Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
  • A61K35/66—Microorganisms or materials therefrom
  • A61K35/74—Bacteria
  • A61K35/741—Probiotics
  • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
• • 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
  • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
  • A23L29/20—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents
• • 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
  • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
  • A23L29/20—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents
  • A23L29/206—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents of vegetable origin
• • 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
  • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
  • A23L29/20—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents
  • A23L29/206—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents of vegetable origin
  • A23L29/238—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents of vegetable origin from seeds, e.g. locust bean gum or guar gum
• • 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
  • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
  • A23L29/20—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents
  • A23L29/206—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents of vegetable origin
  • A23L29/256—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents of vegetable origin from seaweeds, e.g. alginates, agar or carrageenan
• • 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
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
  • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
  • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
  • A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
  • A61K35/66—Microorganisms or materials therefrom
  • A61K35/74—Bacteria
  • A61K35/741—Probiotics
  • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
  • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • 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
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • 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

Definitions

• compositions with a synergistic action between a mucoadherent gelling complex against the passage of antigens, and immunomodulatory anti-IL17 bacteria for use in the treatment of Unrelated autoimmune and neurodegenerative diseases are provided.
• the present invention relates to compositions with a synergistic action between a mucoadherent gelling complex against the passage of antigens, and immunomodulatory anti-IL17 bacteria for use in the treatment of IL17-related autoimmune and neurodegenerative diseases.
• Alteration of the intestinal permeability also referred to as Leaky Gut Syndrome, is known to be at the basis of several diseases among which Candida infection, Crohn's disease, atopic eczema, food intolerances and allergies, asthma, arthritis and all the autoimmune and neurodegenerative diseases in general.
• the immune system exerts its activity of control at lymphatic ganglia of intestine and walls thereof (in particular in the small intestine by the Peyer's plaques) where acts avoiding the passage of body's dangerous or harmful substances.
• the digestive system Under healthy conditions, the digestive system is well functioning and, thus, only few, carefully selected components can cross the intestinal mucosa and enter the bloodstream. However, under non-optimal conditions, inflammation of the intestinal mucosa, in particular of the colon and rectum, can occur, with a consequent reduction of its capability of selective permeability. Furthermore, a dysbiotic intestine, namely with an impaired and poor bacterial flora, allows several toxics to accumulate therein, continuously overloading the immune system (IS), which can lose over time its efficiency and cause several dysfunctions and diseases.
• IS immune system
• a high intestinal permeability referred to as Leaky Gut Syndrome, has been related for example to some forms of arthritis, besides food allergies and intolerances, and is also found in autoimmune diseases.
• cytokines such as, for example, cytokines of IL-17 family, which comprise proinflammatory cytokines (interleukins) such as IL-17A, IL-17B, IL-17C, IL-17D and IL-17F produced by Th17 cells.
• cytokines of IL-17 family which comprise proinflammatory cytokines (interleukins) such as IL-17A, IL-17B, IL-17C, IL-17D and IL-17F produced by Th17 cells.
• Interleukin 17 is produced by T helper 17 lymphocytes (human proinflammatory cells - Th17) and induced by IL-23.
• Th17 cells are involved, by way of a non-limiting example, in psoriasis, rheumatoid arthritis, Crohn's disease, multiple sclerosis, asthma, which is an inflammatory disease characterized by an usually reversible obstruction of lower airways and, therefore, only involves the respiratory tract, epilepsy, cerebral ischemia, lupus erythematosus, uveitis and chronic pelvic pain syndrome (CPPS).
• CPPS chronic pelvic pain syndrome
• IL-17 belongs to the molecules of both innate and adaptive immunity.
• the maintenance of an optimal functionality condition of both the innate (non-specific or natural) and adaptive (specific) immune system is fundamental for the body's defence against invading pathogens.
• An intact and well-functioning intestinal mucosa provides a defence barrier against potentially harmful antigens to the host, controlling the tolerance effects towards them.
• Psoriasis is a chronic inflammatory disease, which affects up to 3% of the world's population.
• the immune system plays a main role in psoriasis development since the immune system (IS) produces several proteins called cytokines, which act as " messengers", coordinating the signalling among the immune cells in response to an infection.
• cytokines act as " messengers"
• IL-17A interleukin-17A
• the occurrence of higher skin levels of IL-17A can trigger an immune response even in the absence of an infectious stimulus, thus causing inflammatory symptoms such as itching and redness.
• IL-17A stimulates the skin production of new cells at a higher than normal rate, thereby leading to symptoms typical of psoriasis, such as skin thickening and plaques (scaly skin), due to the build-up of cells over the skin surface.
• Interleukin-17A is one of the many "messenger" proteins called cytokines, which are responsible, in our body, for the coordination of signals among immune cells. Usually, cytokines act by stimulating the infection-fighting cells to trigger an immune response against a foreign agent. IL-17A proved to have a key role in some immune-mediated diseases, such as moderated to severe plaque psoriasis, and is considered a main target for measuring the efficacy of developing therapies.
• Psoriasis which is characterized by epidermal hyperplasia is, thus, a disease different from atopic dermatitis, since the latter is a chronic inflammatory, but non-autoimmune disease of the skin, which can be caused by a deficient barrier function of the skin and mainly affects pediatric patients (about 0-14 years).
• the most common symptom of atopic dermatitis is the eczema, namely redness of the skin, which results dry, irritated and sometime with small liquid-filled blisters, which can become swollen.
• Psoriasis (autoimmune disease) is a systemic inflammatory disease due to a dysregulation of the immune system.
• IL-17A is found at higher concentrations in the psoriatic skin, with up to six-fold greater amount than those found in a non-psoriatic cutis. Higher skin amounts of IL-17A were also related to a more severe psoriasis.
• Th17 cells and cytokines IL-17 were reported to play a main role in SLE pathogenesis.
• IL-17A cytokines IL-17
• IL-17A triggers a vicious circle in psoriasis, as it sends signals to the skin and immune system cells, provoking the typical symptoms of the disease. For this reason, IL-17A was identified as the main target of the treatment and the pharmacological research focused in developing drugs, which directly or indirectly inhibit IL-17A.
• the technical solution underlying the present invention advantageously solves the technical problem at the basis of the present invention by acting, in a combined way, with a double action: the first one is directed and aimed to reducing/decreasing the intestinal permeability, thereby reducing the antigens which overcome the barrier and, thus, intrinsically reducing the body's overproduction of cytokines such as IL-17, while the second action is directed as interventional activity directly on the immune system so that to decrease/modulate the immune response with a further reduction of the level of cytokines such as IL-17.
• the technical solution underlying the present invention entails that a reduced intestinal permeability leads to a decrease of antigens, which overcome the intestinal barrier.
• IL-17A IL-17A
• the Applicant contrary to the teachings of the known technique, which lead to a "direct or indirect inhibition" of IL-17A, applied a novel therapeutic concept based on the principle of modulating the IL-17 reduction (rather than inhibiting the IL-17 production) to such an extent that IL-17 keeps and maintains its protective function against infections.
• compositions having a synergistic action because of the presence of both a mucoadherent gelling complex, which plays a targeted action against the passage of antigens, and selected immunomodulatory anti-IL17 (IL-17A) bacteria, said compositions being for use in the treatment of IL17-related autoimmune and neurodegenerative diseases.
• IL-17A immunomodulatory anti-IL17
• compositions of the present invention are for oral use and useful in the preventive or curative treatment of an autoimmune disorder or disease or neurodegenerative disease or systemic inflammatory disease due to a dysregulation of the immune system, which reacts by overproducing cytokines such as interleukins-17 (IL-17, IL-17A), wherein said treatment can comprise reducing or inhibiting the production of interleukins-17 (IL-17, IL-17A).
• IL-17, IL-17A interleukins-17
• Table 1 reports a list of strains of Lactobacilli being used in the present in vitro study.
• Table 2 reports a list of strains of Bifidobacteria being used in the present in vitro study.
• Figure 1 reports the interleukin-17 modulation by strains belonging to the genus Lactobacillus.
• Figure 2 reports the interleukin-17 modulation by strains belonging to the genus Bifidobacterium.
• Figure 3 reports the strains with inhibitory ability belonging to the genus Lactobacillus.
• Figure 4 reports the strains with inhibitory ability belonging to the genus Bifidobacterium.
• autoimmune and neurodegenerative diseases and systemic inflammatory disease are meant those related to an overproduction of IL-17 such as, by way of a non- limiting example, psoriasis, rheumatoid arthritis, Crohn's disease, multiple sclerosis, asthma, epilepsy, cerebral ischemia, lupus erythematosus, uveitis, autoimmune prostatitis and chronic pelvic pain syndrome (CPPS).
• CPPS chronic pelvic pain syndrome
• composition of the present invention is meant to encompass pharmaceutical compositions, compositions for medical devices, food compositions and compositions for supplement products.
• composition of the present invention comprises a mixture which comprises or, alternatively, consists of: (i) a first selection of bacterial strains, said bacterial strains producing in situ in the gastrointestinal tract bacterial gums such as exopolysaccharides (briefly, EPS), once administered; (ii) vegetable gums and (iii) a second selection of bacterial strains.
• a first selection of bacterial strains said bacterial strains producing in situ in the gastrointestinal tract bacterial gums such as exopolysaccharides (briefly, EPS), once administered
• EPS exopolysaccharides
• Said bacterial gums being produced by selected bacterial strains (i) in situ in the gastrointestinal tract. Said bacterial gums being produced in the presence of said vegetable gums (ii) after the administration of said mixture present in said composition. Said bacterial gums being produced in situ directly in the gastrointestinal tract by selected bacterial strains (i), along with vegetable gums (ii), are able to preserve and protect the intestinal mucosa so that to avoid, reduce or at least counteract the harmful action of pathogenic bacteria to the mucosa itself.
• Said mixture comprises at least a strain of bacteria (i) (which produces in situ directly in the gastrointestinal tract said bacterial gums such as exopolysaccharides (briefly, EPS)), a vegetable gum (ii) and a second selection of bacterial strains (iii).
• a strain of bacteria i
• EPS exopolysaccharides
• a vegetable gum ii
• a second selection of bacterial strains iii).
• Said at least one strain of bacteria (i) producing EPS is selected from the group comprising the bacterial strains belonging to the genus Streptococcus, Lactobacillus and Bifidobacteria.
• Said at least a strain of bacteria (i) is preferably selected from the group comprising or, alternatively, consisting of bacterial strains belonging to the species Streptococcus thermophilus, Lactobacillus plantarum, Lactobacillus rhamnosus, Lactobacillus pentosus, Lactobacillus acidophilus, Lactobacillus brevis, Lactobacillus reuteri, Bifidobacterium breve, Bifidobacterium bifidum, Bidifobacterium lactis, Lactobacillus fermentum and Lactobacillus delbrueeckii.
• Said at least one strain of bacteria (i) is selected from the group comprising or, alternatively, consisting of bacterial strains belonging to the species Streptococcus thermophilus, Lactobacillus plantarum or Lactobacillus rhamnosus.
• Said bacterial strains (i) should produce, once administered, EPS in situ in the gastrointestinal tract.
• said bacterial strains (i) producing EPS in situ in the gastrointestinal tract belong to the species Streptococcus thermophilus.
• said mixture comprises at least one strain of bacteria (i) (which produces in situ directly in the gastrointestinal tract said bacterial gums such as exopolysaccharides (briefly EPS)) belonging to the species Streptococcus thermophilus, a vegetable gum (ii) and a second selection of bacterial strains (iii).
• Said second selection of bacterial strains (iii) is selected from the group comprising or, alternatively, consisting of the bacterial strains belonging to the species Lactobacillus salivarius.
• Said mixture can comprise at least one, or two or three or four bacterial strains (i) producing EPS, preferably belonging to the species Streptococcus thermophilus, Lactobacillus plantarum or Lactobacillus rhamnosus, combined with a vegetable gum (ii) and a second selection of bacterial strains (iii). Said second selection of bacterial strains (iii) is selected from the group comprising or, alternatively, consisting of bacterial strains belonging to the species Lactobacillus salivarius.
• said at least one, or two or three or four bacterial strains (i) producing EPS in situ in the gastrointestinal tract belong to the species Streptococcus thermophilus.
• Said second selection of bacterial strains (iii) is selected from the group comprising or, alternatively, consisting of bacterial strains belonging to the species Lactobacillus salivarius.
• the present invention further encompasses embodiments comprising mixtures of two or three or four bacterial strains selected from bacterial strains belonging to the species Streptococcus thermophilus and/or Lactobacillus plantarum and/or Lactobacillus rhamnosus, combined with a vegetable gum (ii) and a second selection of bacterial strains (iii). Said second selection of bacterial strains (iii) is selected from the group comprising or, alternatively, consisting of bacterial strains belonging to the species Lactobacillus salivarius.
• a gum is a dehydrated or freeze-dried or dry powdery or flake-like material which, once contacted with water, produces a gel of gum in water (aqueous gel) or a gum gelatin. Alternatively, a previously prepared gel or gelatin can be suitably used. Gums used within the context of the present invention are all gums for oral use being approved and used for food supplement products and medical devices.
• Said vegetable gum (ii) present in said mixture, contained in the compositions of the present invention is selected from the group comprising or, alternatively, consisting of Aloe, Aloe vera (Aloe vera -Aloe barbadensis Miller, is a plant of the Aloeacee family), Aloe arborescens, alginates, xyloglucans (or xylogel), carrageenans, pectins, agar-agar and tara gum.
• the vegetable gum (ii) contained in said mixture is selected from the group comprising or, alternatively, consisting of Aloe, Aloe vera, Aloe arborescens and tara gum.
• Said mixture can comprise at least one, or two or three or four bacterial strains (i) producing EPS, preferably belonging to the species Streptococcus thermophilus, Lactobacillus plantarum or Lactobacillus rhamnosus, combined with a vegetable gum (ii) selected from Aloe, Aloe vera, Aloe arborescens and tara gum, and a second selection of bacterial strains (iii).
• a second selection of bacterial strains (iii) is selected from the group comprising or, alternatively, consisting of the bacterial strains belonging to the species Lactobacillus salivarius.
• said at least one, or two or three or four bacterial strains (i) producing EPS in situ in the gastrointestinal tract belong to the species Streptococcus thermophilus.
• said vegetable gum (ii) is a commercially available tara gum.
• a vegetable gum (ii), such as for example tara gum from its ingestion until it reaches the intestine, is subjected to a slow but continuous degradation during its transit from the stomach to the intestine.
• the vegetable gum (ii) degrades and loses its efficacy of restoring the physiological functions of the intestine walls.
• This degradation is due to multiple factors such as for example pH, enzymes, attacks to the endogenous bacterial flora, the effect of the gastroduodenal barrier and a dilution effect.
• the vegetable gum (ii) such as for example tara gum
• the vegetable gum (ii) such as for example tara gum
• reaches the colon is partially degraded and, thus, is less effective in protecting the intestine walls from pathogenic bacteria, which are able to penetrate them through their flagella.
• the bacterial gum produced in situ by the strains (i) of the present invention selected from the group comprising or, alternatively, consisting of bacterial strains belonging to the species Streptococcus thermophilus, Lactobacillus plantarum or Lactobacillus rhamnosus, on the one hand, and a vegetable gum (ii), on the other hand, they each have their own effect being complementary to each other.
• the first effect is a gelling effect exerted by the vegetable gum (ii), which is maximum in the stomach (maximum protection) and minimum in the colon, because of the degradation and consequent loss of efficacy in protecting the inflamed intestinal mucosae.
• the second effect is a protective effect exerted by the bacterial gum, in particular by exopolysaccharides (EPS) produced in situ by the strains of the present invention selected from the group comprising or, alternatively, consisting of bacterial strains belonging to the species Streptococcus thermophilus, Lactobacillus plantarum or Lactobacillus rhamnosus.
• EPS exopolysaccharides
• This second effect is minimum in the stomach and maximum in the colon where the bacteria of the present invention, which arrive alive and viable and at a high concentration, produce EPS in situ directly in the gastrointestinal tract.
• composition of the present invention as a result of said two complementary effects exerted by the vegetable gum (ii) and the bacterial gum, respectively, allows to reduce/decrease the intestinal permeability, in order to thereby lessening the antigens which overcome the barrier and, thus, intrinsically reducing the body's overproduction of cytokines such as IL-17 (IL-17A) (first action).
• IL-17A IL-17A
• compositions of the present invention are able to restore the deficient barrier effect, resulting from a poor protection of the mucosa of the gastrointestinal tract.
• compositions of the present invention are able to prevent and cure infections, inflammations and disorders of the gastrointestinal system, pathogenic bacteria, candidiasis and intestinal permeability.
• the composition of the present invention is able to form a specific mucoadherent gelling complex, consisting of EPS, bacterial exopolysaccharides (produced by selected strains of bacteria (i) and listed below, in particular belonging to the species Streptococcus thermophilus, such as for example Streptococcus thermophilus ST10 -DSM 25246, Streptococcus thermophilus (Y04) DSM 16592 or mixtures thereof in a weight ratio comprised from 1 :2 to 2: 1 , preferably 1 : 1, and a vegetable gum (ii) such as tara gum, a plant polysaccharide.
• Said gelling complex is able to establish a mechanical barrier effect of protection throughout the gastrointestinal tract.
• composition of the present invention due to the presence of the gelling tara gum, is able to form a hydrogel within few minutes from ingestion because of its thixotropic characteristics and thereby create in the first gastrointestinal tract a mechanical barrier effect against pathogenic bacteria and metabolites with proinflammatory activity.
• a barrier effect is completed and extended throughout the gastrointestinal tract by the presence of exopolysaccharides (EPS), produced in situ by the bacterial strains belonging to the species Streptococcus thermophilus, listed below, such as for example Streptococcus thermophilus ST10, Streptococcus thermophilus YO04 or mixtures thereof, which thereby enhance the viscosity of the surrounding environment through a self-controlled and only mechanical mechanism.
• EPS exopolysaccharides
• the tara gum (similarly to all plant gums) is gradually degraded during its intestinal transit by the resident microbiota, thus progressively reducing its gelling power of mechanical hindrance.
• the gradual lessening of the vegetable gum action is effectively counterbalanced by the increasing release of exopolysaccharides (EPS) in the intestinal lumen by for example the bacterial strain ST10 and/or YO04, which mainly exhibits its peculiarity in the ileum and colon.
• EPS exopolysaccharides
• the synergistic combination among tara gum and exopolysaccharides thus ensures the presence of gelling molecules throughout the gastrointestinal tract, maximizing and optimizing the mechanical barrier action of the product.
• the presence, production and maintenance of the hydrophilic gel in the lumen of the organ can, therefore, be considered for the first time really complete, with a first area wherein the action of the vegetable gum is maximum, and a second area wherein the action of exopolysaccharides (EPS) is maximum.
• the bacterial strains (i) comprised in said mixture contained in turn in the composition of the present invention are selected from the group comprising or, alternatively, consisting of:
• Bacterial strains were deposited according to the Budapest Treaty and are publicly available.
• composition of the present invention comprises a mixture which comprises or, alternatively, consists of at least one, or two or three or four bacterial strains (i) selected from the group comprising or, alternatively, consisting of: Streptococcus thermophilus DSM 16590 (Y02), Streptococcus thermophilus DSM 16592 (Y04), Streptococcus thermophilus DSM 17843 (Y08) and Streptococcus thermophilus DSM 25246 (ST10), combined with a vegetable gum (ii) selected from Aloe, Aloe vera, Aloe arborescens and tara gum, and at least a strain of bacteria selected from a second selection of bacterial strains (iii).
• bacterial strains i) selected from the group comprising or, alternatively, consisting of: Streptococcus thermophilus DSM 16590 (Y02), Streptococcus thermophilus DSM 16592 (Y04), Streptococcus thermophilus DSM 178
• said vegetable gum (ii) is a tara gum
• said second selection of bacterial strains (iii) is selected from the group comprising or, alternatively, consisting of bacterial strains belonging to the species Lactobacillus salivarius, such as those hereinafter referred to as (a), (b), (c), (d) and (e).
• the composition of the present invention comprises a mixture which comprises or, alternatively, consists of Streptococcus thermophilus DSM 25246 (ST10), combined with a vegetable gum (ii) selected from Aloe, Aloe vera, Aloe arborescens and tara gum, and at least a strain of bacteria selected from a second selection of bacterial strains (iii).
• said vegetable gum (ii) is a tara gum
• said second selection of bacterial strains (iii) is selected from the group comprising or, alternatively, consisting of bacterial strains belonging to the species Lactobacillus salivarius, such as those hereinafter referred to as (a), (b), (c), (d) and (e), preferably that referred to as (a).
• composition of the present invention comprises a mixture which comprises or, alternatively, consists of Streptococcus thermophilus DSM 25246 (ST10) and at least a strain selected from Streptococcus thermophilus DSM 16590 (Y02), Streptococcus thermophilus DSM 16592 (Y04), Streptococcus thermophilus DSM 17843 (Y08), combined with a vegetable gum (ii) selected from Aloe, Aloe vera, Aloe arborescens and tara gum, and at least a strain of bacteria selected from a second selection of bacterial strains (iii).
• said vegetable gum (ii) is a tara gum
• said second selection of bacterial strains (iii) is selected from the group comprising or, alternatively, consisting of bacterial strains belonging to the species Lactobacillus salivarius, such as those hereinafter referred to as (a), (b), (c), (d) and (e), preferably that referred to as (a).
• composition of the present invention comprises or, alternatively consists of Streptococcus thermophilus DSM 25246 (ST10) and Streptococcus thermophilus DSM 16592 (Y04), combined with a vegetable gum (ii) selected from Aloe, Aloe vera, Aloe arborescens and tara gum, and at least a strain of bacteria selected from a second selection of bacterial strains (iii).
• said vegetable gum (ii) is a tara gum
• said second selection of bacterial strains (iii) is selected from the group comprising or, alternatively, consisting of bacterial strains belonging to the species Lactobacillus salivarius, such as those hereinafter referred to as (a), (b), (c), (d) and (e), preferably that referred to as (a).
• compositions or a composition for medical devices, or a composition for a supplement product or a composition for a food product, comprising a mixture, which comprises or, alternatively, consists of:
• composition being for use in the preventive or curative treatment of an autoimmune disorder or disease or systemic inflammatory disease due to a dysregulation of the immune system, which reacts by overproducing interleukins-17 -IL-17
• composition being for use in the preventive or curative treatment of an autoimmune or neurodegenerative disorder or disease or systemic inflammatory disease due to a dysregulation of the immune system, which reacts by overproducing interleukins-17 (IL-17, IL- 17A)
• said autoimmune or neurodegenerative disease or systemic inflammatory disease is selected from the group comprising or, alternatively, consisting of psoriasis, rheumatoid arthritis, Crohn's disease, multiple sclerosis, asthma, epilepsy, cerebral ischemia, lupus erythematosus, uveitis, autoimmune prostatitis and chronic pelvic pain syndrome (CPPS).
• CPPS chronic pelvic pain syndrome
• Said treatment preferably comprises the reduction or inhibition of the production of interleukins-17 (IL-17, IL-17A).
• Th17 cells are involved, by way of a non-limiting example, in psoriasis, rheumatoid arthritis, Crohn's disease, multiple sclerosis, asthma, epilepsy, cerebral ischemia, lupus erythematosus, uveitis and chronic pelvic pain syndrome (CPPS).
• CPPS chronic pelvic pain syndrome
• Said second selection of bacterial strains (iii) relates to a selection of lactic bacteria for use in the preventive or curative treatment of an autoimmune disorder or disease or systemic inflammatory disease due to a dysregulation of the immune system, which reacts by overproducing interleukins- 17 -IL-17, having the characteristics as set forth in the appended independent claim.
• Th17 cells are involved, by way of a non-limiting example, in psoriasis, rheumatoid arthritis, Crohn's disease, multiple sclerosis, asthma, epilepsy, cerebral ischemia, lupus erythematosus, uveitis, autoimmune prostatitis and chronic pelvic pain syndrome (CPPS).
• Said strains of lactic bacteria (iii) belong to the species Lactobacillus salivarius.
• said at least one strain of bacteria selected from said second selection of bacterial strains (iii) belongs to the species Lactobacillus salivarius and is selected from the group comprising or, alternatively, consisting of:
• Said at least a strain of bacteria selected from said second selection of bacterial strains (iii) can also be selected from the group comprising or, alternatively, consisting of:
• Lactobacillus plantarum LMG P-21021 (LP01), deposited on 16/10/2001 at the BCCM LMG Institute by Mofin S.r.l.
• Lactobacillus delbruekii DSM 22106 (LDD01), deposited on 10/12/2008 at the DSMZ institute by Probiotical SpA,
• the bacterial strain (iii) is Lactobacillus salivarius DSM 22775 (LS01), deposited on 23/07/2009 at the DSMZ institute by Probiotical SpA.
• the bacterial strain (i) is Streptococcus thermophilus DSM 25246 (ST10), deposited at the DSMZ institute in Germany on 19/03/2011 , combined with a vegetable gum (ii), which is tara gum, and the bacterial strain (iii) is Lactobacillus salivarius DSM 22775 (LS01), deposited on 23/07/2009 at the DSMZ institute by Probiotical SpA.
• Every single bacterial strain (i) and/or (iii) is present in said mixture, contained in the composition of the present invention, at a concentration comprised from 1x10 6 to 1x10 11 CFU/g, preferably from 1x10 8 to 1x10 10 CFU/g.
• Bacterial strains (i) and/or (iii) can be present in said mixture, contained in the composition of the present invention, in a solid or powdery or freeze-dried form.
• Bacterial strains (i) and/or (iii) can be present in said mixture, contained in the composition of the present invention, as live or died, sonicated, tyndallized or lysed cells, or as enzymes or components extracted from bacterial cells.
• bacteria (i) belonging to the species Streptococcus thermophilus are in a protected form (coated bacteria).
• said bacteria can preferably be in a protected form (coated bacteria).
• bacteria (i) and (iii) are in a protected form, they can be coated with a lipid coating (single- coated or single-coating) or with two lipid coatings (bi-coated or double coating) of animal or plant origin (microencapsulated form).
• the lipid coating has a melting point comprised from 35 to 85°C, preferably from 45 to 75°C, even more preferably from 55 to 65°C.
• the lipid coating can be a single coating or a double coating made with the same or different lipids. Coating is prepared by using the equipment, lipids and techniques known to the skilled in the field.
• the mixture is contained in the composition of the present invention in a weight ratio of 1 :1 (50% of the total weight of the composition) or in an amount by weight comprised from 50% to 75%, relative to the total weight of the composition.
• said mixture contained in the composition of the present invention contains the bacterial strains (i) in a weight ratio relative to the vegetable gum (ii) comprised from 2: 1 to 1 :2, preferably 1 : 1.
• said mixture contained in the composition of the present invention contains the bacterial strains (i), said vegetable gum (ii) and said bacterial strains (iii) in a weight ratio of 1 :1 : 1 , or 2: 1 :2.
• the above-cited bacterial strains (i) and (iii) are present in the composition of the present invention in an amount comprised from 0.1 to 50% by weight, preferably from 0.5 to 15% by weight, even more preferably from 1 to 10%, relative to the total weight of the composition or supplement product.
• said percentage is based on the kind of the intended pharmaceutical form to be produced.
• the amount of said bacteria is greater than 30%, for example greater than 35%.
• the composition comprises a mixture of bacterial strains at a concentration comprised from 1x10 6 to 1x10 11 CFU/g, preferably from 1x10 8 to 1x10 10 CFU/g of mixture or single bacterial strain.
• the composition comprises bacterial strains at a concentration comprised from 1x10 s to 1x10 11 CFU/dose, preferably from 1x10 8 to 1x10 10 CFU/dose.
• the dose can be from 0.2 to 10 g, for example can be 0.25 g, 1 g, 3 g, 5 g or 7 g.
• Bacterial strains can be present in the composition in a solid form, for example in the form of powder, dry powder, or freeze-dried powder.
• composition of the present invention is for oral use and for the treatment of an autoimmune disorder, or disease or systemic inflammatory disease due to a dysregulation of the immune system, which reacts by overproducing interleukins-17 -IL-17.
• Th17 cells are involved, by way of a non-limiting example, in psoriasis, rheumatoid arthritis, Crohn's disease, multiple sclerosis, asthma, epilepsy, cerebral ischemia, lupus erythematosus, uveitis and chronic pelvic pain syndrome (CPPS).
• said treatment comprises the reduction of the amount of interleukins-17 (IL-17) in the treated subject.
• said autoimmune disorder or disease or systemic inflammatory disease is selected from psoriasis, rheumatoid arthritis, Crohn's disease, multiple sclerosis, epilepsy, cerebral ischemia, lupus erythematosus, uveitis, particularly noninfectious uveitis, autoimmune prostatitis and chronic pelvic pain syndrome (CPPS). More preferably, said autoimmune disease is selected from asthma, psoriasis, rheumatoid arthritis, even more preferably said autoimmune disease is psoriasis.
• compositions or a composition for medical devices or a composition for supplement products or a composition for food products for the preventive or curative treatment of an autoimmune disorder or disease or systemic inflammatory disease due to a dysregulation of the immune system, which reacts by overproducing interleukins-17 -IL-17.
• Th17 cells are involved, by way of a non-limiting example, in psoriasis, rheumatoid arthritis, Crohn's disease, multiple sclerosis, asthma, epilepsy, cerebral ischemia, lupus erythematosus, uveitis and chronic pelvic pain syndrome (CPPS).
• CPPS chronic pelvic pain syndrome
• said treatment comprises the reduction of interleukins-17 (IL-17) in the treated subject.
• said autoimmune disorder or disease or systemic inflammatory disease is selected from psoriasis, rheumatoid arthritis, Crohn's disease, multiple sclerosis, asthma, epilepsy, cerebral ischemia, lupus erythematosus, uveitis, particularly noninfectious uveitis, autoimmune prostatitis and chronic pelvic pain syndrome (CPPS). More preferably, said autoimmune disease is selected from asthma, psoriasis, rheumatoid arthritis, even more preferably said autoimmune disease is psoriasis.
• composition of the present invention is in a solid, liquid, semiliquid or powdery form and can be formulated by using the suitable technological additives or co-formulants, pH stabilizers, dispersants, flavors and excipients of pharmaceutical grade for oral administration in the form of tablet, lozenge, capsule, packet or stick.
• the Applicant conducted several tests and experiments on a first wide group of both lactic bacteria and bifidobacteria strains thus obtaining, after careful selections, a second group of lactic bacteria (Table 1) and bifidobacteria (Table 2) more effective in reducing IL-17 or IL-17A (rather than inhibiting the production of IL-17 or IL-17A) to an extent in which IL-17 keeps and maintains its protective function against infections.
• Table 1 lactic bacteria
• Table 2 bifidobacteria
• Peripheral blood mononuclear cells comprise cells involved both in natural and specific immunity, and are a valid model for studying the immunological properties of potential probiotic bacteria, in particular for the analysis of cytokine secretion.
• Peripheral blood mononuclear cells were separated by density gradient centrifugation. For this purpose for each experiment 20 ml of "buffy coat" of healthy donors from the Immuno-transfusion Service of Ospedale di Borgomanero were used, thus obtaining an average yield of 200 x 10 6 PBMC/buffy. The amount of separated cells was determined by cell counting in Burker chambers, by using the Turk's solution, which allows to discriminating between mononuclear cells and polymorphonuclear cells.
• Cells were brought to a concentration of 2 x 10 6 cells/ml in growth medium RPMI-1640 (Invitrogen) supplemented with 10% heat-inactivated fetal calf serum (FCS, Gibco), 1% glutamine and 25 mM Hepes.
• RPMI-1640 Invitrogen
• FCS heat-inactivated fetal calf serum
• PBMCs were stimulated for 5 days with all the bacterial strains listed in Tables 1 and 2.
• the internal controls for each experiment are represented by:
• PBMC stimulated with 10 pg/ml Phytohaemagglutinin (PHA-P; Sigma
• Cytokine concentration in the culture supernatants was determined by E.L.I.S.A. assay (Enzyme-Linked Immunoabsorbent Assay). Specifically, for the IL-17A assay the kit "Human ELISA Ready-SET-Go! from eBioscence, (San Diego CA) was used, following the producer's instructions. KIT sensitivity: 4 pg/ml. 2. RESULTS
• Lymphocytes T are the main effector and regulatory cells of the cell-mediated immunity.
• T cells synthesize and secrete a variety of cytokines required for the growing, differentiation and as activation factors for the other immunocompetent cells.
• cytokine IL-17A In order to investigate whether the studied bacterial strains could inhibit the secretion of cytokine IL-17A by human PBMCs, such cells were co-cultured with bacteria for 5 days. The amount of cytokine, released in the culture supernatants, was determined by E.L.I.S.A assay.
• Figure 1 shows the modulation of interleukin 17 by strains belonging to the genus Lactobacillus.
• Horizontal bold line Mean of 8 independent experiments. Box of the experimental data range (minimum- maximum). Box under the dotted line (basal, no stimulation) ⁇ cytokine inhibition; box above the dotted line (basal, no stimulation) ⁇ cytokine induction.
• Figure 2 shows the modulation of interleukin 17 by strains belonging to the genus Bifidobacterium.
• Horizontal bold line Mean of 8 independent experiments. Box of the experimental data range (minimum- maximum). Box under the dotted line (basal, no stimulation) ⁇ cytokine inhibition; box above the dotted line (basal, no stimulation) ⁇ cytokine induction.
• Figure 3 shows the strains with inhibitory ability belonging to the genus Lactobacillus. The analysis was conducted on culture supernatants after 5 days of bacterial stimulation. Values, being expressed as percentage, represent:
• Horizontal bold line Mean of 8 independent experiments. Box of the experimental data range (minimum- maximum). Box under the dotted line (basal, no stimulation) ⁇ cytokine inhibition; box above the dotted line (basal, no stimulation) ⁇ cytokine induction.
• Figure 4 reports the strains with inhibitory ability belonging to the genus Bifidobacterium. The analysis was conducted on culture supernatants after 5 days of bacterial stimulation. The values, being expressed as percentage, represent:
• Cytokine IL-17A; curve range 8 points: 4-500; curve dilution: 1 :2; stock 5 1; buffer: 10 ml.

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