Application of agkistrodon halys to preparation of medicine or preparation for simulating vagina prebiotics and balancing beneficial bacteria and harmful bacteria in vagina

Abstract

The invention discloses application of agkistrodon halys to preparation of drugs or preparations for simulating vagina prebiotics and balancing vagina beneficial bacteria and harmful bacteria. The invention relates to the field of research of probiotics and prebiotics, aims to recover and maintain microecological balance of vagina and improve natural defense capability of vagina, and particularly relates to a method for preparing a medicine or a preparation capable of effectively balancing beneficial bacteria and harmful bacteria of vagina by taking agkistrodon halys as a prebiotic simulant (mimetic) with homology of medicine and food. The research proves for the first time that the water extract of the agkistrodon halys can promote the colonization of beneficial bacteria in the vagina of a mouse, reduce the colonization of harmful bacteria and show characteristics similar to prebiotics. Therefore, the medicinal and edible prebiotic simulant, namely the agkistrodon halys, can be independently used or a mixture prepared from the agkistrodon halys and other substances can be used for preparing medicines or preparations for promoting the growth of probiotics, enriching beneficial bacteria in vagina and inhibiting harmful bacteria in vagina.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of probiotics and prebiotics, and in particular to the application of a prebiotic mimetic (pseudobiotic) of Gekko japonicus to balance the beneficial and harmful bacteria in the vagina and play a role similar to prebiotics. BACKGROUND

[0002] Probiotics are active microorganisms that can colonize in the human body and help change the composition of the microflora at a specific site in the host, and are beneficial to the host. Probiotics can regulate the mucosal and systemic immune function of the host, enhance the defense ability against pathogens, or maintain the normal microbial community structure in the vagina, inhibit the growth of harmful bacteria in the vagina, thereby preventing vaginal infections and playing a role in health promotion. These microorganisms can be single strains or mixed strains in a specific combination. Probiotics are closely related to human health, and there are many types of probiotics that have been identified.

[0003] The growth and colonization of probiotics depend on various nutrients and environmental factors, which make them attract attention in the field of biomedical research. In 1995, Glen Gibson, known as the "father of prebiotics", first proposed the term "prebiotics". Prebiotics are a class of organic substances that cannot be digested and absorbed by the host, and they can selectively promote the metabolism and reproduction of probiotics in the host, thereby improving the health level of the host. In addition to classic prebiotics, some researchers are also exploring other substances, including traditional Chinese medicines, to promote the growth and metabolism of probiotics, but there are few related research reports.

[0004] The application experience of traditional Chinese medicines has had a profound impact on the development of global civilization. Based on extensive research on the safety of traditional Chinese medicines and long-term clinical practice, the Chinese government has developed a list of traditional Chinese medicines that can be used as food. However, to date, no scholars have systematically evaluated the proliferation and growth-promoting effects of these food-compatible traditional Chinese medicines on representative probiotics.

[0005] We conducted a comprehensive investigation of traditional Chinese medicines that can be used in food (i.e., food-compatible traditional Chinese medicines), excluded those that are known to have an impact on microbial growth, and selected food-compatible traditional Chinese medicines that have not yet been studied for their impact on microbial growth. Subsequently, we evaluated the effects of these traditional Chinese medicines on improving the disease status of mice with vaginitis models, as well as their effects on the growth and colonization of probiotics and harmful bacteria in the vaginas of mice.

[0006] The detected medicinal and edible Chinese medicine, i.e. Agkistrodon halys, shows a promoting effect on the growth of representative probiotics, and therefore they can be regarded as analogues of prebiotics. The inventors of the present application, i.e. academicians Wu Junhua, Jiang Chunping and Gu Xiaosong, etc., name such substances capable of simulating the function of prebiotics as "prebiomimetics" in English. The inventors of the present application hope to make original contributions to the research and development of global probiotic-related products.

[0007] Agkistrodon halys, a Chinese medicine name. It is the whole body of Agkistrodon halys (Pallas) of Viperidae after removing the internal organs. It has the effects of relieving pain, improving joint function, enhancing anti-inflammatory effect, promoting blood circulation, enhancing immunity, improving skin condition, lowering blood lipids, etc. It can be used for the treatment of rheumatism, leprosy, sores, scabies, hemorrhoids, tumors and other diseases.

[0008] Up to now, the medicinal and edible Chinese medicine Agkistrodon halys disclosed in the present application, which has an improving effect on the vaginal environment of mice, has not been reported in any aspect of its influence on the growth of bacteria and the vaginal environment of mice. In addition, there is no related research on this kind of medicinal and edible Chinese medicine in promoting the colonization of beneficial bacteria in the vagina and inhibiting the colonization of harmful bacteria in the vagina. SUMMARY

[0009] In the present application, we observed the influence of vaginal administration of Agkistrodon halys Chinese medicine water extract (hereinafter referred to as medicinal and edible Chinese medicine prebiomimetics) on the vaginal flora of mice on a mouse model. Through 16S rRNA analysis, we found the beneficial bacteria that appeared or increased in number in the vagina of mice after treatment with Agkistrodon halys; at the same time, we also analyzed and found the harmful bacteria that disappeared or decreased in number in the vagina of mice after treatment with Agkistrodon halys.

[0010] The details of the present application are as follows: The role and mechanism of medicinal and edible Chinese medicine prebiomimetics in improving the vaginal microecology of mice, the medicinal and edible Chinese medicine prebiomimetics refer to some organic substances that cannot be digested and absorbed by the host, but can selectively promote the metabolism and proliferation of beneficial bacteria in the body, thereby improving the health of the host.

[0011] Application of medicinal and edible Chinese medicine prebiomimetics in the preparation of a medicine or preparation for promoting the proliferation and growth of probiotics, the medicinal and edible Chinese medicine prebiomimetics being Agkistrodon halys.

[0012] Application of medicinal and edible Chinese medicine prebiomimetics in the preparation of a medicine or preparation for promoting the proliferation and growth of probiotics, characterized in that: when used, the extract of one kind of medicinal and edible Chinese medicine prebiomimetics is used alone or the extracts of several kinds of medicinal and edible Chinese medicine prebiomimetics are mixed to form a complex, and then used for preparing a medicine or preparation for promoting the proliferation and growth of probiotics.

[0013] The Gonyu Shengyuan traditional Chinese medicine Gloydius brevicaudus also has the functions of enriching vaginal beneficial bacteria and inhibiting vaginal harmful bacteria, and can be used for preparing a medicine or preparation for enriching vaginal beneficial bacteria and inhibiting vaginal harmful bacteria. BRIEF DESCRIPTION OF DRAWINGS

[0014] Figure 1 The Venn diagram results of the vaginal flora of mice before and after the vaginal administration of Gloydius brevicaudus are summarized: Venn focuses on analyzing the number of unique and common species in different groups, facilitating the understanding of the changes in the number of species under different research conditions. This application can select biomarkers based on unique or common species for research.

[0015] Figure legend: Different colors represent different groups (or samples), and overlapping parts represent common species in multiple groups (or samples). The parts without overlap represent species unique to the group (or sample), and the numbers represent the number of corresponding species. A: blank group, V: treatment group.

[0016] Figure 2 The columnar chart results of the species-level species composition of the vaginal flora of mice before and after the vaginal administration of Gloydius brevicaudus are summarized: To achieve the best view effect, only the top ten species in the abundance level are displayed, and other species are combined as Others in the figure. Unclassified represents species that have not been annotated taxonomically.

[0017] Figure legend: The horizontal coordinate is the sample, and the vertical coordinate is the relative abundance. Different colors represent different species. A: blank group, V: treatment group.

[0018] Figure 3 The cluster heat map results of the species abundance of the vaginal flora of mice before and after the vaginal administration of Gloydius brevicaudus are summarized: Heatmap is a graphical display method that represents the size of the data matrix with a color gradient and clusters according to the similarity of species or sample abundance. High and low abundance species are clustered and aggregated, and the similarity and difference of multiple sample communities are reflected through color gradient and similarity. According to the species composition and relative abundance of each sample, species heat map analysis is performed, and species at each taxonomic level are extracted. R language tools are used for plotting, and Heatmap clustering analysis is performed at the levels of door, class, order, family, genus, and species. The top 50 species in relative abundance are plotted.

[0019] Figure legend: The horizontal coordinate is the sample, and the vertical coordinate is the species. Different colors represent different abundances. A1-A4: blank group, V1-V4: treatment group.

[0020] Figure 4Summary of the results of the α diversity Shannon index of the vaginal flora of mice before and after the vaginal administration of the pit viper: The α diversity index of each sample is displayed by a bar chart, which intuitively displays the size of the α diversity index of different samples. The greater the Shannon index value, the higher the richness of the flora.

[0021] Figure legend: The abscissa is the sample name, and the ordinate is the value of the Shannon index. Different colors represent different groups. A: blank group, V: treatment group.

[0022] Figure 5 Summary of the results of the rarefaction curve analysis of the vaginal flora of mice before and after the vaginal administration of the pit viper: The rarefaction curve randomly selects a certain number of sequences from the sample, counts the number of species represented by these sequences, and constructs a curve with the number of sequences and species to verify whether the amount of sequencing data is sufficient to reflect the species diversity in the sample, and indirectly reflects the richness of species in the sample.

[0023] Figure legend: The abscissa is the amount of randomly selected sequencing data, and the ordinate is the observed population characteristic number. A: blank group, V: treatment group.

[0024] Figure 6 Shannon index curve analysis of the vaginal flora of mice before and after the vaginal administration of the pit viper: The Shannon index curve is drawn according to the Shannon index of each sample at different sequencing depths, reflecting the microbial diversity of each sample at different sequencing amounts. When the curve tends to be flat, it means that the amount of sequencing data is large enough, and the characteristic species will not increase with the increase of the sequencing amount; if the curve does not tend to be flat, it means that it is not saturated, and increasing the data amount can discover more characteristics.

[0025] Figure legend: The abscissa is the amount of randomly selected sequencing data, and the ordinate is the observed Shannon index. A1-A4: blank group, V1-V4: treatment group.

[0026] Figure 7 Summary of the results of the PCA analysis of the vaginal flora of mice before and after the vaginal administration of the pit viper: Principal component analysis (PCA) is a technique for analyzing and simplifying data sets, which reflects the differences between multiple data sets on a two-dimensional coordinate graph by decomposing variance. By analyzing the distance between different samples, the differences between samples can be reflected. PCA uses variance decomposition to reflect the differences between multiple data sets on a two-dimensional coordinate graph, and the coordinate axes take two characteristic values that can best reflect the variance. The closer the distance between two samples, the more similar the composition of the two samples.

[0027] Figure legend: dots represent each sample respectively; different colors and shapes represent different groups; the horizontal coordinate represents the first principal component, and the percentage represents the contribution of the first principal component to the difference between samples; the vertical coordinate represents the second principal component, and the percentage represents the contribution of the second principal component to the difference between samples. A: blank group, V: treatment group.

[0028] Figure 8 Summary of PCoA analysis results of vaginal flora of mice before and after vaginal administration of Agkistrodon: Principal coordinates analysis (PCoA) is a dimensionality reduction sorting method similar to PCA. The principle is that if there is data that measures the difference or distance between N samples, this method can be used to find a rectangular coordinate system to represent N samples as N points, so that the square of the Euclidean distance between the points is exactly equal to the original difference data, achieving quantitative conversion of qualitative data and extracting the most important elements and structures from multi-dimensional data. Through principal coordinates analysis, the classification of multiple samples can be achieved, further showing the difference in species diversity between samples.

[0029] Figure legend: dots represent each sample respectively; different colors and shapes represent different groups; the horizontal coordinate represents the first principal component, and the percentage represents the contribution of the first principal component to the difference between samples; the vertical coordinate represents the second principal component, and the percentage represents the contribution of the second principal component to the difference between samples. R2 represents the degree of explanation of the difference between samples by different groups, and the larger R2 indicates the higher degree of explanation of the difference by the group, indicating that the difference between groups is larger. The P value less than 0.05 indicates that the test has high reliability. A: blank group, V: treatment group.

[0030] Figure 9 Summary of combined analysis results of cluster tree and column chart of vaginal flora of mice before and after vaginal administration of Agkistrodon: UPGMA (Unweighted Pair-group Method with Arithmetic Mean) is a commonly used clustering analysis method. The principle is: the hypothetical precondition is that the number of times of divergence of each lineage is the same in the evolutionary process, that is, the substitution rate of nucleotides or amino acids is equal and constant. The phylogenetic tree generated by UPGMA method can be said to be a simple representation of the species tree, and the length of the branch from the common ancestor node to the two characteristics is the same after each divergence occurs. Therefore, this method is more commonly used for reconstruction of species trees. Based on the four distance matrices obtained by Beta diversity analysis, the hierarchical clustering of samples was carried out by R language tool using unweighted pair-group method with arithmetic mean (UPGMA) to judge the similarity of species composition between samples. The closer the samples are in the hierarchical clustering tree, the shorter the branch length, indicating that the species composition of the two samples is more similar.

[0031] Figure legend: The color on the left bottom of the figure represents the color of the group that the sample of the cluster tree belongs to, and the color on the right of the figure represents the top 10 species in the species abundance table. A1-A4: blank group, V1-V4: treatment group.

[0032] Figure 10 Summary of sample distance heat map analysis of vaginal flora of mice before and after vaginal administration of Agkistrodon: The sample distance heat map is based on the distance matrix between samples, and then the sample heat map is drawn by R language pheatmap tool. The difference between two samples can be directly observed according to the change of color gradient.

[0033] Figure legend: The rows and columns in the figure represent samples, and the color gradient from blue to red represents the distance between samples from near to far. A1-A4: blank group, V1-V4: treatment group.

[0034] Figure 11 Summary of similarity analysis of vaginal flora of mice before and after vaginal administration of Agkistrodon: Similarity analysis (ANOSIM) is a non-parametric test used to test whether the difference between groups (two or more groups) is significantly greater than the difference within the group, so as to determine whether the grouping is meaningful. The closer the R value is to 1, the greater the difference between groups than within groups. The smaller the R value, the less significant the difference between groups and within groups. A p-value less than 0.05 indicates a high degree of reliability for this test.

[0035] Figure legend: There are N+1 boxes in total on the figure, where N is the number of groups. The "Between" box refers to the difference between groups, and the others represent the difference within each group. The vertical axis represents the distance value. A: blank group, V: treatment group.

[0036] Figure 12 Summary of PLS-DA analysis of vaginal flora of mice before and after vaginal administration of Agkistrodon: PLS-DA (Partial Least Squares Discriminant Analysis) is one of the most commonly used pattern recognition methods in omics data analysis. It finds the maximum covariance between the species abundance matrix and the given grouping information, and then sorts the samples in a new low-dimensional coordinate system.

[0037] Figure legend: The points in the figure represent each sample, and different colors represent different groups. The distance between points represents the degree of difference. The closer the samples are on the coordinate graph, the higher the similarity. The ellipse around the data point represents the distribution range of the sample based on the confidence interval. A: blank group, V: treatment group.

[0038] Figure 13ANOVA analysis of vaginal flora of mice before and after vaginal administration of Agkistrodon acutus: ANOVA (Analysis of Variance) is also called F test. It is mainly used to test whether the means of multiple samples are equal, so as to judge the significant difference of the means of two or more samples.

[0039] Figure legend: The vertical coordinate represents the species (the top 15 species with the highest average abundance are shown); the horizontal coordinate represents the relative abundance of the species; and the different colored columns represent different groups. A: blank group, V: treatment group.

[0040] Figure 14 Summary of the results of the rank sum test of the vaginal flora of mice before and after vaginal administration of Agkistrodon acutus: The rank sum test is a method of non-parametric test. The "rank" is also called the order, that is, the sum of the above order numbers is called "rank sum", and the rank sum test is a method of hypothesis testing using rank sum as a statistical quantity. When the distribution type of the population is unknown in practice or the distribution type of the population is known but does not conform to the normal distribution; or some variables may not be accurately measured; and the variances are not equal, the rank sum test can be used for analysis.

[0041] Figure legend: The horizontal coordinate represents the species (the top 20 species with the smallest p value are shown); the vertical coordinate represents the relative abundance of the species; and the different colored columns represent different groups. A: blank group, V: treatment group.

[0042] Figure 15 Summary of the results of the LDA column chart of the vaginal flora of mice before and after vaginal administration of Agkistrodon acutus: LEfSe (Line Discriminant Analysis (LDA) Effect Size) is used to show the significant differences of different classification units (such as genus, species, etc.) in different groups, and can find Biomarkers with statistical differences between different groups.

[0043] Figure legend: The figure shows the species with LDA Score greater than the set value 4, and the length of the column chart represents the impact size of the difference species (i.e. LDA Score), the higher the LDA score, the greater the role of the classification unit in distinguishing different groups. Different colors represent species in different groups. A: blank group, V: treatment group.

[0044] Figure 16 Summary of the results of the LEfSe analysis of the evolutionary branch diagram of the vaginal flora of mice before and after treatment with Agkistrodon acutus water extract: LEfSe (Line Discriminant Analysis (LDA) Effect Size) is used to show the significant differences of different classification units (such as genus, species, etc.) in different groups, and can find Biomarkers with statistical differences between different groups.

[0045] Figure legend: The evolutionary branch diagram, the circles radiating from inside to outside represent the classification levels from door to species; each small circle on different classification levels represents a classification at this level, and the diameter of the small circle is proportional to the size of the relative abundance; the coloring principle is to color the species with no significant difference as yellow, and other different species are colored according to the group with the highest abundance of the species. Different colors represent different groups, and different colored nodes represent important microbial groups in the group represented by the color. A: blank group, V: treatment group.

[0046] Figure 17 Summary of the results of the top 20 species importance column chart of the vaginal flora of mice before and after the vaginal administration of the pit viper: Random Forests is a classic and efficient machine learning algorithm based on Decision tree, which is a Non-linear classifier. It can deeply mine the complex non-linear interdependent relationship between variables, and is especially suitable for microbial community data that often presents discrete and discontinuous distribution. In recent years, studies have shown that this algorithm can effectively, stably and accurately classify microbial community samples. R package randforest was used for analysis. The top 20 species with the highest importance were selected for plotting and display.

[0047] Figure legend: The horizontal axis represents the importance of the species, and the larger the value, the greater the influence of the species on the classification between groups; the vertical axis represents the species.

[0048] Figure 18 Summary of the results of the FAPROTAX functional bubble chart of the vaginal flora of mice before and after the vaginal administration of the pit viper: FAPROTAX is a prokaryotic functional database that integrates multiple published culturable bacterial articles. The database contains more than 7600 functional annotation information of more than 4600 species, which are divided into more than 80 functional groups such as nitrate respiration, methanogenesis, fermentation and plant pathogenesis.

[0049] Figure legend: The horizontal axis of the figure represents the sample or group, and the vertical axis represents the function. Different colors represent different samples or groups, and the size of the bubble represents the relative abundance of the function in the sample or group. A: blank group, V: treatment group. DETAILED DESCRIPTION

[0050] Materials and methods involved in Example 1 Materials for the first part of the experiment (1) Female ICR mice, weighing 18-20 g, were purchased from the Comparative Medicine Center of Yangzhou University, with experimental animal production license number: SCXK (Su) 2022-0009, and experimental animal use license number: SYXK (Su) 2019-0056. They were raised in isolation cages with free access to food and water. The laboratory temperature was (24 ± 1) °C, and the relative humidity was 40% to 80%. After 3 days of adaptive feeding, the experiment began.

[0051] (2) The traditional Chinese medicine Gloydius brevicaudus was purchased from Bozhou Jingwan Chinese Herbal Medicine Slice Factory.

[0052] Second part of the experimental method (1) According to the traditional decoction method, 50 g of Gloydius brevicaudus was added with 10 times the amount of distilled water, soaked for 30 min, decocted for 60 min, the medicinal liquid was filtered with gauze, and then 8 times the amount of distilled water was added for decoction for 40 min. The medicinal liquid was filtered with gauze, and the medicinal liquid was combined and heated to concentrate to 25 ml. The Gloydius brevicaudus water extract corresponding to the crude drug concentration was 2 g / ml, which was placed in a centrifuge tube for standby.

[0053] (2) ICR mice were randomly divided into blank group and treatment group. The mice in the treatment group were injected with 100 μl of traditional Chinese medicine water extract (traditional Chinese medicine dry matter content 16 mg / ml) into the vagina using a pipette on days 1, 2, 3, 4, 5, 6, and 7. The blank group was given the solvent (water). Sampling was performed on day 8 for vaginal microbial analysis. All mice were provided with standard laboratory food, water, and clean cages.

[0054] (3) Swab sampling method: sterile flocked swabs were placed on the lateral wall of the vagina, approximately halfway between the entrance and the cervix, and pressed into the lateral wall with a depth of about the diameter of the swab. The swab was rolled back and forth four times to cover the entire swab, and then removed. The swab was cut off and placed in a 1.5 mL cryotube, frozen in liquid nitrogen, and stored at -80 °C. The dry ice was sent. Vaginal wash sampling method: the vagina was washed with sterile PBS (100 μl) for 5 times to obtain the vaginal wash.

[0055] (4) 16S rRNA gene sequencing takes mouse vaginal swab samples, based on Oxford Nanopore sequencing platform for ONT full-length microbial diversity analysis, using nanopore sequencing method to sequence marker gene, and then through the original fastq sequence quality filtering, dechimeric, sequence alignment, species annotation and abundance analysis, to reveal the species composition of the sample; further α diversity analysis (Alpha Diversity), β diversity analysis (Beta Diversity) and significant species difference analysis, correlation analysis, functional prediction analysis and so on, to mine the differences between samples. PromethION P48 sequencer (Oxford Nanopore Technologies, Oxford, UK) was used for sequencing. The above sequencing work was completed by Wuhan Benagen Technology Co., Ltd. (Contract No.: BN241128NJ01S56N1). All data analysis was performed on the Benagen Cloud platform (https: / / www.benagencloud.com).

[0056] Third part of the experimental results and conclusions Example 1 16s rRNA gene sequencing analysis of the influence of pit viper vaginal administration on mouse vaginal flora (I) Species composition analysis 1. Species distribution Venn diagram

[0057] As Figure 1 shown, to analyze the changes of specific flora in the control group after pit viper vaginal administration intervention, species level Venn diagram analysis of the flora in the mouse vaginal wash was performed, and it was found that the number of specific bacterial genera in the blank control group (A) was 146, the number of new specific bacterial genera in the pit viper vaginal administration group (V) was 197, and the number of bacterial genera shared with the blank control group was 161. This indicates that pit viper vaginal administration can affect the structure of mouse vaginal flora. Further, functional analysis of the above relevant bacterial genera is shown in the following table.

[0058] Table 1 Vaginal bacteria that disappeared from the normal control group specific flora after pit viper vaginal administration (146) Strain Strain Strain Acidovorax caeni Desemzia incerta Prevotella conceptionensis Acinetobacter bouvetii Enhydrobacter aerosaccus Proteus mirabilis Acinetobacter calcoaceticus Enterococcus avium Proteus vulgaris Acinetobacter indicus Enterococcus casseliflavus Pseudomonas alcaliphila Acinetobacter junii Enterococcus cecorum Pseudomonas guguanensis Acinetobacter nosocomialis Enterococcus gallinarum Pseudoxanthomonas suwonensis Acinetobacter oleivorans Flavobacterium cutihirudinis Rheinheimera nanhaiensis Acinetobacter pittii Flavobacterium johnsoniae Rhodobium orientis Acinetobacter radioresistens Flavobacterium orientale Ruminococcus bromii Acinetobacter schindleri Flavobacterium subsaxonicum Saccharopolyspora cavernae Aeromonas caviae Fusobacterium nucleatum Saccharopolyspora rectivirgula Aeromonas hydrophila Gemella sanguinis Sarcina ventriculi Alkalibacterium olivapovliticus Geobacillus thermocatenulatus Savagea faecisuis Altererythrobacter dongtanensis Geobacillus thermoparaffinivorans Schlegelella thermodepolymerans Anoxybacillus tepidamans Haemophilus parainfluenzae Shigella boydii Aquabacterium olei Helicobacter hepaticus Sphingobium xenophagum Arachidicoccus rhizosphaerae Holdemania filiformis Sphingobium yanoikuyae Arthrobacter crystallopoietes Ktedonobacter racemifer Sphingomonas parvus Asticcacaulis excentricus Ktedonobacterales bacterium Sphingopyxis flava Avibacterium gallinarum Lactobacillus crispatus Spirosoma endophyticum Azohydromonas lata Lactobacillus iners Staphylococcus argenteus Azospira oryzae Magnetospirillum moscoviense Staphylococcus equorum Azospirillum lipoferum Massilia oculi Staphylococcus hominis Azospirillum oryzae Massilia putida Staphylococcus lugdunensis Bacillus anthracis Massilia timonae Staphylococcus pasteuri Bacillus cereus Megasphaera stantonii Staphylococcus saccharolyticus Bacillus flexus Methylibium petroleiphilum Staphylococcus stepanovicii Bacillus halosaccharovorans Methylobacterium platani Streptococcus australis Bacillus smithii Microbacterium dextranolyticum Streptococcus cristatus Bacillus thermoamylovorans Microbacterium laevaniformans Streptococcus infantis Bacteroides barnesiae Microvirga guangxiensis Streptococcus mitis Bacteroides salanitronis Microvirga subterranea Streptococcus parasanguinis Bacteroides stercoris Moraxella osloensis Streptococcus pneumoniae Blautia wexlerae Mucispirillum schaedleri Streptococcus respiraculi Bosea vaviloviae Nesterenkonia halobia Streptomyces albidoflavus Brachybacterium ginsengisoli Nesterenkonia jeotgali Streptomyces exfoliatus Brevundimonas terrae Novispirillum itersonii Streptomyces gougerotii Candidatus Babela massiliensis Oceanobacillus chungangensis Streptomyces intermedius Candidatus Saccharimonas aalborgensis Ornithinimicrobium flavum Streptomyces rutgersensis Catabacter hongkongensis Paracoccus aerius Subdoligranulum variabile Cloacibacterium normanense Paracoccus aestuarii Thalassospira marina Comamonas aquatica Paracoccus aminovorans Tyzzerella nexilis Corynebacterium accolens Paracoccus carotinifaciens Veillonella massiliensis Corynebacterium aurimucosum Paracoccus homiensis Veillonella parvula Corynebacterium kroppenstedtii Paracoccus zhejiangensis Virgibacillus alimentarius Craurococcus roseus Paraliobacillus ryukyuensis Weissella confusa Cutibacterium granulosum Pelomonas saccharophila Youngiibacter fragilis Deinococcus aerolatus Peptostreptococcus russellii Youngiibacter multivorans Deinococcus radiopugnans Phreatobacter cathodiphilus Table 2 Vaginal bacteria that recovered from the normal control group flora after pit viper vaginal administration (197)

[0059] Bacterial strain Bacterial strain Bacterial strain Achromobacter insolitus Geobacter grbiciae Nitrospira japonica Acidimicrobium ferrooxidans Granulicatella adiacens Nocardioides alpinus Aciditerrimonas ferrireducens Granulicatella para-adiacens Nocardioides maritimus Acidobacterium capsulatum Haemophilus influenzae Nocardioides pakistanensis Acidovorax avenae Halomonas pantelleriensis Nocardioides pelophilus Acinetobacter ursingii Herbaspirillum seropedicae Oceanobacillus iheyensis Adlercreutzia equolifaciens Herbinix luporum Pannonibacter phragmitetus Aerococcus christensenii Hungatella hathewayi Pantoea agglomerans Anaerostipes caccae Intestinimonas butyriciproducens Pantoea allii Anaerostipes hadrus Intestinimonas massiliensis Pantoea ananatis Anoxybacillus ayderensis Intestinimonas timonensis Pantoea vagans Aquabacterium citratiphilum Janibacter melonis Paraburkholderia caballeronis Aquimonas voraii Jatrophihabitans endophyticus Paracoccus seriniphilus Arenimonas oryziterrae Jeotgalibacillus marinus Paraeggerthella hongkongensis Austwickia chelonae Jeotgalicoccus aerolatus Pediococcus acidilactici Bacillus aquimaris Jeotgalicoccus halotolerans Pelomonas aquatica Bacillus asahii Jeotgalicoccus nanhaiensis Pirellula staleyi Bacillus boroniphilus Kingella kingae Propionibacterium freudenreichii Bacillus circulans Klebsiella quasipneumoniae Prosthecochloris vibrioformis Bacillus drentensis Klebsiella quasivariicola Proteiniborus ethanoligenes Bacillus infernus Klebsiella variicola Pseudomonas azotoformans Bacillus megaterium Lachnoclostridium edouardi Pseudomonas chengduensis Bacillus muralis Lachnoclostridium pacaense Pseudomonas composti Bacillus oceanisediminis Lachnoclostridium urinimassiliense Pseudomonas fluorescens Bacteroides ndongoniae Lactobacillus acidophilus Pseudomonas linyingensis Bavariicoccus seileri Lactobacillus agilis Pseudomonas poae Bergeyella cardium Lactobacillus animalis Pseudomonas protegens Blautia hansenii Lactobacillus apodemi Pseudonocardia kongjuensis Blautia stercoris Lactobacillus aquaticus Rhizobium leguminosarum Brevundimonas aurantiaca Lactobacillus faecis Rhizobium rhizogenes Brevundimonas intermedia Lactobacillus fermentum Rhodococcus pyridinivorans Brevundimonas mediterranea Lactobacillus hayakitensis Roseburia faecis Brevundimonas nasdae Lactobacillus iatae Roseburia hominis Brevundimonas vesicularis Lactobacillus intestinalis Roseburia inulinivorans Burkholderia novacaledonica Lactobacillus mali Roseomonas genomospecies Carnobacterium divergens Lactobacillus plantarum Saccharothrix texasensis Carnobacterium maltaromaticum Lactobacillus ruminis Sellimonas intestinalis Carnobacterium mobile Lactobacillus salivarius Serratia marcescens Cellulosilyticum lentocellum Lactobacillus satsumensis Sphaerobacter thermophilus Chryseobacterium anthropi Lactobacillus sucicola Sphingomonas hankookensis Chryseobacterium indologenes Lactobacillus uvarum Sphingomonas hunanensis Chryseolinea serpens Leuconostoc lactis Sphingomonas paucimobilis Corynebacterium appendicis Luteimonas huabeiensis Sphingomonas sanguinis Corynebacterium callunae Luteimonas terrae Sphingomonas yunnanensis Corynebacterium segmentosum Lysobacter concretionis Staphylococcus gallinarum Corynebacterium tuberculostearicum Lysobacter defluvii Stenotrophomonas maltophilia Curvibacter gracilis Lysobacter deserti Streptococcus iniae Cutibacterium avidum Melioribacter roseus Streptococcus oralis Delftia acidovorans Methylobacterium adhaesivum Streptomyces afghaniensis Delftia lacustris Methylobacterium aquaticum Streptomyces corchorusii Delftia tsuruhatensis Methylobacterium fujisawaense Streptomyces cyaneus Derxia gummosa Methylobacterium hispanicum Streptomyces cyslabdanicus Derxia lacustris Methylobacterium isbiliense Streptomyces muensis Dokdonella koreensis Methylobacterium radiotolerans Sulfuritalea hydrogenivorans Enterobacter asburiae Methylobacterium tardum Taibaiella koreensis Enterobacter cloacae Methylorubrum extorquens Thermaerobacter marianensis Enterococcus columbae Methylorubrum populi Thermaerobacter subterraneus Enterococcus durans Micrococcus terreus Thermoleophilum album Enterococcus hirae Mizugakiibacter sediminis Trichococcus collinsii Enterococcus villorum Mycobacterium barrassiae Trichococcus flocculiformis Enterorhabdus caecimuris Mycobacterium moriokaense Trichococcus pasteurii Fonticella tunisiensis Nannocystis pusilla Truepera radiovictrix Fusicatenibacter saccharivorans Nesterenkonia alkaliphila Turicibacter sanguinis Gaiella occulta Nitrosospira briensis Vagococcus fluvialis Geminicoccus roseus Nitrosospira multiformis Vampirovibrio chlorellavorus Geobacillus kaustophilus Nitrospira defluvii .

[0060] 2. Species composition column chart As Figure 2As shown, the blank control group (A) showed a relatively stable vaginal flora composition, with certain species (such as Muribacter muris, Rodentibacter pneumotropicus, Vulcaniibacterium thermophilum, Anoxybacillus flavithermus, Streptococcus acidominimus, etc.) occupying a high relative abundance. Compared with the blank group, the vaginal flora composition of the pit viper treatment group (V) changed, and the relative abundance of some species enriched in the blank group (such as Muribacter muris, Streptococcus acidominimus) decreased significantly, while the relative abundance of other species (such as Rodentibacter pneumotropicus, Vulcaniibacterium thermophilum, Anoxybacillus flavithermus, Granulicatella elegans) increased, indicating that pit viper water extract may maintain the balance of vaginal flora by changing the relative abundance of vaginal flora.

[0061] 3. Species abundance clustering heat map As Figure 3 shown, the species abundance clustering heat map row represents different vaginal flora species, and the column represents different samples. By clustering similar species or samples together, it can be found that compared with the blank control group, the abundance of certain species in the pit viper treatment group has changed significantly, the abundance of some species has increased (shown as red), while the abundance of some species has decreased (shown as blue). This indicates that pit viper traditional Chinese medicine water extract may have a positive effect on regulating vaginal flora and help restore the balance of vaginal flora.

[0062] (II) Alpha diversity 1. Alpha diversity index

[0063] As Figure 4 shown, compared with the blank control group (A), the median of the ACE index of the pit viper vaginal administration group (V) was higher than that of the blank control group, indicating that the alpha diversity increased after pit viper treatment, but the result was not significantly different (p=0.289). This indicates that pit viper treatment is beneficial to the construction of healthy vaginal flora and the improvement of vaginal microenvironment.

[0064] 2. Dilution curve analysis 3. Shannon index curve

[0065] From Figure 5 and Figure 6The dilution curve shows that as the amount of randomly sampled sequencing data increases, the curve tends to flatten, indicating that the sequencing data of the above two groups is sufficient, and more data will only produce a small amount of new species, and the characteristic species will not increase with the increase of sequencing amount.

[0066] (III) Beta diversity 1. PCA analysis

[0067] As shown in Figure 7 , PCA analysis of the vaginal flora of mice after different sample treatments found that the Viper treatment group (V) samples were significantly separated on PC1 and PC2 compared to the blank control group (A), with PC1 and PC2 contribution rates of 60.33% and 14.01%, respectively. This indicates that there are significant differences in the composition of their vaginal flora.

[0068] 2. PCoA analysis As shown in Figure 8 , PCoA analysis based on the relative abundance of ASVs between groups detected the community structure of vaginal microbiota, and found that the Viper treatment group (V) samples were significantly separated on PC1 and PC2 compared to the blank control group (A), with PC1 and PC2 contribution rates of 22.72% and 15.08%, respectively. This indicates that there are significant differences in the composition of their vaginal flora.

[0069] 3. Cluster tree and column chart combined analysis As shown in Figure 9 , the blank control group (A) and the Viper treatment group (V) are relatively dispersed in the phylogenetic tree, indicating that there is some similarity in the composition of the vaginal flora between the two groups.

[0070] 4. Sample distance heat map analysis The sample distance heat map is based on the distance matrix between samples obtained by distance algorithm, and then the sample heat map is drawn by R language pheatmap tool. The difference between each pair of samples can be directly observed according to the change of color gradient. As shown in Figure 10 , according to the change of color gradient, it can be directly observed that the difference between the control group (A) and the Viper vaginal administration group (V) is not large.

[0071] 5. Similarity analysis (ANOSIM) Similarity analysis (ANOSIM) is a non-parametric test used to test whether the difference between groups (two or more groups) is significantly greater than the difference within the group, so as to determine whether the grouping is meaningful. The closer the R value is to 1, the greater the difference between groups is greater than the difference within the group. The smaller the R value, the less significant the difference between groups and within groups. A p-value less than 0.05 indicates a high reliability of the test. As shown in Figure 11As shown, the inter-group similarity analysis result R value was -0.188, and the p value was 0.828, indicating that the vaginal flora composition of the Gloydius processing group (V) had no significant difference with the blank control group (A), and the samples of the two groups were relatively similar.

[0072] 6. PLS-DA analysis From Figure 12 it can be seen that the distribution of the Gloydius processing group (V) and the blank control group (A) on PLS1 and PLS2 is obviously separated, which indicates that the Gloydius processing group has significant differences with the blank control group in certain characteristics.

[0073] (Four) Species difference analysis and marker species 1. Analysis of variance (ANOVA)

[0074] As Figure 13 shown, the mouse had an impact on the abundance of certain vaginal flora after being treated with Gloydius vaginal administration, and the relative abundance of some vaginal beneficial bacteria was up-regulated, and the relative abundance of some vaginal harmful bacteria was down-regulated. The results show that after being treated with Gloydius, the microbial composition changes, which is beneficial to the formation of healthy vaginal flora.

[0075] Table 3 Compared with the blank group, after being treated with Gloydius vaginal administration, the vaginal species with a relative abundance increase of more than 50 times and a decrease of less than 1 / 50 and their effects Strain Change Anaerovorax odorimutans 50-fold increase Arboricoccus pini 50-fold increase Blautia obeum 50-fold increase Coprococcus comes 50-fold increase Dorea longicatena 50-fold increase Enterococcus faecium 50-fold increase Gimesia maris 50-fold increase Granulicatella balaenopterae 50-fold increase Granulicatella elegans 50-fold increase Klebsiella pneumoniae 50-fold increase Lactobacillus johnsonii 50-fold increase Lactobacillus murinus 50-fold increase Lactobacillus taiwanensis 50-fold increase Megamonas hypermegale 50-fold increase Ralstonia insidiosa 50-fold increase Snodgrassella alvi 50-fold increase Streptomyces viridochromogenes 50-fold increase Bacillus subtilis 50-fold decrease Enterococcus faecalis 50-fold decrease Hathewaya limosa 50-fold decrease Staphylococcus aureus 50-fold decrease Streptococcus sanguinis 50-fold decrease .

[0076] As shown in Table 3, after being treated with Gloydius vaginal administration, there are 17 species with a relative abundance increase of more than 50 times, among which Blautia obeum can naturally produce bile salt hydrolase, thereby effectively treating recurrent Clostridium difficile infection, reference: Mullish, B.H., et al., Microbial bile salt hydrolases mediate the efficacy of faecal microbiota transplant in the treatment of recurrent Clostridioides difficile infection. Gut, 2019.68(10): p. 1791-1800. Among them, the increase in the abundance of Dorea longicatena is related to the improvement of type 2 diabetes and better insulin resistance after gastric bypass surgery, reference: Prudêncio, A.P.A., et al., Red Meat Intake, Indole-3-Acetate, and Dorea longicatena Together Affect Insulin Resistance after Gastric Bypass. Nutrients, 2023.15(5). Among them, Lactobacillus johnsonii can enhance the efficacy of CD8 T cell-mediated αPD-1 immunotherapy to mediate tumor suppression, reference: Jia, D., et al., Microbial metabolite enhances immunotherapy efficacy by modulating T cell stemness in pan-cancer.Cell, 2024. 187(7). Where Lactobacillus murinus promotes M2 macrophage release of interleukin-10 via Toll-like receptor 2 signaling to reduce intestinal ischemia / reperfusion injury, ref: Hu, J., et al., Lactobacillus murinus alleviate intestinal ischemia / reperfusion injury through promoting the release of interleukin-10 from M2 macrophages via Toll- like receptor 2 signaling. Microbiome, 2022. 10(1): p. 38; Fan, J., et al., Novel mechanism by which extracellular vesicles derived from Lactobacillus murinus alleviates deoxynivalenol-induced intestinal barrier disruption. Environment International, 2024. 185: p. 108525. Novel mechanism of extracellular vesicles derived from Lactobacillus murinus attenuate deoxyschizandrin-induced intestinal barrier disruption. Where Lactobacillus taiwanensis can reduce motor dysfunction and loss of dopaminergic neurons in a mouse model of Parkinson's disease, ref: Choi, Y., et al., Lactobacillus taiwanensis BCRC17755 alleviates motor dysfunction and dopaminergic neuronal loss in mouse models of Parkinson's disease. Beneficial Microbes, 2025. 16(4): p. 413-423. Where the relative abundance of Megamonas hypermegale species in the gut is reduced, which can be related to T cell aberrations caused by metabolite changes in patients with Behcet's disease, ref: Shimizu, J., et al., Relative abundance of Megamonas hypermegale and Butyrivibrio species decreased in the intestine and its possible association with the T cell aberration by metabolite alteration in patients with Behcet's disease (210 characters). Clinical Rheumatology, 2019. 38(5): p. 1437-1445. Where Snodgrassella alvi bacteria are key members of the gut microbiome of honeybees and play a role in excluding pathogens, ref: Lariviere, P.J., et al., Single-step genome engineering in the bee gut symbiont Snodgrassella alvi. BioRxiv : the Preprint Server For Biology, 2023. Where Streptomyces viridochromogenes can produce a superior growth-promoting feed additive, avilamycin, which is widely used to promote the growth of poultry by inhibiting gram-positive bacteria, ref: Yu, G., et al., Avilamycin production enhancement by mutagenesis and fermentation optimization in Streptomyces viridochromogenes.World Journal of Microbiology & Biotechnology, 2022. 38(3): p. 50. After the mice were given vaginal administration of Agkistrodon, there were 5 species with a relative abundance of less than 1 / 50, among which Enterococcus faecalis is a human pathogen and one of the common pathogens of nosocomial infections, which exhibits a dual lifestyle of symbiotic and pathogenic bacteria and can use multiple strategies to prevent phagocytes from phagocytosis, Ref: Archambaud, C., et al., Enterococcus faecalis: an overlooked cell invader. Microbiology and Molecular Biology Reviews : MMBR, 2024. 88(3): p. e0006924. Among them, Hathewaya limosa is an anaerobic bacterium associated with various infections, including prosthetic valve endocarditis, Ref: Mada, P.K. and M.H. Khan, Hathewaya limosa Empyema: A Case Report. Cureus, 2024. 16(2): p. e55156. Among them, Staphylococcus aureus is the main cause of hospital and community-acquired infections, which has a heavy burden on the healthcare system. The attachment of Staphylococcus aureus to medical implants and host tissues, as well as the establishment of mature biofilms, plays an important role in the persistence of chronic infections, Ref: Lister, J.L. and A.R. Horswill, Staphylococcus aureus biofilms: recent developments in biofilm dispersal. Frontiers In Cellular and Infection Microbiology, 2014. 4: p. 178. Can cause a variety of infections, including skin infections, respiratory tract infections, and blood infections, etc. Among them, Streptococcus sanguinis is a ubiquitous oral commensal species that is often involved as an opportunistic pathogen in cardiovascular infections, Ref: Alves, L.A., et al., PepO and CppA modulate Streptococcus sanguinis susceptibility to complement immunity and virulence. Virulence, 2023. 14(1): p. 2239519.

[0077] From these results, it can be concluded that pit viper vaginal administration can reduce the corresponding harmful bacteria by enriching the corresponding beneficial bacteria, and has the following effects: treating recurrent Clostridium difficile infection, improving type 2 diabetes, insulin resistance, mediating tumor suppression, reducing intestinal ischemia / reperfusion injury, reducing intestinal barrier damage, reducing motor dysfunction and loss of dopaminergic neurons in a mouse model of Parkinson's disease, reducing T cell aberration, eliminating pathogens, promoting poultry growth, reducing various infections, hospital and community-acquired infections, including skin infections, respiratory tract infections, blood infections, etc., reducing various different effects such as prosthetic valve endocarditis.

[0078] 2. Rank sum test As shown in Figure 14 , pit viper vaginal administration has an impact on the abundance of certain vaginal flora, and this change may help restore the balance of vaginal flora, thereby having a positive impact on host health.

[0079] 3. LDA column chart As shown in Figure 15 , through the LDA column chart, the significant differences of different taxonomic units (such as genus, species, etc.) in different groups can be obtained, which may be related to disease status, treatment effect or natural variation of microbial community.

[0080] 4. LEfSe analysis of evolutionary branch diagram As shown in Figure 16 , through the LEfSe analysis of the evolutionary branch diagram, the microorganisms that play an important role in different groups can be effectively identified. Red represents the taxonomic group enriched in the healthy control group, and green represents the taxonomic group enriched in the pit viper treatment group (no significant difference in taxonomic groups has been screened after pit viper treatment). The size of each circle is directly proportional to the relative abundance of the group.

[0081] 5. Random forest analysis As shown in Figure 17 , through random forest analysis, the most important species for classifying microbial community samples can be effectively identified, such as Klebsiella, Sphingomonas, etc. These species may be related to health status or treatment effect. By further studying the biological functions of these species and their roles in different groups, we can better understand their relationship with host health and disease, and how they respond to pit viper vaginal administration.

[0082] (Five) Functional prediction analysis 1. Rank sum test FAPROTAX functional prediction

[0083] As shown in Figure 18As shown in the figure, different groups show different relative abundances of microbial functions or features, such as animal parasites or symbionts, chemoheterotrophy, fermentation functions are relatively high in the control group (A), animal parasites or symbionts, chemoheterotrophy, fermentation, nitrate reduction functions are relatively high in the pit viper vaginal administration group (V), indicating that animal parasites or symbionts, chemoheterotrophy, fermentation, nitrate reduction functions may be affected by the vaginal administration of traditional Chinese medicine water extract. By analyzing the changes of these functions, we can better understand how the pit viper traditional Chinese medicine water extract affects the vaginal flora, and how these changes are related to the health of the host. This analysis helps to identify potential therapeutic targets and biomarkers, and provides a scientific basis for the development of new treatment strategies.

Claims

1. The use of a medicinal food prebiotic mimetic (pseudobiotic) in the preparation of a medicament or preparation for maintaining vaginal health by mimicking prebiotics, promoting vaginal beneficial bacteria and inhibiting vaginal harmful bacteria, wherein the medicinal food prebiotic mimetic (pseudobiotic) is a Gloydius brevicaudus.

2. The use of the phytogenic prebiotic mimetic (prebiotic mimetic) according to claim 1 for the preparation of a medicament or preparation for the maintenance of vaginal health, which mimics prebiotics, promotes vaginal beneficial bacteria and inhibits vaginal harmful bacteria, characterized in that: The medicinal food prebiotic mimetic (pseudobiotic) or extract thereof is mixed with other substances to form a complex for use in the preparation of a medicament or preparation for mimicking prebiotics and inhibiting vaginal harmful bacteria to maintain vaginal health. ​ 3. The use of a medicinal food prebiotic mimetic (pseudobiotic) in the preparation of a medicament or preparation for maintaining vaginal health by mimicking prebiotics, promoting vaginal beneficial bacteria and inhibiting vaginal harmful bacteria, according to claim 1, wherein the mimicking prebiotics and inhibiting vaginal harmful bacteria refers to promoting the colonization of beneficial bacteria and inhibiting the number of harmful bacteria in the vaginal environment of mice.

4. The use of a medicinal food prebiotic mimetic (pseudobiotic) in the preparation of a medicament or preparation for maintaining vaginal health by mimicking prebiotics, promoting vaginal beneficial bacteria and inhibiting vaginal harmful bacteria, according to claim 2, wherein the mimicking prebiotics and inhibiting vaginal harmful bacteria refers to promoting the colonization of beneficial bacteria and inhibiting the number of harmful bacteria in the vaginal environment of mice.

5. The use of the phytogenic prebiotic mimetic (prebiotic mimetic) according to any one of claims 1 to 4 for the preparation of a medicament or preparation for the maintenance of vaginal health, which mimics prebiotics, promotes vaginal beneficial bacteria and inhibits vaginal harmful bacteria, characterized in that The vaginal beneficial bacteria include Blautia obeum, Dorea longicatena, Lactobacillus johnsonii, Lactobacillus murinus, Lactobacillus taiwanensis, Megamonas hypermegale, Snodgrassella alvi, Streptomyces viridochromogenes.

6. The use of the prebiotic mimicry (biogenic prebiotic) of any one of claims 1-4 in the preparation of a drug or formulation for maintaining vaginal health by mimicking prebiotics, promoting beneficial vaginal flora, and inhibiting harmful vaginal flora, characterized in that the harmful vaginal flora includes: Enterococcus faecalis, Hathewaya limosa, Staphylococcus aureus, Streptococcus sanguinis.

7. The use of the phytogenic prebiotic mimetic (prebiotic mimetic) according to any one of claims 1 to 4 for the preparation of a medicament or preparation for the maintenance of vaginal health, which mimics prebiotics, promotes vaginal beneficial bacteria and inhibits vaginal harmful bacteria, characterized in that: The medicinal food prebiotic mimetic (pseudobiotic) Gloydius brevicaudus or extract thereof is mixed with other substances to form a complex for use in the preparation of a medicament or preparation for mimicking prebiotics, promoting vaginal beneficial bacteria and inhibiting harmful bacteria.

8. The use of a medicinal food prebiotic mimetic (pseudobiotic) in the preparation of a medicament or preparation for maintaining vaginal health by mimicking prebiotics, promoting vaginal beneficial bacteria and inhibiting vaginal harmful bacteria, according to any one of claims 1-4, wherein the medicament or preparation has the following effects: treating recurrent Clostridium difficile infection, improving type 2 diabetes, insulin resistance, mediating tumor suppression, reducing intestinal ischemia / reperfusion injury, reducing intestinal barrier disruption, reducing motor dysfunction and loss of dopaminergic neurons in a mouse model of Parkinson's disease, reducing T cell aberration, excluding pathogens, promoting the growth of poultry, reducing a variety of infections, hospital and community-acquired infections, including skin infections, respiratory tract infections, blood infections, reducing prosthetic valve endocarditis.

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