EP2598155A2 - Utilisation de statut de groupe sanguin de type iii - Google Patents

Utilisation de statut de groupe sanguin de type iii

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Publication number
EP2598155A2
EP2598155A2 EP11808883.0A EP11808883A EP2598155A2 EP 2598155 A2 EP2598155 A2 EP 2598155A2 EP 11808883 A EP11808883 A EP 11808883A EP 2598155 A2 EP2598155 A2 EP 2598155A2
Authority
EP
European Patent Office
Prior art keywords
secretor
individual
band position
group
microbial
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP11808883.0A
Other languages
German (de)
English (en)
Inventor
Pirjo Wacklin
Jaana MÄTTÖ
Harri MÄKIVUOKKO
Jukka Partanen
Janne NIKKILÄ
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
DuPont Nutrition Biosciences ApS
Original Assignee
Suomen Punainen Risti Veripalvelu
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US12/843,409 external-priority patent/US20120020941A1/en
Priority claimed from FI20105825A external-priority patent/FI20105825A/fi
Application filed by Suomen Punainen Risti Veripalvelu filed Critical Suomen Punainen Risti Veripalvelu
Publication of EP2598155A2 publication Critical patent/EP2598155A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/745—Bifidobacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to a microbial composition which is tailored based on the spectrum of microbes found more frequently from the intes- tine of non-secretor individuals than from the intestine of secretor individuals.
  • the present invention further relates to a method of tailoring a microbial composition based on the spectrum of microbes found more frequently from the intestine of non-secretor individuals than from that of secretor blood group status.
  • the present invention also relates to a microbial composition which is tailored based on the spectrum of microbes found more frequently from the intestine of secretor individuals than from the intestine of non-secretor individuals.
  • the present invention further relates to a method of tailoring a microbial composition based on the spectrum of microbes found more frequently from the intestine of secretor individuals than from that of non-secretor blood group status. Further, the present invention relates to use of the secretor status of an individual as a criterion for microbial supplementation tailored based on the differences in the spectra of microbes found between secretor and non-secretor individuals. The present invention relates also to method of assessing the need of an individual for the tailored microbial supplementation by determining the secretory status of the individual. Also, the invention relates to the use of prebiotics, molecular compounds or additional supportive microbial strains, to increase the number of, and/or to augment the growth and/or functionality of these microbial strains.
  • OTUs Orthogonal Taxonomic Units
  • the microbiota has an important role in human health. It contributes to the maturation of the gut tissue, to host nutrition, pathogen resistance, epithelial cell proliferation, host energy metabolism and immune response (e.g. Dethlefsen et al., 2006, Trends Ecol Evol 21 (9):517-23; Round and Mazmanian, 2009, Nat Rev Immunol 9(5):313-23).
  • An altered composition and diversity of gut microbiota have been associated to several diseases (Round and Mazmanian, 2009), such as inflammatory bowel disease, IBD (Sokol et al., 2008, Proc Natl Acad Sci USA, 105(43):16731 -6), irritable bowel syndrome (Matto et al.
  • gut microbes e.g. Helicobacter pylori and pathogenic species of bacteria and viruses have shown to use ABO blood group antigens as adhesion reseptors (Boren et al. Science 1993, 262, 1892-1895).
  • Some microbes e.g. Bifidobacteria and Bacteroides thetaiotaomicron are also able to utilize blood group antigens or glycans found in ABO and Lewis antigens.
  • the ABO blood group antigens are not present in the mucus of all individuals. These individuals, said to have the 'non-secretor' blood group, do not have the functional FUT2 gene needed in the synthesis of secreted blood group antigens (Henry et al., Vox Sang 1995; 69(3):166-82). Hence, they do not have ABO antigens in their secretions and mucosa while those with blood group 'secretor' have the antigens. In most populations, the frequency of non- secretor individuals is substantially lower than that of secretor status; about 15-26% of Scandinavians are non-secretors (Eriksson et al. Ann Hum Biol. 1986 May-Jun; 13(3):273-85).
  • the secretor/non -secretor status can be regarded as a normal blood group system and the phenotype can be determined using standard blood banking protocols (Henry et al. 1995).
  • the genotype that is, the major mutation in the FUT2 gene causing the non- secretor (NSS) phenotype in the European populations (Silva et al. Glycoconj 2010; 27:61 -8) has been identified.
  • Non-secretor phenotype has been demonstrated to be genetically associated for example, with an increased risk for Crohn's disease (McGovern et al.
  • Hum Molec Genet 2010 Advance Access Published June 22, 2010
  • high vitamin B12 levels in the blood Teanaka et al Am J Hum Genet 2009; 84:477-482
  • resistance to Norovirus infection Thorven et al J Virol 2005; 79: 15351 -15355
  • susceptibility to HI virus infection AN et al 2000, J Infect Dis 181 : 737-739
  • experimental vaginal candidiasis Hurd and Domino Infection Immunit 2004; 72: 4279-4281
  • an increased risk for asthma Renchetti et al.
  • Gut microbiota can be modulated by taking probiotics, which currently belong mainly to Bifidobacteria and Lactobacillus genera.
  • the present invention is based on the finding that individuals with non-secretor blood group status showed marked differences in their gut microbial composition in comparison to secretor individuals. Specifically, occurrence or abundance of certain Bacteroides and Clostridium leptum group genotypes, as defined using the method of Denaturating Gradient Gel Electrophoresis (DGGE), were higher in non-secretor individuals than secretor individuals.
  • DGGE Denaturating Gradient Gel Electrophoresis
  • the genotypes were:
  • the present invention is based on the finding that individuals with secretor blood group status showed higher occurrence or abundance of the following genotypes in their microbiota:
  • HIT Human Intestinal Tract
  • the non-secretor blood group status was found to be a host genotype, which determines the composition of intestinal microbes in man.
  • This finding can be used as a basis for targeted modulation of intestinal microbial population tailored according to non-secretor/secretor status of an individual.
  • the present invention can be targeted to stabilisation of the gut microbiota of an individual using those bacteria that were found to be typical to individuals with the same secretor/non -secretor phenotype as the individual to be treated or a bacterial product enriched with those bacteria that were found to be typical to individuals with the same secretor/non-secretor phenotype as the individual to be treated.
  • the stabilisation can be either prophylactic, i.e.
  • the present invention can be targeted to in- creasing the number of those beneficial bacteria scarcely found in individuals with the same secretor/non-secretor phenotype as the individual to be treated by administering the said bacteria to the individual.
  • the invention describes which particular microbes should be enriched in a microbial and/or probiotic supplement or composition to improve the responsiveness and/or effect of the product. This tailoring or optimising or potentiating can be done to an existing microbial, probiotic and/or synbiotic product, or to a microbial strain not currently used as a probiotic.
  • the tailoring can be done by applying fecal transplantion with a fecal microbiota inoculum prepared from fecal material obtained from an individual representing the same secretor group as the fecal transplant donor (balancing of disturbed microbiota) or from an individual representing a different secretor group than the fecal transplant donor i.e., for increasing the richness of the microbiota in cases where the diversity of dominant microbiota is reduced.
  • an object of the present invention is a non- secretor/secretor genotype based microbial composition which is tailored based on the spectrum of bacteria found in the mucosal tissue of at least one individual with non-secretor or secretor blood group phenotype.
  • Another object of the present invention is a microbial composition which comprises at least one of the strains having any of the following genotypes:
  • a further object of the present invention is a microbial composition which is tailored based on the spectrum of microbes found more frequently from the intestine of the non-secretor individuals than from the intestine of se- cretor individuals.
  • An even further object of the present invention is a microbial composition which is tailored based on the spectrum of microbes found more frequently from the intestine of the secretor individuals than from the intestine of non-secretor individuals.
  • an object of the present invention is a method of tailoring a microbial composition based on the spectrum of bacteria found in the mucosal tissue of at least one individual with non-secretor or secretor blood group phenotype.
  • Another object of the invention is use of the secretor blood group status of an individual in assessing the need for tailored microbial supplementation, i.e., as a criterion for microbial supplementation tai- lored based on the differences in the spectra of microbes found between secretor and non-secretor individuals.
  • the present invention relates also to method of assessing the need of an individual for microbial supplementation by determining the secretory status of the individual.
  • an object of the invention is the use of prebiotics, molecular compounds or additional supportive mi- crobial strains, to increase the number of, and/or to augment the growth and/or functionality of microbes in the intestine.
  • a further object of the present invention is a use of the secretor blood group status of an individual in estimating a dose of microbial supplementation needed for a desired effect.
  • Figure 1 shows the RDA plot of HITChip analysis based on data hybridisation signals of species-like (level 1 ) bacterial groups of Example 8.
  • the present invention is based on the finding that a blood group system, secretor/non-secretor status, determines the spectrum or composition of microbial species and/or strains found in the human mucosal tissues, especially in the intestine. Individuals with non-secretor blood group status had marked differences in their gut microbial composition as compared to individuals with secretor status.
  • the blood group system secretor/non-secretor is a major genetic factor in the host determining the variation in the microbiota.
  • the secretor/non-secretor status can be regarded as a normal blood group system and the phenotype can be determined using standard blood banking protocols.
  • the genotype that is, the mutation in the FUT2 gene causing the non-secterot (NSS) phenotype can be detected by various standard DNA-based techniques, such as allele-specific PCR amplification, sequencing, or using oligonucleotide probes, well-known in the art.
  • the gut microbiota has an important role in human health; importantly, an altered composition and/or altered diversity of gut microbiota have been associated to several diseases.
  • occurrence or abundance i.e. band intensity
  • certain genotypes of Eubacterium rectale-Clostridium coc- coides, Bacteroides and Clostridium leptum group were higher in non-secretor individuals than in secretor individuals.
  • the significant difference in gut microbiota between non-secretors and secretors was also demonstrated by HIT chip hybridisation and sequencing of bacterial 16S rRNA gene.
  • Denaturating Gradient Gel Electrophoresis is a method of choice to detect differences in spectrum or abundance of different bacterial genotypes.
  • the method is well described in the art (Vanhoutte et al. FEMS Mi- crob Ecol 2004; 48; 437-446; Matsuki et al. Applied and Environmental Micro- biology 2004; 70; 7220-7228; Satokari et al. AEM 2001 ; 67: 504-513; Matto et al. FEMS Immunol Med Microbiol. 2005; 43: 213-22).
  • specific PCR primers are designed so that in each experimental setting, only the desired bacterial group or groups are analysed.
  • the differences in band positions and/or their occurrence and/or intensity indicate differences in bacterial com- positions between faecal samples.
  • Base composition of the PCR amplified fragment determinates the melting and, thus the mobility of the fragment in the denaturing gradient in gel.
  • the final position of the fragment in gel is consequently specified by the DNA sequence of the fragment, the applied denaturing gradient and the electrophoresis running conditions.
  • the optimised running conditions and denaturing gradient of the gels for the bacterial groups used in this invention are shown in Table 2.
  • the position of each fragment, the "band position", between different gel runs are normalised by using standards.
  • the band position is indicated relative to length of the gel, the top being 0% and the bottom edge being 100%.
  • each band position refers to the band positions of the given %-value +/- 1 % unit, i.e. 25.30% refers to any value between 24.30% and 26.30%, when analysed using the methodology described above. It is noted than depending on the exact conditions the nominant %-value can vary; the relative position of the band to the relevant standard is important.
  • the following bacterial genotypes had a higher abundance and/or higher band intensity in the gut microbiota of non- secretors than in that of secretors:
  • genotypes had higher josdance and/or band intensity in gut microbiota of secretors than in that of non-secretors:
  • genotypes are examples of genotypes here referred to as "genotypes typical to individuals" with secretor or non-secretor phenotype. It is of note that as the secretor/non -secretor trait, that is the expression of ABO structures in mucosa, can be identified in all mucosal tissues, the invention is relevant to all mucosal tissues of an individual and not restricted to the gut or faecal samples.
  • a faecal sample can be cultured on non- selective or selective culture medium in the conditions supporting the growth of the targeted bacterial group.
  • non- selective or selective culture medium for example, Brucella blood agar (BRU) or reinforced clostridial agar with chinablue and horse blood (RCBA) can be used for anaerobic bacteria such as Clostridia and their close relatives.
  • BRU Brucella blood agar
  • RCBA reinforced clostridial agar with chinablue and horse blood
  • RCBA horse blood
  • selective culture media e.g. Bacteroides Bile esculin (BBE) for the isolation of Bacteroides spp.
  • Beerens and Raffinose bifidobacterium (RB) for bifidobacteria, and Rogosa and LAMVAB for lactobacilli, respectively, can be used.
  • the plates are incubated in conditions supporting the growth of the targeted bacteria e.g. anaerobiosis at 37 C.
  • Bacterial isolates can be sub-cultured from the culture plates and identified to the species level by 16S rDNA sequencing. An isolate is then run in DGGE with known control samples with a particular DGGE band position.
  • Steps for tailoring a microbial composition typically comprise:
  • microbiota of a recipient can be stabilized and/or modified by administering the secretor/non-secretor tailored bacterial product to the recipient.
  • the culturing can also be performed in a device mimicking the gastrointestinal tract.
  • TNO TIM-1 model Typically, faecal slur- ries acquired by mixing faeces with artificial saliva and sterile water are used as an input for the TIM-1 model.
  • the faecal slurries can be prepared from study groups, for example, from pooled non-secretor and secretor samples.
  • various parameters can be adjusted, e.g. level of gastric secretion, time to addition of bile and pancreatin, etc.
  • the physiological concentrations of bile salts, pancreatic enzymes and electrolytes simulates an average physiological passage through the small intestine.
  • the survival of targeted bacteria can be compared between the study groups, in order to look for functional differences between bacterial populations.
  • the microbiota composition can also be prepared by using faecal material as an inoculum.
  • the faecal slurry can be prepared either by direct di- lution to an appropriate diluent or by separation of selected bacterial groups from the sample.
  • the present invention provides means for the use of secretor status for tailoring probiotic supplements optimized according to non-secretor (NSS) and secretor (SS) genotype of the host. Optimization is based on the rationale that according to the present invention, certain bacterial genotypes are essentially missing or their proportion of the entire gut microbiota is lower in an individual or host having secretor genotype than in non-secretor genotype. Further, the optimization is based on the rationale that according to the present invention, certain bacterial genotypes are essentially missing or their proportion of the entire gut microbiota is lower in an individual or host having non-secretor genotype than in secretor genotype.
  • the probiotic preparation or product can be tailored so that it contains higher amounts or proportions of those bacterial genotypes or strains that are known to have altered abundances and whose increase in number is desired.
  • the preparation can be tailored so that it contains high amounts or proportions of those bacterial genotypes or strains that are known, according to the present invention, to be typical to the secretor/non-secretor status of the individual to be treated.
  • the non-secretor/secretor geno- type based microbial composition is tailored based on the spectrum of bacteria found in the mucosal tissue of at least one individual with non-secretor or secretor blood group phenotype.
  • the microbial composition comprises at least one of the strains having any of the following genotypes:
  • the microbial composition comprises two or more of the strains specified above.
  • the microbial strains belong to the Clostridium leptum group.
  • the microbial composition comprises at least one of the strains having any of the following genotypes:
  • the microbial composition comprises two or more of the strains specified above.
  • the microbial composition comprises at least one of the strains defined above by universal- DGGE analysis, at least one of the strains defined above by EREC-DGGE analysis, at least one of the strains defined above by Bacteroides-DGGE analysis and at least one of the strains defined above by Clostridium leptum-DGGE analysis.
  • the microbial composition comprises all the strains defined above.
  • the microbial composi- tion comprises the strains defined above by universal-DGGE analysis or the strains defined above by EREC-DGGE analysis or the strains defined above by Bacteroides-DGGE analysis or the strains defined above by Clostridium leptum-DGGE analysis.
  • the microbial composition com- prises at least one of the strains having any of the following genotypes: band position 62.60% as defined by Eubacterium rectale- Clostridium coccoides- group (EREC)-DGGE analysis; or
  • the microbial composition comprises the strains having any of the following genotypes:
  • the microbial composition is tailored based on the spectrum of non-bifidobacterial bacteria found in the mucosal tissue of at least one individual with non-secretor or secretor blood group phenotype.
  • the present invention can be targeted to stabilisation of the gut mi- crobiota of an individual using those bacteria that were found to be typical to individuals with the same secretor/non-secretor phenotype as the individual to be treated or a bacterial product enriched with those bacteria that were found to be typical to individuals with the same secretor/non-secretor phenotype as the individual to be treated.
  • the stabilisation can be either prophylactic, i.e. started before treatments disturbing the balance of gut microbiota, or it can be started once the symptoms develop.
  • the present invention can be targeted to increasing the number of those beneficial bacteria scarcely found in individuals with the same secretor/non-secretor phenotype as the individual to be treated by administering said bacteria or adding the said bacteria into a product.
  • the microbial preparation according to the present invention is targeted, for example, to a relief of symptoms and/or to the therapy of diseases in which gut microbiota plays an important role, such as inflammatory bowel disease, IBD (Sokol et al. 2008.), irritable bowel syndrome (Matto et al. 2005.), rheumatoid arthritis (Vaahtovuo et al. 2008), atopic eczema (Kalliomaki et al. 2003), asthma (Bjorksten, 1999) and type 1 diabetes (Wen et al. 2008).
  • the target is general immunomodulation, for example, induction of regulatory T lymphocytes (Round and Mazmanian PNAS doi/10.1073/pnas.0909122107), which are known to induce immunotolerance in organ and stem cell transplantations or to suppress the immune response.
  • the invention is related to a probiotic composition for prevention or treatment of inflammatory bowel disease (IBD).
  • IBD is an excellent target disease for the invention as an altered microbiota composition in the patients has been reported (Sokol et al. Inflamm Bowel Dis. 2006 Feb;12(2):106-1 1 ). Furthermore, it is established (McGovern et al.
  • the non-secretor phenotype i.e. FUT2 gene defect
  • the composition according to the present invention is particularly effective in IBD.
  • the treatment can be targeted to a relief of the symptoms and/or to prevention of relapses and/or to increasing the overall quality of life in IBD. It also may be administered together with other currently known drugs for IBD.
  • the composition of the present invention is targeted to those IBD patients with the non-secretor phenotype.
  • the invention is related to a probiotic com- position for prevention or treatment of microbial infections i.e. diarrhoea and respiratory tract infections as also in these indications therapeutic potential of probiotics (Chouraqui et al. J Pediatr Gastroenterol Nutr. 2004 Mar; 38(3):242- 3; de Vrese et al. Clin Nutr. 2005 Aug;24(4):479-80), and an increased frequency in non-secretor individuals (Ahmed et al. 2009 Infect Immun. 2009 77(5):2059-64; Raza et al. BMJ. 1991 , 303(6806):815-8) have been described.
  • the invention is related to a probiotic composition for prevention or treatment of irritable bowel syndrome as disturbed microbiota (Matto et al. 2005) and potential of probiotic products have been described in IBS (Kajander et al. Aliment Pharmacol Ther. 2008 27(1 ):48-57).
  • the invention is related to a probiotic composition for prevention or treatment of allergy/atopy in children. It is established that babies who develop allergy have disturbed microbiota in their intestine during the first year of life (Bjorksten et al. J Allergy Clin Immunol. 2001 108(4):516-20). Moreover, it has been shown that bacterial composition in the milk of allergic mothers differs from that of non-allergic mothers (Gronlund et al. Clin Exp Allergy. 2007, 37(12):1764-72). Probiotic products have shown potential in prevention of atopic eczema (Yoo et al. Proc Am Thorac Soc (2007) 4, 277-282).
  • the microbial and/or probiotic composition or the supplement comprising the composition is particularly suitable and effective, in use for the enhancement of the diversity and numbers of intestinal bacteria, or balancing the microbiota in an individual suffering from celiac disease. It has recently been demonstrated that patients with celiac disease and its different clinical forms have disturbed gut microbiota (Wacklin P, Pusa E, Kaukinen K, Maki M, Partanen J, and Matto J. Composition of the mu- cosa-associated microbiota in the small intestine of coeliac disease patients and controls. A poster presented in the Rowett-INRA Gut Microbiology- conference, Aberdeen, UK, 22-25.6. 2010).
  • intestinal microbiota compositions were assessed from mucosal biopsy samples from 26 coeliac disease patients (further sub-grouped to gastrointestinal, anemia and dermatitis herpetiformis symptom groups) and 25 healthy controls. The samples were analysed by PCR-DGGE with universal bacterial primers. Intestinal microbiota of the coeliac disease patients representing different symptom groups clustered in clearly distinct groups. The finding indicates that the microbiota composition is variable be- tween individuals and in intestinal disorders disease-group related differences in the microbiota composition exist, which should be taken into consideration in applications targeting for balancing or modulating the intestinal microbiota of individuals suffering from immunological gastrointestinal disorders.
  • the secretor/non-secretor status can be used to augment the stabilisation of mucosal microbiota composition of an individual after disorders or treatments known to disturb the balance of mucosal microbiota.
  • these comprise treatments with broad spectrum antibiotics, irradiation or cytotoxic therapies related to cancer treatments or bone marrow transplantation or its complications such as graft- versus-host disease and/or gastroenterological infections by e.g. Noro-virus or Helicobacter.
  • PCR-DGGE PCR-DGGE analysis revealed remarkable instability of the intestinal microbiota after transplantation. The similarity of the dominant microbiota was extremely low during the first month after transplantation while up to 94% similarity was detected between the samples obtained 4-6 months from the transplantation.
  • PCR-DGGE specific bacterial group targeted primers revealed absense of several common intestinal bacteria (e.g. bifidobacteria, lactobacilli, C. leptum group) in several samples obtained within one month from transplantation.
  • the present invention is further targeted to treatment of diseases or traits, having the FUT2 gene (i.e. the secretor blood group status) as a genetic susceptibility factor.
  • diseases or traits having the FUT2 gene (i.e. the secretor blood group status) as a genetic susceptibility factor.
  • FUT2 gene i.e. the secretor blood group status
  • diseases or traits comprise, just to give examples, low levels of vitamin B12 in the blood, various clinical forms of inflammatory bowel disease, urinary tract infections, vaginal candidiasis, Noro- and Hl-virus infections and infections by hemorrhagic viruses.
  • Probiotic treatments typically are used to direct or change the microbiological balance in the gut toward healthier one, or toward the microbial spectrum "typical to individuals" with the non- susceptible FUT2 genotype.
  • the present invention is particularly related to treatments directed to individuals with the non-secretor status.
  • Individuals with the non-secretor phenotype typically require higher dosages and/or preparations with more diverse microbial strains than secretors.
  • the present invention relates also to use of the secretor/non-secretor status of an individual to augment the stabilisation of mucosal microbiota composition in disorders related to, or after treatments leading to unbalance of mucosal microbiota.
  • the present invention also relates to a method of identifying an individual at risk for suffering from a disorder related to unbalance of mucosal microbiota, such as a gastrointestinal disorder by determining the secretory status of said individual.
  • the present invention further relates to a use of the secretor/non- secretor status of an individual in estimating a dose of bacterial supplementation needed for a desired effect.
  • the microbial preparation is not orally administered but is a solution or 'salva' which is directly administered onto the target mucosal tissue. Examples of this embodiment are disorders of gingival or vaginal tissues.
  • the invention is related to microbial or probiotic composition targeted to elderly individuals for supporting the maintenance of balanced microbiota in the gut and/or some other mucosal, such as oral, vaginal or skin tissue.
  • the invention is related to microbial or probiotic composition targeted to infants for stabilisation of the mi- crobiota in the gut and/or some other mucosal tissue.
  • Limited repertoire of commensal microbes typical to infants confers them susceptible for infections; optimisation of the composition according to the present invention increases the efficacy of the treatment.
  • the treatment can be either prophylactic before an infection for individuals, e.g. elderly or infants, with a high infection risk (i.e, probiotic type), or therapeutic during the infection.
  • the present invention also provides means for improving responsiveness and/or effect of the microbial and/or probiotic product. Not all individuals are responsive for current probiotic products; a tailored composition enriched with microbial strains which according to the present invention have a better ability to stay alive and grow in the gut or other mucosal tissue improves responsiveness.
  • Severe disturbances in the mucosal or gut microbiota can be a result of treatments related to e.g. cancer therapy, haematopoietic stem cell transplantation or its complications such as graft-versus-host disease, or use of antibiotics.
  • the present invention relates to the use of secretor/non-secretor status in estimating the most effective way for stabilisation of the microbiota. Stabilisation can be achieved most effectively by probiotic products tailored according to the present invention.
  • the present invention provides a novel and effective method for screening and identification of novel probiotic strains.
  • the NSS/SS genotype forms the basis for the selection of the most efficient source of the faecal samples, the starting point for identification of suitable probiotics. Faecal samples from individuals with non-secretor status can be used for isolating efficiently those bacterial strains more abundant in non-secretor geno- type. The fact that these strains, e.g. those belonging to C. leptum or B. fragilis group, are frequent in the microbiota of hosts with NSS genotype indicates that they obviously are particularly viable in the gut of NSS hosts. A good colonization ability and viability in the gut are essential features for a probiotic.
  • mucosal tissue here refers to oro- gastrointestinal, gut, skin, oral, respiratory, and/or uro-genital tissues or samples derived from these or to any of the other indications described above.
  • determination of the secretor/non-secretor status and use of the result to consequently predict the bacterial spectrum of an individual is used to optimize faecal transplantation. This can be done as the only test or in combination with an actual analysis of microbiota composition.
  • the result can be used as a criterion for choosing a donor for faecal transplantation. Bacteria derived from the faecal transplant from a donor representing the same secretor/non-secretor type with the recipient are likely to have a better colonisation ability and efficacy than those de- rived from a mismatched donor. Faecal transplantation can be used for a therapy in severe Clostridium difficile infections (MacConnachie et al.
  • the present invention can improve the efficacy of the treatment.
  • the efficacy can be further improved by giving a secretor/non-secretor matched bacterial preparation post-transplantation in order to improve the sta- bilisation of the gut microbiota of the recipient.
  • the preparation can contain the spectrum of bacteria found commonly in samples classified according to sec- tretor/non-secretor status and can be produced e.g. as a fresh, frozen pellet or freeze-dried product formulation.
  • faecal transplantation once optimised according to the present invention can be used to stabilise gut microbiota in many other disorders related to or resulting to severe disturbances in gut microbiota, for example, diseases requiring intensive antibiotic treatments, chemotherapy or total body irradiation before bone marrow transplantation.
  • the secretor/non-secretor status is used, option- ally together with standard analyses of microbial composition in a sample, in estimating whether microbial composition in a particular mucosal tissue, such as the gut of an individual is in balance.
  • the secretor/non-secretor status or genotype can be determined in vitro from the blood or saliva sample of the host and the microbial composition from the mucosal or faecal samples using standard methods, well known in the art.
  • the microbiota composition of an individual so obtained can be compared to the reference secretor/non-secretor specific compositions that can be obtained by determining the microbiota compositions in a number of samples from healthy individuals whose secretor/non- secretor status are known.
  • the secretor/non -secretor specific compositions can be obtained by identifying the bacterial strains and/or species or geno- types enriched in the secretor samples or in the non-secretor samples.
  • Host secretor/non -secretor genotype together with the standard analysis of microbial spectrum provides a more reliable estimate of the balance than the analysis of the mucosal or faecal sample alone, because the genotype partially determines the assumed, normal composition.
  • This result can be used to estimate the need by an individual for probiotic supplementation in disorders assumed or known to be related to variation in the microbiota. The result can also be used to reduce infection risk.
  • Non-secretors are known to be more vulnerable to infections (Blackwell, C.C. 1989. FEMS Microbiology Immunology 47, 341 - 350).
  • a balanced and diverse population of beneficial commensal gut mi- crobes, achieved or augmented by probiotics tailored according to the present invention, is therefore particularly important for non-secretors.
  • the present invention relates to a method for determining the balance of gut microbiota of an individual wherein the method comprises;
  • probiotic' refers to any bacterial species, strain or their combinations, with health supportive effects, not limited to currently accepted strains or to intestinal effects.
  • the probiotic as defined here may be applied also by other routes than by ingestion, e.g. by applying directly to desired tissue.
  • 'prebiotic' refers to any compound, nutrient, or additional microbe applied as a single additive or as a mixture, together with probiotics or without probiotics, in order to augment a desired probiotic health effect or to stimulate the growth and activity of those microbes in the mucous tissue, such as digestive system, which are assumed to be beneficial to the health of the host body.
  • microbial and bacterial here are used as synonyms and refer to any bacterial or other microbial species, strains or their combinations, with health supportive effects, not limited to strains currently accepted as probiotics.
  • microbial composition or microbial product refer to a microbial preparation and a probiotic or prebiotic product, including those applied by other routes than the traditional ingested probiotic, e.g. applied directly onto mucosal tissues such as skin or uro-genital tract, or a product for faecal transplant.
  • tailoring refers to determining the secretor/non-secretor blood type of the recipient and the typical and/or characteristic mucosal bacterial repertoire of the secretor/non-secretor blood type by methods known in the art and optionally manufacturing a bacterial composition based on the determined bacterial repertoire. Alternatively, it refers to determining the typical and/or characteristic mucosal bacterial repertoire of the secretor or non- secretor blood type and the secretor/non-secretor blood type of the recipient by methods known in the art and optionally manufacturing a bacterial composition based on the determined bacterial repertoire. After this tailoring step the bacteria or the bacterial composition is administered to the recipient.
  • compositions and supplements so designed may have beneficial effects on the health and/or well-being of a human and may be formulated into a functional food product or a nutritional supplement as well as a capsule, emulsion, or powder.
  • a typical probiotic ingredient is freeze-dried powder containing typi- cally 10 10 -10 12 viable probiotic bacterial cells per gram. In addition it normally contains freeze drying carriers such as skim milk, short sugars (oligosaccharides such as sucrose or trehalose).
  • the culture preparation can be encapsulated by using e.g. alginate, starch, xanthan as a carrier.
  • a typical probiotic supplement or capsule preparation contains approximately 10 9 -10 11 viable probiotic bacterial cells per capsule as a single strain or multi-strain combination.
  • a typical probiotic food product which can be among others fermented milk product or juice, contains approximately 10 9 -10 11 viable probiotic bacterial cells per daily dose.
  • Probiotics are incorporated in the product as a probiotic ingredient (frozen pellets or freeze dried powder) or they are cultured in the product during fermentation.
  • the invention will be described in more detail by means of the following examples. The examples are not to be construed to limit the claims in any manner whatsoever.
  • 59 healthy adult volunteers 52 females and 7 males were recruited to the study. Both faecal and blood samples were collected from 59 volunteers. The age of the volunteers ranged from 31 to 61 and was in average 45 years.
  • Faecal samples were frozen within 5 hours from defecation. DNA from 0.3 g of faecal material was extracted by using the FASTDNA® SPIN KIT FOR SOIL (Qbiogene).
  • PCR-DGGE methods were optimised to detect dominant eubacteria (universal group), Eubacterium rectale-Clostridium coccoides (EREC) group, Bac- teroides fragilis group, Clostridium leptum group.
  • Partial eubacterial 16S rRNA gene was amplified by PCR with group specific primers (shown in table 1 ). Amplified PCR fragments were separated in 8% DGGE gel with denaturing gradient ranging from 45% to 60%. DGGE gels were run at 70 V for 960 mins. DGGE gels were stained with SYRBSafe for 30 mins and documented with Safelmager Blue- light table (Invitrogen) and Aplhalmager HP (Kodak) imaging system.
  • the bands were excised from DGGE gels. DNA fragments from bands were eluted by incubating the gel slices in 50 ⁇ of sterile H 2 O at +4°C overnight. The correct positions and purity of the bands were checked for each excised bands by amplifying DNA in bands and re-running the amplified fragments along with the original samples in DGGE. Bands which produced single bands only and were in the correct position in the gels were sequenced. The sequences were trimmed, and manually checked and aligned by ClustalW. The closest relatives of the sequences were searched using Blast and NCBI nr database. Distance matrix of the aligned sequences was used to compare the similarity of the sequences.
  • LactoLad 38-55% 70 V, 960 mins L. plantarum E-79098 bacillus Lac2-GC L. cellubiosis E-98167
  • Secretor status was determined from the blood samples by using an agglutination assay. Secretor status was determined from 59 individual and 48 were secretors and seven were non-secretors. The secretor status of four samples could not be determined; they were excluded from the further analyses.
  • genotypes In universal DGGE analysis of dominant intestinal bacteria, several genotypes occured statistically significantly more often or with a higher intensity in the non-secretor samples than in the secretor samples. All genotypes were 2 to 3.6 times more frequently detected in the non-secretor in comparison to secretor samples. The genotypes can be identified by the band positions on universal DGGE gel corresponding the band positions 25.30%, 26.40%, 50.40% and 56.80%. The band positions, genotypes, which differed between non-secretor and secretor individuals and their detection frequencies, are shown in Table 3.
  • the genotype band position 23.80 as indicated by the controls, referred to Bacteroides uniformis strain DSM6597; this genotype was three times more common in the non-secretor samples than in the secretor samples.
  • Other genotypes corresponded band positions 4.80%, 10.20%, 38.70%, and 41 .10%. These band positions were also three times more com- monly detected in the non-secretor than in secretor samples, except genotypes related to band positions 10.20% and 38.70%. Band positions 10.20% and 38.70% were equally common in the non-secretor and secretor samples, but the band intensity (i.e.
  • the number of volunteers was increased to 71 by recruiting 12 new volunteers in addition to the 59 volunteers of examples 1 -5.
  • secretor status was geno- typed by sequencing the coding exon of FUT2 as described in Silva et al. (Gly- coconj J 2010, 27, 61 -68) and Ferrer-Admetlla et al. (Mol Biol Evol 2009, 26, 1993-2003). Genotyping of FUT2 exon allowed determination of secretor status for the Lewis negative individuals, whose phenotypic secretor status could not be determined.
  • the DGGE analysis and data-analysis were performed as described above. Statistical analyses, Anova and Fisher's exact test, were computed with statistical programming language R, version 2.10.1 .
  • DGGE band positions The analysis of the enlarged dataset with DGGE revealed that the incidence and/or band intensity of several genotypes (i.e. DGGE band positions) were significantly different between the groups. With exception of two genotypes in C. leptum groups and one genotype in EREC group, all the genotypes were more commonly detected in non-secretor individuals than secretor individuals. This confirmed the results of the previous examples 1 -5, that several microbial genotypes are associated to the secretor status of the host.
  • Table 7 The band positions of dominant bacteria, C. leptum, B. fragilis, EREC, and Lactobacillus groups and the incidence of bands in secretor (14) and non-secretor samples (57) analysed by PCR-DGGE. Only the bands with a statistically significant difference between the secretors (SS) and non-secretors (NSS) are shown.
  • the isolation of the bacteria representing a specific PCR-DGGE genotype can be performed as follows.
  • a faecal sample is cul- tured on non-selective or selective culture media in the conditions supporting the growth of the targeted bacterial group.
  • Brucella blood agar (BRU) or reinforced clostridial agar with chinablue and horse blood (RCBA) was used for the cultivation of the anaerobic bacteria e.g. Clostridia and their close relatives.
  • BRU Bac- teroides Bile esculin
  • BBE Bac- teroides Bile esculin
  • faecal slurries acquired by mixing faeces with artificial saliva and sterile water were used as input for the TIM-1 model.
  • T1/2 for emptying the gastric content was set to 20 min, pH change from pH 2.0 to 1 .7 in 30 min and level of gastric secretion on 20%.
  • the gastric content was passed into the duodenal compartment, where it was neutralized to pH 6.4, and bile and pancreatin were added, followed passage (time 10 minutes) into the jejunum compartment and into the ileum compartment.
  • the physiological concentra- tions of bile salts, pancreatic enzymes and electrolytes simulated in combination with an average physiological passage through the small intestine.
  • the samples were collected from after 120-180, 180-240 and 240-300 mins treatment. Samples were collected from faecal slurries before the TIM-1 treatment (intake samples) and after the treatments. Dilution series of collected samples were plated in duplicate on applied culturing media and incubated for 72 hours at 37 °C.
  • the survival of anaerobic bacteria (RCBA) from secretor pool was at least 10 times higher (25% vs 2.5%) than the survival of anaerobic bacteria from non-secretor pool (see Table 8).
  • the Bacteroides population (BBE) in the secretor group showed a higher survival rate in the secretor sam- pies than in non-secretor samples (1 % vs 0%).
  • the population of anaerobic bacteria in non-secretor individuals was less tolerant for the harsh conditions of TNO TIM-1 model, mimicking environments in the stomach and small intestine.
  • Table 8 The survival of anaerobic bacteria from pooled faecal samples of secretor and non-secretor individuals in the TIM-1 model (upper gastrointestinal tract conditions). Viability was determined by plate count cultur- inq using RCBA and BBE media.
  • HIT chip The Human Intestinal Tract (HIT) chip (Rajilic-Stojanovic et al. 2009, Environ Microbiol 1 1 (7): 1736 - 1751 ) was applied for more detailed investigation of the microbiota in non-secretor and secretor individuals.
  • HITchip con- tains approximately 5000 nucleotide probes targeting over 1000 phylotypes of bacteria colonising the human gut.
  • HITChip analysis were performed as described in Rajilic-Stojanovic et al. 2009 for DNA (extracted from 1 g of DNA by the Apajalahti et al. 1998 method) samples of 12 non-secretor and 12 secretor individuals.
  • the secretor subjects included were matched for non-secretors re- garding to ABO blood group, age, and sex.
  • the data was normalised and analysed in R using within-array spatial normalization and quality control as described in Rajilic-Stojanovic et al. 2009. On top of that between-array normalization was performed with quantile normalization.
  • the differences for each bacterial group between the sample groups were studied with linear models and ANOVA-tests, transforming the array intensities into logarithmic scale first.
  • RDA redundancy analysis
  • Clostridium orbiscindens Clostridium orbiscindens et rel. C. leptum (cluster IV) SS>NSS 0.02 *
  • the 16S rRNA gene fragment was PCR amplified using universal primer pair (F28 5'-AGAGTTTGATCMTGGCTCAG-3'; 518R 5'-ATTACCGCGGCTGCTGG-3').
  • the F primer contained adaptor sequence (5'- CGTATCGCCTCCCTCGCGCCATCAG-3') and 6 base-long barcode tag
  • R primer contained adaptor sequence (5'-
  • PCR reaction mixture 25 ⁇ was composed of 0.2 ⁇ of each primer (Sigma-Aldrich, UK), 0.2 mM dNTP mixture, 1 x Phusion HF buffer (Finnzymes, Finland), 0.5 U Phusion polymerase (Finnzymes, Finland), 3% DSMO and 1 ⁇ DNA template diluted to the concentration of 20 ng/ ⁇ .
  • the PCR amplification conditions were one cycle of 98 °C for 1 min, followed by 35 cycles of denaturation 98 °C for 10 s, annealing at 65°C for 30 s and elongation at 72°C for 10 s. All the samples were run in three replicates. The PCR products were quantified and pooled in equal amounts. Emulsion PCR was performed from the pool and 454 pyrosequencing was done on the Genome sequencer FLX Titanium (Roche) in Institute of Biotechnology (University of Helsinki, Finland).
  • the raw sequences (245 806) were trimmed using Mothur (v.1 .19.0) software (Schloss et al. Appl Environ Microbiol 2009, 75, 7537-41 ).
  • the sequences with averaged quality score >30, length over 300 bases, exact matches to barcode tags and forward primer, no ambiguous bases, no homo- polymers longer than 8 bp, and non-chimeric according to Chimera Slayer implemented in Mothur were included to the analysis (127 352 sequences, 52%).
  • One non-secretor sample was excluded from analysis as an outlier sample.
  • the high-quality sequences were binned to samples according the barcode tags, and into operational taxonomic units (OTUs) using threshold distance 0.03.
  • Jaccard Index accounts the presence/absence of OTUs and describes dissimilarity in microbial community membership.
  • Bray-Curtis index accounts also abundance of each OTUs and describes the dissimilarity of community structures.
  • Microbial community membership and structure between non-secretor and secretor samples was compared by AMOVA (analysis of molecular variance) with 1000 randomisations as implemented in Mothur.

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Abstract

La présente invention porte sur une composition microbienne qui est adaptée au patient sur la base du spectre de microbes trouvé plus fréquemment dans l'intestin d'individus non sécréteurs que dans l'intestin d'individus sécréteurs. La présente invention porte en outre sur un procédé d'adaptation au patient d'une composition microbienne sur la base du spectre de microbes trouvé plus fréquemment dans l'intestin d'individus non sécréteurs que dans celui d'individus ayant un statut de groupe sanguin sécréteur. La présente invention porte également sur l'utilisation du statut sécréteur d'un individu en tant que critère pour un apport complémentaire microbien adapté au patient sur la base des différences dans les spectres de microbes trouvés entre des individus sécréteurs et des individus non sécréteurs.
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EP3664823B1 (fr) 2017-08-07 2024-06-05 Finch Therapeutics Holdings LLC Composition pour la prévention ou le traitement d'une infection entérococcique de la circulation sanguine
US11166990B2 (en) 2018-07-13 2021-11-09 Finch Therapeutics Holdings Llc Methods and compositions for treating ulcerative colitis
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