CN107217089A - Determine the method and device of individual state - Google Patents
Determine the method and device of individual state Download PDFInfo
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- CN107217089A CN107217089A CN201610165864.8A CN201610165864A CN107217089A CN 107217089 A CN107217089 A CN 107217089A CN 201610165864 A CN201610165864 A CN 201610165864A CN 107217089 A CN107217089 A CN 107217089A
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Abstract
The invention discloses a kind of ankylosing spondylitis microbial markers, the mark by following microorganism group into：Actinomyces (Actinomyces sp.ICM47), bifidobacterium breve (Bifidobacterium breve), Bifidobacterium (Bifidobacterium sp.12_1_47BFAA), bifidobacterium longum (Bifidobacterium longum), aerogenesis Collins bacterium (Collinsella aerofaciens), bifidobacterium bifidum (Bifidobacterium bifidum), false chainlet Bifidobacterium (Bifidobacterium pseudocatenulatum), slow Ai Gete bacterium (Eggerthella lenta), bifidobacterium catenulatum (Bifidobacterium catenulatum) and bifidobacterium adolescentis (Bifidobacterium adolescentis).Compared to health population, the alleged ankylosing spondylitis mark significant enrichment in patients with ankylosing spondylitis colony.
Description
Technical field
The present invention relates to biomarker field, specifically, the present invention relates to the method and device for determining individual state, having more
Body, utilize tetanic the present invention relates to a kind of ankylosing spondylitis mark, the purposes of ankylosing spondylitis mark, one kind
Property rachitis mark determine that the method for state of individual, a kind of utilization ankylosing spondylitis mark determine the state of individual
Device, a kind of ankylosing spondylitis is treated to method, one kind that multiple individuals are classified using ankylosing spondylitis mark
Medicine and it is a kind of prepare treatment ankylosing spondylitis medicine method.
Background technology
Ankylosing spondylitis (Ankylosing spondylitis, AS) is a kind of main infringement backbone, and involves articulatio sacroiliaca and week
Enclose the chronic progressive inflammatory disease in joint.Onset is generally the ratio between the male of 15~30 years old, the present studies have shown that sick men and women
For 2:1~3:1, the cause of disease of ankylosing spondylitis at present not yet completely clearly, Recent study result show the disease and heredodiathesis,
Infection and the factor such as immune are relevant.
The general onset of ankylosing spondylitis compares concealment, be able to can be shown in early stage without any clinical symptoms, some patients in early days
Slight constitutional symptom, it is such as weak, become thin, long-term or intermittent low grade fever, apocleisis, anemia.Because the state of an illness is lighter,
Patient is unable to early detection mostly, causes the state of an illness to be delayed, and loses best occasion for the treatment.
Ankylosing spondylitis and human leucocyte antigen (HLA) HLA-B27 are closely related, according to epidemiology survey, ankylosing spondylitis
Patient's HLA-B27 positive rates are up to 90%~96%, and general population HLA-27 positive rates only 4%~9%；HLA-B27
Positive ankylosing spondylitis rate is about 10%~20%, and general population's morbidity is 1 ‰~2 ‰, differs about 100 times.
Although HLA-B27, which is detected, certain help to the diagnosis of ankylosing spondylitis, most patient will also by medical history,
Diagnosis is made in sign and x-ray inspection.At present, the early diagnosis of ankylosing spondylitis mainly with CT, radioactive nucleus scan,
The iconographies such as magnetic resonance are checked that checking process is more complicated.
As the high speed development of completion and high throughput sequencing technologies is sequenced in human genome, gene screening turns into ankylosing spondylitis
The direction of diagnosis, for finding that the potential crowd of ankylosing spondylitis is advantageous.Research shows the rigid spine more than 70%
Scorching patient suffers from intestinal inflammatory, and 5~10% intestinal inflammatories are very serious in these patients, may develop into clinically inflammatory
Enteropathy (IBD) or Crohn's disease (CD) (Mielants et al., 1985).Some marker gene of Crohn's disease (CD)
(Parkes et al., 2013) associated with ankylosing spondylitis, illustrates that two kinds of diseases may have similar pathogenesis, may be with intestines
Road imbalance is related.There are some researches show the polygenes related to ankylosing spondylitis plays an important role in intestine immunity, such as relating to
Regulation to the gene pairs intestinal health of interleukin I L-23 approach plays an important role (Wellcome et al., 2007).It is right with health
Photograph ratio, patients with ankylosing spondylitis and its increase of lineal relative's intestinal permeability, illustrate enteric microorganism tatanic again
Important function (Mielants et al., 1991) in rachitis.Up to the present, also without the micro- life of patients with ankylosing spondylitis enteron aisle
The relevant report of substance markers thing.
The content of the invention
It is contemplated that at least solving one of above-mentioned technical problem to a certain extent or providing at a kind of business selection.
According to the first aspect of the present invention there is provided a kind of ankylosing spondylitis microbial markers, the mark is by following micro-
Biotic component：Actinomyces (Actinomyces sp.ICM47), bifidobacterium breve (Bifidobacterium breve), bifid bar
Bacterium (Bifidobacterium sp.12_1_47BFAA), bifidobacterium longum (Bifidobacterium longum), aerogenesis Collins
Bacterium (Collinsella aerofaciens), bifidobacterium bifidum (Bifidobacterium bifidum), false chainlet Bifidobacterium
(Bifidobacterium pseudocatenulatum), slow Ai Gete bacterium (Eggerthella lenta), bifidobacterium catenulatum
(Bifidobacterium catenulatum) and bifidobacterium adolescentis (Bifidobacterium adolescentis).
The ankylosing spondylitis microbial markers that on the one hand the invention described above provides are that inventor passes through to largely suffering from tatanic ridge
The comparison in difference analysis and checking of the abundance of microorganism in the fecal sample of the scorching individual and a large amount of normal healthy controls individual of post,
And decide, it specify that the related microbial markers of ankylosing spondylitis in enteric microorganism.Using alleged tetanic
Property the scorching mark of backbone microorganism, can determine that individual is in ankylosing spondylitis shape probability of state height or in strong
Health shape probability of state height, can be used in early detection or the auxiliary detection ankylosing spondylitis of Noninvasive.
According to the second aspect of the present invention, the present invention provides above-mentioned ankylosing spondylitis microbial markers and is detecting tatanic ridge
Post inflammation, monitoring treatment ankylosing spondylitis, the medicine for preparing treatment ankylosing spondylitis and/or prepare use in functional food
On the way.
Above-mentioned ankylosing spondylitis microbial markers are that inventor analyzes various enteric microorganism tatanic by comparison in difference
The checking of rachitis disease group and the abundance in the fecal sample of health group, and the fecal sample Jing Guo a large amount of known states,
And decide.Compared in health population group, alleged ankylosing spondylitis mark shows in patients with ankylosing spondylitis
Enrichment is write, alleged significant enrichment refers to compared with the abundance in healthy group, what above-mentioned ankylosing spondylitis mark was included
Abundance of the various microorganisms in disease group is higher than or significantly, is substantially higher than at healthy group with being respectively provided with statistical significance
In abundance.The material that can reduce its abundance can be used in treatment ankylosing spondylitis or suffer from beneficial to ankylosing spondylitis
Person is taken, and the material of its abundance reduction can be made to be not limited to treat the medicine and healthy intestinal colony balance of ankylosing spondylitis
Functional food, the ankylosing spondylitis mark that on the one hand the invention described above provides can be used in preparing treatment rigid spine
Scorching medicine and/or for preparing functional food, health care medicinal beneficial to balance intestinal flora etc..
According to the third aspect of the present invention, there is provided a kind of shape that individual is determined using above-mentioned ankylosing spondylitis microbial markers
The method of state, this method includes：(1) determine in the ankylosing spondylitis mark in the individual fecal sample
The abundance of various microorganisms；(2) abundance of the various microorganisms in the ankylosing spondylitis mark that will be determined respectively in (1)
It is compared with its abundance in control group, the individual state, the control group is determined according to the comparative result obtained
It is made up of the individual fecal sample of one or more groups of equal states, the state includes with ankylosing spondylitis and do not suffered from
Ankylosing spondylitis.Alleged ankylosing spondylitis mark is that inventor analyzes various enteric microorganism strong by comparison in difference
Abundance in the fecal sample of straightforward rachitis disease group and health group, and fecal sample Jing Guo a large amount of known states are tested
Card, and decide.
Ankylosing spondylitis microbial markers in fecal sample of the method for the invention described above this aspect based on detection individual
In various microorganisms abundance, will detect that abundance in control group is compared with it for the abundance of various microorganisms that determines respectively
Compared with can determine that individual is that ankylosing spondylitis is individual or be the probability of healthy individuals according to the comparative result obtained.For morning
Phase finds that ankylosing spondylitis provides a kind of aided detection method of Noninvasive.
The utilization ankylosing spondylitis microbial markers of this aspect of the invention described above determine the complete of the method for the state of individual
Portion or part steps, it is possible to use device/system comprising detachable corresponding units functional module is implemented, or by method
Sequencing, machine readable media is stored in, runs the computer-readable recording medium to realize using machine.
According to the fourth aspect of the present invention, there is provided a kind of shape that individual is determined using above-mentioned ankylosing spondylitis microbial markers
The device of state, the device determines the shape of individual to implement the utilization ankylosing spondylitis microbial markers of one aspect of the present invention
The all or part of step of the method for state, the device includes：Data input cell, for input data；Data outputting unit,
For output data；Processor, for performing executable program, performing the executable program includes completing above-mentioned using strong
Straightforward rachitis determines all or part of steps of the method for the state of individual；Memory cell, with the data input cell,
The data outputting unit is connected with the processor, for data storage, including the executable program.It is above-mentioned right
The utilization ankylosing spondylitis microbial markers of one aspect of the present invention determine the technical characteristic and advantage of the method for the state of individual
Description, the device of equally applicable this aspect of the present invention will not be repeated here.
According to the fifth aspect of the present invention individual state is determined there is provided one kind using above-mentioned ankylosing spondylitis microbial markers
System, the system to implement one aspect of the present invention utilization ankylosing spondylitis microbial markers determine individual state
Method all or part of step, the system includes：Bacterial abundance determining unit, for determining the individual excrement
The abundance of the various microorganisms in the ankylosing spondylitis mark in sample；Individual state determining unit, for respectively
By the abundance of the various microorganisms in the ankylosing spondylitis mark of the bacterial abundance determining unit and its
Abundance in control group is compared, and determines the individual state according to the comparative result obtained, the control group is by one group
Or the individual fecal sample composition of multigroup equal state, the state is including with ankylosing spondylitis and with tatanic
Rachitis.The above-mentioned utilization ankylosing spondylitis mark to one aspect of the present invention determines that the technology of the method for the state of individual is special
The description for advantage of seeking peace, the system of equally applicable this aspect of the present invention, will not be repeated here.
Multiple individuals are entered using above-mentioned ankylosing spondylitis microbial markers there is provided one kind according to the sixth aspect of the present invention
The method of row classification, this method includes：The method for being utilized respectively the determination individual state of the invention described above one side determines each
The state of individual；Each described individual is classified according to each the individual state obtained.This method can be according to individual
State different instructions open it is multiple individual or distinguish multiple unknown fecal samples, be easy to sort out, annotation management.Separately
Outside, the above-mentioned utilization ankylosing spondylitis microbial markers to one aspect of the present invention determine the technology of the method for the state of individual
The description of feature and advantage, the method for equally applicable this aspect of the present invention, will not be repeated here.
According to the seventh aspect of the present invention there is provided a kind of medicine for treating ankylosing spondylitis, the medicine promotes above-mentioned tetanic
Property rachitis microbial markers in various microorganisms abundance reduce.Alleged ankylosing spondylitis microbial markers are hairs
Abundance of the person of good sense by the various enteric microorganism of variance analysis in the fecal sample of ankylosing spondylitis disease group and health group,
And the checking of the fecal sample Jing Guo a large amount of known states, and decide.It is alleged strong compared in health population group
Straightforward rachitis mark significant enrichment in ankylosing spondylitis disease group, alleged significant enrichment refers to and in healthy group
Abundance is compared, and abundance of the various microorganisms that above-mentioned ankylosing spondylitis mark is included in disease group is respectively provided with statistics meaning
Free burial ground for the destitute be higher than or significantly, substantially higher than abundance in healthy group.The material of its abundance reduction can be enable to use
Taken in treatment ankylosing spondylitis or beneficial to patients with ankylosing spondylitis, the material conduct of its abundance reduction can be allow
Treat the medicine of ankylosing spondylitis.
Using the medicine or functional food of this aspect of the present invention, the ankylosing spondylitis that rationally and effectively application is determined is micro-
Biomarker, helps the growth of intestinal beneficial bacterium and/or suppresses enteron aisle potentially pathogenic organism, for auxiliary reduction blood endotoxin water
Clinical symptoms that are flat and/or mitigating ankylosing spondylitis are significant.
According to the eighth aspect of the present invention, it is tatanic that the present invention provides a kind for the treatment of for preparing or screening the invention described above one side
The method of the medicine of rachitis, this method includes preparing or screening can promote the rigid spine of the invention described above one side
The step of material of the abundance reduction of each microorganism in scorching mark is as the medicine.
The method that the medicine of ankylosing spondylitis is treated using the production or screening of this aspect of the present invention, by rationally and effectively
Screened using the ankylosing spondylitis biomarker of determination, the growth and/or suppression of intestinal beneficial bacterium can be helped by resulting in
The medicine of enteron aisle potentially pathogenic organism processed, for auxiliary reduction blood endotoxin level and/or the clinical symptoms of mitigation ankylosing spondylitis
It is significant.
Brief description of the drawings
The above-mentioned and/or additional aspect and advantage of the present invention will become bright from description of the accompanying drawings below to embodiment is combined
Show and be readily appreciated that, wherein：
Fig. 1 is the analysis of experiments flow signal of the Screening and Identification ankylosing spondylitis microbial markers in embodiments of the invention
Figure.
Fig. 2 is AUC evaluation result schematic diagram of the microbial species mark in embodiments of the invention as diagnosis index.
Embodiment
Embodiments of the invention are described below in detail, the example of the embodiment is shown in the drawings, wherein, phase from beginning to end
Same or similar label represents same or similar element or the element with same or like function.Below with reference to accompanying drawing
The embodiment of description is exemplary, is only used for explaining the present invention, and is not considered as limiting the invention.Need explanation
, term " first " used herein or " second " etc. are only for convenience of description, it is impossible to be interpreted as indicating or imply
Relative importance, there is sequencing relation between can not being interpreted as.
In the description of the invention, unless otherwise indicated, " multiple " are meant that two or more.Herein, remove
Non- separately to have clearly regulation and limit, the term such as term " connected ", " connection " should be interpreted broadly, for example, it may be solid
Calmly connect or be detachably connected, or be integrally connected；Can be mechanical connection or electrical connection；Can be with
It is to be joined directly together, can also be indirectly connected to by intermediary, can is the connection of two element internals.
Biological markers are cell, biochemistry or the molecular changes that can be detected from biological media.Biology is situated between
Matter includes various body fluid, tissue, cell, excrement, hair, expiration etc..
The abundance of certain alleged microorganism refers to the abundant degree of this kind of microorganism in a certain micropopulation, such as in enteron aisle
The abundant degree of this in micropopulation kind microorganism, is represented by content of this kind of microorganism in the colony.
The uniformity (identity) of alleged sequence and the similarity (similarity) of sequence refer to same or similar between sequence respectively
Degree.
A kind of ankylosing spondylitis biomarker provided according to an embodiment of the invention, detects the biomarker
Change can determine individual with ankylosing spondylitis relative probability height.The ankylosing spondylitis microbial markers
By following microorganism group into：Actinomyces (Actinomyces sp.ICM47), bifidobacterium breve (Bifidobacterium breve),
Bifidobacterium (Bifidobacterium sp.12_1_47BFAA), bifidobacterium longum (Bifidobacterium longum), aerogenesis
Collins bacterium (Collinsella aerofaciens), bifidobacterium bifidum (Bifidobacterium bifidum), false chainlet bifid
Bacillus (Bifidobacterium pseudocatenulatum), slow Ai Gete bacterium (Eggerthella lenta), chain bifid bar
Bacterium (Bifidobacterium catenulatum) and bifidobacterium adolescentis (Bifidobacterium adolescentis).
Alleged ankylosing spondylitis microbial markers are that inventor passes through to the individual and a large amount of health of a large amount of ankylosing spondylitis
The abundance for compareing the microorganism in the fecal sample of individual carries out comparison in difference analysis and checking, and decides, bright
True related microbial markers of ankylosing spondylitis in enteric microorganism.Using alleged ankylosing spondylitis mark,
It can determine that individual is in and suffer from ankylosing spondylitis shape probability of state or the probability in health status, can be used in non-invade
Early detection, auxiliary detection ankylosing spondylitis of entering property etc..
The above-mentioned ankylosing spondylitis microbial markers provided according to one embodiment of the present invention are in detection rigid spine
Inflammation, monitoring treatment ankylosing spondylitis, the medicine and/or the use in functional food is prepared for preparing treatment ankylosing spondylitis
On the way.Institute's ankylosing spondylitis microbial markers are that inventor analyzes various enteric microorganism in tatanic ridge by comparison in difference
The checking of post inflammation disease group and the abundance in the fecal sample of health group, and the fecal sample Jing Guo a large amount of known states, and
Decide.Compared in health population group, alleged ankylosing spondylitis microbial markers are in ankylosing spondylitis disease
Significant enrichment in group, alleged significant enrichment refers to compared with the abundance in healthy group, above-mentioned ankylosing spondylitis mark institute
Comprising abundance of the various microorganisms in disease group be higher than with being respectively provided with statistical significance or significantly, be substantially higher than
Abundance in healthy group.
The material that can reduce alleged ankylosing spondylitis mark abundance can be used in treatment ankylosing spondylitis or beneficial to
Patients with ankylosing spondylitis is taken, and it is tetanic that the material that can reduce alleged ankylosing spondylitis mark abundance is not limited to treatment
Property rachitis medicine and the functional food of healthy intestinal colony balance, the embodiment provide ankylosing spondylitis mark
Thing can be used in preparing treatment ankylosing spondylitis medicine and/or for prepare functional food beneficial to balance intestinal flora,
Health care medicinal etc..
Ankylosing spondylitis mark in a kind of utilization above-described embodiment provided according to another implementation of the invention is true
The method of the state of fixed individual, this method comprises the following steps (1) and (2)：
(1) abundance of the ankylosing spondylitis microbial markers in test individual is determined.
Determine the abundance of the various microorganisms in the ankylosing spondylitis microbial markers in the fecal sample of test individual.
Embodiments in accordance with the present invention, carry out below completing the step：Obtain the nucleic acid sequence in the individual fecal sample
The sequencing data of row, the sequencing data includes multiple reads；The read is compared to various micro- lifes into the mark
The genome of thing, obtains comparison result；According to the comparison result, the abundance of the various microorganisms in the mark is determined.
Alleged sequencing data is got by carrying out sequencing to the nucleotide sequence in sample, is sequenced according to selected microarray dataset
Difference, may be selected but be not limited to semiconductor sequencing technologies platform such as PGM, Ion Proton, BGISEQ-100 platforms, close
Hiseq, Miseq sequence platform and single molecule sequencing platform in real time for the technology platform such as Illumina companies being sequenced into side
Such as PacBio sequences platform.Sequencing mode can select single-ended sequencing, can also select double end sequencings, the lower machine of acquisition
Data are to survey the fragment read out, referred to as read (reads).
Comparing can be carried out using the known software that compares, such as SOAP, BWA and TeraMap, in comparison process,
Typically alignment parameters are configured, setting one or a pair of reads (reads) at most allow have s base mispairing
(mismatch), s≤2 are for example set, if s base is had more than in reads occurs mispairing, being considered as the reads can not compare
To in (in comparison) the assembling fragment.The comparison result of alleged acquisition includes each bar read and the genome of each species
Whether comparison situation, including read can compare the genome of some or some species, only unique compare to a kind of species also
It is genome, the position of the genome of comparison to species, the unique positions of comparison to species gene group compared to a variety of species
Or the information such as multiple positions.According to one embodiment of present invention, it is compared using SOAPalign 2.21, ginseng is set
Number is the-x 1000 of 2-m of-r 100.
The genome of alleged microorganism refers to the sequence of the predetermined microbial species, can be the sample to be tested being obtained ahead of time
Any reference template of category that is affiliated or being included, for example, target is the microorganism in sample to be tested, with reference to sequence
Row may be selected disclosed in the reference gene group and/or HMP, MetaHIT project of the various microorganisms in ncbi database
DACC enteron aisle genomes, it is further possible to be pre-configured with the resources bank for including more reference sequences, for example foundation is treated
Survey the selection of the factors such as individual state, the region of samples sources or determine and assemble closer sequence as reference sequences.
According to one embodiment of present invention, the reference gene group of various microorganisms is obtained from disclosed database, common, and one
Planting the reference gene group of microorganism has multiple versions, i.e., a kind of microorganism has multiple disclosed genomes.
The reference gene group of reads and species is compared, and two parts are divided into comparison：a)Unique reads(U)：
Uniquely compare the genome of a species；These reads are called unique reads.That is, if the gene in reads comparisons
Group is all from same species, defines these reads for unique reads.b)Multiple reads(M)：Compare one with
The genome of upper species, is defined as multiple reads.That is, if the genome in reads comparisons comes from least two species,
These reads are defined for multiple reads.
According to one embodiment of present invention, it is alleged according to sequencing data, it is described according to comparison result, determine the mark
In various microorganisms abundance, microbial species S abundance is determined using below equation：Microbial species S's is rich
Ab (S)=Ab (US)+Ab (MS) is spent, wherein, Ab (US)=US/lS, USFor unique reading for comparing upper this kind of microorganism S
Hop count mesh, lSFor the length of the genome of this kind of microorganism S in comparison,MSTo be not exclusive
The number of this kind of microorganism S read in comparison, i represents the numbering of this kind of microorganism S read in not exclusive comparison, Coi
For the corresponding abundance coefficients of read i of this kind of microorganism S in not exclusive comparison,N is not exclusive ratio
The microbial species species number that read to above this kind of microorganism S is compared, j is this kind of microorganism S in not exclusive comparison
Read compare on species numbering, UjFor unique read number for comparing upper microbial species j.
For given microbial species S, its abundance is Ab (S), related to Unique reads and Multiple reads, on
State the abundance that Ab (U) and Ab (M) in formula are respectively species S Unique reads and Multiple reads contributions.
Each multiple reads, have special species abundance coefficient Co, it is assumed that N number of species in a multiple reads comparison,
This multiple reads Co can be calculated using following equation：I.e. for this kind of multiple reads,
The unique reads for N number of species that it is compared abundance sum is used as denominator.
(2) abundance ratio is compared with to determine individual state.
The abundance of various microorganisms in the ankylosing spondylitis mark that will be determined respectively in (1) is rich in control group with it
Degree is compared, and determines the individual state according to the comparative result obtained, the control group is by one or more groups of identical shapes
The individual fecal sample composition of state, the state includes suffering from ankylosing spondylitis state and health status.It is alleged tatanic
Rachitis mark is that inventor analyzes various enteric microorganism in ankylosing spondylitis disease group and healthy group by comparison in difference
Fecal sample in abundance, and the fecal sample Jing Guo a large amount of known states checking, and decide.
Determine or successively survey while abundance of the various microorganisms in control group in alleged mark can be with test individual
It is fixed.According to one embodiment of present invention, abundance measured in advance of the various microorganisms in mark in control group is preserved,
To the foundation as given threshold.By abundance of the microorganism in mark in test individual sample and alleged threshold value ratio
Compared with the difference degree based on the two carries out the determination of the state of test individual.Alleged threshold value can be a numerical value or numerical value
Scope, for example, the abundance average based on certain microorganism in control group, it is rich that the corresponding threshold value of the microorganism can be set to this
Spend 95% confidential interval of average.
Embodiments in accordance with the present invention, control group is made up of multiple individual fecal samples for suffering from ankylosing spondylitis, the step
(2) include：The abundance of various microorganisms in the ankylosing spondylitis mark determined in the step (1) is all with it right
According to the abundance indifference in group, it is with ankylosing spondylitis to determine the individual state.Embodiments in accordance with the present invention,
The indifference be the ankylosing spondylitis mark from the bacterial abundance determining unit in various microorganisms abundance
First predetermined confidence interval of its abundance in control group is fallen into, optional first predetermined confidence interval is 95% confidence
It is interval.
Alleged indifference both falls within it for the abundance of the various microorganisms in the ankylosing spondylitis mark of determination in step (1)
First predetermined confidence interval of the abundance in control group.Alleged confidential interval refers to the totality constructed by sample statistic
The estimation interval of parameter.In statistics, the confidential interval (Confidence interval) of a probability sample is to this
The interval estimation of some population parameter of sample.What confidential interval showed be this parameter actual value have certain probability fall survey
Measure the degree around result.What confidential interval was provided is the credibility of the measured value of measured parameter, i.e., above required
" certain probability ".This probability is referred to as confidence level.
Embodiments in accordance with the present invention, control group is made up of the fecal sample of multiple healthy individuals, and the step (2) includes：When
The abundance of various microorganisms in the ankylosing spondylitis mark determined in step (1) all with its abundance in control group without
Difference, determines the individual state not suffer from ankylosing spondylitis.Alleged indifference is the tatanic ridge of determination in (1)
The abundance of various microorganisms in post inflammation mark both falls within second predetermined confidence interval of its abundance in control group, optionally
Second predetermined confidence interval be 95% confidential interval.
It should be noted that according to purpose or require different, pair it may determine that the credibility of individual state result has different
It is required that, those skilled in the art can select different significances (α), that is, the probability for selecting different possibility to make mistakes,
In this way, the credibility of the individual state determined is 1- α.For example, determining that individual is in what is determined using the embodiment
State 95% is reliable.
The abundance of the various microorganisms in ankylosing spondylitis mark in fecal sample of this method based on detection individual, point
Abundance in control group is compared the abundance for the various microorganisms that detection is determined with it, according to the comparative result energy obtained
It is enough to determine that individual is that ankylosing spondylitis is individual or be the probability of healthy individuals.One is provided for early detection ankylosing spondylitis
The method for planting auxiliary detection or the assistant interventional treatment of Noninvasive.
Utilization ankylosing spondylitis mark in any of the above embodiment determines all or part of step of the method for the state of individual
Suddenly, it is possible to use device/system comprising detachable corresponding units functional module is implemented, or by methodology programs, deposit
Machine readable media is stored in, runs the computer-readable recording medium to realize using machine.
Ankylosing spondylitis mark in a kind of utilization embodiments of the present invention provided according to an embodiment of the invention
Thing determines the device of the state of individual, and the device is to implement the utilization ankylosing spondylitis mark in the embodiments of the present invention
Thing determines all or part of step of the method for the state of individual, and the device includes：Data input cell, for input data；
Data outputting unit, for output data；Processor, for performing executable program, performing the executable program includes
The method of the state of determination individual in completion the invention described above any embodiment；Memory cell, with the data input cell,
The data outputting unit is connected with the processor, for data storage, including the executable program.It is above-mentioned right
Utilization ankylosing spondylitis mark in any embodiment of the present invention determines the technical characteristic and advantage of the method for the state of individual
Description, the device of equally applicable this aspect of the present invention will not be repeated here.
Ankylosing spondylitis mark in a kind of utilization embodiments of the present invention provided according to an embodiment of the invention
The system that thing determines the state of individual, the device is to implement the utilization ankylosing spondylitis in the invention described above any embodiment
Mark determines all or part of step of the method for the state of individual, and the system includes：Bacterial abundance determining unit, is used
In it is determined that the abundance of the various microorganisms in the ankylosing spondylitis mark in the individual fecal sample；Individual shape
State determining unit, for respectively will be each in the ankylosing spondylitis mark of the bacterial abundance determining unit
The abundance of kind of microorganism is compared with its abundance in control group, and the comparative result according to acquisition determines the individual shape
State, the control group is made up of the individual fecal sample of one or more groups of equal states, and the state is included with tatanic
Rachitis and not suffer from ankylosing spondylitis.It is above-mentioned true to the utilization ankylosing spondylitis mark in any embodiment of the present invention
The technical characteristic of the method for the state of fixed individual and the description of advantage, the system of equally applicable this aspect of the present invention.
Embodiments in accordance with the present invention, the bacterial abundance determining unit is following for carrying out：Obtain the individual excrement
The sequencing data of nucleotide sequence in sample, the sequencing data includes multiple reads；The read is compared to the mark
The genome of various microorganisms in thing, obtains comparison result；According to the comparison result, determine each in the mark
Plant the abundance of microorganism.
Alleged sequencing data is got by carrying out sequencing to the nucleotide sequence in sample, is sequenced according to selected microarray dataset
Difference, may be selected but be not limited to semiconductor sequencing technologies platform such as PGM, Ion Proton, BGISEQ-100 platforms, close
Hiseq, Miseq sequence platform and single molecule sequencing platform in real time for the technology platform such as Illumina companies being sequenced into side
Such as PacBio sequences platform.Sequencing mode can select single-ended sequencing, can also select double end sequencings, the lower machine of acquisition
Data are to survey the fragment read out, referred to as read (reads).
Comparing can be carried out using the known software that compares, such as SOAP, BWA and TeraMap, in comparison process,
Typically alignment parameters are configured, setting one or a pair of reads (reads) at most allow have s base mispairing
(mismatch), s≤2 are for example set, if s base is had more than in reads occurs mispairing, being considered as the reads can not compare
To in (in comparison) the assembling fragment.The comparison result of alleged acquisition includes each bar read and the genome of each species
Whether comparison situation, including read can compare the genome of some or some species, only unique compare to a kind of species also
It is genome, the position of the genome of comparison to species, the unique positions of comparison to species gene group compared to a variety of species
Or the information such as multiple positions.According to one embodiment of present invention, it is compared using SOAPalign 2.21, ginseng is set
Number is the-x 1000 of 2-m of-r 100.
The genome of alleged microorganism refers to the sequence of the predetermined microbial species, can be the sample to be tested being obtained ahead of time
Any reference template of category that is affiliated or being included, for example, target is the microorganism in sample to be tested, with reference to sequence
Row may be selected disclosed in the reference gene group and/or HMP, MetaHIT project of the various microorganisms in ncbi database
DACC enteron aisle genomes, it is further possible to be pre-configured with the resources bank for including more reference sequences, for example foundation is treated
Survey the selection of the factors such as individual state, the region of samples sources or determine and assemble closer sequence as reference sequences.
According to one embodiment of present invention, the reference gene group of various microorganisms is obtained from disclosed database, common, and one
Planting the reference gene group of microorganism has multiple versions, i.e., a kind of microorganism has multiple disclosed genomes.
The reference gene group of reads and species is compared, and two parts are divided into comparison：a)Unique reads(U)：
Uniquely compare the genome of a species；These reads are called unique reads.That is, if the gene in reads comparisons
Group is all from same species, defines these reads for unique reads.b)Multiple reads(M)：Compare one with
The genome of upper species, is defined as multiple reads.That is, if the genome in reads comparisons comes from least two species,
These reads are defined for multiple reads.
According to one embodiment of present invention, it is alleged according to sequencing data, it is described according to comparison result, determine the mark
In various microorganisms abundance, microbial species S abundance is determined using below equation：Microbial species S's is rich
Ab (S)=Ab (US)+Ab (MS) is spent, wherein, Ab (US)=US/lS, USFor unique reading for comparing upper this kind of microorganism S
Hop count mesh, lSFor the length of the genome of this kind of microorganism S in comparison,MSTo be not exclusive
The number of this kind of microorganism S read in comparison, i represents the numbering of this kind of microorganism S read in not exclusive comparison, Coi
For the corresponding abundance coefficients of read i of this kind of microorganism S in not exclusive comparison,N is not exclusive ratio
The microbial species species number that read to above this kind of microorganism S is compared, j is this kind of microorganism S in not exclusive comparison
Read compare on species numbering, UjFor unique read number for comparing upper microbial species j.
For given microbial species S, its abundance is Ab (S), related to Unique reads and Multiple reads, on
State the abundance that Ab (U) and Ab (M) in formula are respectively species S Unique reads and Multiple reads contributions.
Each multiple reads, have special species abundance coefficient Co, it is assumed that N number of species in a multiple reads comparison,
This multiple reads Co can be calculated using following equation：I.e. for this kind of multiple reads,
The unique reads for N number of species that it is compared abundance sum is used as denominator.
Control group in embodiments in accordance with the present invention, the individual state determining unit includes multiple ankylosing spondylitis of suffering from
The fecal sample of individual, the individual state determining unit is following for carrying out：When from the bacterial abundance determining unit
The ankylosing spondylitis mark in various microorganisms abundance all with its abundance indifference in control group, it is determined that
The individual state is with ankylosing spondylitis.
Embodiments in accordance with the present invention, the indifference is the ankylosing spondylitis mark from the bacterial abundance determining unit
The abundance of various microorganisms in will thing falls into first predetermined confidence interval of its abundance in control group, and optional described the
One predetermined confidence interval is 95% confidential interval.
Control group in embodiments in accordance with the present invention, the individual state determining unit includes the excrement sample of multiple healthy individuals
This, the individual state determining unit is following for carrying out：When from the described tatanic of the bacterial abundance determining unit
The abundance of various microorganisms in rachitis mark all with its abundance indifference in control group, determine the individual shape
State is not suffer from ankylosing spondylitis.
Embodiments in accordance with the present invention, the indifference is the ankylosing spondylitis mark from the bacterial abundance determining unit
The abundance of various microorganisms in will thing falls into second predetermined confidence interval of its abundance in control group, and optional described the
Two predetermined confidence intervals are 95% confidential interval.
A kind of ankylosing spondylitis mark of the utilization embodiments of the present invention provided according to another implementation of the invention
The method that thing is classified to multiple individuals, this method includes：It is utilized respectively the determination in the invention described above any embodiment
The method of the state of body determines each individual state；Each individual is classified according to each the individual state obtained.
This method can open multiple individuals according to the different instructions of the state of individual or distinguish multiple unknown fecal samples, be easy to
Classification, annotation management.In addition, the above-mentioned utilization ankylosing spondylitis mark in the embodiment of the present invention determines the shape of individual
The technical characteristic of the method for state and the description of advantage, the method for equally applicable this aspect of the present invention, will not be repeated here.
A kind of medicine for treating ankylosing spondylitis provided according to the further embodiment of the present invention, the medicine can promote
Reduce the abundance of each microorganism in the ankylosing spondylitis mark in the invention described above any embodiment.It is alleged tetanic
Property rachitis mark to be inventor organized by the various enteric microorganism of variance analysis in ankylosing spondylitis disease group and health
Abundance in fecal sample, and the fecal sample Jing Guo a large amount of known states checking, and decide.Compared to
Health population group, alleged ankylosing spondylitis mark significant enrichment, alleged significant enrichment in ankylosing spondylitis disease group
Refer to compared with the abundance in healthy group, the various microorganisms that above-mentioned ankylosing spondylitis mark is included are in disease group
Abundance be higher than with being respectively provided with statistical significance or significantly, substantially higher than abundance in healthy group.It can be made rich
The reduced material of degree can be used in treatment ankylosing spondylitis or be taken beneficial to patients with ankylosing spondylitis, can make its abundance
The material of reduction can be used as the medicine for treating ankylosing spondylitis.
Using the medicine or functional food of this embodiment, the micro- life of ankylosing spondylitis that rationally and effectively application is determined
Thing mark, helps the growth of intestinal beneficial bacterium and/or suppresses enteron aisle potentially pathogenic organism, can prevent the defect of gut barrier,
Improve and recover micro-ecological in intestines, for auxiliary reduction blood endotoxin level and/or the clinical condition of mitigation ankylosing spondylitis
Shape is significant.
According to the further embodiment of the present invention, there is provided a kind of tatanic ridge of the treatment for preparing or screening in above-mentioned embodiment
The method of the scorching medicine of post, this method includes preparing or screening can promote the rigid spine in the embodiments of the present invention
The step of material of the abundance reduction of each microorganism in scorching mark is as the medicine.
Using the production in the embodiment of the invention or the method for the medicine of screening treatment ankylosing spondylitis, by rationally having
The ankylosing spondylitis biomarker that the application of effect ground is determined is screened, result in can help the growth of intestinal beneficial bacterium with/
Or suppress the medicine of enteron aisle potentially pathogenic organism, the defect of gut barrier can be prevented, improves and recovers micro-ecological in intestines,
It is significant for auxiliary reduction blood endotoxin level and/or the clinical symptoms for mitigating ankylosing spondylitis.
The method and/or device of the present invention are described in detail below in conjunction with specific embodiment.It is real below except as otherwise explaining
The reagent do not explained especially being related in example, sequence (joint, label and primer), software and instrument are applied, is all conventional commercial
Product is increased income, for example, buy Illumina transcript profile library construction Kit.
Following examples include first stage and second stage, that is, correspond to discovery phase and Qualify Phase.Discovery phase includes：
Enteric microorganism composition and function based on 73 patients with ankylosing spondylitis of com-parison and analysis and 83 healthy control groups change,
To determine species mark；Qualify Phase includes：Utilize 24 AS patients and 31 healthy control group checking first stage
As a result accuracy.
Embodiment 1
In the example, inventor carries out whole intestines from the fecal specimens of 73 patients with ankylosing spondylitis, 83 normal healthy controls
The association analysis research description fecal microorganism group of road flora microorganism and functional component feature.Generally speaking, under inventor
Carry the high-quality sequencings of 294Gb that the high-quality sequencing datas of about 428.09Gb (LC Healthy Peoples) and experiment sequencing are obtained
Data construct ankylosing spondylitis reference gene collection, and build one more with the LC gene sets, IGC gene sets downloaded
Add whole gene set.Grand genome analysis shows that 17 microbial species and ankylosing spondylitis disease are closely related, its
In 7 bacterium be enriched with the enteric microorganism of Healthy People, 10 bacterium are enriched with the enteric microorganism of ankylosing spondylitis patient.
1st, the acquisition of sequencing data
1.1 samples are collected and DNA is extracted
Patients with ankylosing spondylitis comes from affiliated hospital of Hangzhou Zhejiang University of Traditional Chinese Medicine first, and experiment acquires 73 Ge Zhong Guoqiang altogether
The fecal specimens of straightforward rachitis patient, wherein the fresh excreta sample of each individual is divided into 200mg/ parts, totally 5 parts, immediately
- 80 DEG C of refrigerator freezings are preserved.
STb gene is extracted in the fecal specimens of 73 Chinese patients with ankylosing spondylitis.DNA is extracted in the processing of phenol chloroform
Method extracts DNA.
1.2 build library and sequencing, and are downloaded with reference to data
DNA builds storehouse and carried out by the operating guidance of apparatus manufacturer (Illumina).PE100bp sequencings are carried out to library.
The library of 73 samples is sequenced Illumina HiSeq2000 (Illumina, San Diego, CA) platform.Each sample is put down
4.03Gb (sd. ± 0.64Gb) high-quality sequencing result is produced, 294Gb sequencing data amounts are amounted to.
The sequencing data of 83 normal Chineses, No. accession are downloaded from EBI：ERP005860.
The experiment flow of reference picture 1, identifies the associated biomarkers of ankylosing spondylitis, wherein the step of omitting or thin
Section is well known to those skilled in the art, and several important steps are described below described in the step of face.
2nd, the identification of biomarker
The basic handling of 2.1 sequencing datas
1) sequencing data passes through Quality Control：After the sequencing data for 73 AS samples for obtaining the first stage, it was carried out
Filter, Quality Control is carried out by following standard：A) reads that low quality base (Q20) is more than 50% is removed；B) remove and be more than 5
The reads of individual N bases；C) afterbody low quality (Q20) and N bases are removed.The sequence for losing paired reads is considered as
Wall scroll reads is used to assemble.
2) the healthy personal data that same processing is downloaded.
3) LC gene sets are obtained from Qin, N.et al.Alterations of the human gut microbiome in liver cirrho
Sis.Nature 513,59-64 (2014), from ftp://climb.genomics.cn/pub/10.5524/100001_101000/100064/
1.GeneCatalogs/IGC.fa.gz is downloaded and is obtained IGC gene sets.
2.2 species abundances are analyzed
The paired-end clean reads Jing Guo upper step process are compared into (matching) using SOAPalign 2.21 and arrive redundancy base
Because of group, here, the reference gene group of the bacterium of alleged redundancy genome disclosed in each database.Alignment parameters are-r
2–m 100–x 1000.Reads and redundancy genome alignment, may be divided into two parts：a)Unique reads(U)：
Reads only compares the genome of a species；These reads are defined as unique reads.That is, if these genomes
From same species, these reads are defined as unique reads by reads and more than one genome alignment, inventor.
b)Multiple reads(M)：If reads compares genomes more than a upper species, multiple reads are defined as.That is,
If the genome in comparison comes from different plant species, inventor defines these reads for multiple reads.
For species S, its abundance is Ab (S), related to distinctive U reads and shared M reads, the calculating of abundance
Mode is as follows：
Ab (S)=Ab (U)+Ab (M)
Ab (U)=U/l
Ab (U) and Ab (M) is respectively the abundance of unique reads and the multiple reads from species S, and l represents base
Because of the length of group.Each multiple reads, there is specific species coefficient Co；Assuming that N in a certain multiple reads comparisons
Individual species, calculate this multiple reads Co by the following method：
For these reads, the unique reads of N number of species of the inventor to add sum abundance is used as standard.I.e. for
Multiple reads, the unique reads abundance sums for N number of species that inventor compares it are used as denominator.
2.3 association analysis/screening species label
In order to obtain the enteric microorganism species label closely related with ankylosing spondylitis disease, inventor utilizes tatanic
Rachitis patient group (73) and two groups of enteric microorganism species abundance data of Healthy People group (83), do in species rank
One with disease associated research.
The species abundance table obtained based on upper step, inventor sets standard as follows：(1) patients with ankylosing spondylitis group or strong
The median of health people group species abundance have to be larger than 0.00001；(2) combination Benjamini Hochberg multiple check is passed through
Wilcoxon rank tests test, obtain the correlation p value and q values of each species and ankylosing spondylitis disease；
(3) using a relatively very strict threshold value (q_values<5.0E-05).Then, inventor obtain 28 with it is tetanic
The property closely related enteric microorganism species of rachitis disease.What is be wherein enriched with ankylosing spondylitis (AS) patient has 14
Individual species, enrichment has 14 species in Healthy People (HD).This 28 microbial species labels are as shown in table 1 below.
Table 1
Embodiment 2
In order to which the analysis result confirmed in embodiment 1 can be as ankylosing spondylitis species mark, further to compare
31 Healthy Peoples in colony and the species abundance of 24 patients with ankylosing spondylitis are verified, and to final microbial species mark
Note thing makes screening according to checking situation.The acquisition and processing of the sequencing data of colony are verified, is carried out with reference to embodiment 1.
The result is as follows：In above-mentioned 14 species being enriched in healthy population, 7 obtain high-quality in checking concentration
Verify (p_values<0.05), the p value of the microbial species mark checking of Healthy People enrichment and q values situation such as table 2 below institute
Show.Microbial species are respectively Mao Luo sections bacterium (Lachnospiraceae bacterium 6_1_63FAA), fusobacterium mortiferum
(Fusobacterium mortiferum), bacteroid ([Bacteroides] pectinophilus), enterobacter cloacae (Enterobacter
Cloacae), Eubacterium eligens (Eubacterium eligens), Mao Luo sections bacterium (Lachnospiraceae bacterium
8_1_57FAA), clostridium (Clostridium sp.L2-50).Bacteroid is present in human body intestinal canal, is mainly to aid in decomposing food
Thing is to provide nutrition and the energy of needed by human body.
Table 2
For above-mentioned 14 species being enriched in patients with ankylosing spondylitis, wherein 10 obtain high-quality in checking concentration
Checking (p_values<0.05), the p value and q value feelings of the microbial species mark checking of patients with ankylosing spondylitis enrichment
Condition is as shown in table 3 below, respectively actinomyces (Actinomyces sp.ICM47), bifidobacterium breve (Bifidobacterium breve),
Bifidobacterium (Bifidobacterium sp.12_1_47BFAA), bifidobacterium longum (Bifidobacterium longum), aerogenesis
Collins bacterium (Collinsella aerofaciens), bifidobacterium bifidum (Bifidobacterium bifidum), false chainlet bifid
Bacillus (Bifidobacterium pseudocatenulatum), slow Ai Gete bacterium (Eggerthella lenta), chain bifid bar
Bacterium (Bifidobacterium catenulatum), bifidobacterium adolescentis (Bifidobacterium adolescentis).
Bifidobacterium can pre- anti-diarrhea, reduction constipation, i.e. bidirectional modulation.There are some researches show the rigid spine more than 70%
Scorching patient suffers from intestinal inflammatory, and 5~10% intestinal inflammatories are very serious in these patients, may develop into clinically inflammatory
Enteropathy (IBD) or Crohn's disease (CD) (Mielants et al., 1985), research find bacteroid in patient's IBD enteron aisle,
Clostruidium, firmicutes decline, actinomyces, the rise of mycetozoan ratio.
Table 3
It has been recognised by the inventors that ankylosing spondylitis disease can be regard 7 microbial species labels being enriched with from Healthy People as
Ill reverse index, or the microorganism formulation medicine flora composition researched and developed as treatment ankylosing spondylitis, or conduct
Detect ankylosing spondylitis, monitor the recovery index for the treatment of ankylosing spondylitis process；Patients with ankylosing spondylitis is enriched with
10 microbial species labels, are used as the positive index that ankylosing spondylitis disease is ill, it is especially useful in ankylosing spondylitis
The detection and diagnosis of the non-wound formula of disease.
Inventor utilizes this 17 microbial species labels, builds an overall target, estimates ROC
(Receiver-operating characteristic) TG-AUC AUC, AUC is bigger, represents that diagnosis capability is higher, comments
Valency comprehensive score corresponds to its diagnosis capability to ankylosing spondylitis.By 156 samples to a phase (first stage) and
55 samples of the second stage of (second stage) are evaluated and tested, and concrete condition is as shown in Fig. 2 all show diagnosis energy well
Power, AUC=96.62% is obtained in a phase, and as shown in the figure of Fig. 2 left sides, confidential interval is 93.93%-99.31%；The second stage of
To AUC=89.92%, on the right of Fig. 2 shown in figure, confidential interval is 81.28%-98.56%.
Embodiment 3
The detection of the individual state of samples sources is carried out using 45 fecal samples.
The actinomyces (Actinomyces sp.ICM47), short of table 3 in each fecal sample are determined with reference to the method for embodiment 2
Bifidobacterium (Bifidobacterium breve), Bifidobacterium (Bifidobacterium sp.12_1_47BFAA), long bifid
Bacillus (Bifidobacterium longum), aerogenesis Collins bacterium (Collinsella aerofaciens), bifidobacterium bifidum
(Bifidobacterium bifidum), false chainlet Bifidobacterium (Bifidobacterium pseudocatenulatum), slow angstrom
Lattice spy bacterium (Eggerthella lenta), bifidobacterium catenulatum (Bifidobacterium catenulatum) and bifidobacterium adolescentis
The abundance of (Bifidobacterium adolescentis), judges whether this ten kinds of bacterial strain abundance in each sample fall into each comfortable disease
95% confidential interval of the abundance of sick control group or healthy control group, judges that the abundance of this 10 kinds of strains each falls within disease group
The interval sample of correspondence corresponding to individual state be patients with ankylosing spondylitis, judge that the abundance of ten kinds of strains is each fallen within
Individual state corresponding to the sample in the correspondence interval of health group is non-patients with ankylosing spondylitis.
As a result show, individual state judgement can be carried out to 38 samples therein using the above method, and to this 38
The judgement of all states of 38 sample correspondence individuals in sample, the state consistency with the samples sources individual of record.
In addition, inventor has found to the species joint-detection in table 2 and table 3, such as to detect the species mark quilt in table 3
Enrichment, while species label is not enriched with table 2, can more accurately judge to find patients with ankylosing spondylitis or susceptible
Crowd.
In the scheme of ankylosing spondylitis is treated using mark, inventor has found to make the species mark growth in 3 to obtain
Suppress or remove, while species label in table 2 is enriched with, excellent treatment effect.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specific example ",
Or the description of " some examples " etc. means to combine specific features, structure, material or the feature that the embodiment or example are described
It is contained at least one embodiment of the present invention or example.In this manual, the schematic representation of above-mentioned term is differed
Surely identical embodiment or example are referred to.Moreover, specific features, structure, material or the feature of description can be any
One or more embodiments or example in combine in an appropriate manner.
Although an embodiment of the present invention has been shown and described, it will be understood by those skilled in the art that：Do not departing from
In the case of the principle and objective of the present invention a variety of change, modification, replacement and modification, this hair can be carried out to these embodiments
Bright scope is limited by claim and its equivalent.
Claims (10)
1. a kind of ankylosing spondylitis microbial markers, it is characterised in that the mark by following microorganism group into：
Actinomyces (Actinomyces sp.ICM47), bifidobacterium breve (Bifidobacterium breve), Bifidobacterium
(Bifidobacterium sp.12_1_47BFAA), bifidobacterium longum (Bifidobacterium longum), aerogenesis Collins bacterium
(Collinsella aerofaciens), bifidobacterium bifidum (Bifidobacterium bifidum), false chainlet Bifidobacterium
(Bifidobacterium pseudocatenulatum), slow Ai Gete bacterium (Eggerthella lenta), bifidobacterium catenulatum
(Bifidobacterium catenulatum) and bifidobacterium adolescentis (Bifidobacterium adolescentis).
2. the mark of claim 1 is tetanic in detection ankylosing spondylitis, monitoring treatment ankylosing spondylitis, preparation treatment
The medicine of property rachitis and/or prepare purposes in functional food.
3. the method that a kind of mark of utilization claim 1 determines the state of individual, it is characterised in that including：
(1) abundance of the various microorganisms in the mark in the individual fecal sample is determined；
(2) abundance of the various microorganisms in the mark that will be determined respectively in (1) is carried out with its abundance in control group
Compare, the individual state determined according to the comparative result obtained,
The control group is made up of the individual fecal sample of one or more groups of equal states,
The state includes with ankylosing spondylitis and not suffered from ankylosing spondylitis.
4. the method for claim 3, it is characterised in that (1) include：
The sequencing data of the nucleotide sequence in the individual fecal sample is obtained, the sequencing data includes multiple reads；
The read is compared to the genome of the various microorganisms into the mark, comparison result is obtained；
According to the comparison result, the abundance of the various microorganisms in the mark is determined；
Optional,
The foundation comparison result, determines the abundance of the various microorganisms in the mark, is determined using below equation
Microbial species S abundance：
Microbial species S abundance Ab (S)=Ab (US)+Ab(MS), wherein,
Ab(US)=US/lS,
USUniquely to compare upper this kind of microorganism S read number,
lSFor the length of the genome of this kind of microorganism S in comparison,
<mrow>
<mi>A</mi>
<mi>b</mi>
<mrow>
<mo>(</mo>
<mi>M</mi>
<mi>s</mi>
<mo>)</mo>
</mrow>
<mo>=</mo>
<mrow>
<mo>(</mo>
<munderover>
<mo>&Sigma;</mo>
<mrow>
<mi>i</mi>
<mo>=</mo>
<mn>1</mn>
</mrow>
<mrow>
<mi>M</mi>
<mi>s</mi>
</mrow>
</munderover>
<msub>
<mi>Co</mi>
<mi>i</mi>
</msub>
<mo>)</mo>
</mrow>
<mo>/</mo>
<msub>
<mi>l</mi>
<mi>S</mi>
</msub>
<mo>,</mo>
</mrow>
MSFor the number of this kind of microorganism S read in not exclusive comparison,
I represents the numbering of this kind of microorganism S read in not exclusive comparison,
CoiFor the corresponding abundance coefficients of read i of this kind of microorganism S in not exclusive comparison,
The microbial species species number that the read that N is this kind of microorganism S in not exclusive comparison is compared,
The numbering for the species that the read that j is this kind of microorganism S in not exclusive comparison is compared,
UjFor unique read number for comparing upper microbial species j；
Optional,
(2) control group in includes multiple individual fecal samples for suffering from ankylosing spondylitis, and (2) include：
The abundance of various microorganisms in the mark determined in (1) all with its abundance indifference in control group, it is determined that
The individual state is with ankylosing spondylitis；
Optional,
(2) control group in includes the fecal sample of multiple healthy individuals, and (2) include：
The abundance of various microorganisms in the mark determined in (1) all with its abundance indifference in control group, it is determined that
The individual state is not suffer from ankylosing spondylitis.
5. a kind of mark of utilization claim 1 determines the device of the state of individual, it is characterised in that including：
Data input cell, for input data；
Data outputting unit, for output data；
Processor, for performing executable program, performs the method that the executable program includes completing claim 3 or 4；
Memory cell, is connected with the data input cell, the data outputting unit and the processor, for storing number
According to including the executable program.
6. the system that a kind of mark of utilization claim 1 determines individual state, it is characterised in that including：
Bacterial abundance determining unit, for determining the various microorganisms in the mark in the individual fecal sample
Abundance；
Individual state determining unit, for respectively will be various in the mark from the bacterial abundance determining unit
The abundance of microorganism is compared with its abundance in control group, and the individual state is determined according to the comparative result obtained,
The control group is made up of the individual fecal sample of one or more groups of equal states,
The state includes with ankylosing spondylitis and not suffered from ankylosing spondylitis.
7. the system of claim 6, it is characterised in that the bacterial abundance determining unit is following for carrying out：
The sequencing data of the nucleotide sequence in the individual fecal sample is obtained, the sequencing data includes multiple reads；
The read is compared to the genome of the various microorganisms into the mark, comparison result is obtained；
According to the comparison result, the abundance of the various microorganisms in the mark is determined；
Optional,
The foundation comparison result, determines the abundance of the various microorganisms in the mark, is determined using below equation
Microbial species S abundance：
Microbial species S abundance Ab (S)=Ab (US)+Ab(MS), wherein,
Ab(US)=US/lS,
USUniquely to compare upper this kind of microorganism S read number,
lSFor the length of the genome of this kind of microorganism S in comparison,
<mrow>
<mi>A</mi>
<mi>b</mi>
<mrow>
<mo>(</mo>
<mi>M</mi>
<mi>s</mi>
<mo>)</mo>
</mrow>
<mo>=</mo>
<mrow>
<mo>(</mo>
<munderover>
<mo>&Sigma;</mo>
<mrow>
<mi>i</mi>
<mo>=</mo>
<mn>1</mn>
</mrow>
<mrow>
<mi>M</mi>
<mi>s</mi>
</mrow>
</munderover>
<msub>
<mi>Co</mi>
<mi>i</mi>
</msub>
<mo>)</mo>
</mrow>
<mo>/</mo>
<msub>
<mi>l</mi>
<mi>S</mi>
</msub>
<mo>,</mo>
</mrow>
MSFor the number of this kind of microorganism S read in not exclusive comparison,
I represents the numbering of this kind of microorganism S read in not exclusive comparison,
CoiFor the corresponding abundance coefficients of read i of this kind of microorganism S in not exclusive comparison,
The microbial species species number that the read that N is this kind of microorganism S in not exclusive comparison is compared,
The numbering for the species that the read that j is this kind of microorganism S in not exclusive comparison is compared,
UjFor unique read number for comparing upper microbial species j；
Optional,
Control group in the individual state determining unit includes multiple individual fecal samples for suffering from ankylosing spondylitis, described
Individual state determining unit is following for carrying out：
When the various microorganisms in the mark from the bacterial abundance determining unit abundance all with it in control group
In abundance indifference, determine the individual state be with ankylosing spondylitis；
Optional,
Control group in the individual state determining unit includes the fecal sample of multiple healthy individuals, and the individual state is determined
Unit is following for carrying out：
When the various microorganisms in the mark from the bacterial abundance determining unit abundance all with it in control group
In abundance indifference, determine the individual state not suffer from ankylosing spondylitis.
8. a kind of method that ankylosing spondylitis mark using claim 1 is classified to multiple individuals, its feature exists
In, including：
The method for being utilized respectively claim 3 or 4 determines each individual state；
Each described individual is classified according to each the individual state obtained.
9. a kind of medicine for treating ankylosing spondylitis, it is characterised in that the medicine promotes in the mark of claim 1
Each microorganism abundance reduce.
10. a kind of method for the medicine for producing or screening claim 9, it is characterised in that promote claim including screening
The step of material of the abundance reduction of each microorganism in 1 mark is as the medicine.
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| CN201610165864.8A CN107217089B (en) | 2016-03-22 | 2016-03-22 | Method and device for determining individual state |
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| CN201610165864.8A CN107217089B (en) | 2016-03-22 | 2016-03-22 | Method and device for determining individual state |
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| CN107217089B CN107217089B (en) | 2020-11-03 |
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| CN113913490A (en) * | 2021-11-25 | 2022-01-11 | 上海锐翌生物科技有限公司 | Non-alcoholic fatty liver marker microorganism and application thereof |
| CN113930479A (en) * | 2021-11-25 | 2022-01-14 | 上海锐翌生物科技有限公司 | Marker microorganism of systemic lupus erythematosus and application thereof |
| CN114085886A (en) * | 2021-11-25 | 2022-02-25 | 青岛锐翌精准医学检验有限公司 | Crohn-marking microorganism for children and application thereof |
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| CN114317674A (en) * | 2021-12-31 | 2022-04-12 | 青岛锐翌精准医学检验有限公司 | Marker microorganism for rheumatoid arthritis and application thereof |
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| CN114517228A (en) * | 2021-12-31 | 2022-05-20 | 青岛锐翌精准医学检验有限公司 | Inflammatory bowel disease marker gene and application thereof |
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