+

WO2018171850A1 - Composés ou compositions prébiotiques destiné(e)s à être utilisé(e)s dans le traitement du syndrome de sjögren - Google Patents

Composés ou compositions prébiotiques destiné(e)s à être utilisé(e)s dans le traitement du syndrome de sjögren Download PDF

Info

Publication number
WO2018171850A1
WO2018171850A1 PCT/DK2018/050044 DK2018050044W WO2018171850A1 WO 2018171850 A1 WO2018171850 A1 WO 2018171850A1 DK 2018050044 W DK2018050044 W DK 2018050044W WO 2018171850 A1 WO2018171850 A1 WO 2018171850A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
mammal
colon
xos
orally administered
Prior art date
Application number
PCT/DK2018/050044
Other languages
English (en)
Inventor
Axel Jacob KORNERUP
Anne Marie Lynge PEDERSEN
Camilla Hartmann Friis HANSEN
Original Assignee
Københavns Universitet
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Københavns Universitet filed Critical Københavns Universitet
Publication of WO2018171850A1 publication Critical patent/WO2018171850A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/20—Reducing nutritive value; Dietetic products with reduced nutritive value
    • A23L33/21—Addition of substantially indigestible substances, e.g. dietary fibres
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • Prebiotic compounds or compositions for use in treatment of Sjogren's syndrome are preferred.
  • the present invention relates to hitherto unknown uses of prebiotic compounds or compositions, e.g. to reduce immune cell infiltrations of salivary glands in Sjogren's syndrome patients.
  • the present invention relates to specifically administered xylooligosaccharide (XOS) containing compounds or compositions for use in treatment of Sjogren's syndrome.
  • XOS xylooligosaccharide
  • Sjogren's syndrome is among the most common autoimmune diseases in the Western world.
  • Sjogren's syndrome is an autoimmune disease in which the moisture-producing glands are infiltrated by autoreactive immune cells resulting in oral and ocular dryness.
  • treatment for Sjogren's syndrome has largely been based on treatment of symptoms (e.g, lotion for dry skin, artificial tears for dry eyes).
  • symptoms e.g, lotion for dry skin, artificial tears for dry eyes.
  • commercial drugs like Rituximab have shown promise in the treatment of severe extraglandular manifestations (e.g., vasculitis, cryoglobulinemia, peripheral neuropathy).
  • Complications related to Sjogren's syndrome include for example infection of the parotid gland (typically staphylococcal, streptococcal, or pneumococcal) emergence of parotid tumors, risk for fetal loss in pregnant patients, emergence of pseudolymphomas and non- Hodgkin B-cell lymphomas.
  • the gut microbiota has in the last few decades become a field of extensive research, and increasing evidence demonstrates the extent to which the bacteria colonizing the gut contribute to the development of immune mediated and metabolic disorders (Arora and Backhed, 2016). Identifying means to alleviate gut dysbiosis is much needed to help prevent, treat, and understand a number of such diseases.
  • US2016199424 discloses therapeutic compositions containing e.g. prebiotics, e.g., non- digestible medium and long-chained carbohydrates, in conjunction with microbial populations and/or networks thereof for use in method of reducing (treating) autoimmune or inflammatory disorders.
  • US2016199424 also discloses a large number of various probiotics and/or prebiotics which allegedly are suitable for treatment of a large number of diseases associated with gut dysbiosis.
  • US2016324904 discloses e.g. a dietary supplement for improving e.g.
  • autoimmune diseases by ingestion of mixtures of at least one prebiotic, such as dietary fibers and oligosaccharides, and at least one of L-glutamine, zinc, or vitamin A.
  • the supplement is for improving immunotolerance, intestinal environment and intestinal tract barrier.
  • the probiotic of US2016324904 may be a spore lactic acid bacteria, and the prebiotic may be an indigestible food ingredients such as oligosaccharide,
  • dietary fiber polysaccharides
  • substance stimulating production of Lactobacillus bifidus and cyclic oligosaccharide.
  • WO14150566 relates to a method for reducing autoimmune disease using peptides selected from a casein hydrolysate.
  • the nutritional composition comprises about 0.1 to about 1 g/100 kcal of prebiotic composition, wherein the prebiotic composition comprises at least 20 percent of an oligosaccharide.
  • US2007134391 discloses functional ingredient comprising a prebiotic, such as
  • dietary fibers including, xylooligosaccharides, for the treatment and/or prevention of autoimmune disorders.
  • Dwivedi et al. 2016 discloses the importance of T regulatory cells (Tregs) in e.g. treatment of autoimmunity. Dwivedi et al. 2016 also discloses the impact of probiotics and prebiotics and the associated metabolites (short chain fatty acids, preferably butyrate) on the differentiation and function of Tregs. Dwivedi et al. 2016 also mentions that numerous autoimmune diseases have been shown to present significant number depletion and/or function impairment of Tregs. Hansen et al. 2016 discloses inter alia that germ-free (GF) mice had a very low degree of sialitis, which was restored by colonization with select microbial lineages. Moreover, Hansen et al. 2016 concludes that the severity of sialitis in the tested mice did not correlate with the degree of insulitis in the same animal, i.e. there was a distinction in relation to the requirements for the microbiota for different autoimmune
  • XOS xylooligossacharides
  • XOS-supplemented diets besides other anti-inflammatory effects also have the ability to reduce cellular infiltrations in the salivary glands (sialitis) in non-obese diabetic (NOD) mice prone to the development of Sjogren's syndrome.
  • dietary XOS have the ability to reduce the inflammation caused by autoimmune cellular reactions against salivary glands in NOD mice.
  • microbes may not be necessary for XOS to mediate protection which is a surprising observation compared to the traditional perception of how prebiotics are typically perceived as a source of energy only by the symbiotic elements of the gut microbiota.
  • Eating prebiotic supplement is a more feasible approach that due to its advantage on mucus production may be able to limit environmental triggers constantly in risk of crossing the otherwise compromised barrier of the gut in preclinical individuals predisposed of autoimmune diseases.
  • one aspect of the invention relates to an orally administered prebiotic compound or composition which :
  • (ii) can be fermented by the commensal gut bacteria in the colon of the mammal, for use in treatment of Sjogren's syndrome in the mammal.
  • Another aspect of the invention relates to an orally administered prebiotic compound or composition selected from the group of oligosaccharides containing three to ten monosaccharide units which :
  • (ii) can be fermented by the commensal gut bacteria in the colon of the mammal, for use in treatment of Sjogren's syndrome in the mammal.
  • Still another aspect of the invention relates to an orally administered prebiotic compound or composition comprising xylooligosaccharides (XOS) which :
  • (ii) can be fermented by the commensal gut bacteria in the colon of the mammal, for use in treatment of Sjogren's syndrome in the mammal.
  • Still another aspect of the invention relates to an orally administered prebiotic compound or composition comprising xylooligosaccharides (XOS) which :
  • (ii) can be fermented by the commensal gut bacteria in the colon of the mammal, where the XOS are administered in amounts equal to 1-50%, such as 2-45%, such as 3- 40%, such as 4-35%, such as 5-30%, such as 6-25%, such as 7-20%, such as 8-15% most preferably approx. 5%, of the total daily carbohydrate fraction ingested, for use in treatment of Sjogren's syndrome in the mammal.
  • Still another aspect of the invention relates to an orally administered prebiotic compound or composition comprising xylooligosaccharides (XOS) which :
  • (ii) can be fermented by the commensal gut bacteria in the colon of the mammal, where the XOS are administered in amounts equal to 1-50%, such as 2-45%, such as 3- 40%, such as 4-35%, such as 5-30%, such as 6-25%, such as 7-20%, such as 8-15% most preferably approx. 5%, of the total daily carbohydrate fraction ingested,
  • the present invention relates to xylooligosaccharides (XOS) for use in treatment of Sjogren's syndrome in a mammal, where the XOS are administered in amounts equal to 1-50%, such as 2-45%, such as 3-40%, such as 4-35%, such as 5- 10 30%, such as 6-25%, such as 7-20%, such as 8-15% most preferably approx. 5% of the total daily carbohydrate fraction ingested.
  • XOS xylooligosaccharides
  • the present invention relates to xylooligosaccharides (XOS) for use in treatment of Sjogren's syndrome in a mammal, where the XOS are administered 15 1-3 times daily for a total period of at least 7 days in amounts equal to 1-50%, such as 2- 45%, such as 3-40%, such as 4-35%, such as 5-30%, such as 6-25%, such as 7-20%, such as 8-15% most preferably approx. 5% of the total daily carbohydrate fraction ingested.
  • XOS xylooligosaccharides
  • Another aspect of the invention relates to an orally administered prebiotic compound or composition which :
  • (ii) can be fermented by the commensal gut bacteria in the colon of the human subject, for use in treatment of Sjogren's syndrome in the human subject.
  • Another aspect of the invention relates to an orally administered prebiotic compound or composition selected from the group of oligosaccharides containing three to ten monosaccharide units which :
  • Still another aspect of the invention relates to an orally administered prebiotic compound or composition comprising xylooligosaccharides (XOS) which :
  • Still another aspect of the invention relates to an orally administered prebiotic compound or composition comprising xylooligosaccharides (XOS) which :
  • (ii) can be fermented by the commensal gut bacteria in the colon of the human subject, 5 where the XOS are administered in amounts equal to 1-50%, such as 2-45%, such as 3-
  • Still another aspect of the invention relates to an orally administered prebiotic compound or composition comprising xylooligosaccharides (XOS) which :
  • (ii) can be fermented by the commensal gut bacteria in the colon of the human subject, where the XOS are administered in amounts equal to 1-50%, such as 2-45%, such as 3-
  • the present invention relates to xylooligosaccharides (XOS) for use in treatment of Sjogren's syndrome in a human subject, where the XOS are administered in amounts equal to 1-50%, such as 2-45%, such as 3-40%, such as 4-35%, such as 5-30%, such as 6-25%, such as 7-20%, such as 8-15% most preferably approx. 5% of the total daily carbohydrate fraction ingested.
  • XOS xylooligosaccharides
  • the present invention relates to xylooligosaccharides (XOS) for use in treatment of Sjogren's syndrome in a human subject, where the XOS are administered 1-3 times daily for a total period of at least 7 days in amounts equal to 1- 50%, such as 2-45%, such as 3-40%, such as 4-35%, such as 5-30%, such as 6-25%, 30 such as 7-20%, such as 8-15% most preferably approx. 5% of the total daily
  • XOS xylooligosaccharides
  • Another aspect of the invention relates to an orally administered prebiotic compound or composition which :
  • Another aspect of the invention relates to an orally administered prebiotic compound or composition selected from the group of oligosaccharides containing three to ten
  • (ii) can be fermented by the commensal gut bacteria in the colon of the mammal, for use in reducing cellular infiltrations in the salivary glands (sialitis) of the mammal.
  • Still another aspect of the invention relates to an orally administered prebiotic compound or composition comprising xylooligosaccharides (XOS) which :
  • (ii) can be fermented by the commensal gut bacteria in the colon of the mammal, for use in reducing cellular infiltrations in the salivary glands (sialitis) of the mammal.
  • Still another aspect of the invention relates to an orally administered prebiotic compound or composition comprising xylooligosaccharides (XOS) which :
  • (ii) can be fermented by the commensal gut bacteria in the colon of the mammal, where the XOS are administered in amounts equal to 1-50%, such as 2-45%, such as 3- 40%, such as 4-35%, such as 5-30%, such as 6-25%, such as 7-20%, such as 8-15% most preferably approx. 5%, of the total daily carbohydrate fraction ingested, for use in reducing cellular infiltrations in the salivary glands (sialitis) of the mammal.
  • Still another aspect of the invention relates to an orally administered prebiotic compound or composition comprising xylooligosaccharides (XOS) which :
  • (ii) can be fermented by the commensal gut bacteria in the colon of the mammal, where the XOS are administered in amounts equal to 1-50%, such as 2-45%, such as 3- 40%, such as 4-35%, such as 5-30%, such as 6-25%, such as 7-20%, such as 8-15% most preferably approx. 5%, of the total daily carbohydrate fraction ingested,
  • the present invention relates to xylooligosaccharides (XOS) for use in reducing cellular infiltrations in the salivary glands (sialitis) of the mammal, where the XOS are administered in amounts equal to 1-50%, such as 2-45%, such as 3- 40%, such as 4-35%, such as 5-30%, such as 6-25%, such as 7-20%, such as 8-15% most preferably approx. 5% of the total daily carbohydrate fraction ingested.
  • XOS xylooligosaccharides
  • the present invention relates to xylooligosaccharides (XOS) for use in reducing cellular infiltrations in the salivary glands (sialitis) of the mammal, where the XOS are administered 1-3 times daily for a total period of at least 7 days in amounts equal to 1-50%, such as 2-45%, such as 3-40%, such as 4-35%, such as 5-30%, 5 such as 6-25%, such as 7-20%, such as 8- 15% most preferably approx. 5% of the total daily carbohydrate fraction ingested.
  • XOS xylooligosaccharides
  • Another aspect of the invention relates to an orally administered prebiotic compound or composition which :
  • (ii) can be fermented by the commensal gut bacteria in the colon of the human subject, for use in reducing cellular infiltrations in the salivary glands (sialitis) in the human subject.
  • Another aspect of the invention relates to an orally administered prebiotic compound or composition selected from the group of oligosaccharides containing three to ten
  • (ii) can be fermented by the commensal gut bacteria in the colon of the human subject, 20 for use in reducing cellular infiltrations in the salivary glands (sialitis) in the human
  • Still another aspect of the invention relates to an orally administered prebiotic compound or composition comprising xylooligosaccharides (XOS) which :
  • (ii) can be fermented by the commensal gut bacteria in the colon of the human subject, for use in reducing cellular infiltrations in the salivary glands (sialitis) in the human subject.
  • Still another aspect of the invention relates to an orally administered prebiotic compound or composition comprising xylooligosaccharides (XOS) which :
  • (ii) can be fermented by the commensal gut bacteria in the colon of the human subject, where the XOS are administered in amounts equal to 1-50%, such as 2-45%, such as 3-
  • Still another aspect of the invention relates to an orally administered prebiotic compound or composition comprising xylooligosaccharides (XOS) which :
  • (ii) can be fermented by the commensal gut bacteria in the colon of the human subject, where the XOS are administered in amounts equal to 1-50%, such as 2-45%, such as 3-
  • the present invention relates to xylooligosaccharides (XOS) for use in reducing cellular infiltrations in the salivary glands (sialitis) in the human subject, where the XOS are administered in amounts equal to 1-50%, such as 2-45%, such as 3-40%, such as 4-35%, such as 5-30%, such as 6-25%, such as 7-20%, such as 8-15% most preferably approx. 5% of the total daily carbohydrate fraction ingested.
  • XOS xylooligosaccharides
  • the present invention relates to xylooligosaccharides (XOS) for use in reducing cellular infiltrations in the salivary glands (sialitis) in the human subject, where the XOS are administered 1-3 times daily for a total period of at least 7 days in amounts equal to 1-50%, such as 2-45%, such as 3-40%, such as 4-35%, such as 5-30%, such as 6-25%, such as 7-20%, such as 8-15% most preferably approx. 5% of the total daily carbohydrate fraction ingested.
  • XOS xylooligosaccharides
  • Another aspect of the invention relates to an orally administered prebiotic compound or composition which :
  • Another aspect of the invention relates to an orally administered prebiotic compound or composition selected from the group of oligosaccharides containing three to ten
  • (ii) can be fermented by the commensal gut bacteria in the colon of the mammal, for use in increasing saliva production in the oral cavity of the mammal.
  • Still another aspect of the invention relates to an orally administered prebiotic compound or composition comprising xylooligosaccharides (XOS) which :
  • Still another aspect of the invention relates to an orally administered prebiotic compound or composition comprising xylooligosaccharides (XOS) which :
  • (ii) can be fermented by the commensal gut bacteria in the colon of the mammal, where the XOS are administered in amounts equal to 1-50%, such as 2-45%, such as 3- 40%, such as 4-35%, such as 5-30%, such as 6-25%, such as 7-20%, such as 8-15% most preferably approx. 5%, of the total daily carbohydrate fraction ingested, for use in increasing saliva production in the oral cavity of the mammal.
  • Still another aspect of the invention relates to an orally administered prebiotic compound or composition comprising xylooligosaccharides (XOS) which :
  • (ii) can be fermented by the commensal gut bacteria in the colon of the mammal, where the XOS are administered in amounts equal to 1-50%, such as 2-45%, such as 3- 40%, such as 4-35%, such as 5-30%, such as 6-25%, such as 7-20%, such as 8-15% most preferably approx. 5%, of the total daily carbohydrate fraction ingested,
  • the present invention relates to xylooligosaccharides (XOS) for use in increasing saliva production in the oral cavity of the mammal, where the XOS are administered in amounts equal to 1-50%, such as 2-45%, such as 3-40%, such as 4- 35%, such as 5-30%, such as 6-25%, such as 7-20%, such as 8-15% most preferably approx. 5% of the total daily carbohydrate fraction ingested.
  • XOS xylooligosaccharides
  • the present invention relates to xylooligosaccharides (XOS) for use in increasing saliva production in the oral cavity of the mammal, where the XOS are administered 1-3 times daily for a total period of at least 7 days in amounts equal to 1- 50%, such as 2-45%, such as 3-40%, such as 4-35%, such as 5-30%, such as 6-25%, such as 7-20%, such as 8-15% most preferably approx. 5% of the total daily
  • XOS xylooligosaccharides
  • Another aspect of the invention relates to an orally administered prebiotic compound or composition which :
  • Another aspect of the invention relates to an orally administered prebiotic compound or composition selected from the group of oligosaccharides containing three to ten monosaccharide units which :
  • (ii) can be fermented by the commensal gut bacteria in the colon of the human subject, for use in increasing saliva production in the oral cavity of the human subject.
  • Still another aspect of the invention relates to an orally administered prebiotic compound or composition comprising xylooligosaccharides (XOS) which :
  • (ii) can be fermented by the commensal gut bacteria in the colon of the human subject, for use in increasing saliva production in the oral cavity of the human subject.
  • Still another aspect of the invention relates to an orally administered prebiotic compound or composition comprising xylooligosaccharides (XOS) which :
  • Still another aspect of the invention relates to an orally administered prebiotic compound or composition comprising xylooligosaccharides (XOS) which :
  • (ii) can be fermented by the commensal gut bacteria in the colon of the human subject, where the XOS are administered in amounts equal to 1-50%, such as 2-45%, such as 3-
  • the present invention relates to xylooligosaccharides (XOS) for use in increasing saliva production in the oral cavity of the human subject, where the XOS are administered in amounts equal to 1-50%, such as 2-45%, such as 3-40%, such as 4-35%, such as 5-30%, such as 6-25%, such as 7-20%, such as 8-15% most preferably approx. 5% of the total daily carbohydrate fraction ingested.
  • XOS xylooligosaccharides
  • the present invention relates to xylooligosaccharides (XOS) 5 for use in increasing saliva production in the oral cavity of the human subject, where the XOS are administered 1-3 times daily for a total period of at least 7 days in amounts equal to 1-50%, such as 2-45%, such as 3-40%, such as 4-35%, such as 5-30%, such as 6- 25%, such as 7-20%, such as 8-15% most preferably approx. 5% of the total daily carbohydrate fraction ingested.
  • XOS xylooligosaccharides
  • Another aspect of the invention relates to an orally administered prebiotic compound or composition which :
  • Another aspect of the invention relates to an orally administered prebiotic compound or composition selected from the group of oligosaccharides containing three to ten monosaccharide units which :
  • (ii) can be fermented by the commensal gut bacteria in the colon of the mammal, for use in increasing tear production of the mammal.
  • Still another aspect of the invention relates to an orally administered prebiotic compound 25 or composition comprising xylooligosaccharides (XOS) which :
  • (ii) can be fermented by the commensal gut bacteria in the colon of the mammal, for use in increasing tear production of the mammal.
  • Still another aspect of the invention relates to an orally administered prebiotic compound or composition comprising xylooligosaccharides (XOS) which :
  • (ii) can be fermented by the commensal gut bacteria in the colon of the mammal, where the XOS are administered in amounts equal to 1-50%, such as 2-45%, such as 3-
  • Still another aspect of the invention relates to an orally administered prebiotic compound or composition comprising xylooligosaccharides (XOS) which :
  • XOS are administered in amounts equal to 1-50%, such as 2-45%, such as 3- 40%, such as 4-35%, such as 5-30%, such as 6-25%, such as 7-20%, such as 8-15% most preferably approx. 5%, of the total daily carbohydrate fraction ingested,
  • the present invention relates to xylooligosaccharides (XOS) for use in increasing tear production of the mammal, where the XOS are administered in amounts equal to 1-50%, such as 2-45%, such as 3-40%, such as 4-35%, such as 5-30%, such as 6-25%, such as 7-20%, such as 8- 15% most preferably approx. 5% of the total 15 daily carbohydrate fraction ingested.
  • XOS xylooligosaccharides
  • the present invention relates to xylooligosaccharides (XOS) for use in increasing tear production of the mammal, where the XOS are administered 1-3 times daily for a total period of at least 7 days in amounts equal to 1-50%, such as 2- 20 45%, such as 3-40%, such as 4-35%, such as 5-30%, such as 6-25%, such as 7-20%, such as 8-15% most preferably approx. 5% of the total daily carbohydrate fraction ingested.
  • XOS xylooligosaccharides
  • Another aspect of the invention relates to an orally administered prebiotic compound or 25 composition which :
  • (ii) can be fermented by the commensal gut bacteria in the colon of the human subject, for use in increasing tear production of the human subject.
  • Another aspect of the invention relates to an orally administered prebiotic compound or composition selected from the group of oligosaccharides containing three to ten
  • (ii) can be fermented by the commensal gut bacteria in the colon of the human subject, 35 for use in increasing tear production of the human subject.
  • Still another aspect of the invention relates to an orally administered prebiotic compound or composition comprising xylooligosaccharides (XOS) which :
  • Still another aspect of the invention relates to an orally administered prebiotic compound or composition comprising xylooligosaccharides (XOS) which :
  • (ii) can be fermented by the commensal gut bacteria in the colon of the human subject, where the XOS are administered in amounts equal to 1-50%, such as 2-45%, such as 3- 40%, such as 4-35%, such as 5-30%, such as 6-25%, such as 7-20%, such as 8-15% most preferably approx. 5%, of the total daily carbohydrate fraction ingested, for use in increasing tear production of the human subject.
  • Still another aspect of the invention relates to an orally administered prebiotic compound or composition comprising xylooligosaccharides (XOS) which :
  • the present invention relates to xylooligosaccharides (XOS) for use in increasing tear production of the human subject, where the XOS are administered in amounts equal to 1-50%, such as 2-45%, such as 3-40%, such as 4-35%, such as 5-30%, such as 6-25%, such as 7-20%, such as 8-15% most preferably approx. 5% of the total daily carbohydrate fraction ingested.
  • XOS xylooligosaccharides
  • the present invention relates to xylooligosaccharides (XOS) for use in increasing tear production of the human subject, where the XOS are administered 1-3 times daily for a total period of at least 7 days in amounts equal to 1- 50%, such as 2-45%, such as 3-40%, such as 4-35%, such as 5-30%, such as 6-25%, such as 7-20%, such as 8-15% most preferably approx. 5% of the total daily
  • XOS xylooligosaccharides
  • the orally administered prebiotic compound or composition for any of the above described uses may be incorporated into or part of a drink, beverage, snack bar, tablets, lozenge, capsules, soft gels, gel caps, powders, liquids, functional food products, conventional food products, nutraceuticals, natural health products, nutritional compositions, infant formulas, dairy products, chewing gums, candies.
  • the orally administered prebiotic compound or composition for any of the above described uses may be administered prior to,
  • probiotic(s) preferably bifidobacteria and/or lactobacilli containing probiotic(s) .
  • the present invention relates to a method of treating
  • Sjogren's syndrome in a mammal comprising oral administration into the mammal of a compound and/or composition which :
  • Figure 1 shows the effects on the gut microbiota .
  • the plots show that XOS supplemented diet alters the gut microbiota profile of the mice (being dominated by parabacteroides and lachnospiraceae with anti-inflammatory properties and lack of Prevotella, Rikenellaceae and Bacteroides) which therefore clusters separately on the PCoA plots.
  • the plot shows that dietary XOS reduces number and size of inflammatory foci as collected into a combined 'sialitis score' in the salivary glands of NOD mice. Error bars represent SEM . **** indicate P ⁇ 0.001.
  • Figure 3 shows that XOS fermentation increases acetic acid contents.
  • SCFA short-chain fatty acids
  • SCFA concentrations indicate bacterial fermentation and metabolic activity of the gut microbiota and the plotshows that dietary XOS increases the production of the SCFA acetic acid in the gut.
  • Other SCFAs were not regulated by XOS. Error bars represent SEM. ** indicate P>0.01
  • Figure 4 shows that XOS improves the gut barrier.
  • Spectrophotometric analysis of plasma Fitc dextran level two hours post oral gavage at seven weeks of age (n 6/group).
  • the plot shows that dietary XOS decreases the gut permeability monitored by systemic uptake of orally fed fluorescence-conjugated dextran (FITC-dextran).
  • FITC-dextran fluorescence-conjugated dextran
  • Relative gene expression of Mucl in colon biopsies sampled at 13 weeks of age is also shown.
  • FIG. 5 shows that XOS reduces intestinal inflammation.
  • PPN pancreatic lymph node
  • MN mesenteric lymph node
  • SPL spleen
  • administration refers to any oral administration form, such as ingestion, consumption, eating, drinking or otherwise which will be well-known for the skilled person.
  • commensal gut bacteria refers inter alia to gut bacteria deriving benefit to its host without harming or benefiting the host individual.
  • dietary fiber refers to the edible parts of plants or analogous carbohydrates that are resistant to digestion and absorption in the human small intestine, with complete or partial fermentation in the large intestine.
  • Dietary fiber includes polysaccharides, oligosaccharides, lignin, and associated plant substances. Dietary fibers promote beneficial physiologic effects including laxation, and/or blood cholesterol attenuation, and/or blood glucose attenuation. Dietary fiber means carbohydrate polymers with ⁇ 10 monomeric units, which are not hydrolyzed by the endogenous enzymes in the small intestine of humans.
  • Dietary fiber such as pectin and xylan
  • Dietary fiber are fermentable in the large intestine and forms an important source of short-chain fatty acids with a nutritional role for the epithelial cells lining the gut barrier.
  • the sorts of fiber matter as some polysaccharides such as pectin and xylan, are associated with e.g. higher levels of proinflammatory and stress-related transcripts in the colon and diabetogenic potential in NOD mice whereas
  • XOS shows immunomodulatory effects that seem to be related to immune
  • Dietary fibre is considered the portion of plant cells that are resistant to hydrolysis and human digestion. This allows the fiber to reach the colon undigested, allowing fermentation by the microbiota. Inulin is metabolised in the gut the same way as dietary fibre. Since they are not absorbed in the small intestine, calorie value is significantly lower compared to carbohydrates. As a result of the dietary fibre reaching the colon, there is an increase in biomass. If appropriate liquid intake is met to stay hydrated, the fibres are able to ferment. This results in increased fecal bulk and frequency, promoting regularity and alleviating constipation. Functional food
  • a functional food refers to food similar in appearance to, or may be, a conventional food that is consumed as part of a usual diet, and is demonstrated to have physiological benefits and/or reduce the risk of chronic disease beyond basic nutritional functions, i.e. they contain bioactive compound.
  • Examples of functional foods may be pro- or prebiotics, pro- or prebiotics used in infant formulas, folic acid fortified bread, sports bars (incl. vitamins, proteins, pro- or prebiotics etc.).
  • Non-obese diabetic mice have traditionally been used as an animal model for type 1 diabetes (being an autoimmune disease).
  • NOD mice spontaneously develops polyglandular autoimmune inflammation affecting organs like thyroid and salivary glands in a fashion very comparable to human Sjogren's syndrome they have also turned out to be a useful animal model for assessing Sjogren's syndrome.
  • Sjogren's syndrome is characterized (among other things) by dry mouth (xerostomia and salivary gland hypofunction) and dry eyes
  • inulin refers to a soluble dietary fiber. It is a naturally occurring oligosaccharide belonging to a group of carbohydrates known as fructans. Unlike most carbohydrates, inulin is non-digestible. This allows it to pass through the small intestine and ferment in the large intestine. Through the fermentation process, the inulin becomes healthy intestinal microbiota.
  • nutraceuticals are concentrated forms of food or food constituents that can be taken in pills, powder, or other medicinal forms that have specific health benefits.
  • Prebiotics are concentrated forms of food or food constituents that can be taken in pills, powder, or other medicinal forms that have specific health benefits.
  • prebiotics are defined as a selectively fermented ingredient that allows specific changes, both in the composition and/or activity in the gastrointestinal microbiota that confer benefits upon host's well-being and health.
  • Prebiotics resist digestion in the small intestine, are fermented in the large intestine, contain less energy in the form of calories than starch and sucrose, and increase stool weight and frequency.
  • Prebiotics are a non- digestible food ingredient that improves human health by its selective fermentation by one or a limited number of beneficial bacteria entirely by the colonic flora, and stimulating their growth and/or activity.
  • Dietary fibers can be classified into soluble and non-soluble fibers. Soluble dietary fibers are fermented, but usually not in a selective way. Prebiotics fibers are fermented in a selective way, meaning not all soluble dietary fibers are prebiotic.
  • Non- soluble dietary fibers are not fully fermented by the colonic flora. Prebiotics are fully fermented by the colonic microorganisms. Since some non-soluble dietary fibers are fermented outside the colon, not all non-soluble dietary fibers are prebiotic. Therefore, not all dietary fibers are prebiotic.
  • the most common type of prebiotic is from the soluble dietary fiber inulin.
  • Inulin is common in many plants containing fructan. Furthermore, many of these plants are frequently eaten as vegetables - asparagus, garlic, leek, onion, and artichoke are excellent sources of inulin.
  • probiotics covers a group of diverse bacteria species, including bifidobacteria and lactobacilli, being known probiotics in humans, which are able to ferment e.g. XOS and can, thus, specifically be targeted to propagate in a host that ingests a prebiotic supplemented diet.
  • Probiotics are living microorganisms that individually may provide the host a direct health benefit whereas prebiotics are defined as a selectively fermented ingredient that allows specific changes, both in the composition and/or activity in the gastrointestinal microbiota that confer benefits upon host's well- being and health.
  • Xylooligossacharides are interesting in this regard, as they elicit many of these desired properties.
  • XOS can specifically be targeted to propagate in a host that ingests a prebiotic supplemented diet. This may be beneficial for inflammatory autoimmune diseases regulated by the gut microbiota in humans in a similar manner as in the murine models. In the NOD mouse the inventors have found that XOS further improves the gut barrier and induces less proinflammatory cells in the gut. Sia litis
  • sialitis refers to inflammation of a salivary gland tissue.
  • Sjogren's syndrome (sometimes also referred to as Sjogren's disease or disorder) is a systemic chronic inflammatory disorder characterized by lymphocytic infiltrates in exocrine glands. Most individuals with Sjogren's syndrome present with sicca symptoms, such as dry eyes, dry mouth (xerostomia), and parotid gland enlargement. Primary Sjogren's syndrome occurs in the absence of another underlying rheumatic disorder, whereas secondary Sjogren's syndrome is associated with another underlying rheumatic disease, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), or scleroderma. In the present application, any reference to "Sjogren's syndrome” covers both primary and secondary Sjogren's syndrome. Sjogren's syndrome symptoms
  • Sjogren's syndrome patients are women, and onset is usually at age 40-60 years, but the syndrome also can affect men and children.
  • the most prominent clinical disease manifestations include hyposalivation and keratoconjunctivitis sicca resulting in symptoms of oral and ocular dryness. .
  • bilateral parotid swelling is the most common sign of onset. Symptoms of Sjogren's syndrome can severely decrease the patient's quality of life in terms of its physical, psychological, and social aspects.
  • xerostomia dry mouth
  • hyposalivation in the following ways: inability to eat dry food items because it sticks to the roof the mouth, tongue sticking to the roof of the mouth, difficulty speaking for long periods of time or the development of hoarseness, higher incidence of dental caries and gingival inflammation, altered sense of taste, development of oral candidiasis with angular cheilitis, which can cause pain in the oral mucosa.
  • ocular dryness and decreased tears production cause symptoms of itching and burning as well as sand- and gravel sensation in the eyes, and also increase the risk of ocular infections.
  • treatment of Sjogren's syndrome involves curative treatment as well as treatment which alleviates, lessens or removes Sjogren's syndrome manifestations/symptoms.
  • xerostomia refers to is dryness in the mouth which may be associated with a change in the composition of saliva, or reduced salivary flow (hyposalivation), or have no identifiable cause.
  • xerostomia is the subjective feeling of oral dryness, which is often (but not always) associated with hypofunction of the salivary glands.
  • Xerostomia may be caused by autoimmune damage to the salivary glands. Sjogren's syndrome is one such disease.
  • xylooligossacharides refers to XOS consisting of monomers of xylose units linked by ⁇ -1,4 glycosidic bonds, found in various food sources, and can be chemically or enzymatically produced from lignocellulosic containing sources such as corn cobs.
  • XOS passes undigested through the gastrointestinal tract until it reaches the ascending colon where the saccharide molecules are fermented by residing gut bacteria.
  • a diverse range of bifidobacteria and lactobacilli are able to ferment XOS and can, thus, specifically be targeted to propagate in a host that ingests a prebiotic supplemented diet. It should be noted that embodiments and features described in the context of one of the aspects of the present invention also apply to the other aspects of the invention.
  • NOD mice are prone to develop lymphocytic infiltrations in several organs, including the salivary glands. Histological analysis of these was, thus, made to assess whether the XOS supplemented diet would reduce the degree of sialitis. The effect on foci size and numbers in the salivary gland was evidently very pronounced in 13 weeks old mice. NOD mice - experimental set up
  • the rRNA sequences of the tag-encoded 16S rRNA gene were:
  • the inventors also examined the effects of the XOS-diet on the intestinal barrier morphology as prebiotics have also previously shown to alter gut morphology and function.
  • a FITC-dextran assay was used to evaluate the gut integrity and the barrier was indeed less permeable in mice fed the XOS supplemented diet compared to mice fed control diet ( Figure 4).
  • Gene expression of mucus related genes were up-regulated in mice on a XOS diet ( Figure 4).
  • CD8+ NKT cells and cytotoxic CD8+ T cells were lower in XOS-fed mice compared to control-fed mice, both in the pancreatic- and mesenteric lymph node as well as in the spleen ( Figure 5). These cells are known to infiltrate the organs as the salivary glands in NOD mice.
  • mice 8 weeks old NOD mice are randomly divided into two groups of 12 mice in each.
  • One group is fed ad libitum a modified 1430 Altromin natural diet (Lage, Germany) supplemented with either XOS (Shandong Longlive, Qingdao, China) or standard cornstarch as control to balance the level of polysaccharides in the diets in amounts equal to 10% of the carbohydrate fraction.
  • Lymphocytic inflammatory foci are scored in a blinded fashion on H&E stained 5 pm sections of wax embedded salivary glands from 20 weeks old non-diabetic NOD mice.
  • Salivary flow is tested with pilocarpine a week before euthanization.
  • Salivary cytokines are measured with a pro-inflammatory mesoscale kit.
  • NOD mice treated with antibiotics from 5-8 weeks of age are transplanted with murine or human microbiota from control and XOS dietary groups to investigate the sufficiency of the microbiota to transfer the protective phenotype.
  • mice according to Example 2 The intervention study on mice according to Example 2 will be carried out in the priority year.
  • Interviews will be made using of standardized questionnaire including questions about the general and oral health, including the incidence of diseases and various medical conditions, symptoms of mouth and eye dryness and symptoms from other body structures, past and current medications, tobacco and alcohol consumption, daily fluid intake, dietary habits and dental care habits.
  • the patients will be dosed daily with XOS diluted in water in a dose equivalent to 1-10 % of daily carbohydrate intake.
  • the clinical study include the registration of dental status (Decayed Missed Filled teeth and surfaces), registration of periodontal conditions through plaque and gingival indices, pocket depth (PD) and attachment loss (CAL) at 6 sites per tooth. Oral mucosal changes will also be registered.
  • Sialometri will be performed measuring the unstimulated and chewing-stimulated total salivary secretion within 15 min. and 5 min, respectively.
  • the collected saliva will be placed on ice, distributed in Eppendorf tubes and stored in a freezer until later miRNA, proteom- and microbiome analysis.
  • Labial salivary gland biopsies will be carried out using local anesthesia, where the procurement of 6-8 small salivary glands will investigated for the degree of lymphocytic infiltration (focus score) as routine histological analysis. 1-2 salivary glands will be removed for miRNA and proteomics. Cytokines will be monitored in the blood, and EULAR Sjogren's syndrome disease activity index (ESSDAI) will be made.
  • ESSDAI EULAR Sjogren's syndrome disease activity index
  • RNA analysis is performed on saliva, salivary gland tissue and serum: Total RNA purified after which a panel of 48 miRNA analyzed.
  • Proteome analysis is performed using a 2- dimensional electrophoresis (2DE) and MALDI-TOF-MS, while Western blot analysis and ELISA is used to validate the results of 2DE analyzes.
  • HOMINGS Human Oral Microbiome identification is made using Next Generation Sequencing analysis performed on whole saliva, where up to 600 different bacteria can be identified.
  • Reducing disease symptoms by improving dysbiosis using dietary formulations is a favorable approach.
  • One of the challenges is to investigate how far in the disease progress the patients can be and still gain beneficial effect of XOS intake. This will be possible by including subjects with different stages of Sjogren's syndrome and test the effect of the XOS supplement on disease severity.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Mycology (AREA)
  • Nutrition Science (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

La présente invention concerne une utilisation jusqu'à présent inconnue de composés ou compositions prébiotiques pour réduire les infiltrations de cellules immunitaires des glandes salivaires chez des patients atteints du syndrome de Sjögren. En particulier, la présente invention concerne des composés ou des compositions de xylooligosaccharides (XOS) spécifiquement administré(e)s, destiné(e)s à être utilisé(e)s dans le traitement du syndrome de Sjögren.
PCT/DK2018/050044 2017-03-23 2018-03-13 Composés ou compositions prébiotiques destiné(e)s à être utilisé(e)s dans le traitement du syndrome de sjögren WO2018171850A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DKPA201770204 2017-03-23
DKPA201770204 2017-03-23

Publications (1)

Publication Number Publication Date
WO2018171850A1 true WO2018171850A1 (fr) 2018-09-27

Family

ID=62089557

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DK2018/050044 WO2018171850A1 (fr) 2017-03-23 2018-03-13 Composés ou compositions prébiotiques destiné(e)s à être utilisé(e)s dans le traitement du syndrome de sjögren

Country Status (1)

Country Link
WO (1) WO2018171850A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001206848A (ja) * 2000-01-27 2001-07-31 Snow Brand Milk Prod Co Ltd シアロムチンの分泌促進剤
JP2009114125A (ja) * 2007-11-06 2009-05-28 Nippon Zettoc Co Ltd 口腔用組成物
US20100303782A1 (en) * 2003-08-29 2010-12-02 Cobb Mark L Probiotic composition useful for dietary augmentation and/or combating disease states and adverse physiological conditions
EP2361627A2 (fr) * 2008-10-20 2011-08-31 Benebiosis Co., Ltd. Composition pour prévention ou traitement de maladies oculaires
WO2013032744A2 (fr) * 2011-08-17 2013-03-07 Nume Health, Llc Composition et utilisation d'une formulation pour augmenter le rapport du microbiote gastro-intestinal du phylum des bacteriodites au microbiote du phylum des firmicutes
KR20130109504A (ko) * 2012-03-27 2013-10-08 한국과학기술연구원 에스쿨린을 포함하는 조성물

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001206848A (ja) * 2000-01-27 2001-07-31 Snow Brand Milk Prod Co Ltd シアロムチンの分泌促進剤
US20100303782A1 (en) * 2003-08-29 2010-12-02 Cobb Mark L Probiotic composition useful for dietary augmentation and/or combating disease states and adverse physiological conditions
JP2009114125A (ja) * 2007-11-06 2009-05-28 Nippon Zettoc Co Ltd 口腔用組成物
EP2361627A2 (fr) * 2008-10-20 2011-08-31 Benebiosis Co., Ltd. Composition pour prévention ou traitement de maladies oculaires
WO2013032744A2 (fr) * 2011-08-17 2013-03-07 Nume Health, Llc Composition et utilisation d'une formulation pour augmenter le rapport du microbiote gastro-intestinal du phylum des bacteriodites au microbiote du phylum des firmicutes
KR20130109504A (ko) * 2012-03-27 2013-10-08 한국과학기술연구원 에스쿨린을 포함하는 조성물

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Week 200170, Derwent World Patents Index; AN 2001-609591, XP002781554 *
DATABASE WPI Week 200937, Derwent World Patents Index; AN 2009-J69226, XP002781553 *
DATABASE WPI Week 201404, Derwent World Patents Index; AN 2013-R70615, XP002781555 *

Similar Documents

Publication Publication Date Title
EP3609351B1 (fr) Composition prébiotique multifibres pour la santé digestive, le contrôle du poids, le renforcement de l'immunité et l'amélioration de la santé
KR102085787B1 (ko) 바실러스 속 세균 유래 나노소포 및 이의 용도
JP5877902B2 (ja) バクテロイデス門の胃腸管微生物相対フィルミクテス門の微生物相の比を上昇させるための組成物および製剤の使用
RU2473347C1 (ru) Композиция пребиотиков для нормализации микрофлоры организма
KR20190000937A (ko) 프리바이오틱 제제 및 사용 방법
US9907827B2 (en) Prebiotic mixture
Kherade et al. Fructooligosaccharides: A comprehensive review
CN106072657A (zh) 益生菌组合物及其制备方法
CN109718256A (zh) 用于改善肠道菌群失衡的组合物及其制备方法和应用
EP2635130B1 (fr) Composition de mannanes solubles purifiés pour compléments alimentaires et leurs procédés d'utilisation
CN115606805A (zh) 一种后生元组合物及其在口腔健康中的应用
CN103445175A (zh) 具有解酒保肝作用的组合物
Achmad et al. Chewable Lozenges using White Shrimp Waste (Litopenaeus vannamei) in Reduce Colonization of Bacteria Streptococcus mutans in the Case of Early Childhood Caries.
CA3172064A1 (fr) Composition pour ameliorer la production d'urolithine chez un sujet humain
KR102000170B1 (ko) 체지방 감소 및 장관면역활성 증진을 위한 건강보조식품
AU2014246718B2 (en) Use of a dietary fibre supplement in a food formulation
WO2018171850A1 (fr) Composés ou compositions prébiotiques destiné(e)s à être utilisé(e)s dans le traitement du syndrome de sjögren
EP4151222A1 (fr) Composition permettant d'optimiser la production d'urolithine chez un sujet humain
CN107921058B (zh) 菊糖对鼻窦炎的预防作用
JP2019011315A (ja) 腸バリア改善用組成物
WO2018125735A1 (fr) Composition et procédé pour maintenir une fonction rénale saine
CN111685332A (zh) 一种具有减脂塑形美体功能的组合物及其制备方法
KR102774152B1 (ko) 케스토스를 이용한 프로피온산 증진 용도
KR102788126B1 (ko) 톳 후코이단을 유효성분으로 함유하는 면역기능 증진용 조성물
Mukonazwothe Anti-Streptococcus Mutans Property of Uvaria Chamae, and Its Anticariogenecity

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18720959

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 18720959

Country of ref document: EP

Kind code of ref document: A1

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载