JP2020078273A - Intestinal dysbiosis determination system - Google Patents

Abstract

To provide a method for determining intestinal dysbiosis.SOLUTION: A method for determining intestinal dysbiosis includes: setting a determination criterion value and a determination score for intestinal dysbiosis with respect to at least one index selected from a 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, regarding the intestinal bacteria of a population for determining the criterion value; collating bacterial composition data obtained from an individual subject or a subject groups (users) with the criterion value, and calculating a user value of the determination score for each of the indices; calculating an intestinal flora score by adding the calculated user value; and determining the intestinal dysbiosis of the user by using the intestinal flora score as an index.SELECTED DRAWING: Figure 1

Description

  TECHNICAL FIELD The present invention relates to a system and a determination method for determining non-specific and various states of intestinal dysbiosis.

About 1,000 types of enterobacteria 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. Plays. However, for some reason, (i) the total number of intestinal bacteria is significantly reduced, (ii) its composition ratio changes, (iii) normally, the bacterial species with a low bacterial count level becomes abnormal. Abnormalities such as increase will occur. Such a structural abnormality of the intestinal flora is called Gut Dysbiosis (Non-patent Document 1).
However, the intestinal microbiota is diverse, such as different for each disease and the content of lifestyle, and there are various indicators and bacterial flora, and the definition of intestinal dysbiosis is consistent among researchers. Not (Non-Patent Document 1).

On the other hand, when the clinician (healthcare worker) feeds back the test results of intestinal bacteria to the patient, it is not possible to explain individual indexes or specific characteristics of bacteria. For this reason, it is necessary for medical staff to be able to simply explain to patients, etc., whether they are “good flora” or “bad flora”.
BACKGROUND ART Conventionally, techniques related to a disease prediction system using intestinal bacteria have been known (Patent Documents 1 to 5), but a method for determining a nonspecific and diverse state called intestinal dysbiosis has not been sufficiently researched. Although not advanced, it was difficult to determine intestinal dysbiosis.

Patent No. 5645761 JP2012-165716A Special table 2005-523695 JP-A-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 for making it possible to determine a nonspecific and diverse state of intestinal dysbiosis with a unified index and standardized criteria.

The present inventor, as a result of intensive research to solve the above problems, found that it can be easily evaluated by a unified index and standardized criteria using intestinal indigenous bacteria, to complete the present invention I arrived.
That is, the present invention is as follows.
(1) A method for determining intestinal dysbiosis,
Regarding the intestinal bacteria of the population for determining the criterion value, 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 bacterial-related index and a diarrhea constipation-related index, A step of setting a judgment reference value for intestinal dysbiosis,
Bacterial composition data obtained from individual subjects or subject groups (users) is collated with the determination reference value, and a determination score is calculated for each of the indices.
The method, comprising: adding the calculated determination scores to each other to calculate an intestinal flora score; and determining intestinal dysbiosis of the user using the intestinal flora score as an index.

(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 bacterial species belonging to the phylum Bacteroidetes, and occupancy 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, a lactic acid-producing bacterium group, a butyric acid-producing bacterium group, and the number of butyric acid-producing bacterium species. ..
(4) The intestinal immunity-related index includes at least one item selected from the group consisting of Faicalibacterium spp., Ackermancia spp., Christensenella spp., Aristipes spp., and Clostridium spp. ).
(5) The oral bacterium-related index includes at least one item selected from the group consisting of Fusobacterium, Streptococcus, oral bacterial occupancy, and the number of gamma proteobacteria species, (1) the method of.
(6) The method according to (1), wherein the diarrhea constipation-related index is enterotype.
(7) The determination reference value is set based on a comparison of inspection value distributions of the determination reference value setting population of each item included in the index, any one of (1) to (6) The method described in the section.

(8) A system for determining intestinal dysbiosis,
Means for storing bacterial composition data obtained from individual subjects or a group of subjects (users),
Regarding the intestinal bacteria of the population for determining the criterion value, 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 bacterial-related index and a diarrhea constipation-related index, Means for storing the reference value of intestinal dysbiosis,
A means for calculating a judgment score for each of the indicators by collating the judgment reference value with the bacterial composition data,
The system, which includes a unit that adds the calculated determination scores to each other to calculate an intestinal flora score, and a unit that determines the 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 bacterial species belonging to the genus Bacteroidetes, and occupancy 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 bifidobacteria, lactic acid-producing bacterial groups, butyric acid-producing bacterial groups, and the number of butyric acid-producing bacterial species. ..

(11) The intestinal immunity-related index includes at least one item selected from the group consisting of Faecalibacterium spp., Ackermancia spp., Christensenella spp., Aristiphes spp., and Clostridium spp. ) Described in the system.
(12) 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 species, (8) System of.
(13) The system according to (8), wherein the diarrhea constipation-related index is enterotype.
(14) The determination reference value is set based on a comparison of the inspection value distributions of the determination reference value setting population of each item included in the index, any one of (8) to (13) The system described in paragraph.

(15) A program for determining intestinal dysbiosis, which uses a computer
Regarding the intestinal bacteria of the population for determining the criterion value, 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 bacterial-related index and a diarrhea constipation-related index, Means for storing the reference value of intestinal dysbiosis,
Means for storing bacterial composition data obtained from individual subjects or subject groups (users),
The fungal composition data, collating with the judgment reference value, means for calculating a judgment score for each of the indicators,
The program for functioning as means for adding the calculated determination scores to each other to calculate an intestinal flora score, and as means for determining the intestinal dysbiosis of the user using the 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 bacterial species belonging to the genus Bacteroidetes, and occupancy 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, lactic acid-producing bacterial groups, butyric acid-producing bacterial groups, and the number of butyric acid-producing bacterial species. ..
(18) The intestinal immunity-related index includes at least one item selected from the group consisting of Faikalibacterium spp., Ackermancia spp., Christensenella spp., Aristipes spp. and Clostridium spp. ) Described in the program.
(19) The oral bacterium-related index includes at least one item selected from the group consisting of Fusobacterium, Streptococcus, oral bacterium occupancy, and the number of gamma proteobacteria species, (15) Program of.
(20) The program according to (15), wherein the diarrhea constipation-related index is enterotype.
(21) The determination reference value is set based on the comparison of the inspection value distributions of the determination reference value setting population of each item included in the index, any one of (16) to (20) The program described in the section.

The present invention provides an intestinal dysbiosis determination method and determination system. According to the method of the present invention, it is possible to non-specifically determine intestinal dysbiosis using various indicators.
Hereinafter, the present invention will be described in detail.

1 is a block diagram of the system of the present invention. 6 is a flowchart showing the operation of the system of the present invention. It is a figure which shows distribution of the intestinal flora score of a healthy person cohort and an affected person cohort. It is a figure which shows the result of having calculated the intestinal flora score.

1. Overview The method, system and program of the present invention, a non-specific state of intestinal dysbiosis in which various aspects exist, simple by a unified index using intestinal indigenous bacteria, or by standardized criteria, It can be evaluated. The present inventor has found that there is an intestinal dysbiosis item that is specifically associated with the medical history or medication history of an individual subject. We also found that the flora score, which is a weighted addition of individual intestinal dysbiosis items, is an index that is nonspecifically associated with multiple diseases. The present invention has been completed based on such findings.

   In the present invention, in order to determine intestinal dysbiosis, a determination reference value is set for each intestinal dysbiosis scoring item. The determination reference 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, regarding intestinal bacteria in the determination-reference-value setting population. One is used as an index and is assigned as a unique value corresponding to each index. The judgment reference value setting population includes either one or both of the healthy population and the affected population.

Next, the bacterial composition data (inspection value) of the individual subject or the group of subjects who are the target users of the determination is read, and the determination score is calculated for the date corresponding to the intestinal dysbiosis scoring item in the bacterial composition data. The judgment score means a value (score) assigned by comparing the intestinal dysbiosis scoring item included in the above index with the judgment reference value.
Then, the calculated determination scores are added together to calculate the intestinal flora score. The calculation can be performed by, for example, weighted addition based on the inspection value distribution of the determination reference value setting population (healthy population and affected population). Intestinal dysbiosis is determined based on this intestinal flora score. The judgment score may include a negative value. Therefore, “addition” in the calculation of the intestinal flora score includes addition of a negative value, that is, subtraction.

   The intestinal flora score is a score for determining intestinal dysbiosis possessed by the user. When the user is a plurality of groups, the overall tendency of the intestinal flora score in the group (intestinal flora score distribution) is extracted, and it is determined which position in the whole each individual 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 stratified analysis within the population for setting judgment criteria. If there is a difference in the distribution as a result of the stratified comparison, the region or numerical value in which the difference appears may be used as the threshold value and used as the determination threshold value for intestinal dysbiosis.

2. Intestinal dysbiosis judgment method (1) Setting of judgment standard value and judgment score
In the present invention, first, human resident bacterial data and questionnaire data regarding a determination reference value setting population (hereinafter also referred to as “reference value population”) are acquired. 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 enough to produce a statistically significant difference or tendency. Human indigenous bacteria can be obtained from, for example, a fecal sample collected from humans, but can also be collected from the intestinal mucosa or the like by colonoscopy. Human resident bacterial data can be obtained by any known method, and for example, a commercially available kit (Mykinso (registered trademark)) or the like can be used.

  The questionnaire data is data of answers to questions from each subject in the reference value group. The questionnaire includes questions regarding the subject's medical history, what they ate in the days before collecting the stool sample, and questions regarding the content of the meal. The subject's subjective feeling of health may be conducted separately after a predetermined period (for example, several weeks to several months) after collecting the stool sample, or may be conducted simultaneously with another questionnaire. After collecting the questionnaire, all or part of the response contents are digitized while appropriately weighted and stored in the database.

The intestinal dysbiosis scoring items are selected according to the selection criteria (a) and (b) below.
(A) Based on the bacterial composition data contained in the intestinal bacteria database (also referred to as a database) and the basic attributes and questionnaire information of the subjects accumulated so far, the disruption of bacterial composition or the balance of bacterial composition From the viewpoint of stability, the characteristic genus bacteria and indicators were selected.
(B) Intestinal dysbiosis, based on whether or not there are findings that are in agreement with previous studies in the database that contains literature that compares indigenous bacteria of diseases in which enterobacteria are involved in pathological conditions with healthy subjects. Select relevant genus and indicators.

The indexes selected in this manner are diversity-related indexes, short-chain fatty acid production indexes, intestinal immunity-related indexes, oral bacteria-related indexes, and diarrhea constipation-related indexes.
The standard value of the above scoring items is a group for setting a judgment standard value, for example, a healthy cohort (of the users listed in the database, those who have a medical history, have diarrhea/constipation complaints, and are 60 years of age or older. It is set based on the comparison of the distribution of each test value between the excluded adult population) and the affected cohort (adult population who has a history of chronic diseases 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 evenness of the occupancy of each bacterium, and the items that belong to this index are diversity, FB ratio, and Bacteroidetes phyla. The number of bacterial species and the most dominant genus are mentioned.
Diversity is a calculated value obtained by multiplying the number of bacterial species in a sample by the evenness of the occupancy of each microorganism. The test value of diversity is converted into a predetermined numerical range based on the Shannon index. The numerical range is, for example, 0 to 10, preferably 3 to 8. The determination score of diversity is assigned to the test value (converted value) of diversity in the range of -10 to 10, for example, in the range of -10 to 10.
Table 1 (Example) described later is a list of the judgment reference value and the judgment score of each judgment item. For example, for the diversity, the judgment score is in the range of -10 to 10 for the inspection value of 3 to 8. It is assigned. For other items, similarly to the variety, the inspection value, the judgment reference value, and the judgment score are set.

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

The number of strains belonging to the phylum Bacteroidetes is set in the numerical range of 0 to 100, for example, 0 to 20. The judgment score is assigned in the range of -10 to 10, for example, in the range of -5 to 3, with respect to the test value (converted value) of the number of bacteria belonging to the phylum Bacteroidetes.
The occupancy of the most dominant genus is the value of the occupancy of the species having the highest occupancy in the sample. The occupancy of the most predominant bacterium is set within a range of 0 to 1 with 1 to 5, for example, 2 numerical values as a reference value. As for the judgment score, if two reference values of occupancy ratio are set to 0.35 and 0.4, for example, the judgment score is -1 to -5 in the case of 0.35 or more (e.g. -3), and -2 in the case of 0.4 or more. Assign like a decision score of -10 (eg -5). The occupancy of the most predominant bacterium has a negative effect in the intestine (for example, a decrease in diversity, especially a decrease in the evenness of the occupancy of each bacterium). It becomes a 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, and items belonging to this index include bifidobacteria and lactic acid-producing bacteria. Group, butyric acid-producing bacteria group and butyric acid-producing bacteria group.
Bifidobacterium represents the occupancy rate of Bifidobacterium per feces. Bifidobacteria are set in a numerical range of 0 to 1, for example, 0 to 1. The determination score is assigned to the test value (converted value) of Bifidobacterium in the range of -10 to 10, for example, the range of -3 to 7.

   The lactic acid-producing bacteria group represents the occupancy rate of a plurality of bacteria selected from Lactobacillus, Pediococcus, Leuconostoc, and Lactococcus per feces. The lactic acid-producing bacteria group is set to a numerical range of 0 to 1, for example, 0 to 1. The determination score is assigned to the test value (converted value) of the lactic acid-producing bacteria group in the range of -10 to 10, for example, the range of -10 to 3. Since the lactic acid-producing bacteria group has a negative influence in the intestine (for example, it shows a positive association with diarrhea symptom), the larger the test value, the more negative the judgment score.

The butyric acid-producing bacteria group represents the occupancy rate of a plurality of bacteria selected from butyricimonas, coprococcus, roseburia, butyricococcus, and faicalibacterium per faeces. The butyric acid-producing bacteria group is set to a numerical range of 0 to 1, for example, 0 to 1. The determination score is assigned to the test value (converted value) of the butyric acid-producing bacteria group in the range of -10 to 10, for example, -5 to 10.
The bacterial species number of butyric acid-producing bacteria means the bacterial species number belonging to the above-mentioned butyric acid-producing bacterial group.
The number of bacterial species belonging to the butyric acid-producing bacterial group is set in a numerical range of 0 to 5, for example, 0 to 5.
The determination score is assigned in the range of -10 to 10, for example, in the range of -5 to 5 with respect to the test value (converted value) of the number of butyric acid-producing bacteria.

(iii) Intestinal immunity-related index The intestinal immunity-related index means an intestinal bacterium group that is recognized to produce a substance that modifies intestinal immunity. , Ackermansia spp, Christensenella spp, Alistipes spp and Clostridium spp.
The bacterium belonging to the genus Fecalibacterium represents the occupancy rate of the bacteria belonging to the genus Fecalibacterium per stool. For the bacterium of the genus Feicaribacterium, it is set to a numerical range of 0 to 1, for example, 0 to 1. The determination score is assigned in the range of -10 to 10, for example, in the range of -5 to 5 with respect to the test value (converted value) of the bacterium of the genus Feicaribacterium.

The bacterium of the genus Ackermancia represents the occupancy rate of the bacterium belonging to the genus Ackermancia per stool. Ackermansia is set in a numerical range of 0 to 1, for example, 0 to 1. The judgment score is assigned in the range of -10 to 10, for example, the range of 0 to 3, with respect to the test value (converted value) of the bacterium of the genus Ackermancia.
The Kristen Senera genus represents the occupancy rate of the bacteria belonging to the genus Kristen Senera per stool. The Kristen Senella spp. is set in a numerical range of 0 to 1, for example, 0 to 1. The determination score value is assigned in the range of -10 to 10, for example, the range of 0 to 3, with respect to the test value (converted value) of Kristen Senella spp.

  The bacterium of the genus Alistipes represents the occupancy rate of the bacterium belonging to the genus Alistipes per stool. The alistipes spp is set in a numerical range of 0 to 1, for example, 0 to 1. The determination score is assigned in the range of -10 to 10, for example, the range of 0 to 3, with respect to the test value (converted value) of the bacterium of the genus Aristipez.

 The Clostridium genus represents the occupancy rate of the bacteria belonging to the genus Clostridium per stool. The Clostridium genus is set to a numerical range of 0 to 1, for example, 0 to 1. The judgment score is assigned in the range of -10 to 10, for example, in the range of -5 to 0 with respect to the test value (converted value) of Clostridium. In addition, since there are multiple types of substances that act on intestinal immunity in the intestine of Clostridium (for example, cytokine substances that enhance inflammation, cytokine substances that suppress inflammation, etc.), Both set a negative judgment score.

(iv) Oral bacterium-related index The oral bacterium-related index means an intestinal bacterium group that is recognized to be present in the oral cavity in large numbers, and items belonging to this index include Fusobacterium and oral bacterium. Occupancy and the number of gamma proteobacteria species.
The Fusobacterium genus represents the occupancy rate of the bacterium belonging to the genus Fusobacterium per stool. Fusobacterium is converted into a numerical range of 0 to 1, for example, 0 to 1. The determination score is assigned in the range of -10 to 10, for example, the range of -10 to 0 with respect to the test value (converted value) of Fusobacterium. In addition, since Fusobacterium has a negative effect in the intestine (for example, a large amount thereof is present in the intestine of patients with colorectal cancer), the larger the test value, the more negative the judgment score.

   The Streptococcus genus represents the occupancy rate of the bacterium belonging to the genus Streptococcus per stool. Streptococcus is set in a numerical range of 0 to 1, for example, 0 to 1. The judgment score is assigned in the range of -10 to 10, for example, in the range of -5 to 0 with respect to the test value (converted value) of Streptococcus. Since Streptococcus bacteria have a negative effect in the intestine (for example, a large amount thereof is present in the intestine of patients with ulcerative colitis), a larger test value results in a negative determination score.

   The oral bacterial occupancy represents the occupancy of a plurality of bacteria selected from the group consisting of Streptococcus spp, Fusobacterium spp, Trouxsiella spp, and Klebsiella spp. The bacterial occupancy in the oral cavity is set to 1 to 5 in the numerical range of 0 to 1, for example, one numerical value as a reference value. If the reference value of the occupancy rate is set to, for example, 0.2 (one numerical value), the determination score is assigned as -10 when the value is 0.2 or more. Since oral bacteria have a negative effect in the intestine (for example, many in the intestine of patients with Crohn's disease), a larger test value results in a negative determination score.

   The number of gamma proteobacteria species indicates the number of species belonging to the gamma proteobacteria class per stool. The number of gamma proteobacteria species is converted into a numerical range of 0 to 100, for example, 0 to 10. The judgment score is assigned in the range of -10 to 10, for example, in the range of -7 to 0 with respect to the test value (converted value) of gamma proteobacteria. Since the number of gamma proteobacteria species has a negative effect in the intestine (for example, many in the intestine of patients with irritable bowel syndrome), the larger the test value, the more negative the judgment score.

(v) Diarrhea constipation-related index The diarrhea constipation-related index means a bacterial composition type (enterotype) that is strongly associated with diarrhea symptoms and constipation symptoms, and items belonging to this index include diarrhea-type enterotypes and constipation-type enterotypes. Type and enterotype R type.

  The enterotype R type represents a dominant bacterial composition of the genus Luminococcus. Enterotype R type is converted into a numerical range of 0 to 1, for example, 0 to 1. The determination score is assigned in the range of -10 to 10, for example, in the range of -5 to 5 with respect to the test value (converted value) of enterotype R type. Since enterotype R type has a negative effect as a bacterial composition type having a strong association with diarrhea symptoms and constipation symptoms (for example, increased constipation symptoms), a larger test value results in a negative determination score.

The diarrhea-type enterotype represents a bacterial composition type that is strongly associated with diarrhea symptoms. The diarrhea type enterotype is converted into a numerical range of 0 to 1, for example, 0 to 1. The determination score is assigned to the test value (converted value) of the diarrhea enterotype in the range of -10 to 10, for example, -5 to 5.
The constipation enterotype represents a bacterial composition type that is strongly associated with constipation symptoms. The constipation enterotype is converted into a numerical range of 0 to 1, for example, 0 to 1. The judgment score is assigned to the test value (converted value) of the constipation type enterotype in the range of -10 to 10, for example, -5 to 5.

(2) Intestinal flora score calculation and determination In this section, in order to calculate the test value of the intestinal dysbiosis scoring item of each user, a diversity-related index, short-chain fatty acid production index, intestinal immunity-related index, oral bacteria At least one index selected from the group consisting of related indices and diarrhea/constipation related indices is appropriately selected. Next, the scoring items included in the selected index are appropriately selected. In the present invention, it is preferable to adopt all the scoring items (18 items) included in the above-mentioned related indexes.
Next, each inspection value is compared and collated with the judgment reference value, and the score of the scoring item (that is, the judgment score) is calculated by a method such as weighted addition.

  After the calculation, the respective judgment scores are added together to calculate the intestinal flora score. The intestinal flora score is the basic information for determining intestinal dysbiosis. The threshold of the intestinal flora score 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 affected subject group. For example, if the threshold of the intestinal flora score is 50, if the score is less than 50, it is determined that the subject has intestinal dysbiosis or is at risk of intestinal dysbiosis.

  By the way, in the present invention, a statistical analysis process is performed on a predetermined number of subjects (primary mother sample), the correlation between the intestinal dysbiosis determination item and the user data is examined, and the result is stored in a database (DB). ). Therefore, when testing or judging individual test subjects (one person), the data from the plurality of test subjects is used as a mother sample, and the data of the subject of each subject is located in the data of the mother samples stored in the database. Intestinal dysbiosis can be determined for the individual subject by investigating whether or not it is true or true. The data of the individual subject may be incorporated into the values of the mother sample, and the statistical analysis process may be performed again, and then the position of the individual subject in the mother sample may be examined.

3. Information Processing Device and Program Next, an information processing device 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 addition, below, a test subject group or a test subject individual is demonstrated as a "user."

  The information processing device 10 is a server type computer including a CPU, a ROM, a RAM, an input/output interface, and the like. The information processing device 10 is communicatively connected to a plurality of user devices 30a to 30n (collectively referred to as “user device 30”) via a network 20 such as the Internet or a LAN.

  The information processing device 10 collates the intestinal dysbiosis scoring item of the user (referred to as "target user") to be surveyed or focused on with the intestinal dysbiosis scoring item of a healthy person stored in the database, and uses it as a comparison result. Based on this, a judgment score is calculated. Then, the information processing device 10 calculates the intestinal flora score by adding the calculated determination scores to each other, and determines whether the target user has intestinal dysbiosis based on the calculated intestinal flora score. Then, the information processing device 10 transmits the intestinal dysbiosis determination result of the user to the user device 30.

  The user device 30 is a device such as a computer including an information input unit and a display unit, or a device such as a smartphone or a tablet, and is communicatively connected to the information processing device 10 via the network 20. The user device 30 provides an interface for displaying various information received from the information processing device 10 on a display or inputting information to be sent to the information processing device 10 through a browser or an application.

  The information processing system 1 may include an inspection body 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 device 10 acquires information (human intestinal bacteria data) about the human intestinal bacteria of the user, which is associated with the identification information of the user, from the inspection institution 40 via the network 20. The information processing apparatus 10 may directly acquire the human intestinal bacteria data from the inspection organization 40 without the network 20. Further, when the human intestinal bacterium data is sent from the inspection institution 40 to the user device 30, the information processing device 10 may acquire the human intestinal bacterium data from the user device 30. Furthermore, the inspection organization 40 and the information processing apparatus 10 may belong to the same organization, or may belong to different organizations.

  The human intestinal bacterial 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 indexes are as described above.

  The information processing device 10 includes an information acquisition unit 101, a scoring item extraction unit 102, and a judgment reference value setting function unit that is realized by a program stored in a ROM or a RAM and a CPU working together. The unit 103, the comparison unit 104, the intestinal flora score calculation unit 105, and the determination unit 106 are included. Further, the information processing device 10 includes a storage unit 110 provided in a ROM (or a RAM), and the storage unit 110 includes an intestinal bacterium database (DB) 111, a scoring item information database (DB) 112, and a determination reference database. (DB) 113 is included.

  The information acquisition unit 101 acquires various types of information from the user device 30 and/or the inspection organization 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 inspection organization 40 includes intestinal bacterial data of the user, information (questionnaire data) regarding answers to questions (questionnaire) to the user, and user identification information (name and birth date of the user). The date, address, telephone number, mail address used by the user, ID set by the user, etc.) are included. The user identification information may include the identifier of the user device 30 used by the user.

  Upon receiving the intestinal bacterium data of the user, the information acquisition unit 101 stores the intestinal bacterium information DB 111 in association with the user identification information. The intestinal bacterium information DB 111 stores intestinal bacterium data thus collected from a plurality of users. The intestinal bacterium information DB 111 includes user identification data and questionnaire information data. When the information acquisition unit 101 receives the user questionnaire data, the information acquisition unit 101 stores it in the scoring item DB 112 in association with the user identification information. The scoring item DB 112 stores questionnaire data collected from users in this way. The determination standard DB 113 stores information obtained by a statistical analysis process for extracting features by the determination standard value setting unit 104 described later. Since the information changes depending on the number of members and the number of members of the user mother sample subjected to the statistical analysis process, the information is stored in association with the information for identifying them.

Questions (questionnaire) provided to the user include the user's name, age, height, weight, BMI value, family composition, work type, living environment, exercise frequency, sleep satisfaction, dietary habits, constitution, medical history, and stool collection. Information may be included regarding time of day health status, medication history at stool collection, and mental status at stool collection.
Regarding the questionnaire data, the information processing apparatus 10 may transmit information regarding a question (questionnaire) to the user device 30, and the information acquisition unit 101 may receive information regarding an answer to the question from the user device 30. When the inspection institution 40 handles the questionnaire data, the information acquisition unit 101 may acquire the questionnaire data from the inspection institution 40.

FIG. 2 is a processing flowchart by the information processing device 10 according to the present embodiment.
In step S1, the information acquisition unit 101 of the information processing device 10 acquires human intestinal bacterium data and questionnaire data from the user and stores it in the intestinal bacterium information DB 111.
In step S2, the scoring item extraction unit 102 determines from the information stored in the intestinal bacterium information DB 111 from the diversity-related index, short-chain fatty acid production index, intestinal immunity-related index, oral bacteria-related index and 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. Further, in step S2, the determination reference value setting unit 103 sets the determination reference value and the determination score for each scoring item from the information stored in the scoring item information DB 112, and stores them in the determination reference DB.

  In step S3, the comparing unit 104 compares the intestinal bacterium information DB 111 and the scoring item information DB 112 with the determination reference value setting group (a healthy person group or an affected person group) and the test value of each index related to the intestinal bacterium of the target person. The reference value in the index is extracted, and the reference value and the inspection 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 determination score assigned to the target user (including a 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. The determination by the determination unit 106 is to extract the features of each of the plurality of indices while changing the determination reference value and the determination score within a predetermined range (step S2) (repeating steps S2 to 5).

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

  Hereinafter, the present invention will be described more specifically by way of examples. However, the present invention is not limited to these examples.

(1) Selection of intestinal dysbiosis scoring items <Selection criteria 1>
Cykinso doctors and researchers review bacterial composition data contained in the intestinal bacteria database, basic attributes of each of multiple subjects, and questionnaire information to determine the disruption of bacterial composition and stability of bacterial composition balance. From this point of view, the characteristic genera and indicators were selected.
<Selection criteria 2>
Based on whether or not there were findings that were consistent with previous studies published in overseas Disbiome databases, we sorted out genus bacteria and indicators related to intestinal dysbiosis.

The selected scoring items are as follows.
1. Diversity
2. FB ratio
3. Bifidobacteria
4. Lactic acid producing bacteria
5. Butyric acid-producing bacteria
6. Enterotype
7. Number of Bacteroidetes species
8. Number of gamma proteobacteria species
9. Faecalibacterium sp.
10. Ackermansia
11. Kristen Senera
12. Alistipes spp.
13. Clostridium spp.
14. Fusobacterium
15. Streptococcus
16. Occupancy of oral bacteria (Streptococcus, Fusobacterium, Trabulsiella, Klebsiella)
17. Occupancy of the most dominant genus
18. Number of butyric acid-producing bacteria

Table 1 shows specific examples of the judgment reference value.

<Example of judgment reference value setting>
In the case of Bifidobacterium, the median value of healthy subjects is 5.75, so the following judgment reference values and judgment scores are set.
If the inspection value is 0 or more and less than 0.03: 3 points deduction If the inspection value is 0.03 or more and less than 0.06: 3 points addition If the inspection value is 0.06 or more and less than 0,1: 5 points addition If the inspection value is 0.1 or more Case: 7 points added

(2) Calculation of Flora Score The determination reference value and the determination score of the intestinal dysbiosis scoring item were set based on the comparison of the distribution of the test values of the healthy cohort and the affected cohort.
The healthy cohort was a group of adults excluding the users listed in the database from those listed below in the answers to the questionnaire.
"Medical history", "Complaint of diarrhea/constipation", "Age over 60 years old"

(3) Flora score calculation algorithm
In Step 1, the test values of Bifidobacteria, butyric acid-producing bacteria, and lactic acid-producing bacteria of each user were calculated.
(i) bifidobacteria = 0.013, (ii) butyric acid-producing bacteria = 0.0643, (iii) lactic acid-producing bacteria = 0.0001.
In Step 2, the judgment score of each item was calculated by collating with the reference values of the bifidobacteria, butyric acid-producing bacteria and lactic acid-producing bacteria shown in Table 1 above. In this case, a large number of deduction points indicate the tendency of intestinal dysbiosis.
(i) Bifidobacteria=-3, (ii) Butyric acid-producing bacteria=3, (iii) Lactic acid-producing bacteria=-3
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 score is set to 60 and the judgment score of each item is added.
・Intestinal flora score = 58.5

(4) Results and Discussion Results are shown in FIG.
We found that an intestinal flora score of less than 50 strongly reflects the nonspecific intestinal dysbiosis common to multiple diseases.
The present inventor has shown that about half of the intestinal dysbiosis items associated with individual medical history and medication history are bacteria and bacterial groups that respond nonspecifically to multiple diseases.
Therefore, many of the associations found in selected intestinal dysbiosis items are not disease-specific, but rather likely to be biomarkers of nonspecific 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. The analysis was performed by generalized linear model and logistic regression analysis.

The results are shown in Fig. 4.
The first line of the category 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, a portion showing a positive association with a disease is red, a portion showing a negative association with a disease is blue, and a color intensity shows 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 category in FIG. 4 is a heat map showing the intensity of disease-specific/non-specific intestinal dysbiosis in the index relating 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 the index related to intestinal immunity.
In both diabetes and dyslipidemia, it was found that the number of Kristensenella spp. was low.

The fourth row of the category in FIG. 4 is a heat map showing the intensity of disease-specific/non-specific intestinal dysbiosis in the index relating to oral bacteria.
In the case of dyslipidemia, it was found that both Fusobacterium and Streptococcus are common.

The fifth line in the category of FIG. 4 is a heat map showing the intensity of disease-specific/non-specific intestinal dysbiosis in the index related to diarrhea constipation.
It was found that there are few enterotypes R in 3 diseases of hypertension, dyslipidemia, and diabetes.

1: system of the present invention, 10: information processing device, 20: network, 30: user equipment, 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: Rating item information DB, 113: Judgment criteria DB

Claims (21)

A method for determining intestinal dysbiosis,
Regarding the intestinal bacteria of the population for determining the criterion value, 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 bacterial-related index and a diarrhea constipation-related index, A step of setting a judgment reference value for intestinal dysbiosis,
Bacterial composition data obtained from individual subjects or subject groups (users) is collated with the determination reference value, and a determination score is calculated for each of the indices.
The method, comprising: adding the calculated determination scores to each other to calculate an intestinal flora score; and using the intestinal flora score as an index to determine the intestinal dysbiosis of the user.   The method according to claim 1, wherein the diversity-related index includes at least one item selected from the group consisting of diversity, FB ratio, the number of bacterial species belonging to the phylum Bacteroidetes, and occupancy of the most dominant genus.   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, a lactic acid-producing bacterial group, a butyric acid-producing bacterial group, and the number of butyric acid-producing bacterial species.   The intestinal immunity-related index includes at least one item selected from the group consisting of Faicalibacterium spp., Ackermansia spp., Christensenella spp., Aristipes spp., and Clostridium spp. the method of.   The method according to claim 1, wherein the oral bacterium-related index includes at least one item selected from the group consisting of Fusobacterium, Streptococcus, oral bacterial occupancy, and gamma proteobacteria species number.   The method according to claim 1, wherein the diarrhea constipation-related index is enterotype.   The method according to any one of claims 1 to 6, wherein the determination reference value is set based on a comparison of inspection value distributions of the determination reference value setting population of each item included in the index. .. A determination system for intestinal dysbiosis,
Means for storing bacterial composition data obtained from individual subjects or a group of subjects (users),
Regarding the intestinal bacteria of the population for determining the criterion value, 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 bacterial-related index and a diarrhea constipation-related index, Means for storing the reference value of intestinal dysbiosis,
A means for calculating a judgment score for each of the indicators by collating the judgment reference value with the bacterial composition data,
The system, which includes a unit that adds the calculated determination scores to each other to calculate an intestinal flora score, and a unit that determines the intestinal dysbiosis of the user using the intestinal flora score as an index.   The system according to claim 8, wherein the diversity-related index includes at least one item selected from the group consisting of diversity, FB ratio, the number of bacterial species belonging to the phylum Bacteroidetes, and occupancy of the most dominant genus.   The system according to claim 8, wherein the short-chain fatty acid production index includes at least one item selected from the group consisting of bifidobacteria, a lactic acid-producing bacterial group, a butyric acid-producing bacterial group, and the number of butyric acid-producing bacterial species.   9. The intestinal immunity-related index includes at least one item selected from the group consisting of Faicalibacterium spp., Ackermancia spp., Christensenella spp., Aristipeth spp. and Clostridium spp. System of.   The system according to claim 8, wherein the intraoral bacterium-related index includes at least one item selected from the group consisting of Fusobacterium, Streptococcus, oral bacterium occupancy, and gamma proteobacteria species number.   The system according to claim 8, wherein the diarrhea constipation-related indicator is enterotype.   The system according to any one of claims 8 to 13, wherein the determination reference value is set based on a comparison of inspection value distributions of the determination reference value setting population of each item included in the index. .. A computer program for determining intestinal dysbiosis
Regarding the intestinal bacteria of the population for determination criterion value setting, 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 bacterial related index and a diarrhea constipation related index, Means for storing the reference value of intestinal dysbiosis,
Means for storing bacterial composition data obtained from individual subjects or a group of subjects (users),
The fungal composition data, collating with the judgment reference value, means for calculating a judgment score for each of the indicators,
The program for functioning as means for adding the calculated determination scores to each other to calculate an intestinal flora score, and as means for determining the intestinal dysbiosis of the user by using the intestinal flora score as an index.   16. The program according to claim 15, wherein the diversity-related index includes at least one item selected from the group consisting of diversity, FB ratio, number of bacterial species belonging to the phylum Bacteroidetes, and occupancy of the most dominant genus.   16. The program according to claim 15, wherein the short-chain fatty acid production index includes at least one item selected from the group consisting of bifidobacteria, lactic acid-producing bacterial groups, butyric acid-producing bacterial groups, and the number of butyric acid-producing bacterial species.   The intestinal tract immunity-related index includes at least one item selected from the group consisting of Ficaribacterium spp., Ackermancia spp., Christensenella spp., Aristipes spp. and Clostridium spp. Program of.   The program according to claim 15, wherein the oral bacterium-related index includes at least one item selected from the group consisting of Fusobacterium, Streptococcus, oral bacterium occupancy, and the number of gamma proteobacteria species.   The program according to claim 15, wherein the diarrhea constipation-related index is enterotype. 21. The program according to claim 16, wherein the determination reference value is set based on a comparison of inspection value distributions of determination reference value setting populations of respective items included in the index. ..