CN114807392A - Schizophrenia marker microorganism and application thereof - Google Patents
Schizophrenia marker microorganism and application thereof Download PDFInfo
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- CN114807392A CN114807392A CN202111491973.6A CN202111491973A CN114807392A CN 114807392 A CN114807392 A CN 114807392A CN 202111491973 A CN202111491973 A CN 202111491973A CN 114807392 A CN114807392 A CN 114807392A
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Abstract
The invention proposes schizophrenia marker microorganisms comprising a first set of microorganisms, and uses thereof, and thus further proposes a kit comprising reagents suitable for detecting at least one species of the first set of microorganisms, said first set of microorganisms consisting of: eubacterium (Eubacterium sp.) CAG:115, Eubacterium (Eubacterium sp.) CAG:252, Mycobacteria (Firmicutes bacterium) CAG:227, Pseudomonas agaricus (Pseudomonas agaricii). The abundance of the marker microorganism provided by the invention has obvious difference in healthy people and schizophrenia patients, and can be used as a marker for detecting and/or treating schizophrenia.
Description
Technical Field
The present invention relates to the field of biotechnology, specifically, the present invention relates to a schizophrenia marker microorganism and use thereof, and more specifically, the present application relates to a kit, use of a reagent in preparation of the kit, a pharmaceutical composition or a food composition for preventing or treating schizophrenia, a method for determining whether an individual has schizophrenia, a device, a method for screening drugs.
Background
Schizophrenia (SCZ) is a devastating psychiatric disease associated with hallucinations, delusions, and thought disorders that affect perception and social interaction. The etiology of schizophrenia has not been elucidated, but a variety of factors, such as genetics and environment, may be involved. Abnormalities in the neurotransmitter system have been extensively studied, particularly with regard to abnormalities in dopamine, glutamate and gamma-aminobutyric acid signals. There is increasing evidence that schizophrenia may be a systemic disease of neuropsychiatric diseases other than psychosis. In addition, the importance of inflammation and the involvement of the gastrointestinal system in schizophrenia has also received attention.
Intestinal microbiota is reported to play an important role in the neurogenesis process, and perturbations in microbiota and microbial products have been shown to affect behavior. A great deal of research shows that intestinal microorganisms can regulate brain functions and behaviors through flora-intestine-brain axis, and have been reported to influence the emotion, memory, cognition and spontaneous activities of a host, and can also regulate neurotransmitters such as 5HT, gamma aminobutyric acid (GABA), Norepinephrine (NE), DA, acetylcholine (Ach) and the like, thereby participating in the occurrence and development of mental diseases and becoming a potential intervention target point for mental disorders.
Recent clinical and preclinical studies show that potential relation exists between disorder of intestinal flora and occurrence of SCZ, intestinal microbiota plays an important role in schizophrenia metabolism, and researches show that the number of bacteroides of patients with schizophrenia is increased, the number of bifidobacteria is reduced, flora proportion imbalance exists, the number of bacteroides of conditional pathogens is obviously increased, the number of probiotic bifidobacteria is obviously reduced, and imbalance states exist between the bacteroides and the bifidobacteria, so that the researches on characteristics of the intestinal microbiota of the patients with schizophrenia have important significance for detecting and treating the schizophrenia.
Disclosure of Invention
The present application is based on the discovery and recognition by the inventors of the following facts and problems:
through a great deal of research in the early period, the applicant of the present application unexpectedly finds that some microorganisms can be used as marker microorganisms for detecting schizophrenia, and provides a non-invasive method for early detection of schizophrenia; the marker microorganisms are reasonably and effectively applied, the growth of beneficial bacteria in the intestinal tract is supported, potential pathogenic bacteria in the intestinal tract are inhibited, and the clinical symptoms of schizophrenia can be treated or relieved.
To this end, in a first aspect of the invention, the invention proposes a kit. According to an embodiment of the invention, reagents suitable for detecting at least one species in a first set of microorganisms are included, said first set of microorganisms consisting of the following species: eubacterium (Eubacterium sp.) CAG:115, Eubacterium (Eubacterium sp.) CAG:252, Mycobacteria (Firmicutes bacterium) CAG:227, Pseudomonas agaricus (Pseudomonas agaricii). According to the kit prepared by the reagent provided by the embodiment of the invention, at least one strain in the first microorganism set can be accurately detected, and schizophrenia patients and healthy individuals can be very accurately distinguished.
In a second aspect of the invention, the invention proposes the use of a reagent suitable for detecting at least one species of a first collection of microorganisms in the preparation of a kit. According to an embodiment of the invention, the kit is for diagnosing schizophrenia or for detecting the therapeutic effect of schizophrenia, the first set of microorganisms consists of the following species: eubacterium (Eubacterium sp.) CAG:115, Eubacterium (Eubacterium sp.) CAG:252, Mycobacteria (Firmicutes bacterium) CAG:227, Pseudomonas agaricus (Pseudomonas agaricii). The reagent kit prepared by the reagent according to the embodiment of the invention can accurately detect at least one species in the first microorganism group, and can accurately distinguish schizophrenia patients from healthy individuals, thereby effectively diagnosing schizophrenia in an early stage or detecting the change of schizophrenia in the course of treatment.
In a third aspect of the present invention, the present invention provides a pharmaceutical composition or food composition for preventing or treating schizophrenia. According to an embodiment of the invention, at least one species of a first microbial collection is contained, said first microbial collection consisting of the following species: eubacterium (Eubacterium sp.) CAG:115, Eubacterium (Eubacterium sp.) CAG:252, Mycobacteria (Firmicutes bacterium) CAG:227, Pseudomonas agaricus (Pseudomonas agaricii). The strains of the first microorganism group in the schizophrenia marker microorganisms according to the embodiment of the invention can be non-invasively discovered or assisted to detect schizophrenia in early stage, and determine the probability that an individual has schizophrenia or the probability that the individual is in a healthy state; meanwhile, increasing the strains in the first microorganism group in the intestinal tract of people at high risk of schizophrenia or patients with schizophrenia can reduce the probability of suffering from schizophrenia or slow down and cure schizophrenia, so that the medicine or food composition containing at least one strain in the first microorganism group can be used for balancing the intestinal flora and effectively preventing or treating schizophrenia.
In a fourth aspect of the invention, a method of determining whether an individual has schizophrenia is presented. According to an embodiment of the invention, comprising: (1) determining an abundance of a marker microorganism in a fecal sample of the individual, the marker microorganism comprising at least one species of the first set of microorganisms and the second set of microorganisms; (2) comparing the abundance obtained in step (1) with a predetermined threshold value to determine whether the individual has schizophrenia; wherein the first microbial collection consists of the following species: eubacterium (Eubacterium sp.) CAG:115, Eubacterium (Eubacterium sp.) CAG:252, Mycobacteria (fungi bacterium) CAG:227, Pseudomonas agaricus (Pseudomonas agaricii); the second microbial set consists of the following species: actinomycetes (Actinomyces sp.) oral taxon 180, Exmanella vulgaris (Akkermansia muciniphila) CAG 154, Exmanella vulgaris (Akkermansia sp.) UNK.MGS-1, Alloscardia omnicola, Bacillus subtilis, Cryptobacterium currum, Demanococcus sedentarius, and Cryptobacterium pyogenes. The method according to the embodiment of the invention can determine whether the individual has schizophrenia or not according to the abundance of the marker microorganism in the individual fecal sample, wherein the marker microorganism is determined by verifying a large number of fecal samples with known states and analyzing the abundance of various intestinal microorganisms in the fecal samples of the schizophrenia group and the healthy group through difference comparison.
In a fifth aspect of the invention, an apparatus for determining whether an individual has schizophrenia is presented. According to an embodiment of the invention, comprising: an abundance determination unit for determining an abundance of a marker microorganism in a fecal sample of the individual, the marker microorganism comprising at least one species of the first set of microorganisms and the second set of microorganisms; a comparison unit for comparing the obtained abundance with a predetermined threshold value in order to determine whether the individual suffers from schizophrenia; wherein the first microbial collection consists of the following species: eubacterium (Eubacterium sp.) CAG:115, Eubacterium (Eubacterium sp.) CAG:252, Mycobacteria (fungi bacterium) CAG:227, Pseudomonas agaricus (Pseudomonas agaricii); the second microbial set consists of the following species: actinomycetes (Actinomyces sp.) oral taxon 180, Exmanella vulgaris (Akkermansia muciniphila) CAG 154, Exmanella vulgaris (Akkermansia sp.) UNK.MGS-1, Alloscardia omnicola, Bacillus subtilis, Cryptobacterium currum, Demanococcus sedentarius, and Cryptobacterium pyogenes. The marker microorganism is determined by analyzing the abundance of various intestinal microorganisms in the stool samples of schizophrenic patients and healthy people through difference comparison and verifying a large number of stool samples with known states, and the device provided by the embodiment of the invention can accurately determine whether the individual is a high-risk group of schizophrenic patients or schizophrenic patients.
In a sixth aspect of the invention, an apparatus is presented. According to an embodiment of the invention, comprising: a computer-readable storage medium having stored thereon a computer program for executing the method of the fourth aspect; and one or more processors for executing the program in the computer-readable storage medium. The device according to the embodiment of the invention can accurately determine whether the individual is a high-risk group of schizophrenia or a schizophrenia patient.
In a seventh aspect of the invention, a method of screening for a drug is presented. According to an embodiment of the invention, the medicament is for the treatment or prevention of schizophrenia, the method comprising: administering a candidate drug to a subject, said subject's stool having an abundance of a marker microorganism comprising at least one species of a first set of microorganisms and a second set of microorganisms measured before and after administration, wherein a candidate drug satisfying at least one of the following conditions is suitable for use in the treatment or prevention of schizophrenia: (1) said abundance of at least one species in said first collection of microorganisms is increased following said administering; and (2) said abundance of at least one species in said second set of microorganisms is reduced after said administering; wherein the first microbial collection consists of the following species: eubacterium (Eubacterium sp.) CAG:115, Eubacterium (Eubacterium sp.) CAG:252, Mycobacteria (fungi bacterium) CAG:227, Pseudomonas agaricus (Pseudomonas agaricii); the second microbial pool consists of the following species: actinomycetes (Actinomyces sp.) oral taxon 180, Exmanella vulgaris (Akkermansia muciniphila) CAG 154, Exmanella vulgaris (Akkermansia sp.) UNK.MGS-1, Alloscardia omnicola, Bacillus subtilis, Cryptobacterium currum, Demanococcus sedentarius, and Cryptobacterium pyogenes. According to the method provided by the embodiment of the invention, the medicines for promoting the growth of various strains in the first microorganism set in the marker microorganisms and/or inhibiting the growth of various strains in the second microorganism set in the intestinal marker microorganisms can be produced or screened, and the method has important significance for assisting in relieving the clinical symptoms of schizophrenia.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Drawings
The above and/or additional aspects and advantages of the present invention will become apparent and readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings of which:
FIG. 1 is a schematic diagram of an experimental analysis procedure for screening schizophrenia marker microorganisms according to an embodiment of the present invention; and
FIG. 2 is a schematic diagram showing the evaluation results of the marker microorganism combination indicator AUC according to the embodiment of the present invention, wherein Specificity represents Specificity, i.e., predicted to be positive and actually positive, true positive, and ordinate Sensitivity represents Sensitivity, i.e., true negative, and CI (confidence interval) represents confidence interval:
2-A is a graph of AUC values and confidence interval results under ROC curves of 122 sample data in the first stage;
and 2-B is a result graph of AUC values and confidence intervals under the ROC curve of the second stage sample data.
Detailed Description
Reference will now be made in detail to embodiments of the present invention, examples of which are illustrated in the accompanying drawings. The embodiments described below with reference to the drawings are illustrative and intended to be illustrative of the invention and are not to be construed as limiting the invention.
Furthermore, the terms "first", "second" and "first" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one such feature. In the description of the present invention, "a plurality" means at least two, e.g., two, three, etc., unless specifically limited otherwise.
The term "optionally" is used for descriptive purposes only and is not to be construed as indicating or implying relative importance. Thus, a feature defined as "optionally" may or may not explicitly include the feature.
A biological marker is a cellular/biochemical or molecular change that can be detected from a biological medium. Biological media include various body fluids, tissues, cells, feces, hair, breath, and the like.
The abundance of a microorganism refers to the abundance of that microorganism in a population of microorganisms, for example, the population of gut microorganisms, and can be expressed as the amount of that microorganism in that population.
According to one embodiment of the invention, a kit is provided comprising reagents suitable for detecting at least one species in a first collection of microorganisms consisting of: eubacterium (Eubacterium sp.) CAG:115, Eubacterium (Eubacterium sp.) CAG:252, Mycobacteria (Firmicutes bacterium) CAG:227, Pseudomonas agaricus (Pseudomonas agaricii).
According to a particular embodiment of the invention, the kit further comprises reagents suitable for detecting at least one species of a second microbiome consisting of: actinomycetes (Actinomyces sp.) oral taxon 180, Exmanella vulgaris (Akkermansia muciniphila) CAG 154, Exmanella vulgaris (Akkermansia sp.) UNK.MGS-1, Alloscardia omnicola, Bacillus subtilis, Cryptobacterium currum, Demanococcus sedentarius, and Cryptobacterium pyogenes.
According to a particular embodiment of the invention, said kit comprises reagents suitable for detecting all of said species in said first microbial collection.
According to a particular embodiment of the invention, said kit comprises reagents suitable for detecting all of said species in said second set of microorganisms.
According to a specific embodiment of the invention, the marker microorganism is determined by comparing, analyzing and verifying the abundance of the microorganism in the fecal samples of a plurality of individuals suffering from schizophrenia and a plurality of healthy control individuals, and the marker microorganism related to schizophrenia in the intestinal microorganisms is determined. The kit containing the reagent for detecting the marker microorganism can determine the probability that an individual is in a state with schizophrenia symptoms or in a healthy state, and can be used for non-invasive early detection or auxiliary detection of schizophrenia.
According to a specific embodiment of the present invention, the reagent suitable for detecting the first microorganism collection or the second microorganism collection is not particularly limited, and any reagent capable of detecting the microorganism species is included in the scope of the present invention, such as reagents for detecting the microorganism species through morphological characteristics, physiological biochemical reaction characteristics, ecological characteristics, serological reactions, sensitivity to bacteriophage, molecular biology, and the like, specifically, antibodies, enzymes, nucleic acid molecules, and the like.
Herein, the microbial morphological characteristics refer to: the shape, arrangement, etc. of the microorganism, the cell structure, gram staining reaction, the ability to move, the number and position of flagella, the presence or absence of spores, capsules, the size and position of spores, the shape and structure of the reproductive organs of actinomycetes and fungi, the number, shape, size, color and surface characteristics of spores, etc. were observed under a microscope.
Herein, the microorganism is physiologically livingThe chemical reaction characteristics refer to: the ability of the microorganism to utilize substances, specificity of metabolites, e.g. production of H 2 S, indole, CO 2 Alcohol, organic acid, whether to reduce nitrate, whether to coagulate or freeze milk, growth environment (temperature, humidity, concentration of oxygen, carbon dioxide, and other gases, pH, whether to be hypertonic, whether to have halophilicity, etc.), relationship with other organisms (such as symbiosis, parasitism, host range, and pathogenic conditions), and the like.
Herein, the microbial serological response refers to: identification of similar species is achieved by highly sensitive specific reaction of antigen and antibody, or by typing of the same species of microorganism, such as antisera made with known species, type or strain, and serological reaction of specificity with the microorganism to be identified.
Herein, the detection of microorganisms by molecular biological methods mainly comprises: PCR technology and high-throughput sequencing are used.
Use of an agent provided according to the invention for the preparation of a kit suitable for the detection of at least one species in a first microbiome set for the diagnosis of schizophrenia or for the detection of the therapeutic effect of schizophrenia, said first microbiome set consisting of the following species: eubacterium (Eubacterium sp.) CAG:115, Eubacterium (Eubacterium sp.) CAG:252, Mycobacteria (Firmicutes bacterium) CAG:227, Pseudomonas agaricus (Pseudomonas agaricii).
According to the specific embodiment of the invention, the marker microorganism is determined by comparing, analyzing and verifying the difference of abundance of the microorganism in the fecal samples of a large number of individuals suffering from schizophrenia and a large number of healthy control individuals, and the microorganism marker related to schizophrenia in the intestinal microorganisms is determined. The reagent for detecting the marker microorganism can be used for determining whether the individual has schizophrenia or is in a healthy state, and can be used for non-invasive early detection or auxiliary detection of schizophrenia.
According to some specific embodiments of the invention, the reagent is further adapted to detect at least one species of a second set of microorganisms, the second set of microorganisms consisting of: actinomycetes (Actinomyces sp.) oral taxon 180, Exmanella vulgaris (Akkermansia muciniphila) CAG 154, Exmanella vulgaris (Akkermansia sp.) UNK.MGS-1, Alloscardia omnicola, Bacillus subtilis, Cryptobacterium currum, Demanococcus sedentarius, and Cryptobacterium pyogenes.
According to a specific embodiment of the present invention, the reagent suitable for detecting the first microorganism collection or the second microorganism collection is not particularly limited, and reagents capable of detecting the microorganism species are all included in the scope of the present invention, such as reagents for detecting the microorganism species through morphological characteristics, physiological biochemical reaction characteristics, ecological characteristics, serological reactions, sensitivity to bacteriophage, molecular biology, and the like, specifically, antibodies, enzymes, nucleic acid molecules.
Herein, the microbial morphological characteristics refer to: the shape, arrangement, etc. of the microorganism, the cell structure, gram staining reaction, the ability to move, the number and position of flagella, the presence or absence of spores, capsules, the size and position of spores, the shape and structure of the reproductive organs of actinomycetes and fungi, the number, shape, size, color and surface characteristics of spores, etc. were observed under a microscope.
Herein, the physiological and biochemical reaction characteristics of the microorganisms refer to: the ability of the microorganism to utilize substances, specificity of metabolites, e.g. production of H 2 S, indole, CO 2 Alcohol and organic acid, whether nitrate can be reduced, whether milk can be coagulated or frozen, the growth environment (temperature and humidity suitable for growth, concentration of gases such as oxygen and carbon dioxide, PH, whether hypertonic resistance exists, whether halophilic property exists, and the like), the relationship with other organisms (such as symbiosis, parasitism, host range and pathogenic condition), and the like.
Herein, the microbial serological response refers to: identification of similar species is achieved by highly sensitive specific reaction of antigen and antibody, or by typing of the same species of microorganism, such as antisera made with known species, type or strain, and serological reaction of specificity with the microorganism to be identified.
Herein, the detection of microorganisms by molecular biological methods mainly comprises: PCR technology, high-throughput sequencing and other methods are utilized.
According to the present invention, there is provided a pharmaceutical composition or food composition for preventing or treating schizophrenia, comprising at least one species of a first microorganism group, said first microorganism group consisting of: eubacterium (Eubacterium sp.) CAG:115, Eubacterium (Eubacterium sp.) CAG:252, Mycobacteria (Firmicutes bacterium) CAG:227, Pseudomonas agaricus (Pseudomonas agaricii).
The marker microorganisms are determined by analyzing the abundance of various intestinal microorganisms in the fecal samples of the schizophrenic disease group and the healthy group through difference comparison and verifying a large number of fecal samples with known states. The species of the first microbiome species of the marker microorganisms are significantly enriched in the healthy population group compared to the schizophrenic patient group, wherein significantly enriched is a statistically significant higher or significantly, substantially higher abundance of the species in the healthy group compared to the abundance in the schizophrenic patient group; the substance capable of improving the abundance of the partial strains can be used for treating schizophrenia or is beneficial for administration to patients with schizophrenia, and the substance capable of improving the abundance is not limited to drugs for treating schizophrenia and functional foods with beneficial intestinal flora balance. The marker microorganism provided by the embodiment can be used for preparing a medicament for treating schizophrenia and/or preparing a functional food, a health-care medicine and the like which are beneficial to balancing intestinal flora, and the medicament or the food can effectively treat or relieve schizophrenia.
According to the present invention, there is provided a method of determining whether an individual has schizophrenia, comprising the steps of (1) and (2).
(1) Determining the abundance of marker microorganisms in a fecal sample of the individual.
The marker microorganism includes at least one species of the first set of microorganisms and the second set of microorganisms. Wherein the first microbial set consists of the following species: eubacterium (Eubacterium sp.) CAG:115, Eubacterium (Eubacterium sp.) CAG:252, Mycobacteria (fungi bacterium) CAG:227, Pseudomonas agaricus (Pseudomonas agaricii); the second microbial set consists of the following species: streptococcus paracasei (Streptococcus _ paraanguitis), Streptococcus salivarius (Streptococcus _ salivarius), Eubacterium _ rectangle, Coprococcus (Coprococcus _ comes), Lachnospiraceae bacteria (Lachnospiraceae _ bacteria) _5163FAA, and Roseburia hominis (Roseburia _ hominis).
According to some specific embodiments of the present invention, the step (1) further comprises: obtaining nucleic acid sequencing data in a stool sample of the individual; aligning the sequencing data to a reference genome; determining the abundance of the marker microorganism based on the results of the alignment.
According to a specific embodiment of the present invention, in step (1), the abundance of the marker microorganism is determined according to the following formula: ab(s) ═ Ab (U) S )+Ab(M S ) Wherein S represents the number of the marker microorganism, Ab (S) represents the abundance of the marker microorganism S, Ab (U) S )＝U S /l S ，U S Number of reads, l, uniquely aligned to the reference genome of the marker microorganism S in the sequencing data S Is the total length of the reference genome of the marker microorganism S,
M S for the number of reads in the sequencing data that are non-uniquely aligned to the reference genome of the marker microorganism S, i represents the number of the non-uniquely aligned reads, Co i The abundance coefficient corresponding to the ith read,
Co i,s representing the abundance coefficient of said non-uniquely aligned reads i for said marker microorganism S, N is the total number of microorganisms that said non-uniquely aligned reads i can align, j represents said marker microorganism SThe non-uniquely aligned reads i are the numbers of the microorganisms that can be aligned.
Alignment can be performed by using known alignment software, such as SOAP, BWA, TeraMap, etc., in the alignment process, alignment parameters are generally set, one or a pair of reads (reads) is set to allow at most s base mismatches (mismatches), for example, s is set to be ≦ 2, and if more than s bases in reads are mismatched, it is considered that the reads cannot be aligned (aligned) to the assembled fragment. The obtained comparison result comprises comparison conditions of each read and the reference genome of each species, and comprises information of whether the read can be compared with the reference genome of a certain or some species, only one species or multiple species, the position of the reference genome of the species, the unique position or multiple positions of the reference genome of the species, and the like.
The reference genome of the strain/microorganism refers to a predetermined sequence of the microorganism species, and may be any reference template of a biological category to which a sample to be tested belongs or which is obtained in advance, for example, the target is a microorganism in the sample to be tested, the reference sequence may be a reference genome of various microorganisms in an NCBI database and/or a DACC intestinal reference genome disclosed in HMP and MetaHIT projects, and further, a resource library including more reference sequences may be configured in advance, for example, a more similar sequence is selected or determined and assembled as the reference sequence according to factors such as a state of an individual from which the sample to be tested is derived, a region, and the like. According to one embodiment of the invention, the reference genomes of the various microorganisms are obtained from public databases, typically, the reference genome of a microorganism has multiple versions, i.e., a microorganism has multiple public reference genomes.
reads are aligned to the reference genome of the species, which can be divided into two parts: a) unique reads (U): uniquely aligning the reference genome of the previous species; these reads are referred to as unique reads. That is, if the reference genomes on the reads alignment are from the same species, the reads are defined as unique reads; b) multiple reads (M): aligning reference genomes of more than one species, defined as multiple reads. That is, if the reference genome on which reads align is from at least two species, these reads are defined as multiple reads.
(2) Abundance comparisons to determine whether an individual has schizophrenia.
According to one embodiment of the invention, the abundance obtained in step (1) is compared to a predetermined threshold value in order to determine whether the individual has schizophrenia.
According to some embodiments of the invention, the threshold is predetermined, and comprises an abundance with schizophrenia threshold and an abundance without schizophrenia threshold. And comparing the abundance of the marker microorganisms in the sample of the individual to be tested with the threshold value to determine the state of the individual to be tested. The threshold may be a value or range of values, for example, based on a mean value of the abundance of a marker microorganism in an individual with a known disease or health state, the corresponding threshold for that microorganism may be set to a 95% Confidence interval (Confidence interval) of the mean value of the abundance.
The confidence interval refers to an estimation interval of the overall parameter constructed by the sample statistic. In statistics, the confidence interval for a probability sample is an interval estimate for some overall parameter of the sample. The confidence interval exhibits the extent to which the true value of this parameter has a certain probability of falling around the measurement. The confidence interval indicates the degree of plausibility of the measured value of the measured parameter, i.e. the "certain probability" required above, which is referred to as the confidence level.
According to some embodiments of the invention, the individual is determined to have schizophrenia when the abundance of the marker microorganism determined in step (1) reaches the abundance threshold for schizophrenia and does not reach the abundance threshold for schizophrenia, and the individual is determined not to have schizophrenia when the abundance of the marker microorganism determined in step (1) reaches the abundance threshold for schizophrenia and does not reach the abundance threshold for schizophrenia.
It is to be noted that, depending on the purpose or requirement, there may be different requirements on the confidence level of the result of determining the state of an individual, and that a person skilled in the art may select different significance levels or thresholds.
The method is based on detecting the abundance of various strains in the marked microorganisms in the fecal sample of the individual, respectively comparing the detected abundance of various strains with the threshold value thereof, and determining the probability that the individual is a schizophrenia individual or a healthy individual according to the obtained comparison result. Provides a non-invasive auxiliary detection or auxiliary intervention treatment method for the early detection of schizophrenia.
All or a part of the steps of the method for determining whether an individual has schizophrenia using the marker microorganism in any of the above embodiments may be performed using an apparatus/system including detachable functional modules of the respective units, or may be implemented by programming the method, storing the method in a machine-readable medium, and operating the readable medium by a machine.
According to the present invention there is provided an apparatus for determining whether an individual has schizophrenia, the apparatus comprising: an abundance determination unit for determining the abundance of marker microorganisms in a stool sample of the individual; a comparison unit for comparing the obtained abundance with a predetermined threshold value in order to determine whether the individual suffers from schizophrenia; wherein the first microbial collection consists of the following species: eubacterium (Eubacterium sp.) CAG:115, Eubacterium (Eubacterium sp.) CAG:252, Mycobacteria (fungi bacterium) CAG:227, Pseudomonas agaricus (Pseudomonas agaricii); the second microbial set consists of the following species: actinomycetes (Actinomyces sp.) oral taxon 180, Exmanella vulgaris (Akkermansia muciniphila) CAG 154, Exmanella vulgaris (Akkermansia sp.) UNK.MGS-1, Alloscardia omnicola, Bacillus subtilis, Cryptobacterium currum, Demanococcus sedentarius, and Cryptobacterium pyogenes. The above description of the technical features and advantages of the method for determining whether an individual has schizophrenia using marker microorganisms according to any of the embodiments of the present invention is equally applicable to the device according to this aspect of the present invention, and will not be described herein again.
According to an embodiment of the invention, the abundance determination unit is adapted to determine the abundance by: obtaining nucleic acid sequencing data in a stool sample of the individual; aligning the sequencing data to a reference genome; determining the abundance of the marker microorganism based on the results of the alignment.
The alignment can be performed by using known alignment software, such as SOAP, BWA, TeraMap, etc., in the alignment process, the alignment parameters are generally set, one or a pair of reads (reads) is set to allow at most s base mismatches (mismatches), for example, s is set to be less than or equal to 2, and if more than s bases in the reads are mismatched, it is considered that the reads cannot be aligned (aligned) to the assembled fragment. The obtained comparison result comprises comparison conditions of each read and the reference genome of each species, and comprises information of whether the read can be compared with the reference genome of a certain or some species, only one species or multiple species, the position of the reference genome of the species, the unique position or multiple positions of the reference genome of the species, and the like. According to one embodiment of the invention, alignment is performed using SOAPalign 2.21 with the setting parameter-r 2-m 100-x 1000.
The reference genome of the microorganism refers to a predetermined sequence of the species of the microorganism, and may be any reference template of a biological category to which a sample to be tested belongs or contains, which is obtained in advance, for example, the target is the microorganism in the sample to be tested, the reference sequence may be a reference genome of various microorganisms in an NCBI database and/or a DACC intestinal genome disclosed in HMP and MetaHIT projects, and further, a resource library containing more reference sequences may be configured in advance, for example, a more similar sequence is selected or determined to be assembled as the reference sequence according to factors such as the state of an individual from which the sample to be tested is derived, a region, and the like. According to one embodiment of the invention, the reference genomes of the various microorganisms are obtained from public databases, typically, multiple versions of a reference genome of a microorganism, i.e., multiple public reference genomes for a microorganism.
reads are aligned to the reference genome of the species, which can be divided into two parts: a) unique reads (U): uniquely aligning the genome of the previous species; these reads are referred to as unique reads. That is, if the reference genomes on the reads alignments are from the same species, the reads are defined as unique reads. b) Multiple reads (M): aligning reference genomes of more than one species, defined as multiple reads. That is, if the reference genome on which reads align is from at least two species, these reads are defined as multiple reads.
According to one embodiment of the invention, the abundance of the marker microorganism is determined according to the following formula: ab(s) ═ Ab (U) S )+Ab(M S ) Wherein S represents the number of the marker microorganism, Ab (S) represents the abundance of S of the marker microorganism, Ab (U) S )＝U S /l S ，U S Number of reads, l, uniquely aligned to the reference genome of the marker microorganism S in the sequencing data S Is the total length of the reference genome of the marker microorganism S,
M S for the number of reads in the sequencing data that are non-uniquely aligned to the reference genome of the marker microorganism S, i represents the number of the non-uniquely aligned reads, Co i The abundance coefficient corresponding to the ith read,
Co i,s representing the abundance coefficient of the non-uniquely aligned reads i for the marker microorganism S, N being the total number of microorganisms that the non-uniquely aligned reads i can align to, j representing the number of microorganisms that the non-uniquely aligned reads i can align to. The above description of the technical features and advantages of the method for determining whether an individual has schizophrenia using marker microorganisms according to any of the embodiments of the present invention is equally applicable to the device according to this aspect of the present invention, and will not be described herein again.
According to yet another embodiment of the present invention, there is provided an apparatus comprising: a computer-readable storage medium having stored thereon a computer program for performing one of the foregoing methods of determining whether an individual has schizophrenia; and one or more processors for executing the program in the computer-readable storage medium.
According to still another embodiment of the present invention, there is provided a method of screening a drug for treating or preventing schizophrenia, the method including: administering a candidate drug to a subject, and measuring the abundance of a marker microorganism in the subject's stool before and after administration, the marker microorganism comprising at least one species of a first set of microorganisms and a second set of microorganisms, wherein a candidate drug that satisfies at least one of the following conditions is suitable for use in treating or preventing schizophrenia: (1) said abundance of at least one species in said first collection of microorganisms is increased following said administering; and (2) said abundance of at least one species in said second set of microorganisms is reduced after said administering; wherein the first microbial collection consists of the following species: eubacterium (Eubacterium sp.) CAG:115, Eubacterium (Eubacterium sp.) CAG:252, Mycobacteria (fungi bacterium) CAG:227, Pseudomonas agaricus (Pseudomonas agaricii); the second microbial set consists of the following species: actinomycetes (Actinomyces sp.) oral taxon 180, Achromobacter (Akkermansia muciniphila) CAG 154, Achromobacter (Akkermansia sp.) UNK.MGS-1, Alloscardovia omnigenes, Bacillus vallisportis, Cryptobacterium curtum, Deuterococcus sedentarius, Cryptobacterium pyogenes.
By utilizing the method for producing or screening the medicament for treating the schizophrenia, the medicament which can support the growth of beneficial bacteria in the intestinal tract and/or inhibit potential pathogenic bacteria in the intestinal tract can be obtained by reasonably and effectively applying the determined schizophrenia biomarker for screening, and the method has important significance for assisting in relieving the clinical symptoms of the schizophrenia.
The embodiments will be described in detail below. The reagents, sequences, software and equipment not specifically submitted to the following examples are all conventional commercial products.
Example 1 identification of biomarkers
In this example, the inventors have studied stool samples of 64 schizophrenic patients and 58 healthy controls to obtain the characteristics of the microbial community and functional composition of the intestinal flora. In summary, the inventors downloaded high quality sequencing data of about 334 Gb. Metagenomic analysis showed that 27 microbial species were closely related to schizophrenia disease, of which 6 were enriched in intestinal microbes of healthy people and 21 were enriched in intestinal microbes of schizophrenic patients.
1. Obtaining sequencing data:
samples of schizophrenia and healthy persons were obtained from the first subsidiary hospital of Chongqing medical university and a total of 64 samples of Chinese schizophrenia and 58 samples of healthy persons were collected in the experiment, wherein each individual fresh stool sample was divided into 200 mg/portion and 5 portions, and immediately stored in a refrigerator at-80 ℃.
Total DNA was extracted from all stool samples. DNA is extracted by a method of extracting DNA by phenol trichloromethane treatment.
2. Library construction and sequencing, and reference data download
DNA pooling was performed according to the instructions of the instrument manufacturer (Illumina). The library was sequenced at PE150 bp. The Illumina HiSeq2000 (Illumina, San Diego, CA) platform sequenced a library of 122 samples. Each sample yielded on average 11.21Gb (sd. + -2.1 Gb) high quality sequencing results, totaling 1368Gb sequencing data volume.
The relevant biomarkers of schizophrenia are identified with reference to the experimental procedure shown in fig. 1, wherein the omitted steps or details are well known to those skilled in the art and several important steps are described below.
3. Microbial species abundance analysis
3.1 sequence optimization statistics
1) Firstly, performing first-stage sequencing, collecting data of 122 samples in the current-stage sequencing, filtering the data after obtaining the sequencing data of the 122 samples in the first stage, and performing quality control according to the following standards: a) removing reads greater than 5N bases; b) (ii) removing reads greater than 50% of the low quality base (Q20); c) the tail low mass (Q20) and N bases were removed. Missing pairs of reads sequences are considered a single read for assembly.
2) And (3) processing the downloaded data of the healthy people by adopting the method 1).
2.2 species abundance analysis
SOAPalign 2.21 was used to match paired-end clean reads against redundant genomes, here called redundant genomes from reference genomes of bacteria disclosed in each database, with alignment parameters-r 2-m 200-x 1000. The comparison between Reads and redundant genomes can be divided into two parts: a) unique reads (U): reads align the genomes of only the previous species; these reads are defined as unique reads. That is, if the genomes are from the same species, the inventors define these reads as unique reads. b) Multiple reads (M): multiplex reads are defined if they align the genomes of two or more species. That is, if the aligned genomes are from different species, the inventors define these reads as multiple reads.
For species S, the abundance is ab (S), related to the characteristic U reads and shared M reads, and is calculated as follows:
Ab(S)＝Ab(U S )+Ab(M S )，
wherein S represents the number of the marker microorganism,
ab (S) represents the abundance of the marker microorganism S,
Ab(U S )＝U S /l S ，
U S the number of reads in the sequencing data that are uniquely aligned with the reference genome of the marker microorganism S,
l S is the total length of the reference genome of the marker microorganism S,
M S is the number of reads in the sequencing data that are non-uniquely aligned to the reference genome of the marker microorganism S,
Co i the corresponding abundance coefficient for the ith read,
i represents the number of the non-unique alignment reads,
Co i,s means that with respect to the marker microorganism S,
abundance coefficients of the non-uniquely aligned reads i,
n is the total number of microorganisms that the non-uniquely aligned reads i are capable of aligning,
j represents the number of microorganisms that the non-uniquely aligned reads i are capable of aligning.
And (4) obtaining a normalized species abundance table after all dividing the species abundance value obtained by calculation in each sample by the total abundance of each sample.
3.3 screening microbial species markers
In order to obtain intestinal microbial species markers closely related to schizophrenia diseases, the inventors conducted a disease-related study at the species level using the abundance data of intestinal microbial species in the two groups of schizophrenic patients (SCZ) group (64 cases) and healthy people (HC) group (58 cases). Based on the abundance of species table obtained in step 3.2, the inventors set criteria as follows: (1) the median abundance of species in schizophrenic patient groups or healthy human groups must be greater than 0; (2) the differential p-value for each species and schizophrenia disease was obtained by Wilcoxon rank sum test combined with multiple tests of Benjamini Hochberg; (3) screening was performed using the above parameters using a strict threshold p _ values < 0.01. The inventors obtained 27 intestinal microbial species closely related to schizophrenia diseases, wherein 21 species of the microbes are enriched in intestinal tracts of patients with schizophrenia, and 6 species of the microbes are enriched in healthy people, and the 27 microbial species markers are shown in table 1.
Table 1:
example 2 validation of microbial species markers
To verify the findings in example 1, the inventors further analyzed the abundance of the 27 genera in the stool samples of 23 healthy persons and 26 schizophrenic patients in the validation population, and selected the 27 microbial species markers based on the enrichment of each species in the healthy and disease groups, and the DNA extraction, sequencing and species abundance analyses of the validation population were performed with reference to example 1.
The verification results are as follows: the above 6 species enriched in healthy population, 4 in the validation set resulted in high quality validation (P values <0.01), and the mean and P value results of the validation of the microorganism species markers enriched in healthy population are shown in table 2.
Table 2:
for the 21 species enriched in schizophrenic patients described above, 8 of which were high quality validated in the validation set (p-value <0.01), the p-value and q-value cases validated for 2 microbial markers enriched in schizophrenic patients in the validation set data are shown in table 3.
Inhibition of the production of norepinephrine and epinephrine by certain bacillus metabolites may have a significant effect on the sympathetic nervous system and adrenal secretion neurotransmitters and this change appears to be a major factor in schizophrenia. Cryptococcus pyogenes (Trueperella pyogenes) is an important opportunistic pathogen.
Table 3:
the inventor believes that 4 microbial species markers enriched from healthy people can be used as a reverse index of schizophrenia disease development, or as a microbial preparation medicinal flora component for treating schizophrenia, or as a recovery index for detecting schizophrenia and monitoring the treatment progress of schizophrenia; the 8 microorganism species markers enriched in the schizophrenia patients are used as positive indicators of the schizophrenia disease, and are particularly used for non-invasive detection and diagnosis of the schizophrenia disease.
The inventor utilizes the 12 microbial species markers to construct a comprehensive index, estimates the area AUC under the ROC (Receiver-operating characteristic) curve, and evaluates the comprehensive score corresponding to the diagnosis capability of schizophrenia, wherein the higher the AUC is, the higher the diagnosis capability is. By evaluating 122 samples in the first stage (the first stage) and 49 samples in the second stage (the second stage), as shown in fig. 2, the samples showed good diagnostic ability, and the AUC obtained in the first stage was 91.1%, as shown in fig. 2-a, and the confidence interval was 86.2% -96%; AUC obtained in stage ii was 88.6%, as shown in fig. 2-B, with a confidence interval of 74.9% to 97.8%.
Example 3 detection of Individual State
In this example, the inventors performed the examination of the individual status of the sample source using 60 stool samples.
The abundances of actinomycetes (Actinomyces sp.) orataxon 180, Exophiala (Akkermansia muciniphila) CAG:154, Alloscardovia omnigenes, Bacillus (Bacillus vallisportis), Cryptobacterium currum, Exophiala sedentarius, and Cryptobacterium pyogenes (Trueperella pyogenes) shown in Table 3 in each fecal sample were determined by referring to the method of example 2, whether the abundances of these 7 strains in each sample fall within the confidence interval of 95% of the abundance of each of the disease control group or the healthy control group was determined, the status of the individual corresponding to the sample in which the abundance of these 7 strains all fall within the corresponding interval of the disease group was determined as a schizophrenia patient, and the status of the individual corresponding to the sample in which the abundance of 7 strains all fall within the corresponding interval of the healthy group was determined as a non-schizophrenia patient.
The result shows that the method of the embodiment can be used for judging the individual state of 56 samples, and the judgment of the individual state corresponding to 50 samples in the 56 samples is consistent with the recorded state of the individual from which the sample is derived.
In addition, the inventors have found that the combined detection of the species in table 2 and table 3, for example, the detection of the enrichment of the species markers in table 3, while the detection of the non-enriched species markers in table 2, can more accurately determine and find the patients with schizophrenia or the susceptible people.
In the scheme of treating schizophrenia by using the markers, the inventors found that the growth of the species markers in the formula 3 is inhibited or eliminated, and the species markers in the formula 2 are enriched, so that the treatment effect is excellent.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (13)
1. A kit comprising reagents suitable for detecting at least one species in a first collection of microorganisms consisting of: eubacterium (Eubacterium sp.) CAG:115, Eubacterium (Eubacterium sp.) CAG:252, Mycobacteria (Firmicutes bacterium) CAG:227, Pseudomonas agaricus (Pseudomonas agaricii).
2. The kit of claim 1, further comprising reagents suitable for detecting at least one species in a second collection of microorganisms consisting of: actinomycetes (Actinomyces sp.) oral taxon 180, Exmanella vulgaris (Akkermansia muciniphila) CAG 154, Exmanella vulgaris (Akkermansia sp.) UNK.MGS-1, Alloscardia omnicola, Bacillus subtilis, Cryptobacterium currum, Demanococcus sedentarius, and Cryptobacterium pyogenes.
3. The kit of claim 1, comprising reagents suitable for detecting all of said species in said first collection of microorganisms.
4. The kit of claim 2, comprising reagents suitable for detecting all of said species in said second collection of microorganisms.
5. Use of an agent suitable for detecting at least one species in a first microbiome set for diagnosing schizophrenia or for detecting the therapeutic effect of schizophrenia in the preparation of a kit, said first microbiome set consisting of the following species: eubacterium (Eubacterium sp.) CAG:115, Eubacterium (Eubacterium sp.) CAG:252, Mycobacteria (Firmicutes bacterium) CAG:227, Pseudomonas agaricus (Pseudomonas agaricii).
6. Use according to claim 5, characterized in that said reagent is further suitable for detecting at least one species of a second group of microorganisms consisting of: actinomycetes (Actinomyces sp.) oral taxon 180, Exmanella vulgaris (Akkermansia muciniphila) CAG 154, Exmanella vulgaris (Akkermansia sp.) UNK.MGS-1, Alloscardia omnicola, Bacillus subtilis, Cryptobacterium currum, Demanococcus sedentarius, and Cryptobacterium pyogenes.
7. A pharmaceutical or food composition for the prevention or treatment of schizophrenia, comprising at least one species of a first microbiome consisting of: eubacterium (Eubacterium sp.) CAG:115, Eubacterium (Eubacterium sp.) CAG:252, Mycobacteria (Firmicutes bacterium) CAG:227, Pseudomonas agaricus (Pseudomonas agaricii).
8. A method of determining whether an individual has schizophrenia, comprising:
(1) determining an abundance of a marker microorganism in a fecal sample of the individual, the marker microorganism comprising at least one species of the first set of microorganisms and the second set of microorganisms;
(2) comparing the abundance obtained in step (1) with a predetermined threshold value to determine whether the individual has schizophrenia;
wherein the first microbial collection consists of the following species: eubacterium (Eubacterium sp.) CAG:115, Eubacterium (Eubacterium sp.) CAG:252, Mycobacteria (fungi bacterium) CAG:227, Pseudomonas agaricus (Pseudomonas agaricii); (Subdoligranum _ variabilie), Veillonella dispar (Veillonella _ dispar) and Salmonella lavandustria (Sutterella _ wadsworthensis);
the second microbial set consists of the following species: actinomycetes (Actinomyces sp.) oral taxon 180, Exmanella vulgaris (Akkermansia muciniphila) CAG 154, Exmanella vulgaris (Akkermansia sp.) UNK.MGS-1, Alloscardia omnicola, Bacillus subtilis, Cryptobacterium currum, Demanococcus sedentarius, and Cryptobacterium pyogenes.
9. The method of claim 8, wherein step (1) further comprises:
obtaining nucleic acid sequencing data in a stool sample of the individual;
aligning the sequencing data to a reference genome;
determining the abundance of the marker microorganism based on the results of the alignment.
10. An apparatus for determining whether an individual has schizophrenia, comprising:
an abundance determination unit for determining an abundance of a marker microorganism in a fecal sample of the individual, the marker microorganism comprising at least one species of the first set of microorganisms and the second set of microorganisms;
a comparison unit for comparing the obtained abundance with a predetermined threshold value in order to determine whether the individual suffers from schizophrenia;
wherein the first microbial collection consists of the following species: eubacterium (Eubacterium sp.) CAG:115, Eubacterium (Eubacterium sp.) CAG:252, Mycobacteria (fungi bacterium) CAG:227, Pseudomonas agaricus (Pseudomonas agaricii);
the second microbial set consists of the following species: actinomycetes (Actinomyces sp.) oral taxon 180, Achromobacter (Akkermansia muciniphila) CAG 154, Achromobacter (Akkermansia sp.) UNK.MGS-1, Alloscardovia omnigenes, Bacillus vallisportis, Cryptobacterium curtum, Deuterococcus sedentarius, Cryptobacterium pyogenes.
11. The apparatus of claim 10, wherein the abundance determination unit is adapted to determine the abundance by:
obtaining nucleic acid sequencing data in a stool sample of the individual;
aligning the sequencing data to a reference genome;
determining the abundance of the marker microorganism based on the results of the alignment.
12. An apparatus, comprising:
a computer-readable storage medium having stored thereon a computer program for executing the method of claim 8 or 9;
and one or more processors for executing the program in the computer-readable storage medium.
13. A method of screening for a drug for treating or preventing schizophrenia, the method comprising:
administering a candidate drug to the subject,
detecting an abundance of a marker microorganism in the subject's stool, the marker microorganism comprising at least one species of the first set of microorganisms and the second set of microorganisms, before and after administration,
wherein a drug candidate satisfying at least one of the following conditions is suitable for use in the treatment or prevention of schizophrenia:
(1) said abundance of at least one species in said first collection of microorganisms is increased following said administering; and
(2) said abundance of at least one species in said second collection of microorganisms is reduced after said administering;
wherein the first microbial collection consists of the following species: eubacterium (Eubacterium sp.) CAG:115, Eubacterium (Eubacterium sp.) CAG:252, Mycobacteria (fungi bacterium) CAG:227, Pseudomonas agaricus (Pseudomonas agaricii);
the second microbial set consists of the following species: actinomycetes (Actinomyces sp.) oral taxon 180, Exmanella vulgaris (Akkermansia muciniphila) CAG 154, Exmanella vulgaris (Akkermansia sp.) UNK.MGS-1, Alloscardia omnicola, Bacillus subtilis, Cryptobacterium currum, Demanococcus sedentarius, and Cryptobacterium pyogenes.
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| CN110241205A (en) * | 2019-06-06 | 2019-09-17 | 西安交通大学医学院第一附属医院 | A kind of schizophrenia biomarker combinations and its application and screening based on intestinal flora |
| CN111020020A (en) * | 2019-07-05 | 2020-04-17 | 深圳华大生命科学研究院 | Biomarker combination for schizophrenia, application thereof and metaplan 2 screening method |
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| CN105407728A (en) * | 2013-07-21 | 2016-03-16 | 霍勒拜欧姆公司 | Methods and systems for microbiome characterization, monitoring and treatment |
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