WO2013012332A1 - Identification des sujets à risque de développer le syndrome de l'intestin irritable - Google Patents

Identification des sujets à risque de développer le syndrome de l'intestin irritable Download PDF

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Publication number
WO2013012332A1
WO2013012332A1 PCT/NL2012/050519 NL2012050519W WO2013012332A1 WO 2013012332 A1 WO2013012332 A1 WO 2013012332A1 NL 2012050519 W NL2012050519 W NL 2012050519W WO 2013012332 A1 WO2013012332 A1 WO 2013012332A1
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Prior art keywords
ibs
subject
enterotype
developing
risk
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PCT/NL2012/050519
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English (en)
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Lambertus Tuk
Mirjana Rajilic-Stojanovic
Willem Meindert De Vos
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Aak Patent B.V.
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Publication of WO2013012332A1 publication Critical patent/WO2013012332A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
    • C12Q1/04—Determining presence or kind of microorganism; Use of selective media for testing antibiotics or bacteriocides; Compositions containing a chemical indicator therefor
    • C12Q1/10—Enterobacteria
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6888—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for detection or identification of organisms
    • C12Q1/689—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for detection or identification of organisms for bacteria

Definitions

  • the present invention is in the field of microbiology and gastrointestinal health, and relates to the use of the gastrointestinal microbiota as a biomarker for intestinal aberrations, notably Irritable Bowel Syndrome.
  • the gastro-intestinal tract is colonized since birth by complex communities of microbes, including bacteria, archaea and fungi, that develop in time and space. These microbial communities were collectively termed gut microflora in previous times but are now known as gut microbiota that is of a highly complex nature. (Rajilic-Stojanovic et al. 2007. Environ Microbiol 9: 2125-2136).
  • the gut microbiota is involved in a variety of metabolic functions, such as the processing of food components that are not digested by the host, the synthesis of vitamins and the production of short chain fatty acids.
  • IBD Inflammatory Bowel Disease
  • IBS Irritable Bowel Syndrome
  • enterotypes enterotypes
  • IBS is a multi-factorial and complex disorder clinically characterized by recurrent episodes of abdominal discomfort or pain, altered bowel habit and urge.
  • IBD and IBS also other diseases are known to be associated with aberrations in microbiota and these include obesity, the various types of diabetes such as type I diabetes and type II diabetes, Autistic Spectrum Disorder (ASD) related diseases, celiac disease and some forms of cancer (Zoetendal et al, 2008, supra).
  • ASD Autistic Spectrum Disorder
  • IBS is the most prevalent functional bowel disorder, that affects up to 20 percent of the general population in the world. Furthermore, IBS is associated with a high rate of absenteeism from work, a significant impairment in quality of life and substantial health care costs. The economic consequences of IBS are substantial.
  • the annual direct and indirect medical costs of IBS management in the US are as high as US$ 8 billion and $25 billion, respectively (Horwitz, B. & Fisher, R. The irritable bowel syndrome. N. Engl. J. Med. 344, 1846-1850 (2001)).
  • IBS-C constipation
  • IBS-D diarrhea
  • IBS-A alternating constipation/diarrhea subtypes
  • IBS is only diagnosed by exclusion of IBD and other (bowel) disorders (such as celiac disease, colorectal cancer, ovarian cancer, diverticulosis, gallstones, food allergies, bacterial infections, intestinal parasites, endometriosis and lactose malabsorption) and is dependent on an anamnesis as laid down in the Rome criteria.
  • IBS bowel
  • biomarkers that are indicative of IBS, as is confirmed by the US National Institute of Health that states that no test for IBS is known (http://digestive.niddk.nih.gov/ddiseases/pubs/ibs/).
  • biomarkers are needed to develop a diagnostic test for IBS. These biomarkers can be used to diagnose IBS but also may be instrumental in identifying subjects at increased risk of developing IBS. Moreover, the identification of such biomarkers may lead to the discovery and development of new and innovative therapeutic or preventive interventions for IBS.
  • IBS The pathophysiologic pathway of IBS is unknown, and diagnostic procedures, among other by blood analysis, endoscopy, histology and radiologic procedures, do not reveal any common structural abnormalities in the digestive tract. While for a long time IBS has been considered a psychosomatic aberration, in recent years support has been provided for the involvement of biological and hereditary factors concerning the hypersensitivity of the brain- gut axis. Recent studies provide several lines of evidence that support a relation between intestinal microbiota and IBS. In various cases IBS is triggered in previously healthy individuals by acute Gl tract infection (gastro-enteritis) by external microbiota resulting in the so called post-infective IBS: up to 25% of patients with acute Gl tract infection develop IBS.
  • Gl tract infection gastro-enteritis
  • WO 2011/043654 which is herein incorporated by reference, describes a method for diagnosing and/or subtyping IBS in a test sample, which method uses the increased or decreased level of specific gut microbes in IBS patients compared to healthy subjects to establish a diagnosis of IBS.
  • the present invention provides for the use of enterotyping of the gut microbiota for identifying a subject at risk of developing Irritable Bowel Syndrome (IBS) and/or diagnosing a subject suffering from IBS.
  • IBS Irritable Bowel Syndrome
  • assignment of the gut microbiota of a subject to enterotype 3 is indicative of an increased risk of developing IBS.
  • the invention is also concerned with a method for identifying a subject at risk of developing IBS and/or for diagnosing a subject suffering from IBS, said method comprising the step of enterotyping the gut microbiota of said subject.
  • Said method may further comprise the steps of: a) providing a test sample of a subject; b) determining the enterotype of said subject from said test sample; and c) determining whether the enterotype of said subject is indicative of an increased risk of developing IBS.
  • a determination of enterotype 3 is indicative of an increased risk of developing IBS.
  • enterotype is well known from the publication by Arumugam et al. (2011), supra. It refers to a characteristic gastrointestinal microbial community of which only a limited number exist across individuals. The enterotype is characteristic for an individual, in line with gut microbiota being quite stable in individuals and capable of being restored even after perturbation. It may be compared to the blood type, of which also a limited number exist, and which is also characteristic for an individual. For further details on enterotypes we refer to the publication by Arumugam et al. (201 1), supra, which is herein incorporated by reference. Presently, 3 of such enterotypes have been identified. Enterotype 1 is enriched in
  • Enterotype 2 is enriched in Prevotella and the co-occurring Desulfovibrio, Streptococcus, Enterococcus, and Lachnosipraceae.
  • Enterotype 3 is enriched in Ruminococcus and co-occurs with Akkermansia, Allistipes, Klebsiella, Escherichia/ Shigella, Dialister, Mitsuokella, Methanobrevibacter, Eggerthella, Ruminococcaceae, Subdoligranulum, Coprococcus, Collinsella, Blautia, Eubacteri urn and Dorea.
  • Table 3 of WO 2011/043654 which is herein incorporated by reference, discloses accession numbers for 16S rRNA genes for said genera.
  • enterotype i.e., a characteristic gastrointestinal microbial community as defined above. Enterotypes may be determined in a variety of ways. They have been discovered based on deep metagenome sequencing of DNA isolated from fecal samples that was cloned and characterized by the so-called Sanger sequencing, providing long about 500 nucleotide reads (Arumugam et al. 201 1 , supra). Similarly, fecal metagenome libraries characterized by lllumina sequencing that generate short approximately 50 nucleotide reads were used to derive enterotypes
  • enterotypes were also found using information derived from fragments of the 16S rRNA genes that were characterized by pyrosequencing, an approach that generated a few hundred nucleotide long reads (Arumugam et al. 201 1 , supra).
  • information generated by hybridization of rRNA gene sequences derived from fecal samples to the Human Intestinal Tract (HIT)Chip, a phylogenetic microarray was described to generate the enterotypes (Arumugam et al. 201 1 , supra).
  • HIT Human Intestinal Tract
  • sequence information of metagenomes as well as 16S rRNA genes, phylogenetic microarray analysis, or proteome information can be used to classify a subject's fecal microbiota into enterotypes.
  • transcriptome and metabolome analysis can be used to classify a subject's fecal microbiota into enterotypes.
  • enterotypes As in the original description of the enterotypes (Arumugam et al. 201 1 , supra) a listing is provided of microbes that contribute to various extent to the enterotypes, this information can be used by those skilled in the art to design various ways to determine enterotypes.
  • enterotype 1 , 2, and 3 have been identified (i.e., enterotype 1 , 2, and 3), with characteristic
  • a subject may be an animal or a human being.
  • any subject could be diagnosed using the method of the invention.
  • the diagnosis method may be applied as often as necessary in a subject.
  • the subject is a human being.
  • a "healthy subject” as referred to herein does not suffer from any conditions or diseases of the gastrointestinal tract such as IBS, and preferably does not suffer from any conditions or diseases.
  • test sample is preferably a biological sample.
  • a biological sample refers to a biological tissue or biological fluid from a subject.
  • samples can be useful in practicing the invention including, for example, faeces, an intestinal sample, blood, serum, plasma, urine, breath (exhaled air), DNA, salivary fluid, ascite fluid, and the like.
  • microbial metabolites may be found in the urine, blood, fecal water or extracts of fecal material or exhaled air. It is known that specific host-microbe interactions occur in the human body and hence it is feasible that host genomic sequences may be correlated with specific enterotypes.
  • intestinal sample refers to all samples that originate from the intestinal tract, including, without limitation, feces samples, rectal swap samples, but also samples obtained from other sites in the intestinal tract, such as mucosal biopsies, as was shown previously (Zoetendal et al 2002 . Appl. Environ. Microbiol. 68:3401-7 and Kerkhoffs et al., 2009, supra).
  • a test sample may be obtained from any subject, such as a subject suffering from IBS, a healthy subject, a subject with unknown diagnosis of IBS, or a subject with complaints related to the gastro-intestinal tract.
  • the test sample may have been processed; for example, DNA and/or RNA and/or protein may have been isolated from feces samples, rectal swap samples, or samples obtained from other sites in the intestinal tract.
  • gut microbiota refers to the microorganisms that inhabit the digestive tract (also referred to as “gut” or "gastrointestinal tract”).
  • IBS patients carried almost exclusively microbiota belonging to enterotype 3 (hereinafter also referred to as "ES3") (98.4 %) which is significantly higher (p value 0.0004) than that found in healthy subjects. Since it is unlikely that a transition between enterotypes may occur, it is hypothesized that individuals with an ES3 microbiota have a propensity to develop one of the specific types of IBS. As such, it is possible to determine the risk for IBS by determining the enterotype. Specifically, subjects with enterotype 3 have a higher risk for IBS than subjects with other enterotypes. Subjects at increased risk for IBS may be monitored for development of IBS, and may be subjected to intervention preventing the development of IBS.
  • enterotype 3 enterotype 3
  • the present invention provides for use of enterotyping of the gut microbiota for identifying a subject at risk of developing Irritable Bowel Syndrome (IBS) and/or diagnosing a subject suffering from IBS.
  • IBS Irritable Bowel Syndrome
  • said subject has an increased risk of developing IBS.
  • Said use is carried out ex vivo, i.e., on an ex vivo test sample.
  • enterotype 3 As subjects suffering from IBS are known to have enterotype 3 exclusively, it is obvious that subjects having enterotype 3 have a propensity to develop IBS. Thus, determining the enterotype results in identification of a subject at risk of developing IBS. Subjects having enterotype 3 may have an increased risk of developing IBS compared to subjects having enterotype 1 or enterotype 2. Enterotyping may therefore exclude subjects having enterotype 1 or enterotype 2 from running a risk of developing IBS.
  • the method of the present invention may also be used in diagnosing a subject suffering from IBS.
  • determining the enterotype may be a first step in diagnosing a subject suffering from IBS.
  • Subjects having enterotype 1 or enterotype 2 may be excluded from receiving a diagnosis of IBS.
  • Subjects having enterotype 3 may in a second step be subjected to further IBS diagnosis methods, for example, those described in WO 201 1/ 043654 to unequivocally establish a diagnosis of IBS.
  • the enterotype is preferably determined using an ex vivo sample as described above in the definitions section.
  • the present invention also provides for a method for identifying a test sample derived from a subject at risk of developing IBS and/or from a subject suffering from IBS.
  • the enterotype may be determined in various way which have been set out in Arumugam et al. 201 1 , vide supra.
  • the enterotype may be determined by determining the level of bacteria belonging to the enterotype genera.
  • One of the most researched microbial nucleic acids is that of the 16S rRNA.
  • This 16S rRNA also known as small subunit (SSU) RNA, is encoded by an approximately 1500 bp gene that is present in a variable number of copies, usually 1-10 per microbial genome.
  • SSU small subunit
  • the nucleotide sequence of the 16S rRNA genes is frequently used in diagnostics as it shows differences between microbial species. In fact 16S rRNA gene sequences are instrumental in defining the taxonomic position of microbes.
  • these 16S rRNA sequences may also identify microbes that have not yet been cultured but are only known because of the presence of a 16S rRNA gene sequence. In case this gene sequence differs significantly (usually less than 98 % similarity) from the 16S rRNA gene sequence of a known species, this is indicated as a new phylotype (a new species consisting of microbes that have not been cultured yet). However, a growing number of microbes are brought into culture and otherwise described by sequence analysis of their complete or partial genomes. Up to now over several thousands of microbial genomes have been sequenced and are publicly available (see http://genomesonline.org or http://www.ncbi.nlm.nih.gov).
  • V1-V8 A growing database of over a million microbial 16S rRNA sequences can be found in publicly available databases such as http://www.arb-silva.de (Pruesse et al., 2007. Nucleic Acid Res. 35:7188) and http://rdp.cmu.mse.edu (Cole et al., 2008. Nucleic Acids Res. 35 (Database issue): D169-D172). It has been well-established that the 16S rRNA sequence contains a limited number of variable regions of several dozens of nucleotides, termed V1-V8, that are targets for developing nucleic acid probes, PCR primers or LCR probes.
  • variable regions in the microbes that are found in the human intestinal tract By analyzing the variable regions in the microbes that are found in the human intestinal tract, it was observed that the most diagnostic information for developing nucleic acid probes were the V1 and V6 regions (Rajilic-Stojanovic et al., 2009, supra). Hence, based on the sequences of these variable regions a total of over 3,699 unique oligonucleotide probes of around 16-30 nucleotides have been developed that are present on the so called Human Intestinal Tract (HIT) Chip, a phylogenetic microarray (Rajilic-Stojanovic et al 2009, supra). These oligonucleotides are called HIT probes.
  • HIT Human Intestinal Tract
  • Hybridization to the HIT probes can be used to deduce what microbe is present and allows its taxonomic identification at different level, the most important ones including genus-like groups (sequence similarity > 90% - so called level 2 groups) and phylotype-like groups (sequence similarity > 98% - so called level 3 groups) (Rajilic-Stojanovic et al 2009, supra).
  • the level of bacteria belonging to enterotype 1 , enterotype 2 and/or enterotype 3 may be measured by determining the level of specific nucleic acid sequences in said test sample, which nucleic acid sequences are preferably 16S rRNA gene sequences of said one or more bacteria, more preferably one or more variable regions of said 16S rRNA gene sequences, e.g., one or more of the variable regions V1 and/or V6 of said 16S rRNA gene sequences.
  • biomarkers can serve as biomarkers for subjects at risk of developing IBS alone or in combination.
  • a biomarker, or biological marker is in general a substance used as an indicator of a biologic state.
  • Biomarkers can include a variety of stable macromolecular molecules, including nucleic acids, proteins or lipids but also metabolites or a combination thereof.
  • nucleic acids including DNA and RNA, that are present in the intestinal microbiota as they are stable but can be isolated easily.
  • proteins encoded by the said DNA can be considered useful biomarkers, notably when they are stable.
  • An affected intestinal bacteria as used in this context means either more or less prevalent in subjects at risk of developing IBS as compared to subjects not at risk of developing IBS (i.e., those having enterotypes 1 or 2).
  • an assignment of the gut microbiota of a subject to enterotype 3 is indicative of an increased risk of developing IBS.
  • the assignment of the enterotype can be done as shown by Arumugam et al. (2011), supra, which is herein incorporated by reference, and which is discussed above in the definitions section.
  • the present invention pertains to a method for identifying a subject at risk of developing IBS and/or for diagnosing a subject suffering from IBS, said method comprising the step of enterotyping the gut microbiota of said subject.
  • the method may comprise the steps of: a) providing a test sample of a subject; b) determining the enterotype of said subject from said test sample; and c) determining whether the enterotype of said subject is indicative of an increased risk of developing IBS.
  • a determination or assignment of enterotype 3 is indicative of an increased risk of said subject developing IBS.
  • Example 1 Enterotype determination of the fecal microbiota of IBS and healthy subjects Fecal samples were obtained from a of a total of 62 IBS subjects and a total of 46 healthy individuals that were matched for age, gender and body mass index. Microbial DNA was isolated from these fecal samples following the method of Ahlroos & Tynkynnen (Ahlroos T, Tynkkynen S. Quantitative strain-specific detection of Lactobacillus rhamnosus GG in human faecal samples by real-time PCR J Appl Microbiol.

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Abstract

Cette invention concerne l'utilisation de l'entérotypage du microbiote intestinal pour identifier un sujet à risque de développer le syndrome de l'intestin irritable (SII) et/ou pour diagnostiquer un sujet atteint de SII, ainsi qu'une méthode pour identifier un sujet à risque de développer le SII et/ou pour diagnostiquer un sujet atteint de SII par entérotypage d'un échantillon d'essai dérivé dudit sujet.
PCT/NL2012/050519 2011-07-19 2012-07-19 Identification des sujets à risque de développer le syndrome de l'intestin irritable WO2013012332A1 (fr)

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WO2015003000A1 (fr) * 2013-07-01 2015-01-08 Counterpoint Health Solutions, Inc. Approche biologie des systèmes pour thérapie
EP2969012A4 (fr) * 2013-03-12 2016-09-14 Univ Yale Compositions et méthodes pour identifier des microbes liés à des anticorps sécrétoires
US9603837B2 (en) 2012-03-28 2017-03-28 Ixcela, Inc. IPA as a therapeutic agent and a biomarker for disease risk for Huntington's disease
CN110838365A (zh) * 2019-09-27 2020-02-25 康美华大基因技术有限公司 肠易激综合症相关菌群标志物及其试剂盒
WO2020149719A3 (fr) * 2019-01-18 2020-09-10 주식회사 천랩 Biomarqueur microbien spécifique du syndrome de l'intestin irritable et procédé de prédiction du risque de syndrome du l'intestin irritable à l'aide de celui-ci
US10925953B2 (en) 2014-08-28 2021-02-23 Yale University Compositions and methods for treating an inflammatory disease or disorder
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US11488699B1 (en) 2018-12-09 2022-11-01 Cerner Innovation, Inc. Microbiota activity sensor and decision support tool
US11842795B1 (en) 2018-12-17 2023-12-12 Cerner Innovation, Inc. Irritable bowel syndrome diagnostic sensor and decision support tool

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US9636325B2 (en) 2012-03-28 2017-05-02 Ixcela, Inc. Indole lactic acid or a mixture of indole lactic acid and indole-3-propionic acid for treatment of Huntington's disease
US10278958B2 (en) 2012-03-28 2019-05-07 Ixcela, Inc. IPA as a protective agent
US9744155B2 (en) 2012-03-28 2017-08-29 Ixcela, Inc. IPA as a therapeutic agent, as a protective agent, and as a biomarker of disease risk
US9603837B2 (en) 2012-03-28 2017-03-28 Ixcela, Inc. IPA as a therapeutic agent and a biomarker for disease risk for Huntington's disease
US9758838B2 (en) 2013-03-12 2017-09-12 Yale University Compositions and methods for identifying secretory antibody-bound microbes
EP2969012A4 (fr) * 2013-03-12 2016-09-14 Univ Yale Compositions et méthodes pour identifier des microbes liés à des anticorps sécrétoires
US11299790B2 (en) 2013-03-12 2022-04-12 Yale University Compositions and methods for identifying secretory antibody-bound microbes
US10428392B2 (en) 2013-03-12 2019-10-01 Yale University Compositions and methods for identifying secretory antibody-bound microbes
US10774392B2 (en) 2013-03-12 2020-09-15 Yale University Compositions and methods for identifying secretory antibody-bound microbes
CN105378475A (zh) * 2013-07-01 2016-03-02 伊克斯塞拉公司 治疗的系统生物学方法
WO2015003000A1 (fr) * 2013-07-01 2015-01-08 Counterpoint Health Solutions, Inc. Approche biologie des systèmes pour thérapie
US10925953B2 (en) 2014-08-28 2021-02-23 Yale University Compositions and methods for treating an inflammatory disease or disorder
US11488699B1 (en) 2018-12-09 2022-11-01 Cerner Innovation, Inc. Microbiota activity sensor and decision support tool
US11842795B1 (en) 2018-12-17 2023-12-12 Cerner Innovation, Inc. Irritable bowel syndrome diagnostic sensor and decision support tool
WO2020149719A3 (fr) * 2019-01-18 2020-09-10 주식회사 천랩 Biomarqueur microbien spécifique du syndrome de l'intestin irritable et procédé de prédiction du risque de syndrome du l'intestin irritable à l'aide de celui-ci
US11287420B2 (en) 2019-01-25 2022-03-29 Ixcela, Inc. Detection and modification of gut microbial population
US11287418B2 (en) 2019-01-25 2022-03-29 Ixcela, Inc. Detection and modification of gut microbial population
US11287419B2 (en) 2019-01-25 2022-03-29 Ixcela, Inc. Detection and modification of gut microbial population
US11287417B2 (en) 2019-01-25 2022-03-29 Ixcela, Inc. Detection and modification of gut microbial population
US11041847B1 (en) 2019-01-25 2021-06-22 Ixcela, Inc. Detection and modification of gut microbial population
CN110838365A (zh) * 2019-09-27 2020-02-25 康美华大基因技术有限公司 肠易激综合症相关菌群标志物及其试剂盒

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