JP7295547B2 - Intestinal dysbiosis determination system - Google Patents

Description

The present invention relates to a system and method for determining non-specific and diverse conditions of intestinal dysbiosis.

Approximately 1,000 types of intestinal bacteria live in the human intestine, and these bacteria play an important role in maintaining human health by supplying nutrients and suppressing the growth of pathogenic bacteria. play. However, for some reason, (i) the total number of intestinal bacteria has decreased significantly, (ii) the composition ratio has changed, and (iii) bacterial strains with normally low levels of bacteria have become abnormal. Abnormality such as an increase occurs. Such a structural abnormality of the intestinal flora is called Gut Dysbiosis (non-patent document 1).
However, the intestinal microbiota is diverse, such as differing from disease to disease and lifestyle content, and there are a wide variety of indicators and microbiota. not (Non-Patent Document 1).

On the other hand, when a clinician (medical worker) gives feedback to a patient about the test results of intestinal bacteria, it is not possible to explain the specific characteristics of individual indicators or bacteria. For this reason, it is necessary for medical professionals to be able to simply explain to patients, etc., whether the bacterial flora is comprehensively "good" or "bad."
Conventionally, technologies related to disease prediction systems using intestinal bacteria are known (Patent Documents 1 to 5), but there is still insufficient research on methods for determining non-specific and diverse states of intestinal dysbiosis. It was not advanced and it was difficult to determine intestinal dysbiosis.

Patent No. 5645761 JP 2012-165716 Special Table No. 2005-523695 JP 2015-7985 Special table 2014-523589

Walker AD, Lavley TD. Pharmacological Research 69,(2013) 75-86.

An object of the present invention is to provide a method that enables determination of non-specific and diverse states of intestinal dysbiosis using unified indices and standardized criteria.

As a result of intensive research to solve the above problems, the present inventors found that simple evaluation can be performed by a unified index and standardized criteria using intestinal indigenous bacteria, and to complete the present invention. Arrived.
That is, the present invention is as follows.
(1) A method for determining intestinal dysbiosis, comprising:
At least one indicator selected from the group consisting of a diversity-related indicator, a short-chain fatty acid production indicator, an intestinal immunity-related indicator, an oral bacteria-related indicator, and a diarrhea-constipation-related indicator, concerning the intestinal bacteria of the population for setting the criterion value, setting a criterion value for intestinal dysbiosis;
A step of comparing bacterial composition data obtained from an individual subject or a group of subjects (users) with the criterion value to calculate a determination score for each of the indicators;
adding the calculated determination scores to calculate an intestinal flora score; and using the intestinal flora score as an index to determine intestinal dysbiosis of the user.

(2) The method according to (1), wherein the diversity-related index includes at least one item selected from the group consisting of diversity, FB ratio, the number of species belonging to the phylum Bacteroidetes, and the occupancy rate of the most dominant genus. .
(3) The method according to claim 1, wherein the short-chain fatty acid production index includes at least one item selected from the group consisting of bifidobacteria, lactic acid-producing bacteria, butyric acid-producing bacteria, and the number of species of butyric acid-producing bacteria. .
(4) the intestinal immunity-related index includes at least one item selected from the group consisting of Faecalibacterium, Akkermansia, Christensenela, Aristipes and Clostridium, (1 ).
(5) The oral bacteria-related index includes at least one item selected from the group consisting of Fusobacterium, Streptococcus, oral bacterial occupancy, and the number of gammaproteobacterial species. the method of.
(6) The method according to (1), wherein the diarrhea-constipation-related index is an enterotype.
(7) Any one of (1) to (6), wherein the criterion value is set based on a comparison of the test value distribution of the criterion value setting group for each item included in the index. The method described in section.

(8) A system for determining intestinal dysbiosis,
means for storing bacterial composition data obtained from an individual subject or a subject group (user);
At least one indicator selected from the group consisting of a diversity-related indicator, a short-chain fatty acid production indicator, an intestinal immunity-related indicator, an oral bacteria-related indicator, and a diarrhea-constipation-related indicator, concerning the intestinal bacteria of the population for setting the criterion value, a means for storing a criterion value for intestinal dysbiosis;
means for comparing the determination reference value with the bacterial composition data to calculate a determination score for each of the indicators;
The system, comprising means for calculating an intestinal flora score by adding the calculated determination scores, and means for determining intestinal dysbiosis of the user using the intestinal flora score as an index.
(9) The system according to (8), wherein the diversity-related index includes at least one item selected from the group consisting of diversity, FB ratio, the number of species belonging to the phylum Bacteroidetes, and the occupancy rate of the most dominant genus. .
(10) The system according to (8), wherein the short-chain fatty acid production index includes at least one item selected from the group consisting of Bifidobacterium, a group of lactic acid-producing bacteria, a group of butyric acid-producing bacteria, and the number of species of butyric acid-producing bacteria. .

(11) Intestinal immune-related indicators include at least one item selected from the group consisting of Faecalibacterium, Akkermansia, Christensenela, Aristipes and Clostridium, (8 ).
(12) According to (8), the oral bacteria-related index includes at least one item selected from the group consisting of Fusobacterium, Streptococcus, oral bacterial occupancy, and the number of gamma proteobacteria. system.
(13) The system according to (8), wherein the diarrhea-constipation-related indicator is an enterotype.
(14) Any one of (8) to (13), wherein the criterion value is set based on a comparison of the test value distribution of the criterion value setting population for each item included in the index. The system described in paragraph.

(15) A program for determining intestinal dysbiosis, comprising:
At least one indicator selected from the group consisting of a diversity-related indicator, a short-chain fatty acid production indicator, an intestinal immunity-related indicator, an oral bacteria-related indicator, and a diarrhea-constipation-related indicator, concerning the intestinal bacteria of the population for setting the criterion value, a means for storing a criterion value for intestinal dysbiosis;
means for storing bacterial composition data obtained from an individual subject or a subject group (user);
means for comparing the bacteria composition data with the judgment reference value to calculate a judgment score for each of the indicators;
means for calculating an intestinal flora score by adding the calculated determination scores; and said program for functioning as means for determining intestinal dysbiosis of said user using said intestinal flora score as an index.
(16) The program according to (15), wherein the diversity-related index includes at least one item selected from the group consisting of diversity, FB ratio, the number of species belonging to the phylum Bacteroidetes, and the occupancy rate of the most dominant genus. .
(17) The program according to (15), wherein the short-chain fatty acid production index includes at least one item selected from the group consisting of bifidobacteria, a group of lactic acid-producing bacteria, a group of butyric acid-producing bacteria, and the number of species of butyric acid-producing bacteria. .
(18) Intestinal immune-related indicators include at least one item selected from the group consisting of Faecalibacterium, Akkermansia, Christensenela, Aristipes and Clostridium, (15 ).
(19) According to (15), the oral bacteria-related index includes at least one item selected from the group consisting of Fusobacterium, Streptococcus, oral bacterial occupancy, and the number of gamma proteobacteria. program.
(20) The program according to (15), wherein the diarrhea-constipation-related index is an enterotype.
(21) Any one of (16) to (20), wherein the criterion value is set based on a comparison of the test value distribution of the criterion value setting group for each item included in the index. The program described in Section.

The present invention provides a method and system for determining intestinal dysbiosis. According to the method of the present invention, it has become possible to determine intestinal dysbiosis in a non-disease-specific manner using various indicators.
The present invention will be described in detail below.

1 is a block diagram of the system of the present invention; FIG. 4 is a flow chart showing the operation of the system of the present invention; FIG. 10 is a diagram showing the distribution of intestinal flora scores in a cohort of healthy subjects and a cohort of diseased subjects. FIG. 10 is a diagram showing the results of calculating an intestinal flora score;

1. Outline The method, system, and program of the present invention can easily detect a non-specific condition called intestinal dysbiosis, which has various aspects, by a unified index using indigenous bacteria or by standardized criteria. It is what makes it possible to evaluate The inventors have discovered that there are intestinal dysbiosis terms that are specifically related to individual subject's medical history or medication history. We also found that the flora score, which is a weighted addition of individual intestinal dysbiosis items, is an index that is non-specifically related to multiple diseases. The present invention has been completed based on such findings.

In the present invention, in order to determine intestinal dysbiosis, a criterion value is set for each of the intestinal dysbiosis scoring items. The criterion value is at least selected from the group consisting of a diversity-related index, a short-chain fatty acid production index, an intestinal immunity-related index, an oral bacterium-related index, and a diarrhea-constipation-related index for the intestinal bacteria of the population for setting the criterion value. One index is assigned as a unique value corresponding to each index. The population for setting the criterion value includes either one or both of the healthy subject population and the diseased patient population.

Next, the bacterial composition data (inspection values) of an individual subject or a group of subjects who are the target users of the determination are read, and the determination score is calculated for the data corresponding to the intestinal dysbiosis scoring item among the bacterial composition data. A judgment score means a value (score) assigned by comparing the intestinal dysbiosis scoring item included in the above index with the relevant judgment reference value.
Then, the calculated determination scores are added to calculate the intestinal flora score. The calculation can be performed, for example, by weighted addition based on the test value distribution of the criteria value setting population (healthy subject population and diseased patient population). Based on this intestinal flora score, intestinal dysbiosis is determined. Note that the determination score may include negative values. Therefore, "addition" in calculating the intestinal flora score includes addition of negative values, that is, subtraction.

The intestinal flora score is a score for determining intestinal dysbiosis of the user. If there are multiple groups of users, extract the overall tendency of the intestinal flora score (intestinal flora score distribution) in that group and determine where each subject belonging to the group belongs to. . For example, the intestinal flora score distribution is drawn as a two-dimensional or three-dimensional graph based on statistical analysis, and the position on the graph to which the subject belongs is determined. Perform a stratified analysis within the population for setting the judgment criteria. As a result of the stratified comparison, if there is a difference in distribution, the region or numerical value showing the difference may be used as the threshold for determining intestinal dysbiosis.

2. Intestinal dysbiosis judgment method (1) Setting of judgment standard value and judgment score
In the present invention, first, human indigenous bacteria data and questionnaire data relating to a population for determination reference value setting (hereinafter also referred to as "reference value population") are obtained. The number of subjects is not particularly limited as long as it is two or more, but it is preferable that the number is sufficient to produce a statistically significant difference or tendency. Human indigenous bacteria can be obtained, for example, from stool samples collected from humans, but can also be collected from the intestinal mucosa and the like by colonoscopy. Human indigenous bacteria data can be obtained by any known method, and for example, a commercially available kit (Mykinso (registered trademark)) can be used.

Questionnaire data is data of answers to questions from each subject in the reference value group. The questionnaire included questions about the subjects' medical history, what they ate in the days prior to stool sampling, and what their diet consisted of. A questionnaire regarding the subject's subjective health may be conducted separately after a predetermined period of time (for example, several weeks to several months) after collection of the stool sample, or may be conducted simultaneously with other questionnaires. After collecting the questionnaires, all or part of the answers are converted into numerical values while appropriately weighted, and stored in a database.

Intestinal dysbiosis scoring items are selected according to the following selection criteria (a) and (b).
(a) Disturbance of bacterial composition or balance of bacterial composition based on the bacterial composition data listed in the intestinal bacteria database (also referred to as database), basic attributes of subjects accumulated so far and questionnaire information From the viewpoint of the stability of the strain, characteristic genus and indicators were selected.
(b) Intestinal dysbiosis and intestinal dysbiosis, based on whether or not there are findings consistent with previous studies in the database that contains literature comparing the indigenous bacteria of diseases related to the pathogenesis of intestinal bacteria with those of healthy subjects. Select relevant genera and indicators.

The indicators selected in this way are diversity-related indicators, short-chain fatty acid production indicators, intestinal immunity-related indicators, oral bacteria-related indicators, and diarrhea-constipation-related indicators.
The reference values for the above scoring items are defined as a population for setting the judgment reference values, for example, a cohort of healthy individuals (among the users listed in the database, those with a history of illness, complaints of diarrhea and constipation, and those who are 60 years of age or older) set based on a comparison of the distribution of each test value between the adult population excluded) and the affected cohort (adult population with a history of chronic disease among users listed in the database).

(i) Diversity-related index The diversity-related index is an index that reflects the number of bacterial species and the degree of equality of the occupancy rate of each bacterium. The number of fungal species and the most dominant genus are listed.
Diversity is a calculated value obtained by multiplying the number of fungal species in a sample by the evenness of the occupancy of each fungus. Diversity test values are converted to a given numerical range based on the Shannon index. The numerical range is, for example, 0-10, preferably 3-8. Diversity judgment scores are assigned in the range of -10 to 10, for example, in the range of -10 to 10, with respect to the test value (converted value) of diversity.
Table 1 (Examples) below is a list of the judgment criteria values and judgment scores for each judgment item. assigned. As for the other items, the inspection value, the judgment reference value, and the judgment score are set in the same manner as for the diversity.

The FB ratio is the ratio between the phylum Firmicutes and the phylum Bacteroidetes, which are the major phyla of human intestinal bacteria, and includes both the phylum Firmicutes/Bacteroidetes and the phylum Bacteroidetes/Firmicutes, for example, the phylum Firmicutes/Bacteroidetes. Gate ratios are adopted. The FB ratio inspection value is set (converted) within a numerical range of 0 to infinity, for example, 0 to ∞. A judgment score is assigned to the test value (converted value) of the FB ratio in the range of -10 to 10, for example, in the range of -10 to 3.

The number of species belonging to the phylum Bacteroidetes is set to a numerical range of 0-100, for example 0-20. A judgment score is assigned in the range of -10 to 10, for example, in the range of -5 to 3, for the inspection value (converted value) of the number of bacterial species belonging to the phylum Bacteroidetes.
The occupancy rate of the most dominant genus is the value of the occupancy rate of the bacterial species with the highest occupancy rate in the sample. For the occupancy rate of the most dominant genus, a numerical value of 1 to 5, for example 2, is set as a reference value within a numerical range of 0 to 1. For the judgment score, if two reference values for example, 0.35 and 0.4 are set for the occupancy rate, -1 to -5 judgment score (for example -3) if 0.35 or more, -2 to -2 if 0.4 or more Assign a decision score of -10 (eg -5). In addition, since the occupancy rate of the most dominant bacterium has a negative impact in the intestine (e.g., a decrease in diversity, especially a decrease in the evenness of the occupancy rate of each bacterium), the higher the test value, the more negative the judgment. score.

(ii) Short-chain fatty acid production index The short-chain fatty acid production index means a group of intestinal bacteria recognized to have the ability to produce short-chain fatty acids. group, butyrate-producing bacteria group and butyrate-producing bacteria group.
Bifidobacterium represents the occupancy of bifidobacteria per faeces. Bifidobacterium is set to a numerical range of 0-1, eg 0-1. A judgment score is assigned to the test value (converted value) of bifidobacteria in the range of -10 to 10, for example, in the range of -3 to 7.

The group of lactic acid-producing bacteria represents the occupancy rate of a plurality of bacteria selected from the genus Lactobacillus, the genus Pediococcus, the genus Leuconostoc, and the genus Lactococcus per feces. The group of lactic acid-producing bacteria is set to a numerical range of 0-1, for example, 0-1. A judgment score is assigned in the range of -10 to 10, for example, in the range of -10 to 3, to the test value (converted value) of the lactic acid-producing bacteria group. In addition, since the lactic acid-producing bacteria group has a negative effect in the intestine (for example, exhibits a positive relationship with diarrhea), the larger the test value, the negative the judgment score.

The group of butyric acid-producing bacteria represents the occupancy rate of a plurality of bacteria selected from the genus Butyricococcus, the genus Coprococcus, the genus Rosebria, the genus Butyricococcus, and the genus Faecalibacterium per feces. The group of butyric acid-producing bacteria is set to a numerical range of 0-1, for example, 0-1. A judgment score is assigned in the range of -10 to 10, for example, in the range of -5 to 10, for the test value (converted value) of the butyric acid-producing bacteria group.
The number of species of butyric acid-producing bacteria means the number of species belonging to the group of butyric acid-producing bacteria described above.
The number of species belonging to the group of butyric acid-producing bacteria is set to a numerical range of 0-5, for example, 0-5.
A judgment score is assigned in the range of -10 to 10, for example, in the range of -5 to 5, for the inspection value (converted value) of the number of species of butyric acid-producing bacteria.

(iii) Gut immunity-related index Gut immunity-related index means a group of intestinal bacteria that are recognized to produce substances that modify intestinal immunity. , Akkermansia, Christensenela, Aristipes and Clostridium.
Faecalibacterium represents the occupancy of Faecalibacterium per feces. Faecalibacterium is set to a numerical range of 0-1, eg 0-1. A judgment score is assigned to the test value (converted value) of Faecalibacterium in the range of -10 to 10, for example, in the range of -5 to 5.

Akkermansia spp. represents the occupancy rate of bacteria belonging to the genus Akkermansia per feces. Akkermansia is set to a numerical range of 0-1, eg 0-1. A judgment score is assigned in the range of -10 to 10, for example, in the range of 0 to 3, to the test value (converted value) of Akkermansia spp.
Christensenella represents the occupancy rate of bacteria belonging to the genus Christensenella per feces. Christensenella is set to a numerical range of 0-1, eg 0-1. A judgment score value is assigned in the range of -10 to 10, for example, in the range of 0 to 3, to the test value (converted value) of Christensenella.

Aristipes represents the occupancy rate of bacteria belonging to the genus Aristipes per feces. Aristipes is set to a numerical range of 0-1, eg 0-1. A determination score is assigned in the range of -10 to 10, for example, in the range of 0 to 3, to the test value (converted value) of the genus Aristipes.

Clostridium bacteria represent the occupancy rate of bacteria belonging to the genus Clostridium per feces. Clostridia is set to a numerical range of 0-1, eg 0-1. A judgment score is assigned to the test value (converted value) of Clostridium spp. in the range of -10 to 10, for example, in the range of -5 to 0. In addition, Clostridium bacteria have multiple types of substances that act on intestinal immunity in the intestine (for example, cytokine substances that promote inflammation, cytokine substances that suppress inflammation, etc.). Set a negative judgment score for both.

(iv) Oral bacteria-related index The oral bacteria-related index means a group of intestinal bacteria that are recognized to exist in large numbers in the oral cavity. Occupancy and number of gammaproteobacterial species are included.
Fusobacterium represents the occupancy of bacteria belonging to the genus Fusobacterium per stool. Fusobacterium is converted to a numerical range of 0-1, for example 0-1. A determination score is assigned to the Fusobacterium spp. test value (converted value) in the range of -10 to 10, for example, in the range of -10 to 0. Since Fusobacterium spp. has a negative effect in the intestine (for example, it is abundant in the intestines of colon cancer patients), the higher the test value, the negative the judgment score.

The Streptococcus genus represents the occupancy rate of bacteria belonging to the genus Streptococcus per feces. Streptococcus is set to a numerical range of 0-1, eg 0-1. A determination score is assigned to the test value (converted value) of Streptococcus spp. in the range of -10 to 10, for example, in the range of -5 to 0. Since Streptococcus spp. has a negative effect in the intestine (for example, many of them are present in the intestines of patients with ulcerative colitis), the higher the test value, the negative the judgment score.

The oral bacterial occupancy rate represents the occupancy rate of a plurality of bacteria selected from the group consisting of Streptococcus, Fusobacterium, Troublesiella, and Klebsiella. The occupancy rate of oral bacteria is set in a numerical range of 0 to 1, and 1 to 5, for example, 1 is set as a reference value. Assuming that the reference value of the occupancy rate is set to, for example, 0.2 (one numerical value), the judgment score is assigned as -10 if it is 0.2 or higher. Since oral bacteria have a negative effect in the intestine (for example, many of them are present in the intestines of Crohn's disease patients), the larger the test value, the negative the judgment score.

The number of strains belonging to the class Gammaproteobacteria represents the number of strains belonging to the class Gammaproteobacteria per stool. The number of gammaproteobacteria strains is converted to a numerical range of 0-100, for example, 0-10. A judgment score is assigned to the test value (converted value) of gammaproteobacteria in the range of -10 to 10, for example, in the range of -7 to 0. Since the number of species of gammaproteobacteria has a negative effect in the intestine (for example, many of them are present in the intestines of patients with irritable bowel syndrome), the larger the test value, the negative the judgment score.

(v) Diarrhea-constipation-related index Diarrhea-constipation-related index means a bacterial composition type (enterotype) that shows a strong relationship with diarrhea symptoms and constipation symptoms. type and enterotype R-type.

Enterotype R represents a Ruminococcus dominant bacterial composition. Enterotype R forms are scaled to a numerical range of 0-1, eg 0-1. A determination score is assigned to the enterotype R test value (converted value) in the range of -10 to 10, for example, in the range of -5 to 5. Enterotype R has a negative impact (for example, an increase in constipation symptoms) as a bacterial composition type that is strongly associated with diarrhea and constipation symptoms, so the higher the test value, the negative the judgment score.

Diarrheal enterotype represents a bacterial composition type that is strongly associated with diarrhea symptoms. Diarrheal enterotypes are converted to a numerical range of 0-1, eg 0-1. Determination scores are assigned in the range of -10 to 10, for example, in the range of -5 to 5, for the test values (converted values) of diarrhea type enterotypes.
The constipation enterotype represents a bacterial composition type that is strongly associated with symptoms of constipation. The constipation type enterotype is converted to a numerical range of 0-1, eg 0-1. Determination scores are assigned in the range of -10 to 10, for example, in the range of -5 to 5, for the test values (converted values) of constipation type enterotypes.

(2) Intestinal Flora Score Calculation and Judgment At least one indicator selected from the group consisting of a related indicator and a diarrhea-constipation related indicator is selected as appropriate. Next, the scoring items included in the selected index are selected as appropriate. In the present invention, it is preferable to employ all the scoring items (18 items) included in the above related indicators.
Next, each inspection value is compared with the judgment reference value, and the score of the marking item (that is, the judgment score) is calculated by a method such as weighted addition.

After the calculation, the respective judgment scores are added to calculate the intestinal flora score. The intestinal flora score provides basic information for determining intestinal dysbiosis. The intestinal flora score threshold for determining intestinal dysbiosis can be appropriately set in the range of 1 to 99 based on the score distribution of the healthy subject group and the diseased subject group. For example, if the intestinal flora score threshold is 50, the subject is determined to have intestinal dysbiosis or be at risk of intestinal dysbiosis if the score is less than 50 points.

By the way, in the present invention, statistical analysis processing is performed on a predetermined number of subjects (primary population sample), the correlation between intestinal dysbiosis determination items and user data is examined, and the results are stored in a database (DB ) is stored. Therefore, when testing or judging an individual subject (one person), the data derived from the above multiple subjects are used as a mother sample, and where the subject data of the individual subject is located in the mother sample data stored in the database Intestinal dysbiosis for the subject individual can be determined by examining whether or not it is true. It should be noted that after incorporating the data of the individual subject into the values of the mother sample and performing statistical analysis processing again, it is possible to examine where the individual subject is positioned in the mother sample.

3. Information Processing Apparatus and Program Next, an information processing apparatus and a program according to an embodiment of the present invention will be described below with reference to the drawings.
FIG. 1 is a schematic configuration diagram of an intestinal dysbiosis determination system 1 including an information processing device 10 according to this embodiment. In the following description, a group of subjects or an individual subject is referred to as a "user".

The information processing apparatus 10 is a server computer including a CPU, ROM, RAM, input/output interfaces, and the like. The information processing apparatus 10 is communicably connected to a plurality of user devices 30a to 30n (collectively referred to as "user devices 30") via a network 20 such as the Internet or LAN.

The information processing device 10 compares the intestinal dysbiosis scoring items of a user to be investigated or focused on (referred to as a “target user”) with the intestinal dysbiosis scoring items of healthy subjects stored in a database, and compares the results with Based on this, the judgment score is calculated. Then, the information processing apparatus 10 adds the calculated determination scores to calculate an intestinal flora score, and determines whether the target user has intestinal dysbiosis based on the calculated intestinal flora score. Then, the information processing device 10 transmits the user's intestinal dysbiosis determination result to the user device 30 .

The user device 30 is a device such as a computer, a smart phone, a tablet, or the like, which includes information input means and display means, etc., and is connected to the information processing apparatus 10 via the network 20 so as to be communicable. The user device 30 displays various types of information received from the information processing apparatus 10 on a display and provides an interface for inputting information to be sent to the information processing apparatus 10 through a browser, an application, or the like.

The information processing system 1 may include an inspection agency 40 that inspects a plurality of types of human intestinal bacteria collected from the feces of the user and provides the information. The information processing apparatus 10 acquires information (human intestinal bacterium data) related to the user's human intestinal bacteria associated with the user's identification information from the laboratory 40 via the network 20 . The information processing apparatus 10 may directly acquire the human intestinal bacteria data from the laboratory 40 without going through the network 20 . Further, when the human intestinal bacteria data is sent from the testing institution 40 to the user device 30 , the information processing apparatus 10 may acquire the human intestinal bacteria data from the user device 30 . Furthermore, the inspection agency 40 and the information processing device 10 may belong to the same agency, or may belong to different agencies.

The human intestinal bacteria data includes at least one index selected from the group consisting of a diversity-related index, a short-chain fatty acid production index, an intestinal immunity-related index, an oral bacteria-related index, and a diarrhea-constipation-related index. The details of these indicators are as described above.

The information processing apparatus 10 includes an information acquisition unit 101, a scoring item extraction unit 102, a determination reference value setting unit, and the like as functional units realized by cooperation between a program stored in a ROM or placed in a RAM and a CPU. It includes a section 103 , a comparison section 104 , an intestinal flora score calculation section 105 and a determination section 106 . The information processing apparatus 10 also includes a storage unit 110 provided in a ROM (or RAM). The storage unit 110 includes an intestinal bacteria database (DB) 111, a scoring item information database (DB) 112, and a criteria database. (DB) 113.

The information acquisition unit 101 acquires various types of information from the user device 30 and/or the inspection agency 40 via the network 20 and stores the information in the storage unit 110 . The information received from the user device 30 and/or the testing institution 40 includes the user's intestinal bacteria data, information (questionnaire data) regarding answers to questions (questionnaire) to the user, and user identification information (user's name, date of birth, date, address, telephone number, e-mail address used by the user, ID set for the user, etc.). Note that the user identification information may include the identifier of the user device 30 used by the user.

Upon receiving the user's intestinal bacteria data, the information acquisition unit 101 stores the data in the intestinal bacteria information DB 111 in association with the user identification information. The intestinal bacteria information DB 111 stores intestinal bacteria data collected from a plurality of users in this way. The intestinal bacteria information DB 111 includes user identification data and questionnaire information data. When the information acquisition unit 101 receives the user's questionnaire data, it associates it with the user identification information and stores it in the scoring item DB 112 . The scoring item DB 112 stores questionnaire data collected from users in this manner. The criterion DB 113 stores information obtained by statistical analysis processing for extracting features by the criterion value setting unit 104, which will be described later. Since this information changes according to the number of members of the user population sample subjected to statistical analysis processing, it is stored in association with the information identifying them.

Questions (questionnaire) provided to the user include the user's name, age, height, weight, BMI value, family composition, type of work, living environment, exercise frequency, sleep satisfaction, eating habits, constitution, medical history, and stool collection. It may also include information about the health status at the time, medication history at the time of stool collection, and mental state at the time of stool collection.
Regarding the questionnaire data, information regarding a question (questionnaire) may be transmitted from the information processing apparatus 10 to the user device 30, and information regarding the answer to the question may be received by the information acquisition unit 101 from the user device 30. When the inspection agency 40 handles the questionnaire data, the information acquisition unit 101 may acquire the questionnaire data from the inspection agency 40 .

FIG. 2 is a processing flowchart by the information processing apparatus 10 according to this embodiment.
In step S<b>1 , the information acquisition unit 101 of the information processing apparatus 10 acquires human intestinal bacteria data and questionnaire data from the user, and stores them in the intestinal bacteria information DB 111 .
In step S2, the scoring item extraction unit 102 extracts from the information stored in the intestinal bacteria information DB 111, the diversity-related index, the short-chain fatty acid production index, the intestinal immunity-related index, the oral bacteria-related index, and the diarrhea-constipation-related index. At least one index selected from the group or a scoring item included in the index is extracted and stored in the scoring item information DB 112 . In step S2, the criterion value setting unit 103 sets the criterion value and the score for each scoring item from the information stored in the scoring item information DB 112, and stores them in the criterion DB.

In step S3, the comparison unit 104, from the intestinal bacterium information DB 111 and the scoring item information DB 112, determines the criterion value setting group (healthy subject group or diseased patient group) and the test values of each index related to the intestinal bacteria of the subject and , the reference value of the index is extracted, and the reference value and the test value are compared and collated between the healthy subject group and the subject.

In step S4, the intestinal flora score calculation unit 105 adds the judgment score assigned to the target user (including subtraction in the case of a negative value) to calculate the intestinal flora score.
In step S5, the determination unit 106 determines intestinal dysbiosis in the target user. Judgment by the judging unit 106 is to extract the characteristics of each of the plurality of indices while changing the judgment reference value and the judgment score within a predetermined range (step S2) (repeating steps S2 to S5).

Here, the target user may be a person included in the user population used for extracting features by the scoring item extraction unit 102, or a new user (one individual) not included in the user population. There may be. In step S5, the determination unit 106 generates a result for the target user according to the determination result as to what kind of intestinal dysbiosis the target user belongs to or is at risk for, and transmits the result to the user device 30 of the target user. do.

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to Examples. However, the present invention is not limited to these examples.

(1) Selection of intestinal dysbiosis scoring items <Selection criteria 1>
Doctors and researchers belonging to Cykinso review the bacterial composition data listed in the intestinal bacteria database and the basic attributes and questionnaire information of each of multiple subjects, From this point of view, we selected characteristic genus and indicators.
<Selection Criteria 2>
Genus and indicators related to intestinal dysbiosis were selected based on the existence of findings consistent with previous studies listed in overseas Disbiome databases.

The selected scoring items are as follows.
1. Diversity
2.FB ratio
3. Bifidobacterium
4. Lactic acid-producing bacteria
5. Butyrate-producing bacteria
6. Enterotype
7. Number of Bacteroidetes Species
8. Number of Species of Gammaproteobacteria
9. Faecalibacterium
10. Akkermansia
11. Christensenella
12. Aristipes spp.
13. Clostridia
14. Fusobacterium
15. Streptococcus
16. Oral Bacteria (Streptococcus, Fusobacterium, Trabulsiella, Klebsiella) Occupancy
17. Occupancy of the most dominant genus
18. Number of species of butyric acid-producing bacteria

Table 1 shows specific examples of the criterion values.

<Example of judgment reference value setting>
In the case of bifidobacteria , the following criteria and scores are set.
If the test value is 0 or more and less than 0.01 : 3 points deduction
If the test value is 0.01 or more and less than 0.03: 0 points
If the inspection value is 0.03 or more and less than 0.06: Add 3 points If the inspection value is 0.06 or more and less than 0.1 : Add 5 points If the inspection value is 0.1 or more: Add 7 points

(2) Calculation of Flora Score Criteria values and judgment scores for intestinal dysbiosis scoring items were set based on a comparison of the distribution of test values between a cohort of healthy subjects and a cohort of affected subjects.
The cohort of healthy subjects was defined as a group of adults, excluding users listed in the database who responded to the questionnaire as follows.
"Medical history", "Complaints of diarrhea/constipation", "Age over 60"

(3) Flora score calculation algorithm
In Step 1, the test values for bifidobacteria, butyrate-producing bacteria, and lactic acid-producing bacteria for each user were calculated.
(i) Bifidobacteria = 0.013, (ii) Butyrate-producing bacteria = 0.0643, (iii) Lactic acid-producing bacteria = 0.0001
In Step 2, the reference values for bifidobacteria, butyric acid-producing bacteria, and lactic acid-producing bacteria in Table 1 above were compared, and the judgment scores for each item were calculated. In this case, the large number of demerit points indicates the tendency of intestinal dysbiosis.
(i) bifidobacteria = 0 , (ii) butyrate-producing bacteria = -3 , (iii) lactic acid-producing bacteria = 0
In Step 3, the intestinal flora score was calculated by a method such as weighted addition of the judgment scores of multiple scoring items. In this case, the reference point is 60, and the judgment scores for each item are added.
・Intestinal flora score = 58.5

(4) Results and discussion The results are shown in FIG.
We found that an intestinal flora score of less than 50 points strongly reflects intestinal dysbiosis, which is common and nonspecific in multiple diseases.
The present inventors have shown that approximately half of the intestinal dysbiosis items related to individual medical histories and medication histories are bacteria and bacterial groups that non-specifically respond to multiple diseases.
Therefore, many of the associations found in the selected intestinal dysbiosis items are likely not disease-specific, but rather biomarkers of non-specific and common responses to health and disease.

In this example, analysis was performed for the purpose of confirming disease-specific/non-specific characteristics for each item. Analysis was performed by generalized linear model and logistic regression analysis.

The results are shown in FIG.
The first category row in FIG. 4 is a heat map showing the intensity of disease-specific/non-specific intestinal dysbiosis in the diversity-related index. In each panel, portions showing a positive association with the disease are shown in red, portions showing a negative association with the disease are blue, and the intensity of the color indicates the strength of the association.
In the case of hypertension and ulcerative colitis, it can be seen that the overall diversity is low.

The second row of the category in FIG. 4 is a heat map showing the intensity of disease-specific/non-specific intestinal dysbiosis in indices related to short-chain fatty acid production.
In the case of diabetes (Fig. 5), it can be seen that there are many lactic acid-producing bacteria and few butyric acid-producing bacteria.

The third row of the category in FIG. 4 is a heat map showing the intensity of disease-specific/non-specific intestinal dysbiosis in indices related to intestinal immunity.
Both diabetes and dyslipidemia were found to have low levels of Christensenella spp.

The fourth row of the category in FIG. 4 is a heat map showing the intensity of disease-specific/non-specific intestinal dysbiosis in indices related to oral bacteria.
In the case of dyslipidemia, both Fusobacterium and Streptococcus were found to be prevalent.

The fifth row of the category in FIG. 4 is a heat map showing the strength of disease-specific/non-specific intestinal dysbiosis in indices related to diarrhea and constipation.
It was found that enterotype R was low in three diseases: hypertension, dyslipidemia, and diabetes.

1: System of the Present Invention, 10: Information Processing Device, 20: Network, 30: User Device, 40: Inspection Agency,
101: information acquisition unit, 102: scoring item extraction unit, 103: determination reference value setting unit, 104: comparison unit, 105: intestinal flora score calculation unit, 106: determination unit 110: storage unit, 111: intestinal bacteria information DB, 112: Grading item information DB, 113: Criteria DB

Claims (6)

A method of providing information for determining non-disease-specific intestinal dysbiosis, comprising:
Intestinal dysbiosis judgment criteria for each scoring item included in the diversity-related index, short-chain fatty acid production index, intestinal immunity-related index, and oral bacteria-related index regarding the intestinal bacteria of the population for setting the criterion value and assigning a judgment score to the judgment criterion value ;
A step of collating the test values of the scoring items obtained from the individual subject or the subject group (user) with the judgment reference value, and calculating a judgment score corresponding to the collated judgment reference value ;
calculating an intestinal flora score by adding the calculated determination scores; and providing the intestinal flora score as information for determining non-disease-specific intestinal dysbiosis of the user. the method comprising:
The diversity-related index is an index that reflects the number of bacterial species and the evenness of the occupancy rate of each bacterium, and from the group consisting of diversity, FB ratio, the number of bacterial species belonging to the phylum Bacteroidetes, and the occupancy rate of the most dominant genus including at least one item selected,
The short-chain fatty acid production index is a group of intestinal bacteria recognized to have the ability to produce short-chain fatty acids, which consists of bifidobacteria, a group of lactic acid-producing bacteria, a group of butyric acid-producing bacteria, and the number of species of butyric acid-producing bacteria. including at least one item selected from
The intestinal immunity-related index is a group of intestinal bacteria that are recognized to produce substances that modify intestinal immunity, including Faecalibacterium, Akkermansia, Christensenera, and Aristipes. and at least one item selected from the group consisting of Clostridium spp.
The oral bacterium-related index is a group of enteric bacteria that are recognized to be abundant in the oral cavity, and consists of Fusobacterium spp., Streptococcus spp., oral bacterium occupancy, and gamma proteobacteria including at least one item selected from the group
the aforementioned method. 2. The method according to claim 1 , wherein the criterion value is set based on a comparison of test value distributions of a criterion value setting population for each item included in the index. A system for determining non-disease-specific intestinal dysbiosis,
Memorize the criterion values for intestinal dysbiosis for each item included in the diversity-related index, short-chain fatty acid production index, intestinal immunity-related index, and oral bacteria-related index regarding the intestinal bacteria of the population for setting the criterion value. means for assigning a judgment score to the judgment criterion value by
means for comparing the test values of the scoring items obtained from individual subjects or subject groups (users) with the criterion values, and calculating a criterion score corresponding to the collated criterion values ;
The system, comprising means for calculating an intestinal flora score by adding the calculated determination scores together, and means for determining non-disease-specific intestinal dysbiosis of the user using the intestinal flora score as an index. and
The diversity-related index is an index that reflects the number of bacterial species and the evenness of the occupancy rate of each bacterium, and from the group consisting of diversity, FB ratio, the number of bacterial species belonging to the phylum Bacteroidetes, and the occupancy rate of the most dominant genus including at least one item selected,
The short-chain fatty acid production index is a group of intestinal bacteria recognized to have the ability to produce short-chain fatty acids, which consists of bifidobacteria, a group of lactic acid-producing bacteria, a group of butyric acid-producing bacteria, and the number of species of butyric acid-producing bacteria. including at least one item selected from
The intestinal immunity-related index is a group of intestinal bacteria that are recognized to produce substances that modify intestinal immunity, including Faecalibacterium, Akkermansia, Christensenera, and Aristipes. and at least one item selected from the group consisting of Clostridium spp.
The oral bacterium-related index is a group of enteric bacteria that are recognized to be abundant in the oral cavity, and consists of Fusobacterium spp., Streptococcus spp., oral bacterium occupancy, and gamma proteobacteria including at least one item selected from the group
said system . 4. The system according to claim 3 , wherein the criterion value is set based on a comparison of test value distributions of a criterion value setting group for each item included in the index. A program for determining non-disease-specific intestinal dysbiosis, comprising:
For each item included in the diversity-related index, short-chain fatty acid production index, intestinal immunity-related index, and oral bacteria-related index regarding the intestinal bacteria of the population for setting the criterion value, the judgment criterion value of intestinal dysbiosis is set. means for storing and assigning a decision score to the decision criteria value ;
means for comparing the test values of the scoring items obtained from individual subjects or subject groups (users) with the criterion values, and calculating a criterion score corresponding to the collated criterion values ;
A means for calculating an intestinal flora score by adding the calculated determination scores together, and a means for determining non-disease-specific intestinal dysbiosis of the user using the intestinal flora score as an index. The program ,
The diversity-related index is an index that reflects the number of bacterial species and the evenness of the occupancy rate of each bacterium, and from the group consisting of diversity, FB ratio, the number of bacterial species belonging to the phylum Bacteroidetes, and the occupancy rate of the most dominant genus including at least one item selected,
The short-chain fatty acid production index is a group of intestinal bacteria recognized to have the ability to produce short-chain fatty acids, which consists of bifidobacteria, a group of lactic acid-producing bacteria, a group of butyric acid-producing bacteria, and the number of species of butyric acid-producing bacteria. including at least one item selected from
The intestinal immunity-related index is a group of intestinal bacteria that are recognized to produce substances that modify intestinal immunity, including Faecalibacterium, Akkermansia, Christensenera, and Aristipes. and at least one item selected from the group consisting of Clostridium spp.
The oral bacterium-related index is a group of enteric bacteria that are recognized to be abundant in the oral cavity, and consists of Fusobacterium spp., Streptococcus spp., oral bacterium occupancy, and gamma proteobacteria including at least one item selected from the group
Said program . 6. The program according to claim 5 , wherein the criterion value is set based on a comparison of test value distributions of a criterion value setting population for each item included in the index.

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