CN118028445A - Alzheimer disease biomarker based on intestinal flora and application thereof - Google Patents
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Abstract
The invention discloses an Alzheimer disease biomarker based on intestinal flora and application thereof. The Alzheimer disease biomarker is intestinal microorganisms, wherein the intestinal microorganisms comprise any one or at least two of Flavobacteriaceae, majorandaceae, deiron-rod bacteriaceae, olfactory bacillaceae or Vibrionaceae. The invention discovers that the flavobacteriaceae, the trichosporoceae, the deironized bacillus, the olfactory bacillaceae and the desulphurized vibriosaceae in the intestinal flora are related to the Alzheimer disease for the first time, the relative abundance of the flavobacteriaceae, the trichosporoaceae, the deironized bacillaceae, the olfactory bacillaceae and the desulphurized vibriosae are obviously different between healthy individuals and AD individuals, the method can be used for the symptom auxiliary judgment of the Alzheimer disease, has the characteristics of high detection accuracy, convenience, rapidness, safety and noninvasive property, and has important clinical guidance significance for auxiliary diagnosis and early warning of the AD.
Description
Technical Field
The invention belongs to the technical field of biology, and relates to an Alzheimer disease biomarker based on intestinal flora and application thereof.
Background
Alzheimer's disease (Alzheimer disease, AD), also known as senile dementia, is a degenerative disease of the central nervous system that occurs in the progressive development of the elderly, characterized by progressive memory impairment and decline in cognitive functioning and loss of daily life, accompanied by neuropsychiatric symptoms such as personality changes, severely affecting social and life functions. Because the pathogenesis of Alzheimer's disease is not completely defined, and the early symptoms are more secret, alzheimer's disease patients are easy to miss or misdiagnose. At present, diagnosis of AD mainly depends on memory scale, PET, and level detection of pathological indexes such as Abeta, phosphorylated tau and the like in cerebrospinal fluid and blood, however, the detection results of the diagnostic indexes in clinic are still in a certain dispute, and effective detection evidence for early symptoms of AD is still lacking.
Finding biomarkers of high sensitivity and high accuracy, which are important for diagnosis and pharmaceutical intervention of Alzheimer's disease, for example, CN106062563A discloses a biomarker and a method for early diagnosis of Alzheimer's disease, wherein the AD biomarker is selected from brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), tumor growth factor beta 1 (TGF-beta 1), vascular Endothelial Growth Factor (VEGF), interleukin 18 (IL-18) and monocyte chemotactic protein-1 (MCP-1), and the expression level of the AD biomarker can be analyzed to assist early diagnosis of AD.
Recent researches show that various neuropsychiatric diseases such as Parkinson's disease, depression, autism and the like are related to intestinal flora imbalance, and more than 80% of AD patients have the phenomenon of intestinal flora imbalance, which suggests that intestinal flora steady state is closely related to the pathogenesis of neurodegenerative diseases such as AD and the like. As CN114657270a discloses an intestinal flora-based biomarker for alzheimer's disease and application thereof, it has been found that Moryella, hydrogenphagostimula, rhodosporidium and takoff are related to alzheimer's disease, the abundance of which shows significant differences in alzheimer's disease and healthy people, ROC curve analysis has higher accuracy, specificity and sensitivity as a detection variable, and Moryella, hydrogenphagostimula, rhodosporidium and takoff can be applied to diagnosis of alzheimer's disease as detection targets.
In summary, although a plurality of alzheimer's disease biomarkers have been disclosed at present, the applicability is limited and the method is not suitable for all potential patients, so in order to further improve the detection rate and detection accuracy of alzheimer's disease, a new alzheimer's disease biomarker needs to be continuously developed to expand the detection index of alzheimer's disease.
Disclosure of Invention
Aiming at the problem that abundant effective biomarkers are needed for early diagnosis and early warning of Alzheimer's disease, the novel Alzheimer's disease biomarker is developed to expand Alzheimer's disease detection indexes and further improve the detection rate and detection accuracy of Alzheimer's disease.
In order to achieve the above purpose, the invention adopts the following technical scheme:
In a first aspect, the invention provides an intestinal flora-based biomarker for alzheimer's disease, which is an intestinal microorganism comprising any one or a combination of at least two of flavobacteriaceae, chaetoceraceae, desferribaceae, olfactory bacidae or vibriosphakoridae.
Based on Illuminate MiSeq sequencing platform, the invention further analyzes intestinal flora of Alzheimer's disease individuals and healthy individuals, discovers that relative abundance levels of Flavobacterium (Flavobacteriaceae), mucor (Lachnospiraceae) and Deiron rod (Deferribacteraceae) in AD mice are obviously increased compared with normal mice, relative abundance levels of olfactory bacterium (Odoribacteraceae) and Vibrionaceae (Desulfovibrionaceae) are obviously reduced compared with healthy mice, and the relative abundance levels are used as detection indexes for auxiliary judgment or early warning of Alzheimer's disease symptoms, and the invention has the characteristics of high detection accuracy, convenience, rapidness, safety and noninvasive, and has important clinical guidance significance for auxiliary diagnosis and early warning of AD.
Preferably, the alzheimer's disease biomarker is derived from a biological sample of a subject, the biological sample comprising stool from the subject.
In a second aspect, the invention provides the use of a substance for detecting an intestinal flora-based biomarker for alzheimer's disease according to the first aspect, for the preparation of a product for diagnosing whether a subject has alzheimer's disease or for predicting the risk of whether a subject has alzheimer's disease.
The invention is based on the development of intestinal flora-based biomarkers for Alzheimer's disease, and the use of substances that detect their relative abundance allows the development of products for diagnosing or predicting the risk of whether a subject has Alzheimer's disease.
In a third aspect, the invention provides a product for diagnosing whether a subject has or is predicted to have risk of alzheimer's disease, the product comprising reagents and/or apparatus for detecting the relative abundance and/or amount of gut flora-based biomarkers of alzheimer's disease according to the first aspect.
The product for diagnosing whether the subject suffers from Alzheimer's disease or predicting whether the subject suffers from Alzheimer's disease or not can effectively characterize Alzheimer's disease samples by taking the relative abundance level as a detection index and assist AD diagnosis and early warning.
In the present invention, the product may be a kit.
In a fourth aspect, the invention provides the use of an intestinal flora-based biomarker for alzheimer's disease according to the first aspect for constructing an early diagnosis model and/or for preparing an early diagnosis device for alzheimer's disease.
In a fifth aspect, the present invention provides an early-stage diagnosis model of alzheimer's disease, wherein the input variables of the early-stage diagnosis model of alzheimer's disease comprise the relative abundance values of the intestinal flora-based biomarkers of the first aspect, and the output variables of the early-stage diagnosis model of alzheimer's disease comprise the fold difference, and the calculation formula of the fold difference is as follows:
The positive judgment criteria for Alzheimer's disease were:
The difference multiple of the flavobacteriaceae is more than or equal to 1.31, the difference multiple of the chaetoviridae is more than or equal to 1.74, the difference multiple of the desferribacteriaceae is more than or equal to 1.65, the difference multiple of the olfactory bacteriaceae is less than or equal to 0.35 or the difference multiple of the desulfurated vibriaceae is less than or equal to 0.63.
According to the invention, through fully comparing and analyzing the relative abundance of the flora in the normal fecal sample and the AD fecal sample and carrying out rational design, an early diagnosis model of the Alzheimer's disease is constructed, the model takes the relative abundance value as an input variable and the difference multiple as an output variable, so that a result can be rapidly output, and the samples with abnormal intestinal flora can be fully represented, thereby assisting the early diagnosis of the Alzheimer's disease.
In a sixth aspect, the present invention provides an early diagnosis device for Alzheimer's disease, the device comprising the following units:
an analysis unit for performing operations comprising:
Detecting the relative abundance value of the intestinal flora-based alzheimer's disease biomarker according to the first aspect in a test sample of a subject;
An evaluation unit for performing operations comprising:
inputting the relative abundance value of the Alzheimer's disease biomarker detected by the analysis unit into the Alzheimer's disease early diagnosis model in the fifth aspect for calculation, outputting the difference multiple, and judging whether the Alzheimer's disease biomarker is positive.
In the early diagnosis device for the Alzheimer's disease, the units are effectively matched, the device is simple and efficient, sample processing, detection and difference multiple obtaining can be rapidly completed, and meanwhile, positive evaluation of the Alzheimer's disease is carried out by reasonably designed judgment standards, so that the device has important significance for early diagnosis of the Alzheimer's disease.
Preferably, the sample to be tested comprises a fecal sample.
In a seventh aspect, the present invention provides the use of the intestinal flora-based alzheimer's disease biomarker as described in the first aspect as a target in the screening of a medicament for preventing or treating alzheimer's disease.
The biomarker related to the Alzheimer's disease discovered by the invention is used as a target point, and can be used for screening medicines for preventing or treating the Alzheimer's disease, wherein the screening can comprise the step of determining whether the candidate medicine can be used for preventing or treating the Alzheimer's disease based on the influence of the candidate medicine on the Alzheimer's disease biomarker before and after the use.
Compared with the prior art, the invention has the following beneficial effects:
The invention discovers that the flavobacteriaceae, the trichosporoceae, the deironized corynebacteriaceae, the olfactory bacteriaceae and the desulphurized vibraceae in the intestinal flora are related to the Alzheimer disease for the first time, the relative abundance of the flavobacteriaceae, the trichosporobacteriaceae, the olfactory bacteriaceae and the desulphurized vibriaceae are obviously different in healthy individuals and AD individuals, and the relative abundance is used for the symptom auxiliary judgment of the Alzheimer disease, and has the characteristics of high detection accuracy, convenience, rapidness, safety and noninvasive property, and has important clinical guidance significance for auxiliary diagnosis and early warning of the AD.
Drawings
FIG. 1 is a graph of intestinal flora diversity results for AD mice and wild-type mice (WT);
FIG. 2 is a graph of results of relative abundance of Flavobacteriaceae in AD mice and wild-type mice (WT);
FIG. 3 is a graph of results of the relative abundance of the chaetomiaceae family for AD mice and wild-type mice (WT);
FIG. 4 is a graph of the relative abundance results of the desferribacteriaceae for AD mice and wild-type mice (WT);
FIG. 5 is a graph of the olfactory bacitracin relative abundance results for AD mice and wild-type mice (WT);
FIG. 6 is a graph showing the results of the relative abundance of Vibrionaceae in AD mice and wild-type mice (WT).
Detailed Description
The technical means adopted by the invention and the effects thereof are further described below with reference to the examples and the attached drawings. It is to be understood that the specific embodiments described herein are merely illustrative of the invention and are not limiting thereof.
The specific techniques or conditions are not identified in the examples and are described in the literature in this field or are carried out in accordance with the product specifications. The reagents or apparatus used were conventional products commercially available through regular channels, with no manufacturer noted.
The terms used in the present invention have meanings commonly understood by those of ordinary skill in the relevant art. However, for a better understanding of the present invention, some definitions and related terms are explained as follows:
"Alzheimer's disease" is a neurological disorder characterized by progressive cognitive dysfunction and behavioral impairment that occurs in the elderly and in the earlier stages of the age, and is primarily manifested by memory impairment, aphasia, disuse, disrecognition, impairment of visual space ability, impairment of abstract thinking and computing power, personality and behavioral changes, etc., which can be ameliorated by pharmacological treatment.
"Biomarker" refers to "an objectively detectable and evaluable property that can be used as an indicator of normal biological processes, pathological processes, or pharmacological responses to therapeutic interventions. For example, nucleic acid markers (which may also be referred to as gene markers, e.g., DNA), protein markers, cytokine markers, chemokine markers, carbohydrate markers, antigen markers, antibody markers, species markers (markers of species/genus), and functional markers (KO/OG markers), etc. The meaning of the nucleic acid marker is not limited to the existing gene which can be expressed as a protein with biological activity, but also includes any nucleic acid fragment, which can be DNA, RNA, modified DNA or RNA, unmodified DNA or RNA, and a collection consisting of the modified DNA or RNA. In the present invention, "biomarker" refers to intestinal microbial markers, which may also be denoted as "intestinal microorganisms", "intestinal flora", and the microbial markers associated with Alzheimer's disease used in the present invention are derived from fecal samples after intestinal metabolism of a subject.
The biomarker can be used for analyzing stool samples of healthy individuals and Alzheimer disease individuals in batches by using high-throughput sequencing. Based on the high throughput sequencing data, healthy individuals are aligned with the population of Alzheimer's disease individuals to determine specific nucleic acid sequences associated with the population of Alzheimer's disease individuals. By bioinformatic analysis methods, specific intestinal microbial nucleic acid sequences associated with individuals with Alzheimer's disease are determined. First, the sequenced sequences (reads) are aligned with a reference gene set (also referred to as a reference gene set, which may be a newly constructed gene set or a database of any known sequences, for example, using a known intestinal microflora non-redundant gene set). Next, based on the comparison results, the relative abundance of each gene in the nucleic acid samples from the stool samples of healthy individuals and the alzheimer's disease individual population, respectively, was determined. By comparing the sequencing sequence with the reference gene set, a corresponding relationship can be established between the sequencing sequence and the genes in the reference gene set, so that the number of the sequencing sequences corresponding to the specific genes in the nucleic acid sample can effectively reflect the relative abundance of the genes. Thus, the relative abundance of genes in a nucleic acid sample can be determined by comparison and conventional statistical analysis. Finally, after determining the relative abundance of each gene in the nucleic acid sample, the relative abundance of each gene in the nucleic acid sample from the feces of healthy individuals and Alzheimer's disease individuals is statistically examined, thereby making it possible to determine whether there is a gene whose relative abundance is significantly different in the healthy population and the population of Alzheimer's disease patients, and if there is a significant difference in the gene, the gene is regarded as a biomarker of an abnormal state, i.e., a nucleic acid marker. For known or newly constructed reference gene sets, they typically contain genetic species information and functional annotations, whereby, based on determining the relative abundance of genes, the species information and functional annotations of genes can be further categorized to determine the relative abundance of species and functional relative abundance of each microorganism in the intestinal flora, and thus further determine the species markers and functional markers of abnormal states.
For example, in one embodiment, the following method may be used:
High throughput sequencing analysis was performed on hypervariable regions of nucleic acid sequences encoding ribosomal RNAs based on Illuminate MiSeq sequencing platform. A set of primers is designed by utilizing a conserved region in bacterial 16S rDNA to amplify the gene of the 16S rRNA V3-V4 region of the intestinal flora, and a qualified PCR product is used for library construction and high-throughput sequencing of a Illumina Miseq sequencer. Sequencing data can obtain analysis results of the flora composition and abundance of the sample, species with obvious differences among groups and the like by a series of biological information analysis methods such as filtering low quality, reads splicing, OTU clustering, species annotation, diversity analysis and the like.
In a specific embodiment of the invention, a product for use in comprising a substance for detecting a biomarker as described above is provided, for use in diagnosing whether a subject has or predicting the risk of having alzheimer's disease. Such products include, but are not limited to, reagents and/or devices for detecting the relative abundance and/or amount of a biomarker in a sample to be tested. The relative abundance information of the biomarker is obtained using a sequencing method, further comprising: isolating a nucleic acid sample from a sample (stool) of a subject, constructing a DNA library based on the obtained nucleic acid sample, sequencing the DNA library to obtain a sequencing result, and comparing the sequencing result to a reference gene set based on the sequencing result to determine relative abundance information of the biomarker.
In still another embodiment of the present invention, an early diagnosis model of alzheimer's disease is provided, wherein the input variables of the early diagnosis model of alzheimer's disease include the relative abundance value of the intestinal flora-based biomarker of alzheimer's disease, the output variables of the early diagnosis model of alzheimer's disease include a multiple of difference, and the calculation formula of the multiple of difference is:
The positive judgment criteria for Alzheimer's disease were:
The difference multiple of the flavobacteriaceae is more than or equal to 1.31, the difference multiple of the chaetoviridae is more than or equal to 1.74, the difference multiple of the desferribacteriaceae is more than or equal to 1.65, the difference multiple of the olfactory bacteriaceae is less than or equal to 0.35 or the difference multiple of the desulfurated vibriaceae is less than or equal to 0.63.
In still another embodiment of the present invention, there is provided an early diagnosis device for Alzheimer's disease, the device comprising the following units:
an analysis unit for performing operations comprising:
detecting the relative abundance value of the Alzheimer disease biomarker based on intestinal flora in a sample to be detected of a subject;
An evaluation unit for performing operations comprising:
Inputting the relative abundance value of the Alzheimer's disease biomarker detected by the analysis unit into the Alzheimer's disease early diagnosis model for calculation, outputting a difference multiple, and judging whether the Alzheimer's disease biomarker is positive.
In yet another embodiment of the present invention, there is provided the use of said intestinal flora-based Alzheimer's disease biomarker as a target in the screening of a medicament for the prevention or treatment of Alzheimer's disease, based on the influence of the candidate medicament on said Alzheimer's disease biomarker before and after use, thereby determining whether the candidate medicament can be used for the prevention or treatment of Alzheimer's disease.
Example 1
The present embodiments provide intestinal flora-based biomarkers of alzheimer's disease, including any one or a combination of at least two of the families flavobacteriaceae, chaetoviridae, desferribaceae, olfactory bacidae or desulphurized vibrio.
Intestinal flora abundance and diversity analysis was performed on fecal samples from AD model male mice (purchased from university of south Beijing model animal institute) and wild type healthy male mice (WT) control groups. Fecal samples were collected from AD model mice (10) and wild type healthy mice (10), and total DNA isolation was performed using a nucleic acid isolation kit. The primer is obtained according to the design of the conserved region, a sequencing joint is added at the tail end of the primer, PCR amplification is carried out, and the product is purified, quantified and homogenized to form a sequencing library, the established library is subjected to library quality inspection, and the library qualified in quality inspection is subjected to high-throughput sequencing by using a Illumina Miseq/HiSeq2500 system. Those reads containing more than 10 low quality (< Q20) bases were filtered from the raw data. The filtered reads were then annotated with classifications using QIIME2 software (version 2020.11.1): first, high quality paired end reads are ligated into tags using vsearch; second, amplicon Sequence Variants (ASV) were detected for all samples using deblur software; third, a sklearn-based classifier was applied to make classification annotations against the Greengenes database (version 13-8-99). The Shannon diversity index (Shannon index) was calculated using the "vegan" package in R to detect alpha diversity of bacteria. After obtaining the mycological classification spectra, the difference in abundance of the mycological at the top 10 th of the abundance rank of the diseased and normal control groups (p < 0.05) was compared using Wilcoxon rank sum test.
The Shannon index showed a significant difference in the diversity of the 9 month old healthy mice and AD mice (p=0.035, fig. 1). As shown in fig. 2 to 6, further differential analysis of the flora abundance levels found that the relative abundance levels of flavobacteriaceae (Flavobacteriaceae), chaetoceraceae (Lachnospiraceae) and desferriaceae (Deferribacteraceae) in AD mice were significantly increased compared to healthy mice, while the relative abundance of olfactory bacitraceae (Odoribacteraceae) and vibrio desulphurase (Desulfovibrionaceae) was significantly decreased compared to healthy mice.
These biomarkers are all indicated as biological markers for the detection of Alzheimer's disease, and it is possible to effectively determine whether a subject is suffering from or susceptible to Alzheimer's disease (i.e., predicts the risk of suffering from Alzheimer's disease) by determining whether one or two or more of these markers are present in the intestinal flora of the subject. Thus, by detecting the level of at least one of these biomarkers in the test sample in the intestinal flora, it is determined whether the subject is suffering from or susceptible to Alzheimer's disease, while at the same time being useful for monitoring the effectiveness of the treatment in Alzheimer's disease patients.
In conclusion, the invention discovers that the flavobacteriaceae, the trichosporoceae, the deironidae, the olfactory bacillaceae and the desulphurized vibriosae in the intestinal flora are related to Alzheimer's disease for the first time, the relative abundance of the flavobacteriaceae, the trichosporoaceae, the deironidae, the vibriosae and the desulphurized vibriosae are obviously different between healthy individuals and AD individuals, and the relative abundance is used for assisting in judging or early warning the symptoms of the Alzheimer's disease.
The applicant states that the detailed method of the present invention is illustrated by the above examples, but the present invention is not limited to the detailed method described above, i.e. it does not mean that the present invention must be practiced in dependence upon the detailed method described above. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.
Claims (10)
1. An intestinal flora-based biomarker for alzheimer's disease, characterized in that the biomarker for alzheimer's disease is an intestinal microorganism comprising any one or a combination of at least two of flavobacteriaceae, chaetoviridae, desferribaceae, olfactory bacidae or vibriosidae.
2. The gut flora-based biomarker of claim 1, wherein the biomarker is derived from a biological sample of a subject, the biological sample comprising stool from the subject.
3. Use of a substance for detecting an intestinal flora-based biomarker for alzheimer's disease according to claim 1 or 2, in the manufacture of a product for diagnosing whether a subject has alzheimer's disease or predicting whether a subject is at risk for developing alzheimer's disease.
4. A product for diagnosing whether a subject has or is predicted to have risk of alzheimer's disease, characterized in that the product comprises reagents and/or devices for detecting the relative abundance and/or amount of gut flora-based alzheimer's disease biomarkers according to claim 1 or 2.
5. Use of the intestinal flora-based alzheimer's disease biomarker according to claim 1or 2 for constructing an early diagnosis of alzheimer's disease model and/or for preparing an early diagnosis of alzheimer's disease device.
6. An early diagnosis model of alzheimer's disease, characterized in that the input variables of the early diagnosis model of alzheimer's disease comprise the relative abundance values of the gut flora-based alzheimer's disease biomarkers of claim 1 or 2;
The output variables of the early diagnosis model of the Alzheimer disease comprise difference multiples, and the calculation formula of the difference multiples is as follows:
The positive judgment criteria for Alzheimer's disease were:
The difference multiple of the flavobacteriaceae is more than or equal to 1.31, the difference multiple of the chaetoviridae is more than or equal to 1.74, the difference multiple of the desferribacteriaceae is more than or equal to 1.65, the difference multiple of the olfactory bacteriaceae is less than or equal to 0.35 or the difference multiple of the desulfurated vibriaceae is less than or equal to 0.63.
7. An early diagnosis device for alzheimer's disease, characterized in that the device comprises the following units:
an analysis unit for performing operations comprising:
Detecting the relative abundance value of the gut flora-based alzheimer's disease biomarker of claim 1 or 2 in a test sample of a subject;
An evaluation unit for performing operations comprising:
inputting the relative abundance value of the Alzheimer's disease biomarker detected by the analysis unit into the Alzheimer's disease early diagnosis model according to claim 6 for calculation, outputting the difference multiple, and judging whether the Alzheimer's disease biomarker is positive.
8. The device of claim 7, wherein the sample to be tested comprises a fecal sample.
9. Use of the intestinal flora-based alzheimer's disease biomarker according to claim 1 or 2 as a target in screening for a medicament for preventing or treating alzheimer's disease.
10. The use of claim 9, wherein the screening comprises determining whether a drug candidate can be used to prevent or treat alzheimer's disease based on its effect on the biomarker of alzheimer's disease before and after use.
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| KR102130485B1 (en) * | 2017-10-13 | 2020-07-06 | 주식회사 엠디헬스케어 | Method for diagnosis of Alzheimer's dementia using analysis of bacteria metagenome |
| TR201818373A2 (en) * | 2018-12-03 | 2020-06-22 | T C Erciyes Ueniversitesi | MINIMAL BIOMARKERS AND RELATED NEW GENERATION sequencing kit for the diagnosis of Alzheimer's disease from the gut microbiome. |
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