阅读说明：本技术 用于缓解肠易激综合征和用于缓解其它胃肠道疾病的乳酸杆菌组合 (Lactobacillus combination for relieving irritable bowel syndrome and for relieving other gastrointestinal diseases ) 是由 S·卡里埃 于 2019-02-28 设计创作，主要内容包括：本文描述了组合物和方法,所述组合物和方法涉及活乳酸杆菌细菌,特别是活嗜酸乳杆菌、活干酪乳杆菌和活鼠李糖乳杆菌的组合用于缓解不期望的胃肠道健康问题的用途,所述胃肠道健康问题例如肠易激综合征(IBS)、腹痛、腹部不适、腹胀、液状便和便秘。这种活乳酸杆菌细菌的组合也可以用于改善患有IBS的受试者的生活质量、用于缓解IBS和/或用于IBS的预防和/或治疗。(Described herein are compositions and methods relating to the use of live lactobacillus bacteria, in particular the combination of live lactobacillus acidophilus, live lactobacillus casei and live lactobacillus rhamnosus, for alleviating undesirable gastrointestinal health problems, such as Irritable Bowel Syndrome (IBS), abdominal pain, abdominal discomfort, abdominal distension, fluid stools and constipation. Such a combination of live lactobacillus bacteria may also be used for improving the quality of life of a subject suffering from IBS, for alleviating IBS and/or for the prevention and/or treatment of IBS.)

1. A method of ameliorating a gastrointestinal disorder in a subject in need thereof, the method comprising administering to the subject a combination of live Lactobacillus acidophilus (Lactobacillus acidophilus), live Lactobacillus casei (Lactobacillus casei) and live Lactobacillus rhamnosus (Lactobacillus rhamnosus), wherein the gastrointestinal disorder is selected from Irritable Bowel Syndrome (IBS), abdominal pain, abdominal distension, and constipation.

2. A method for improving the quality of life of a subject with Irritable Bowel Syndrome (IBS), comprising administering to the subject a combination of live lactobacillus acidophilus, live lactobacillus casei, and live lactobacillus rhamnosus, wherein the administration provides at least one benefit to the subject selected from the group consisting of: satisfaction with bowel habits, IBS with minimal interference with normal activities, improved physical appearance, reduced food avoidance, increased social activity, reduced sexual dysfunction, and improved interpersonal relationships.

3. The method according to claim 1 or 2, wherein said lactobacillus acidophilus is the lactobacillus acidophilus deposited at CNCMWherein the Lactobacillus casei is Lactobacillus casei deposited at CNCMAnd wherein the Lactobacillus rhamnosus is Lactobacillus rhamnosus deposited at CNCM

4. The method according to any one of claims 1 to 3, wherein the administering comprises administering a nutritionally acceptable composition comprising the combination of Lactobacillus.

5. The method of any one of claims 1 to 4, wherein the administering comprises administering a combination of at least 100 to 2,000 billion of the lactobacilli.

6. The method of any one of claims 1 to 4, wherein the combination of live Lactobacillus acidophilus, live Lactobacillus casei and live Lactobacillus rhamnosus comprises about 1-10% Lactobacillus acidophilus, 70-90% Lactobacillus casei and about 5-20% Lactobacillus rhamnosus of combined Colony Forming Units (CFU).

7. The method of any one of claims 1 to 6, wherein the administering comprises administering the combination of lactobacilli at least once daily.

8. The method of any one of claims 1 to 7, wherein the administering comprises administering a capsule comprising the combination of lactobacilli.

9. The method of any one of claims 1 to 8, wherein the administering comprises administering a ferment comprising a fermentation protein in addition to the combination of lactobacilli.

10. The method of claim 9, wherein the fermented protein is selected from the group consisting of fermented soy protein, fermented milk protein, fermented rice protein, fermented pea protein, fermented hemp protein, fermented almond protein, and fermented insect protein.

11. A method of relieving Irritable Bowel Syndrome (IBS) in a human subject in need thereof, comprising administering to the subject live Lactobacillus acidophilusLive lactobacillus caseiAnd live mouse lactobacillus rhamnosusCombinations of (a) and (b).

12. The method of claim 11, wherein the IBS comprises at least one of constipation predominant IBS (IBS-C), diarrhea predominant IBS (IBS-D), and mixed bowel mode IBS (IBS-M).

13. The method of claim 11 or 12, wherein the method provides simultaneous relief of multiple symptoms of IBS.

14. The method of claim 13, wherein the symptom is selected from abdominal pain, abdominal distension, and constipation.

15. The method according to any one of claims 11 to 14, wherein the administering comprises administering a nutritionally acceptable composition comprising a combination of the lactobacilli.

16. The method of any one of claims 11 to 15, wherein the administering comprises administering a combination of at least 100 to 2,000 billion of the lactobacilli.

17. The method of any one of claims 11 to 16, wherein the combination of live lactobacillus acidophilus, live lactobacillus casei and live lactobacillus rhamnosus comprises about 1-10% lactobacillus acidophilus, 70-90% lactobacillus casei and about 5-20% lactobacillus rhamnosus of the combined Colony Forming Units (CFU).

18. The method of any one of claims 11 to 17, wherein the administering comprises administering the combination of lactobacilli at least once daily.

19. The method of any one of claims 11 to 17, wherein the administering comprises administering a capsule comprising the combination of lactobacilli.

20. The method of any one of claims 11 to 19, wherein the administering comprises administering a ferment comprising a fermentation protein in addition to the combination of lactobacilli.

21. The method of claim 20, wherein the fermented protein is selected from the group consisting of fermented soy protein, fermented milk protein, fermented rice protein, fermented pea protein, fermented hemp protein, fermented almond protein, and fermented insect protein.

22. An alternative method of drug therapy for the prevention and/or treatment of Irritable Bowel Syndrome (IBS), the method comprising: (i) identifying a human subject in need of drug therapy to prevent and/or treat IBS; and (ii) administering to the human subject a nutritionally acceptable composition comprising a combination of live microorganisms in addition to or in place of the drug therapy, the combination of live microorganisms comprising live Lactobacillus acidophilus, live Lactobacillus casei and live Lactobacillus rhamnosus.

23. The replacement method of claim 22, wherein the lactobacillus acidophilus is lactobacillus acidophilus deposited at CNCMWherein the Lactobacillus casei is Lactobacillus casei deposited at CNCMAnd wherein the Lactobacillus rhamnosus is Lactobacillus rhamnosus deposited at CNCM

24. The replacement method of claim 22 or 23, wherein the administering comprises administering the nutritionally acceptable composition at least once per day.

25. The replacement method according to any one of claims 22 to 24, wherein the administering comprises administering a capsule comprising the nutritionally acceptable composition.

26. The alternative method according to any one of claims 22 to 25, wherein the nutritionally acceptable composition comprises a combination of at least 100 to 2,000 billion of the lactic acid bacteria.

27. The method of any one of claims 22 to 26, wherein the combination of live lactobacillus acidophilus, live lactobacillus casei and live lactobacillus rhamnosus comprises about 1-10% lactobacillus acidophilus, 70-90% lactobacillus casei and about 5-20% lactobacillus rhamnosus of combined Colony Forming Units (CFU).

28. The alternative process according to any one of claims 22 to 27, wherein the nutritionally acceptable composition is in the form of a ferment comprising fermentation proteins in addition to the combination of lactic acid bacteria.

29. The alternative method according to claim 28, wherein the fermented protein is selected from the group consisting of fermented soy protein, fermented dairy protein, fermented rice protein, fermented pea protein and fermented hemp protein.

30. The method of any one of claims 22 to 29, wherein the administration provides the subject with at least one benefit selected from: satisfaction with bowel habits, IBS with minimal interference with normal activities, improved physical appearance, reduced dietary avoidance, increased social activity, reduced sexual dysfunction and improved interpersonal relationships.

31. A composition for alleviating gastrointestinal disorders in a subject in need thereof, the composition comprising live Lactobacillus acidophilusLive lactobacillus caseiLive lactobacillus rhamnosusWherein the gastrointestinal disorder is selected from the group consisting of: irritable Bowel Syndrome (IBS), abdominal pain, days of pain, flatulence, stool consistency and defecation frequency.

32. A composition for relieving Irritable Bowel Syndrome (IBS) in a subject in need thereof, the composition comprising live Lactobacillus acidophilusLive lactobacillus caseiAnd Lactobacillus rhamnosusCombinations of (a) and (b).

33. The composition of claim 31 or 32, wherein the composition comprises a fermentation protein in addition to the combination of lactobacilli.

34. The composition of claim 33, wherein the fermented protein is selected from the group consisting of fermented soy protein, fermented milk protein, fermented rice protein, fermented pea protein, fermented hemp protein, fermented almond protein, and fermented insect protein.

35. The composition of any one of claims 31 to 34, wherein the composition comprises a combination of at least 100 to 2,000 billion of the lactobacilli.

36. The composition of any one of claims 31 to 35, wherein the composition comprises about 1-10% lactobacillus acidophilus, 70-90% lactobacillus casei, and about 5-20% lactobacillus rhamnosus of a combined Colony Forming Unit (CFU).

37. The composition of any one of claims 31 to 36, wherein the composition is a nutritionally acceptable composition.

38. Use of a combination of live lactobacillus acidophilus, live lactobacillus casei and live lactobacillus rhamnosus for alleviating a gastrointestinal disorder in a subject in need thereof, wherein the gastrointestinal disorder is selected from Irritable Bowel Syndrome (IBS), abdominal pain, abdominal distension and constipation.

39. The use of claim 38, wherein the lactobacillus acidophilus is lactobacillus acidophilus with deposit number CNCM I-4099Wherein the Lactobacillus casei is Lactobacillus casei with accession number CNCM I-3989And wherein the Lactobacillus rhamnosus is Lactobacillus rhamnosus with deposit number CNCM I-3990

40. The use of claim 38 or 39, wherein the administration provides the subject with at least one benefit selected from the group consisting of: satisfaction with bowel habits, IBS with minimal interference with normal activities, improved physical appearance, reduced food avoidance, increased social activity, reduced sexual dysfunction, and improved interpersonal relationships.

41. Live Lactobacillus acidophilusLive lactobacillus caseiAnd live mouse lactobacillus rhamnosusIn a subject in need thereofFor the prevention, treatment and/or alleviation of Irritable Bowel Syndrome (IBS).

42. The use of any one of claims 38 to 41, wherein the combination of live Lactobacillus acidophilus, live Lactobacillus casei and live Lactobacillus rhamnosus comprises about 1-10% Lactobacillus acidophilus, 70-90% Lactobacillus casei and about 5-20% Lactobacillus rhamnosus of combined Colony Forming Units (CFU).

43. The use of any one of claims 38 to 42, wherein the live Lactobacillus acidophilus, Lactobacillus casei and Lactobacillus rhamnosus are present in a composition comprising a fermented protein.

44. The use according to claim 43, wherein the fermented protein is selected from the group consisting of fermented soy protein, fermented milk protein, fermented rice protein, fermented pea protein, fermented hemp protein, fermented almond protein and fermented insect protein.

45. The use of any one of claims 38-44, wherein the subject ingests a combination of at least 100 to 2,000 billion of the Lactobacillus per day.

Technical Field

The present invention relates to the field of gastrointestinal disorders, more specifically to the use of live lactobacillus bacterial combinations for alleviating undesired gastrointestinal health problems such as Irritable Bowel Syndrome (IBS), abdominal pain, abdominal discomfort, abdominal distension, liquid stools and constipation.

Background

Irritable Bowel Syndrome (IBS) is a chronic recurrent gastrointestinal disorder affecting 5-20% of the us population. Many risk factors for IBS have been identified, including female gender, psychological problems, stress, food intolerance, and small intestinal bacterial overgrowth (Aagaard et al, 2013). The main symptoms of IBS include abdominal pain, abdominal distension, and altered bowel habits (Aagaard et al, 2013). The pathophysiology of this syndrome is well-defined and the syndrome is not accompanied by abnormalities in the intestinal structure. The quality of life of individuals with IBS is severely compromised, which has a major impact on the health care system and requires visits to primary care physicians and gastroenterology physicians (Coffin et al, 2004). In fact, IBS is the most common diagnosis in gastroenterology practice, and also one of the most common diagnoses in primary health care practice (Peery et al, 2012). Depending on the particular symptoms, IBS patients can be subdivided into three major groups: constipation predominates (IBS-C), diarrhea predominates (IBS-D) and mixed bowel pattern (IBS-M), with approximate average distribution in each group. These IBS symptoms afflict patients, lead to a reduction in quality of life, and interfere with social interactions (Coffin et al, 2004).

The ultimate therapeutic goal of IBS is to provide relief from multiple symptoms of this condition by using a single well-tolerated agent. Drug therapy may alleviate some of the symptoms associated with this condition, but none may cure. Thus, long-term treatment efficacy has limited prospects in view of current treatment options. There is clearly a need for a safe, effective and cost-effective IBS mitigation procedure (Foxx-Orenstein, 2006).

Probiotics are living microorganisms that, when administered in sufficient doses, can provide health benefits to the host. In recent years, probiotics have been commonly used to alleviate the symptoms of various gastrointestinal disorders. Since dysbiosis may be part of the multi-factorial cause of IBS, a number of probiotics have been tested in clinical trials to determine their efficacy and the results are included in some meta-analysis (meta-analysis) and review articles (Ford et al, 2014 b; Hoveyda et al, 2009; McFarland and Dublin, 2008; Ortiz-Lucas et al, 2013; Whelan and Myers, 2010; Yoon et al, 2015). There is no definitive conclusion about the efficacy of strain-specific probiotics in relieving IBS symptoms. Strong placebo effects, psychological factors and sex effects make interpretation of the study results difficult (Ford and Moayyedi, 2010; Lyra et al, 2016; Moayyedi et al, 2010).

Probiotic products containing lactobacilli and bifidobacteria have been tested to improve IBS (Niv et al, 2005; O' Mahony et al, 2005). Some lactobacillus strains have proved to be positive results, for example 214 patients reported by duclotte et al after 4 weeks of treatment with lactobacillus plantarum (l.plantarum)299V, all major IBS symptoms including abdominal pain were resolved (duclotte et al, 2012). Halpern et al indicate that they contain 5x 10⁹A capsule of heat-inactivated lactobacillus acidophilus (l. acidophilus) can significantly reduce the IBS symptom index (Halpern et al, 1996). Other lactobacillus strains, such as lactobacillus salivarius UCC4331, did not show any therapeutic benefit in 75 patients over placebo (O' Mahony et al, 2005), as did lactobacillus reuteri (l.reuteri) ATCC55730 (Niv et al, 2005), suggesting that some strains of lactobacillus may be more effective than others in this indication.

Although products comprising Lactobacillus acidophilus (Lactobacillus acidophilus), Lactobacillus casei (Lactobacillus casei) and/or Lactobacillus rhamnosus strains (Lactobacillus rhamnosus) have been tested in the past during clinical studies (Beausoleil et al, 2007; Gao et al, 2010; Maziade et al, 2015; Sampalis et al, 2010), these clinical trials have never shown or suggested the effectiveness of Lactobacillus in relieving Irritable Bowel Syndrome (IBS), abdominal pain, abdominal distension and/or constipation.

Accordingly, there is a need for combinations of bacterial strains effective in relieving gastrointestinal disorders such as Irritable Bowel Syndrome (IBS), abdominal pain, abdominal distension, and/or constipation.

These needs and others are met by the present invention, as will become apparent from the following disclosure and description of the features of the invention.

Disclosure of Invention

The present invention relates to the use of a combination of live lactobacillus bacteria for alleviating undesired gastrointestinal health problems such as Irritable Bowel Syndrome (IBS), abdominal pain, abdominal discomfort, abdominal distension, liquid stools and constipation.

According to a particular aspect, the present invention relates to a method for alleviating a gastrointestinal disorder in a subject in need thereof, the method comprising administering to the subject a combination of live lactobacillus acidophilus, live lactobacillus casei and live lactobacillus rhamnosus, wherein the gastrointestinal disorder is selected from Irritable Bowel Syndrome (IBS), abdominal pain, abdominal distension and constipation.

According to another particular aspect, the present invention relates to a method for improving the quality of life of a subject suffering from Irritable Bowel Syndrome (IBS), the method comprising administering to said subject a combination of live lactobacillus acidophilus, live lactobacillus casei and live lactobacillus rhamnosus, wherein said administration provides to said subject at least one benefit selected from the group consisting of: satisfaction with bowel habits, IBS with minimal interference with normal life, improved physical image, reduced food avoidance, increased social activity, reduced sexual dysfunction, and improved interpersonal relationships.

According to another particular aspect, the present invention relates to a method for alleviating Irritable Bowel Syndrome (IBS) in a human subject in need thereof, comprising administering to said subject live lactobacillus acidophilusLive lactobacillus caseiAnd live mouse lactobacillus rhamnosus

According to another particular aspect, the present invention relates to an alternative method of drug therapy for the prevention and/or treatment of Irritable Bowel Syndrome (IBS), comprising: (i) identifying a human subject in need of drug therapy to prevent and/or treat IBS; and (ii) administering to the human subject, in addition to or in place of the drug therapy, a nutritionally acceptable composition comprising a combination of living microorganisms comprising live Lactobacillus acidophilus, live Lactobacillus casei and live Lactobacillus rhamnosus.

According to another particular aspect, the present invention relates to a composition for alleviating gastrointestinal disorders in a subject in need thereof, the composition comprising live lactobacillus acidophilusLive lactobacillus caseiLive lactobacillus rhamnosusWherein the gastrointestinal disorder is selected from Irritable Bowel Syndrome (IBS), abdominal pain, number of pain days, flatulence, stool consistency and stool frequency.

According to another particular aspect, the present invention relates to a composition for relieving Irritable Bowel Syndrome (IBS) in a subject in need thereof, the composition comprising live lactobacillus acidophilusLive lactobacillus caseiAnd live mouse lactobacillus rhamnosusCombinations of (a) and (b).

According to another particular aspect, the present invention relates to the use of a combination of live lactobacillus acidophilus, live lactobacillus casei and live lactobacillus rhamnosus for alleviating a gastrointestinal disorder in a subject in need thereof, wherein the gastrointestinal disorder is selected from Irritable Bowel Syndrome (IBS), abdominal pain, abdominal distension and constipation.

According to another particular aspect, the invention relates to live Lactobacillus acidophilusLive lactobacillus caseiAnd live mouse lactobacillus rhamnosusFor preventing, treating and/or alleviating Irritable Bowel Syndrome (IBS) in a subject in need thereof.

Detailed Description

The present invention relates to the prevention, treatment and/or amelioration of gastrointestinal disorders in a subject.

As used herein, the term "gastrointestinal disorder" refers to a gastrointestinal disorder characterized by symptoms such as abdominal pain, abdominal distension, and constipation (e.g., stool consistency and frequency). The term includes, but is not limited to, Irritable Bowel Syndrome (IBS), which includes constipation predominant IBS (IBS-C), diarrhea predominant IBS (IBS-D), and mixed bowel pattern IBS (IBS-M).

As used herein, the term "alleviating a gastrointestinal disorder" or "alleviating irritable bowel syndrome" or "alleviating IBS" encompasses health benefits including, but not limited to, stabilizing, treating, curing, moderating, relieving, altering, remedying, reducing exacerbations, alleviating, ameliorating, or affecting a disease or disorder, a symptom of a disease or disorder, or a risk (or predisposition) to a disease or disorder. The term encompasses at least the relief of undesirable health problems, including but not limited to abdominal pain, extended abdominal pain duration (continuous or discontinuous), abdominal distension, stool consistency and/or frequency problems (e.g., constipation), decreased quality of life (QOL) associated with one or more of the above, and inadequate relief of such health problems upon medication or other treatment.

As used herein, the term "subject" includes living organisms in which gastrointestinal diseases may occur. The term "subject" includes animals (e.g., mammals (e.g., cats, dogs, horses, pigs, cows, goats, sheep, rodents (e.g., mice or rats), rabbits, squirrels, bears, primates (e.g., chimpanzees, monkeys, gorillas, and humans)) as well as avians (e.g., chickens, ducks, peking ducks, geese) and transgenic species thereof.

According to a particular aspect, the present invention provides the use of a combination of live lactobacilli for the prevention, treatment and/or alleviation of gastrointestinal disorders, in particular IBS. According to a particular embodiment, the combination of live lactobacilli comprises live lactobacillus acidophilus, live lactobacillus casei and live lactobacillus rhamnosus.

In an embodiment, the combination comprises about 10% lactobacillus acidophilus, 70-90% lactobacillus casei and about 5-20% lactobacillus rhamnosus of a combined Colony Forming Unit (CFU).

In a particular embodiment, the Lactobacillus acidophilus is the Lactobacillus acidophilus deposited at the National Collection of Microorganisms Cultures (CNCM) in Paris under the accession number CNCM I-4099Lactobacillus casei deposited at CNCM under accession number CNCM I-3989Lactobacillus rhamnosus deposited at CNCM under accession number CNCM I-3990

In embodiments, the invention comprises the simultaneous administration of at least 100, or at least 200, or at least 300, or at least 400, or at least 500, or at least 750, or at least 1000, or at least 1500, or at least 2000 billion of such combinations of lactobacilli.

In embodiments, the present invention comprises administering a combination of live lactobacilli once daily, twice daily, three times daily or more.

In an embodiment, the combination of live lactobacilli is administered as a nutritionally acceptable composition. As used herein, the term "nutritionally acceptable composition" refers to a substance, such as an edible substance, which upon ingestion provides nutritional support and nutrients, such as carbohydrates, fats, proteins, vitamins, and/or minerals, and the like. Once ingested, in addition to providing health benefits (e.g., relief of undesirable gastrointestinal problems), nutritionally acceptable compositions will also provide energy as other food substances. The nutritionally acceptable composition according to the invention is substantially different from compositions used in pharmacotherapy, which consist of food ingredients, preferably natural ingredients, which are considered safe, non-toxic to humans and substantially free of side effects associated with typical prescription drugs (e.g. headache, nausea, allergies, etc.).

Nonetheless, the nutritionally acceptable composition may further comprise additional safe and non-toxic components, such as preservatives, solubilizers, stabilizers, emulsifiers, emollients, colorants, odorants, antioxidants and the like.

The nutritionally acceptable composition may be in solid form (e.g. dried form) or in liquid form for oral administration. The nutritionally acceptable composition may be in various ingestible forms of foods or food supplements including, but not limited to, milk, yogurt, curd, fermented milks, milk based fermented products, soy based fermented products, fermented cereal based products, milk based powders, infant formulas, protein concentrates (e.g. concentrates for hospital use), and the like.

In embodiments, the nutritionally acceptable composition comprises a combination of lactobacillus and fermented proteins including, but not limited to, fermented soy protein, fermented milk protein, fermented rice protein, fermented pea protein, fermented hemp protein, fermented almond protein, and fermented insect protein (e.g., larval protein).

The combination of lactobacilli and nutritionally acceptable composition may be incorporated into any suitable carrier for oral delivery, such as a gel, capsule, tablet, suspension or any other suitable carrier known to those skilled in the art. Preferably, the amount of lactobacillus included in a single capsule, a single tablet, a volume of suspension, etc., is in the range of about 100 to 2000 billion.

The invention also includes kits and containers comprising multiple doses of a nutritionally acceptable composition, including, for example, blister packs, reclosable bottles, and the like, containing a quantity of the composition (e.g., 25ml, 50ml, 100ml or more) or a number of capsules or tablets (e.g., 10, 15, 25, 50 or more). Such kits or containers may advantageously include instructions in the form of a brochure or any other printed carrier, indicating the amount of composition to be administered, instructions for administration, instructions for mixing with the components (e.g., if in powder form), and the like.

The preparation of the nutritionally acceptable composition according to the invention is within the capabilities of the person skilled in the art. For example, the lactobacillus may be incorporated in a suitable nutritionally acceptable carrier. Alternatively, a nutritionally acceptable composition comprising a combination of lactobacilli may be obtained by: live lactobacillus bacteria are fermented in a suitable medium to obtain a ferment comprising the lactobacillus and fermented proteins (e.g. fermented soy protein, fermented milk protein, fermented rice protein, fermented pea protein, fermented hemp protein, etc.).

Examples

The following examples are intended to illustrate the scope of use of the invention, but not to limit its scope. Modifications and variations may be made without losing the intent and scope of the invention. Materials and preferred methods are described, although other methods or equivalent products may be used which are equivalent to the methods found herein for testing or practicing the present invention.

Example 1: acidophilus milkBacillusLactobacillus caseiAnd Lactobacillus rhamnosusAmelioration of symptoms of QOL and IBS-C, IBS-D: double-blind, randomized, placebo-controlled study

The aim of this clinical trial was to evaluate the specialized probiotic product lactobacillus acidophilus+ Lactobacillus casei+ Lactobacillus rhamnosusRelief of specific IBS-related symptoms, improvement of quality of life, impact on stool consistency and frequency, and achievement of Adequate Relief (AR) in otherwise healthy adults with irritable bowel syndrome of constipation (IBS-C), diarrhea (IBS-D) and mixed (IBS-M) subtypes.

Materials and methods

Experimental design, study implementation and data Collection

The protocol for this prospective, double-blind, randomized, placebo-controlled study was approved by the independent IRB IntegReview. All participating subjects signed informed consent. Subjects 18 years or older were enrolled at 3 clinical research centers in california, usa.

Subjects ingested 2 capsules of either Active or Placebo (Placebo) product per day for breakfast. Each active agent capsule contains 500 hundred million colony units (c.f.u) of a living organism (lactobacillus acidophilus)Lactobacillus caseiAnd Lactobacillus rhamnosus) Adding inert components. Placebo capsules contained only inert ingredients.

Subjects were asked to meet the roman iii (rome iii) criteria for IBS (Shih and Kwan, 2007). The roman III standard involves repeated abdominal pain or discomfort in the last 3 months for at least 3 days/month, with 2 or more of the following: through improved defecation, episodes associated with altered frequency of defecation, and episodes associated with altered stool form (appearance). Onset of symptoms must be at least 6 months prior to diagnosis.

Subjects were asked to complete a 7 day placebo run-in period to demonstrate compliance with study product (IP) intake and to complete a daily diary, recording IP consumption, frequency of defecation, Stool consistency as defined by Bristol Stool Chart (BSC), pain severity, and concomitant medication. Successful completion of the break-in period also requires at least 2 days for development of abdominal pain associated with at least two of the following: through improved defecation, episodes associated with altered frequency of defecation, and episodes associated with altered form or appearance of stool. The following potential subjects were excluded: gastrointestinal disorders other than IBS, previous abdominal surgery or systemic disease that may confound the results of the study or compromise safety, less than 6 months of life expectancy, pregnancy or breast feeding, lactose intolerance, immunodeficiency, eating disorders, recent use of antibiotics, allergy to the product under study or daily consumption of probiotics, fermented milk or yogurt. After successful completion of the break-in period, 113 subjects were randomly assigned to the active study product or placebo at a ratio of 2: 1.

Subjects returned to the study site every 6 weeks for a total of 12 study weeks. At each visit (visit), the subjects filled in two questionnaires, IBS-SSS (symptomatic Severity Scale) and IBS-QOL (Quality of Life), including overall scores and QOL assessments in eight areas of identification, dysphoria, disturbed activities, physical image, health concerns, food avoidance, social activities, sex, and interpersonal relationships, please see the online published "Irritable Bowel Syndrome Quality of Life Scale Information table (Information sleep on the Irritable bo business-Quality of Life measures, IBS-QOL)" published by washington university.

Subjects were asked at each visit whether their IBS symptoms had been adequately alleviated. Subjects continued to record stool consistency and frequency, symptom severity, IP consumption and concomitant medications in a diary, all collected at each visit and checked for readability and integrity. The returned IPs are counted to evaluate compliance (compliance) and a new IP is issued at visit 3. Subjects were asked any Adverse Events (AEs) recorded in the diary to determine the onset and recovery date and severity. The investigator then classified (relevant, possibly irrelevant, irrelevant) the reported AEs according to their relationship to the IP.

Study endpoint

Study endpoints included abdominal pain scores, flatulence scores, pain days, improvement in scores for IBS-SSS and IBS-QOL (including QOL field), and changes in AR. Changes in stool frequency and stool consistency were examined within IBS subtypes and within subgroups of IBS subtypes and gender during the study. The safety endpoint is the incidence, severity and IP versus reported adverse events.

Study population

A population with altered intent-to-treat (mITT) is defined as subjects, randomly grouped and receiving at least one dose of IP; this population was used for efficacy and safety analysis.

Data management

Data is collected from hardcopy source documents at a research site and entered into a network (Web) based relational database. On-site monitoring for 100% of the clinical data field of the source document was done by Clinical Research Assistant (CRA); the on-site clinical team generates queries according to solution needs. After all data is entered and all queries are fulfilled, the database will be hard-locked (hard-locked) for analysis. The data file is then extracted by the study biometist and the subject ID number is matched to its treatment assignment to dismiss blinded studies.

Statistical analysis

The number of subjects screened, the number of random cohorts, the number of early withdrawals (number with dry early) and the number of completions are tabulated by treatment group.

The mITT population as a whole was analyzed for symptom endpoints and QOL endpoints, as well as for IBS subtypes and gender subpopulations. Stool consistency and frequency changes were analyzed for IBS-C and IBS-D subtypes and gender classification within the subtypes.

Descriptive statistics were calculated for baseline and demographic characteristics and tabulated by treatment group. Descriptive statistics include mean, standard deviation, median, range, and percentage, depending on the form of each variable. The inference method is not applied to baseline features.

Compliance was calculated as a percentage of IP expected to be used, determined from returned bottle (bottle) counts and subject diaries at week 6 and week 12, and compared between groups. Compliance is also defined as intake of 70% or more of the expected IP and analyzed using the chi-square test.

Two treatment groups were analyzed for changes in scores between visit 2 and visit 4 in the following: IBS-SSS, IBS-QOL universe and field, pain severity, number of pain days in the last 10 days, flatulence severity, satisfaction with bowel habits, and IBS interference with general life. Stool consistency scores were assigned by the subjects using the BSC, daily records were made in the subjects' diaries, and the stool number entered in the diary determined the frequency of defecation per day. Changes in stool consistency and stool frequency were compared for the 7 day break-in period and the last 7 days in the study. Stool consistency score is expressed as the median weekly BSC score, while stool frequency is expressed as the median daily stool count.

Data analysis shows that efficacy endpoints must be assessed within a subtype of IBS and separately for each gender, and that many subgroup sample sizes (sizes) are small. A greater placebo effect was noted for many endpoints. Therefore, we chose to control placebo effects by comparing changes in the active versus placebo groups; the average improvement from visit 2 to visit 4 was calculated for each treatment group, and the placebo value was subtracted from the active value, divided by the placebo value, and multiplied by 100. For example, a mean change in pain severity of 15.0 in the active group and a mean change of 10.0 in the placebo group, a 50% improvement in the active group over the placebo group was reported. This method was used to compare the changes in IBS-SSS, IBS-QOL and field, pain severity, pain days, flatulence severity, satisfaction with bowel habits and IBS interference with general life. Changes in stool consistency and frequency were compared using the same method.

Stool consistency and frequency change analysis was performed on subjects of IBS-C and IBS-D subtypes, as well as male and female subjects in these subtypes. In each subtype, the "percent improvement" is defined as the percent change in that subtype in the ideal direction. Thus, the results table reports "improvement" as a positive change in two subtypes, but with different definitions: for the IBS-C subtype, an increase in the mean BSC score (corresponding to stool softening) and an increase in defecation frequency were positive scores, indicating an improvement for this endpoint. For IBS-D subjects, a decrease in mean BSC score (indicating harder stools) and a decrease in stool frequency using a positive number were reported as improvements.

AR is a common primary endpoint in IBS trials when writing protocols (protocols) and is used as the endpoint for the trial. In therapeutic IBS trials with alosetron (almisetron) (Camilleri et al 1999), Granisetron (cilansetron) and tegaserod (Kellow et al 2003; Tack et al 2005), it has been shown that endpoint IBS-AR is a clinically and statistically relevant benefit. AR consists of one problem: "is your IBS symptoms sufficiently relieved during the past week? ".

Safety was assessed by calculating the ratio of subjects with adverse events in the active and placebo groups and comparing them descriptively. A list of adverse events of a particular category is described. A comparison of subjects with a particular adverse event is described.

Results

A total of 113 subjects were enrolled, of which 86 (76.1%) completed the study. The completion rate was 73.0% in the placebo group and 77.6% in the active group. Reasons for early discontinuation included follow-up failure (10.6%), consent withdrawn (7.1%) and others/unknowns (6.1%). No subjects were withdrawn due to adverse events.

Demographic and baseline subject characteristics

Table 1 shows the population structure and the distribution of baseline characteristics for the mITT population. The placebo and active groups were comparable in age, gender and race.

TABLE 1,Demographic and baseline subject characteristics at visit screening by treatment group, mITT population

Distribution of IBS subtypes

The investigator classified 113 patients as IBS-C, IBS-D or IBS-M at each site based on their symptoms and medical history at the time of study entry. The distribution of subjects in the three subtypes varied from clinical site to clinical site, as shown in table 2.

TABLE 2,Number and percentage of subjects in each IBS subtype divided by the survey site for the mITT cohort

Compliance

Subjects in the placebo group consumed 87.0 + -17.8% of the expected dose, while subjects in the active group consumed 77.3 + -19.9%. According to the protocol, compliance was determined as 84.4% of subjects in the placebo group and 87.3% of subjects in the active group consumed at least 70% of the expected IP.

IBS symptom severity scale-IBS-SSS

IBS-SSS consists of problems in the following areas: the severity of abdominal pain, the number of days of pain within the last 10 days, the severity of abdominal distension, satisfaction with bowel habits, and the extent to which IBS generally interferes with the subject's life. All of these were scored on the Rickett (Likert) scale, ranging from 0 to 100, except for the number of painful days. When the overall scores were calculated, no mean improvement of 30% or more was demonstrated that was beneficial for the active agent group.

In the active group compared to the placebo group, the abdominal pain severity in no subgroup of patients changed by up to 30%. However, clinical improvement of individual symptoms constituting IBS-SSS was found in many subgroups. Table 3 shows that the highest percentage improvement in IBS-D subtypes, especially in women, was found in the score of the IBS-SSS problem, where the percentage improvement in active treatment benefit varied from 50% to 144%. Men with a subset of diarrhea showed less improvement in "satisfaction of bowel habits" (43%) and "activity disturbance" (39%). Advantages in the IBS-C subtype are manifested in "days of pain" (42%) in women and in "satisfaction of bowel habits" (30% and 33%) in men and women.

TABLE 3 summary of individual IBS-SSS problems for which the mITT population shows a mean difference of 30% or more beneficial for active agent treatment

In many subgroups, the percentage of active treatment over placebo was well above the 30% threshold we set for at each issue.

Quality of life-IBS QOL overall score

The overall score of IBS-QOL was examined for the overall population in the IBS-C and IBS-D subtypes, gender and gender in the subtypes. The percent improvement in the active versus placebo group (table 4) was comparable to the results obtained for IBS-SSS, with positive reactions concentrated in IBS-D subtypes and women. In men with the IBS-D subtype, a lower degree of improvement (38%) was found for the active group.

TABLE 4,Summary of overall QOL score improvement for the mltt population showing 30% or more mean difference of benefit of active agent treatment

Quality of life IBS-QOL Domain scores

In female subjects, the overall QOL score (table 4) and each of the eight fields (table 5) demonstrated the therapeutic effect of active IP over placebo. Effects on female subtypes were observed in both IBS-C and IBS-D subtypes. In the male IBS-D subgroup, overall QOL score and four fields of treatment were observed.

TABLE 5,Summary of 8 IBS-QOL domain scores for the mITT population. Changes in mean Domain score of 30% or more that would be beneficial for active agent treatment are shown in bold

Negative number indicates that the improvement in the placebo group is greater than the improvement in the active group

Adequate relief

There were no differences in AR for IBS symptoms between the two study groups at visits 2, 3 and 4 for the entire study population. A strong placebo effect was noted.

We also analyzed the data for each IBS subtype to see if there were any differences in the AR of IBS within the subtype at any study visit. No difference was found between the two study groups in any of the three IBS subtypes. Analysis of male and female subgroups, as well as gender-specific subgroups within each of the 3 IBS subtypes gave similar results.

Consistency of stool

In stool consistency analysis, a positive change ("improvement") indicates an increased BSC score in IBS-C and a decreased BSC score in IBS-D. Table 6 shows the percent change of active compared to placebo, with 30% or more change of active relative to placebo for the subgroups.

TABLE 6,Subgroup in which the mITT population showed an average difference of 30% or more in improvement of fecal consistency

The median stool consistency was improved for both placebo and active treatment groups. Median change for placebo group was typically about one BSC scale point, ranging from 0.88 to 1.50, while active group was about 1.75BSC scale point, ranging from 1.17 to 1.88. Percent change corresponded to the change observed in the earlier proposed endpoint: compared to placebo, men and women gave the greatest response among the active IBS-D subtypes. For men in the IBS-C subtype, the active agent had an advantage over placebo, but this advantage was not seen for both IBS-C group population and IBS-C women. Among the IBS-D subtypes, the difference between treatment groups is greatest in both men and women. The male subgroup as well as the male subgroup for IBS-C showed an improvement in stool consistency compared to placebo.

Frequency of defecation

In the stool frequency analysis, a positive change ("improvement") indicates an increase in frequency in IBS-C and a decrease in frequency in IBS-D. The frequency of bowel movements was improved in both the placebo and active groups, with subjects of the IBS-C subtype having a higher frequency of bowel movements than in the break-in phase in the last week of the study, while subjects of the IBS-D subtype reported a reduction in bowel movement frequency during this period. Table 7 shows that for the improvement of defecation frequency, active agents outperform placebo for IBS subtypes and subgroups of 30% or higher.

TABLE 7,Subgroup of the mITT population that showed an average difference of 30% or more in defecation frequency improvement

Site-specific impact

A particularly interesting subgroup of subjects in the gardengfarov clinical site: of the 16 subjects undergoing treatment by gardenglov, 12 women had severe refractory chronic constipation. In this subgroup, the average daily stool frequency (important end point for IBS-C according to FDA guidelines) for the placebo group increased on average by 0.25 stools/day, while the active subgroup increased on average by 0.75 stools/day, with a 200% increase in active over placebo. It is also noteworthy that for this clinical site, subjects who received randomized active treatment had fewer average bowel movements per week at baseline (0.38 bowel movements/day versus 0.75 bowel movements/day) compared to subjects in the placebo group, which resulted in a greater increase in bowel movements in the active group.

TABLE 8 atSummary of the improvement of daily defecation frequency by visit and treatment groups in patients with constipation of IBS subtype in the mITT population of the Gadengovir site

Safety feature

A total of 7 subjects in the study reported one or more AEs. Of these subjects, 3 were in the placebo group and 4 were in the active group. A total of 14 AEs were reported for 7 subjects; all AEs were mild or moderate in severity, except that one subject in the active group reported severe spasms. Researchers believe that the following four events may be relevant to the study product: dry mouth is associated with increased thirst, increased respiration, nausea and fatigue. One subject in the placebo group reported all of these events; dry mouth and increased thirst continued throughout the study, but resolved the day before the subjects' last study visit. No AE was considered absolutely related to the study product, nor was there a serious AE.

Discussion of the related Art

In recent years, the discovery of effective treatments for IBS has been the goal of drug and probiotic research. Although the population of subjects for many probiotic studies is small, some meta-analyses have been published and suggest that certain probiotic species and strains are more effective than others in alleviating symptoms of IBS (McFarland and Dublin, 2008; Ortiz-Lucas et al, 2013). The study of IBS is complicated by patients often showing psychological characteristics of anxiety and depression (Ford et al, 2014 a); these psychological effects may be exacerbated by the lack of effective treatment and public perception of IBS as a non-severe condition. The impact of race, ethnicity, diet and culture must also be considered when evaluating treatment (Fava et al, 2013; Hughes, 2012).

In this study, Lactobacillus acidophilus was evaluatedLactobacillus caseiAnd Lactobacillus rhamnosusThe effect of the combination of (a) on the symptoms of IBS and the quality of life of the 3 IBS subtypes (IBS-C, IBS-D and IBS-M). As reported in many studies, the placebo product used in this study improved IBS symptoms to a level of therapeutic effect such as that described in FDA guidelines. According to this guideline, a 30% improvement in active product over placebo is defined as a significant increase in therapeutic value for changes in QOL (overall and field) study endpoints as well as changes in abdominal pain, abdominal distension, pain days, satisfaction with bowel habits, and interference with daily living. Strains in the active product compared to placeboEffectively relieving the clinical symptoms of both IBS-C and IBS-D to varying degrees in both men and women. Defecation frequency is improved in both subtypes; stool consistency as measured by BSC was improved in both male and female subjects with IBS-D and in male subjects of the IBS-C subtype. These endpoints are those currently recommended by the U.S. and European regulatory agencies for demonstrating efficacy in drug trials involving IBS-C and IBS-D patients. These results indicate that the benefits on these symptoms reflect a parallel trend of IBS-QOL measures developed specifically for IBS (Drossman et al, 2000).

Female subjects, especially of the IBS-D subtype, respond well to active agent products in terms of stool frequency and stool consistency, and are most responsive in terms of symptoms and improvement of QOL. Men also respond well in terms of stool frequency and stool consistency, but men respond less significantly to the active product than the subgroup of women compared to placebo.

Symptom responses were observed in both IBS-C and IBS-D subtypes, indicating that our 3 lactobacillus strains are effective in relieving symptoms and improving QOL for this indication.

Safety profiles of the products used in this study have been documented in previous clinical trials (beaussoleil et al, 2007; Gao et al, 2010; Sampalis et al, 2010) and quality improvement studies (Maziade et al, 2015). The mechanism of action of the study product has been demonstrated in some intestinal pathologies, but has not been studied in this study (Auciar et al, 2015). Interestingly, the therapeutic benefit observed with our 3 strains of Lactobacillus exceeds that seen in drug studies compared to placebo, whereas drugs are not without significant adverse events (Cremonini et al, 2003; Kellow et al, 2003; Tack et al, 2005). The approved drugs show a poorer safety profile than the probiotic regimen, which shows a favourable safety profile.

Interestingly, few studies have evaluated the effect of probiotics on QOL, and many of those evaluated have not found significant improvements (Halpern et al, 1996; Kellow et al,2003; kim et al, 2003; moayyedi et al, 2010; niv et al, 2005). Some studies have shown improvement in certain areas (Guglielmetti et al, 2011; Kajander et al, 2008;et al, 2014; o' Mahony et al, 2005), but to our knowledge no impact on the "activity disruption" field has been previously recorded. Omaoni (O 'Mahony) et al found that l.salivarius ssp. and b.infarnis had lower IBS-QOL scores for most areas (O' Mahony et al, 2005).

This study provides evidence of consistently observed therapeutic effects in specific IBS subtypes and subgroups for the following different endpoints: frequency and consistency of stool, quality of life, improvement in flatulence severity, number of painful days, and satisfaction with bowel habits. Our findings are consistent with other studies conducted on probiotics and drugs (Somberg, 2012).

In previous studies using this study product, a lower incidence of AEs was observed. This regimen was based on previous clinical studies conducted in canada and the united states, using the optimal dosage of the product. The study product has also been previously evaluated for the prevention of antibiotic-associated diarrhea and clostridium difficile (c.difficile) in adults, confirming that the risk of diarrhea is greatly reduced during outbreaks of clostridium difficile in china (Gao et al, 2010). In the last decade of clinical research involving this study product, there were no Serious Adverse Events (SAEs) associated with this study product in any clinical trial (Beausoleil et al, 2007; Gao et al, 2010; Maziade et al, 2015; Sampalis et al, 2010).

Conclusion

The specific combinations of live bacteria used in this study produced results that varied between gender and subtype. However, it has a significant positive impact on both male and female stool consistency and stool frequency, quality of life, and IBS symptoms without serious adverse events. These findings provide promising treatment options for subjects with IBS.

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Headings are included herein for reference and to aid in locating certain sections. These headings are not intended to limit the scope of the concepts described therein under, and these concepts may have applicability in other sections throughout the entire specification. Thus, the present invention is not intended to be limited to the implementations shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

The singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes one or more of such compounds and reference to "the method" includes reference to equivalent steps and methods known to those of ordinary skill in the art, and modifications or substitutions may be made to the methods described herein.

Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, concentrations, properties, and so forth, used in the specification and claims are to be understood as being modified in all instances by the term "about". Each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. Notwithstanding that the numerical ranges and parameter settings setting forth the broad scope of the embodiments are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the variations in experimentation, testing measurements, statistical analysis, and the like.

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the scope of the present invention and appended claims.