BE1028144B1 - Probiotic composition comprising Lactobacillus, Bifidobacterium and a saffron extract for the treatment or prevention of disorders of the large intestine - Google Patents

Abstract

Disclosed are compositions intended for use in the treatment or prevention of disorders of the large intestine, in which the composition comprises at least one strain of Bifidobacterium, at least one strain of Loctobacillus and at least one extract of saffron.

Description

Probiotic composition comprising LoctobacHlus, Bifidobacterium and saffron extract for the treatment or prevention of disorders of the large intestine Technical area Disorders of the large intestine - in particular irritable bowel syndrome, frequently called IBS - are gastrointestinal disorders common functionalities that affect between 10 and 20% of the population in Europe and the United States.

The pathophysiology of bowel syndrome is not clearly understood.

This condition is multifactorial, affected by environmental, hereditary and psychosocial factors.

Suggested mechanisms include visceral hypersensitivity, gut-brain axis dysfunction, disturbances in the integrity of the epithelial barrier leading to abnormal change in intestinal permeability, impaired gastrointestinal motility, immune activation, abnormal enteroendocrine signaling, as well as dysbiosis in the gut microbiota, see e.g. Lacy et al, Bowel disorders.

Gastroenterology. 2016; 150: 1393-1407. doi: 10.1053 / j.gastro.2016.02.031, or Barbara et al. , The intestinal microenvironment and functional gastrointestinal disorders.

Gastroenterology. 2016; 150: 1305-1318. doi: 10.1053 / j.gastro.2016.02.028. Symptoms vary widely and include bloating, gas, abdominal pain, discomfort, diarrhea, or constipation.

It is suggested that alterations in the composition of the gut microbiota contribute to the generation of symptoms of irritable bowel syndrome.

In some studies, lactobacilli have been reported to be both more numerous and less numerous in patients with irritable bowel syndrome than in healthy controls, see Parkes 2010; Treating irritable bowel syndrome with probiotics: the evidence; Proceedings of the Nutrition Society 69, 187 doi: 10.1017 / S002966511000011X.

However, the presence of bifidobacteria in reduced amounts has been reported in stool samples from patients with irritable bowel syndrome (see e.g. Kerckhos et al.), Which reduces the number of bifidobacteria in the duodenal mucosa and in the microbiota. faeces of patients with irritable bowel syndrome. World J. Gastroenterol. 2009, 15, 2887-2892, or Kassinenet et al. The fecal microbiota of patients with irritable bowel syndrome differs significantly from that of healthy subjects, Gastroenterology 2007, 133, 24-33, and Durban et al, Instability of the fecal microbiota in diarrhea-predominant irritable bowel syndrome. FEMS Microbiol. School. 2013, 86, 581-589. Improvement in symptoms of irritable bowel syndrome has been observed in patients consuming probiotic compositions containing Bifidobacterium. Therefore, probiotic bacteria have been proposed to rebalance the gut microbiota of patients with irritable bowel syndrome.

One study suggests the superiority of Bifidobacterium over Lactobacillus in the treatment of irritable bowel syndrome (see Mahony et al., Lactobacillus and Bifidobacterium in Irritable Bowel Syndrome: symptom responses and relationship to cytokine profiles, gastroenterology 2006; 128: 541-551).

However, it is still not clear which strain combination is most effective, see for example the overview presented in Dale, Probiotics in Large intestine disorder: an up-to-date systematic review, Nutrients 2019, 11, 2048. There is therefore an urgent need to further study improved combinations of probiotic strains for use in the treatment and prevention of irritable bowel syndrome.

Crocus sativus On the other hand, the stigmas of crocus sativus, a plant in the iris family (Iridaceae) commonly known as saffron, have been proposed to treat symptoms of irritable bowel syndrome, see overview provided by Ashktorab 2019, Nutrients 2019, 11, 943; doi: 10.3390 / nu11050943. The components of saffron have been shown to downregulate the expression of several pro-inflammatory cytokines. The effects of crocin and crocetin against oxidative stress include reducing the level of malondialdehyde, improving the levels of glutathione and antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase, as well as reducing lipid peroxidation. Therefore, saffron extracts, mainly due to the carotenoids crocin and crocetin, have a positive effect on inflammatory disorders, especially gastritis and gastrointestinal ulcer.

duodenal, irritable bowel syndrome, inflammatory bowel disease and hepatitis. Saffron is also known for its antidepressant properties. This is why it is suggested that saffron has the ability to treat both irritable bowel syndrome in the gastrointestinal tract as well as mental disorders such as anxiety and depression. Considering the potential association of psychological stressors and depression with many cases of irritable bowel syndrome, a recent study compared the effectiveness of saffron extract and the antidepressant fluoxetine in improving the quality of life of patients. patients with irritable bowel syndrome, Najafabadi et al, Therapeutic effect of saffron versus fluoxetine on Irritable Bowel Syndrome: A double-blind randomized clinical trial; Adv. Integr. Med. 2019, https://doi.org/10.1016/j.aimed.2019.01.001.

Combinations of Lactobacillus, Bifidobacterium and saffron have recently been proposed for the treatment of mental disorders.

For example, FR3004110 from Green Plants Extracts reveals the combination of probiotic bacteria and a crocus sativus extract as a dietary supplement. According to this disclosure, the combination of a crocus sativus extract and at least one probiotic bacterial strain has a synergistic effect and simultaneous action on the digestive system and the central nervous system for overall stress management and balance. emotional.

Downey 2019, À probiotic solution to depression and anxiety, Life Extension Magazine November 2019, reveals the combination of Lactobacillus helveticus RO052 and Bifidobacterium longum RO175 as well as saffron extract for the treatment of depression and anxiety.

However, the combination of a probiotic based on Lactobacillus and Bifidobacterium with a saffron extract has not yet been proposed for the treatment and prevention of disorders of the large intestine, in particular for irritable bowel syndrome.

Problem to be solved by the present invention: There is an urgent need to provide new compositions which are more effective in the treatment and prevention of disorders of the large intestine or of gastrointestinal disorders related thereto.

The present invention demonstrates that the synergistic combination of a probiotic based on Lactobacillus and Bifidobacterium with saffron extract is surprisingly advantageous for the treatment and prevention of irritable bowel syndrome and related gastrointestinal disorders.

Summary of the Invention: A first aspect of the invention is a composition for use in the treatment or prevention of disorders of the large intestine, wherein the composition comprises: a. at least one strain of Bifidobacterium; b. at least one strain of Lactobacillus; and C. at least one extract of saffron. In another aspect of the invention, the large intestine disorder is selected from the group consisting of irritable bowel syndrome, diarrhea, normal transit constipation, slow transit constipation, inflammatory bowel disease, diverticulitis, pouchitis or a combination of these diseases. In another aspect of the invention, the strain of Bifidobacterium is Bifidobacterium animalis subspecies lactis. In another aspect of the invention, the strain of Lactobacillus is Lactobacillus rhamnosus. In another aspect of the invention, the composition is administered at a daily dose of Bifidobacterium of 300 million to 3 billion CFU.

In another aspect of the invention, the composition is administered at a daily dose of Lactobacillus of 300 million to 3 billion CFU.

In another aspect of the invention, the composition is administered at a daily dose of Bifidobacterium of 1 to 2 billion CFUs. In another aspect of the invention, the composition is administered at a daily dose of Lactobacillus of 1 to 2 billion CFU.

In another aspect of the invention, the composition is administered at a daily dose of saffron extract of 20 mg to 80 me.

In another aspect of the invention, the ratio of Lactobacillus to Bifidobacterium is from 1: 2 to 2: 1. In another aspect of the invention, the composition further comprises a probiotic bacterium selected from the group comprising Archaea, Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, Verrucomicrobia, Fusobacteria, Metanobacteria, Spirochaetes, Fibrobacteres, Deferribacteres, Deinococcus, Thermiaus, Cyanobacteres, Deinococcus, Thermiaus, Methanobrevibacterium, Peptostreptococcus, Ruminococcus, Coprococcus, Subdolingranulum, | Dorea, Bulleidia, Anaerofustis, Gemella, Roseburia, Catenibacterium, Dialister, Anaerotruncus, Staphylococcus,… Micrococcus, Propionibacterium, Enterobacteriaceae, Faecalibacterium, Bacteroides, Parabacteroides, Prevotibella, Eubacteriv, Akkermus etyransia combination, Bacillus etyrosia, Eubacterium, Akkermus etyrosia, combination this.

In another aspect of the invention, the composition further comprises additives selected from the group consisting of antioxidants, stabilizers, thickeners, nutrients, fatty acids and a combination thereof.

In another aspect of the invention, the composition is a nutritional composition, a food additive, a medical food product or a drug.

Another aspect of the invention is a method of manufacturing the composition of the invention comprising the steps of mixing the strain of Lactobacillus, the strain of Bifidobacterium and the extract of saffron.

Another aspect of the invention is the use of the composition of the invention for the treatment or prevention of disorders of the large intestine, in particular irritable bowel syndrome. Detailed description of the invention The composition of the present invention comprises at least one strain of Lactobacillus and at least one strain of Bifidobacterium as well as at least one extract of saffron. A wide variety of strains of Lactobacillus and Bifidobacterium may be suitable for the composition of the present invention. In one embodiment, the strains are non-pathogenic. In another, the strains are of human origin. In another, the strains are resistant to intestinal acid. In another fashion, the strains have the ability to adhere to human epithelial cells. In another variant, the strains have anti-inflammatory properties. Lactobacillus In one embodiment, the strain of Lactobacillus is selected from the group comprising, but not limited to, Lactobacillus acidophilus, Lactobacillus delbrueckii, Lactobacillus bulgaricus, Lactobacillus rhamnosus, Lactobacillus helveticus, Lactobacillus or a combination thereof. In one embodiment, the strain of Lactobacillus is Lactobacillus rhamnosus.

In one embodiment, the strain of Lactobacillus is strain n ° LMG S-28148 of Lactobacillus rhamnosus, deposited with the BCCM (Belgian Coordinated Collections of Microorganisms) and the LMG (Laboratorium voor Microbiologie-Bacteriënverzameling) on January 27, 2014 in the framework of the Budapest Treaty. In one embodiment, the composition comprises two or even three different strains of Lactobacillus. In another variation, the composition is administered at a daily dose of Lactobacillus of 300 million CFU to 3 billion CFU, preferably 1 billion CFU to 2 billion CFU and even more preferably 1.25 billion CFU to 1, 75 billion CFU.

Bifidobacterium In one embodiment, the strain of Bifidobacterium is selected from the group comprising, inter alia, Bifidobacterium animalis, Bifidobacterium breve, Bifidobacterium infantis, Bifidobacterium bifidum, Bifidobacterium longum, Bifidobacterium longet, Bifidobidobacterium animalis, Bifidobacterium breve and this. In one embodiment, the strain of Bifidocaterium is the lactis subspecies of Bifidocaterium animalis.

In another variant, the strain of Bifidobacterium is Bifidobacterium animalis ssp. lactis. A particularly suitable strain of Bifidobacterium is described in LMG P-28149 BCCM (Belgian Coordinated Collections of Micro-organisms) and LMG (Laboratorium voor Microbiologie - Bacteriënverzameling) filed on January 27, 2014, as described in WO2015121458A2.

In another embodiment, the composition comprises two or even three different strains of Bifidobacterium.

In another variation, the composition is administered at a daily dose of Bifidobacterium of 300 million CFU to 3 billion CFU, preferably 1 billion CFU to 2 billion CFU and still more preferably 1.25 billion CFU to 1, 75 billion CFU.

Saffron extract A wide range of extracts of crocus sativus are suitable for the composition of the present invention. Crocus sativus is a perennial plant belonging to the Iridaceae. Saffron or saffron is obtained by collecting and drying its stigmas. However, the stigmas of Crocus sativus can also be cultivated in vitro. Other parts of Crocus sativus may also be suitable for the composition of the present invention. In one embodiment, the saffron extract is liquid and obtained by drying, grinding, mixing with water and alcohol, filtration and concentration in vacuo.

In one embodiment, the saffron extract is a dried powder extract.

Ratio of Lactobacillus, Bifidobacterium and saffron extract The ratio between Lactobacillus and Bifidobacterium in the composition of the invention can vary considerably.

In one embodiment, the ratio of Lactobacillus to Bifidobacterium is 1: 2 to 2: 1, preferably 1: 1.7 to 1.7: 1, and more preferably 1: 1.5 to 1.5: 1, preferably from 1: 1.3 to 1.3: 1 and even more preferably from 1: 1.1 to 1.1: 1. The composition of the invention can comprise a saffron extract in an amount between 20 mg and 80 mg, preferably between 30 and 70, and even more preferably between 40 and 60 mg and even more preferably 30 mg.

Dosage regimen The daily dose should be administered once a day or several times a day, for example one, two, three or four or more times a day.

Preferably, the daily dose of the present invention is administered once a day.

Other probiotics Other probiotics, for example, a probiotic selected from the group consisting of Archaea, Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, Verrucomicrobia, Fusobacteria, Metanobacteria, Spirochaetes, Fibrobacter, Deferribacteres, Deinococcus, Thermus, Cyanoboccibacterium, Cophanoccus, Cyanoboccibacterium, Subdolingranulum, Dorea, Bulleidia, Anaerofustis, Gemella, Roseburia, Catenibacterium, Dialister, Anaerotruncus, Staphylococcus, Micrococcus, Propionibacterium, Enterobacteriaceae, Faecalibacterium, Bacteroides, Parabacteroides, Previbillella or akermidium, butrio and Eubyridium, Previbillus, and akermidia, Eubacteroides, Previbillella or akermidia, Eubyracterium, Bacivotella or those of Eubyracterium, Previbillus or Eubyridium this.

Prebiotics

In another case, the composition can include a prebiotic component. In another variant, the prebiotic component is chosen from the group comprising oligosaccharides, fructooligosaccharides, galactooligosaccharides, xylooligosaccharides, inulin or its derivatives, lactulose or its derivatives, mannan oligosaccharides or a combination of these. Yeasts In another variation, the composition can include a yeast component. In another variation, the yeast component is selected from the group consisting of Saccharomyces, Candida, Pichia, Debaryomyces, Torulopsis, Aspergillus, Rhizopus, Mucor and Penicillium or combinations or fragments thereof. Other Ingredients In another variant, the composition of the present invention further comprises an additive selected from the group comprising antioxidants, stabilizers, thickeners, nutrients, fatty acids and mixtures thereof. Examples of antioxidants are flavonoids, carotenoids, tocotrienol, tocopherol or other terpenes. In another variant, the composition of the invention further comprises monosaccharides, polysaccharides, amino acids, peptides, proteins, vitamins, halogen salts, alkali metals, alkaline earth metals, glycerol, zinc acetates, zinc chlorides, zinc lactates, ascorbic acid, citric acid, vegetable oils, milk fat or a combination of these.

Form The composition of the present invention can be administered in any suitable form, for example in the form of liquid, powder, capsules, capsules or granules.

In one embodiment, the composition can be microencapsulated. Encapsulation can increase the viability of probiotic bacteria. In another variation, the microencapsulated composition can be coated. The coating can help further increase the viability of probiotic bacteria.

In another variant, the coating is selected from the group comprising ethylcellulose, hydroxypropylcellulose, carboxymethylcellulose and polymers such as Eudragit® or a combination thereof. In another variant, the composition of the present invention may comprise a second coating, for example chosen from the group comprising alginate, chitosan, pectin, pullulan, gelatin, agar gel, cellulose, hemicellulose, ethyl cellulose, carboxymethyl cellulose, or combinations thereof.

The composition of the present invention can be administered in the form of a nutritional composition, a food additive, a medical food product or a drug.

Large Intestine Disorders and Irritable Bowel Syndrome The composition of the invention may be useful in the treatment or prevention of large intestine disorders, in particular irritable bowel syndrome.

In one embodiment, the large intestine disorder is selected from the group consisting of irritable bowel syndrome, diarrhea, normal transit constipation, slow transit constipation, inflammatory bowel disease, diverticulitis, pouchitis or a combination of these diseases.

The composition may further be useful in the treatment of gastrointestinal disorders selected from the group consisting of gastroenteritis, mucosal inflammation, gastrointestinal immune activation, bloating, gas, abdominal pain or a combination. of these troubles.

In one embodiment, the composition of the present invention is also useful in the treatment of bacterial overgrowth of the small intestine. This excessive presence of bacteria in the small intestine can cause chronic diarrhea and malabsorption. In post-infectious irritable bowel syndrome, symptoms develop after infection. Bacterial overgrowth in the small intestine often causes symptoms similar to those of irritable bowel syndrome, particularly bloating associated with food consumption. Patients with irritable bowel syndrome have an abnormal interleukin-to-interleukin-12 ratio. Interleukin-10 is known to be an anti-inflammatory cytokine. Interleukin-12 is known as a pro-inflammatory cytokine. In patients with irritable bowel syndrome, a higher ratio between pro-inflammatory IL-12 and anti-inflammatory IL-10 was observed.

In addition, patients with irritable bowel syndrome exhibit increased permeability of the intestinal wall. Effect The composition of the present invention uses synergistic mechanisms to target both the cause and the symptoms associated with disorders of the large intestine.

In particular, the composition of the present invention uses the effects of saffron by its antidepressant and anti-anxiolytic activity, its anti-inflammatory and anti-oxidant properties of low grade and by its influence on the composition of the microbiome.

In addition, the composition of the present invention utilizes the activity of selected probiotics on disorders of the large intestine. These effects include specific immunomodulation and interaction with cells of the intestinal wall. Inflammatory and anti-inflammatory cytokines are positively or negatively influenced, which leads to a normalization of the ratio between interleukin 12 and interleukin 10. This helps to control the inflammation present in disorders of the large intestine, especially in patients with the condition. irritable bowel syndrome. Finally, intestinal permeability is positively influenced.

The inventors have discovered that the combination of Lactobacillus and Bifidobacterium is surprisingly more effective in the treatment and prevention of disorders of the large intestine than the combination of Lactobacillus and Bifidobacterium without saffron. In particular, the combination of Lactobacillus, Bifidobacterium and a saffron extract positively reduces intestinal permeability, decreases [intestinal inflammation and normalizes the Interleukin 12 to 10 ratio. This improvement is due to the synergistic combination of the following mechanisms o Combination of psychotic activity of saffron extract with probiotics o Increased anti-inflammatory activity of saffron extract and probiotics o Increase the immune component by transforming IL12 / IL10 in healthy conditions o Modify the microbiome to obtain a more diverse composition while increasing both Lactobacilli and Bifidobacteria

Claims (15)

CLAIMS BE2020 / 5581 1. A composition for use in the treatment or prevention of disorders of the large intestine, wherein the composition comprises: a. at least one strain of Lactobacillus; and B. at least one saffron extract. 2. The composition of claim 1, wherein the large intestine disorder is selected from the group comprising irritable bowel syndrome, diarrhea, normal transit constipation, slow transit constipation, inflammatory bowel disease, diverticulitis, pouchitis, or a combination of these. 3. The composition of one of the preceding claims, wherein the strain of Bifidobacterium is Bifidobacaterium animalis subspecies lactis. 4. The composition of one of the preceding claims, wherein the strain of Lactobacillus is Lactobacillus rhamnosus. 5. The composition of one of the preceding claims, wherein the composition is administered with a daily dose of Bifidobacterium of 300 million CFU to 3 billion CFU. 6. The probiotic composition of one of the preceding claims, wherein the composition is administered at a daily dose of Lactobacillus of 300 million CFU to 3 billion CFU. 7. The composition of one of the preceding claims, wherein the composition is administered at a daily dose of Bifidobacterium of 1 to 2 billion CFU. 8. The composition of one of the preceding claims, wherein the composition is administered at a daily dose of Lactobacillus of 1 to 2 billion CFU. 9. The composition of one of the preceding claims, wherein the composition is administered at a daily dose of saffron extract of 20 mg to 80 mg. 10. The composition of one of the preceding claims, wherein the ratio between Lactobacillus and Bifidobacterium is from 1: 2 to 2: 1. 11.The composition of one of the preceding claims, wherein the composition further comprises a probiotic bacterium selected from the group comprising Archaea, Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, Verrucomicrobia, Fusobacteria, Metanobacteria, Spirochaetes, Fibrobacteres, Deferribacteres, Deinococcus , Thermus, Cyanobacteria, Methanobrevibacterium, Peptostreptococcus, Ruminococcus, Coprococcus, Subdolingranulum, Dorea, Bulleidia, Anaerofustis, Gemella, Roseburia, Catenibacterium, Dialister, Anaerotruncus, Staphylococcus, Coprococcus, Subdolingranulum, Dorea, Bulleidia, Anaerofustis, Gemella, Roseburia, Catenibacterium, Dialister, Anaerotruncus, Staphylococcus, Micrococceaacteria, EucotacteriaBiacacteriaBiacacteriaBiacacteria, EnteroacteriaBacteriaBiacacteriaBiacacteriaBiacacteriaBiacacteriaBacteriaBacteriaBacteriaBiacacteriaBacteriaBacteriaBacteriaBacteriaBacteriaBiacacteriaBacteriaBacteriaBacteria , Bacillus, Butyrivibrio, and Clostridium, or a combination thereof. 12. The composition of one of the preceding claims, wherein the composition further comprises additives selected from the group consisting of antioxidants, stabilizers, thickeners, nutrients, fatty acids and a combination thereof. 13. The composition of any of the preceding claims, wherein the composition is a nutritional composition, a food additive, a medical food product or a drug. 14. A method of manufacturing the composition according to claims 1 to 13 comprising the steps of mixing the strain of Lactobacillus, the strain of Bifidobacterium and the extract of saffron. 15. Use of a composition according to claims 1 to 13 or manufactured according to the manufacturing method of claim 14 for the treatment or prevention of disorders of the large intestine.