CN116083294B - Lactobacillus reuteri and application thereof in preparation of preparation product for preventing or treating preeclampsia - Google Patents

Lactobacillus reuteri and application thereof in preparation of preparation product for preventing or treating preeclampsia Download PDF

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CN116083294B
CN116083294B CN202211469452.5A CN202211469452A CN116083294B CN 116083294 B CN116083294 B CN 116083294B CN 202211469452 A CN202211469452 A CN 202211469452A CN 116083294 B CN116083294 B CN 116083294B
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preeclampsia
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lactobacillus reuteri
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周宏伟
张冬鑫
李炳宇
曾山水
陈慕璇
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Southern Medical University Zhujiang Hospital
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Abstract

The application discloses a strain, lactobacillus reuteri (Limosilactobacillus reuteri, CALM 603), with a preservation number of CGMCC No.25407. The strain has outstanding effects in regulating intestinal flora, improving vascular endothelial function, improving preeclampsia symptoms and the like, can effectively balance intestinal microecology after being planted in intestinal tracts, increases intestinal beneficial bacteria, avoids intestinal flora disorder and improves the condition of intestinal flora disorder in preeclampsia; the intervention of lactobacillus reuteri can promote the organism in preeclampsia to produce nitric oxide which is a substance for regulating vascular endothelial activity, inhibit the expression level of anti-angiogenic factors and up-regulate the expression level of pro-angiogenic factors, improve the related symptoms in preeclampsia, and has wide market application prospect.

Description

Lactobacillus reuteri and application thereof in preparation of preparation product for preventing or treating preeclampsia
Technical Field
The application relates to the technical field of medical microorganisms, in particular to lactobacillus reuteri and application thereof in preparation of a preparation product for preventing or treating preeclampsia.
Background
Preeclampsia refers to pregnancy syndrome of pregnant women with normal pre-pregnancy blood pressure, which has clinical symptoms such as hypertension, proteinuria and the like after 20 weeks of pregnancy, is a main cause of morbidity and mortality of mothers and fetuses, seriously endangers the health of babies and infants, but clinically has no effective treatment mode except delivery, and at present, low-dose aspirin is clinically usually given for prevention or magnesium sulfate is given for alleviation when the morbidity.
A large number of researches show that normal intestinal microecology plays a vital role in maintaining human health and resisting diseases, and the intestinal microecology structure of pregnant women can be adaptively adjusted along with the occurrence and development of pregnancy, which is very important for maintaining normal pregnancy ending, and once maladaptation or dysbacteriosis occurs, pregnancy complications such as preeclampsia and the like can be caused. The research shows that the intestinal flora structure of the preeclampsia mice is abnormally changed, the bacterial abundance is obviously reduced, meanwhile, beneficial bacteria are obviously down-regulated, harmful bacteria are obviously increased, and the animal model of fecal bacteria transplantation is utilized to prove that the pregnant mice show typical clinical symptoms of preeclampsia after the preeclampsia patients are transplanted with fecal bacteria.
The probiotic products can improve intestinal microenvironment, but the conditions that the effect of improving preeclampsia by the probiotic products is not stable enough or the curative effect is not exact enough can occur, the components of the probiotic products are relatively complex, the specific beneficial components of the probiotics are not specific, the specific effects are not specific, the conditions that the effect of improving preeclampsia by different probiotic products is not stable enough or the curative effect is not exact enough can occur, and finally the real clinical effect is difficult to ensure.
Disclosure of Invention
The application aims to at least partially overcome the defects of the prior art and provide a strain and application of the strain in preparation of a preparation product for preventing or treating preeclampsia.
In order to achieve the technical purpose, the application adopts the following technical scheme:
a strain, the strainThe strain is Lactobacillus reuteriLimosilactobacillus reuteri) The preservation number of the strain is CGMCC NO.25407.
The use of the strain in the preparation of a formulation product for preventing or treating preeclampsia.
The preparation product is used for improving preeclampsia caused by vascular endothelial dysfunction.
The preparation product is used for regulating alpha diversity and beta diversity of intestinal flora.
The preparation product is used for improving the alpha diversity of intestinal flora. The preparation product is used for reducing colony structure difference of intestinal flora.
The preparation product is used for regulating placenta angiogenesis regulator.
The regulatory factor includes an anti-angiogenic factor, a pro-angiogenic factor, and nitric oxide.
The preparation product is used for inhibiting the expression of anti-angiogenic factors, promoting the expression of pro-angiogenic factors and promoting the synthesis of nitric oxide.
The active ingredient of the preparation product is the microbial inoculum of the strain.
The product comprises a medicament.
Biological preservation information:
lactobacillus reuteri of the applicationLimosilactobacillus reuteriCALM 603) strain, which was preserved in the China general microbiological culture collection center (CGMCC) (address: the preservation number is CGMCC NO.25407 in North Chen Xili No. 1 and 3 in the Chaoyang area of Beijing city.
Compared with the prior art, the application has the following advantages:
1) The strain can maintain intestinal microecology balance by adjusting the intestinal flora structure and the intestinal flora diversity, avoid preeclampsia caused by intestinal flora disorder, and relieve related symptoms by intervention of the strain after preeclampsia.
2) The strain of the application can promote the organism to produce and regulate vascular endothelial active substances and promote the expression of the angiogenesis factors by regulating the angiogenesis regulatory factors, inhibit the expression of the anti-angiogenesis factors, further improve the vascular endothelial cell function and realize the aim of improving preeclampsia.
3) The strain of the application can be used for adding into medicines for industrialized application and has wide market prospect.
Drawings
FIG. 1 is a colony growth morphology of the strain of the present application cultured on MRS plates;
FIG. 2 shows the mass spectrum identification results of the strain of the application;
FIG. 3 is a graph showing the results of intestinal colonization of a preeclampsia mouse model by the strain of the present application;
FIG. 4 is a graph showing the effect of the strain of the present application on the regulation of intestinal flora α diversity in a preeclampsia mouse model;
FIG. 5 is a graph showing the effect of the strain of the present application on the regulation of β -diversity in intestinal flora in a preeclampsia mouse model;
FIG. 6 is a graph showing the effect of the applied strain on the regulation of intestinal flora structure in a preeclampsia mouse model;
FIG. 7 is a graph showing the effect of the strain of the present application on preeclampsia mouse model intervention;
FIG. 8 is a graph showing the effect of the strain of the present application on placental angiogenesis in a pre-eclamptic mouse model;
FIG. 9 is a graph showing the effect of the strain of the present application on placental angiogenesis modulators in a pre-eclamptic mouse model;
FIG. 10 is a graph showing the regulation of nitric oxide synthesis by the strain of the present application in a preeclampsia mouse model.
Detailed Description
The application is described in further detail below with reference to the drawings and detailed description.
Culture and identification of CALM603
Lactobacillus reuteri of the applicationLimosilactobacillus reuteriCALM 603) was obtained by laboratory autonomous isolation screening, 16S rDNA sequencing and mass spectrometry.
Lactobacillus reuteri obtained by laboratory screening was inoculated directly on MRS medium, and the medium was subjected to anaerobic culture at 37 ℃ for 28 hours to obtain growing colonies, as shown in fig. 1.
Extracting a plurality of single colony DNAs, amplifying and measuring the 16S rDNA sequences of the single colony, comparing the sequence of the sequencing results, simultaneously carrying out mass spectrum identification on the strain, and screening through a series of functional experiments to obtain the strain of the application, wherein the strain is Lactobacillus reuteri capable of improving preeclampsia and vascular endothelial functionsLimosilactobacillus reuteriCALM 603), the sequence of the 16S rDNA is shown as SEQ ID N0.1, and the mass spectrum identification result is shown as fig. 2.
CALM603 applied to animal model experiments
ABX gastric lavage treatment is performed on mice to kill intestinal microorganisms in the mice, resulting in relatively sterile mice. ABX gastric lavage treatment refers to the use of antibiotics, typically tetranectins, including vancomycin (vancomycin), penicillin (ampicillin), metronidazole (metronidazole), and neomycin (neomycin sulfate).
(1) 18 female C57BL/6j mice of 8 weeks of age were randomly assigned to control group (CTRL), preeclampsia model group (L-NAME), lactobacillus reuteri intervention group (L-NAME+ L.r), 6 mice per group.
(2) Mice were placed in animal centers for 5 days of acclimatization. After 5 days, based on ABX gavage treatment for 5 consecutive days in all mice, the concentration of the tetrad antibiotic is as follows: vancomycin, 100 mg/kg, neocomycin sulfate, metanidazole and ampicillin, 200 mg/kg.
(3) The mice were pregnant in the cage, during the period of 9.5-17.5 days of gestation, L-NAME (40 mg/kg/day) was subcutaneously injected into the nuchal and dorsum of 9 consecutive days for preeclampsia and Lactobacillus reuteri intervention groups, while the control group was synchronously injected with PBS. Meanwhile, the Lactobacillus reuteri intervention group continuously performs stomach infusion intervention (1 x 10) on 0.5-17.5 days of gestation 9 CFU/mL, 200 ul/day). Mouse faeces were collected on day 17.5 of gestation.
(4) Fecal DNA was extracted using a QIAamp PowerFecal DNA Kit (Qiagen) kit, where the abundance of colonization of the gut by lactobacillus reuteri was detected by qPCR, and the results of the flora were amplified and library constructed based on the V4 segment of the 16S rRNA gene, high throughput sequencing was performed by Illumina MiSeq platform, and finally bioinformatic analysis was performed on the sequencing result data.
As shown in FIG. 3 (in all the figuresL. reuteriAndL.rall represent lactobacillus reuteri shorthand), the abundance of lactobacillus reuteri in the preeclampsia modeling module is significantly lower than that in the control group, while the abundance of lactobacillus reuteri is multiplied in the lactobacillus reuteri intervention group. Therefore, the lactobacillus reuteri has strong in vivo colonization capability, the abundance of the lactobacillus reuteri in the intestinal tract can be effectively changed through the intervention of the lactobacillus reuteri, the content of the lactobacillus reuteri in the intestinal tract is improved, and the microecology of intestinal flora is improved, so that the aim of improving the preeclampsia symptoms is fulfilled.
Alpha diversity refers to diversity within a particular area or ecosystem, and is a comprehensive indicator reflecting richness and uniformity. Alpha diversity is primarily related to two factors: first is the number of individual species, i.e., richness; and secondly, diversity of species, and uniformity in the number of species in a community.
The index of the community richness mainly comprises a Chao1 index, and the larger the Chao1 index is, the higher the richness of the community is; the sampled OUTs represent species type information; PD whole tree is a diversity index calculated based on phylogenetic tree, it constructs the distance of phylogenetic tree with the representative sequence of OTUs in each sample, add the branch length of all representative sequences in a certain sample, thus the value obtained, the larger the value, the higher the community diversity; shannon index comprehensively considers the richness and uniformity of communities, and the higher Shannon index value is, the higher the diversity of communities is indicated.
As shown in fig. 4, the indexes of the pre-eclampsia module were significantly lower than those of the control group and the lactobacillus reuteri intervention group, so that the intestinal flora enrichment and diversity of the module were the lowest; the indexes of the interference group of the lactobacillus reuteri are close to those of the control group, so that the method can be used for effectively improving the richness and diversity of intestinal flora of a preeclampsia mouse through the interference of the lactobacillus reuteri, enabling the intestinal flora to be close to the intestinal environment of a normal organism, maintaining intestinal microecological balance, avoiding intestinal flora disorder and further avoiding pregnancy complications such as preeclampsia.
Beta diversity is often used to compare differences between different ecosystems, reflecting heterogeneity of biological species due to the environment, and in general terms, different treatments (environmental, health, etc.) can lead to changes in the community structure.
As shown in fig. 5, the intestinal flora distribution (beta diversity) of the preeclampsia modeling group is significantly deviated from that of the control group and the intervention group, so that the intestinal flora of the modeling group is significantly different, and the intestinal flora is disordered; the intestinal flora distribution of the lactobacillus reuteri intervention group is obviously regressed compared with that of the control group. Therefore, the interference of lactobacillus reuteri can effectively adjust the difference between intestinal flora, promote the intestinal flora to maintain a stable environment, and avoid the phenomenon of flora disturbance.
As shown in FIG. 6, compared with the control group, the flora structure of the preeclampsia modeling group has obviously reduced intestinal firmicutes and Proteus and increased bacteroides, so that the preeclampsia can influence the intestinal flora structure and deviate the intestinal flora structure; the intestinal flora structure distribution of the Lactobacillus reuteri intervention group is close to that of the control group, the intestinal thick-wall fungus of the mice is increased by the intervention of the Lactobacillus reuteri, and the bacteroides is reduced to be close to that of the control group.
Intervention effect of CALM603 on preeclampsia mouse model
The clinical manifestations of preeclampsia are mainly: hypertension, proteinuria, fetal growth limitation, and pathological lesions of the placenta and kidneys. Therefore, the experiment can evaluate the intervention effect of the lactobacillus reuteri on the preeclampsia according to the clinical manifestation.
As shown in fig. 7, graph a shows that the blood pressure of the preeclampsia modeling group was continuously increased, significantly higher than that of the intervention group and the control group, while the blood pressure of the lactobacillus reuteri intervention group was always leveled with that of the control group, and the blood pressure was not significantly different. Therefore, the condition of hypertension of a preeclampsia mouse can be effectively improved through the intervention of lactobacillus reuteri; the diagram B shows proteinuria, and the diagram shows that the proteinuria of the preeclampsia modeling group is worse than that of the control group and the intervention group, and the proteinuria of a preeclampsia mouse can be effectively improved through the intervention of lactobacillus reuteri, so that the intervention group and the control group tend to be close; the graph C shows the sizes of the placenta and the fetus of the mice, and the placenta and the fetus of the preeclampsia modeling group can be observed to be obviously smaller than those of a control group and an intervention group through naked eyes, and the problems of the sizes of the placenta and the fetus of the preeclampsia mice can be effectively improved through the intervention of lactobacillus reuteri; the graph D shows the weight of the fetus and placenta from left to right, and shows the weight of the fetus and the weight of the placenta, and the graph shows that the interference group and the control group of the lactobacillus reuteri are higher than the preeclampsia modeling group, the data of the interference group are close to the control group, and the weight of the fetus of the preeclampsia mouse can be effectively improved through the interference of the lactobacillus reuteri, so that the normal development of the fetus is facilitated; as shown in a diagram E, the diagram shows the injury condition of the glomerulus of the mice, compared with a control group, the preeclampsia modeling group can obviously observe the abnormal glomerulus structure and endothelial hyperplasia, and the injury condition of the glomerulus of the preeclampsia mice can be effectively improved through the intervention of lactobacillus reuteri; as shown in the diagram F, the diagram shows the damage condition of the placenta of the mice, and the ratio of the placenta labyrinth area of the preeclampsia modeling module to the connecting area is increased, the vascular endothelial hyperplasia of the labyrinth area is observed, and the damage condition of the placenta of the preeclampsia mice can be effectively improved through the intervention of lactobacillus reuteri.
The above results indicate that L-NAME-induced development of preeclampsia symptoms was somewhat alleviated by the intervention of Lactobacillus reuteri, and that each indicator tended to be in normal mice.
Regulating effect of CALM603 on placenta vascular endothelial function of preeclampsia mouse model
As shown in fig. 8, placental vascular endothelial cells were labeled with CD31 (green fluorescence). The graph shows that the interference of the lactobacillus reuteri can effectively improve the generation condition of the placental vascular endothelial cells in preeclampsia, and the lactobacillus reuteri has obvious promotion effect on the placental angiogenesis of the preeclampsia mice.
As shown in FIG. 9, the preeclampsia modeling group has a remarkable promotion effect on the expression of the anti-angiogenic factor sFlt-1 and has an inhibition effect on the expression of the pro-angiogenic factor PlGF; the Lactobacillus reuteri intervention group has an inhibitory effect on the expression of the anti-angiogenic factor sFlt-1, while having an accelerating effect on the expression of the pro-angiogenic factor PlGF. Therefore, the expression of the placenta vascular endothelial function related regulator can be effectively regulated through the intervention of lactobacillus reuteri, the angiogenesis is promoted, the development of the placenta is ensured, and the preeclampsia related symptoms are avoided.
As shown in fig. 10, lactobacillus reuteri has a promoting effect on nitric oxide synthesis in preeclampsia mice. The nitrogen monoxide level in the serum of a preeclampsia mouse can be effectively increased through the intervention of lactobacillus reuteri; lactobacillus reuteri promotes up-regulation of phosphorylation levels of pre-eclamptic mouse placental nitric oxide synthase eNOS (endothelial nitric oxide synthase), where p-eNOS represents phosphorylated eNOS and β -actin represents β actin.
Application of CALM603
The strain can be prepared into a microbial inoculum and applied to medicines, or can be used for intervening preeclampsia and vascular endothelial dysfunction by means of intravenous transfusion or intramuscular injection and the like.
The oral product takes the microbial inoculum of the strain of the application as an active component, and plays the role of improving or treating preeclampsia and vascular endothelial dysfunction after entering a human body through an oral mode. The oral products include, but are not limited to, liquid beverages, extracts, powders, pills, granules/powders, capsules, tablets, pills, and the like, by dosage form classification. In order to realize the formulation, auxiliary materials which can be used in food and pharmaceutical preparations are added in the preparation process: such as fillers, disintegrants, lubricants, suspending agents, binders, sweeteners, flavoring agents, preservatives, and the like. The filler comprises: starch, lactose, mannitol, microcrystalline cellulose, sucrose, xylitol, and the like; the disintegrating agent comprises: starch, microcrystalline cellulose, sodium carboxymethyl starch, low-substituted sodium hydroxypropyl cellulose, and the like; the lubricant comprises: talc, silica, sodium lauryl sulfate, magnesium stearate, and the like; the suspending agent comprises: polyvinylpyrrolidone, microcrystalline cellulose, agar, hydroxymethyl cellulose, and the like; the adhesive comprises: starch slurry, polyvinylpyrrolidone, hydroxymethyl cellulose, and the like; the sweetener comprises: saccharin sodium, aspartame, sucrose, sodium cyclamate, glycyrrhetinic acid, etc.; the flavoring agent comprises: sweetener and various flavors; the preservative comprises: nipagin, benzoic acid, sodium benzoate, benzalkonium bromide, chlorhexidine acetate, eucalyptus oil, sorbic acid and salts thereof, etc. The auxiliary materials are not only used for shaping various dosage forms, but also used for protecting active components of oral products and avoiding inactivation caused by the influence of external environment.
The injection intervention takes the bacterial agent of the strain as an active component, uses sterile water or physiological saline to re-dissolve the bacterial agent or the preparation containing the strain to obtain injection, injection liquid, and plays the effect of improving or treating preeclampsia and vascular endothelial dysfunction after entering a human body through injection or transfusion.
In conclusion, the strain of the application is lactobacillus reuteri @Limosilactobacillus reuteriCALM 603), the preservation number of the strain is CGMCC NO.25407, the bacterial strain is utilized to regulate intestinal microecology so as to achieve the aim of treating preeclampsia, and the bacterial strain has the advantages of low cost, small risk, almost no side effect, easy clinical transformation and the like, and has outstanding effects in regulating intestinal flora, improving vascular endothelial function, improving preeclampsia symptoms and the like. After lactobacillus reuteri is planted in the intestinal tract, intestinal microecology can be effectively balanced, beneficial intestinal bacteria are increased, intestinal flora disturbance is avoided, and the situation of intestinal flora disturbance in preeclampsia is improved; the intervention of lactobacillus reuteri can promote the organism in preeclampsia to produce nitric oxide which is a substance for regulating vascular endothelial activity, up-regulate the expression level of the angiogenesis promoting factors, improve the related symptoms in preeclampsia and have wide market application prospect.
The above embodiments are preferred embodiments of the present application, but are not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principles of the present application should be made therein and are intended to be equivalent substitutions within the scope of the present application.

Claims (8)

1. A strain is Lactobacillus reuteriLimosilactobacillus reuteri) The preservation number of the strain is CGMCC NO.25407.
2. Use of a strain according to claim 1 for the preparation of a formulation product for the prevention or treatment of preeclampsia.
3. The use according to claim 2, wherein the formulation product is for ameliorating preeclampsia caused by vascular endothelial dysfunction.
4. The use according to claim 2, wherein the formulation product is for modulating intestinal flora alpha-diversity and beta-diversity.
5. The use according to claim 4, wherein the formulation product is for increasing intestinal flora alpha diversity; the preparation product is used for reducing colony structure difference of intestinal flora.
6. The use according to claim 2, wherein the formulation product is for inhibiting the expression of an anti-angiogenic factor, promoting the expression of a pro-angiogenic factor and promoting nitric oxide synthesis.
7. The use according to claim 2, wherein the active ingredient of the formulated product is a microbial inoculum of the strain.
8. The use of claim 2, wherein the formulation product comprises a medicament.
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Citations (2)

* Cited by examiner, † Cited by third party
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