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WO2019203422A1 - Prédiction du risque d'accouchement prématuré utilisant le changement de la communauté microbienne du sang - Google Patents

Prédiction du risque d'accouchement prématuré utilisant le changement de la communauté microbienne du sang Download PDF

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WO2019203422A1
WO2019203422A1 PCT/KR2019/000280 KR2019000280W WO2019203422A1 WO 2019203422 A1 WO2019203422 A1 WO 2019203422A1 KR 2019000280 W KR2019000280 W KR 2019000280W WO 2019203422 A1 WO2019203422 A1 WO 2019203422A1
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strain
blood
women
genus
mother
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WO2019203422A9 (fr
Inventor
김영주
유영아
이경주
두지은
권은진
박미혜
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Ewha Womans University
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6888—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for detection or identification of organisms
    • C12Q1/689—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for detection or identification of organisms for bacteria
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2531/00—Reactions of nucleic acids characterised by
    • C12Q2531/10—Reactions of nucleic acids characterised by the purpose being amplify/increase the copy number of target nucleic acid
    • C12Q2531/113—PCR

Definitions

  • the present invention relates to compositions, diagnostic kits and diagnostic methods for diagnosing premature birth risk by detecting microbiomes from maternal blood. More specifically, the present invention relates to a strain of genus Weissel la, genus Thermacetogenium, strain Lactobaci 1 lus, or Clostr idium from maternal blood. A composition, diagnostic kit and diagnostic method for diagnosing premature risk by detecting strains.
  • Preterm birth usually means delivery between 20 and 37 weeks of gestation, and infants born prematurely have a high risk of death, accounting for about 60% of all infant deaths. Nervous system developmental disorders, respiratory complications, and postnatal growth delays are necessary for neonatal intensive care. Furthermore, the morbidity rate of severe long-term or short-term diseases is high. About 70% of preterm births occur due to preterm labor (PTL) and premature rupture of membrane (PPR0M) due to various pathological processes such as intrauterine infection and inflammation.
  • PTL preterm labor
  • PPR0M premature rupture of membrane
  • the mechanisms associated with premature birth are not yet clear, and risk factors commonly associated with natural labor are genital infections, multiple pregnancies, bleeding in the second and third trimesters, and previous preterm history.
  • the minimum gestational age for improving the survival rate of premature babies is 27 weeks and birth weight is 0.9 kg, and the morbidity and mortality of newborn babies is influenced by the gestational age, ie maturity, rather than birth weight. Therefore, when signs of premature birth occur early in the week, increasing the maturity of the newborn by delaying the delivery week through appropriate treatment is an important factor for the health, quality of life and cost of the mother and newborn.
  • the risk of premature birth is predicted, and the preterm risk of premature birth is selected. It is necessary to develop. In addition, the earlier the premature birth, the greater the likelihood of leaving sequelae in the newborn and the greater the degree of sequelae.
  • the present inventors have completed the present invention by characterizing microorganisms in the blood in mothers with premature labor or premature amnion rupture, which are the main causes of preterm birth, and identifying the microbial community in the blood predicting preterm birth using gene sequence analysis.
  • the present invention seeks to contribute to the prevention of premature birth by analyzing the microbiome in the blood of the mother to discover predictive markers of premature birth suggesting the risk of premature birth.
  • one embodiment provides a composition for diagnosing the risk of premature birth of a mother, comprising an agent capable of detecting a microorganism of Bisella 3361 13) in the blood.
  • Another example provides a kit for diagnosing the risk of premature birth of a mother comprising the composition.
  • Another example provides a method of providing information necessary for diagnosing premature birth risk, including detecting microorganisms of Bisella from the mother's blood.
  • the present invention is a strain of Bisella ( ⁇ 3361 1) genus, strains of thecematogenium (3 ⁇ 461'111% 61: 611 ä), Pecali
  • the present invention relates to a composition for diagnosing the risk of premature birth risk of a mother comprising an agent capable of detecting one or more microorganisms selected from the group consisting of the genus strain and Clostridium genus strain.
  • the diagnostic composition of the present invention may further include an agent capable of detecting microorganisms of the genus Lactobacillus ( ⁇ 1 1113).
  • the agent capable of detecting the microorganism in the present invention may be a primer, probe, antisense oligonucleotide, aptamer or antibody specific for the microorganism.
  • the primer may be a primer capable of amplifying 163 shows (165 ⁇ ⁇ ) of microorganisms.
  • 163 Primer that can be amplified may be a primer consisting of the sequence of SEQ ID NO: 1 or SEQ ID NO: 2. 2019/203422 1 »(: 1 ⁇ 1 ⁇ 2019/000280
  • the present invention relates to a kit for diagnosing the risk of premature birth of mothers comprising the composition.
  • the present invention provides a strain of the genus Bisella (6 361 13) from the mother's blood to provide the information necessary for diagnosing the risk of premature birth,
  • the method for providing information necessary for diagnosing the risk of premature birth of the present invention may further comprise detecting a microorganism of the strain of the genus Lactobacillus.
  • the amount of amplified product of Bisella spp., Thermocetoginium strain, Pecalibacterium spp., Or Clostridium spp. Strain detected from the mother's blood is further increased compared to the normal mother Or, it may be a method of evaluating a high risk of premature birth.
  • the amount of the amplification product of genome 0 of the strain consisting of Bisella genus strain, Thermocetoginium strain, Clostridium strain, Pecalibacterium strain and Lactobacillus strain detected from the mother's blood If the increase is more than the normal mother, it may be a method of evaluating the risk of maternal acid. 2019/203422 1 »(: 1 ⁇ 1 ⁇ 2019/000280
  • the effect of the composition of the microbial community on premature birth in the mother's blood blood which was hospitalized due to preterm labor and premature amniotic rupture, increased the bisella genus, Lactobacillus (Genk 1 1). Increase in the genus , An increase in the genus, an increase in the genus Thermocetoginium, and / or an increase in the genus Clostridium ((: 10 (1 ⁇ 1111)) was found to affect preterm birth.
  • the present invention by detecting the microorganisms of the genus Bisella, Pecalibacterium, Thermocetoginium, or Clostridium from the mother's blood, the risk of premature birth of the mother can be diagnosed.
  • the present invention provides compositions, kits and methods for detecting microorganisms of the genus Pecalibacterium, Genus Thermocetoginium, or Clostridium.
  • the present invention is capable of diagnosing maternal premature risk by further detecting Lactobacillus sp.
  • Microorganisms and also provides compositions, kits and methods for the same.
  • microbiome refers to the entire genetic information of microorganisms that coexist together in the human body.
  • the microbiome in the blood refers to the entire genetic information of the microorganisms present in the blood.
  • risk diagnosis or “risk prediction” refers to whether the mother is likely to give birth less than 37 weeks of gestational weeks, the likelihood of premature birth is less than 37 weeks, or less than 37 weeks.
  • the present invention can be used to delay or prevent premature birth through special and appropriate management for mothers who are at high risk of preterm birth for less than 37 weeks with respect to mothers.
  • the present invention can be used clinically to make treatment decisions by early diagnosis of preterm birth of less than 37 weeks and selecting the most appropriate treatment regimen.
  • bisellar means taxonomically belonging to the genus Bisella. Refers to a composed microorganism or its community.
  • bisella is preferably 70% or more, more preferably 80% or more, as compared with conventionally reported strains, as well as the conventionally reported bisella 163 show sequence. 2019/203422 1 »(: 1 ⁇ 1 ⁇ 2019/000280
  • microorganisms having at least 90%, most preferably at least 95% sequence homology are included in the scope of the present invention.
  • thermocetoginium refers to the taxonomy belonging to the genus Thermocetogenium. Refers to a composed microorganism or its community.
  • thermocetoginium as well as the strains reported in the prior art, Microorganisms having a sequence homology of at least 70%, more preferably at least 80%, even more preferably at least 90%, and most preferably at least 95% when comparing sequences are all included in the scope of the present invention.
  • lactobacillus refers to the genus Lactobacillus. Refers to a composed microorganism or its community. In the present invention, Lactobacillus is preferably at least 70%, more preferably at least 80%, even more preferably at least 90% when comparing the previously reported Lactobacillus with the 163 rRNA sequence as well as the strains reported in the prior art. Most preferably, microorganisms having 95% or more sequence homology are included in the scope of the present invention.
  • Clostridium refers to the genus Clostridium Refers to a composed microorganism or its community.
  • Clostridium is preferably not less than 70%, more preferably at least 80%, even more preferably 90 compared with conventionally reported Clostridium and 165 rRNA sequence All microorganisms having at least% and most preferably at least 95% sequence homology are within the scope of this invention.
  • pecalibacterium is a taxonomy belonging to the genus Pecalibacterium. Refers to a microorganism or its community. In the present invention, pecalibacterium is preferably 70% or more, more preferably 80% or more, and more preferably, compared with conventionally reported strains, as well as the conventionally reported pecalibacterium and 165 rRNA sequences. Are all within the scope of the present invention are microorganisms having at least 90%, most preferably at least 95% sequence homology.
  • the term “detectable agent” means bisella, lactobacillus, clostridium, and / or which are diagnostic markers for premature birth risk in the blood. Means a substance that can be used to detect the presence of pecalibacterium.
  • organics such as proteins, nucleic acids, lipids, glycolipids, glycoproteins or sugars (monosaccharides, disaccharides, oligosaccharides, etc.) that are specifically present in Bisella, Lactobacillus, Clostridium and / or Pecalibacterium It may be a primer, a probe, an antisense oligonucleotide, an aptamer, an antibody, or the like that can specifically detect a biological molecule.
  • the agent detectable in the present invention may be a primer capable of detecting Bisella, Lactobacillus, Thermocetoginium, Clostridium, and / or Pecalibacterium.
  • the primer specifically detects genomic sequences of Bisella, Lactobacillus, Thermocetoginium, Clostridium and / or Pecalibacterium and does not specifically bind to the genomic sequences of other microorganisms. More preferably, it may be a primer capable of amplifying 16S rRNA of one or more microorganisms selected from the group consisting of bisella, Lactobacillus, thermocetoginium, clostridium and pecalibacterium.
  • the term “primer 1 ” refers to seven to fifty nucleic acid sequences that can form base pairs complementary to the template strand and serve as a starting point for copying the template strand. Primers are usually synthesized but can also be used in naturally occurring nucleic acids. The sequence of the primer does not necessarily have to be exactly the same as the sequence of the template, but only if it is sufficiently complementary to hybridize with the template. Additional features may be incorporated that do not change the basic properties of the primer. Examples of additional features that may be incorporated include, but are not limited to, methylation, encapsulation, substitution of one or more nucleic acids with homologues, and modifications between nucleic acids.
  • the primer of the present invention may be a primer capable of amplifying 16S rRNA of Bisella, Lactobacillus, Thermocetoginium, Clostridium and / or Pecalibacterium microorganisms.
  • 16S rRNA refers to a rRNA constituting the 30S subunit of prokaryotic ribosomes, a conserved region common to all species and a hypervar i able region that can classify a particular species.
  • Microorganisms can be identified through sequencing. In particular, since there is little diversity among homogeneous species, while diversity appears among other species, prokaryotes can be usefully identified by comparing sequences of 16S rRNA.
  • 16S rDNA Since it is a gene encoding 16S rRNA, microorganisms can be identified using 16S rDNA.
  • the primers in the present invention amplify a 16S rRNA (or 16S rDNA) sequence specific for Bisella, Lactobacillus, Thermocetoginium, Clostridium and / or Pecalibacterium
  • the presence of the genus Bisella, Lactobacillus, Thermocetoginium, Clostridium, and / or Pecalibacterium can be detected through sequence amplification to produce the desired product. Sequence amplification method using a primer can be used a variety of methods known in the art.
  • PCR polymerase chain reaction
  • RT-PCR reverse transcriptase-polymerase chain reaction
  • RT-PCR multiplex PCR
  • touchdown PCR hot start PCR
  • Booster PCR real-time PCR
  • DD-PCR fractional display PCR
  • RACE rapid ampl ifi cat ion of cDNA ends
  • Inverse polymerase chain reaction vectorette PCR
  • TAIL-PCR thermal asymmetr ic inter lced PCR
  • ligase chain reaction repair chain reaction
  • transcription-mediated amplification self-maintaining sequence replication
  • a selective amplification reaction of the target sequence may be used, but the scope of the present invention is not limited thereto.
  • the microbial detection agent in the present invention may be an antibody, it can detect the microorganism using an immunological method based on the antigen-antibody reaction.
  • Analytical methods for this purpose include Western blot, enzyme l inked immunosorbent asay (ELISA), radioimmunoassay (RIA), radioimmunodi f fus ion (Ouchter lony) immunodiffusion method, locator (rocket) immunoelectrophoresis, tissue immunostaining, immunoprecipitation assay, complement fixation ion assay, fluorescence act ivated cel l sorter, or protein chip
  • ELISA enzyme l inked immunosorbent asay
  • RIA radioimmunoassay
  • radioimmunodi f fus ion Ouchter lony
  • locator rocket
  • Diagnostic composition comprising the microorganism detection agent of the present invention, may be provided implemented in the form of a diagnostic kit.
  • Kit of the present invention is a primer for detecting the microorganisms, probes, antisense oligonucleotides, aptamers, 2019/203422 1 »(: 1 ⁇ 1 ⁇ 2019/000280
  • detection agents such as antibodies, as well as one or more other component compositions, solutions, or devices suitable for the assay method.
  • the genus Bisella, Lactobacillus, Genus Thermocetogenium, Clostridium. And / or a kit comprising primers specific to Pecalibacterium may be a kit containing essential elements for carrying out an amplification reaction, such as a need.
  • the ⁇ 1? Kits for use include test tubes or other suitable containers, reaction buffers, deoxynucleotides (predetermined, enzymes such as 13 (1-polymerase and reverse transcriptase, 336, Chessho36 inhibitors, ), Or sterile water.
  • the present invention provides a method for diagnosing the risk of premature birth of the mother by detecting microorganisms of the genus Bisella, Thermocetoginium, Clostridium and / or Pecalibacterium from the mother's blood.
  • the present invention provides a method for detecting microorganisms of the genus Bisella, Thermocetoginium, Clostridium and / or Pecalibacterium from the mother's blood to provide information necessary for diagnosing the risk of premature birth of the mother.
  • the method may further comprise detecting the microorganism of the genus Lactobacillus.
  • the method can be implemented comprising the following steps:
  • Extraction of genome 0 from maternal blood in this step can be carried out by applying general techniques known in the art and specific for the microorganisms of the genus Bisella, Lactobacillus, Pecalibacterium and / or Clostridium. Typical primers are as described above.
  • the method for amplifying the reactants in step (C) is a general amplification techniques known in the art, such as polymerase chain reaction, reverse transcription-polymerase chain reaction, multiplex PCR, touchdown PCR, hot start PCR, nested PCR, booster PCR, real-time PCR, fractional display PCR, rapid amplification of cDNA ends, inverse PCR, Bectoret PCR, TAIL-PCR, ligase chain reaction, repair chain reaction, transcription-mediated amplification, self-sustained sequence replication, target Selective amplification of the nucleotide sequence may be used, but the scope of the present invention is not limited thereto.
  • step (c) the step of comparing the amount of amplification product of the reactant with the amplification product or cut-of f of normal maternal blood may be further performed, wherein the amplification product of bisella in maternal blood If it is judged to be significantly increased compared to amplification products or cut-of f of normal mother blood, the mother may be considered to have a high risk of premature birth.
  • the method may further comprise detecting a microorganism of the genus Lactobacillus, the amplification product of the genus Lactobacillus in the mother's blood compared to the amplification product or cut-of f of the normal maternal blood is significant If the risk is increased, the mother may be considered at high risk of premature birth.
  • the ratio of the microorganism means that the 16s rRNA sequence amplification amount of the corresponding microorganism is included in the total amount of the 16s rRNA sequence amplification products of the whole microbiome in the sample, for example, the weight percentage of the amplification product indicating the amount of amplification of the 16s rRNA sequence (w / w%), or the copy number ratio of the amplified product.
  • the present invention provides a microbial biomarker for diagnosing the risk of premature birth, it is possible to quickly detect the risk of premature birth through a simple blood collection, it is possible to develop a rapid diagnostic kit for this.
  • La shows the microbial diversity of non-pregnant women, normal birth women and PTB women by Pr incipal coordinate analys is.
  • FIG. Lb shows the microbial diversity of non-pregnant women, normal birth women and PTB women in a two-dimensi onal scatter plot with the first and second components as axes.
  • Figure lc shows the hitmap of microbial diversity of non-pregnant women, normal birth women, and PTB women.
  • Figure 2a shows the number of 16s metagenomic leads in non-pregnant women, normal birth women, and PTB women.
  • 2B shows the Shannon index of non-pregnant women, normal birth women, and PTB women.
  • Figure 3a shows the difference in microbial composition in blood samples of non-pregnant women, normal birth women, and PTB women at the phyla level.
  • Figure 3b shows the difference in microbial composition in blood samples of non-pregnant women, normal birth women, and PTB women at the class level.
  • Figure 4a shows the proportion of Bisella genus strains in blood samples of non-pregnant women, normal birth women, and PTB women.
  • Figure 4b shows the proportion of Lactobacillus strains in blood samples of non-pregnant women, normal birth women, and PTB women.
  • Figure 4c shows the proportion of strains of Clostridium in blood samples of non-pregnant women, normal birth women, and PTB women.
  • Figure 4d shows the ratio of the strains of the genus Thermocetoginium in blood samples of non-pregnant women, normal birth women and PTB women.
  • FIG. 4E shows the proportion of WD2101 strain in blood samples of non-pregnant women, normal birth women and PTB women.
  • 4F shows the proportion of TM7 strains in blood samples of non-pregnant women, normal birth women and PTB women.
  • Non-pregnant women were selected as healthy women who did not suffer from pregnancy-related diseases according to a routine medical examination.
  • Bacterial DNA was extracted from the blood samples of Example 1 using PowerMax Soi l DNA Isol at ion Kit (M0BI0, Carsbad, Calif., USA) according to the manufacturer's protocol.
  • the 16S rRNA gene V3-V4 hypervariable region (519F-816R) in bacterial genomic DNA was amplified according to the I lumina 16S meta genome sequencing library protocol (I lumina, San Diego, CA, USA).
  • the barcode fusion primer sequence used for amplification is as follows.
  • Example 2 The sequence information obtained in Example 2 was processed according to a barcode algorithm and a primer sequence using MiSeq (II lumina ⁇ S ⁇ . Taxonomic analysis was performed by a profiling program program MDx-Pro ver .1 (MD Heal thcare, Seoul, Korea) It was performed using.
  • MDx-Pro ver .1 MD Heal thcare, Seoul, Korea
  • the experimental results are expressed as mean ⁇ standard deviation.
  • the basic characteristics such as age, maternal characteristics, and outcomes of women with normal birth and PTB women were compared using the Student i-test.
  • the nonpregnant women were women on average 36 years old. General characteristics of pregnant women are shown in Table 1.
  • the mean age of the female group with normal birth was 31.6 years, and the mean age of the preterm woman group was 30.9 years. At birth, the preterm group had significantly lower gestational age, newborn weight, and show 31 -3 (: 6) (Afga score) (1) ⁇ 0.05). 2. Microbial community diversity
  • Microbial community composition in blood of PTB women is different from normal birth women
  • the phylum shown in more than 1% is shown in a pie graph (FIG. 3A).
  • Firmicutes, Bacteoidetes, Proteobacteria, and Actinobacteria were abundant in all groups. Crenarchaeota and Euryarchaeota statements belonging to ArcAaea were more abundant in pregnant women than non-pregnant women ( P ⁇ 0.001).
  • Lactobacillus genus, Weissel la genus, Clostridium genus, Thermacetogenium genus, WD2101 throat, TM7-1 steel showed a significant increase in PTB women ⁇ 0.01).
  • Four of the genus Lactobacillus, Weissel la, Clostridium, and Thermacetogenium belong to Firm and cutes phylum. p ⁇ 0.001).
  • the potential pathogenic TM7-1 was increased in PTB women (p ⁇ 0.001).
  • the present invention The characteristics of microorganisms in blood of female, non-pregnant and pregnant women were investigated. In addition, the present invention first identified the microbial composition and system in the blood during pregnancy. Although the composition of individual microbial communities between late birth women and 3 ⁇ 4 women was similar, the composition of the microbial community in 3 ⁇ 4 female blood differed from late birth women and non-pregnant women.
  • ⁇ ⁇ / 3 door strain were found in all groups, but ⁇ 3 Strains belonging to the female strains are more pregnant than non-pregnant women , In women, Lactobacillus, ieissel la, and potent al pathogeni c TM7 showed high contents.
  • FIG. 3A is a graph showing microbial content in blood samples of non-pregnant women, normal birth women, and PTB women at the level of phyl.
  • FIG. 3B is a graph showing microbial content in blood ascending levels of non-pregnant women, normal birth women, and PTB women.
  • bacterial infections can affect pregnant tissues such as decidua, placenta, and fetal membranes, which can threaten pregnant women and the fetus.
  • 80% of premature births occurring before 30 weeks of pregnancy result from bacterial infections.
  • the main paths of infection are: (1) infection through the lower urinary tract to the uterus, (2) infection from the peritoneal cavity into the uterus, and (3) infection by maternal circulation.
  • Healthy human blood is thought to be sterile, where microorganisms cannot live.
  • the presence of blood microorganisms is associated with various infectious and noncommunicable diseases.
  • Microorganisms in the blood can be transferred mainly from the gastrointestinal tract or the oral cavity, and the transformation of the microorganisms into a pathogenic state is called dysbi os is 1 .
  • Imbalance of microorganisms in the blood is associated with secondary diabetes and cardiovascular disease.
  • metastasis of oral bacteria into the blood is associated with endocarditis and myocardial and / or cerebral infarction, particularly from premature birth, resulting from periodontal disease.
  • the diversity of the microbial community in the blood was reduced in normal birth women and PTB women compared to non-pregnant women, but the metagenome sequence reading showed the highest level in PTB women.
  • Firmi cutes and Bacteoi detest were the lowest, and proteobacteria showed increased levels.
  • Clostridia and Bacteroidia strains were significantly increased in the blood of PTB women and non-pregnant women than normal birth women.
  • the Faecal i bacterium genus strain and Clostridium genus strains belonging to the Clostridia river were dominant in non-pregnant and PTB women, but these microorganisms were less in normal-birth women.
  • 4A-4F compare the proportion of each microbe in the blood sample of non-pregnant women, normal birth women, and PTB women.
  • Clostr idium genus strains are an important member of the human anaerobic intestinal and cervical flora. Human Clostridia infections can arise from endogenous or exogenous infections and can cause diseases such as clostridial hi st iotoxic syndrome. The Bacteroidia class contains only one order, and Bacteroides spp. Offers benefits to the host by eliminating potential pathogens. However, Bacteroides strains such as B. fragilis and B. thetaiotaomicron are pathogens that cause opportunist ic infect ion, which can inactivate peritoneal infection, beta-lactam antibiotics, and are associated with premature birth. . In addition, the TM7 phylum was increased in the blood of preterm (PTB) women than in full-term women. The TM7 statement is often associated with inflammatory mucosal diseases in humans, such as inflammatory bowel disease and periodontal disease.
  • the present invention revealed that Lactobacillus spp. And Weissel la spp. Strains were more in the blood of PTB women than normal Joulean females. However, in our previous study, the reduction of Lactobacillus and FeisseJla ⁇ in the vaginal environment in the premature group was related to premature birth compared to the normal birth group.
  • the present invention analyzed the microbiome in the blood of PTB women and normal birth women.
  • microbiomes in the blood of pregnant women show microbial imbalances associated with the disease
  • microbiomes in the blood of settled women contain microbiomes associated with healthy conditions
  • Microbiomes in the blood were found to be present in increased amounts of several pathogenic microbiomes.
  • Table 6 shows the microorganisms in the blood of non-pregnant women, PTB women and normal birth women. 2019/203422 1 »(: 1/10 ⁇ 019/000280 content is shown at the genus level.

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Abstract

La présente invention concerne la prédiction d'accouchement prématuré en utilisant un changement du microbiome sanguin et, plus particulièrement, fournit une composition de diagnostic d'un risque d'accouchement prématuré en détectant les souches de Weissella spp., Thermacetogenium spp., Faecalibacterium spp., Clostridium spp., ou Lactobacillus spp. dans le sang des femmes enceintes.
PCT/KR2019/000280 2018-04-20 2019-01-08 Prédiction du risque d'accouchement prématuré utilisant le changement de la communauté microbienne du sang Ceased WO2019203422A1 (fr)

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