LU503461B1 - Lactobacillus fermentum TY-G03 and application thereof - Google Patents
Lactobacillus fermentum TY-G03 and application thereof Download PDFInfo
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- LU503461B1 LU503461B1 LU503461A LU503461A LU503461B1 LU 503461 B1 LU503461 B1 LU 503461B1 LU 503461 A LU503461 A LU 503461A LU 503461 A LU503461 A LU 503461A LU 503461 B1 LU503461 B1 LU 503461B1
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- preparation
- flora
- intestinal
- lactobacillus fermentum
- intestinal flora
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Abstract
The present invention belongs to the technical field of microorganisms, and specifically, relates to Lactobacillus fermentum TY-G03 and an application thereof. The Lactobacillus fermentum TY-G03 is assigned with the accession number of CGMCC No.23753. The lactobacillus fermentum may maintain the diversity and abundance of imbalanced intestinal flora on (or even superior to) a normal level, may effectively balance an intestinal flora structure of the imbalanced intestinal flora, may significantly reduce a ratio of Firmicutes flora to Bacteroidetes flora in the imbalanced intestinal flora, may significantly reduce the relative abundance of Proteobacteria flora in the imbalanced intestinal flora, may significantly improve the relative abundance of Lachnospiraceae flora in the imbalanced intestinal flora, may significantly improve the flora abundance of beneficial bacteria in the imbalanced intestinal flora, or may significantly reduce the flora abundance of harmful bacteria in the imbalanced intestinal flora.
Description
LACTOBACILLUS FERMENTUM TY-G03 AND APPLICATION THEREOF LU503461
The present invention belongs to the technical field of microorganisms, and specifically, relates to Lactobacillus fermentum TY-GO3 and an application thereof.
The human intestinal tract is homed by a large number and variety of microorganisms, which are mainly bacteria and collectively known as intestinal flora. The human intestinal flora has more than 35,000 species of bacteria, numbering up to 100 trillion, which is 10 times the number of human body cells. In normal cases, the intestinal flora and the host are interdependent and restricted with each other, which maintains a dynamic ecological balance, participates a series of vital activities such as nutrient digestion and absorption, biological antagonism, immunity and an anti-tumor effect, and maintains the health of an organism.
When the intestinal flora is adversely affected by changes in the host and external environments, a balance state is broken, resulting in imbalance of intestinal flora (which means that the type, number and proportion of normal intestinal flora are abnormally changed, deviating from a normal physiological combination and transforming into a pathological combination state), thereby causing and aggravating various diseases. Correlational research has verified that, the intestinal flora is associated with metabolic diseases, immune diseases, gastrointestinal diseases and even psychiatric diseases.
Currently, the imbalance of intestinal flora caused by adverse external environments is treated with antibiotics. However, long-term use of antibiotics, especially broad-spectrum antibiotics, may also kill some normal flora, resulting in secondary imbalance of intestinal flora.
Hence, existing technologies to improve the imbalance of intestinal flora still have shortcomings.
Therefore, a preparation that is high in safety, small in toxic and side effect and may effectively adjust the imbalance of intestinal flora is necessary.
In view of the above problems, one of the objectives of the present invention is to provide
Lactobacillus fermentum TY-GO3 which is conductive to the prevention of the imbalance of intestinal flora. The Lactobacillus fermentum TY-GO3 can maintain the diversity and abundance of flora, change the structure of the flora, suppress the growth of harmful bacteria and promote the growth of beneficial bacteria, so as to prevent or treating the imbalance of intestinal floray503461 thereby maintaining the health of the intestinal tracts.
In order to achieve the above purpose, the following technical solution may be adopted.
An aspect of the present invention provides Lactobacillus fermentum TY-GO3. The
Lactobacillus fermentum TY-GO3 is deposited with the China General Microbiological Culture
Collection Center (CGMCC) and is assigned with the accession number of CGMCCNo.23753.
Another aspect of the present invention provides a composition. The composition may include one or a mixture of a plurality of the following substances: (a) the Lactobacillus fermentum TY-GO3; (b) lysate of the Lactobacillus fermentum TY-GO3; (c) cultures of the
Lactobacillus fermentum TY-GO3; and (d) fermentation broths of the Lactobacillus fermentum
TY-GO3.
Still another aspect of the present invention provides a preparation. The preparation includes the Lactobacillus fermentum TY-GO3 or the composition, and a carrier. The carrier is a medicinal carrier or an edible carrier.
Still another aspect of the present invention provides an application of the Lactobacillus fermentum TY-GO3 or the composition in preparation of preparations used for preventing or treating imbalance of intestinal flora in an organism.
The Lactobacillus fermentum TY-GO3 of the present invention was deposited with the
China General Microbiological Culture Collection Center (CGMCC) at No. 3, Yard 1, BeiChen
West Road, Chaoyang District, Beijing on November 8, 2021, and was assigned with the accession number of CGMCCNo.23753, with the classification name being Lactobacillus fermentum.
The beneficial effects of the present invention at least include the following. (1) The Lactobacillus fermentum TY-GO3 provided in the present invention can maintain the diversity and abundance of intestinal flora in the organism with imbalance of intestinal flora on (or even superior to) a normal level. (2) The Lactobacillus fermentum TY-GO3 provided in the present invention can effectively balance the structure of the intestinal flora in the organism with imbalance of intestinal flora. (3) The Lactobacillus fermentum TY-G03 provided in the present invention can significantly reduce a ratio of Firmicutes/Bacteroidetes in the intestinal flora in the organism with imbalance of intestinal flora. (4) The Lactobacillus fermentum TY-GO3 provided in the present invention may significantly reduce the relative abundance of Proteobacteria in the intestinal flora in the organism with imbalance of intestinal flora. LU503461 (5) The Lactobacillus fermentum TY-GO3 provided in the present invention may significantly improve the relative abundance of Lachnospiraceae in the intestinal flora in the organism with imbalance of intestinal flora. (6) The Lactobacillus fermentum TY-GO3 provided in the present invention may significantly improve the abundance of flora such as norank-f-Muribaculaceae, Desulfovibrio, Enterorhabdus, unclassified-f-Oscillospiraceae, Alistipes and unclassified-f-Ruminococcaceae in the intestinal flora in the organism with imbalance of intestinal flora. (7) The Lactobacillus fermentum TY-GO3 provided in the present invention may significantly reduce the abundance of flora such as Escherichia-Shigella, Clostridium-sensu-stricto-1,
Parasutterella, Enterococcus and Clostridioides in the intestinal flora in the organism with imbalance of intestinal flora. (8) The Lactobacillus fermentum TY-GO3 provided in the present invention belongs to probiotics, which is high in safety and small in toxic and side effect.
Fig. 1 is a colonial morphology diagram of isolated strains.
Fig. 2 is a result diagram of gram staining.
Fig. 3 is a diagram of an API 50CH reaction result of Lactobacillus fermentum TY-GO3.
Fig. 4 is a comparison diagram of Ace indexes of each group.
Fig. 5 is a comparison diagram of Shannon indexes of each group.
Fig. 6 is a comparison diagram of Simpson indexes of each group.
Fig. 7 is a diagram of B diversity analysis results of each group.
Fig. 8 is a comparison diagram of Firmicutes/Bacteroidota in each group.
Fig. 9 is a comparison diagram of the abundance of Proteobacteria in each group.
Fig. 10 is a comparison diagram of the abundance of Lachnospiraceae in each group.
Fig. 11 is a species difference chart of a drug group and a treatment group on a genus level.
In Fig. 4 to Fig. 6, there is no significant difference (p>0.05) between groups that are marked with the same lowercase English letters (a, b, c); and there is a significant difference (p<0.05) between groups that are marked with different lowercase English letters (a, b, c). In Fig. 8 to Fig. 10, there is no significant difference (p>0.05) between groups that are marked with the same lowercase English letters (a, b, c); and there is a significant difference (p<0.05)
between groups that are marked with different lowercase English letters (a, b, c). In Fig. 11,LU503461 horizontal ordinate represents species names on a genus level, an ordinate represents percentage values of the abundance of a certain species of a sample, and the rightmost is a P value, where *0.01<p<0.05, **0.001<p<0.01, ***p<0.001.
The embodiments are given to better describe the present invention, but the content of the present invention is not limited only to the given embodiments. Therefore, non-essential improvements and adjustments to the embodiments made by a person skilled in the art in accordance with the content of the above present invention still fall within the scope of protection of the present invention.
An aspect of the present invention provides Lactobacillus fermentum G03. The
Lactobacillus fermentum TY-GO3 is deposited with the China General Microbiological Culture
Collection Center (CGMCC) and is assigned with the accession number of CGMCCNo.23753. The
Lactobacillus fermentum TY-GO3 has the characteristics of being high in safety and low in side effect, and may promote the growth of intestinal beneficial bacteria, suppress the growth of intestinal harmful bacteria, maintain the diversity and abundance of intestinal flora and improve the conditions of imbalanced intestinal tracts.
Specifically, the Lactobacillus fermentum TY-GO3 is a strain that is obtained by diluting, with sterile normal saline, naturally fermented yak yogurt from herdsmen in Hongyuan County, Aba
Tibetan and Qiang Autonomous Prefecture, Sichuan Province, then spread the yogurt on an
MRS plate for culture, selecting flora after the culture is completed, and perform purification by means of a streak plate method. Single colonies formed by the strain by means of culture are consistent in morphology, moist and smooth in surface, medium in size, raised, neat in edge, and hemispherical in shape. The colonies are opaque and milk white in color. After gram staining, if cells are all in purple under a microscope, the strain is gram-positive bacteria (G*) which has a rod-like shape and conform to features of lactobacillus, such that the strain is determined as the gram-positive bacteria (G*).
Further, PCR amplification is performed on the purified strain; sequencing is performed after a sequence is amplified; and a 16SrDNA sequence includes a sequence shown as
SEQIDNO.1. After the sequence is obtained, searching and similarity comparison are performed in GenBank by using BLAST, and results show that the strain is Lactobacillus fermentum. An
API50CH kit is further used to analyze the utilization of TY-G03 to 49 different carbohydrates,
then an APllabplus system is used for identification, and results show that the strain is th&J503461
Lactobacillus fermentum.
It is to be noted that, the Lactobacillus fermentum TY-GO3 belongs to the Lactobacillus fermentum, which is a kind of probiotics with the characteristics of being high in safety and 5 small in side effect. In addition, it is to be further noted that, the Lactobacillus fermentum
TY-G03 may prevent the imbalance of intestinal flora by means of the following mechanisms: (1) a mechanism of suppressing the growth of harmful bacteria by means of competition between dominant bacteria; (2) a mechanism of forming an anaerobic environment by consuming most of the oxygen in the intestinal tract, so as to suppress the reproduction of aerobic harmful bacteria; (3) a mechanism of effectively resist the invasion of harmful bacteria to an organism by forming a layer of compact mycoderm; (4) a mechanism of, by producing a large number of substances such as antimicrobial active peptides and low molecular acids in the intestinal tract or forming a biological barrier by means of colonization, competition and exclusion, promoting the immunoregulation of the organism, so as to suppress the growth of pathogenic bacteria in the intestinal tract, thereby producing positive effects on intestinal microecology; and (5) a molecular mechanism interacting with intestinal epithelial cells of the organism, for example, combining bacterial surface molecules with protein molecules related to the adhesion of a host, so as to suppress the colonization of harmful bacteria flora in the intestinal tract, thereby promoting intestinal cells to secrete bacteriocin and organic acid that may suppress or kill the harmful bacteria flora.
Another aspect of the present invention provides a composition. In some embodiments, the composition may include one or a mixture of a plurality of the following substances: (a) the
Lactobacillus fermentum TY-GO3; (b) lysate of the Lactobacillus fermentum TY-GO3; (c) cultures of the Lactobacillus fermentum TY-GO3; and (d) fermentation broths of the Lactobacillus fermentum TY-GO3.
Specifically, when the Lactobacillus fermentum TY-G03 achieves an effect, the Lactobacillus fermentum TY-GO3 may achieves the effect by means of various manners. For example, the
Lactobacillus fermentum TY-GO3 may be directly introduced into a product to achieve the effect.
For example, the Lactobacillus fermentum TY-GO3 may also be cracked and mixed into the product to achieve the effect. For example, protein, peptide, secretion or metabolite obtained from the culture of Lactobacillus fermentum may also achieve the effect. For example, the fermentation broths of the Lactobacillus fermentum TY-GO3 after fermentation may also achieve the effect. It is be understood that, the Lactobacillus fermentum TY-G03 may achieve the effect in the form of viable bacteria or in the form of inactivated bacteria. LU503461
Further, in some embodiments, the composition may further include one or a combination of probiotics, dietary fiber and an active compound. Specifically, the composition may also be combined with other components to enhance the effect of regulating the imbalanced intestinal tracts. For example, the composition may be combined with other probiotics, and the probiotics are well-known in the art, such as yeast, probiotic bacillus, Clostridium butyricum, bifidobacterium or actinomycetes. For example, the composition may also be combined with the dietary fiber, and the dietary fiber is well-known in the art, such as inulin or polydextrose.
For example, the composition may also be combined with the active compound such as rhein, and the rhein can significantly increase the number of Lactobacillus in the intestinal tract.
Still another aspect of the present invention provides a preparation. In some embodiments, the preparation includes the Lactobacillus fermentum TY-G03 or the composition, and a carrier.
The carrier is a medicinal carrier or an edible carrier. Specifically, for ease of administration, the
Lactobacillus fermentum TY-GO3 or the composition may be prepared into various medicinal or edible preparations by adding the carrier. The carrier is an excipient well-known in the art for preparing the preparations.
Further, the preparation may be in the form of tablets, pills, capsules, powder, cataplasm, gel, granules or a liquid preparation. It is be understood that, according to the dosage form of different preparations, there is a difference between the selected carriers. For example, the preparation of tablets mainly uses a diluent (such as starch, dextrin, sucrose or sugar), an absorbent (such as calcium sulfate, calcium hydrogen phosphate or light magnesium oxide), an adhesive (such as povidone, syrup or hydroxypropyl methylcellulose), a wetting agent (such as water), or a disintegrating agent (such as dry starch, sodium hydroxymethyl starch or cross-linked povidone). For example, the preparation of the liquid preparation mainly uses a bulking agent, a suspending agent, an emulsifying agent, a colorant, or the like. In certain specific embodiments, the preparation may be biscuits, powder or milk tablets. In another specific embodiment, the preparation may be a stirred yogurt or a probiotic beverage. In other specific embodiments, the preparation may be jelly, milk foam or a set yogurt. In other specific embodiments, the preparation may be tablets or capsules.
Still another aspect of the present invention provides an application of the Lactobacillus fermentum TY-GO3 or the composition in preparation of preparations used for preventing or treating imbalance of intestinal flora. It is to be noted that, the imbalance of intestinal flora means that the type, number and proportion of normal intestinal flora are abnormally changed,
thereby deviating from a normal physiological combination and transforming into a pathologicaU503461 combination state. The preparation containing the Lactobacillus fermentum TY-GO3 may effectively restore the imbalanced intestinal flora to normal. In addition, it is to be noted that, the imbalance of intestinal flora may cause some diseases to the organism, such as chronic diarrhea, liver diseases or cancer. The preparation prepared by the Lactobacillus fermentum
TY-G03 and the composition may regulate the intestinal flora, so as to prevent or treat various diseases caused by the imbalance of the intestinal tract.
Further, in some embodiments, the application may include one or more of the following: (a) an application in preparation of a preparation used for maintaining or improving the diversity and abundance of intestinal flora in the organism: (b) an application in preparation of a preparation used for balancing the structure of the intestinal flora in the organism; (c) an application in preparation of a preparation used for maintaining or reducing a ratio of Firmicutes flora to Bacteroidetes flora in the intestinal flora in the organism; (d) an application in preparation of a preparation used for promoting the growth of intestinal beneficial bacteria in the intestinal flora in the organism; (e) an application in preparation of a preparation used for suppressing the growth of intestinal harmful bacteria in the intestinal flora in the organism; (f) an application in preparation of a preparation used for maintaining or reducing the relative abundance of Proteobacteria flora in the intestinal flora in the organism; and (g) an application in preparation of a preparation used for maintaining or improving the relative abundance of
Lachnospiraceae flora in the intestinal flora in the organism.
Specifically, if the intestinal flora in the organism is imbalanced, the diversity and abundance of intestinal flora are reduced. The preparation may restore the diversity and abundance of the imbalanced intestinal flora to a normal level or event superior to the normal level. For the intestinal flora in the organism that is not imbalanced, the preparation may play a role in preventing the diversity and abundance of the intestinal flora from reducing.
In addition, the imbalance of the structure of the intestinal flora is also a reason of causing the imbalance of the intestinal flora. The preparation may balance the intestinal flora with the imbalanced structure by spontaneously forming new intestinal flora, such that the bad development of the structure of the intestinal flora is reversed, thereby balancing the structure of the intestinal flora.
Furthermore, the increasing of the ratio of Firmicutes/Bacteroidetes is often considered as one of the manifestations of unhealthy intestinal flora. The preparation may reduce the ratio of
Firmicutes/Bacteroidetes in the intestinal flora of the organism to the normal level of the organism. Likewise, for the intestinal flora in the organism that is not imbalanced, th&J503461 preparation may play a role in preventing the ratio of Firmicutes/Bacteroidetes from increasing.
Furthermore, flora in the intestinal tract of the organism is classified into intestinal beneficial bacteria and intestinal harmful bacteria. When the intestinal beneficial bacteria are reduced, the intestinal harmful bacteria is increased accordingly, resulting in the imbalance of the intestinal flora. The preparation may promote the growth of the intestinal beneficial bacteria, such as norank-f-Muribaculaceae, Desulfovibrio, Enterorhabdus, unclassified-f-Oscillospiraceae, Alistipes and unclassified-f-Ruminococcaceae. The preparation may suppress the growth of the intestinal harmful bacteria, such as Escherichia-Shigella,
Clostridium-sensu-stricto-1, Parasutterella, Enterococcus and Clostridioides.
Furthermore, Proteobacteria is important proinflammatory bacteria, and is tightly related to the occurrence and development of intestinal inflammation. That is to say, the increasing of the Proteobacteria is also a reason of causing the imbalance of the intestinal flora. The preparation may reduce the relative abundance of Proteobacteria flora, so as to regulate the imbalance of the intestinal flora. Likewise, for the intestinal flora in the organism that is not imbalanced, the preparation may play a role in preventing the relative abundance of the
Proteobacteria flora from increasing.
Furthermore, on a family level, Lachnospiraceae is conductive to maintaining normal functions of the intestinal tract. The reduction of the abundance of Lachnospiraceae flora is also one of the signals of the imbalance of the intestinal flora. The preparation may improve the relative abundance of the Lachnospiraceae flora. Likewise, for the intestinal flora in the organism that is not imbalanced, the preparation may play a role in preventing the relative abundance of the Lachnospiraceae flora from reducing.
Further, in (d), the intestinal beneficial bacteria include one or more of norank-f-Muribaculaceae, Desulfovibrio, Enterorhabdus, unclassified-f-Oscillospiraceae, Alistipes and unclassified-f-Ruminococcaceae. In (e), the intestinal harmful bacteria include one or more of Escherichia-Shigella, Clostridium-sensu-stricto-1, Parasutterella, Enterococcus and
Clostridioides.
In order to better understand the present invention, the content of the present invention is further described below with reference to specific embodiments, but is not only limited to the following examples.
Embodiment 1: Separation, purification and identification of TY-GO3 (1) Experimental material
Naturally fermented yak yogurt from herdsmen in Hongyuan County, Aba Tibetan andJ503461
Qiang Autonomous Prefecture, Sichuan Province is collected. The homemade yak yogurt from the herdsman is taken by using a sterile spoon, and is put into a 15 mL sterile capped centrifuge tube containing a proper amount of sterile calcium carbonate and soluble starch (a mass ratio of the calcium carbonate to the soluble starch being 1:1). The tube is screwed up after the mixture is uniformly stirred, then put into a freezer, and transported back to a laboratory for immediate purification and separation of lactic acid bacteria. (2) Purification and separation of TY-G03
Under sterile conditions, 1 mL of a sample in (1) is pipetted to 9 mL of sterile normal saline, and a 10* sample diluent is obtained after the mixture is well mixed by means of vortex. Then 10-fold gradient dilution is performed to 107. 100 pL of diluent at 10°, 10°, or 107 is selected, and uniformly spread on an MRS plate for inverted culture for 48h at 37°C. After culture is completed, colonial morphology on the MRS plate is observed. Raised, whitish or yellowish, moist and circular colonies with medium sizes and neat edges are selected strain purification by using a streak plate method, and this streaking operation is repeated until the purified strains are obtained. (3) Morphological structure observation
The purified strains in (2) are inoculated in 5 mL of sterile MRS broth (which is provided by
Beijing Land Bridge Technology Co., Ltd.) for culture for 18h at 37°C. 1 mL of bacterial fluid is taken and centrifuged for 1 min at 12000r/min. After the bacterial fluid is washed for two times with the sterile normal saline, isochoric sterile normal saline is then added to resuspend the bacteria. A small amount of the bacteria is taken and spread uniformly on a glass slide by using an inoculating loop. After fixation, gram staining, microscopic examination, and photographing are performed. After staining, cells of Gram-positive bacteria (G*) are blue-purple, and cells of
Gram-negative bacteria (G) are red. Colonial morphology of the strains and gram staining results are observed and recorded.
The colonial morphology of the strains is shown in Fig. 1. The strains form single colonies in solid medium after purification, and the colonies are consistent in morphology, hemispherical in shape, white, smooth and moist in surface, and neat in edge.
The gram staining results are shown in Fig. 2. After gram staining, purple cell morphology (grey processing is performed in Fig. 2, and an original drawing is purple) with a rod-like shape is observed under a microscope, such that it is determined as gram-positive bacteria (G*). (4) Identification of biochemical characteristics of an API 50CH kit
Phenotypic identification of the level of a Lactobacillus species is mainly based on L4J503461 carbohydrate fermentation test. That is to say, the purified strains are inoculated in 5 mL of the sterile MRS broth for culture for 18h at 37°C. Centrifugation is performed for 15 min at 3000 r/min to collect bacteria; the bacteria are washed with the sterile normal saline and then resuspended as bacterial suspension; and an API5OCH kit (refer to the instructions of the
API50CH kit for operation) is used to identify the utilization of the TY-GO3 bacterial suspension to 49 different carbohydrates. The API50CH reactions of the Lactobacillus fermentum TY-GO3 to 49 carbohydrates are shown in Fig. 3. No. 5, 10, 11, 12, 28, 29, 30, 31, 35 and 47 tubes are subjected to reaction, which are positive; and detailed statistics are shown in Table 1 below.
API5OCH identification results of the Lactobacillus fermentum TY-GO3 are shown in Table 2 below. The results show that, among 49 test carbon sources, the strains are able to use 10 of these carbohydrates. Final identification is performed by means of an APllabplus system, experimental strains are Lactobacillus fermentum, and its ID value is 99.60% and T value is 1, which reach an identification requirement (ID value > 99.0% and T value > 0.5).
Table 1 Fermentation test results of Lactobacillus fermentum TY-GO3 to 49 carbohydrates
Tube | Carbohydrate Reaction | Tube | Carbohydrate Reactio numb result numb n result er er pme NZ
Gem Ewe per | 7 rame
Fem ee
DC TE meee [oe 5 ie 7 Jove A me
Tet Tm we
Methyl-beta-D-xylopyran 34 D-melezitose
Cl EE ede rw me gi IP ee IE
[res | [mbes
EB [weer pw Hew
Eo Cc CO Cc E
Fa [A [ewes 5e TE ew
Methyl-alpha-D-mannop 45 D-arabinitol
El I a 21 Methyl-alpha-D-glucopyr 46 L-arabinitol
Come mem
Baie ||| Pme 23 Amygdalin 48 Potassium
CT ee 24 ARBULIN 49 Potassium ee
Note: “+” represents a positive reaction; and “-” represents a negative reaction.
Table 2 API 50CH identification result of Lactobacillus fermentum TY-G0O3
I wm
Ps
(5) PCR amplification of 16S rDNA sequence
A 25puL reaction system and the following PCR amplification procedure are used for 16SrDNA gene amplification. The 25uL reaction system includes a 1uL of a template, 1uL (10puM) of an upstream primer (of which sequence is shown as SEQIDNO.2), 1uL (10uM) of a downstream primer (of which sequence is shown as SEQIDNO.3), 12.5uL of 2xTagPCRMasterMix, and making up to 25 pL with sterile ultrapure water. The PCR amplification procedure includes performing pre-denaturation for 5 min at 94°C; performing denaturation for 30s at 94°C, performing annealing for 30s at 55°C, performing extension for 1 min at 72°C, there being 35 cycles in total; performing end extension for 10 min at 72°C; after sequence amplification, entrusting Sangon Biotech (Shanghai) Co., Ltd. to sequence qualified PCR amplification products, the obtained sequence being shown as SEQIDNo.1; and using BLAST (http://www.ncbi.nlm.nih.gov/BLAST) for search and homology analysis in GenBank. Homology analysis results show that, TY-GO3 is Lactobacillus fermentum.
Embodiment 2 Preventive effect validation of TY-GO3 on imbalance of intestinal flora (1) Experimental material
The Lactobacillus fermentum TY-GO3 conductive to the prevention of the imbalance of intestinal flora is isolated from the naturally fermented yak yogurt from the herdsmen in
Hongyuan County, Sichuan Province, is deposited with the CGMCC, and is assigned with the accession number of CGMCC No.23753. (2) Grouping and treatment of experimental animals 7-week-old BALB/c male mice (20 g to 25 g) are selected and fed in a standardization laboratory at room temperature of 25+2°C and relative humidity of 50+5% and under a condition of 12h light/12h dark, and an experiment starts after a week of adaptive feeding.
After the adaptive phase ends, the mice are randomly grouped into a normal group, a drug group and a TY-GO3 treatment group, and each group has 10 mice.
An experimental period is 18 days, and a TY-GO3 intervention duration is 1-14d. The normal group and the drug group are intragastrically administered with 10mL/kg.BW of normal saline; and the treatment group is intragastrically administered with 10° CFU/kg.BW of TY-GO3 bacterial fluid, and an intragastric administration volume is the same as that of the normal group and the drug group. A modeling experiment for the mice with the imbalance of intestinal flora starts at Day 15. 10mg/kg-BW of a loperamide hydrochloride solution is intragastrically administered to the mice in the groups other than the normal group; 10mL/kg.BW of the)503461 normal saline is intragastrically administered to the mice in the normal group. After 1h interval, 10mL/kg.BW of the normal saline is intragastrically administered to the mice in the normal group and the drug group, 10° CFU/kg.BW of the TY-GO3 bacterial fluid is intragastrically administered to the mice in the treatment group, and the experiment lasts 3d until Day 17.
After intragastric administration is completed, all of the mice start to fast. After 16h of fasting, the mice are killed and dissected, and then the caecum tissue (with contents) of each mouse is collected and put into a sterile centrifuge tube. (3) Sequencing of intestinal flora and processing of sequencing results 1) Sample collection
Under sterile conditions, the cecal contents of the mice in each group are collected for microbial diversity sequencing. 2) DNA extraction and PCR amplification
The total DNA of microbial flora in the cecal contents is extracted according to the specification of an E.Z.N.A.® soil DNA kit; 1% agarose gel electrophoresis is used to detect the extraction quality of DNA; NanoDrop2000 is used to measure the concentration and purity of the DNA; and 338F (5’-ACTCCTACGGGAGGCAGCAG-3’) and 806R (5’-GGACTACHVGGGTWTC
TAAT-3’) are used to perform PCR amplification on V3-V4 variable regions of a 16S rRNA gene. An amplification procedure includes performing pre-denaturation for 3 min at 95°C, there being 25 cycles (denaturation for 30s at 95°C, annealing for 30s at 55°C, and extension for 45s at 72°C); then performing stable extension for 10 min at 72°C; and finally, performing storage at 4°C (a PCR instrument: ABI GeneAmp® 9700). A PCR reaction system includes 4 pL of a 5xTransStart FastPfu buffer solution, 2 pL of 2.5mM dNTPs, 0.8 pL (5uM) of an upstream primer, 0.8 ul (5uM) of a downstream primer, 0.4 ul of TransStart FastPfu DNA polymerase, 10 ng of template DNA, and making up to 20 pL with ddH,0. 3) Illumina Miseq sequencing
After PCR products of the same sample are mixed, 2% agarose gel is used to recycle the
PCR products, and an AxyPrep DNA Gel Extraction Kit is used to purify the recycled products; then electrophoresis detection is performed by using the 2% agarose gel, and a Quantus™
Fluorometer is used to detect and quantify the recycled products; and a NEXTflexTM Rapid
DNA-Seq Kit is used for library building, including: (1) linking connectors; (2) using magnetic beads for screening, so as to remove connector self-connecting fragments; (3) performing enrichment of library templates by means of PCR amplification; and (4) using the magneti&J503461 beads to recycle the PCR products, so as to obtain a final library. A NovaSeq PE250 platform of lumina is used for sequencing, and the sequencing is completed by entrusting Shanghai
Majorbio Technology Co., Ltd.. 4) Sequencing data processing
FASTP (https://github.com/OpenGene/fastp, version 0.20.0) software is used to perform quality control on an original sequencing sequence, and FLASH (http://www.cbcb.umd.edu/software/flash, version 1.2.7) software is used for splicing; on the basis of default parameters, a DADA2 plug-in in a Qiime2 process to perform noise reduction on the optimized sequence after quality control splicing; the sequence after noise reduction by
DADA2 is usually called ASVs (that is, Amplicon Sequence Variants); on the basis of a Sliva 16S rRNA database (v 138), and a Naive bayes classifier in Qiime2 is used to perform species taxonomic analysis on the ASVs; and subsequent data analysis is performed by means of a diversity cloud analysis platform (the Qiime2 process, cloud.majorbio.com) of Shanghai
Majorbio Technology Co., Ltd. (4) Data analysis 1) a-diversity analysis of intestinal flora
The diversity analysis of intestinal flora mainly includes a-diversity and B-diversity. The a-diversity is mainly used to study the flora diversity of a certain sample, which may be evaluated by means of a series of a-diversity indexes, so as to obtain information of abundance and diversity of species in the flora; the diversity indexes commonly used to reflect the abundance of the flora include Ace indexes, and the like; and the diversity indexes commonly used to reflect the diversity of the flora includes Shannon indexes, Simpson indexes, and the like.
Generally, if the Ace indexes and the Shannon indexes are higher, it indicates that the abundance and diversity of the flora are higher; and if the Simpson indexes are higher, it indicates that the diversity of the flora is lower.
Changes in the a-diversity indexes of the mice in each group are shown in Fig. 4, Fig. 5 and
Fig. 6. Results show that, on the Ace and Simpson indexes, there is a significant difference between the drug group and the normal group, which indicates that the loperamide hydrochloride changes the diversity and abundance of intestinal flora in the mice, the Ace indexes and the Shannon indexes of the treatment group are significantly higher than those of the drug group, and the Simpson indexes are significantly lower than those of the drug group (p<0.05). The results indicate that, the loperamide hydrochloride reduces the diversity and abundance of the intestinal flora, while the intervention of TY-G03 may maintain the diversity503461 and abundance of the intestinal flora on (or superior to) a normal level. 2) B-diversity analysis of intestinal flora
Different from the a-diversity, the B-diversity focuses on comparing microbial diversity among different species. Non-metric Multidimensional Scaling analysis (NMDS analysis) is a data analysis method that simplifies research objects (samples or variables) in a multidimensional space to a low-dimensional space for positioning, analysis and categorization, while preserving an original relationship between the objects. Generally, the NMDS analysis is used to compare the similarity between samples. On the basis of the B-diversity analysis method, overall cognition of changes in the intestinal flora after the intervention of TY-G03 may be achieved.
Fig. 7 is a diagram of NMDS analysis results of each group. Data points with different shapes and colors represent intestinal flora samples of the mice in each group, and if the data points are closer to each other, it indicates that the intestinal flora of the two samples are more similar. It may be learned from Fig. 7 that, an ellipse formed by the data points (triangles) of the drug group is moved downward from an ellipse formed by the data points (circles) of the normal group, indicating that the loperamide hydrochloride causes the imbalance of the structure of the intestinal flora of the mice. An ellipse formed by the data points (diamonds) of the treatment group is moved upward, which is completely separated from the drug group, indicating that TY-GO3 significantly reverses the bad development of the structure of the intestinal flora which is induced by the loperamide hydrochloride. Although the ellipse formed by the data points (diamonds) of the treatment group does not completely overlap with the ellipse formed by the data points (circles) of the normal group, it indicates that under the treatment of TY-G03, new balance of the intestinal flora is spontaneously formed in the mice, so asto avoid a problem caused by the loperamide hydrochloride. 3) Impact of TY-GO3 on the composition of intestinal flora
By means of comparing specific differences of the normal group, the drug group and the treatment group on a phylum level, a family level and a genus level, the composition of species of different grouped samples on different classification levels may be learned, so as to more clearly understand which species specifically changed in abundance by the loperamide hydrochloride and the TY-GO3.
At the phylum level, the intestinal flora of the mice in each group is mainly based on
Firmicutes and Bacteroidetes, and is supplemented by Actinobacteria, Proteobacteria,
Verrucomicrobia, and the like. The ratio of Firmicutes/Bacteroidetes is often considered as on&J503461 of the manifestations of unhealthy intestinal flora. Research has found that, the Proteobacteria is important proinflammatory bacteria, and is tightly related to the occurrence and development of intestinal inflammation. on the family level, Lachnospiraceae is conductive to maintaining normal functions of the intestinal tract. on the genus level, norank-f-Muribaculaceae, Desulfovibrio, Enterorhabdus, unclassified-f-Oscillospiraceae, Alistipes, and unclassified-f-Ruminococcaceae are generally considered as beneficial species; and
Escherichia-Shigella, Clostridium-sensu-stricto-1, Parasutterella, Enterococcus, and Clostridioides are generally considered as harmful species.
Changes in the abundance of specific species of the mice in each group on different classification levels are shown in Fig. 8 to Fig. 11.
It may be learned from Fig. 8 that, the ratio of Firmicutes/Bacteroidetes in the drug group is significantly increased compared with the normal group, while the ratio of
Firmicutes/Bacteroidetes in the treatment group is significantly reduced (p<0.05).
It may be learned from Fig. 9 to Fig. 10 that, the loperamide hydrochloride significantly improves the relative abundance of Proteobacteria of the intestinal flora of the mice on the phylum level, and significantly reduces the relative abundance of Lachnospiraceae on the family level; and the intervention of the TY-GO3 significantly reduces the relative abundance of the
Proteobacteria and improves the relative abundance of the Lachnospiraceae (p<0.05).
It may be learned from Fig. 11, the TY-GO3 significantly improves the abundance of species such as norank-f-Muribaculaceae, Desulfovibrio, Enterorhabdus, unclassified-f-Oscillospiraceae,
Alistipes and unclassified-f-Ruminococcaceae on the genus level, and significantly reduces the abundance of species such as Escherichia-Shigella, Clostridium-sensu-stricto-1, Parasutterella,
Enterococcus and Clostridioides (*0.01<p<0.05, **0.001<p<0.01, ***p<0.001).
Through the above, the TY-G03 promotes the growth of the beneficial bacteria of the intestinal tract and suppresses the growth of the harmful bacteria of the intestinal tract.
It may be seen from the animal experiment results of the prevent invention that, the loperamide hydrochloride induces the imbalance of the intestinal flora in the mice, and the
Lactobacillus fermentum TY-GO3 prevents the imbalance of the flora induced by the loperamide hydrochloride by means of maintaining the diversity and abundance of intestinal flora, changing the structure of the flora, suppressing the growth of the harmful bacteria and promoting the growth of the beneficial bacteria. After the Lactobacillus fermentum TY-GO3 enters the intestinal tract, disturbed flora structures in the intestinal tracts of mice may be regulated by means of occupancy competition, such that a new steady state can be formed with thé/503461 probiotics in the intestinal tract, thereby restoring the balance of the flora in the intestinal tract.
It is finally to be noted that, the above embodiments are merely for describing and not intended to limit the technical solutions of the present invention. Although the present invention is described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention may be modified or equivalently replaced without departing from the purpose and scope of the technical solutions of the present invention, and shall all fall within the scope defined by the claims of the present invention.
<110> Chongqing Tianyou Dairy Co., Ltd.
LU503461 <120> Lactobacillus fermentum TY-G03 and application thereof <160> 3 <170> SIPOSequencelisting 1.0 <210> 1 <211> 1110 <212> DNA <213> Lactobacillus fermentum <400> 1 ggaaagggcg agtgctataa tgcaagtcga acgegttgge ccaattgatt gatggtectt 60 gcacctgatt gattttggtc gccaacgagt ggeggacggg tgagtaacac gtaggtaacc 120 tecccagaag cgggggacaa catttggaaa cagatgctaa taccgcataa caacgttgtt 180 cgcatgaaca acgcttaaaa gatgecttct cgetatcact tctggatgga cctgeggtge 240 attagcttgt tggtggggta acggectace aaggcgatga tgeatagecg agttgagaga 300 ctgatcggcc acaatgggac tgagacacgg cccatactec tacgggagge agcagtaggg 360 aatcttccac aatgggcgca agectgatgg agcaacaccg cgtgagtgaa gaagggtttc 420 ggctcgtaaa getctgttgt taaagaagaa cacgtatgag agtaactgtt catacgttga 480 cggtatttaa ccagaaagtc acggctaact acgtgccagc agccgcggta atacgtaggt 540 ggcaagcegtt atccggattt attgggcgta aagagagtgc aggeggtttt ctaagtctga 600 tetgaaagcc ttcgecttaa ccggagaagt gcatcggaaa ctggataact tgagtgcaga 660 agagggtagt ggaactccat gtgtageggt ggaatgcgta gatatatgga agaacaccag 720 tggcgaaggc gectacctgg tctgcaactg acgetgagac tcgaaagcat gggtagegaa 780 caggattaga taccctggta gtccatgccg taaacgatga gtgctatgtg ttggaggett 840 tcegecectte agtgecggag ctaacgcatt aagcactccg cctggggagt acgaccgcaa 900 agttgaaact caaatgaatt gacgggggce cgcacaageg gtggageatg tggtttaatt 960 cgaagctacg cgaagaaccc ttaccagtct tgacatcttg cgecaaccct agagataggc 1020 gtttecttcg gacgcaatga cagtgtgeat ggtegtegte agetegtgte gtgagatgtt 1080 gggttaagtc cecgcaacga gcgccaacec 1110 <210> 2 <211> 20 <212> DNA <213> Artificial Sequence <400> 2 18 agagtttgat cctggctcag 20
LU503461 <210> 3 <211> 20 <212> DNA <213> Artificial Sequence <400> 3
Tacgacttaaccccaatcgc 20 19
Claims (9)
1. Lactobacillus fermentum TY-GO3, deposited with the China General Microbiological Culture Collection Center (CGMCC) and assigned with the accession number of CGMCC
No.23753.
2. The Lactobacillus fermentum TY-GO3 as claimed in claim 1, wherein a 16SrDNA sequence comprises a sequence shown as SEQIDNO.1.
3. A composition, comprising one or a mixture of a plurality of the following substances: (a) the Lactobacillus fermentum TY-GO3 as claimed in claim 1 or 2; (b) lysate of the Lactobacillus fermentum TY-GO3 as claimed in claim 1 or 2; (c) cultures of the Lactobacillus fermentum TY-GO3 as claimed in claim 1 or 2; and (d) fermentation broths of the Lactobacillus fermentum TY-GO3 as claimed in claim 1 or 2.
4. The composition as claimed in claim 3, further comprising one or a combination of probiotics, dietary fiber and a pharmacologically active compound.
5. À preparation, comprising the Lactobacillus fermentum TY-GO3 as claimed in claim 1 or 2 or the composition as claimed in claim 3 or 4, and a carrier, wherein the carrier is a medicinal carrier or an edible carrier.
6. The preparation as claimed in claim 5, wherein the preparation is in tablets, pills, capsules, powder, gel, granules or a liquid preparation.
7. An application of the Lactobacillus fermentum TY-G03 as claimed in claim 1 or 2 or the composition as claimed in claim 3 or 4 in preparation of preparations used for preventing or treating imbalance of intestinal flora in an organism.
8. The application as claimed in claim 7, comprising one or more of the following: (a) an application in preparation of a preparation used for maintaining or improving the diversity and abundance of intestinal flora in the organism: (b) an application in preparation of a preparation used for balancing the structure of the intestinal flora in the organism; (c) an application in preparation of a preparation used for maintaining or reducing a ratio of Firmicutes flora to Bacteroidetes flora in the intestinal flora in the organism; (d) an application in preparation ofa or preparation used for promoting the growth of intestinal beneficial bacteria in the intestinal flora in the organism; (e) an application in preparation of a preparation used for suppressing the growth of intestinal harmful bacteria in the intestinal flora in the organism; (f) an application in preparation of a preparation used for maintaining or reducing the relative abundance of Proteobacteria flora in the intestinal flora in the organism; and (g) an application in preparation of a preparation used for maintaining or improving the relative abundance of Lachnospiraceae flora in the intestinal flora in the organism.
9. The application as claimed in claim 8, in (d), the intestinal beneficial bacteria comprise one or more of norank-f-Muribaculaceae, Desulfovibrio, Enterorhabdus, unclassified-f-Oscillospiraceae, Alistipes and unclassified-f-Ruminococcaceae; and in (e), the intestinal harmful bacteria comprise one or more of = Escherichia-Shigella, Clostridium-sensu-stricto-1, Parasutterella, Enterococcus and Clostridioides.
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