CN114622022A - Method and device for detecting expression abundance of Alzheimer's disease intestinal flora marker - Google Patents
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Abstract
The invention provides a method and a device for detecting expression abundance of an Alzheimer's disease intestinal flora marker, wherein the method comprises the following steps: (1) designing a specific primer according to the Alzheimer's disease intestinal flora marker, and carrying out PCR amplification by using DNA of a sample to be detected as a template to obtain a PCR amplification product; (2) constructing a library from the PCR amplification product and performing high-throughput sequencing, performing quality control and OTU clustering on obtained sequencing data, and calculating the relative abundance of an OTU sequence; (3) and comparing the OTU sequence with the 16S rRNA reference genome to determine the genus type of the OTU sequence and obtain the relative abundance of different genera. The invention detects the marker of the Alzheimer's disease intestinal flora based on high-throughput sequencing, and takes the abundance level of the flora as a detection index, thereby realizing the effect of sensitively, accurately and auxiliarily judging the Alzheimer's disease.
Description
Technical Field
The invention belongs to the technical field of biology, and relates to a method and a device for detecting expression abundance of an Alzheimer's disease intestinal flora marker.
Background
Alzheimer's Disease (AD), also known as senile dementia, is a progressive degenerative disease of the central nervous system that occurs in the elderly, characterized by progressive memory impairment, cognitive decline and loss of daily living ability, accompanied by neuropsychiatric symptoms such as personality changes, which severely affects social and living abilities. Because the pathogenesis of the Alzheimer disease is not completely clear and the early symptoms are secret, patients with the Alzheimer disease are easy to miss diagnosis or misdiagnose. Therefore, the method finds the biomarkers with high sensitivity and high accuracy, and has important significance for early diagnosis and drug intervention of the Alzheimer's disease. At present, the diagnosis of AD mainly depends on memory scale, PET, and pathological indicators such as a β, phosphorylated tau in cerebrospinal fluid and blood, but the clinical application of these diagnostic indicators is still controversial, and there is no effective detection basis for early diagnosis of AD.
Recent researches show that the intestinal flora imbalance is related to the occurrence and development of various neuropsychiatric diseases such as Parkinson, depression and autism, and more than 80 percent of AD patients have the intestinal flora imbalance phenomenon, which indicates that the intestinal flora steady state is closely related to the pathogenesis and progress of neurodegenerative diseases. It has been reported that the composition of the intestinal flora of AD patients differs from that of healthy peers, and that elevated levels of bacterial toxins and inflammatory factors can be detected in the blood of AD patients, suggesting that a dysbacteriosis may be associated with the development of immune inflammation, and that immune activation may further lead to central nervous system inflammation through blood circulation. With age, the permeability of the intestinal mucosal barrier increases, so that opportunistic pathogens and metabolites thereof penetrate through the barrier to invade internal tissues and organs, thereby inducing chronic intestinal tract and systemic inflammation.
CN110693917A discloses application of Akkermansia Muciniphila in preparation of antidepressant drugs or health care products, and through the Akkermansia Muciniphila bacterium transplantation on a depressed mouse model, the movement distance of the mouse is improved, the immobility time of a tail suspension experiment and a forced swimming experiment is reduced, the depressed state of the mouse is obviously relieved, and the good antidepressant effect is shown without side effect.
However, there is currently no systematic study on the intestinal flora and the incidence relationship of AD.
Disclosure of Invention
Aiming at the defects and actual requirements of the prior art, the invention provides a method and a device for detecting the expression abundance of an Alzheimer's disease intestinal flora marker, wherein the intestinal flora marker is closely related to the onset of AD, can be used as an AD early diagnosis biomarker to improve the diagnosis accuracy, and has important significance in the aspects of early warning, pathological typing, prediction and development stage and the like of diseases.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the present invention provides an intestinal flora marker for alzheimer's disease comprising any one of Clostridium (Clostridium), Akkermansia (Akkermansia), albobaculum, zurich bacillus (Turicibacter), Devosia, oscillaspira (Oscillospira), odonobacter or Ruminococcus (Ruminococcus) or a combination of at least two thereof.
Preferably, the markers of intestinal flora of alzheimer's disease comprise the genera Clostridium (Clostridium), eckmansia (Akkermansia), albobaculum, zurich (rhizobacter), Devosia, oscillatoria (Oscillospira), odonobacter and Ruminococcus (Ruminococcus).
In a second aspect, the present invention provides a method for detecting the expression abundance of the marker for intestinal flora of alzheimer's disease according to the first aspect, comprising the following steps:
(1) designing a specific primer according to the Alzheimer's disease intestinal flora marker, and carrying out PCR amplification by using DNA of a sample to be detected as a template to obtain a PCR amplification product;
(2) constructing a library from the PCR amplification product and performing high-throughput sequencing, performing quality control and OTU clustering on obtained sequencing data, and calculating the relative abundance of the OTU sequence;
(3) and comparing the OTU sequence with a 16S rRNA reference genome to determine the genus type of the OTU sequence and obtain the relative abundance of different genera.
Preferably, the OTU clusters are clustered according to sequence identity.
Preferably, the sequence identity is greater than 97% to form an OTU.
In a third aspect, the present invention provides a device for detecting the expression abundance of the marker of intestinal flora of alzheimer's disease according to the first aspect, the device comprising:
a PCR amplification unit: the specific primers for the marker of the intestinal flora of Alzheimer's disease are adopted, and the DNA of a sample to be detected is used as a template for PCR amplification;
high throughput sequencing unit: used for carrying out library construction and high-throughput sequencing on the PCR amplification products;
a clustering and abundance calculating unit: the method is used for performing quality control processing and OTU clustering on sequencing data and calculating the relative abundance of an OTU sequence;
a genus determination unit: the genus type of the OTU sequence was determined by aligning the OTU sequence to the 16S rRNA reference genome.
Preferably, the OTU clusters are clustered according to sequence identity.
Preferably, the sequence identity is greater than 97% to form an OTU.
In a fourth aspect, the present invention provides the use of the device of the third aspect for the preparation of a diagnostic reagent and/or a diagnostic medical device for alzheimer's disease.
In a fifth aspect, the present invention provides the use of the device of the third aspect for screening for a therapeutic and/or prophylactic agent for alzheimer's disease.
Compared with the prior art, the invention has the following beneficial effects:
(1) the method and the device for detecting the marker of the intestinal flora of Alzheimer's disease realize the effects of strain identification, abundance detection, strain diversity analysis and the like on the basis of high-throughput sequencing and bioinformatics analysis;
(2) the Alzheimer's disease intestinal flora marker is closely related to AD morbidity, the abundance level of the Alzheimer's disease intestinal flora marker is used as a detection index, the Alzheimer's disease intestinal flora marker is used for auxiliary judgment of symptoms of Alzheimer's disease, and the Alzheimer's disease intestinal flora marker has the characteristics of high detection accuracy, convenience, rapidness, safety and no wound, and has important clinical guiding significance for auxiliary diagnosis of AD related indexes.
Drawings
Fig. 1A is an ACE index of alpha diversity of AD mice and WT control group, fig. 1B is a Chao1 index of alpha diversity of AD mice and WT control group, and fig. 1C is OTU classification of AD mice and WT control group;
fig. 2A is Clostridium (Clostridium) genus with abundance difference between AD mouse and WT control group, fig. 2B is Akkermansia (Akkermansia) genus with abundance difference between AD mouse and WT control group, fig. 2C is albobacillus genus with abundance difference between AD mouse and WT control group, fig. 2D is periwinia (tulicibacter) genus with abundance difference between AD mouse and WT control group, fig. 2E is Devosia genus with abundance difference between AD mouse and WT control group, fig. 2F is rhodospirillum (Oscillospira) genus with abundance difference between AD mouse and WT control group, fig. 2G is edobacter genus with abundance difference between AD mouse and WT control group, fig. 2H is Ruminococcus genus with abundance difference between AD mouse and WT control group.
Detailed Description
To further illustrate the technical means adopted by the present invention and the effects thereof, the present invention is further described below with reference to the embodiments and the accompanying drawings. It is to be understood that the specific embodiments described herein are merely illustrative of the invention and are not limiting of the invention.
The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications. The reagents or apparatus used are conventional products commercially available from normal sources, not indicated by the manufacturer.
Example 1
In this embodiment, an Illuminate MiSeq sequencing platform is used for detecting the relative expression abundance difference of the intestinal flora in a disease sample and a health sample, and an alzheimer intestinal flora marker is screened, and the steps are as follows:
collecting excrement samples of patients with Alzheimer's disease and normal healthy volunteers, and extracting total DNA by using a nucleic acid separation kit; designing primers according to 16S rRNA V3-V4 region genes of a flora, adding an Illumina sequencing joint, and performing PCR amplification by taking extracted DNA as a template;
constructing a sequencing library from the amplified product, carrying out Illumina sequencing after quality inspection is qualified to obtain an original image data file, analyzing and converting the original image data file into original sequencing read length (Sequenced Reads) through Base identification (Base Calling), and splicing the sequencing read length of each sample through overlay by using FLASH v1.2.7 software to obtain original data (Raw Reads); then filtering Raw reads by using Trimmomatic v0.33 software to obtain high-quality data, and identifying and removing a chimera sequence by using UCHIME v4.2 software;
according to the similarity level of high-quality sequencing data, performing OTU division on all sequences, clustering the sequences with the sequence consistency of more than 97 percent into an OTU, and estimating the relative abundance of the OTU; selecting the most abundant sequence as a representative sequence of each OTU by using QIIME and UCLUST, classifying each OTU according to a SILVA 16S rRNA gene reference alignment database, assigning a taxonomic identifier to each OTU, classifying the abundance of classification units of each sample according to phyla, class, order, family and genus, analyzing the abundance difference (p <0.05) of different groups of genera by using LEfSe, and performing alpha diversity analysis and beta diversity analysis.
Example 2
Stool samples from 9-month-old AD model mice (FTG) and WT wild-type control group (FWT) were analyzed for abundance and diversity of intestinal flora according to the method of example 1.
As shown in fig. 1A, 1B, 1C and table 1, the α diversity analysis results showed a significant difference in the flora diversity of WT and AD mice.
TABLE 1 analysis of alpha diversity in AD mice and WT control groups
| ACE(p value) | Chao1(p value) | OTU(p value) | |
| WT and APP/PS1 | 0.02022* | 0.044696* | 0.043153* |
This example further performed differential analysis of the flora abundances, and as a result, as shown in fig. 2A, fig. 2B, fig. 2C, fig. 2D, fig. 2E, fig. 2F, fig. 2G, fig. 2H, it was found that the relative abundances of Clostridium (Clostridium), Akkermansia (Akkermansia), Allobaculum, zurich (Turicibacter), and Devosia in AD mice were significantly increased compared to the WT wild-type control group, while the relative abundances of dithianum (Oscillospira), edobacter, and Ruminococcus (Ruminococcus) in AD mice were significantly decreased compared to the wild-type control group.
In conclusion, the intestinal flora markers closely related to the onset of AD, namely Clostridium (Clostridium), Akkermansia (Akkermansia), albobaculum, zurich (Turicibacter), Devosia, Oscillatoria (Oscillospira), Odoribacter and Ruminococcus (Ruminococcus) are screened based on high-throughput sequencing and bioinformatics analysis, and have important clinical guidance significance for auxiliary diagnosis of AD-related indexes.
The applicant states that the present invention is illustrated in detail by the above examples, but the present invention is not limited to the above detailed methods, i.e. it is not meant that the present invention must rely on the above detailed methods for its implementation. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
Claims (10)
1. A method for detecting the expression abundance of an Alzheimer's disease intestinal flora marker, which comprises the following steps:
(1) designing a specific primer according to the Alzheimer's disease intestinal flora marker, and carrying out PCR amplification by using DNA of a sample to be detected as a template to obtain a PCR amplification product;
(2) constructing a library from the PCR amplification product and performing high-throughput sequencing, performing quality control and OTU clustering on obtained sequencing data, and calculating the relative abundance of an OTU sequence;
(3) and comparing the OTU sequence with the 16S rRNA reference genome to determine the genus type of the OTU sequence and obtain the relative abundance of different genera.
2. The method of claim 1, wherein the markers of intestinal flora of alzheimer's disease comprise any one of Clostridium (Clostridium), Akkermansia (Akkermansia), albobaculum, zurich bacillus (Turicibacter), Devosia, oscillatoria (Oscillospira), odonibacter or Ruminococcus (Ruminococcus) or a combination of at least two thereof;
preferably, the markers of intestinal flora of alzheimer's disease comprise the genera Clostridium (Clostridium), eckmansia (Akkermansia), albobaculum, zurich (rhizobacter), Devosia, oscillatoria (Oscillospira), odonobacter and Ruminococcus (Ruminococcus).
3. The method according to claim 1 or 2, wherein the OTU clusters are clustered according to sequence identity.
4. The method of claim 3, wherein the sequence identity is greater than 97% to form an OTU.
5. A device for detecting the expression abundance of an Alzheimer's disease intestinal flora marker, which is characterized by comprising:
a PCR amplification unit: the specific primers for the marker of the intestinal flora of Alzheimer's disease are adopted, and the DNA of a sample to be detected is used as a template for PCR amplification;
high throughput sequencing unit: the PCR amplification product library is used for library construction and high-throughput sequencing;
a clustering and abundance calculating unit: the method is used for performing quality control processing and OTU clustering on sequencing data and calculating the relative abundance of an OTU sequence;
a genus determination unit: the genus type of the OTU sequence was determined by aligning the OTU sequence to the 16S rRNA reference genome.
6. The device of claim 5, wherein the markers of intestinal flora of Alzheimer's disease comprise any one of or a combination of at least two of Clostridium (Clostridium), Akkermansia (Akkermansia), Allobaculum, Rhizoctonia (Turciobacter), Devosia, Oscillatoria (Oscillopira), Odoribacter, or Ruminococcus (Ruminococcus);
preferably, the markers of intestinal flora of alzheimer's disease comprise the genera Clostridium (Clostridium), eckmansia (Akkermansia), albobaculum, zurich (rhizobacter), Devosia, oscillatoria (Oscillospira), odonobacter and Ruminococcus (Ruminococcus).
7. The apparatus according to claim 5 or 6, wherein the OTU clusters are clustered according to sequence identity.
8. The apparatus of claim 7, wherein the sequence identity is greater than 97% forming an OTU.
9. Use of the device according to any one of claims 5-8 for the manufacture of a diagnostic reagent and/or a diagnostic medical device for alzheimer's disease.
10. Use of the device of any one of claims 5-8 for screening for a drug for treating and/or preventing alzheimer's disease.
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