaux ces désordres et fourni un traitement prophylactique plus efficace pour l’humain ou les animaux.[0008] Immune dysfunction and cytokine storm are complex mechanisms. The present invention targets at different levels these disorders and provides a more effective prophylactic treatment for humans or animals.
EXPOSE DE L’INVENTION DISCLOSURE OF THE INVENTION
[0009] Dans un mode de réalisation, l’invention se rapporte à une composition comprenant au moins un probiotique, au moins un composé antioxydant et des polysaccharides issus des plantes adaptogènes à titre notamment, de prebiotique ; le probiotique étant préférentiellement sous forme de souches probiotiques. Ces souches probiotiques étant choisies parmi les souches probiotiques suivantes, seul ou en mélange : Lactobacillus rhamnosus, Lactobacillus easel, Lactobacillus paracasei, Lactobacillus gasseri, Bifidobacterium longum, Lactobacillus plantarum, Bifidobacterium adolescentis, Lactobacillus reuteri, Bifidobacterium infantis. Dans le cadre de l’invention, l'utilisation des probiotiques pour lutter contre les infections respiratoires notamment virales est liée à i) une symptomatologie digestive avec une multiplication virale digestive de l'infection comme dans le cas de la COVID-19, ii) le lien entre le tube digestif et le poumon (axe intestin-poumon) et iii) le rôle de certaines souches probiotiques spécifiques sur l'équilibre entre les cytokines pro et anti-inflammatoires (c'est-à-dire le rapport entre les cytokines de type 1 et de type 2) respectivement, IL6 i IL12 i IL1 , TNF-alpha et IL-10 i TGF-b). In one embodiment, the invention relates to a composition comprising at least one probiotic, at least one antioxidant compound and polysaccharides from adaptogenic plants, in particular as a prebiotic; the probiotic being preferentially in the form of probiotic strains. These probiotic strains being chosen from the following probiotic strains, alone or in a mixture: Lactobacillus rhamnosus, Lactobacillus easel, Lactobacillus paracasei, Lactobacillus gasseri, Bifidobacterium longum, Lactobacillus plantarum, Bifidobacterium adolescentis, Lactobacillus reuteri, Bifidobacterium infantis. In the context of the invention, the use of probiotics to fight against respiratory infections, in particular viral infections, is linked to i) digestive symptoms with digestive viral multiplication of the infection as in the case of COVID-19, ii) the link between the digestive tract and the lung (gut-lung axis) and iii) the role of certain specific probiotic strains on the balance between pro and anti-inflammatory cytokines (i.e. the ratio between cytokines type 1 and type 2) respectively, IL6 i IL12 i IL1, TNF-alpha and IL-10 i TGF-b).
[00010] Les probiotiques sont des « micro-organismes vivants » qui, lorsqu'ils sont administrés en quantités adéquates, confèrent un avantage à l'hôte (FAO i OMS, 2001 ). Les produits vendus contenant des probiotiques comprennent des aliments (comme certains yaourts, les laits fermentés type kéfir ...), des compléments alimentaires et quelques produits qui ne sont pas utilisés par voie orale, comme des crèmes pour la peau. Les probiotiques sont connus comme étant extrêmement bénéfiques pour la santé via un rééquilibrage du microbiome intestinal et le contrôle de souches pathogènes. [00010] Probiotics are “live microorganisms” which, when administered in adequate quantities, confer a benefit on the host (FAO i WHO, 2001). Products sold containing probiotics include foods (such as certain yogurts, kefir-type fermented milks, etc.), food supplements and some products that are not used orally, such as skin creams. Probiotics are known to be extremely beneficial for health by rebalancing the intestinal microbiome and controlling pathogenic strains.
[00011] Lactobacillus plantarum est une bactérie polyvalente trouvée dans une variété de niches écologiques, allant des fermentations végétales au tractus gastro-intestinal humain. Les Lactobacillus plantarum ont une forme de bâtonnet avec des extrémités arrondies, droites, généralement de 0,9 à 1 ,2 pm de large et de 3 à 8 pm de long, se présentant individuellement, par paires ou en courtes chaînes. Le génome de la première bactérie isolée d’un tube digestif humain L. plantarum souche WCFS1 a été séquencé (Kleerebezem et al., PNAS 2003, vol.100 tome 4 ; 1990-1995) et sa taille de 3,3 Mb est parmi les plus importantes connues pour les bactéries vivant dans le tube digestif (Makarova K. et al., PNAS 2006, 103 vol.42 ; 15611-15616) ; Makarova et Koonin, J. Bacteriol.2007, tome189 vol.4 1199- 1208). On pense qu'une telle longueur de génome est liée à la diversité des niches environnementales dans lesquelles L. plantarum est rencontré. [00011] Lactobacillus plantarum is a versatile bacterium found in a variety of ecological niches, ranging from plant fermentations to the human gastrointestinal tract. Lactobacillus plantarum are rod-shaped with rounded, straight ends, usually 0.9-1.2 µm wide and 3-8 µm long, occurring singly, in pairs, or in short chains. The genome of the first bacterium isolated from a human digestive tract L. plantarum strain WCFS1 was sequenced (Kleerebezem et al., PNAS 2003, vol.100 tome 4; 1990-1995) and its size of 3.3 Mb is among the most important known for bacteria living in the digestive tract (Makarova K. et al., PNAS 2006, 103 vol.42; 15611-15616); Makarova and Koonin, J. Bacteriol.2007, tome189 vol.4 1199-1208). Such genome length is thought to be related to the diversity of environmental niches in which L. plantarum is encountered.
[00012] Lactobacillus reuteri est une bactérie symbiotique intestinale typique qui joue un rôle important dans le maintien de la stabilité de la flore intestinale et de la santé de l'hôte. Dans un article récent, des auteurs ont publié que Lactobacillus reuteri pourrait activer les macrophages et que les macrophages traités avec Lactobacillus reuteri ont une capacité accrue de phagocytose et d’élimination de Salmonella typhimurium intracellulaire. [00012] Lactobacillus reuteri is a typical intestinal symbiotic bacterium which plays an important role in maintaining the stability of the intestinal flora and the health of the host. In a recent article, authors published that Lactobacillus reuteri could activate macrophages and that macrophages treated with Lactobacillus reuteri have an increased capacity for phagocytosis and elimination of intracellular Salmonella typhimurium.
Lactobacillus rhamnosus et notamment Lactobacillus rhamnosus GG (souche ATCC53103) est une souche probiotique extrêmement bien étudiée. Il a été découvert en 1985 et de nombreuses études ont prouvé plus de 40 avantages pour la santé. Lactobacillus rhamnosus GG, a une très bonne adhérence à la paroi intestinale et est donc considéré comme un bon probiotique. Ce probiotique stimule le système immunitaire, combat les allergies et apporte un bénéfice digestif sur le Syndrome du Côlon irritable (SCI) et la constipation. Les avantages de Lactobacillus rhamnosus GG sont nombreux : gestion du diabète, effets stimulants de l’immunité : combat les infections bactériennes, inhibe les ulcères induit par H. pylori, stimule l'immunité générale, améliore l'immunité chez les patients atteints du VIH / sida, diminue les symptômes du VIH / sida. Le potentiel antiinflammatoire de Lactobacillus rhamnosus souche 4B15 et Lactobacillus gasseri souche 4M13 isolés à partir de matières fécales infantiles a été également récemment décrit (Nam Su et al., PloSone, 2018 vol.13, tome 2). Lactobacillus rhamnosus and in particular Lactobacillus rhamnosus GG (strain ATCC53103) is an extremely well-studied probiotic strain. It was discovered in 1985 and numerous studies have proven over 40 health benefits. Lactobacillus rhamnosus GG, has a very good adhesion to the intestinal wall and is therefore considered a good probiotic. This probiotic stimulates the immune system, fights allergies and provides a digestive benefit on Irritable Bowel Syndrome (IBS) and constipation. The benefits of Lactobacillus rhamnosus GG are numerous: diabetes management, immunity boosting effects: fights bacterial infections, inhibits H. pylori-induced ulcers, boosts general immunity, improves immunity in HIV patients / AIDS, decreases symptoms of HIV / AIDS. The anti-inflammatory potential of Lactobacillus rhamnosus strain 4B15 and Lactobacillus gasseri strain 4M13 isolated from infant faeces has also recently been described (Nam Su et al., PloSone, 2018 vol.13, tome 2).
[00013] Les bifidobactéries sont des habitants naturels du tractus gastro-intestinal possédant des adaptations génétiques qui permettent la colonisation de cet habitat difficile et complexe. Les bifidobactéries interagissent avec des éléments clés du fonctionnement intestinal et contribuent ainsi au maintien de l'homéostasie. [00013] Bifidobacteria are natural inhabitants of the gastrointestinal tract with genetic adaptations that allow the colonization of this difficult habitat and complex. Bifidobacteria interact with key elements of intestinal functioning and thus contribute to the maintenance of homeostasis.
[00014] Des progrès scientifiques récents ont démontré que les bifidobactéries, grâce à des interactions avec l'hôte, peuvent réduire la charge antigénique mucosale en améliorant la barrière intestinale et en privilégiant la régulation des réponses immunitaires locales et systémiques. En raison de leurs bienfaits reconnus pour la santé humaine, les bifidobactéries sont utilisées comme probiotiques. [00014] Recent scientific progress has demonstrated that bifidobacteria, through interactions with the host, can reduce the mucosal antigenic load by improving the intestinal barrier and favoring the regulation of local and systemic immune responses. Due to their recognized benefits for human health, bifidobacteria are used as probiotics.
[00015] Une douzaine de souches de Bifidobacterium aux effets cliniquement documentés sont disponibles dans le commerce. La moitié d'entre elles sont des Bifidobacterium animalis subsp. lactis et les autres sont Bifidobacterium longum subsp. longum, B. longum subsp. infantis ou souches de Bifidobacterium breve. Bifidobacterium adolescentis qui a été pour la 1ère fois isolée dans l'intestin d'un adulte (Reuter, Current Issues Intest. Microbiol. 2001 ; vol.2 T. 2 ;43-53). Des souches de B. adolescentis sont fréquemment détectées dans le tractus intestinal humain adulte en bonne santé (healthy gut) (Turroni et al., 2009 Apply Environnement Microbiol. 2009, vol.75 tome 6, pp 1534-1545). [00015]A dozen strains of Bifidobacterium with clinically documented effects are commercially available. Half of them are Bifidobacterium animalis subsp. lactis and the others are Bifidobacterium longum subsp. longum, B.longum subsp. infantis or strains of Bifidobacterium breve. Bifidobacterium adolescentis which was isolated for the 1st time in the intestine of an adult (Reuter, Current Issues Intest. Microbiol. 2001; vol.2 T. 2;43-53). Strains of B. adolescentis are frequently detected in the healthy adult human intestinal tract (healthy gut) (Turroni et al., 2009 Apply Environment Microbiol. 2009, vol.75 tome 6, pp 1534-1545).
[00016] David Groeger et al, (Gut Microbes, 2013 ; vol.4 ; 325-339) montrent que l'administration orale de B. infantis souche 35624 module le milieu des cytokines à la fois gastro-intestinales et non gastro-intestinales dans les troubles inflammatoires et chez les sujets sains. L'administration orale de B. infantis 35624 était suffisante pour réduire les biomarqueurs inflammatoires systémiques à la fois gastro-intestinaux et extra-intestinaux dans les troubles inflammatoires. [00016] David Groeger et al, (Gut Microbes, 2013; vol.4; 325-339) show that oral administration of B. infantis strain 35624 modulates both gastrointestinal and non-gastrointestinal cytokine milieu in inflammatory disorders and in healthy subjects. Oral administration of B. infantis 35624 was sufficient to reduce both gastrointestinal and extraintestinal systemic inflammatory biomarkers in inflammatory disorders.
[00017] Dans le cadre de l’invention, la composition telle que décrite précédemment comprend au moins une souche probiotique de préférence vivante sous la forme suivante: lyophilisée, liquide en suspension, ou sous la forme d’extrait et/ou de sécrétome partiel ou complet, de molécule extraite et/ou purifiée. [00017] In the context of the invention, the composition as described above comprises at least one probiotic strain, preferably live, in the following form: freeze-dried, liquid in suspension, or in the form of an extract and/or partial secretome or complete, of extracted and/or purified molecule.
[00018] D’une manière générale, les quantités des différents ingrédients dans les compositions selon l’invention, sont des quantités efficaces ou substantielles. Par quantité efficace ou substantielle, il est entendu une quantité pour un ou plusieurs ingrédients donnés, suffisante pour permettre de constater un effet pour un état à un temps précis par comparaison avec un état initial, c’est-à-dire sans prise du ou des ingrédients visés. [00018] In general, the amounts of the various ingredients in the compositions according to the invention are effective or substantial amounts. By effective or substantial quantity, it is meant a quantity for one or more given ingredients, sufficient to make it possible to observe an effect for a state at a precise time by comparison with an initial state, that is to say without taking the or target ingredients.
[00019] Dans le contexte de l’invention, les antioxydants utilisés sont de nature exogène ou endogène. A titre d’exemple on peut citer la vitamine E, la lutéine, la vitamine G, le béta- carotène, le Resveratrol, les flavonoïdes, et bioflavonoïdes et le lycopène. In the context of the invention, the antioxidants used are of exogenous or endogenous nature. Examples include vitamin E, lutein, vitamin G, beta-carotene, Resveratrol, flavonoids, and bioflavonoids and lycopene.
[00020] Dans un mode de réalisation particulier, l’invention se rapporte à une composition dans laquelle le composé antioxydant est choisi parmi la quercétine et/ou un analogue de la quercétine et/ou d’un extrait de plante(s) la contenant, seul ou en mélange. La quercétine est un flavonoïde aux propriétés antioxydantes. On prétend que la capacité de la quercétine exerce de nombreux effets bénéfiques sur la santé, y compris la protection contre diverses maladies telles que l'ostéoporose, le cancer du poumon et les maladies cardiovasculaires. La quercétine (3,3',4',5,7-pentahydroxyflavone) est de couleur jaune et est peu soluble dans l'eau chaude, assez soluble dans l'alcool et les lipides et est insoluble dans l'eau froide. On dit que la quercétine est l'un des bioflavonoïdes les plus largement utilisés pour le traitement des troubles métaboliques et inflammatoires. In a particular embodiment, the invention relates to a composition in which the antioxidant compound is chosen from quercetin and/or an analogue of quercetin and/or of a plant extract(s) containing it. , alone or in a mixture. quercetin is a flavonoid with antioxidant properties. The ability of quercetin is claimed to exert many beneficial health effects, including protection against various diseases such as osteoporosis, lung cancer, and cardiovascular disease. Quercetin (3,3',4',5,7-pentahydroxyflavone) is yellow in color and sparingly soluble in hot water, fairly soluble in alcohol and lipids, and insoluble in cold water. Quercetin is said to be one of the most widely used bioflavonoids for the treatment of metabolic and inflammatory disorders.
[00021] De plus, la quercétine et ses analogues sont connus pour présenter des effets antibactériens contre presque toutes les souches de bactéries, affectant en particulier le système gastro-intestinal, respiratoire, urinaire et cutané. Leur capacité anti-infectieuse et anti-replicatifs contribue éventuellement à leurs caractéristiques antivirales. Les virus qui répondent généralement aux flavonoïdes sont l'adénovirus, le virus de l'herpès simplex, le virus de l'encéphalite japonaise et le virus respiratoire syncytial. La quercétine est l'un des flavonoïdes alimentaires les plus abondants trouvés dans les fruits (principalement les agrumes) et les baies comme les myrtilles. Les concentrations les plus élevées de quercétine ont été trouvées dans des légumes tels que l’oseille (Rumex sp), la coriandre (Coriandrum sativum), les oignons, les asperges (Asparagus officinalis), le cresson (Capucine officinalis), le chou (Brassica oleracea), les pommes, les cerises et les baies. [00021] Additionally, quercetin and its analogs are known to exhibit antibacterial effects against almost all strains of bacteria, particularly affecting the gastrointestinal, respiratory, urinary and cutaneous systems. Their anti-infective and anti-replicative capacity possibly contributes to their antiviral characteristics. Viruses that typically respond to flavonoids are adenovirus, herpes simplex virus, Japanese encephalitis virus, and respiratory syncytial virus. Quercetin is one of the most abundant dietary flavonoids found in fruits (mainly citrus fruits) and berries like blueberries. The highest concentrations of quercetin have been found in vegetables such as sorrel (Rumex sp), coriander (Coriandrum sativum), onions, asparagus (Asparagus officinalis), watercress (Nasturtium officinalis), cabbage ( Brassica oleracea), apples, cherries and berries.
[00022] Dans un mode de réalisation particulier de l’invention, la composition selon l’invention comprend de la quercétine et/ou un analogue de quercétine. Les analogues de la quercétine sont définis comme des flavonoïdes naturels qui présentent un large éventail d'activités biologiques comme l'isoquercétine (quercétine-3b-o-glucoside), la quercétagétine, la quercétine-3-gallate. Ainsi, l’analogue de la quercétine est notamment choisi parmi l’isoquercétin (quercetin-3b-o-glucoside), la quercétagetin, la quercétin-3- gallate. La quercétine peut également être un extrait de plantes en contenant est choisi parmi les extraits de plantes suivantes : oseille (Rumex sp), coriandre (Coriandrum sativum), oignons, asperges (Asparagus officinalis), cresson (Nasturtium officinalis), okra (Abelmoschus esculentus), le chou (Brassica oleracea). La quercétine est également présente dans des extraits d’arbre des pagodes (Sophora japonica). In a particular embodiment of the invention, the composition according to the invention comprises quercetin and/or a quercetin analogue. Quercetin analogues are defined as natural flavonoids that exhibit a wide range of biological activities like isoquercetin (quercetin-3b-o-glucoside), quercetagetin, quercetin-3-gallate. Thus, the quercetin analogue is chosen in particular from isoquercetin (quercetin-3b-o-glucoside), quercetagetin, quercetin-3-gallate. Quercetin can also be a plant extract containing it is chosen from the following plant extracts: sorrel (Rumex sp), coriander (Coriandrum sativum), onions, asparagus (Asparagus officinalis), watercress (Nasturtium officinalis), okra (Abelmoschus esculentus ), cabbage (Brassica oleracea). Quercetin is also present in extracts of the pagoda tree (Sophora japonica).
[00023]Selon un autre de mode de réalisation de l’invention, l’antioxydant est la S-Adénosyl- méthionine (SAMe) qui est impliqué dans l'activité de l’ADN méthyltransférase ou des histones méthyltransférases. Une supplémentation en SAMe régule la méthylation de l’ADN et intervient ainsi sur différents désordres cardio-vasculaires, hépatiques ou la dépression et le vieillissement, et dans le développement des cancers à travers différents mécanismes. According to another embodiment of the invention, the antioxidant is S-Adenosylmethionine (SAMe) which is involved in the activity of DNA methyltransferase or histone methyltransferases. SAMe supplementation regulates DNA methylation and thus intervenes in various cardiovascular and hepatic disorders or depression and aging, and in the development of cancers through various mechanisms.
[00024] L’invention se rapporte dans un mode particulier de réalisation à une composition telle que décrite précédemment et comprenant des polysaccharides de plante(s) adaptogène(s). Ces polysaccharides sont extraits ou purifiés à partir de plante se présentant sous les formes suivantes : feuilles et/ou racines lyophilisées, extraits complets ou partiels. Dans un mode préféré, les polysaccharides sont extraits de plante adaptogène choisie parmi les genres Astragalus, Dioscorea, Schisandra, Panax, Eleuterococcus, Rosmarinus , Pfaffia , Morinda, Cordyceps ou Lepidium genera, notamment sous forme d’extrait sec ou purifié. Ils peuvent jouer un rôle de prébiotiques c’est à dire de substrat favorisant la survie des souches probiotiques. The invention relates in a particular embodiment to a composition as described above and comprising polysaccharides from plant(s) adaptogen(s). These polysaccharides are extracted or purified from plants in the following forms: freeze-dried leaves and/or roots, complete or partial extracts. In a preferred mode, the polysaccharides are extracted from an adaptogenic plant chosen from the genera Astragalus, Dioscorea, Schisandra, Panax, Eleuterococcus, Rosmarinus, Pfaffia, Morinda, Cordyceps or Lepidium genera, in particular in the form of a dry or purified extract. They can play a role of prebiotics, ie of substrate favoring the survival of probiotic strains.
[00025] Les adaptogènes sont des plantes non toxiques commercialisées pour aider le corps à résister aux facteurs de stress de toutes sortes, qu'ils soient physiques, chimiques ou biologiques. Ces herbes et racines sont utilisées depuis des siècles dans les traditions de guérison chinoises et ayurvédiques, mais elles connaissent une renaissance aujourd'hui. Les adaptogènes agissent pour contrer les effets du stress. Le stress provoque des changements physiques très réels dans le corps, y compris des dommages aux systèmes neurologique, endocrinien et immunitaire. Les adaptogènes ont des propriétés stimulantes qui aident à contrer ces effets nocifs. Les adaptogènes ont été développés et vraiment étudiés pour la première fois, pendant la Seconde Guerre mondiale. Les scientifiques cherchaient un moyen d'aider les pilotes en bonne santé à travailler à des niveaux encore plus élevés. Fondamentalement, ils recherchaient une pilule de « super-héros » qui permettrait aux pilotes de mieux voler, plus vite et plus longtemps. [00025] Adaptogens are non-toxic herbs marketed to help the body resist stressors of all kinds, whether physical, chemical or biological. These herbs and roots have been used for centuries in Chinese and Ayurvedic healing traditions, but are experiencing a renaissance today. Adaptogens work to counter the effects of stress. Stress causes very real physical changes in the body, including damage to the neurological, endocrine, and immune systems. Adaptogens have stimulating properties that help counter these harmful effects. Adaptogens were first developed and really studied, during World War II. Scientists were looking for a way to help healthy pilots perform at even higher levels. Basically, they were looking for a "superhero" pill that would allow pilots to fly better, faster, and longer.
[00026] Le groupe des plantes adaptogène comprend notamment les plantes appartenant aux genres suivants : Astragalus, Dioscorea, Withania, Ginkgo, Schisandra, Panax, Eleuterococcus, Rhodiola, Schisandra, Lepidium, Rosmarinus, Pfaffia, Morinda, Cordyceps. The group of adaptogenic plants includes in particular plants belonging to the following genera: Astragalus, Dioscorea, Withania, Ginkgo, Schisandra, Panax, Eleuterococcus, Rhodiola, Schisandra, Lepidium, Rosmarinus, Pfaffia, Morinda, Cordyceps.
[00027] Pour la réalisation de l'invention on choisira, de préférence, des extraits polysaccharidiques issus de plantes appartenant au genre Astragalus et/ou, Dioscorea et/ou Lepidium. De telles plantes, en particulier Astragalus membranaceus (Astragale) ou Dioscorea villosa ou opposita ou encore Lepidium meyenii (ou Maca) ont pour effet de restaurer et normaliser les différents organes et fonctions de notre organisme, notamment par l'augmentation du nombre de cellules souches dans la moelle osseuse et le tissu lymphatique. Ces plantes réactivent les cellules immunitaires au repos, en stimulant les macrophages et favorisent la régénération des lymphocytes T et NK ; inhibent la peroxydation lipidique en particulier dans le myocarde ; stimulent la télomérase rallongeant ainsi les télomères les plus courts et protègent l'ADN du vieillissement cellulaire. For carrying out the invention, polysaccharide extracts from plants belonging to the genus Astragalus and/or Dioscorea and/or Lepidium will preferably be chosen. Such plants, in particular Astragalus membranaceus (Astragalus) or Dioscorea villosa or opposita or even Lepidium meyenii (or Maca) have the effect of restoring and normalizing the various organs and functions of our body, in particular by increasing the number of stem cells. in bone marrow and lymphatic tissue. These plants reactivate resting immune cells, stimulating macrophages and promoting the regeneration of T and NK lymphocytes; inhibit lipid peroxidation particularly in the myocardium; stimulate telomerase thus lengthening the shortest telomeres and protect DNA from cellular aging.
[00028]Selon un mode de réalisation de l’invention, les compositions selon celle-ci comprennent des vitamines. Par « une vitamine », on entend toutes les vitamines : A, B1 , B2, B3, B5, B6, B8, B9, B12, C, D, E K1 , K2, leurs précurseurs respectifs, ou un mélange de vitamines et/ou de précurseurs respectifs. Avantageusement, ladite vitamine est une vitamine du groupe B, en particulier B6, B9, B12, la vitamine C, la vitamine D ou un mélange de celles-ci. En effet, la vitamine B6 favorise notamment l'absorption du magnésium et la synthèse de la sérotonine (un neurotransmetteur essentiel). La vitamine B9 ou acide folique possède la propriété d'agir également sur le métabolisme des acides aminés et la synthèse des protéines ; elle participe au renouvellement des cellules de l'immunité, à la formation des globules rouges et à l'apport en oxygène dont l'organisme a besoin. La vitamine B12 est essentielle au bon fonctionnement du système nerveux central et périphérique. La vitamine D est connue pour son rôle sur la réponse immunitaire et son activité antiinflammatoire sur les cytokines du groupe 1 , c’est-à-dire IL-1 b, IL-6, TNF-alpha, notamment. According to one embodiment of the invention, the compositions according to the latter comprise vitamins. By “a vitamin”, we mean all the vitamins: A, B1, B2, B3, B5, B6, B8, B9, B12, C, D, E, K1, K2, their respective precursors, or a mixture of vitamins and/or or respective precursors. Advantageously, said vitamin is a B group vitamin, in particular B6, B9, B12, vitamin C, vitamin D or a mixture thereof. Indeed, vitamin B6 notably promotes the absorption of magnesium and the synthesis of serotonin (an essential neurotransmitter). Vitamin B9 or folic acid also has the property of acting on amino acid metabolism and protein synthesis; it participates in the renewal of immune cells, the formation of red blood cells and the supply of oxygen that the body needs. Vitamin B12 is essential for the proper functioning of the central and peripheral nervous system. Vitamin D is known for its role in the immune response and its anti-inflammatory activity on group 1 cytokines, that is to say IL-1 b, IL-6, TNF-alpha, in particular.
[00029] Dans un mode particulier de l’invention, la composition décrite précédemment comprend des polysaccharides d’Astragale notamment choisi parmi un galacto- oligosaccharides ou des fructo-oligosaccharides pour leur capacité à jouer le rôle de prébiotique. In a particular embodiment of the invention, the composition described above comprises Astragalus polysaccharides chosen in particular from galacto-oligosaccharides or fructo-oligosaccharides for their ability to act as a prebiotic.
[00030]Selon un mode avantageux de l’invention, la composition décrite comprend une quantité de probiotique(s) pour réduire : i. la libération et/ou la production des médiateurs de l’inflammation notamment les cytokines IL6, TNF-a et I L1 b, en particulier une libération et/ou une production excessive des médiateurs de l’inflammation. Au sens de la présente invention, une libération et/ou une production des médiateurs de l’inflammation est considérée comme excessive, lorsque la libération et/ou la production de ceux-ci est au- dessus de 2 fois la quantité normalement constatée chez un sujet sans dysfonctionnement; et/ou il. les désordres immunologiques responsables d’une plus grande susceptibilité aux infections virales et/ou bactériennes et/ou ill. les dysbioses, responsables d’une plus grande susceptibilité aux infections virales et/ou bactériennes. According to an advantageous mode of the invention, the composition described comprises a quantity of probiotic(s) to reduce: i. the release and/or production of inflammatory mediators, in particular the cytokines IL6, TNF-a and I L1b, in particular an excessive release and/or production of inflammatory mediators. Within the meaning of the present invention, a release and/or a production of inflammatory mediators is considered excessive, when the release and/or the production thereof is above 2 times the amount normally observed in a subject without dysfunction; and/or he. immunological disorders responsible for a greater susceptibility to viral and/or bacterial infections and/or ill. dysbiosis, responsible for a greater susceptibility to viral and/or bacterial infections.
En particulier, la composition comprend une quantité de souche(s) probiotique(s) pour réduire et/ou prévenir les troubles pathologiques ou les affections sub-cliniques issus notamment d’une dysbiose du tube digestif qu’elle soit d’origine endogène ou exogène due à une infection, la pollution, le stress notamment. In particular, the composition comprises a quantity of probiotic strain(s) for reducing and/or preventing pathological disorders or sub-clinical conditions resulting in particular from dysbiosis of the digestive tract, whether of endogenous origin or exogenous due to infection, pollution, stress in particular.
[00031] Dans un mode préféré de l’invention, la composition décrite se présente sous la forme d’un complément nutritionnel solide ou liquide. Ce dernier étant utilisé pour une application non-thérapeutique. L’invention se rapporte également à une utilisation non-thérapeutique de la composition selon l’invention, décrite précédemment, pour corriger une dysbiose cutanée et/ou les désordres subcliniques ou cliniques (i.e. dermatologiques) associés à ces dysbioses. In a preferred embodiment of the invention, the composition described is in the form of a solid or liquid nutritional supplement. The latter being used for a non-therapeutic application. The invention also relates to a non-therapeutic use of the composition according to the invention, described above, for correcting cutaneous dysbiosis and/or the subclinical or clinical (ie dermatological) disorders associated with these dysbiosis.
[00032] COMMENTAIRES SOMMAIRES DES FIGURES [00032] SUMMARY COMMENTS ON THE FIGURES
La figure 1 illustre l’incubation dans les différents groupes expérimentaux, contenant 6 réplicons par groupe (n = 6) de l’exemple 2. Les groupes expérimentaux ont été incubés pendant 24 heures avec la composition de l’exemple 1 , en présence d'IL-6 (8 ng/ml). Figure 1 illustrates the incubation in the different experimental groups, containing 6 replicons per group (n=6) of example 2. The experimental groups were incubated for 24 hours with the composition of example 1, in the presence of IL-6 (8ng/ml).
Le groupe « Stress » a reçu uniquement le traitement avec IL-6 (8 ng/ml) afin de mimer un « orage cytokinique », tandis que le groupe « Contrôle » a été non traité. La dexaméthasone (1 pM) a été utilisé comme référence. The “Stress” group received only the treatment with IL-6 (8 ng/ml) in order to mimic a “cytokine storm”, while the “Control” group was untreated. Dexamethasone (1 µM) was used as a reference.
La figure 2 montre les taux de carbonylation obtenus pour 2 concentrations différentes de la composition selon l’exemple 1 et leur effet protecteur selon le protocole décrit dans l’exemple 2. Figure 2 shows the carbonylation rates obtained for 2 different concentrations of the composition according to example 1 and their protective effect according to the protocol described in example 2.
Les exemples ci-dessous illustrent l’invention sans pour autant limiter son champ d’application. The examples below illustrate the invention without limiting its field of application.
EXEMPLES EXAMPLES
[00033] Exemple 1 : formulation sous forme de complément alimentaire [00033] Example 1: formulation in the form of a food supplement
La composition suivante est un mode de réalisation de l’invention de type complément alimentaire sous la forme d’une gélule végétale gastro-résistante : The following composition is an embodiment of the invention of the food supplement type in the form of a gastro-resistant vegetable capsule:
- Bifidobacterium adolescentis : 5 Milliard de CFU - Bifidobacterium adolescentis: 5 billion CFUs
- Lactobacillus rhamnosus GG : 5 Milliard de CFU - Lactobacillus rhamnosus GG: 5 billion CFU
- Extrait de racine d’Astragale (Astragalus membranaceus) à 20% de polysaccharides, (plante issue de la pharmacopée chinoise et utilisée dans la composition pour une activité prébiotique) : 200mg - Astragalus root extract (Astragalus membranaceus) with 20% polysaccharides, (plant from the Chinese pharmacopoeia and used in the composition for prebiotic activity): 200mg
- Quercétine (extrait à 95% de Sophora japonica) : 180 mg - Quercetin (95% extract of Sophora japonica): 180 mg
- Vitamine B6 : 2.1 mg (750% des AR) - Vitamin B6: 2.1 mg (750% of AR)
- Vitamine B12 : 5 g (200% des AR) - Vitamin B12: 5 g (200% of AR)
(EPS 1 600 mg) Enveloppe : gélule végétale HPMC (EPS 1,600 mg) Envelope: HPMC vegetable capsule
[00034] Exemple 2 : Evaluation in vitro des effets protecteurs de la composition de l’exemple 1 , selon l’invention, dans un modèle cellulaire stressé : Le but de cette étude est d’évaluer dans un modèle in vitro de fibroblastes humains issus du derme, l’effet protecteur d’une formule selon l’invention (à 2 concentrations différentes) pour prévenir les effets délétères de la réponse hyper-inflammatoire liées au COVID-19 (« orage cytokinique » ou « cytokine Storm »). [00034] Example 2: In vitro evaluation of the protective effects of the composition of Example 1, according to the invention, in a stressed cell model: The aim of this study is to evaluate, in an in vitro model of human fibroblasts derived from the dermis, the protective effect of a formula according to the invention (at 2 different concentrations) to prevent the deleterious effects of the hyper-inflammatory response. related to COVID-19 (“cytokine storm” or “cytokine storm”).
En effet, Les protéines sont impliquées dans les fonctions cellulaires clés et notre santé dépend du niveau d'oxydation cellulaire. Indeed, proteins are involved in key cellular functions and our health depends on the level of cellular oxidation.
La carbonylation des protéines est l'une des modifications oxydatives des protéines irréversibles les plus nocives. Elle est considérée comme une caractéristique majeure des troubles liés au stress oxydatif et elle est souvent quantifiée pour évaluer ces troubles. Dans une forme aigüe, cette carbonylation, si elle est massive, peut conduire à une destruction cellulaire. L'accumulation de protéines endommagées par oxydation est également, une caractéristique de processus délétères tels que l'inflammation chronique, l'étape inflammatoire infectieuse, le vieillissement et de nombreux troubles liés à l'âge. Protein carbonylation is one of the most harmful irreversible protein oxidative changes. It is considered a major feature of oxidative stress-related disorders and is often quantified to assess these disorders. In an acute form, this carbonylation, if massive, can lead to cell destruction. Accumulation of oxidatively damaged proteins is also a hallmark of deleterious processes such as chronic inflammation, the infectious inflammatory stage, aging, and many age-related disorders.
Il apparait essentiel pour déterminer si ces protéines modifiées ont un impact sur ces troubles et comment elles agissent. Aussi pour évaluer cet impact, il est nécessaire d’avoir recours aux principales méthodes de détection, de quantification et d'identification des protéines oxydées associées aux études protéomiques visant à surveiller l'étendue de la carbonylation des protéines et à identifier les protéines ciblées. It appears essential to determine if these modified proteins have an impact on these disorders and how they act. Also to assess this impact, it is necessary to use the main methods of detection, quantification and identification of oxidized proteins associated with proteomic studies aimed at monitoring the extent of protein carbonylation and identifying targeted proteins.
Dans ce contexte, la technique d’électrophorèse sur gel 2D à base de fluorescence et des méthodes de spectrométrie de masse, pour surveiller au niveau du protéome, l'étendue de la carbonylation des protéines dans un modèle cellulaire stressé par le mix dit de « cytokines Storm » ont été utilisées. L'effet du mélange selon la composition revendiquée, est évalué dans ce modèle. Cette méthode est publiée dans J. Proteomics, M.Baraibar et al, 2013 et WO2012/175519 et inclus par référence quant à la mise en oeuvre de cette méthode qui est une méthode de marquage sélectif, de détection et de quantification des protéines carbonylées dans un échantillon contenant des protéines. In this context, the technique of 2D gel electrophoresis based on fluorescence and mass spectrometry methods, to monitor at the proteome level, the extent of protein carbonylation in a cell model stressed by the so-called "mix Storm cytokines” were used. The effect of mixing according to the claimed composition is evaluated in this model. This method is published in J. Proteomics, M.Baraibar et al, 2013 and WO2012/175519 and included by reference as to the implementation of this method which is a method for the selective labeling, detection and quantification of carbonyl proteins in a sample containing protein.
La composition selon l’exemple 1 est évaluée dans le modèle décrit ci-dessus à 2 concentrations différentes. The composition according to example 1 is evaluated in the model described above at 2 different concentrations.
Protocole expérimental : Experimental protocol :
La composition selon l’exemple 1 , a été directement solubilisé dans le milieu de culture à 2 concentrations différentes (50 pg/ml; 200 pg/ml). Il a été stocké à 4°C dans l'obscurité jusqu'à l'utilisation. The composition according to Example 1 was directly dissolved in the culture medium at 2 different concentrations (50 pg/ml; 200 pg/ml). It was stored at 4°C in the dark until use.
Des fibroblastes dermiques humains ont été cultivés dans un milieu DMEM exempt de calcium, avec 2 % de SVF, à 37°C et une atmosphère humide avec 5 % de CO2. Des cellules ont été placées (20000 cellules/puits) au jour 0 (DO) dans des plaques 96 puits contenant un milieu de culture et distribuées dans plusieurs groupes expérimentaux, contenant 6 réplicons par groupe (n = 6), tels que représentés dans la figure 1. Les groupes expérimentaux ont été incubés pendant 24 heures avec la composition selon l’exemple 1 , en présence d'IL-6 (8 ng/ml). Le groupe « Stress » a reçu uniquement le traitement avec IL-6 (8 ng/mL), tandis que le groupe contrôle a été non traité. La dexaméthasone (1 pM) a été utilisé comme référence. Human dermal fibroblasts were cultured in DMEM-free medium. calcium, with 2% FCS, at 37°C and a humid atmosphere with 5% CO2. Cells were placed (20,000 cells/well) on day 0 (DO) in 96-well plates containing culture medium and distributed in several experimental groups, containing 6 replicons per group (n = 6), as represented in the FIG. 1. The experimental groups were incubated for 24 hours with the composition according to example 1, in the presence of IL-6 (8 ng/ml). The “Stress” group received only the treatment with IL-6 (8 ng/mL), while the control group was untreated. Dexamethasone (1 µM) was used as a reference.
Après 24 heures, les cellules ont été fixées et les protéines carbonylées ont été marquées in situ avec une sonde fluorescente spécifique. After 24 hours, the cells were fixed and the protein carbonyls were labeled in situ with a specific fluorescent probe.
L'émission de fluorescence a été détectée et enregistrée à l'aide d'un lecteur de plaque à fluorescence (Varioskan, Thermo Scientific). Fluorescence emission was detected and recorded using a fluorescence plate reader (Varioskan, Thermo Scientific).
La gestion des données et les analyses statistiques ont été réalisées à l'aide du logiciel GraphPad (La Jolla, Californie, USA -Statistics : ANOVA- Dunnett’s post-hoc multi comparisons test ** p<0.01 ; *** p<0.001) Data management and statistical analyzes were performed using GraphPad software (La Jolla, California, USA -Statistics: ANOVA- Dunnett's post-hoc multi comparisons test ** p<0.01; *** p<0.001)
Résultats : Results :
Dans cette étude, une augmentation significative des protéines carbonylées (oxydées) a été observée après le traitement par IL-6 des fibroblastes dermiques humains. In this study, a significant increase in carbonyl (oxidized) proteins was observed after IL-6 treatment of human dermal fibroblasts.
La composition selon l’exemple 1 a montré un effet protecteur contre l'oxydation des protéines induite par l'IL-6 de : The composition according to example 1 showed a protective effect against the oxidation of proteins induced by IL-6 of:
• 89% de protection lorsqu'il est appliqué sur des cellules à 200 pg / ml • 89% protection when applied to cells at 200 pg/ml
• d’au moins 100% de protection lorsqu'il est appliqué sur les cellules à 50 pg / ml • at least 100% protection when applied to cells at 50 pg/ml
Les résultats sont représentés dans le tableau 1 ci-dessous : The results are shown in Table 1 below:
Tableau 1 : Table 1:
Cette étude vise à évaluer l'efficacité protectrice in vitro de la composition selon l’exemple 1 , formulée à différentes concentrations contre l'inflammation aiguë induisant des dommages aux protéines. This study aims to evaluate the in vitro protective efficacy of the composition according to example 1, formulated at different concentrations against acute inflammation inducing protein damage.
Des fibroblastes dermiques humains ont été incubés (ou non) avec le produit pendant 24h en présence d'un inducteur d'inflammation (cytokine inflammatoire IL-6). Un niveau de carbonylation (dommage aux protéines) a été obtenu pour chaque échantillon après marquage in situ de protéines carbonylées avec une sonde fluorescente spécifique. L'émission de fluorescence a été détectée et enregistrée à l'aide d'un lecteur de plaque à fluorescence (Varioskan, Thermo Scientific). Human dermal fibroblasts were incubated (or not) with the product for 24 hours in the presence of an inflammation inducer (inflammatory cytokine IL-6). A level of carbonylation (protein damage) was obtained for each sample after in situ labeling of carbonylated proteins with a specific fluorescent probe. Fluorescence emission was detected and recorded using a fluorescence plate reader (Varioskan, Thermo Scientific).
Une augmentation significative des dommages oxydatifs des protéines a été observée lors du traitement cellulaire avec une cytokine inflammatoire (I L-6). A significant increase in oxidative protein damage was observed upon cell treatment with an inflammatory cytokine (IL-6).
Dans les conditions expérimentales utilisées dans cette étude, cette augmentation a été inhibée de 89% et de plus de 100% en présence de la composition selon l’exemple 1 (200 et 50 pg /ml respectivement). Under the experimental conditions used in this study, this increase was inhibited by 89% and by more than 100% in the presence of the composition according to Example 1 (200 and 50 pg/ml respectively).
Conclusion : Conclusion :
Ainsi, l'analyse des résultats obtenus dans un modèle cellulaire stressé induit par le mix dit de « cytokine Storm » (traduit par le terme de tempête inflammatoire impliquée dans certaines formes critiques de troubles infectieux) a montré un effet protecteur de la composition décrite et revendiquée, notamment lorsqu’elle est administrée à une dose entre 50pg/ml et 200 pg/ml. Cet effet protecteur à l’oxydation peut aussi expliquer une protection des tissus et organes contre les méfaits structuraux et tissulaire du cytokine Storm, décrits dans les formes graves de la COVID-19 Thus, the analysis of the results obtained in a stressed cell model induced by the so-called "cytokine storm" mix (translated by the term inflammatory storm involved in certain critical forms of infectious disorders) showed a protective effect of the composition described and claimed, in particular when it is administered at a dose between 50 pg/ml and 200 pg/ml. This protective effect to oxidation may also explain the protection of tissues and organs against the structural and tissue damage of the cytokine Storm, described in the severe forms of COVID-19.
[00035] Exemple 3 : questionnaire de suivi de traitement de la formulation selon l’exemple 1 [00035] Example 3: formulation treatment follow-up questionnaire according to example 1
Le traitement est proposé aux volontaires sains dans le cadre de la prévention des rhinovirus (grippe, covid-19...). Il est orienté vers la réorganisation du microbiote afin d’éviter les complications pathologiques liées à son déséquilibre notamment en cas d’invasion par un rhinovirus. Ce test est proposé aux volontaires acceptant une formule de compléments alimentaires utilisant des souches probiotiques ainsi que des prébiotiques. Le protocole repose sur la prise de 2 gélules du complément alimentaire dont la composition est décrite dans l’exemple 1 par jour pendant les deux mois d’hiver. Le questionnaire ci-dessous est remis aux volontaires qui ont bénéficié du complément alimentaire en fin de traitement. Ce questionnaire est orienté essentiellement sur la prise en compte des inconforts intestinaux (gastrite, gastroentérite, sensibilité digestives et pulmonaires) et des conséquences d’une dysbiose intestinale. The treatment is offered to healthy volunteers as part of the prevention of rhinoviruses (influenza, covid-19, etc.). It is oriented towards the reorganization of the microbiota in order to avoid the pathological complications linked to its imbalance, particularly in the event of invasion by a rhinovirus. This test is offered to volunteers accepting a formula of food supplements using probiotic strains as well as prebiotics. The protocol is based on taking 2 capsules of the food supplement whose composition is described in Example 1 per day during the two winter months. The questionnaire below is given to volunteers who received the food supplement at the end of treatment. This questionnaire is essentially oriented towards taking into account intestinal discomfort (gastritis, gastroenteritis, digestive and pulmonary sensitivities) and the consequences of intestinal dysbiosis.
Tableau 2 : Table 2:

Claims

REVENDICATIONS
1. Composition comprenant au moins un probiotique, un composé antioxydant et des polysaccharides de plante adaptogène. 1. Composition comprising at least one probiotic, one antioxidant compound and adaptogenic plant polysaccharides.
2. Composition selon la revendication 1 , caractérisée en ce que le composé antioxydant est choisi seul ou en mélange, parmi : la quercétine et/ou d’un analogue de quercétine et/ou un extrait de plantes en contenant. 2. Composition according to claim 1, characterized in that the antioxidant compound is chosen alone or as a mixture, from: quercetin and / or a quercetin analogue and / or a plant extract containing it.
3. Composition selon la des revendication 1 , caractérisée en ce que le composé antioxydant est la S-Adénosyl-méthionine (SAM). 3. Composition according to claim 1, characterized in that the antioxidant compound is S-Adenosyl-methionine (SAM).
4. Composition selon l’une des revendications 1 à 3, caractérisée en ce que le probiotique est préférentiellement sous forme de souches probiotiques, choisies parmi les souches probiotiques suivantes seules ou en mélange : Lactobacillus rhamnosus, Lactobacillus rhamnosus GG, Lactobacillus easel, Lactobacillus gasseri, Bifidobacterium longum, Lactobacillus plantarum, Bifidobacterium adolescentis, Lactobacillus reuteri, Bifidobacterium infantis. 4. Composition according to one of claims 1 to 3, characterized in that the probiotic is preferably in the form of probiotic strains, chosen from the following probiotic strains alone or in a mixture: Lactobacillus rhamnosus, Lactobacillus rhamnosus GG, Lactobacillus easel, Lactobacillus gasseri , Bifidobacterium longum, Lactobacillus plantarum, Bifidobacterium adolescentis, Lactobacillus reuteri, Bifidobacterium infantis.
5. Composition selon la revendication 4, caractérisée en ce qu’elle comprend au moins une souche probiotique de préférence vivante sous la forme suivante : lyophilisée, liquide en suspension, sous la forme d’extrait et/ou de sécrétome partiel ou complet et/ou de molécule extraite et/ou purifiée. 5. Composition according to claim 4, characterized in that it comprises at least one probiotic strain, preferably live, in the following form: freeze-dried, liquid in suspension, in the form of extract and/or partial or complete secretome and/ or extracted and/or purified molecule.
6. Composition selon les revendications 1 à 5, caractérisée en ce que la quercétine et/ou un analogue de quercétine est choisi notamment parmi isoquercetin (quercetin-3b-o-glucoside), quercetagetin, quercetin-3-gallate et/ou un extrait de plantes en contenant est choisi parmi les extraits de plantes suivantes : oseille (Rumex sp.), coriandre (Coriandrum sativum), oignons, asparagus (Asparagus officinalis), cresson (Nasturtium officinalis), okra (Abelmoschus esculentus), chou (Brassica oleracea), Sophora japonica. 6. Composition according to claims 1 to 5, characterized in that quercetin and / or a quercetin analogue is chosen in particular from isoquercetin (quercetin-3b-o-glucoside), quercetagetin, quercetin-3-gallate and / or an extract of plants in the container is chosen from the following plant extracts: sorrel (Rumex sp.), coriander (Coriandrum sativum), onions, asparagus (Asparagus officinalis), watercress (Nasturtium officinalis), okra (Abelmoschus esculentus), cabbage (Brassica oleracea ), Sophora japonica.
7. Composition selon les revendications 1 à 6, caractérisée en ce les polysaccharides de plante adaptogène sont extraits ou purifiés à partir de plante sous les formes suivantes: feuille et/ou racine lyophilisée, extraits complets ou partiels. 7. Composition according to claims 1 to 6, characterized in that the adaptogenic plant polysaccharides are extracted or purified from plants in the following forms: freeze-dried leaf and/or root, complete or partial extracts.
8. Composition selon la revendication 7, caractérisée en ce que les polysaccharides sont extraits de plante adaptogène choisie parmi les genres Astragalus, Dioscorea, Schisandra, Panax, Eleuterococcus, Rosmarinus, Pfaffia, Morinda sp., Cordyceps or Lepidium genera, notamment sous forme d’extrait sec ou purifié. 8. Composition according to claim 7, characterized in that the polysaccharides are extracts of an adaptogenic plant chosen from the genera Astragalus, Dioscorea, Schisandra, Panax, Eleuterococcus, Rosmarinus, Pfaffia, Morinda sp., Cordyceps or Lepidium genera, in particular in the form of dry or purified extract.
9. Composition selon les revendications 1 à 8, dans laquelle la composition peut comprendre un galacto-oligosaccharide ou des fructo-oligosaccharides issus de plante adaptogène utilisés comme prébiotique. 9. Composition according to claims 1 to 8, in which the composition may comprise a galacto-oligosaccharide or fructo-oligosaccharides derived from an adaptogenic plant used as a prebiotic.
10. Composition selon les revendications 1 à 9, comprenant une quantité de probiotique(s) pour réduire la libération et/ou la production des médiateurs de l’inflammation notamment les cytokines IL-6, TNF-alpha et ILI béta. 10. Composition according to claims 1 to 9, comprising an amount of probiotic(s) to reduce the release and/or production of inflammation mediators, in particular the cytokines IL-6, TNF-alpha and ILI beta.
11. Composition selon les revendications 1 à 9, comprenant une quantité de probiotique(s) pour réduire les désordres immunologiques, en particulier pour réduire les dysbioses. 11. Composition according to claims 1 to 9, comprising a quantity of probiotic(s) to reduce immunological disorders, in particular to reduce dysbiosis.
12. Composition selon les revendications 1 à 9, comprenant une quantité de probiotique(s) pour réduire i) la libération et/ou la production des médiateurs de l’inflammation notamment les cytokines IL6, TNF-alpha et ILI béta et/ou ii) les désordres immunologiques et/ou iii) les dysbioses, responsables d’une plus grande susceptibilité aux infections virales et/ou bactériennes. 12. Composition according to claims 1 to 9, comprising a quantity of probiotic(s) to reduce i) the release and/or the production of inflammation mediators, in particular the cytokines IL6, TNF-alpha and ILI beta and/or ii ) immunological disorders and/or iii) dysbiosis, responsible for a greater susceptibility to viral and/or bacterial infections.
13. Composition selon les revendications 1 à 9, comprenant une quantité efficace de probiotique(s) pour réduire et/ou prévenir les troubles (pathologiques ou sub-cliniques) issus notamment d’une dysbiose du tube digestif subclinique qu’elle soit d’origine endogène ou exogène due à une infection, la pollution, le stress. 13. Composition according to claims 1 to 9, comprising an effective amount of probiotic(s) for reducing and/or preventing disorders (pathological or sub-clinical) resulting in particular from dysbiosis of the subclinical digestive tract, whether it is of endogenous or exogenous origin due to infection, pollution, stress.
14. Complément nutritionnel solide ou liquide caractérisé en ce qu’il contient une composition selon les revendications 1 à 9. 14. Solid or liquid nutritional supplement characterized in that it contains a composition according to claims 1 to 9.
15. Utilisation non-thérapeutique d’un complément nutritionnel, selon la revendication 14.15. Non-therapeutic use of a nutritional supplement, according to claim 14.
16. Utilisation non-thérapeutique de la composition selon les revendications 1 à 9, pour corriger une dysbiose cutanée et/ou les désordres subcliniques ou cliniques (i.e. dermatologiques) associés à ces dysbioses. 16. Non-therapeutic use of the composition according to claims 1 to 9, for correcting cutaneous dysbiosis and/or the subclinical or clinical (i.e. dermatological) disorders associated with these dysbiosis.
EP21726953.9A 2021-01-04 2021-03-30 Composition comprising at least one probiotic, at least one antioxidant and polysaccharides from adaptogenic plant(s) Pending EP4271209A1 (en)

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US6368617B1 (en) * 2001-05-15 2002-04-09 Reliv' International, Inc. Dietary supplement
US7923044B2 (en) * 2008-07-15 2011-04-12 Paradise Herbs & Essentials, Inc. Composition for high-ORAC value dietary supplement
FR2943248B1 (en) * 2009-03-17 2012-09-28 Oreal USE OF A WOLFBERRY EXTRACT FOR THE TREATMENT OF SCALP LEATHER DISORDERS
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