JP2003146888A - Preventive and therapeutic agent of inflammatory intestinal disease - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a preventive and therapeutic agent for inflammatory intestinal diseases containing a safe material as an effective ingredient. SOLUTION: Fucoidan or an extract of sea weeds such as Nemacystus decipiens and the like containing fucoidan is used as an effective ingredient of the inflammatory intestinal diseases.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a safe prophylactic / therapeutic agent for inflammatory bowel disease.

[0002]

2. Description of the Related Art Inflammatory bowel disease (IBD) such as ulcerative colitis and Crohn's disease is a digestive tract disease whose cause has not been clarified yet.
Currently, there is an urgent need to establish various treatment / prevention methods.
Inflammatory bowel disease is characterized by the repeated recovery and recurrence of enteritis lesions over a long period of time, and at present, the only treatment is a long-term drug administration method.

On the other hand, according to our research to date, STAT (Signal Transducing) was observed in intestinal mucosal epithelial cells in the lesion site in both human IBD and animal IBD models.
er and Activator of Transcripution) -3 phosphorylation response has been found to be enhanced. Interleukin (IL) -6, leukemia growth inhibitory factor (LIF), oncostatin M (OSM) and the like are known as molecules involved in phosphorylation of STAT-3 molecule.

It has also been clarified that IL-6 production in intestinal epithelial cells is enhanced in IBD model animals and human IBD. Therefore, the STAT-3 phosphorylation of intestinal epithelial cells observed in IBD model animals and human IBD is likely due to IL-6 produced in intestinal epithelial cells with inflammation.

IL-6 is a soluble IL secreted by intestinal epithelial cells, monocytes and macrophages during an inflammatory reaction.
It forms a complex with the -6 receptor (IL-6R). The gp130 molecule of the membrane glycoprotein, which is a signal transduction chain of IL-6 receptor expressed in almost all cells including non-lymphoid cells, associates with complexed IL-6 / IL-6R and Signal to.

Therefore, complexed IL-6 / IL-6R
Binds to the gp130 molecule and thus transmits a signal to a cell line that does not express IL-6R, and induces an inflammatory response. From the above, control of the IL-6 / STAT-3 phosphorylation response system is currently drawing attention as a method for suppressing various inflammatory diseases.

[0007]

In inflammatory bowel disease, side effects have become a problem in the conventional treatment by a long-term drug administration method. Therefore, it is considered that the development of a disease state suppressing method using a safe food with few side effects is very useful for the treatment of inflammatory bowel disease.

Further, as described above, the regulation of the STAT-3 phosphorylation response system, which is also enhanced in lesioned intestinal epithelial cells of inflammatory bowel disease, can be expected to suppress inflammatory lesions of inflammatory bowel disease. As a method of controlling this STAT-3 phosphorylation response system, an inhibitory effect on IL-6 production is considered.

Therefore, if a prophylactic / therapeutic agent containing a substance that has an IL-6 production inhibitory effect and is safe at the same time can be obtained, inflammatory bowel disease can be effectively and safely prevented or treated. It will be possible.

In view of the above problems, an object of the present invention is to provide a prophylactic / therapeutic agent for inflammatory bowel disease containing a safe substance as an active ingredient.

[0011]

In order to achieve the above object, the preventive / therapeutic agent for inflammatory bowel disease according to the invention of claim 1 contains fucoidan as an active ingredient.

Further, the preventive / therapeutic agent for inflammatory bowel disease according to the invention of claim 2 is the same as the preventive / therapeutic agent for inflammatory bowel disease according to claim 1, which comprises a fucoidan-containing seaweed extract as an active ingredient. Is.

Furthermore, the preventive / therapeutic agent for inflammatory bowel disease according to the invention of claim 3 is the same as the preventive / therapeutic agent for inflammatory bowel disease according to claim 2, wherein a mozuku extract containing fucoidan is used as an active ingredient. It is a thing.

Lipopolysaccharide (LPS) is a cell wall component of Gram-negative bacteria such as Bacteroides and Escherichia coli. It is well known that the total number of Bacteroides bacteria in the intestinal flora is increasing in patients with inflammatory bowel disease, and that overgrowth of Bacteroides spp. Also exacerbates enteritis in transgenic rats HLA-B27. Has been done. It has also been reported that colitis is milder in mice in which the gene for the cell surface LPS receptor (TLR4) is disrupted than in control mice.

Therefore, the LPS signal is an important factor in the onset and exacerbation of inflammatory bowel disease. It is believed that bacterial components such as LPS directly affect the intestinal surface and elicit an immune response in intestinal epithelial cells. That is, the LPS signal causes the production of IL-6 in intestinal epithelial cells,
It seems to cause colitis. Therefore, removal of these signals from intestinal epithelial cells is likely to contribute to amelioration of enteritis.

The present invention has been reported by the present inventors to have many biological effects such as prevention of Helicobacter pylori colonization in human gastric cell lines and prevention of infection of human viruses with certain viruses. We focus on fucoidan, which is highly safe and can be obtained from seaweed and has no toxicity or irritation to the polysaccharide, and uses lipopolysaccharide (LPS: lipopolysaccharide).
Examination of the IL-6 production inhibitory effect of various seaweed-derived fucoidan in the mouse intestinal epithelial cell line in which colitis was induced by stimulation, it was found that some of the fucoidan has an IL-6 production inhibitory effect Further, they have found that it can be an active ingredient of a prophylactic / therapeutic agent for inflammatory bowel disease, and have completed the present invention.

Among them, fucoidan derived from mozuku, particularly fucoidan derived from Okinawa mozuku, has a higher effect of suppressing IL-6 production than fucoidan derived from other substances and is desirable as an active ingredient of a prophylactic / therapeutic agent for inflammatory bowel disease. I found that there is.

[0018] Fucoidan is a sulfated polysaccharide mainly composed of fucose, which is abundantly contained in brown algae such as mozuku, kelp, and wakame seaweed, and the wall of the sea cucumber body. Therefore, it can be obtained from various highly safe foods that have been eaten since ancient times, and high safety can be ensured even for a prophylactic / therapeutic agent for inflammatory bowel disease containing fucoidan or an extract containing fucoidan as an active ingredient. .

[0019]

BEST MODE FOR CARRYING OUT THE INVENTION The fucoidan used in the present invention is Kjellmaniella cras , a fucoidan derived from the brown alga Cladoshipon okamuranus Tokida, a so-called Okinawa mozuku.
Fucoidan derived from sifolia, so-called Gagome kelp , also Himm
Fucoidan derived from anthalia elongata , Sargassum horn
Examples thereof include fucoidan derived from eri , fucoidan derived from Lamanaria digtata , and fucus idans derived from Fucus vesiculosus .

As a method for preparing fucoidan from each seaweed, a conventionally used method may be used. For example, as a typical example, the acid extraction method exemplified below,
There is a hot water extraction method.

Acid extraction method Seaweed is suspended in water in an amount of 1 to 3 times its wet weight, and an aqueous acetic acid solution or dilute hydrochloric acid is added to pH 2 to 4, preferably pH.
Adjust to 2-3. Then about 50 ° C or higher, preferably 8
After heating to 0 to 100 ° C. to elute fucoidan, centrifugation is performed to remove the precipitate, and the supernatant is neutralized with sodium hydroxide to obtain an extract. If necessary, further ultrafiltration,
High-purity fucoidan can be obtained by performing dialysis or the like to remove low molecular weight impurities and freeze-drying.

Heat extraction method Seaweed is suspended in water in an amount of 1 to 3 times its wet weight, and about 10
Heat to 100 ° C. for minutes to 1 hour. Then, the mixture is centrifuged to remove the precipitate, and an extract containing fucoidan is obtained. If necessary, calcium chloride or barium acetate is added to the supernatant to remove precipitated alginic acid. Further, dialysis is carried out to remove low molecular weight impurities, followed by freeze-drying to obtain highly pure fucoidan.

In the present invention, it is preferable to use high-purity fucoidan free of low-molecular-weight impurities as an active ingredient of a prophylactic / therapeutic agent for inflammatory bowel disease. In addition, it is particularly preferable to convert the sulfate ester group of fucoidan into a free acid form or an alkali metal salt form by performing an ion exchange treatment at an arbitrary stage of removing low molecular weight impurities (water-soluble components, salts, etc.). Ion exchange treatment includes, for example, electrodialysis, acid cleaning using an ultrafiltration membrane, ion exchange resin treatment,
Alternatively, any of these treatments and subsequent neutralization treatment or the like can be performed. Any of these treatments may be carried out according to a conventional method, and an alkali metal salt can be obtained by neutralizing the fucoidan after the ion exchange treatment with an alkali metal hydroxide such as caustic soda and caustic potash.

In addition, since the active ingredient of the prophylactic / therapeutic agent for inflammatory bowel disease of the present invention is fucoidan, it is safe to administer it orally as it is, but if necessary, it may be shaped. Agent, binder, disintegrant, lubricant, coating agent,
Emulsifiers, dispersants, solvents, stabilizers, etc. may be added as long as they do not inhibit the effect of fucoidan, and may be used by formulating into tablets, granules, powders, powders, capsules and the like. good. The appropriate dose of fucoidan is
Approximately 50 mg to 3 g / person / day, preferably 100 mg to 1 g
/ Person / day.

Further, the preventive / therapeutic agent for inflammatory bowel disease of the present invention is not limited to oral administration as a therapeutic agent, and can be taken daily in the form of preventive food added to any food or drink. At this time, the active ingredient fucoidan is not only highly pure, but if a fucoidan-containing extract extracted from seaweed in a simple process is used, a preventive food for inflammatory bowel disease can be easily produced at a lower cost, Can be provided.

[0026]

The present invention will be described in detail below with reference to examples, but the present invention is not limited thereto. In the following examples, high-purity fucoidan excluding low-molecular weight impurities prepared by the above-mentioned conventional method and commercially available fucoidan of the same level as this are used.

(1) Materials Okinawa mozuku ( Cladoshipon okamuranus Tokida ) was cultivated in Okinawa and purchased from the Tropical Techno Center as salted food, and other seaweed ( Kjellmaniella c
rassifolia , Himmanthalia elongata , Sargassum horne
ri , Lamanaria digitata ) was provided by SCETI as a dry matter, and high-purity fucoidan was extracted from each of these seaweeds by the above-mentioned conventional method. Fucoidan derived from Fucus vesiculosus was purchased from Sigma.

(2) All the data shown in the examples after the data analysis are mean ± SE
It was expressed as (statistical error). A P value smaller than 0.05 is statistically significant.

Example 1 In this Example, the IL-6 production inhibitory effect of various fucoidans was examined by stimulating mouse colon cancer cells CMT-93 with ILs after LPS stimulation.
-6 Check for production. At the beginning of this experiment, first, CMT-9 was applied to various concentrations of LPS stimulation.
3 cell lines were tested for IL-6 production.

(A) Production of IL-6 in LPS-stimulated CMT-93 cells Mouse colon cancer cell line CMT-93 was purchased from ATCC. The LPS used was derived from E. coli purchased from Sigma. CMT-93 cells were treated with 10% FCS / 10mM Hepes / penic
illin-streptomycin / 2-ME / non-essential aminoacid / DM
Using EM culture solution, LP at 37 ° C, 5% CO ₂
Culture was performed for 72 hours under the condition that S was not added or that LPS of various concentrations was added. After culturing, the culture solution is collected and
Stored at 4 ° C. The amount of IL-6 produced was determined by measuring the anti-IL-6mAbs (clone: MP5-20F) of the mouse purchased from BD PharMingen.
3, MP5-32C11) and measured by the ELISA method.

As a result, as shown in FIG. 1, CMP-93
The IL-6 production in the cells reached the maximum when LPS was 5 to 10 μm / ml, and was saturated at 10 μg / ml.

(B) IL-6 production inhibitory effect of fucoidan on LPS-stimulated CMP-93 cells Regarding the fucoidan derived from each seaweed, LPS-stimulated CM
It was investigated whether IL-6 production in P-93 cells could be suppressed. That is, 10 μg / ml LPS was added to a CMT-93 cell culture system containing 1 μg / ml of various fucoidans,
It was cultured for 2 hours. After culturing, the culture broth was collected, and the amount of IL-6 produced was measured by the ELISA method as described above.

As a result, as shown in FIG. 2 (a), fucoidan derived from Okinawa mozuku ( Cladoshipon okamuranus Tokida ) and gagomekomb ( Kjellmaniella crassi)
fucoidan from folia ) suppressed IL-6 production in LPS-stimulated CMP-93 cells. However, other
Fucus vesiculosus , Himmanthalia elongata , Sargassu
Fucoidan derived from m horneri and Lamanaria digitata is I
It did not suppress L-6 production.

Next, the inhibitory effect on IL-6 production in LPS-stimulated CMP-93 cells at different fucoidan addition concentrations was examined for the above-mentioned fucoidan derived from Okinawa mozuku and fucoidan derived from Gagomecomb which were found to suppress IL-6 production. . I by cell culture and ELISA
The measurement of the L-6 amount is the same as above.

As a result, as shown in FIG. 2 (b), in either fucoidan, depending on the added concentration, I
L-6 production was suppressed.

Example 2 In this example, the improving effect of fucoidan on chronic colitis in mice in vivo was examined.

(C) Animal In this example, a female Balb / c mouse (8 weeks old) (purchased from Japan Clear Research Institute) was used. These mice are bred in an SPF (Specific pathogen-free) environment during the experiment.

(D) Induction of chronic DSS colitis Induction of chronic colitis in Balb / c mice was performed with dextran sodium sulfate (DSS). After administering 4% DSS (molecular weight 40 kDa: manufactured by ICN) water as drinking water for 7 days to a 10-week-old mouse, the resting period was 10 days, followed by 1 cycle. Was triggered.

(E) Fucoidan effect in mouse chronic colitis in vivo Standard mouse feed (MF) and fucoidan-containing (0.05% w / w) MF feed derived from Cladoshipon okamuranus Tokida or Hibamata ( Fuscus v)
esiculosus- derived fucoidan-containing (0.05% w / w) MF
In the Balb / c mice fed with each of the diets, colitis was induced by the DSS-containing drinking water as described above, and the fucoidan effect in colitis was analyzed by various disease parameters.

(1) Evaluation of enteritis disease In the evaluation of enteritis disease, the characteristic changes of the diseases such as body weight, diarrhea, and fecal occult blood are used as parameters and converted into a score with a graded value of 0 to 4, respectively. , DSS colitis was confirmed as a reflection of changes in the clinical course.

As shown in FIG. 3 (a), the scores of all parameters were the same as those of the standard feed or the fucoidan derived from hibamatata, and the Balb / fed fed the Okinawa mozuku fucoidan-containing feed. c The number was low in mice.

(2) Evaluation of intestinal tissue length The length of the large intestine from the cecum to the anus was measured as a severity parameter of DSS colitis.

As a result, as shown in FIG. 3 (b), the intestinal tissue length of the colitis-induced Balb / c mice fed the diet containing fucoidan derived from Okinawa mozuku was that of the mice fed the standard diet. It was significantly longer. Also,
In the colitis-induced Balb / c mice fed the standard diet and the diet containing fucoidan derived from Hibamata, the length of the large intestine was shortened due to the severity of enteritis.

(3) Myeloperoxidase (MPO) measurement In order to confirm the above results, the MPO activity of intestinal tissues was compared among the three groups. The MPO activity was measured by the following procedure. That is, first, each mouse large intestine tissue was crushed by a polytron homogenizer in a hexadecyltrimethylammonium bromide (manufactured by Sigma) buffer, and the suspension was sonicated on ice and then centrifuged at 15,000 rpm for 30 minutes. went. 0.167mg / ml of each supernatant
With O-dianisidine hydrochloride (manufactured by Sigma)
Mix with enzyme substrate buffer containing 0.0005% hydrogen peroxide and measure the change in absorbance at 405 nm wavelength.
The PO activity (U / g proten) was determined.

As a result, as shown in FIG. 4, intestinal tissue MP
O activity was lower in mice fed the fucoidan-containing diet derived from Okinawa mozuku than in mice fed the fucoidan-containing diet derived from Hibamata or the standard diet.

From the above results, it was revealed that fucoidan derived from Okinawa mozuku has an effect of improving chronic colitis in mice.

Example 3 In this example, immunological characteristics of fucoidan derived from Okinawa mozuku were examined.

(F) Lymphocyte production and flow cytometry control Balb / c mice and DSS-induced colitis-induced Balb / c mice had colonic lamina propria (IL-LPL).
s) phenotypes were compared.

0.45 mM of large intestine pieces cut into 1 cm pieces
The cells were incubated in Hank's balanced salt solution (HBSS) containing DTT and 2 mM EDTA at 37 ° C. for 15 minutes twice with shaking. After removal of the liquid layer by decantation, the remaining colon pieces were removed with 2.5% fetal calf serum (FC
S), 300 μg / ml collagenase (collagenase-Yakult S; manufactured by Yakult Honsha), and 50 μg / ml deoxyribonuclease I (manufactured by Sigma) in RPMI1640 culture solution,
While shaking with a CO ₂ thermostat, the cells were incubated at 37 ° C. for 45 minutes three times. Then, the cell mass was suspended in ice-cooled 2.5% FCS / 10 mM Hepes / RPMI solution and passed through a nylon column. Lymphocyte populations were separated from the 44/100% boundary of a Percoll density gradient (Sigma).
The obtained cells were TCRβ, CD4, CD45RB, CD69.
Alternatively, it was stained with mAbs against B220. The stained cells were analyzed by an Epics EL cell analyzer (Beckman).

Based on these results, the phenotypes of IL-LPLs among three groups of colitis-induced Balb / c mice were fed with the standard diet, the diet containing fucoidan derived from Okinawa mozuku, and the diet containing fucoidan derived from hibamata, respectively. Were compared.

As a result, as shown in FIG. 5, the total number of B220-positive B cells was significantly lower in the mice administered with fucoidan containing Okinawa mozuku derived from the diet than in the other groups.

(G) Cell Culture and Cytokine Measurement Mucosal lamina propria cells (1.0 × 10 ⁶ cells) from each of the three groups of colitis-induced mice were subjected to 10% FCS / 10 mM Hepes / using a 24-well tissue culture plate. Anti-TCRβ mAb (H57-597, 10 μg / ml) solidified in 2-ME / RPMI culture solution, anti-C
The cells were cultured under stimulation with D28 mAb (37.51, 1 μg / ml). After culturing for 72 hours, the culture solution is collected and
It was stored at -84 ° C until it was subjected to A measurement.

The cytokine-specific ELISA measurement was carried out by using the following antibody binding. That is, anti-interferon (IFN) -γ (clone: XMG1.2, R4-6A2),
Anti-interleukin 4 (IL-4) (clone: 11B11,
BVD6-24G2), all of which were purchased from BD pharMingen. For the measurement of IL-10 and TGF-β1,
Biosource International, Genzyme
The measurement kits purchased from each company were used.

In the colonic lamina propria cells (IL-LPLs) stimulated with TCRβ / CD28 antigen, FIG. 6 (a)
As shown in (b), IFN (interferon) -γ
The production amount of inflammatory cytokines such as and IL-6 was significantly lower in colitis-induced mice treated with fucoidan derived from Okinawa mozuku than in the standard diet and mice treated with fucoidan derived from Hibamata.

On the other hand, the production amount of TGF-β1 which is an anti-inflammatory cytokine was significantly higher in the colitis-induced mice treated with the fucoidan derived from Okinawa mozuku than in the standard diet and the mice treated with the fucoidan derived from Hibamata ( FIG. 6 (e)). The production amount of IL-10, which is also an anti-inflammatory cytokine, was higher in the mice treated with fucoidan derived from Okinawa mozuku than in the standard diet-treated mice (Fig. 6).
(D)). The amount of IL-4 produced was the lowest in the standard diet-treated mice.

(H) Immunoglobulin G in the intestinal piece
Measurement of (IGG) A crushed sample of the large intestine of the mice in the above-mentioned 3 groups was prepared in the same manner as above, and the amount of total IgG, IgG ₁ and IgG ₂ produced was measured by the specific sandwich ELISA method.

As a result of the measurement of IgG in the large intestine mucosa in the three experimental groups, as shown in FIG.
IgG ₁ and IgG _2a were increased in the colitis-induced Balb / c mice fed with the standard diet and the diet containing Fucoidan derived from Hibamata, respectively.

Example 4 In this example, IL-6 mRNA levels on colonic epithelial cells of colitis-induced Balb / c mice fed with a diet containing fucoidan derived from Okinawa mozuku were measured as follows. Colb-induced Balb / c fed standard diet
It was measured by the RT-PCR method using mice as a control.

Colonic epithelial cells were obtained from a colib-uninduced Balb / c mouse, and a colitis-induced Balb / c mouse fed with a standard diet or a diet containing fucoidan derived from Okinawa mozuku.

Total RNA was also prepared from these three groups of mice. After reverse transcription reaction of 1.0 μg of total RNA, PCR reaction was performed using G3PDH, IL-6, TNF-α and TLR-4 specific primers. After gel electrophoresis, PCR products were detected by staining with ethidium bromide.

As a result, as shown in FIG. 8, IL-6m
RNA is a standard feed-administered DSS colitis-induced Balb
/ c in mice. However, the induction of IL-6 mRNA was induced by the administration of feed containing Fucoidan derived from Okinawa mozuku.
It was suppressed in colon epithelial cells of lb / c mice. TNF
(Tumor necrosis factor) -α and TLR-4 mRNA were also suppressed in colon epithelial cells of Balb / c mice fed with diet containing fucoidan derived from Okinawa mozuku.

In the above examples, fucoidan, especially fucoidan derived from Okinawa mozuku, shows an IL-6 production inhibitory effect on colon epithelial cells in vivo and in vitro, and also has an improving effect on colitis lesions. It can be expected to have a high preventive and therapeutic effect on inflammatory bowel disease.

[0063]

INDUSTRIAL APPLICABILITY According to the present invention, fucoidan which is an active ingredient has been established to have high safety, and its mechanism of action is I
Since the effect of ameliorating enteritis lesions based on the L-6 production inhibitory effect is high, it becomes possible to provide a safe and effective preventive / therapeutic agent for inflammatory bowel disease.

[Brief description of drawings]

FIG. 1 is a bar graph showing the measurement results of IL-6 production in LPS-stimulated CMT-93 cells of Example 1 (horizontal axis: IL-
6 Production amount pg / ml, vertical axis: LPS addition amount μg / ml).

FIG. 2 IL-of LPS-stimulated CMP-93 cells of Example 1.
6 is a bar graph showing the effect of fucoidan on the production of 6; (a) shows the inhibitory rate of IL-6 secretion of fucoidan derived from various brown algae (horizontal axis:%), and (b) shows fucoidan derived from Okinawa mozuku. 2 shows the IL-6 secretion inhibition rate (horizontal axis:%) with respect to the added amount of fucoidan derived from Gagomecomb (vertical axis: μg / ml).

FIG. 3 is a bar graph showing the measurement results of fucoidan effect on in vivo mouse chronic colitis of Example 2.
(A) shows a score (horizontal axis: 0 to 4 point numerical value) for each parameter (vertical axis) of the pathological condition of enteritis,
(B) shows the colon tissue length (horizontal axis: cm) in three groups of mice (vertical axis: administration of fucoidan containing hibamata, administration of fucoidan containing Okinawa mozuku, administration of fucoidan-free feed).

FIG. 4 shows the myeloperoxidase (MP) of each intestinal tissue of the three mouse groups (horizontal axis) in Example 2.
It is a graph showing the measurement results of O) activity (vertical axis: U / g protein).

FIG. 5 shows colonic mucosa lamina propria cells (B220 B cells, TCR) of the three mouse groups (vertical axis) in Example 3.
It is a bar graph showing the number of αβ type T cells) (horizontal axis: number of cells, × 10 ⁶ cells).

FIG. 6 is a bar graph showing production amounts of various cytokines (vertical axis: pg / ml) of colonic mucosa lamina propria cells of the three mouse groups (vertical axis) in Example 3, (a) showing IFN-. γ, (b) IL-6, (c) IL-4, (d)
Shows the production of IL-10 and (e) shows the production of TGF-β, respectively.

FIG. 7: IgG in the large intestine segment of the three mouse groups (horizontal axis) in Example 3 (vertical axis: ng / mg protein)
It is a graph which shows the measurement result of (a) is a total amount of IgG,
(B) shows the amount of IgG1, and (c) shows the amount of IgG2a.

FIG. 8 is an electrophoretic image of RT-PCR reaction products showing IL-6 mRNA levels on colonic epithelial cells of the colitis-uninduced mouse and the fucoidan-administered and non-administered colitis-induced mouse of Example 4.

Continued front page    F term (reference) 4C086 AA01 EA24 GA17 MA01 MA04                       NA14 ZA66 ZB11                 4C088 AA13 AC01 BA08 CA02 CA03                       MA52 NA14 ZA66 ZB11                 4C090 AA09 BA97 BB08 BB34 BB54                       BB63 BB95 BC06 BD41 DA23

Claims (3)

[Claims] 1. A prophylactic / therapeutic agent for inflammatory bowel disease, which comprises fucoidan as an active ingredient. 2. The prophylactic / therapeutic agent for inflammatory bowel disease according to claim 1, which comprises a seaweed extract containing fucoidan as an active ingredient. 3. The prophylactic / therapeutic agent for inflammatory bowel disease according to claim 2, which comprises a mozuku extract containing fucoidan as an active ingredient.