WO2018216912A1 - Procédé de diagnostic de l'autisme par analyse du métagénome bactérien - Google Patents

Procédé de diagnostic de l'autisme par analyse du métagénome bactérien Download PDF

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Publication number
WO2018216912A1
WO2018216912A1 PCT/KR2018/004795 KR2018004795W WO2018216912A1 WO 2018216912 A1 WO2018216912 A1 WO 2018216912A1 KR 2018004795 W KR2018004795 W KR 2018004795W WO 2018216912 A1 WO2018216912 A1 WO 2018216912A1
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derived
extracellular vesicles
bacteria
group
autism
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PCT/KR2018/004795
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English (en)
Korean (ko)
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김윤근
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주식회사 엠디헬스케어
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Priority claimed from KR1020180047608A external-priority patent/KR102008451B1/ko
Application filed by 주식회사 엠디헬스케어 filed Critical 주식회사 엠디헬스케어
Priority to US16/616,214 priority Critical patent/US20230132988A1/en
Priority to CN201880034821.3A priority patent/CN110869519A/zh
Priority to EP18805473.8A priority patent/EP3636780B1/fr
Priority to JP2019565317A priority patent/JP6993723B2/ja
Publication of WO2018216912A1 publication Critical patent/WO2018216912A1/fr

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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
    • C12Q1/6888—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

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  • the present invention relates to a method for diagnosing autism through bacterial metagenome analysis. More specifically, autism is determined by analyzing the increase and decrease of specific bacterial-derived extracellular vesicles by performing bacterial metagenomic analysis using a sample derived from a normal person and a subject. It relates to a method of diagnosis.
  • Autism is a neurodevelopmental disorder that impairs your ability to communicate and understand social interactions. The cause of this condition is not yet clear, but some researchers speculate that it is a genetic developmental disorder rather than an emotional cause. The incidence is about 1 in 1000 and the ratio of men and women is about 4: 1 in the US. According to the 2011 survey, the prevalence of autism in Korea is more than 2% and is drawing attention. Autism is generally referred to as 'Autism Spectrum Disorder' or 'Autism Spectrum Disorder', which is discussed in three academic circles. First, high functional autism, including Autism (Kanner's Syndrome), defined by Leo Kanner, and Second, Asperger's Syndrome, as discussed by Hans Asperger, and, finally, Savant Syndrome. Autism).
  • Microbiota refers to a microbial community including bacteria, archaea and eukarya that exist in a given settlement.Intestinal microbiota is an important role in human physiology. It is known to have a great effect on human health and disease through interaction with human cells.
  • the symbiotic bacteria secrete nanometer-sized vesicles to exchange information about genes and proteins in other cells.
  • the mucous membrane forms a physical protective film that particles larger than 200 nanometers (nm) in size can't pass through, so that the symbiotic bacteria cannot pass through the mucosa, but bacterial-derived vesicles are usually less than 100 nanometers in size. It passes freely through the mucous membrane and is absorbed by our body.
  • Metagenomics also called environmental genomics, can be said to be an analysis of metagenomic data obtained from samples taken from the environment (Korean Patent Publication No. 2011-073049). Recently, it has become possible to list the bacterial composition of the human microflora by a method based on 16s ribosomal RNA (16s rRNA) sequencing. Next generation sequencing of 16s rDNA sequencing gene of 16s ribosomal RNA is performed. , NGS) platform.
  • NGS Next generation sequencing of 16s rDNA sequencing gene of 16s ribosomal RNA
  • the present inventors In order to diagnose the cause and risk of developing autism in advance, the present inventors extracted genes from bacterial extracellular vesicles present in urine, a sample derived from a normal person and a subject, and performed a metagenome analysis on them. Bacterial-derived extracellular vesicles that can act as factors have been identified, and thus the present invention has been completed.
  • an object of the present invention is to provide a method for providing information for diagnosing autism, a method for diagnosing autism, and a method for predicting the risk of developing autism through a metagenomic analysis of bacterial extracellular vesicles.
  • the present invention provides an information providing method for diagnosing autism, comprising the following steps:
  • the present invention also provides a method for diagnosing autism, comprising the following steps:
  • the present invention also provides a method for predicting the risk of developing autism, comprising the following steps:
  • the normal person and the subject sample may be urine.
  • the step (c) can compare the increase or decrease of the content of one or more phylum bacteria-derived extracellular vesicles selected from the group consisting of Armatimonadetes and Thermi have.
  • step (c) in step (c), at least one class selected from the group consisting of Fimbriimonadia, Alphaproteobacteria, and Deinococci )
  • the increase or decrease in the content of bacterial extracellular vesicles can be compared.
  • step (c) consisting of Fimbriimonadales, Rizobiales, Sphingomonadales, Desulfovibrionales (Desulfovibrionales)
  • the increase or decrease in the content of one or more order bacteria-derived extracellular vesicles selected from the group can be compared.
  • Fimbriimonadaceae (Rimzobiaceae), Rhizobiaceae (Alcaligenaceae), Sphingomonadaceae (Sphingomonadaceae), and desulfur
  • Rhizobiaceae Alcaligenaceae
  • Sphingomonadaceae Sphingomonadaceae
  • desulfur The increase or decrease in the content of one or more family bacteria-derived extracellular vesicles selected from the group consisting of Desulfovibrionaceae can be compared.
  • Fimbriimonas (Ambobacter), Achromobacter (Rchromate), Agrobacterium (Agrobacterium), Spingomonas (Sphingomonas), Cocu Comparison of the increase or decrease in the content of one or more genus bacteria-derived extracellular vesicles selected from the group consisting of Kocuria, Desulfovibrio, Halomonas, and Jeotgalicoccus have.
  • step (c) in the step (c), one or more phylum bacteria-derived extracellular vesicles selected from the group consisting of Armatimonadetes and Thermi,
  • One or more ordered bacterial extracellulars selected from the group consisting of Fimbriimonadales, Rhizobiales, Sphingomonadales, and Desulfovibrionales parcel,
  • Fimbriimonas Achromobacter, Roseceles, Agrobacterium, Sphingomonas, Kocuria, Desulfovibrio, Desulfovibrio
  • the increase or decrease of the content of one or more genus bacteria-derived extracellular vesicles selected from the group consisting of Halomonas, and Zeotgalicoccus can be compared.
  • step (c) in the step (c), compared to the sample derived from normal,
  • Extracellular vesicles derived from the family Desulfovibrionaceae family, or
  • genus bacteria-derived extracellular vesicles selected from the group consisting of Kocuria, Desulfovibrio, Halomonas, and Jeotgalicoccus If present, autism can be diagnosed.
  • step (c) in the step (c), compared to the sample derived from normal,
  • Extracellular vesicles derived from the Armatimonadetes phylum bacterium Extracellular vesicles derived from the Armatimonadetes phylum bacterium
  • One or more class bacterial-derived extracellular vesicles selected from the group consisting of Fimbriimonadia, and Alphaproteobacteria,
  • Extracellular vesicles derived from one or more order bacteria selected from the group consisting of Fimbriimonadales, Rhizobiales, and Sphingomonadales,
  • One or more genus bacteria-derived cells selected from the group consisting of Fimbriimonas, Achromobacter, Rosateles, Agrobacterium, and Sphingomonas. Autism can be diagnosed when the content of external vesicles is reduced.
  • Extracellular vesicles secreted by microorganisms such as bacteria and archaea in the environment can be absorbed into the body and directly affect the development of inflammation.Autism, which is characterized by an inflammatory response, is difficult to diagnose early, so effective treatment It is difficult. Therefore, the risk of developing autism can be diagnosed and predicted early by meta-genomic analysis of bacterial-derived extracellular vesicles using a human-derived sample according to the present invention. You can slow it down or prevent it.
  • Figure 1a is a photograph of the distribution of bacteria and vesicles by time after the oral administration of enteric bacteria and bacterial-derived vesicles (EV) to the mouse
  • Figure 1b is 12 hours after oral administration, urine, And several organs were extracted to evaluate the distribution of bacteria and vesicles in the body.
  • Figure 2 is a result of showing the distribution of bacteria-derived vesicles (EVs) with significant diagnostic performance at the phylum level by separating the bacteria-derived vesicles in autistic patients and normal urine.
  • EVs bacteria-derived vesicles
  • FIG. 3 is a result showing the distribution of bacteria-derived vesicles (EVs) with significant diagnostic performance at the class level by separating bacteria-derived vesicles from autistic patients and normal urine, and performing a metagenome analysis.
  • EVs bacteria-derived vesicles
  • EVs bacteria-derived vesicles
  • FIG. 5 is a result showing the distribution of bacteria-derived vesicles (EVs) with significant diagnostic performance at the family level by separating the bacteria-derived vesicles in autistic patients and normal urine, and performing a metagenome analysis.
  • EVs bacteria-derived vesicles
  • FIG. 6 is a result showing the distribution of bacteria-derived vesicles (EVs) with significant diagnostic performance at the genus level by separating the bacteria-derived vesicles in autistic patients and normal urine.
  • EVs bacteria-derived vesicles
  • the present invention relates to a method for diagnosing autism through bacterial metagenome analysis.
  • the present inventors extracted genes from extracellular vesicles derived from bacteria using samples derived from normal persons and subjects, and performed metagenomic analysis on them. Bacterial-derived extracellular vesicles that could act as factors were identified.
  • the present invention comprises the steps of (a) extracting DNA from extracellular vesicles isolated from normal and subject samples;
  • (c) provides an information providing method for diagnosing autism, comprising comparing the increase and decrease of the content of the normal-derived sample and the bacterial-derived extracellular vesicles by sequencing the PCR product.
  • the term "diagnosis of autism” means to determine whether autism is likely to develop, a relatively high probability of developing autism, or whether autism has already occurred in a patient.
  • the method of the present invention can be used to prevent or delay the onset of the disease through special and appropriate management as a patient at high risk of developing autism for any particular patient.
  • the methods of the present invention can be used clinically to determine treatment by early diagnosis of autism and selecting the most appropriate treatment regimen.
  • metagenome used in the present invention, also referred to as “metagenome”, refers to the total of the genome including all viruses, bacteria, fungi, etc. in an isolated area such as soil, animal intestine, It is mainly used as a concept of genome explaining the identification of many microorganisms at once using sequencer to analyze microorganisms which are not cultured.
  • metagenome does not refer to one species of genome or genome, but refers to a kind of mixed dielectric as the genome of all species of one environmental unit. This is a term from the point of view of defining a species in the course of the evolution of biology in terms of functional species as well as various species that interact with each other to create a complete species.
  • rapid sequencing is used to analyze all DNA and RNA, regardless of species, to identify all species in one environment, and to identify interactions and metabolism.
  • metagenome analysis was preferably performed using bacterial-derived extracellular vesicles isolated from serum.
  • the normal and subject sample may be urine, but is not limited thereto.
  • the metagenome analysis of the bacterial-derived extracellular vesicles was performed, and analyzed at the phylum, class, order, family, and genus levels, respectively. By identifying the bacterial vesicles that can actually act as a cause of autism.
  • the bacterial metagenome of the vesicles present in the subject-derived urine sample at the gate level the results of the extracellular vesicles derived from Armatimonadetes and Thermi-gate bacteria between the autism patients and normal people There was a significant difference (see Example 4).
  • the content of the extracellular vesicles derived from Fimbriimonadia, Alphaproteobacteria, and Deinococci-river bacteria There was a significant difference between normal individuals (see Example 4).
  • the content of extracellular vesicles derived from Fimbriimonadales, Rhizobiales, Sphingomonadales, and Desulfovibrionales throat bacteria There was a significant difference between patients and normal subjects (see Example 4).
  • the results of analysis of bacterial metagenome at the exaggerated level of the vesicles present in the urine sample derived from the subject the content of Fimbriimonadaceae, Rhizobiaceae, Alcaligenaceae, Sphingomonadaceae, Desulfovibrionaceae and bacteria-derived extracellular vesicle
  • the bacterial metagenome of the vesicles present in the subject-derived urine sample at the genus level Fimbriimonas, Achromobacter, Roseateles, Agrobacterium, Sphingomonas, Kocuria, Desulfovibrio, Halomonas, and Jeotgalicoccus
  • the fluorescently labeled 50 ⁇ g of bacteria and bacteria-derived vesicles were administered in the same manner as above 12 hours.
  • Blood, Heart, Lung, Liver, Kidney, Spleen, Adipose tissue, and Muscle were extracted from mice.
  • the intestinal bacteria (Bacteria) were not absorbed in each organ, whereas the intestinal bacteria-derived extracellular vesicles (EVs) were urine, heart, lung as shown in FIG. And distribution in liver, kidney, spleen, adipose tissue, and muscle.
  • the urine was first placed in a 10 ml tube and centrifuged (3,500 x g, 10 min, 4 ° C.) to settle the suspended solids to recover only the supernatant and then transferred to a new 10 ml tube. After removing the bacteria and foreign substances from the recovered supernatant using a 0.22 ⁇ m filter, transfer to centripreigugal filters (50 kD) and centrifuged at 1500 xg, 4 °C for 15 minutes to discard the material smaller than 50 kD and 10 ml Concentrated until.
  • centripreigugal filters 50 kD
  • PCR was performed using the 16S rDNA primer shown in Table 1 to amplify the gene and perform sequencing (Illumina MiSeq sequencer). Output the result as a Standard Flowgram Format (SFF) file, convert the SFF file into a sequence file (.fasta) and a nucleotide quality score file using GS FLX software (v2.9), check the credit rating of the lead, and window (20 bps) The part with the average base call accuracy of less than 99% (Phred score ⁇ 20) was removed.
  • SFF Standard Flowgram Format
  • the Operational Taxonomy Unit performed UCLUST and USEARCH for clustering according to sequence similarity. Specifically, the clustering is based on 94% genus, 90% family, 85% order, 80% class, and 75% sequence similarity. OTU's door, river, neck, family and genus level classifications were performed, and bacteria with greater than 97% sequence similarity were analyzed using BLASTN and GreenGenes' 16S DNA sequence database (108,453 sequences) (QIIME).
  • Example 3 By the method of Example 3, the vesicles were isolated from the urine of 20 autistic patients and 28 normal people with age and sex matched with metagenome sequencing. In the development of the diagnostic model, the strains whose p-value between the two groups is 0.05 or less and more than two times different between the two groups are selected in the t-test. under curve), accuracy, sensitivity, and specificity.
  • Method for providing information on the diagnosis of autism through bacterial metagenomic analysis by performing bacterial metagenomic analysis using a sample derived from normal people and subjects by analyzing the increase or decrease in the content of specific bacteria-derived extracellular vesicles Can be used to predict and diagnose autism.

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Abstract

La présente invention concerne un procédé de diagnostic de l'autisme par analyse du métagénome bactérien et, plus spécifiquement, un procédé de diagnostic de l'autisme par exécution d'une analyse du métagénome bactérien à l'aide d'échantillons provenant d'une personne normale et provenant d'un sujet, pour analyser une augmentation ou une diminution de la teneur en vésicules extracellulaires produites par des bactéries spécifiques. Les vésicules extracellulaires sécrétées à partir de micro-organismes tels que des bactéries, des archaebactéries, etc., présentes dans l'environnement, sont absorbées dans le corps humain et réparties dans divers organes, y compris le cerveau, et peuvent ainsi directement affecter des réactions inflammatoires et des fonctions cérébrales. Un diagnostic précoce de l'autisme caractérisé par une inflammation avant l'apparition de symptômes est difficile, et un traitement efficace est donc difficile. Par conséquent, comme la présente invention prédit le risque d'autisme par l'analyse du métagénome de vésicules extracellulaires produites par des bactéries, à l'aide d'échantillons provenant d'un corps humain, il est possible de retarder le moment de l'apparition de l'autisme ou d'empêcher l'apparition de l'autisme par le biais d'une gestion appropriée consécutive à un diagnostic précoce et à la prédiction du groupe à risque d'autisme, et même après l'apparition de l'autisme, un diagnostic précoce est possible, ce qui permet d'abaisser le taux d'apparition de l'autisme et d'augmenter les effets thérapeutiques.
PCT/KR2018/004795 2017-05-26 2018-04-25 Procédé de diagnostic de l'autisme par analyse du métagénome bactérien WO2018216912A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US16/616,214 US20230132988A1 (en) 2017-05-26 2018-04-25 Method for diagnosing autism by analyzing bacterial metagenome
CN201880034821.3A CN110869519A (zh) 2017-05-26 2018-04-25 通过分析细菌宏基因组来诊断自闭症的方法
EP18805473.8A EP3636780B1 (fr) 2017-05-26 2018-04-25 Procédé de diagnostic de l'autisme par analyse du métagénome bactérien
JP2019565317A JP6993723B2 (ja) 2017-05-26 2018-04-25 細菌メタゲノム分析を通した自閉症の診断方法

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KR20170065329 2017-05-26
KR10-2017-0065329 2017-05-26
KR10-2018-0047608 2018-04-24
KR1020180047608A KR102008451B1 (ko) 2017-05-26 2018-04-24 세균 메타게놈 분석을 통한 자폐증 진단방법

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021534777A (ja) * 2018-12-10 2021-12-16 エムディー ヘルスケア インコーポレイテッドMd Healthcare Inc. スフィンゴモナス属細菌由来のナノ小胞及びその用途
JP2022106991A (ja) * 2018-12-10 2022-07-20 エムディー ヘルスケア インコーポレイテッド スフィンゴモナス属細菌由来のナノ小胞及びその用途
JP7132661B2 (ja) 2018-12-10 2022-09-07 エムディー ヘルスケア インコーポレイテッド スフィンゴモナス属細菌由来のナノ小胞及びその用途
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US11944652B2 (en) 2018-12-10 2024-04-02 Md Healthcare Inc. Nano-vesicles derived from genus Sphingomonas bacteria and use thereof

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