WO2008069102A1 - Agent prophylactique/thérapeutique pour maladie intestinale inflammatoire - Google Patents

Agent prophylactique/thérapeutique pour maladie intestinale inflammatoire Download PDF

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Publication number
WO2008069102A1
WO2008069102A1 PCT/JP2007/073086 JP2007073086W WO2008069102A1 WO 2008069102 A1 WO2008069102 A1 WO 2008069102A1 JP 2007073086 W JP2007073086 W JP 2007073086W WO 2008069102 A1 WO2008069102 A1 WO 2008069102A1
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Prior art keywords
genus bacillus
culture
inflammatory bowel
bacillus
bacterium belonging
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PCT/JP2007/073086
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English (en)
Japanese (ja)
Inventor
Kazuhito Rokutan
Kenji Kusumoto
Hiromi Suzuki
Shigeru Fujiwara
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Calpis Co., Ltd.
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Priority to JP2008548248A priority Critical patent/JP5199884B2/ja
Publication of WO2008069102A1 publication Critical patent/WO2008069102A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/742—Spore-forming bacteria, e.g. Bacillus coagulans, Bacillus subtilis, clostridium or Lactobacillus sporogenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a novel prophylactic and therapeutic agent for inflammatory bowel disease and / or irritable bowel syndrome, in particular, suppression of intestinal epithelial cell-derived reactive oxygen production and intestinal epithelial cell-derived IL by TNF-a stimulation of intestinal epithelial cells. -8 production inhibitor is provided.
  • the prophylactic and therapeutic agent for inflammatory bowel disease and / or irritable bowel syndrome of the present invention can be given by the oral route, such as inflammatory bowel diseases such as ulcerative colitis and Crohn's disease in the human digestive tract!
  • Typical diseases of inflammatory bowel disease include ulcerative colitis (UC) and Crohn's disease (CD).
  • IBD inflammatory bowel disease
  • UC ulcerative colitis
  • CD Crohn's disease
  • UC ulcerative colitis
  • CD Crohn's disease
  • Symptoms have been reported such as growth retardation, straight bowel, iron deficiency, anemia, exhaustion, malaise, fever and weight loss in schoolchildhood.
  • the etiology is unknown at present, and it is an intractable disease that repeats relapse and remission.
  • tissue damage in these diseases resulted in the breakdown of mucosal immune tolerance and activation of immunocompetent cells against antigens present in various intestinal lumens, including enteric bacteria. It has been suggested to be triggered. In addition, overproduction of inflammatory site force-in derived from macrophages has been observed. On the other hand, no clinically established effective treatment is currently available, and nutritional therapy, sulfa drugs, steroids, use of 5-ASA derivatives, pharmacotherapy, immunosuppressants, etc. Has been studied.
  • IBS irritable bowel syndrome
  • QOL quality of life
  • therapies are treated according to symptoms such as anticholinergic agents, laxatives, intestinal agents, mucosal palsy agents, autonomic nerve regulators, anxiolytics, antidepressants, hypnotics, antipsychotics, etc. There are gradual drug therapies. Side effects of these drugs are a problem.
  • TNF-a tumor necrosis factor
  • IL-1 interleukins IL-1
  • IL-6 interleukins IL-6
  • IL-8 interferon ⁇
  • Inhibitors of inflammatory site force-in such as TNF-a and IL-8 have the effect of regulating the immune system. It is thought to improve symptoms.
  • Patent Document 1 JP 2003-95963 A
  • the present inventors have reported that Bacillus subtilis bacteria, particularly C-3102 cells and / or their fermentation products, inhibit intestinal epithelial cells! And the present invention was completed by finding that it has an IL-8 production inhibitory action.
  • the present invention relates to an inhibitor of production of active oxygen from intestinal epithelial cells and IL-8 from intestinal epithelial cells, comprising as an active ingredient a fermentation product, culture supernatant, or culture of a bacterium belonging to the genus Bacillus.
  • a production inhibitor is provided.
  • the present invention relates to a prophylactic and therapeutic agent for inflammatory bowel disease and / or irritable bowel syndrome, comprising a fermentation product, culture supernatant, or culture of a bacterium belonging to the genus Bacillus as an active ingredient.
  • the bacterium belonging to the genus Bacillus is Bacillus subtilis, more preferably Bacillus subtilis C 3102 (FERM BP-1096).
  • the inflammatory bowel disease is ulcerative colitis.
  • the “culture” refers to a mixture containing bacterial cells, a medium, and a fermentation product obtained by culturing a bacterium belonging to the genus Bacillus in an appropriate medium.
  • “Fermentation product” refers to a portion of the culture other than the cells, and includes a preparation obtained by removing cells from the culture.
  • “fermented products” include those obtained by extracting fermented product containing substances other than cells from the culture.
  • a “fermentation product” when a liquid medium is used is referred to as “culture supernatant”.
  • “Fermentation product” and “culture supernatant” can be obtained by means usually used in the technical field for removing cells from the culture, for example, filtration or centrifugation. It should be noted that fermentation products and culture supernatants do not mean that cells or fragments thereof do not exist at all when obtained by an operation such as centrifugation.
  • FIG. 1 shows the effect of pretreatment with viable C-3102 on the enhancement of 0-production by stimulation with TNF- ⁇ in a human colon cancer-derived cell line.
  • FIG. 2 shows the effect of pretreatment of C-3102 viable, dead, and culture supernatants on the enhancement of 0 2 — production by TNF- ⁇ stimulation in a human colon cancer-derived cell line.
  • FIG. 3 shows the effect of pretreatment of the C-3102 culture supernatant on the enhancement of 0-production by TNF- ⁇ stimulation in a human colon cancer-derived cell line.
  • FIG. 4 shows the effects of viable, dead, and culture supernatants of C-3102 on TNF-stimulated IL-8 mRNA expression in a human colon cancer-derived cell line.
  • FIG. 5 shows the results of examining the effect of C-3102 culture supernatant on TNF- ⁇ .
  • FIG. 6 shows changes in body weight of DSS-induced ulcerative colitis model rats fed with a diet supplemented with C-3102 strain soybean culture.
  • FIG. 7 shows the incidence of symptoms such as bloody stool and melena in DSS-induced ulcerative colitis model rats fed a diet supplemented with a C-3102 strain soybean culture.
  • FIG. 8 shows the expression rate of IL-8 in plasma of a DSS-induced ulcerative colitis model fed with a diet supplemented with a C-3102 strain soybean culture.
  • FIG. 9 shows the change in body weight of DSS-induced ulcerative colitis model rats fed with a diet supplemented with C-3102 strain soybean culture.
  • FIG. 10-1 shows the incidence of symptoms such as bloody stool and melena in DSS-induced ulcerative colitis model rats fed a diet supplemented with C-3102 strain soybean culture.
  • Fig. 10-2 shows the incidence of symptoms such as bloody stool and melena in DSS-induced ulcerative colitis model rats fed a diet supplemented with C-3102 strain soybean culture.
  • Bacillus spp. (Including Bacillus subtilis) are old and are deeply involved in human diet, and there is much information on their functionality, but they are effective in preventing and treating inflammatory bowel disease That hasn't been reported yet!
  • This reagent as well as DSS, is used in the ulcerative colitis test system! (Charles O. Elson, et al., 1995, Gastroenterology 109: 1344-1367) and the Bacillus according to the present invention. Bacterial cultures belonging to the genus are considered to have a therapeutic / preventive effect on irritable bowel syndrome.
  • Bacillus subtilis C-3102 has a preventive or therapeutic effect on inflammatory bowel disease and irritable bowel syndrome.
  • the culture supernatant of C-3 102 exhibits an inhibitory action on reactive oxygen and IL-8 production caused by TNF-a stimulation on human colonic epithelial cells.
  • IL-8 mRNA expression by TNF- ⁇ stimulation was suppressed, Anti-inflammatory effect was observed.
  • the preventive and therapeutic agent for inflammatory bowel disease and / or irritable bowel syndrome of the present invention comprises a bacterial culture belonging to the genus Bacillus, preferably a culture of Bacillus subtilis as an active ingredient. It is characterized by including.
  • the bacteriological properties of Bacillus subtilis are described in, for example, Virgie's' Manual 'Ob' Batterology 1 Vol. 11 (1986), and specifically have the following characteristics.
  • Bacillus subtilis used in the preventive and therapeutic agent for inflammatory bowel disease and / or irritable bowel syndrome of the present invention include, for example, Bacillus subtilis C-3102 strain (Biotechnology Industrial Technology Research Institute deposit number FERM BP). — 1096, deposit date 25 December 1985).
  • Bacillus subtilis can be obtained, for example, by the method described in JP-A-63-209580.
  • the medium can be cultured using a liquid medium or a solid medium containing a carbon source, a nitrogen source, an inorganic substance and the like that are usually used for microbial culture.
  • a carbon source any carbon source that can be assimilated by Bacillus subtilis should be used, for example, glucose, fructose, sucrose, starch, molasses, etc.
  • the nitrogen source for example, peptone, casein hydrolyzate, meat The ability to list extracts, ammonium sulfate, etc.
  • culture may be performed using natural product-derived substances such as soybean oil cake.
  • culture conditions aerobic conditions are preferred.
  • aeration and agitation liquid culture with a jar mentor, shelf-type solid culture, and automatic fermenter culture temperature is 20-50 ° C.
  • the culture time of 30 to 45 ° C. is preferably 12 hours to 7 days, and the initial pH of culture is pH 5 to 9, particularly preferably pH 6 to 8.
  • the culture thus obtained may be used as it is, or the culture may be concentrated and used.
  • the fermentation cells or the culture supernatant may be prepared by separating the cells from the culture by filtration, centrifugation, extraction or the like.
  • excipients or the like may be added to these cultures, fermentation products, or culture supernatants, and used as preparations such as dry powders, granules, and tablets.
  • Bacillus subtilis is cultivated and cultivated using a natural product-derived substance suitable for edible use such as soybean oil cake, boiled soybean, boiled soybeans, cooked rice, barley rice, wheat bran, boiled corn, and other cereals. It is added to food as it is without separating the cells from the food.
  • the preventive and therapeutic agent for inflammatory bowel disease and / or irritable bowel syndrome of the present invention is used in foods and drinks as food additives that may be administered in the form of liquids, powders, granules, tablets and the like. May be taken in combination.
  • Examples of the food and drink include beverages, confectionery tablets, pastes, breads, processed fish products, and dairy products.
  • the preventive and therapeutic agents for inflammatory bowel disease and / or irritable bowel syndrome of the present invention can be added to these various food materials to provide health drinks, health foods or functional foods.
  • Example 1 Verification of the effect of Bacillus subtilis C-3102 strain on human colonic epithelial cells
  • Bacillus subtilis C 3102 strain (Deposit number FERM BP-1096, Deposit date: December 25, 1985) was used as an example of bacteria belonging to the genus Bacillus.
  • the Bacillus subtilis C-3102 soy culture has the effects of improving the gut microbiota, increasing body weight, protecting against infection, strengthening eggshell, improving meat quality, improving stool odor, etc. (Exclusion 4-24022).
  • the health effects of this strain are known to include bowel regulation and reduction of intestinal spoilage products. (Journal of Enterobacteriaceae Society Vol. 18, No. 2, 93-99 (2004)).
  • Bacillus subtilis C 3102 is characterized in that a fragment of about 700 bps is amplified when PCR reaction is carried out using PCR primers of the following sequence 1 and sequence 2. In other Bacillus subtilis, amplification does not occur with this PCR primer.
  • the approximately 700 bps fragment grown in Bacillus subtilis C-3102 has the characteristic of not having homology with the amylase sequence and is clearly distinguished from other Bacillus subtilis. No. 1) No. 2)
  • Bacillus subtilis C-3102 strain has the following properties:
  • the cell used was a T84 cell line derived from human colon cancer. Culture is performed using DMEM / HAM-F12 (l: 1) mixed medium (DF) supplemented with 5% fetal calf serum (FCS), 100 g / ml streptomycin, and 100 U / ml penicillin. T84 cells were seeded in 24-well culture plates or 35 mm culture dishes and cultured for 2 days at 37 ° C in a 5% CO 2 atmosphere. Later cells were used.
  • TS medium Tripticase Soy Broth: BBL ⁇ t + 2% agar
  • TS broth medium excluding the above-mentioned medium agar
  • Inoculated and incubated at 37 ° C—spider culture was used as a Balta starter.
  • 3 ml Baltastater was added to 300 ml TS broth, and the cells were collected by centrifugation (7000 rpm, 20 min) after 37 ° C-shaking culture. The collected pellet was washed with sterile water, and the pellet obtained by centrifugation again was frozen overnight and then lyophilized.
  • the bacterial powder thus obtained was dissolved in (1) viable C_3102 (L): bacterial powder by adding serum-free DF and stirring for 15 minutes with a vortex mixer.
  • T84 cells cultured for 2 days in a 37 ° C, 5% CO 2 atmosphere were washed 5 times with PBS and replaced with serum-free DF.
  • C-3102 live bacteria (L) or dead bacteria (HK) were added to a concentration of 0-2 cfo per T84 cell.
  • CM culture supernatant
  • a supernatant obtained by culturing viable C-3102 for 24 hours was added in an amount corresponding to a concentration of 0 to 2 cfo ell.
  • Human recombinant TNF- ⁇ (R & D systems) was added at a concentration of 20 ng / ml to T84 cells cultured in a 24-well culture plate or 35 mm culture dish.
  • the cells were cultured in a 24-well culture plate, pretreated for 2 hours with viable bacteria (L), dead bacteria (HK) or culture supernatant (CM) of C-3102, and stimulated with TNF- ⁇ . After 24 hours, the cells were washed 5 times with HBSS, cytochrome c (lmg / ml) + PMA solution was added, and the cells were incubated at 37 ° C. in a 5% CO 2 atmosphere for 1 hour. The absorbance (550 nm) of the reaction solution was measured, and the remaining cells were washed 3 times with HBSS, and the protein was quantified using the modified Lowry method. The amount of 0— produced per well was calculated and expressed as nmol / mg-protein / h. [0032] (F) RT-PCR
  • RNA was extracted using ISOGEN (Nibonbon Gene, Toyama). The obtained RNA (1 g) was reverse-transcribed using TA KARA RT-PCR kit (Takara, Tokyo).
  • the obtained reverse transcription product was prepared as follows: sense primer 5, _TTGGCAGCCTTCCTGATTT CT-3, (SEQ ID NO: 3); antisense primer, 5, TTTCCTTGGGGTCCAGACAG A-3 '(SEQ ID NO: 4); PCR was performed using seraldehyde triphosphate dehydrogenase (GAPDH) sense primer, 5, TCATGACCACAGTCCATGCCATCACT-3, (SEQ ID NO: 5), and antisense primer 5- GCCTGCTTCACCACCTTCTTGATGT-3 '(SEQ ID NO: 6).
  • sense primer 5 _TTGGCAGCCTTCCTGATTT CT-3
  • antisense primer 5, TTTCCTTGGGGTCCAGACAG A-3 '(SEQ ID NO: 4
  • PCR was performed using seraldehyde triphosphate dehydrogenase (GAPDH) sense primer, 5, TCATGACCACAGTCCATGCCATCACT-3, (SEQ ID NO: 5), and antisense primer 5- GCC
  • T84 cells cultured in a 24-well culture plate were pretreated with 0-2 cfo ell viable bacteria (L) for 2 hours, and then 20 ng / ml TNF- ⁇ was added.
  • 0-production from T84 cells was not affected by pretreatment with virulent bacteria (L) enhanced by TNF- ⁇ stimulation.
  • L virulent bacteria
  • 2cfo ell cells were damaged, and it was considered that 0-production was enhanced as the number of cells decreased (Fig. 1).
  • T84 cells cultured in a 24-well culture dish were pretreated for 2 hours with 0.5 liters of viable bacteria (L), dead bacteria (HK) and culture supernatant (CM), and then 20 ng / ml TNF- ⁇ was added. Added. 0— was enhanced by TNF-a stimulation (M) compared to no treatment (as compared to). As a result of examining the effects of 2 hours of pretreatment, the viable bacteria had no effect on the production of 0—.
  • the killed bacteria were unable to measure 0- because the cells were severely damaged and the cells were peeled off, but the culture supernatant (CM) significantly suppressed the production of 0- by stimulation with TNF-a. Then! /, ( Figure 2).
  • concentration at which the inhibitory effect by the culture supernatant (CM) was observed was examined below.
  • 24-well T84 cells cultured in a Lucy dish were pretreated with 0.05-lcfoell culture supernatant (CM) for 2 hours, and then 20 ng / ml TNF- ⁇ was added.
  • CM 0.05-lcfoell culture supernatant
  • a significant 0-production inhibitory effect was observed from the concentration of 0.05cib ell of culture supernatant (Fig. 3).
  • CM culture supernatant
  • TNF-a 20 ng / ml TNF-a was added to T84 cells cultured in a 35 mm culture dish, and IL-8 mRNA expression was analyzed over time using the RT-PCR method.
  • T84 cells were subjected to TNF- ⁇ stimulation, IL-8 mRNA was expressed from 1 hour and peaked at 3 hours.
  • IL-8 mRNA was analyzed. IL-8 mRNA expression was not observed in cells that had been pretreated for 2 hours with live bacteria (L) or culture supernatant (CM) alone, and IL-8 mRNA expression in dead bacteria (HK) It was observed. This was thought to be due to the absence of production of anti-inflammatory components in killed bacteria (HK). Furthermore, the same experiment was repeated, and those pretreated with culture supernatant (CM) suppressed IL-8 mRNA expression, strongly suggesting that the product has an anti-inflammatory effect. From the above results, it was clarified that the culture supernatant (CM) acts to suppress the expression of IL-8 mRNA by TNF-a stimulation.
  • CM culture supernatant
  • CM culture supernatant
  • a rat fed with dextran sulfate sodium was used as an ulcerative colitis model animal.
  • IGS 5-week-old male Sp rague Dawl ey
  • soybean oil residue granulated product which is the base of the fungus powder, was pulverized with a pulverizer and mixed with CE-2 powdered feed in the same amount as in the test group.
  • Dextrane sodium sulfate (molecular weight 5000, sulfur content 15.0-20.0%, Wako Pure Chemical Industries, Ltd.) was administered as drinking water (3% w / v) during the control and test diets.
  • CINC_1 IL-8 Panafarm Laboratories
  • body weight, fecal properties, and plasma IL-8 were measured, and the animals were sacrificed and dissected the day after the last administration of the test meal.
  • Spleen weight, colon length and cecal weight were measured.
  • Fig. 6 shows changes in body weight
  • Fig. 7 shows stool properties
  • Fig. 8 shows IL-8 in plasma.
  • Table 1 shows the anatomical data.
  • the star in Fig. 7 is 0.01 for the test food group compared to the number of days administered in the control group (bonferrous adjusted% 2 test). Shows significant difference.
  • ⁇ indicates a significant difference in the test food group with a p value of 0.05 (bon ferro two-adjusted 2 test) with respect to the number of days in the control group.
  • Example 2 since the anti-inflammatory effect was observed in the C-3102 strain soybean culture, it was examined whether the effective component was present in the bacterial cells, the fermentation product, or the culture supernatant component. In addition, by heating the water extract obtained by mixing the C-31 02 soybean culture with water and centrifuging it, the components with protease activity are deactivated, which affects the anti-inflammatory effect. I investigated whether or not.
  • the animals used and the test method are the same as in Example 2. There are 4 rats per group, and the test diet is CE-2 powder feed.

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Abstract

L'invention concerne un agent permettant d'inhiber la production d'oxygène actif d'une cellule d'épithélium intestinal, un agent permettant d'inhiber la production d'IL-8 d'une cellule d'épithélium intestinal, et un agent prophylactique et thérapeutique destiné à une maladie intestinale inflammatoire et/ou au syndrome du côlon irritable, chacun d'eux comprenant un produit de fermentation, un supernageant de culture et/ou une culture de bactérie appartenant au genre Bacillus comme principe actif. Cette bactérie appartenant au genre Bacillus est de préférence Bacillus subtilis, et mieux, Bacillus subtilis C-3102 (FERM BP-1096). Cet agent permettant la production d'oxygène actif d'une cellule d'épithélium intestinal, cet agent permettant d'inhiber la production de IL-8 d'une cellule d'épithélium intestinal, et cet agent prophylactique thérapeutique destiné à une maladie intestinale inflammatoire et/ou au syndrome du côlon irritable peuvent être administrés par voie orale et conviennent pour le traitement et la prévention des maladies comprenant la colite ulcéreuse, la maladie de Crohn et le syndrome du côlon irritable.
PCT/JP2007/073086 2006-12-06 2007-11-29 Agent prophylactique/thérapeutique pour maladie intestinale inflammatoire WO2008069102A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
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JP2013147469A (ja) * 2012-01-20 2013-08-01 Calpis Co Ltd 腸内酪酸産生菌増加剤
CN105358166A (zh) * 2013-05-17 2016-02-24 可尔必思株式会社 用于反刍动物的乳腺炎的预防剂或治疗剂
KR20220092737A (ko) * 2020-12-24 2022-07-04 에이앤펩주식회사 검은콩 발효 여과물 유래 고 기능성 항염 성분의 제조 방법 및 이를 활용한 화장료 조성물

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JP2013147469A (ja) * 2012-01-20 2013-08-01 Calpis Co Ltd 腸内酪酸産生菌増加剤
CN105358166A (zh) * 2013-05-17 2016-02-24 可尔必思株式会社 用于反刍动物的乳腺炎的预防剂或治疗剂
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KR20220092737A (ko) * 2020-12-24 2022-07-04 에이앤펩주식회사 검은콩 발효 여과물 유래 고 기능성 항염 성분의 제조 방법 및 이를 활용한 화장료 조성물
KR102488533B1 (ko) 2020-12-24 2023-01-16 에이앤펩주식회사 검은콩 발효 여과물 유래 고 기능성 항염 성분의 제조 방법 및 이를 활용한 화장료 조성물

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