Use of aakmanmuciniphilus or outer vesicle thereof in preparation of a drug for treating schistosomiasis

Abstract

The application belongs to the technical field of biological medicine, and relates to application of mucinophilic Akkermansia or outer vesicles thereof in preparation of a schistosomiasis treatment drug. The application enhances host anti-infection immunity by regulating intestinal flora balance (restoring diversity and composition), improving immune response (regulating macrophages, CD8+ T cell recruitment and Th1 / Th2 balance), improving intestinal barrier function, reducing pathogen invasion and inflammation, significantly reducing liver granuloma and liver fibrosis caused by schistosome infection, and improving liver function. The application reveals the key role of MIF gene in immune regulation, and provides a new direction for schistosomiasis immunotherapy. In addition, the probiotic treatment has high safety, no obvious side effects, can be combined with chemotherapy, enhances the curative effect, reduces the side effects of chemical drugs and drug resistance, provides a persistent and comprehensive adjuvant treatment scheme for schistosomiasis, and has important clinical application potential.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to the application of Akkermansia myxophilus or its external vesicles in the preparation of drugs for treating schistosomiasis. Background Technology

[0002] Schistosomiasis is a parasitic disease caused by the schistosome *Schistosoma*, widely distributed in tropical and subtropical regions, posing a significant threat to global public health. Currently, treatment for schistosomiasis still relies on praziquantel, but this drug suffers from poor solubility, the risk of drug resistance, and limited protection against reinfection; therefore, there is an urgent need to develop new treatment strategies.

[0003] Schistosoma japonicum ( Schistosoma japonicum , S. japonicum The parasite resides in the portal and mesenteric veins. After mating, the male and female produce eggs which are excreted in the feces. The eggs are the main pathogenic stage of schistosomiasis. The soluble antigens in the eggs trigger an immune response, leading to granulomas, which subsequently develop into fibrosis and cause schistosomiasis lesions.

[0004] Recent studies have shown that schistosomiasis infection is also associated with gut microbiota dysbiosis. Among the beneficial gut bacteria is *Akkermansia myxophilus* (…). Akkermansia muciniphila , A. muciniphila In various disease models, it plays an important role by maintaining intestinal barrier function, improving metabolism, and regulating immunity.

[0005] The prior art CN118217265A discloses a probiotic exovesicle loaded with chemotherapy drugs and PDT photosensitizer. The probiotic exovesicles are exovesicles extracted from probiotics, and the probiotics are selected from at least one of Lactobacillus rhamnosus, Escherichia coli, Lactobacillus plantarum, and Akkermansia myxotroph.

[0006] Prior art CN119770525A discloses a type of Akkermansia myxophilus ( Akkermansia muciniphila The application of (or its extracellular vesicles) in the preparation of drugs to alleviate alcoholic avascular necrosis of the femoral head.

[0007] Existing technology CN115671141A discloses the application of probiotics and their outer membrane vesicles in the preparation of agents for treating smoking-related diseases. Akk's outer membrane vesicles (AkkOMV) were extracted from the culture supernatant of Akk's myxotroph (Akk bacteria) through density gradient centrifugation, filtration, concentration, and exosome extraction reagent chromatography. A smoking-induced COPD mouse model was constructed, and Akk's myxotroph and / or AkkOMV were used for intervention. The results, based on the detection of relevant physiological characteristics in the mice after intervention, confirmed that both Akk's myxotroph and AkkOMV can significantly alleviate multi-system diseases such as respiratory, cardiovascular, and metabolic diseases caused by smoking, and promote the repair of multi-organ damage. The application and industrialization prospects in the prevention and treatment of smoking-induced systemic diseases are promising.

[0008] Existing technology CN115518079A discloses the application of probiotics and their outer membrane vesicles in the preparation of agents for the prevention and treatment of bronchial asthma. Akk's outer membrane vesicles (AkkOMV) were extracted from the culture supernatant of Akk's myxotroph (Akk bacteria) through density gradient centrifugation, filtration, concentration, and exosome extraction reagent chromatography. An asthmatic mouse model was constructed, and Akk's myxotroph / AkkOMV was used for intervention. The results, based on the detection of relevant physiological characteristics in the mice after intervention, confirmed the effects of Akk's myxotroph and AkkOMV in inhibiting airway and lung tissue inflammation, reducing airway mucus secretion, and possessing immunomodulatory functions. These can serve as alternatives to existing drugs or adjunctive therapies for the preparation of drugs, foods, and health products to improve acute and chronic asthma.

[0009] Existing technology CN120078815A discloses the application of *Ackermannii myxotropicis* in the preparation of products related to diabetic metabolic disease-related kidney injury. The *Ackermannii myxotropicis* strain described herein, with accession number CGMCC No. 20955, can significantly reduce blood urea nitrogen, serum creatinine, and urinary protein levels, thus improving renal function; alleviate renal oxidative stress by reducing malondialdehyde levels and increasing the activities of SOD, CAT, and GSHPx; reduce TNFα and IL1β secretion by inhibiting the TLR4 / NFκB pathway, thereby alleviating inflammatory responses; and ultimately exert renal protective effects through antioxidant, anti-inflammatory, and anti-fibrotic actions.

[0010] Existing technology CN116211896A discloses the application of *Ackermania myxophilus* JF3 in improving tissue fibrosis and repairing mucosal damage in the intervention of radiation-induced rectal disease. Studies have found that *Ackermania myxophilus* JF3 can effectively improve rectal fibrosis, rectal mucosal damage, anal injury, and colorectal inflammation caused by radiation-induced rectal disease. Therefore, the novel *Ackermania myxophilus* strain JF3 can be considered a potentially safe live bacterial drug for the treatment of rectal fibrosis, rectal mucosal damage, anal injury, and colorectal inflammation caused by radiation-induced rectal disease.

[0011] Existing technologies (Jenkins TP, et al.) Schistosoma mansoni infection is associated with quantitative and qualitative modifications of the mammalian intestinal microbiota[J]. Sci Rep, 2018, 8(1):12072 and Floudas A, et al. Schistosoma mansoni Worm Infection Regulates the Intestinal Microbiota and Susceptibility to Colitis [J]. Infect Immun, 2019, 87(8): e00275-19.) disclosed the Schistosoma mansoni ( S. mansoni Mice infected with mixed female and male parasites showed decreased α-diversity and significantly increased β-diversity in their gut microbiota, with increased abundance of Akkermansia myxophilus, Lactobacillus, Alistipes, and Bacteroides.

[0012] Prior art (Chen H, et al. Metagenomic analysis of the intestinal microbiome reveals the potential mechanism involved in Bacillus amyloliquefaciens in treating schistosomiasis japonica (in mice. MicrobiolSpectr 12:e03735-23.) To explore... B. amyloliquefaciens Intervention on infection S. japonicum The influence of the mouse gut microbiota was analyzed using radar charts to illustrate the composition of four gut microbiota groups. Among the top 10 species in relative abundance, Akkermansia muciniphila , Bacteroides caecimuris and Bacteroides sp. CBA7301 It increased significantly in the SJ group.

[0013] based on A. muciniphila , A. muciniphila The discovery of extravesicles (Akk-Evs) and their secreted proteins is of great significance in developing new strategies for the treatment of schistosomiasis that utilize the microbiome to address issues of drug resistance, reinfection, and treatment, and is crucial for advancing the prevention and control of schistosomiasis. Summary of the Invention

[0014] The present invention first provides an application of Akkermansia myxophilus or its exovesicles, wherein the application is one of the following;

[0015] a) Preparation of drugs for treating schistosomiasis;

[0016] b) Prepare drugs for treating schistosomiasis infection.

[0017] In some embodiments, the treatment is to regulate the gut microbiota following schistosomiasis infection.

[0018] In some embodiments, the treatment is to improve the immune response following schistosomiasis infection.

[0019] In some embodiments, the treatment is to reduce intestinal inflammation following schistosomiasis infection.

[0020] In some embodiments, the treatment is to alleviate liver fibrosis caused by schistosomiasis infection.

[0021] In some embodiments, the schistosome is Schistosoma japonicum. S. japonicum .

[0022] In some embodiments, A. muciniphila or Akk -Evs, administered at appropriate doses of probiotics or exovesicles, can significantly restore the diversity and balance of the gut microbiota and increase the abundance of beneficial bacteria.

[0023] In some embodiments, A. muciniphila or Akk -Evs treatment can significantly modulate the host's immune response, promoting macrophages and CD8+. + T cell recruitment and restoration of Th1 / Th2 immune balance.

[0024] In some embodiments, A. muciniphila or Akk -Evs treatment can significantly alleviate the effects of S. japonicum Infection causes accumulation of small intestinal schistosomiasis eggs and damage to intestinal villi, which counteract the effects of... S. japonicum Infection causes an increase in the length of intestinal villi.

[0025] In some embodiments, A. muciniphila or Akk Treatment with Evs can reduce liver damage, including reducing the formation of hepatic granulomas and slowing the progression of liver fibrosis.

[0026] This invention also provides an evaluation method in a MIF-deficient mouse model. A. muciniphila The study of the effects of external vesicle therapy on the immune response demonstrates the crucial role of MIF in this treatment.

[0027] In some embodiments, A. muciniphila or Akk -Evs' active ingredient is available in oral or other forms and in dosages suitable for the treatment of Schistosoma japonicum infection.

[0028] The present invention also provides a treatment S. japonicum Infected probiotic composition, including A. muciniphila or Akk -Evs is used as an active ingredient to treat Schistosoma japonicum infection by regulating gut microbiota, improving immune response and reducing liver fibrosis.

[0029] The present invention also provides an application of the composition, wherein the application is one of the following;

[0030] a) Preparation of drugs for treating schistosomiasis;

[0031] b) Preparation of drugs for treating schistosomiasis infection;

[0032] The composition contains Akkermansia mycotoxinus and its exovesicles as active ingredients.

[0033] In some embodiments, the composition includes a probiotic composition.

[0034] The present invention also provides a method for treating schistosomiasis infection in vitro, the method comprising the step of administering Akkermansia myxophilus or Akkermansia myxophilus exovesicles or a composition comprising Akkermansia myxophilus or Akkermansia myxophilus exovesicles.

[0035] The present invention also provides a combined treatment method for improving the efficacy of in vitro anti-schistosomiasis therapy, wherein the method combines Akkermansia myxotropicum or Akkermansia myxotropicum exovesicles or a composition containing Akkermansia myxotropicum or Akkermansia myxotropicum exovesicles with chemotherapy, thereby enhancing the efficacy of anti-schistosomiasis therapy and preventing long-term complications by improving immune response, intestinal health and liver function.

[0036] Compared with the prior art, the present invention has at least the following beneficial effects:

[0037] 1. Effectively restores the balance of intestinal flora: This invention A. muciniphila and Akk -Evs treatment can significantly regulate the composition of the gut microbiota, restore the diversity and balance of the microbiota, and help alleviate the dysbiosis caused by schistosomiasis infection.

[0038] 2. Improves immune response: By regulating immune cells (such as macrophages and CD8+). + Recruitment of T cells and restoration of Th2 / Th1 immune balance. A. muciniphila and Akk-Evs treatment can enhance the host's immune response and improve immunity against schistosomiasis infection.

[0039] 3. Improves intestinal barrier function: The treatment of this invention can effectively regulate intestinal barrier function, reduce the invasion of harmful pathogens, and thus alleviate intestinal inflammatory response.

[0040] 4. Relief of liver fibrosis: The probiotic treatment of the present invention can significantly reduce liver damage caused by schistosomiasis infection, including the formation of hepatic granulomas and liver fibrosis, slow the progression of the disease, and improve the functional status of the liver.

[0041] 5. The role of MIF in immune regulation: This invention reveals the role of the MIF gene in immune regulation. A. muciniphila The important role of MIF in immune regulation during treatment provides new insights for future research on the potential of MIF in schistosomiasis immunotherapy.

[0042] 6. No toxic side effects: As a probiotic therapy, the method of this invention has low toxicity and side effects, making it suitable for long-term use as an adjunct to chemotherapy and helping to reduce the side effects and drug resistance of chemical drugs.

[0043] 7. Potential combination therapy strategies: This treatment method can be combined with traditional chemotherapy, improve immune response and gut health through probiotics, thereby enhancing the effectiveness of anti-schistosomiasis treatment and helping to prevent long-term complications of schistosomiasis, providing a more comprehensive treatment option.

[0044] In summary, this invention provides a novel and effective adjunctive treatment for schistosomiasis, which can provide more lasting and comprehensive therapeutic effects through intestinal flora regulation, enhanced immune response and relief of liver fibrosis, and has significant clinical application potential. Attached Figure Description

[0045] Figure 1 ,yes Akk - Identification results of EVS; Figure A is a representative image from a transmission electron microscope, scale bar at 200 nm; Figure B is the particle size analysis result; Figure C is... Akk - Evs protein SDS-PAGE silver staining of major protein distribution map.

[0046] Figure 2 Figure 1 shows the weight data of WT mice and MIF-deficient mice; Figure A shows the weekly weight change of wild-type mice; Figure B shows the weekly weight change of MIF-deficient mice.

[0047] Figure 3 Figures 1 and 2 show the α-diversity analysis of mouse gut microbiota; Figures A and D are the Sobs, Chao1, Shannon, and Simpson indices of mouse gut microbiota α-diversity, respectively.

[0048] Figure 4 The figure shows the PCoA analysis of β-diversity in the mouse gut microbiota.

[0049] Figure 5 Figure 1 shows the results of flow cytometry analysis of mouse spleen lymphocytes; Figure A illustrates the strategy for sorting cell subsets using flow cytometry; Figures B and D represent F4 / 80 respectively. + CD8a + and CD4 + Percentage of cells in lymphocytes; Figures E and F represent CD4+ cells, respectively. + CD4 in cells + IL4 + and CD4 + IFN-γ + The percentage of T cells; Figure G is the Th2 / Th1 ratio.

[0050] Figure 6 1. Pathological analysis of small intestine H&E stained sections; A is a representative section of small intestine tissue after H&E staining, 200×, scale bar 20μm; Figures B and C are pathological scoring diagrams of intestinal tissue; Figure D is a diagram of the number of parasite eggs per gram of intestinal tissue; Figure E is a diagram of intestinal villus length.

[0051] Figure 7 Figure 1 shows a pathological analysis image of a PAS-stained section of the small intestine; Figure A is a characteristic image of a PAS-stained section of the intestine, 100 ×, scale bar 50 μm. Figure B is a quantitative analysis result of goblet cells.

[0052] Figure 8 Figure 1 shows the H&E staining analysis results of liver pathological sections; Figure A shows the characteristic H&E staining results of the liver, 200×, scale bar 20μm; Figure B shows the quantitative results of the area of ​​a single parasite egg granuloma. Figure C shows the characteristic Masson staining results of the liver, 40×, scale bar 200μm; Figure D shows the quantitative results of the collagen area. Detailed Implementation

[0053] To make the technical problems, technical solutions and advantages of the present invention clearer, a detailed description will be given below in conjunction with the accompanying drawings and specific embodiments.

[0054] Example 1, Materials and Grouping

[0055] (1) Experimental animals, strains and positive Oncomelania snails

[0056] In the experiment, the number of male and female mice was equal (8-10 mice per group), and the age was 6-8 weeks. All mice were raised in a pathogen-free facility with free access to food and water. The day-night cycle was 12 hours, and the ambient temperature was 21-25℃. A.muciniphila Strain 33894T (ATCC BAA-835) was purchased from the Japan Microbial Culture Collection. The cercariae of *Schistosoma japonicum* were obtained from positive *Oncomelania hupensis* snails purchased from the Jiangsu Provincial Institute of Parasitic Diseases.

[0057] (2) Formulation preparation

[0058] A. muciniphila Suspension preparation: cultured under anaerobic conditions A. muciniphila Upon reaching the logarithmic growth phase, the bacterial cells were collected by centrifugation, resuspended in PBS containing 25% glycerol, and the concentration was adjusted to 1×10⁻⁶. 9 CFU / mL.

[0059] Akk -Evs Extraction and Identification: Anaerobic Culture A. muciniphila When OD 600 When the nm value is 1.0, centrifuge at 11,000 × g for 30 min at 4℃, discard the precipitate, and collect the supernatant. Repeat twice. Pass the supernatant sequentially through 0.45 μm and 0.22 μm filter membranes, collect the filtrate into a fused-seal tube, and ultracentrifuge at 200,000 × g for 2.5 h at 4℃. Discard the supernatant, resuspend the bacterial exovesicle pellet in PBS, and store at -80℃. Analysis was performed using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), SDS-PAGE silver staining of proteins, and BCA protein quantification. Akk The morphology, size, and concentration of -Evs were ultimately used to prepare a product containing... Akk -Evs 50 μg / mL PBS suspension.

[0060] Result: See Figure 1 Through transmission electron microscopy observation and nanoparticle tracking analysis, Akk -Evs exhibits a typical spherical structure with an average diameter of 84.14 ± 25.62 nm. Further silver-stained SDS-PAGE analysis results show that... Akk -Evs protein molecules are mainly concentrated in the 55-70 kDa range, and low molecular weight proteins are abundant.

[0061] (3) Experimental grouping and intervention plan

[0062] After 7 days of acclimatization, WT mice and MIF KO mice were randomly assigned to 4 groups of 8-10 mice each, including an uninfected control group plus a PBS gavage group (CP). S. japonicum Infected mice + PBS gavage group (SP) S. japonicum Infected mice + A. muciniphila Gavage group (SA) S. japonicum Infected mice + Akk-Evs gavage group (SE). Mice in the SA group were gavage for 7 consecutive days before infection. A. muciniphila Bacterial solution; mice in the SE group were administered the solution via gavage. Akk -Evs; while mice in the CP and SP groups were given an equal volume of PBS by gavage.

[0063] Result: See Figure 2 Mice in S. japonicum Weight loss began in the fifth week of infection, and gavage was administered. A. muciniphils or Akk -Evs did not significantly improve mouse body weight, and the trend of body weight change was consistent in WT mice and MIF KO mice.

[0064] Example 2: 16S assay of gut microbiota

[0065] Bacterial DNA was extracted and quantified from fecal samples of the aforementioned groups of mice. Using the V3-V4 hypervariable region of the 16S rRNA gene as a template, amplification, library construction, and sequencing were performed, followed by comparative analysis of changes in the mouse gut microbiota. Alpha diversity indices, including Chao1 and Shannon indices, were calculated using Mothur software, and Wilcoxon rank-sum tests were used to analyze differences in alpha diversity between different groups. Beta diversity of the microbial community structure was analyzed using the Bray-Curtis distance algorithm and PCoA.

[0066] Result: See Figure 3 , A. muciniphila and Akk -Evs' intervention changed what was S. japonicum Infected mouse gut microbiota remodeled Alpha and Beta diversity, producing different effects between WT mice and MIF KO mice.

[0067] The observed species (Sobs), Chao1, and Shannon indices in the SP group were significantly lower than those in the CP group (all p < 0.001), while the Simpson index showed an increasing trend in the SP group (p < 0.010). In WT mice, A. muciniphila or Akk -Evs interventions can all counteract these changes, indicating A. muciniphila and Akk - Evs intervention remodeled the alpha diversity of the gut microbiota in mice (SA p<0.050, p<0.050, p<0.001; SE p<0.050, p<0.050, p<0.010), while this intervention effect was not significant in MIF KO mice.

[0068] SeeFigure 4 PCoA analysis based on Bray-Curtis distance shows that S. japonicum The microbial community composition differed significantly between the infection group and the control group. S. japonicum Compared to the infection group, except for the MIF KO SA group, A. muciniphila or Akk -Evs intervention also caused significant differences in microbial composition, while Akk The differences were most pronounced in MIF KO mice treated with -Evs.

[0069] Example 3: Flow cytometry

[0070] Spleens were harvested from the mice in the above-mentioned groups under aseptic conditions. After mechanical grinding, a lymphocyte suspension was obtained using a lymphocyte separation medium (density gradient centrifugation). The cell concentration was adjusted to 3 × 10⁻⁶ cells / mL. 6 Cells / 100 μL were incubated with PE-labeled anti-mouse CD8a antibody and APC-labeled anti-mouse F4 / 80 antibody at 4°C in the dark for 20 minutes. After incubation, the cells were washed twice with cell staining buffer to remove unbound antibodies. The remaining lymphocytes were resuspended in RPMI 1640 medium containing 10% fetal bovine serum, 1% penicillin / streptomycin, and 50 μmol / L β-mercaptoethanol, and the cell density was adjusted to 5 × 10⁶ cells / mL. 6 Cells / mL. Add cell stimulants (PMA / Ionomycin / Brefeldin A) to a final concentration of 2 μL / mL and incubate at 37°C for 6 hours. After centrifugation and discarding the supernatant, resuspend the cells in cell staining buffer and add FITC-labeled anti-mouse CD4 antibody, incubate at 4°C in the dark for 20 minutes. Use True-Nuclear... TM The membrane was fixed and perforated using a transcription factor buffer system. PE-labeled anti-mouse IL-4 antibody and APC-labeled anti-mouse IFN-γ antibody were added, and the mixture was incubated at room temperature in the dark for 20 minutes. Finally, True-Nuclear... TM Cells were washed with permeabilization buffer and resuspended in cell staining buffer. Cell samples were analyzed using a Cytoflex flow cytometer, and data processing and analysis were performed using FlowJo 10.4 software.

[0071] Result: See Figure 5 Gavage A. muciniphila or Akk -Evs can promote macrophages and CD8 + T cell recruitment and regulation of Th2 / Th1 immune balance.

[0072] In MIF KO mice, compared with S. japonicum Comparison of infection groups,A. muciniphila or Akk -Evs intervention significantly increased F4 / 80 + Cells (all p<0.001) and CD8a + Cell count ( A. muciniphila Treatment p < 0.001, Akk-Evs treatment p = 0.022); the same trend was observed in WT mice, but the difference was not statistically significant.

[0073] In WT mice or MIF KO mice, infection S. japonicum Post-CD4 + The number of cells was significantly reduced (p<0.001, p<0.001); in CD4 + In cells, CD4 + IL-4 + The percentage of cells (Th2 cells) increased significantly (all p < 0.001), CD4 + IFN-γ + The proportion of cells (Th1 cells) decreased (all p<0.001). A.muciniphila or Akk -Evs intervention can effectively reverse these changes and increase CD4 levels. + Cells, especially Th1 cells ( Akk -Evs treatment WT p<0.001, MIFKO p = 0.002), reduced Th2 cells ( A.muciniphila The values ​​were WT p = 0.009 and MIF KO p = 0.049. Akk -Evs treatment (WT p < 0.001, MIF KO p = 0.027) was beneficial in restoring the Th1 / Th2 balance. Compared with WT mice, although the number of the above-mentioned immune cells was lower in MIF KO mice, the above changes were more pronounced when MIF was absent.

[0074] Example 4: Histopathological Section Analysis

[0075] Tissue samples were fixed in 4% paraformaldehyde, followed by graded ethanol dehydration (70%–100%), xylene clearing, and paraffin impregnation (58–60°C). 5μm serial sections were prepared using a microtome. Small intestinal tissue was assessed for damage after H&E staining, and blinded analysis was performed under a microscope based on the degree of epithelial damage and inflammatory infiltration. Goblet cells were counted after PAS staining, and villus length was measured. Sections were observed using an optical microscope (Olympus BX53F), and images were acquired using Olympus CellSens Standard 1.13 software. Liver tissue was stained using both H&E and Masson methods, and at least 20 well-defined, well-segmented single granulomas with ova were randomly selected from each group. The area of ​​individual granulomas and fibrosis was calculated using FijiImageJ software.

[0076] Result: See Figure 6 The degree of damage to the small intestine tissue in the SP group was higher than that in the SA and SE groups. A. muciniphila Mice receiving intervention showed lower histological scores compared to the infection group (WT p<0.001, MIF KO p = 0.020), and the histological scores of WT mice were lower than those of MIF KO mice (p<0.001). Akk Compared with the SP group, the SE group with Evs intervention had a significantly lower histological score (WT p = 0.012, MIF KO p < 0.001). The results showed that... S. japonicum Infection significantly increased the number of parasite eggs in the intestinal tissue of mice (p<0.001) and the length of intestinal villi (p<0.001), while gavage significantly increased the number of parasite eggs (p<0.001). A. muciniphila and Akk -Evs significantly reduced the number of eggs per gram of intestinal tissue, and also reduced the length of intestinal villi. Although in A. muciniphila An increase in intestinal villus length was observed in the intervened MIF KO mice, but other test results showed no significant differences between WT mice and MIF KO mice.

[0077] See Figure 7 , S. japonicum Infection significantly reduced the number of goblet cells in the gut (WT p<0.001; MIFKO p<0.001). A. muciniphila or Akk-Evs treatment significantly increased goblet cell number (p < 0.001 for both). Similar trends were observed in both WT and MIF KO mouse models. Notably, in the SA group, MIF KO mice had a higher number of goblet cells than WT mice (p = 0.044), while in the SE group, the opposite trend was observed, with MIF KO mice having a lower number of goblet cells than WT mice (p < 0.001).

[0078] See Figure 8 In WT mice and MIF KO mice infected S. japonicum Subsequently, the area of ​​granulomas from individual eggs increased dramatically (p<0.001). However, after supplementation... A. muciniphila or Akk In mice with -Evs, the number of single ovarian granulomas was significantly reduced (p<0.001). Changes in fibrosis area measured by Masson staining were consistent with this result. S. japonicum Compared to the infection group, A. muciniphila or Akk -Evs treatment reduced collagen deposition (p<0.001 for both). Therefore, gavage... A. muciniphila and Akk -Evs reduced the incidence of infection S. japonicum This leads to granulomas of parasite eggs and liver fibrosis.

[0079] The above description represents the preferred embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A type of myxotrophic Akkermansia ( Akkermansia muciniphila The application of external vesicles, characterized in that, The application is one of the following; a) Preparation of drugs for treating schistosomiasis; b) Prepare drugs for treating schistosomiasis infection.

2. The application according to claim 1, characterized in that, The treatment described is to regulate the intestinal flora after schistosomiasis infection.

3. The application according to claim 1, characterized in that, The treatment described is to improve the immune response after schistosomiasis infection.

4. The application according to claim 1, characterized in that, The treatment described is to reduce intestinal inflammation following schistosomiasis infection.

5. The application according to claim 1, characterized in that, The treatment described is to alleviate liver fibrosis caused by schistosomiasis infection.

6. The application according to any one of claims 1-5, characterized in that, Schistosoma japonicum is the schistosome. Schistosome japonicum .

7. The application of a composition, characterized in that, The application is one of the following; a) Preparation of drugs for treating schistosomiasis; b) Preparation of drugs for treating schistosomiasis infection; The composition contains the exovesicles of Akkermansia muciniphila as the active ingredient.

8. The application according to claim 7, characterized in that, The composition includes a probiotic composition.

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