CN116115648A - Bacteroides fragilis and application of capsular polysaccharide A thereof in radioactive intestinal injury - Google Patents
Bacteroides fragilis and application of capsular polysaccharide A thereof in radioactive intestinal injury Download PDFInfo
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- CN116115648A CN116115648A CN202211431477.6A CN202211431477A CN116115648A CN 116115648 A CN116115648 A CN 116115648A CN 202211431477 A CN202211431477 A CN 202211431477A CN 116115648 A CN116115648 A CN 116115648A
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- bacteroides fragilis
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- radiation
- intestinal
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Abstract
The invention relates to bacteroides fragilis and application of capsular polysaccharide A thereof in radioactive intestinal injury. Researches show that the bacteroides fragilis can relieve radioactive intestinal injury, promote proliferation of intestinal mucosa epithelial cells, mucus secretion and tight connection restoration, and participate in regulation of intestinal flora, and the bacteroides fragilis has wide clinical transformation prospect and can be applied to prevention or treatment of intestinal complications caused by clinical tumor radiotherapy. The invention explores a new therapeutic application of bacteroides fragilis and reveals potential therapeutic prospect. The bacteroides fragilis can be used for preparing a pharmaceutical composition related to the prevention and/or treatment of the radioactive intestinal injury according to the probiotic characteristics of the bacteroides fragilis.
Description
The microbial strain used in the implementation process of the invention is preserved in China general microbiological culture Collection center (CGMCC) (No. 3 of North Chen West Lu 1 of the Korean area of Beijing city) in China general microbiological culture Collection center (CGMCC) of 4 months and 2 days of 2015. Classification naming: bacteroides fragilis ZY-312 (bacteroides fragilis ZY-312) with the preservation number of CGMCC No.10685. Bacteroides fragilis ZY-312 was isolated by the applicant's entity and has been under the authority of the patent protection (patent No. 2015175508. X), and under the provisions of the patent prosecution guidelines, the public was able to buy from commercial sources or has been granted without preservation, i.e. without providing proof of preservation.
Technical Field
The invention relates to the technical field of application of bacteroides fragilis, in particular to application of bacteroides fragilis and capsular polysaccharide A thereof in preparation of a medicament for preventing and/or treating radiation intestinal injury.
Background
In recent years, with the continuous rise of tumor incidence and the increasing application of radiotherapy, the incidence of radioactive intestinal injury is also increasing year by year, and the radioactive intestinal injury is receiving general attention of medical circles at home and abroad. The radioactive intestinal injury is unavoidable healthy intestinal injury caused by the radiotherapy of malignant tumors of abdominal cavity and pelvic cavity, is a common complication after the radiotherapy of tumor, and mainly affects small intestine. Susceptibility factors include treatment-related factors (radiation dose, radiation pattern) and patient-individual factors (low body weight, wasting, acute intestinal response during radiation, history of diabetes, history of pelvic surgery, personal history of smoking, history of anticoagulant use, etc.).
Since the intestinal mucosa layer is a sensitive part of radiation, correspondingly, the intestinal mucosa is mainly damaged, and the pathological changes of intestinal flora disorder, immune imbalance, nerves and blood vessels are caused. According to pathological stage, characteristics, clinical manifestations and the like, radioactive intestinal injury can be divided into an acute phase and a chronic phase, and the acute phase is more represented by inflammatory reaction of intestinal mucosa, and the pathological basis of the chronic phase is intestinal wall ischemia and fibrosis, wherein the limit is generally 3-6 months; the radioactive intestinal injury can be classified into small intestinal injury and rectal injury according to the location, and thus the radioactive intestinal injury can be classified into 4 subtypes, i.e., acute radioactive small intestinal injury, acute radioactive rectal injury, chronic radioactive small intestinal injury, chronic radioactive rectal injury. Acute (early) reactions of radiation intestinal injury include nausea, vomiting, diarrhea, ileus, hematochezia and perforation due to damaged intestinal mucosa, and chronic (late) reactions can manifest after months, generally due to inflammation, tissue necrosis and fibroplasia, such as diarrhea, intestinal canal stenosis, ileus, fistulae and bleeding.
Therapeutic agents for radiation intestinal injury include anti-inflammatory drugs, antibiotics, somatostatin drugs, probiotic preparations, antidiarrheal agents, sucralfate, etc. The Chronic Radiation Proctitis (CRP) mainly caused by hemorrhage can be selected from sulcotriol enema or compound preparation enema based on the same, and the like, and the Chronic Radiation Proctitis (CRP) mainly caused by inflammation can be selected from non-steroidal anti-inflammatory drugs, glucocorticoid, mucous membrane protective agent (sulcotriol), antibiotics, and the like. However, the current therapeutic efficacy of drugs for the treatment of radiation intestinal injury is not ideal.
Intestinal flora disorder caused by radioactive intestinal injury is mainly characterized by reduction of the number of the thick-walled bacteria and the bacteroides, and based on the reduction, the recovery of the intestinal flora structure and the balance of the flora proportion are taken as the emergence points, and corresponding probiotics, intestinal flora transplantation, antibiotic treatment and the like are taken as microorganism treatment modes for effectively treating the radioactive intestinal injury. Among them, probiotics have unique advantages in the treatment of gastrointestinal diseases, and particularly play an important role in protecting and repairing intestinal mucosa. At present, the treatment effect and the regulation mechanism of probiotics including the phylum of the firmicutes in the radioactive intestinal injury are correspondingly reported, and the treatment effect of the corresponding probiotics including the phylum of the bacteroides in the radioactive intestinal injury is ambiguous. In addition, candidate probiotics with significant therapeutic effects in radiation intestinal injury are still freshly reported at present.
Bacteroides fragilis (Bacteroides fragilis) belong to gram-negative bacteria, are obligate anaerobic, are shaped like rods, are round at two ends and are densely dyed, and are structurally capsular and non-spore and unpowered. As symbiotic bacteria, bacteroides fragilis has a certain proportion of colonization in healthy gastrointestinal tracts of human beings and animals, and is mainly located in small intestines and colon. Bacteroides fragilis is divided into enterotoxigenic strains and enterotoxigenic non-strains. The strain of bacteroides fragilis can cause the occurrence and development of septicemia and colon cancer. But not the strain bacteroides fragilis, which is conventionally defined as bacteroides fragilis, has the characteristics of probiotics, and can induce the adaptive immune cells to secrete anti-inflammatory factors through capsular Polysaccharide (PSA) to inhibit colonitis, autoimmune cerebrospinal meningitis, hepatitis and the like. However, it is unclear whether bacteroides fragilis has a protective effect in radiation intestinal injury and the corresponding regulatory mechanism. In addition, no report is currently made on the application of bacteroides fragilis in preparing a medicament for preventing or treating the radioactive intestinal injury.
Therefore, the method for exploring the therapeutic effect and the regulating mechanism of the bacteroides fragilis in the radioactive intestinal injury and preparing the corresponding medicines for preventing or treating the radioactive intestinal injury has wide clinical transformation prospect.
Disclosure of Invention
The invention aims to provide the application of bacteroides fragilis and capsular polysaccharide A thereof in preventing and/or treating the radioactive intestinal injury.
In a first aspect, the invention provides application of bacteroides fragilis in preparing a medicament or food for preventing and/or treating radioactive intestinal injury, wherein the bacteroides fragilis is bacteroides fragilis ZY-312 with a preservation number of CGMCC No.10685.
In some embodiments, the bacteroides fragilis is a live or inactivated bacterium.
In some embodiments, the bacteroides fragilis is one or more of a live bacteroides fragilis thallus, a bacteroides fragilis lysate, a bacteroides fragilis liquid culture supernatant, a recombinant, engineered or modified, attenuated, chemically treated, physically treated or inactivated bacteroides fragilis.
In some embodiments, the inactivation means comprises one or more of heat inactivation, pasteurization, dry heat inactivation, short wave Ultraviolet (UVC) methods.
In some of these embodiments, the radiation intestinal injury comprises a radiation injury of the small intestine, colon, rectum.
In some of these embodiments, the radiation intestinal injury comprises radiation injury to the mucosa of the small intestine, colon, rectum.
In some of these embodiments, the radiation intestinal injury comprises an acute radiation intestinal injury, a chronic radiation intestinal injury.
In some of these embodiments, the radiation intestinal injury comprises acute radiation small intestine injury, acute radiation rectal injury, chronic radiation small intestine injury, chronic radiation rectal injury.
In some of these embodiments, the treatment comprises an improvement in clinical symptoms, preferably an improvement in clinical symptoms of radiation bowel injury including diarrhea, abdominal pain, hematochezia, and gastrointestinal bleeding.
In some embodiments, the food product is selected from any one of milk powder, cheese, curd, yogurt, ice cream, milk-based fermented food, fermented cereal. The food product may also be an animal food product, such as a feed or the like. The food product may also be an infant food or a pet food.
In some embodiments, the medicament comprises one or more of the following pharmaceutically acceptable excipients: diluents, excipients, binders, lubricants, suspending agents, coating agents and solubilizing agents; preferably, the pharmaceutically acceptable excipients are: water, saline solution, alcohol, silicone, wax, petrolatum, vegetable oil, polyethylene glycol, propylene glycol, liposomes, sugars, gelatin, lactose, amylose, magnesium stearate, talc, surfactants, silicic acid, viscous paraffin, aromatic oil, one or more of mono-and di-fatty acid glycerides, petrochemical (fatty) esters, hydroxymethyl cellulose, polyvinylpyrrolidone.
In some embodiments, the pharmaceutical is in the form of a pill, tablet, granule, capsule, oral liquid, or tube feeding formulation.
In some embodiments, the medicament comprises a human medicament or an animal medicament, and is useful for humans or animals.
In some embodiments, the bacteroides fragilis may be administered prophylactically or therapeutically alone, or in combination with other probiotics and/or probiotic materials; when administered in combination, the administration may be performed in a single formulation or in separate formulations, simultaneously or at different times, using the same or different routes of administration.
In a second aspect, the invention provides application of bacteroides fragilis capsular polysaccharide A or bacteroides fragilis extract containing polysaccharide capsular A in preparing a medicament or food for preventing and/or treating radiation intestinal injury, wherein bacteroides fragilis is bacteroides fragilis ZY-312 with a preservation number of CGMCC No.10685, and the weight average molecular weight of bacteroides fragilis capsular polysaccharide A is 5-110KD;
preferably, the weight average molecular weight of the bacteroides fragilis capsular polysaccharide A is 80-90KD.
In some of these embodiments, the radiation intestinal injury comprises a radiation injury of the small intestine, colon, rectum.
In some of these embodiments, the radiation intestinal injury comprises radiation injury to the mucosa of the small intestine, colon, rectum.
In some of these embodiments, the radiation intestinal injury comprises an acute radiation intestinal injury, a chronic radiation intestinal injury.
In some of these embodiments, the radiation intestinal injury comprises acute radiation small intestine injury, acute radiation rectal injury, chronic radiation small intestine injury, chronic radiation rectal injury.
In some of these embodiments, the treatment comprises an improvement in clinical symptoms, preferably an improvement in clinical symptoms of radiation bowel injury including diarrhea, abdominal pain, hematochezia, and gastrointestinal bleeding.
In some of these embodiments, the content of bound lipid in bacteroides fragilis capsular polysaccharide a is less than 0.02%, and/or the protein residue is less than 1%, and/or the nucleic acid residue is less than 0.05%.
In some of these embodiments, the Bacteroides fragilis capsular polysaccharide A has a Mw/Mn of 1.0-1.3 and/or the portion of the Mw distribution from 70KD to 100KD is 70-80% of the total amount.
In some embodiments, the food product is selected from any one of milk powder, cheese, curd, yogurt, ice cream, milk-based fermented food, fermented cereal. The food product may also be an animal food product, such as a feed or the like. The food product may also be an infant food or a pet food.
In some embodiments, the medicament comprises one or more of the following pharmaceutically acceptable excipients: diluents, excipients, binders, lubricants, suspending agents, coating agents and solubilizing agents; preferably, the pharmaceutically acceptable excipients are: water, saline solution, alcohol, silicone, wax, petrolatum, vegetable oil, polyethylene glycol, propylene glycol, liposomes, sugars, gelatin, lactose, amylose, magnesium stearate, talc, surfactants, silicic acid, viscous paraffin, aromatic oil, one or more of mono-and di-fatty acid glycerides, petrochemical (fatty) esters, hydroxymethyl cellulose, polyvinylpyrrolidone.
In some embodiments, the pharmaceutical is in the form of a pill, tablet, granule, capsule, oral liquid, or tube feeding formulation.
In some embodiments, the medicament comprises a human medicament or an animal medicament, and is useful for humans or animals.
In some embodiments, the Bacteroides fragilis capsular polysaccharide A may be administered prophylactically or therapeutically alone, or in combination with other probiotics and/or probiotic materials; when administered in combination, the administration may be performed in a single formulation or in separate formulations, simultaneously or at different times, using the same or different routes of administration.
In some of these embodiments, the method of preparing bacteroides fragilis capsular polysaccharide a comprises the steps of:
(1) Taking bacterial sludge of a Bacteroides fragilis ZY-312 fermentation culture, adding purified water to suspend the bacterial sludge, adjusting the pH of the bacterial sludge to 3.5 by using a hydrochloric acid solution, extracting, cooling to room temperature, centrifuging, and taking a supernatant to obtain a crude sugar solution; preferably, the pH is adjusted by using 1mol/L hydrochloric acid solution, and/or the extraction condition is 100 ℃, the extraction time is 1.5h, and/or the centrifugation condition is 12000g and the centrifugation is carried out at normal temperature for 10min;
(2) Ultrafiltering and concentrating the crude sugar solution with 10KD ultrafilter membrane to remove small molecular impurities until the conductivity is stable, and collecting the reflux;
(3) Adding 40mmol/L Tris-HCl salt in equal volume into the reflux liquid; DEAE Sepharose Fast Flow separating by ion exchange column chromatography, tracking and monitoring by SEC-HPLC, mixing components with single and symmetrical peak absorption peak at 206nm, ultrafiltering with 10KD ultrafilter membrane, adding purified water, ultrafiltering repeatedly until conductivity is stable, collecting reflux liquid, and lyophilizing to obtain Bacteroides fragilis capsular polysaccharide A; preferably, the column used in DEAE Sepharose Fast Flow ion exchange column chromatography is 16mm by 200mm, the flow rate is 20mL/min,20mmol/LTris-HCl gradient elution is 25 column volumes, and the column is collected in sections, 100 mL/bottle.
In some embodiments, the method of preparing a bacterial sludge of a bacteroides fragilis fermentation culture comprises:
inoculating a single colony into plant source peptone broth for fermentation culture, centrifuging and precipitating the obtained bacterial liquid, removing supernatant, and collecting precipitate to obtain Bacteroides fragilis ZY-312 bacterial mud; preferably, the conditions of the fermentation culture are 8 hours, 37 ℃, and/or the conditions of centrifugal precipitation are 3000r/min rotational speed and 15min centrifugation.
In a third aspect, the invention provides a composition for preventing and/or treating radiation intestinal injury, which comprises bacteroides fragilis ZY-312 with the preservation number of CGMCC No.10685.
In some of these embodiments, the composition is a food composition or a pharmaceutical composition.
In some embodiments, the bacteroides fragilis is a live or inactivated bacterium.
In some embodiments, the bacteroides fragilis is one or more of a live bacteroides fragilis thallus, a bacteroides fragilis lysate, a bacteroides fragilis liquid culture supernatant, a recombinant, engineered or modified, attenuated, chemically treated, physically treated or inactivated bacteroides fragilis.
In some embodiments, the inactivation means comprises one or more of heat inactivation, pasteurization, dry heat inactivation, short wave Ultraviolet (UVC) methods.
In some of these embodiments, the radiation intestinal injury comprises a radiation injury of the small intestine, colon, rectum.
In some of these embodiments, the radiation intestinal injury comprises radiation injury to the mucosa of the small intestine, colon, rectum.
In some of these embodiments, the radiation intestinal injury comprises an acute radiation intestinal injury, a chronic radiation intestinal injury.
In some of these embodiments, the radiation intestinal injury comprises acute radiation small intestine injury, acute radiation rectal injury, chronic radiation small intestine injury, chronic radiation rectal injury.
In some of these embodiments, the treatment comprises an improvement in clinical symptoms, preferably an improvement in clinical symptoms of radiation bowel injury including diarrhea, abdominal pain, hematochezia, and gastrointestinal bleeding.
In some embodiments, the food product is selected from any one of milk powder, cheese, curd, yogurt, ice cream, milk-based fermented food, fermented cereal. The food product may also be an animal food product, such as a feed or the like. The food product may also be an infant food or a pet food.
In some embodiments, the medicament comprises one or more of the following pharmaceutically acceptable excipients: diluents, excipients, binders, lubricants, suspending agents, coating agents and solubilizing agents; preferably, the pharmaceutically acceptable excipients are: water, saline solution, alcohol, silicone, wax, petrolatum, vegetable oil, polyethylene glycol, propylene glycol, liposomes, sugars, gelatin, lactose, amylose, magnesium stearate, talc, surfactants, silicic acid, viscous paraffin, aromatic oil, one or more of mono-and di-fatty acid glycerides, petrochemical (fatty) esters, hydroxymethyl cellulose, polyvinylpyrrolidone.
In some embodiments, the pharmaceutical is in the form of a pill, tablet, granule, capsule, oral liquid, or tube feeding formulation.
In some embodiments, the medicament comprises a human medicament or an animal medicament, and is useful for humans or animals.
In some embodiments, the bacteroides fragilis may be administered prophylactically or therapeutically alone, or in combination with other probiotics and/or probiotic materials; when administered in combination, the administration may be performed in a single formulation or in separate formulations, simultaneously or at different times, using the same or different routes of administration.
In a fourth aspect, the invention provides a composition for preventing and/or treating radiation intestinal injury, the composition comprises bacteroides fragilis capsular polysaccharide A or bacteroides fragilis extract containing polysaccharide capsular A, bacteroides fragilis is bacteroides fragilis ZY-312 with a preservation number of CGMCC No.10685, and the weight average molecular weight of the bacteroides fragilis capsular polysaccharide A is 5-110KD;
preferably, the weight average molecular weight of the bacteroides fragilis capsular polysaccharide A is 80-90KD.
In some of these embodiments, the composition is a food composition or a pharmaceutical composition.
In some of these embodiments, the radiation intestinal injury comprises a radiation injury of the small intestine, colon, rectum.
In some of these embodiments, the radiation intestinal injury comprises radiation injury to the mucosa of the small intestine, colon, rectum.
In some of these embodiments, the radiation intestinal injury comprises acute radiation intestinal injury, chronic acute radiation intestinal injury.
In some of these embodiments, the radiation intestinal injury comprises acute radiation small intestine injury, acute radiation rectal injury, chronic radiation small intestine injury, chronic radiation rectal injury.
In some of these embodiments, the treatment comprises an improvement in clinical symptoms, preferably an improvement in clinical symptoms of radiation bowel injury including diarrhea, abdominal pain, hematochezia, and gastrointestinal bleeding.
In some of these embodiments, the content of bound lipid in bacteroides fragilis capsular polysaccharide a is less than 0.02%, and/or the protein residue is less than 1%, and/or the nucleic acid residue is less than 0.05%.
In some of these embodiments, the Bacteroides fragilis capsular polysaccharide A has a Mw/Mn of 1.0-1.3 and/or the portion of the Mw distribution from 70KD to 100KD is 70-80% of the total amount.
In some embodiments, the food product is selected from any one of milk powder, cheese, curd, yogurt, ice cream, milk-based fermented food, fermented cereal. The food product may also be an animal food product, such as a feed or the like. The food product may also be an infant food or a pet food.
In some embodiments, the medicament comprises one or more of the following pharmaceutically acceptable excipients: diluents, excipients, binders, lubricants, suspending agents, coating agents and solubilizing agents; preferably, the pharmaceutically acceptable excipients are: water, saline solution, alcohol, silicone, wax, petrolatum, vegetable oil, polyethylene glycol, propylene glycol, liposomes, sugars, gelatin, lactose, amylose, magnesium stearate, talc, surfactants, silicic acid, viscous paraffin, aromatic oil, one or more of mono-and di-fatty acid glycerides, petrochemical (fatty) esters, hydroxymethyl cellulose, polyvinylpyrrolidone.
In some embodiments, the pharmaceutical is in the form of a pill, tablet, granule, capsule, oral liquid, or tube feeding formulation.
In some embodiments, the medicament comprises a human medicament or an animal medicament, and is useful for humans or animals.
In some embodiments, the Bacteroides fragilis capsular polysaccharide A may be administered prophylactically or therapeutically alone, or in combination with other probiotics and/or probiotic materials; when administered in combination, the administration may be performed in a single formulation or in separate formulations, simultaneously or at different times, using the same or different routes of administration.
In some of these embodiments, the method of preparing bacteroides fragilis capsular polysaccharide a comprises the steps of:
(1) Taking bacterial sludge of a Bacteroides fragilis ZY-312 fermentation culture, adding purified water to suspend the bacterial sludge, adjusting the pH of the bacterial sludge to 3.5 by using a hydrochloric acid solution, extracting, cooling to room temperature, centrifuging, and taking a supernatant to obtain a crude sugar solution; preferably, the pH is adjusted by using 1mol/L hydrochloric acid solution, and/or the extraction condition is 100 ℃, the extraction time is 1.5h, and/or the centrifugation condition is 12000g and the centrifugation is carried out at normal temperature for 10min;
(2) Ultrafiltering and concentrating the crude sugar solution with 10KD ultrafilter membrane to remove small molecular impurities until the conductivity is stable, and collecting the reflux;
(3) Adding 40mmol/L Tris-HCl salt in equal volume into the reflux liquid; DEAE Sepharose Fast Flow separating by ion exchange column chromatography, tracking and monitoring by SEC-HPLC, mixing components with single and symmetrical peak absorption peak at 206nm, ultrafiltering with 10KD ultrafilter membrane, adding purified water, ultrafiltering repeatedly until conductivity is stable, collecting reflux liquid, and lyophilizing to obtain Bacteroides fragilis capsular polysaccharide A; preferably, the column used in DEAE Sepharose Fast Flow ion exchange column chromatography is 16mm by 200mm, the flow rate is 20mL/min,20mmol/LTris-HCl gradient elution is 25 column volumes, and the column is collected in sections, 100 mL/bottle.
In some embodiments, the method of preparing a bacterial sludge of a bacteroides fragilis fermentation culture comprises:
inoculating a single colony into plant source peptone broth for fermentation culture, centrifuging and precipitating the obtained bacterial liquid, removing supernatant, and collecting precipitate to obtain Bacteroides fragilis ZY-312 bacterial mud; preferably, the conditions of the fermentation culture are 8 hours, 37 ℃, and/or the conditions of centrifugal precipitation are 3000r/min rotational speed and 15min centrifugation.
The beneficial effects of the invention are as follows:
the invention explores a new application of bacteroides fragilis and opens up a new application field. Experiments prove that the bacteroides fragilis and the capsular polysaccharide A thereof are safe and nontoxic, have strong pharmacological action and have good treatment effect on the radioactive intestinal injury, thereby indicating that the bacteroides fragilis and the capsular polysaccharide A thereof have good diet therapy and medicinal prospect. The bacteroides fragilis can be used as a probiotic for preparing foods or medicines for treating acute radioactive intestinal injury.
Drawings
FIG. 1 is a graph of colony characteristics of Bacteroides fragilis ZY-312 of example 1;
FIG. 2 is a view of a gram-stained Bacteroides fragilis ZY-312 of example 1 after microscopic observation;
FIG. 3 is a chart of the analysis of the capsular polysaccharide A nuclear magnetic resonance spectrometer of example 2;
a-E are respectively 1H spectrum, 13C spectrum, COSY spectrum, HSQC spectrum, HMBC spectrum of capsular polysaccharide a nmr spectrometer analysis of example 2;
FIG. 4 shows the chemical structural formula of the structural unit of Bacteroides fragilis capsular polysaccharide A prepared in example 2.
FIG. 5 is a graph showing apparent therapeutic effects of example 3, wherein A is the weight loss fraction, B is the small intestine length, and C is the colon length (. P)<0.05，**P<0.01，***P<0.001 represents a significant difference compared to group B; # P<0.05， ## P<0.01， ### P<0.001 represents a significant difference compared to group C1).
FIG. 6 is a schematic diagram of the pathology of example 3, wherein A is a diagram of intestinal tissue pathology in different fold views, and B is a histopathology scoreC is the intestinal crypt length (<0.001 represents a significant difference compared to group B; # P<0.05, ## P<0.01, ### P<0.001 represents a significant difference compared to group C1).
FIG. 7 is a schematic representation of the staining of proliferation indexes Ki-67, lgr5 of example 3, wherein the immunohistochemical staining pattern of the small intestinal mucosa Ki-67 (upper), the immunofluorescent staining pattern of Ki-67 (middle), and the immunofluorescent staining pattern of Lgr5 (middle) are shown, respectively.
Fig. 8 is a schematic diagram of intestinal mucus index AB-PAS (Alcian blue and Periodic acid Schiff staining, chikungunya periodate staining) and MUC2 staining of example 3, wherein immunofluorescence staining patterns of small intestinal mucosa MUC2 are shown (top), respectively; AB-PAS staining chart (bottom).
FIG. 9 is a schematic representation of staining of tight junction molecules Claudin-1, ZO-1 of example 3, wherein immunofluorescence staining patterns of small intestinal mucosa Claudin-1 are shown, respectively (upper); immunofluorescence staining pattern of ZO-1 (bottom).
FIG. 10 is a schematic diagram showing detection of proliferation signaling pathway of STAT3 in example 3, wherein A is western blotting diagram of expression level of each proliferation pathway of intestinal mucosa epithelial cells, and B is immunohistochemical staining diagram of STAT3 phosphorylation of intestinal tissue.
FIG. 11 is a schematic diagram of intestinal flora sequencing in example 3, A is a histogram of the relative abundance of intestinal fecal flora between each sample, B is a histogram of the relative abundance of intestinal fecal flora between groups, C is a differential bacterial flora analysis between groups of LEfSe (Line Discriminant Analysis (LDA) Effect Size), and D is a branching chart of the evolution of the LEfSe analysis.
Detailed Description
The technical scheme of the invention will be further described in detail below with reference to specific embodiments. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention.
Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods.
Example 1: fermentation culture of bacteroides fragilis
The bacteroides fragilis ZY-312 strain is streaked and inoculated on a blood plate for anaerobic culture for 48 hours. Colony morphology, staining characteristics, size, sphere shape, distribution, etc. were observed.
Colony characteristics: after the bacteroides fragilis ZY-312 is cultured on a blood plate for 48 hours, the bacteroides fragilis ZY-312 is slightly convex, semitransparent, white, smooth in surface and free from hemolysis, and the colony diameter is between 1 and 3mm, as shown in figure 1.
Morphology under microscope: the bacteroides fragilis ZY-312 was subjected to gram-stain microscopic examination to show a typical rod shape for gram-negative bacteria, and was rounded at both ends to be densely stained, and the non-colored part in the middle of the thallus was formed as a cavitation, see FIG. 2.
(1) And (3) selecting a single colony, inoculating the single colony into plant source peptone broth, fermenting and culturing for 8 hours (the temperature is 37 ℃), centrifuging and precipitating the obtained bacterial liquid at the rotating speed of 3000r/min for 15min, removing the supernatant, and collecting the precipitate to obtain the bacteroides fragilis ZY-312 bacterial sludge. And preparing ZY-312 viable bacteria liquid.
(2) And taking the bacterial liquid, and carrying out conventional heat inactivation treatment and pasteurization treatment to respectively prepare the bacteroides fragilis ZY-312 heat inactivation bacterial liquid and the pasteurization bacterial liquid.
(3) The same method is used for fermentation culture to prepare NCTC9343 viable bacteria liquid and Bd-312 viable bacteria liquid. EXAMPLE 2 preparation of Bacteroides fragilis capsular polysaccharide A
Experiments were performed using the bacterial sludge prepared in example 1.
(1) Taking 50g of bacterial sludge, adding 300g of purified water to enable the bacterial sludge to be re-suspended, adjusting the pH of the bacterial sludge to 3.5 by using 1mol/L hydrochloric acid solution, extracting for 1.5h at 100 ℃, cooling to room temperature, centrifuging for 10min at 12000g of room temperature, and taking the supernatant to obtain a crude sugar solution;
(2) Ultrafiltering and concentrating the crude sugar solution with 10KD ultrafilter membrane to remove small molecular impurities until the conductivity is stable, and collecting the reflux;
(3) Adding an equal volume of 40mmol/L Tris-HCl (pH 8.5) salt to the reflux liquid; DEAE Sepharose Fast Flow ion exchange column chromatography (16 mm. Times.200 mm), gradient eluting with 20mL/min flow rate, 20mmol/L Tris-HCl (pH 8.5, containing 0.2mol/L NaCl) for 25 column volumes, collecting in sections, collecting 100 mL/bottle (component), tracking and monitoring by SEC-HPLC, combining components with 206nm absorption peak as single and symmetrical peak, ultrafiltering with 10KD ultrafiltration membrane, adding purified water, repeatedly ultrafiltering until conductivity is stable, collecting reflux liquid, and lyophilizing to obtain Bacteroides fragilis extract;
(4) Weighing 30mg of the Bacteroides fragilis extract in step (3), and dissolving in 0.5mL D 2 O, 1. Mu.l of acetone (1H, 2.22;13C, 30.89) was added for calibration. Analysis of the 1H and 13C, COSY, HSQC, HMBC spectra (see FIGS. 3A-E) using a 500MHz Bruker NMR spectrometer confirmed that the Bacteroides fragilis extract collected in step (3) was capsular polysaccharide A, the bound lipid content was less than 0.02%, the protein residue was less than 1%, and the nucleic acid residue was less than 0.05%. The weight average molecular weight of the prepared capsular polysaccharide A is 80-90kDa, mw/Mn is 1.0-1.3, and the Mw is distributed in 70KD-100KD and accounts for 70-80% of the total weight by GPC (gel permeation chromatography) analysis; see fig. 4 for chemical structure.
EXAMPLE 3 therapeutic Effect of Bacteroides fragilis and capsular polysaccharide A (PSA) on radiation-induced intestinal injury
The following experiments were conducted using the live bacterial liquid of Bacteroides fragilis ZY-312, the heat-inactivated bacterial liquid of Bacteroides fragilis ZY-312, the pasteurized bacterial liquid of Bacteroides fragilis ZY-312, the live bacterial liquid of Bacteroides fragilis NCTC9343, and the live bacterial liquid of Bacteroides fragilis Bd-312 prepared in example 1, and the PSA prepared in example 2.
(1) Model building and grouping
240C 57BL/6 mice were randomly divided into 5 groups, wherein group A is a blank group (N=30), group B is a conventional dose irradiation group (N=30), group C is a Bacteroides fragilis ZY-312 treatment group (N=90), group D is a Bacteroides fragilis capsular polysaccharide A (PSA) treatment group (N=30), group E is a Bacteroides fragilis NCTC9343 treatment group (N=30), and group F is a Bacteroides fragilis Bd-312 treatment group (N=30). Mice were fasted for 4h, weighed, anesthetized with pentobarbital sodium (50 mg/kg) and fixed in supine position on a plexiglass plate, irradiated with high energy X-ray linac to the whole abdomen, from the xiphoid process to the pubic symphysis, irradiated at an area of 3.7X 3.7cm 2 The rest parts are shielded by lead plates with the thickness of 5cm, the irradiation depth is 4cm, and the occurrence dose rate is 500cGy/min. Wherein the irradiation dose of the B group is 10Gy, and the C group, the E group and the F group are all 10Gy abdomenAdministration of 10 on the basis of partial irradiation 9 cfu/ml, 200ul of each of the Bacteroides fragilis gastric lavage treatments per day, and 50 ug/each of the group D is given with 10Gy abdominal irradiation, and 200ul of each of the group D is given with PSA gastric lavage treatments per day; group A mice were not irradiated and were perfused with 200 ul/saline.
Experimental group C was randomized into 3 groups: groups C1, C2 and C3, 30 groups each, 10 groups after C1 irradiation 9 cfu/ml, 200ul of live bacterial liquid of bacteroides fragilis per day are irrigated with stomach (n=30); administration of 10 after C2 group irradiation 9 The cells/ml, each 200ul of the pasteurized inactivated bacteria liquid of Bacteroides fragilis per day is irrigated with stomach (N=30); administration of 10 after C3 group irradiation 9 cells/ml, 200ul of each of the heat-inactivated bacterial solutions of Bacteroides fragilis per day were perfused (n=30).
(2) Observation index and specimen collection
After successful modeling, mice were observed daily for general conditions including mental state, mobility, weight, diarrhea, and bowel movement. Each group was tested for draw material 15 on days 15 and 28, respectively. Taking intestinal feces in a strict sterile state after the dislocation of cervical vertebra and the sacrifice, and carrying out 16srRNA sequencing to detect the proportion of intestinal flora; the small intestine between the distal stomach end and the proximal cecum end was then divided on average into 4 equal swiss rolls for pathological section, intestinal mucus staining, and molecular biological detection, respectively.
(3) Experimental results
After irradiation, mice in groups B-F showed reduced mobility, hair rise, weight loss, with varying degrees of diarrhea and bloody stool. As shown in FIG. 5, there was a significant difference in both group D (PSA group) and group C1 (ZY-312 viable bacteria group) compared to group B (modeling group) (P<0.05,P<0.01 or P<0.001 Group C1 mice had better mental state, high mobility, low weight loss, low diarrhea and bloody stool severity, and low intestinal and colon shortening; the C1 groups all have significant differences compared to the E and F groups (P<0.05；P<0.01 or P<0.001 The weight recovery of the mice is quick, the diarrhea and the bloody stool symptoms are improved to a great extent, and the small intestine and colon are shortened to a small extent. And (3) injection: * P (P)<0.05，**P<0.01，***P<0.001 represents a significant difference compared to group B; # P<0.05， ## P<0.01， ### P<0.001 represents a significant difference compared to group C1.
The results of small intestine histopathology are shown in fig. 6, wherein B, C, C2, C3, D, E and F small intestine villi are shed and eroded to different degrees, villi height and crypt depth are reduced, cell mitosis phase in intestinal crypt is reduced, inflammatory cell infiltration is accompanied, wherein group B (modeling group) villi is the most sparse, shedding is the most severe, and other groups are relatively light in severity. Compared with group B, the C1, C2, C3 and D all have significant differences (P<0.001 The villi of the C1 and D groups are complete, the villi height and the crypt depth are large, the mitotic phase of cells in the crypt is common, a small amount of inflammatory cells infiltrate, and the villi is C2 and C3 times. The C1 group had a significant difference compared to the E, F group (P<0.05，P<0.01 or P<0.001 The inflammatory cell infiltration is less severe, with a concomitant decrease in pathology score and increase in crypt length. And (3) injection: * P:<0.001 represents a significant difference compared to group B; # P<0.05, ## P<0.01, ### P<0.001 represents a significant difference compared to group C1.
As shown in FIG. 7, the intestinal proliferation index staining results show that the expression level of the proliferation index Ki-67 and the proliferation index Lgr5 in the B group is obviously reduced, and the expression level of the proliferation index Ki-67 and the proliferation index Lgr5 in the C1 and the D groups is higher compared with that in the A group.
As shown in FIG. 8, the results of intestinal tract mucus staining are shown in the following figures, compared with the group A, the group B has less intestinal tract goblet cell density, sparse mucus distribution and low MUC2 expression content, while the group C1 and group D have dense small intestinal goblet cell distribution, more secretory mucus and higher MUC2 expression level.
The results of the barrier index staining are shown in FIG. 9, wherein C1 significantly up-regulates the expression of the barrier indices ZO-1, claudin-1 compared to group B.
The western blot and immunohistochemical results are shown in fig. 10, and compared with group B, group C1 significantly up-regulates STAT3 signaling in the intestinal mucosal epithelium.
The 16srRNA sequencing results are shown in FIG. 11, in which the proportion of the Deuteromycota in group B was down-regulated and the proportion of the Deuteromycota in group A was up-regulated. Compared with group B, the C1 thick-walled mycota has higher abundance, the Proteus has lower abundance and is accompanied by up-regulation of a certain proportion of beneficial clostridium bacteria.
The experimental results show that: bacteroides fragilis ZY-312 and capsular polysaccharide A thereof can improve radioactive intestinal injury of mice by promoting intestinal mucosa proliferation repair (including epithelial cell proliferation, mucus secretion and tight junction repair). The bacteroides fragilis promotes small intestine mucous membrane proliferation, mucous secretion and tight connection repair mainly through up-regulating STAT3 signal pathway, and has a regulating effect on intestinal flora. The treatment effect of the live bacteria ZY-312 of the bacteroides fragilis is better than that of the bacteroides fragilis after pasteurization and heat inactivation.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (8)
1. An application of bacteroides fragilis in preparing a medicine or food for preventing and/or treating radioactive intestinal injury, wherein the bacteroides fragilis is bacteroides fragilis ZY-312 with a preservation number of CGMCC No. 10685;
preferably, the bacteroides fragilis is a live bacterium or an inactivated bacterium;
preferably, the bacteroides fragilis is one or more of live bacteroides fragilis thallus, bacteroides fragilis subjected to gene recombination, transformation or modification, attenuation, chemical treatment, physical treatment or inactivation, bacteroides fragilis lysate and bacteroides fragilis liquid culture supernatant;
preferably, the inactivation means comprises one or more of heat inactivation, pasteurization, dry heat inactivation, short wave Ultraviolet (UVC) methods;
preferably, the radiation intestinal injury comprises radiation injury of small intestine, colon and rectum;
preferably, the radioactive intestinal injury comprises radioactive injury of mucous membranes of small intestine, colon and rectum;
preferably, the radiation intestinal injury comprises acute radiation intestinal injury and chronic radiation intestinal injury;
preferably, the radioactive intestinal injury comprises acute radioactive small intestine injury, acute radioactive rectal injury, chronic radioactive small intestine injury, and chronic radioactive rectal injury;
preferably, the treatment comprises an improvement in clinical symptoms, more preferably an improvement in clinical symptoms of radiation intestinal injury comprising diarrhea, abdominal pain, hematochezia, and gastrointestinal bleeding.
2. The use according to claim 1, wherein,
the food is selected from any one of milk powder, cheese, curd, yogurt, ice cream, milk-based fermented food, and fermented cereal; the food may also be an animal food, such as feed, etc.; the food product may also be an infant food or a pet food.
3. The use according to claim 1, wherein,
the medicine comprises one or more of the following pharmaceutically acceptable auxiliary materials: diluents, excipients, binders, lubricants, suspending agents, coating agents and solubilizing agents; preferably, the pharmaceutically acceptable excipients are: one or more of water, saline solution, alcohol, silicone, wax, petrolatum, vegetable oil, polyethylene glycol, propylene glycol, liposomes, saccharides, gelatin, lactose, amylose, magnesium stearate, talc, surfactants, silicic acid, viscous paraffin, aromatic oil, mono-and di-fatty acid glycerides, petrochemical (fatty acid esters), hydroxymethyl cellulose, polyvinylpyrrolidone;
preferably, the dosage form of the medicine is pill, tablet, granule preparation, capsule, oral liquid or tube feeding preparation;
preferably, the medicament comprises a human medicament or an animal medicament, which is useful for humans or animals;
preferably, the bacteroides fragilis can be administered prophylactically or therapeutically alone or in combination with other probiotics and/or probiotic materials; when administered in combination, the administration may be performed in a single formulation or in separate formulations, simultaneously or at different times, using the same or different routes of administration.
4. An application of bacteroides fragilis capsular polysaccharide A or bacteroides fragilis extractive containing polysaccharide capsular A in preparing medicines or foods for preventing and/or treating radioactive intestinal injury, wherein the bacteroides fragilis is bacteroides fragilis ZY-312 with a preservation number of CGMCC No.10685, and the weight average molecular weight of the bacteroides fragilis capsular polysaccharide A is 5-110KD;
preferably, the weight average molecular weight of the bacteroides fragilis capsular polysaccharide A is 80-90KD;
preferably, the radiation intestinal injury comprises radiation injury of small intestine, colon and rectum;
preferably, the radioactive intestinal injury comprises radioactive injury of mucous membranes of small intestine, colon and rectum;
preferably, the radiation intestinal injury comprises acute radiation intestinal injury and chronic radiation intestinal injury;
preferably, the radioactive intestinal injury comprises acute radioactive small intestine injury, acute radioactive rectal injury, chronic radioactive small intestine injury, and chronic radioactive rectal injury;
preferably, the treatment comprises an improvement in clinical symptoms, more preferably an improvement in clinical symptoms of radiation bowel injury including diarrhea, abdominal pain, hematochezia, gastrointestinal bleeding;
preferably, the content of bound lipids in bacteroides fragilis capsular polysaccharide a is less than 0.02%, and/or the protein residue is less than 1%, and/or the nucleic acid residue is less than 0.05%;
preferably, the Bacteroides fragilis capsular polysaccharide A has a Mw/Mn of 1.0-1.3 and/or the Mw is distributed in a fraction of 70KD-100KD accounting for 70-80% of the total.
5. The use according to claim 4, wherein,
the food is selected from any one of milk powder, cheese, curd, yogurt, ice cream, milk-based fermented food, and fermented cereal; the food may also be an animal food, such as feed, etc.; the food product may also be an infant food or a pet food.
6. The use according to claim 4, wherein,
the medicine comprises one or more of the following pharmaceutically acceptable auxiliary materials: diluents, excipients, binders, lubricants, suspending agents, coating agents and solubilizing agents; preferably, the pharmaceutically acceptable excipients are: one or more of water, saline solution, alcohol, silicone, wax, petrolatum, vegetable oil, polyethylene glycol, propylene glycol, liposomes, saccharides, gelatin, lactose, amylose, magnesium stearate, talc, surfactants, silicic acid, viscous paraffin, aromatic oil, mono-and di-fatty acid glycerides, petrochemical (fatty acid esters), hydroxymethyl cellulose, polyvinylpyrrolidone;
preferably, the dosage form of the medicine is pill, tablet, granule preparation, capsule, oral liquid or tube feeding preparation;
preferably, the medicament comprises a human medicament or an animal medicament, which is useful for humans or animals;
preferably, the bacteroides fragilis capsular polysaccharide A can be administered prophylactically or therapeutically alone or in combination with other probiotics and/or probiotic materials; when administered in combination, the administration may be performed in a single formulation or in separate formulations, simultaneously or at different times, using the same or different routes of administration.
7. The use according to any one of claims 4-6, wherein,
the preparation method of the bacteroides fragilis capsular polysaccharide A comprises the following steps:
(1) Taking bacterial sludge of a Bacteroides fragilis ZY-312 fermentation culture, adding purified water to suspend the bacterial sludge, adjusting the pH of the bacterial sludge to 3.5 by using a hydrochloric acid solution, extracting, cooling to room temperature, centrifuging, and taking a supernatant to obtain a crude sugar solution; preferably, the pH is adjusted by using 1mol/L hydrochloric acid solution, and/or the extraction condition is 100 ℃, the extraction time is 1.5h, and/or the centrifugation condition is 12000g and the centrifugation is carried out at normal temperature for 10min;
(2) Ultrafiltering and concentrating the crude sugar solution with 10KD ultrafilter membrane to remove small molecular impurities until the conductivity is stable, and collecting the reflux;
(3) Adding 40mmol/L Tris-HCl salt in equal volume into the reflux liquid; DEAE Sepharose Fast Flow separating by ion exchange column chromatography, tracking and monitoring by SEC-HPLC, mixing components with single and symmetrical peak absorption peak at 206nm, ultrafiltering with 10KD ultrafilter membrane, adding purified water, ultrafiltering repeatedly until conductivity is stable, collecting reflux liquid, and lyophilizing to obtain Bacteroides fragilis capsular polysaccharide A; preferably, the column used in DEAE Sepharose Fast Flow ion exchange column chromatography is 16mm by 200mm, the flow rate is 20mL/min,20mmol/L Tris-HCl gradient elution is 25 column volumes, and the column is collected in sections, 100 mL/bottle.
8. The use according to claim 7, wherein,
the preparation method of the bacterial sludge of the bacteroides fragilis fermentation culture in the step (1) comprises the following steps:
inoculating a single colony into plant source peptone broth for fermentation culture, centrifuging and precipitating the obtained bacterial liquid, removing supernatant, and collecting precipitate to obtain Bacteroides fragilis ZY-312 bacterial mud; preferably, the conditions of the fermentation culture are 8 hours, 37 ℃, and/or the conditions of centrifugal precipitation are 3000r/min rotational speed and 15min centrifugation.
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