WO2024028479A1 - Dysosmobacter pour le traitement du cancer du sein - Google Patents

Dysosmobacter pour le traitement du cancer du sein Download PDF

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Publication number
WO2024028479A1
WO2024028479A1 PCT/EP2023/071660 EP2023071660W WO2024028479A1 WO 2024028479 A1 WO2024028479 A1 WO 2024028479A1 EP 2023071660 W EP2023071660 W EP 2023071660W WO 2024028479 A1 WO2024028479 A1 WO 2024028479A1
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bacteria
composition
dysosmobacter
breast cancer
use according
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PCT/EP2023/071660
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English (en)
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Patrice Cani
Bénédicte Jordan
Emilie MOENS DE HASE
Caner YELEK
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Universite Catholique De Louvain
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • C12N1/205—Bacterial isolates
    • 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
    • A61K2035/11—Medicinal preparations comprising living procariotic cells
    • A61K2035/115—Probiotics
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales

Definitions

  • the present invention relates to the treatment and/or prevention of breast cancer using bacteria from the genus Dysosmobacter or extracts thereof.
  • BACKGROUND OF INVENTION Cancer has become one of the most important diseases of the last century and the leading cause of premature death on a global scale. It is estimated that roughly 19.3 million new cases of cancer occurred worldwide in 2020 while 10 million died from it. Among all cancers, breast cancer (BC) is now the most diagnosed cancer with an estimated 2.3 million cases representing 11.7% of all diagnoses and 25% of diagnosed women.
  • breast cancer is a highly heterogeneous disease divided in subtypes based on the (over)expression of progesterone (PR), estrogen (ER) and human epidermal growth factor receptors (HER-2).
  • PR progesterone
  • ER estrogen
  • HER-2 human epidermal growth factor receptors
  • TNBC triple-negative breast cancer
  • the gut microbiota is a key regulator of whole-body metabolism and low-grade inflammation (Cani et al., 2019) but also gaining important focus in the modulation of cancer and breast cancer progression and therapy (Sampsell et al., 2020).
  • the inventors have investigated the impact of Dysosmobacter welbionis, a novel bacteria discovered, isolated, and named at UCLouvain (Brussels, Belgium) (Le Roy et al., 2020 and WO2020011856).
  • Dysosmobacter welbionis is found in 70% of the general population and therefore can be considered as a highly prevalent bacterium, like Akkermansia muciniphila.
  • Dysosmobacter welbionis is a butyrate producer and Dysosmobacter spp and Dysosmobacter welbionis have been found to be less abundant in the intestine of subjects with obesity and type 2 diabetes.
  • Dysosmobacter welbionis J115 T reduces body weight gain, fat mass gain and improves glucose tolerance, lipid and energy metabolism by acting on mitochondrial activity (Le Roy, Moens de Hase et al.2022).
  • the inventors showed that Dysosmobacter welbionis J115 T could reduce breast cancer growth.
  • the present invention relates to a composition
  • a composition comprising at least (a) bacteria from the genus Dysosmobacter, and/or variants, and/or extracts and/or fragments thereof, and/or (b) a culture supernatant of bacteria from the genus Dysosmobacter and/or variants thereof, for use in preventing and/or treating breast cancer in a subject in need thereof.
  • the bacteria belong to the species Dysosmobacter welbionis.
  • the bacteria belong to the strain J115 T , deposited at the BCCM/LMG on March 14, 2018 as LMG P-30603.
  • the breast cancer comprises at least one mutation on the gene encoding a receptor selected from the group comprising or consisting of Progesterone Receptor (PR), Estrogen Receptor (ER), and Human Epidermal Growth Factor Receptor-2 (HER2).
  • a receptor selected from the group comprising or consisting of Progesterone Receptor (PR), Estrogen Receptor (ER), and Human Epidermal Growth Factor Receptor-2 (HER2).
  • the breast cancer is selected from the group comprising or consisting of luminal A breast cancer, luminal B breast cancer, HER2-positive breast cancer, and triple negative breast cancer (TNBC), preferably said breast cancer is triple negative breast cancer.
  • TNBC triple negative breast cancer
  • the subject further suffers from one or more disease or condition that accelerates tumor growth selected from the group comprising or consisting of obesity-related disorders, liver diseases, metabolic disorders, adipokine-related disorders and inflammatory diseases, and combinations thereof.
  • the subject further suffers from one or more disease or condition that accelerates tumor growth selected from the group comprising or consisting of obesity, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver (NAFL), cirrhosis, diabetes mellitus, glucose intolerance, hyperglycemia, abnormal lipid metabolism, dyslipidemia, high cholesterol, elevated LDL-cholesterol, decreased HDL- cholesterol, elevated triglycerides and intestinal inflammation, and combinations thereof.
  • NASH non-alcoholic steatohepatitis
  • NAFL non-alcoholic fatty liver
  • the composition comprises a therapeutically effective amount of said bacteria, preferably from 1 ⁇ 10 2 to about 1 ⁇ 10 15 CFU.
  • the composition comprises live bacteria.
  • the composition comprises dead or killed bacteria.
  • the composition comprises pasteurized bacteria.
  • the composition further comprises at least another anticancer agent.
  • the composition is in the form of a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.
  • the present invention further relates to a prebiotic comprising one or more active ingredients or substances that increase the level of bacteria from the genus Dysosmobacter in the microbiota of a subject in need thereof, for use in preventing and/or treating breast cancer in said subject.
  • the present invention further relates to a composition comprising at least one bacterium from the genus Dysosmobacter, and/or variants, extracts or fragments thereof, for use as an adjuvant to a treatment administered to a subject suffering from breast cancer.
  • DEFINITIONS [0020] In the present invention, the following terms have the following meanings: [0021] “About” preceding a figure means plus or less 10% of the value of said figure.
  • “Bacterial strain” refers to a subtype of a bacterial species.
  • “Dysosmobacter” [Dys.os.mo.bac'ter. Gr. masc. adj. dysosmos bad smelling; N.L. masc. n. bacter a rod; N.L. masc. n.
  • Dysosmobacter a bad-smelling rod refers to a genus of bacteria described herein that have the following properties: cells are obligatory anaerobic, non-pigmented, non-spore-forming, non-motile, Gram-stain-negative. Cells form straight rods mainly 1.8 – 3.0 ⁇ m but often form elongated rods up to 20 ⁇ m whatever the growing phase. No respiratory menaquinones are produced. The genus belongs to the family of Ruminococcaceae. The type species is Dysosmobacter welbionis. In one embodiment, the diagnostic diamino acid in the cell wall is meso-2,6- diaminopimelic acid.
  • Dysosmobacter welbionis [wel.bi.o'nis. N.L. gen. n. welbionis] refers to a species of bacteria described herein that have the following properties in addition to the properties of the genus Dysosmobacter described hereinabove: colonies on solid modified YCFA after 72h of incubation at 37°C under anaerobic conditions are punctiform, cream, translucent, circular, entire, slightly convex and smooth. Growth is inhibited by the presence of 2% w/v bile or 2% w/v NaCl. Aesculin is not hydrolysed. Indole is not produced. Nitrate is not reduced. Gelatin is not digested.
  • Urease is not produced. Catalase is not produced. Acid is produced from myo-inositol but not from D-glucose, D- arabinose, D-ribose and D-xylose. Positive reactions are obtained for arginine dihydrolase and glutamic acid decarboxylase. All the other tests from API 20A and Rapid ID 32A (bioMérieux, Lyon, France) are negative. Major fermentation end-products from myo- inositol are butyrate.
  • the DNA GC content of the type strain is 59.3 mol% by High Performance Liquid Chromatography (HLPC). In one embodiment, the DNA GC content of the type strain is 58.9 mol% on the basis the genomic sequence.
  • Type strain is J115 T (deposited at the Belgian Coordinated Collections of Microorganisms/Laboratory of Microbiology (BCCM/LMG), Universiteit Gent, K.L. Ledeganckstraat 35, 9000 Gent, Belgium, on March 14, 2018 as LMG P-30603) and was isolated from human faeces.
  • the major cellular fatty acids are saturated branched-chain fatty acids and DMAs.
  • the major DMA fatty acid is C 18:0 DMA and major saturated branched-chain fatty acids are iso-C15:0 and anteiso-C15:0.
  • “Fermentation” refers to the metabolic process that consumes sugar in the absence of oxygen.
  • the products are organic acids, gases, or alcohol. It occurs in yeast and bacteria, and also in oxygen-starved muscle cells, as in the case of lactic acid fermentation.
  • “Gut microbiota” or “gastrointestinal microbiota” are used interchangeably to refer to the complex community of microorganisms that live in the digestive tracts of humans and other animals. The composition of the gastrointestinal microbiota changes over the lifetime of the host organism or when the diet of the host changes. It also varies across the digestive tract. The digestive tract contains a densely-populated microbial ecosystem with up to 10 12 cells per gram of intestinal content. Many species in the gut have not been studied outside of their hosts because most cannot be cultured.
  • the four dominant bacterial phyla in the human gut are Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria. Most bacteria belong to the genera Bacteroides, Clostridium, Faecalibacteria, Eubacteria, Ruminococcus, Peptococcus, Peptostreptococcus, Blautia, Subdoligranulum, Alistipes, Coprococcus, Dialister, Lachnoclostridium, Oscillospira, Parabacteroides, Prevotella, Roseburia, Ruminiclostridium, Sutterella and Bifidobacteria.
  • gut microbiota is thought to function in the defense again pathogens, by competing with potential pathogens and by participating in the development of enteric protection and the immune system, metabolism, by assisting the digestion of consumed aliments, aiding the absorption of nutrients and synthetizing vitamins.
  • the gut microbiota also interacts with the function of the central nervous system and the neuroendocrine and neuroimmune systems.
  • “Mutant”, as used herein, refers to a biological entity which has undergone a natural or induced (i.e. by mutagenesis) change in its genetic structure that does not interfere with the defining properties of said biological entity.
  • the change in its genetic structure may be an insertion or deletion or substitution of one or several nucleotides in the genomic sequence.
  • a Dysosmobacter welbionis mutant refers to a Dysosmobacter welbionis strain which has undergone a change, natural or by techniques of genetic engineering, in its genetic structure that does not interfere with its belonging to the Dysosmobacter welbionis species.
  • nutraceutically effective amount refers to the amount of a nutraceutical composition, food or dietary supplement or functional food necessary and sufficient for providing a physiological benefit or alleviating a discomfort in a subject.
  • “Pasteurized bacterium” refers to a bacterium submitted to a heat treatment (or heating process).
  • “Pharmaceutically acceptable carrier or excipient” refers to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to a subject, especially a human, as appropriate. It includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • preparations should meet, pyrogenicity, general safety and purity standards as required by regulatory offices, such as FDA Office or EMA.
  • a pharmaceutically acceptable carrier or excipient may thus refer to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • Prebiotic refers to a substance, which may not be digested by a subject (for example, by humans), but which modulates composition and/or activity of the gut microbiota through its metabolization by microorganisms in the gut, thus conferring a beneficial physiological effect on the host.
  • Probiotics refers to microbial cell preparations (for example, living microbial cells) which, when administered in an effective amount, provide a beneficial effect on the health or well-being of a subject. By definition, all probiotics have a proven non- pathogenic character. In one embodiment, these health benefits are associated with improving the balance of human or animal microbiota in the gastro-intestinal tract, and/or restoring normal microbiota.
  • Subject refers to a warm-blooded animal, preferably a human, a pet or livestock.
  • the terms “pet” and “livestock” include, but are not limited to, dogs, cats, guinea pigs, rabbits, pigs, cattle, sheep, goats, horses and poultry.
  • the subject is a male or female subject, preferably a female subject.
  • the subject is an adult or a child.
  • the subject may be a “patient”, i.e., a subject who/which is awaiting the receipt of or is receiving medical care or was/is/will be the object of a medical procedure according to the methods of the present invention or is monitored for the development of a disease.
  • “Therapeutically effective amount” refers to the level or amount of an agent that is aimed at, without causing significant negative or adverse side effects to the target, (1) delaying or preventing the onset of a disease, disorder, or condition; (2) slowing down or stopping the progression, aggravation, or deterioration of one or more symptoms of the disease, disorder, or condition; (3) bringing about ameliorations of the symptoms of the disease, disorder, or condition; (4) reducing the severity or incidence of the disease, disorder, or condition; or (5) curing the disease, disorder, or condition.
  • a therapeutically effective amount may be administered prior to the onset of the disease, disorder, or condition, for a prophylactic or preventive action.
  • the therapeutically effective amount may be administered after initiation of the disease, disorder, or condition, for a therapeutic action.
  • Treatment refers to both therapeutic treatment and prophylactic or preventative measures wherein the object is to prevent or slow down (lessen) the targeted pathologic condition or disorder, preferably wherein said condition is breast cancer.
  • Those in need of treatment include those already with the disorder as well as those prone to have the disorder or those in whom the disorder is to be prevented.
  • a subject or mammal is successfully "treated” if, after receiving a therapeutic amount of Dysosmobacter welbionis and/or a variant thereof and/or a fragment thereof according to the present invention the patient shows one or more of the following observable and/or measurable changes: amelioration related to one or more of the symptoms associated with the specific disease or condition, preferably breast cancer, reduction of morbidity and mortality and improvement in quality of life issues.
  • the above parameters for assessing successful treatment and improvement in the disease are readily measurable by routine procedures familiar to a physician.
  • Type strain refers to as defined in the International Code of Nomenclature of Bacteria, as the nomenclatural type of the species and the reference point to which all other strains are compared to know whether they belong to that species.
  • strain J115 T isolated from a faecal sample of a healthy 25 years old female, is the type strain of the species Dysosmobacter welbionis.
  • Variant refers to all the genetically or phenotypically distinct strains of a species that retain the species-defining characteristics. The term variant is also used in reference to other phylogenetic taxa such as for a genus or for a strain.
  • variants refers to both naturally occurring and specifically developed variants or mutants of the bacteria disclosed and exemplified herein.
  • variants may or may not have the same identifying biological characteristics of the bacteria exemplified herein, provided they share similar advantageous properties in terms of treating or preventing diseases.
  • a variant of the bacteria of the invention has the same functional and/or therapeutic properties as the bacteria of the invention.
  • Illustrative examples of suitable methods for preparing variants of the microbial strains exemplified herein include, but are not limited to, gene integration techniques such as those mediated by insertion of elements or transposons or by homologous recombination, other recombinant DNA techniques for modifying, inserting, deleting, activating or silencing genes, intraspecific protoplast fusion, mutagenesis by irradiation with ultraviolet light or X-rays, or by treatment with a chemical mutagen such as nitrosoguanidine, methyl methane sulfonate, nitrogen mustard and the like, and bacteriophage - mediated transduction.
  • gene integration techniques such as those mediated by insertion of elements or transposons or by homologous recombination
  • other recombinant DNA techniques for modifying, inserting, deleting, activating or silencing genes, intraspecific protoplast fusion, mutagenesis by irradiation with ultraviolet light or X-rays, or by treatment with a
  • This invention relates to a composition
  • a composition comprising at least (a) bacteria from the genus Dysosmobacter, and/or variants, extracts or fragments thereof, and/or (b) a culture supernatant of bacteria from the genus Dysosmobacter, and/or variants thereof, for use in preventing and/or treating breast cancer in a subject in need thereof.
  • bacteria from the genus Dysosmobacter comprised in the composition for use according to the invention belong to the species selected from the group comprising or consisting of Dysosmobacter welbionis, Dysosmobacter acutus, Dysosmobacter segnis, and Dysosmobacter hominis.
  • bacteria from the genus Dysosmobacter comprised in the composition for use according to the invention belong to the species selected from the group comprising or consisting of Dysosmobacter welbionis.
  • Biological characteristics of Dysosmobacter welbionis have been reported previously by the inventors in WO2020011856.
  • the bacteria belong to the strain selected from the group comprising or consisting of J115 T , Dysosmobacter acutus MSJ-2 T (CGMCC Accession number: 1.32896T; KCTC Accession number: 15976T), Dysosmobacter segnis BX15 (CGMCC Accession number: 1.32894), Marseille-Q4140, MM13, and Dysosmobacter hominis NSJ-60 (CGMCC Accession number: 1.32836; KCTC Accession number: 25148).
  • the bacteria belong to the strain J115 T , deposited at the BCCM/LMG on March 14, 2018 as LMG P-30603, and/or a variant thereof.
  • the J115 T strain is the type strain of the species Dysosmobacter welbionis.
  • the invention relates to a composition comprising bacteria from the strain Dysosmobacter welbionis J115 T (deposit number LMG P-30603), and/or variants, extracts or fragments thereof, for use in preventing and/or treating breast cancer in a subject in need thereof.
  • the genome sequence of the bacteria has the sequence SEQ ID NO: 1, or has a sequence presenting at least about 65% identity with SEQ ID NO: 1, preferably at least about 70%, 75%, 80%, 85%, 90% identity with SEQ ID NO: 1, more preferably at least about 91%, 92%, 93%, 94%, 95%, 96%, 96.5%, 97%, 97.5%, 97.6%, 97.7%, 97.8%, 97.9%, 98.0%, 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.65%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% or more identity with SEQ ID NO: 1.
  • the bacteria have an Average Nucleotide Identity (ANI) score above about 60, preferably above about 74, 75, 80, 85, 90, more preferably above about 95, even more preferably above about 96, 97, 98, 98.5, 98.65, 99 or more when compared to the genome of sequence SEQ ID NO: 1.
  • ANI Average Nucleotide Identity
  • Techniques to determine the ANI value are known to the person skilled in the art (such as methods implemented in Kim et al., Int J Syst Evol Microbiol.2014 Feb;64(Pt 2):346-51).
  • ANI correspond to corresponds to the sum for each bidirectional best hit (BBH – orthologs sequences identified on the basis of their position in the genome and sequence identity) of the identity multiplied by the length of the alignment divided by the total length of BBH genes.
  • the bacteria have a hybrid DNA-DNA hybridization value (also referred to as DDH value) with SEQ ID NO: 1 above about 60%, preferably above about 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, more preferably above about 70%.
  • the hybrid DDH value is usually specified relative to the DDH value obtained by hybridizing a reference genome with itself. DDH values ⁇ 70% may be considered as an indication that the tested organism belongs to a different species than the type strain used as reference. The DDH value may also evaluated on the basis of the genomic sequence of the strains to be compared using in publicly available computer programs.
  • the bacteria have an intergenome distance with SEQ ID NO: 1, below about 0.5, preferably below about 0.22, 0.21, 0.20, 0.19, 0.18, 0.17, 0.16, 0.15,0.14 more preferably bellow about 0.13, 0.12, 0.11, 0.10, or less.
  • Techniques to determine the intergenome distance, or genome-genome distance (GGD) are known to the skilled artisan. For example, methods described by Meier- Kolthoff et al. (BMC Bioinformatics 2013;21:14-60; Int J Syst Evol Microbiol 2014;1:352–6) may be used.
  • Such method may be implemented using the genome calculator 2.1 (Deutsche Sammlung von Mikroorganismen und Zellkulturen – DSMZ) using BLAST+ as a local alignment tool and the sum of all identities found in high- scoring segment pairs (HSP) divided by overall HSP length.
  • HSP high- scoring segment pairs
  • the nucleotide sequence of the 16S rRNA gene of the bacteria has the sequence SEQ ID NO: 2, or has a sequence presenting at least about 90% identity with SEQ ID NO: 2, preferably at least about 91%, 92%, 93%, 94%, 95%, 95,5%, 96%, 96.5%, 97%, 97.1%, 97.2%, 97.3%, 97.4%, 97.5%, 97.6%, 97.7%, 97.8%, 97.9%, 98.0%, 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.65%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% or more identity with SEQ ID NO: 2 (deposited under the GenBank/EMBL/DDBJ accession number MG
  • the nucleotide sequence of the 16S rRNA gene of the bacteria has the sequence SEQ ID NO: 2, or has a sequence presenting at least about 99.9% identity with SEQ ID NO: 2, preferably at least about 99.91%, 99.92%, 99.93%, 99.94%, 99.95%, 99.96%, 99.97%, 99.98%, 99.99%, or more identity with SEQ ID NO: 2.
  • the nucleotide sequence of the 16S rRNA gene of the bacteria has the sequence SEQ ID NO: 2, or has a sequence presenting at least about 90% identity or more identity over the entire length of SEQ ID NO: 2, preferably at least about 91%, 92%, 93%, 94%, 95%, 96%, 96.5%, 97%, 97.1%, 97.2%, 97.3%, 97.4%, 97.5%, 97.6%, 97.7%, 97.8%, 97.9%, 98.0%, 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.65%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99,6%, 99.7%, 99.8%, 99.9%, 99.91%, 99.92%, 99.93%, 99.94%, 99.95%,
  • identity when used in a relationship between the sequences of two or more polypeptides or of two or more nucleic acid molecules, refers to the degree of sequence relatedness between polypeptides or nucleic acid molecules, as determined by the number of matches between strings of two or more amino acid or nucleotide residues. “Identity” measures the percent of identical matches between the smaller of two or more sequences with gap alignments (if any) addressed by a particular mathematical model or computer program (i.e., “algorithms”). Identity of related polypeptides can be readily calculated by known methods.
  • the composition for use according to the invention may comprise variants of the bacteria as described hereinabove.
  • the variant of the bacteria may also be referred as a derived strain of the bacteria.
  • the variant of the bacteria may be obtained by mutation, variation or recombination of the bacteria described herein. Within the scope of the present invention, a variant may also be referred to as a mutant.
  • the variant of the bacteria from the genus Dysosmobacter comprised in the composition for use according to the invention is a variant of Dysosmobacter welbionis.
  • the variant of the bacteria from the genus Dysosmobacter comprised in the composition for use according to the invention is a variant of Dysosmobacter welbionis strain J115 T .
  • the variant of the bacteria has a genome at least about 70%, preferably at least about 80%, at least about 90%, at least about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99,6%, 99.7%, 99.8%, 99.9, or more identical to the genome of the bacteria from which it derives.
  • the genome sequence of the variant of the bacteria has at least about 65% identity with sequence of the genome of the bacterium from which it derives, preferably at least about 70%, 75%, 80%, 85%, 90% identity with sequence of the genome of the bacterium from which it derives, more preferably at least about 91%, 92%, 93%, 94%, 95%, 96%, 96.5%, 97%, 97.1%, 97.2%, 97.3%, 97.4%, 97.5%, 97.6%, 97.7%, 97.8%, 97.9%, 98.0%, 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.65%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99,6%, 99.7%, 99.8%, 99.9%, or more, identity with the sequence of the genome
  • the variant of the bacteria has the same function and/or therapeutic properties as the bacterium from which it derives.
  • the bacteria from the genus Dysosmobacter and/or variant thereof comprised in the composition for use according to the invention are live bacteria or killed bacteria.
  • live bacteria is interchangeably used with the term “viable bacteria” and refers to bacteria that are able to proliferate in opposition to “killed bacteria” (or “non-viable bacteria”) that are not able to proliferate. Methods for measuring viability and proliferation are known to one skilled in the art.
  • bacteria viability and proliferation may be assessed by spreading a solution containing at least one bacterium of the invention across a petri dish and counting the number of colonies after a determined time of incubation in optimal growth conditions.
  • bacteria may be grown in liquid medium, and proliferation may be measured by measuring optical density of the bacterial culture after a determined time of incubation in optimal growth conditions. It is also possible to determine the number of bacteria, including viable as well as non-viable bacteria by microscopic observation. While phase-contrast microscopy is a well-known method to do so, the microbial bacteria can be further visualized by specific staining with dyes, fluorescent probes or antibodies to facilitate microscopic observations or count bacteria by flow cytometry.
  • the bacteria from the genus Dysosmobacter and/or variant thereof comprised in the composition for use according to the invention are live bacteria. In some embodiments, the bacteria are metabolically active. [0062] In some embodiments, the bacteria from the genus Dysosmobacter and/or variant thereof comprised in the composition for use according to the invention are killed bacteria. In some embodiments, the bacteria and/or variant thereof are unable to proliferate. In some embodiments, the bacteria and/or variant thereof are metabolically inactive. In some embodiments, the bacteria and/or variant thereof are heat-inactivated or heat-killed.
  • Heat-inactivated or heat-killed bacterium can be obtained by heating at a temperature of at least about 90°C, preferably at least about 100°C, 105°C, 110°C, 115°C or 120°C, more preferably at least about 121°C, 125°C, 130°C, 135°C, 140°C or more. Heating may be performed for at least about 5 minutes, preferably for at least about 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes or more. Heating may be performed using a saturating steam pressure of at least about 10 psig, preferably at least about 11, 12, 13, 14, 15 or more psig.
  • the bacteria from the genus Dysosmobacter and/or variant thereof comprised in the composition for use according to the invention are pasteurized bacteria.
  • the pasteurized bacteria and/or variant thereof were heated at a temperature ranging from about 50°C to about 100°C, preferably from about 60°C to about 95°C, more preferably from about 70°C to about 90°C.
  • the pasteurized bacteria and/or variant thereof were heated at a temperature of about 50, 51, 52, 53, 54, 55, 56, 57, 58 or 59°C.
  • the pasteurized bacteria and/or variant thereof were heated at a temperature of about 60, 61, 62, 63, 64, 65, 66, 67, 68 or 69°C. In yet another embodiment, the pasteurized bacteria and/or variant thereof were heated at a temperature of about 70, 71, 72, 73, 74, 75, 76, 77, 78 or 79°C. In yet another embodiment, the pasteurized bacteria and/or variant thereof were heated at a temperature of about 80, 81, 82, 83, 84, 85, 86, 87, 88 or 89°C.
  • the pasteurized bacteria and/or variant thereof were heated at a temperature of about 90, 91, 92, 93, 94, 95, 96, 97, 98, 99°C or 100°C. [0066] In one embodiment, the pasteurized bacteria and/or variant thereof were not heated at a temperature superior to about 100°C. In a particular embodiment, the pasteurized bacteria and/or variant thereof were not heated at an ultra-high temperature, for example at a temperature ranging from about 110°C to about 140°C. In one embodiment, the pasteurized bacteria and/or variant thereof were not heated at a temperature superior to about 90°C. Accordingly, in one embodiment of the invention, the bacteria and/or variant thereof were not sterilized.
  • Sterilization is a treatment intended to destroy, kill or inactivate all life forms and other biological agents. This includes microorganisms and their spores as well as viruses and prions. Unlike sterilization, pasteurization is not intended to kill all microorganisms but is usually applied to food with the aim to reduce the number of viable pathogens. [0067] In one embodiment of the invention, the pasteurized bacteria and/or variant thereof were heated for at least about 10 minutes. In another embodiment of the invention, the pasteurized bacteria and/or variant thereof were heated for at least about 15, 20, 25, 30, 35 or 45 minutes. In one embodiment, the pasteurized bacteria and/or variant thereof were heated for a period from about 10 to about 45 minutes.
  • the pasteurized bacteria and/or variant thereof were not heated for a short time. In a particular embodiment, the pasteurized bacteria and/or variant thereof were not heated for less than about 30 seconds, less than about 60 seconds, less than about 90 seconds or less than about 120 seconds. In a preferred embodiment, the pasteurized bacteria and/or variant thereof were not heated for a time of less than about 1 minute, preferably for a time of less than about 5, 6, 7, 8, or 9 minutes. [0069] In one embodiment, the pasteurized bacteria and/or variant thereof were heated at a temperature ranging from about 50°C to about 100°C for at least about 10 minutes.
  • the pasteurized bacteria and/or variant thereof were heated to about 60°C for about 20 or about 30 minutes. In another particular embodiment, the pasteurized bacteria and/or variant thereof were heated to about 70°C for about 20 or about 30 minutes. In another particular embodiment, the pasteurized bacteria and/or variant thereof were heated to about 80°C for about 20 or about 30 minutes. In another particular embodiment, the pasteurized bacteria and/or variant thereof were heated to about 90°C for about 20 or about 30 minutes. [0070] In a particular embodiment, the pasteurized bacteria and/or variant thereof were not heated at a temperature superior to about 110°C for about 1 to about 120 seconds.
  • the pasteurized bacteria and/or variant thereof were not heated at a temperature superior to about 100°C for about 1 to about 120 seconds. In another particular embodiment, the pasteurized bacteria and/or variant thereof were not heated at a temperature superior to about 90°C for about 1 to about 120 seconds. [0071] In one embodiment, the bacteria and/or variant thereof are treated with an ultra- high temperature (UHT) treatment.
  • UHT ultra- high temperature
  • a “UHT” treatment refers to an Ultra-high temperature processing or an ultra-heat treatment (both abbreviated UHT) involving the at least partial sterilization of a composition by heating it for a short time, such as from about 1 to about 60 seconds, preferably from about 1 to about 30 seconds, more preferably from about 1 to about 10 seconds, at a temperature of at least about 135°C.
  • UHT Ultra-high temperature processing
  • UHT ultra-heat treatment
  • Combinations of UHT systems may be applied at any step or at multiple steps in the process of product preparation.
  • the bacteria and/or variant thereof are flash pasteurized. Accordingly, in one embodiment, the bacteria and/or variant thereof are treated at a temperature ranging from about 71.5°C to about 74° C for a period of time ranging from about 15 to about 30 seconds.
  • the bacteria from the genus Dysosmobacter and/or variant thereof comprised in the composition for use according to the invention are fresh.
  • fresh as used herein mean that the bacteria were not frozen between the last amplification phase and the use.
  • the bacteria from the genus Dysosmobacter and/or variant thereof comprised in the composition for use according to the invention are not fresh.
  • the bacteria and/or variant thereof were frozen at least once.
  • the bacteria and/or variant thereof are frozen.
  • the term ‘frozen’ refers to a bacterium that is cooled down at or below a temperature allowing a phase transition from liquid to solid in said bacterium. In one embodiment said temperature is about -5°, -20°C, -70°C, -80°C or -190°C.
  • recovered frozen bacteria and/or variant thereof are viable.
  • the bacteria from the genus Dysosmobacter and/or variant thereof comprised in the composition for use according to the invention are frozen and viable.
  • the composition for use according to the invention comprises fragments of bacteria from the genus Dysosmobacter, preferably fragments of Dysosmobacter welbionis, more preferably fragments of Dysosmobacter welbionis strain J115 T .
  • fragment refers to bacterial components, metabolites, secreted molecules and/or vesicles and compounds resulting from the metabolism of the bacteria and/or variant thereof comprised in the composition for use according to the invention, and the like.
  • bacterial components include, but are not limited to, bacterial cell wall components such as peptidoglycan, bacterial nucleic acids such as DNA and RNA, bacterial membrane components, and bacterial structural components such as proteins, carbohydrates, lipids and combinations of these such as lipoproteins, glycolipids and glycoproteins, bacterial metabolites, organic acids, inorganic acids, bases, peptides, enzymes and co-enzymes, amino acids, carbohydrates, lipids, glycoproteins, lipoproteins, glycolipids, vitamins, bioactive compounds and metabolites containing an inorganic component.
  • bacterial cell wall components such as peptidoglycan, bacterial nucleic acids such as DNA and RNA, bacterial membrane components, and bacterial structural components such as proteins, carbohydrates, lipids and combinations of these such as lipoproteins, glycolipids and glycoproteins, bacterial metabolites, organic acids, inorganic acids, bases, peptides, enzymes and co-enzymes, amino acids, carbohydrates, lipids, glycoproteins
  • Fragments may be obtained by recovering the supernatant of a culture of the bacteria and/or variant thereof or by extracting cell components or cell fractions, metabolites or secreted compounds from a culture of the bacteria and/or variant thereof, a degradation product, a component in the isolated form, any mixture of one or more components derived from the bacteria and/or variant thereof, or one or more components present in the bacteria and/or variant thereof that are produced in another way, for example using recombinant DNA technology, in a microbial host or in any other (bio)synthetic process.
  • the fragments are comprised in the culture medium of the bacteria, i.e., the fragments are not purified nor isolated.
  • the fragments are purified by methods known in the art, e.g., affinity purification.
  • the composition for use according to the invention comprises an extract of the supernatant of the culture medium of the bacteria from the genus Dysosmobacter, and/or variant thereof.
  • Culture medium suitable for bacterial culture are known in the art.
  • the culture medium is a Yeast extract – casein hydrolysate – fatty acids (YCFA) medium.
  • YCFA Yeast extract – casein hydrolysate – fatty acids
  • the YCFA medium is modified.
  • the YCFA medium comprises yeast extract in an amount of about 8 g/L, KH2PO4 in an amount of about 2 g/L, sodium propionate in an amount of about 1 g/L, cysteine in an amount of about 0.5 g/L, hemin in an amount of about 1 g/L, L-cysteine in an amount of about 1 g/L, and a vitamin solution as described below.
  • the modified YCFA medium further or instead comprises soy peptone in an amount ranging from more than 0 g/L to about 20 g/L, preferably from about 2 g/L to about 6 g/L, more preferably in an amount of about 4 g/L.
  • the modified YCFA medium comprises wheat peptone in an amount ranging from more than 0 g/L to about 20 g/L, preferably from about 2 g/L to about 6 g/L, more preferably in an amount of about 4 g/L.
  • the modified YCFA medium comprises Na 2 CO 3 in an amount ranging from more than 0 g/L to about 20 g/L, preferably from about 2 g/L to about 6 g/L, more preferably in an amount of about 3 g/L.
  • the modified YCFA medium comprises MgCl2 in an amount ranging from more than 0 mg/L to about 500 mg/L, preferably from about 25 mg/L to about 75 mg/L, more preferably in an amount of about 50 mg/L.
  • the modified YCFA medium comprises glutathione in an amount ranging from more than 0 g/L to about 5 g/L, preferably from about 0.5 g/L to about 1.5 g/L, more preferably in an amount of about 1 g/L.
  • the modified YCFA medium comprises ascorbate in an amount ranging from more than 0 g/L to about 1 g/L, preferably from about 0.25 g/L to about 0.75 g/L, more preferably in an amount of about 0.5 g/L.
  • the modified YCFA medium comprises soy peptone in an amount of about 4 g/L, wheat peptone in an amount of about 4 g/L, Na2CO3 in an amount of about 3 g/L, glutathione in an amount of about 1 g/L, ascorbate in an amount of about 1 g/L, ascorbate in an amount of about 0.5 g/L and.
  • the modified YCFA medium comprises 8 g of yeast extract, 4 g of soy peptone, 4 g of wheat peptone, 5 g of KH2PO4, 3 g of Na2CO3, 50 mg of MgCl2, 50 mg of CaCl 2 , 1 mg of hemin, 1 mL Resazurin solution (1g/L), 10 g of myo-inositol, 1 g of cysteine, 1 g of glutathion reduced, 0.5 g of ascorbate, 0.3 g of uric acid, 1 mL of vitamin solution and quantum satis 1000 mL of H2O.
  • the vitamin solution used to prepare the modified YCFA medium comprises 2 mg of biotin, 2 mg of folic acid, 10 mg of pyridoxine-HCl, 2 mg of thiamine-HCl x 2 H, 5 mg of riboflavin, 5 mg of nicotinic acid, 5 mg of D-Ca-pantothenate, 12 mg of vitamin B, 5 mg of p- aminobenzoic acid, 5 mg of lipoic acid and quantum satis 1000 mL of H2O.
  • the modified YCFA medium comprises soy peptone in an amount of about 4 g/L, wheat peptone in an amount of about 4 g/L, Na 2 CO 3 in an amount of about 3 g/L, glutathione in an amount of about 1 g/L, ascorbate in an amount of about 1 g/L, ascorbate in an amount of about 0.5 g/L, MgCl2 in an amount of 0.5 g/L, yeast extract in an amount if 8 g/L, KH 2 PO 4 in an amount of 2g/L, sodium propionate in an amount of 1g/L, cysteine in an amount of 0.5 g/L, hemin in an amount of 1 g/L, L-cysteine in an amount of 1g/L, and a vitamin solution as described hereinabove.
  • the culture medium is free of living bacteria, i.e., the medium is sterilized.
  • Means to sterilize a culture medium are known in the art and comprise, e.g., heating and irradiation.
  • the culture medium comprises living bacteria, preferably a substantially pure population of bacteria from the genus Dysosmobacter, and/or variant thereof.
  • the culture medium is frozen and stored for future use, at a temperature of about -5°, -20°C, -70°C, -80°C or -190°C.
  • the culture medium is fermented.
  • the fermentation of the culture medium comprises the steps of: 1) incubating from about 10 8 to about 10 9 living bacteria from the genus Dysosmobacter, preferably from Dysosmobacter welbionis, more preferably from Dysosmobacter welbionis strain J115 T , in 50 mL of the modified YCFA medium for 48 hours at a temperature of 37°C in anaerobic conditions; 2) incubating the culture of step 1) in 3,5 L of the modified YCFA medium for 48 hours at a temperature of 37°C in anaerobic conditions; 3) collecting the culture medium from step 2), wherein the medium is fermented; 4) and optionally, removing the living bacteria from the collected medium of step 3) (i.e., sterilizing the medium).
  • the extract from the bacteria from the genus Dysosmobacter, and/or variant thereof, or from the culture supernatant comprised in the composition for use according to the invention comprises at least one metabolite secreted by the bacteria.
  • the composition for use according to the invention comprises metabolites produced and/or secreted by bacteria from the genus Dysosmobacter, preferably from Dysosmobacter welbionis, more preferably from Dysosmobacter welbionis strain J115 T .
  • the at least one metabolite is selected from the group comprising or consisting of short chain fatty acids (SCFA) such as butyrate and acetate.
  • SCFA short chain fatty acids
  • the at least one metabolite is selected from the group comprising or consisting of butyrate, acetate, C8-3OH, C10-3OH, C12-3OH, C16-2OH C16-3OH, C18-2OH C18-3OH, C18-130H, C18, C18:2 n-6, C22:2 n-6, C22:6 n-3, C18:1 n-9c, C22:1 n-9, C18:2 n-6, 10-TriHOME, 10-TriHOME, C12asn, C12asnGABAOH, 9,10-DiHOME, 12,13-DiHOME, 13-oxoODE, 8-HETE and 9-HODE.
  • the at least one metabolite is butyrate. In some embodiments, the at least one metabolite is acetate.
  • the Inventors have demonstrated that the effect of the bacteria from the genus Dysosmobacter, preferably from Dysosmobacter welbionis, more preferably from Dysosmobacter welbionis strain J115 T , is not limited to said metabolites produced and/or secreted by said bacteria. In particular, they have demonstrated that this effect is not limited to the presence or secretion of short chain fatty acids (SCFA) such as butyrate and acetate.
  • SCFA short chain fatty acids
  • the composition for use according to the invention comprises an active agent from the supernatant of the culture medium of the bacteria from the genus Dysosmobacter, and/or variant thereof.
  • the active agent is a metabolite produced and/or secreted by the bacteria of the present invention as described hereinabove.
  • Another object of the present invention is a culture supernatant of the bacteria from the genus Dysosmobacter, and/or variants thereof, for use in preventing and/or treating breast cancer in a subject in need thereof.
  • the culture supernatant is obtained by harvesting the culture medium of the bacteria from the genus Dysosmobacter, and/or variant thereof.
  • the culture supernatant is the fermented culture medium obtained after culture of the bacteria of the invention.
  • the culture of the bacteria from the genus Dysosmobacter, and/or variant thereof is performed as disclosed hereinabove.
  • the culture supernatant is obtained by the following steps: 1) incubating from about 10 8 to about 10 9 living bacteria from the genus Dysosmobacter, preferably from Dysosmobacter welbionis, more preferably from Dysosmobacter welbionis strain J115 T , in 50 mL of the modified YCFA medium for 48 hours at a temperature of 37°C in anaerobic conditions; 2) incubating the culture of step 1) in 3,5 L of the modified YCFA medium for 48 hours at a temperature of 37°C in anaerobic conditions; 3) collecting the culture medium from step 2), wherein the medium is fermented; 4) and optionally, removing the living bacteria from the collected medium of step 3).
  • breast cancer refers to histologically or cytologically confirmed cancer of the breast.
  • the breast cancer is a carcinoma.
  • the breast cancer is an adenocarcinoma.
  • the breast cancer is a sarcoma.
  • the breast cancer is a hormone receptor-positive (HR+) breast cancer or a hormone receptor-negative (HR-) breast cancer.
  • the hormone receptor positive breast cancer is an estrogen receptor-positive (ER+) breast cancer and/or a progesterone receptor-positive (PR+) breast cancer.
  • the ER+ breast cancer is luminal A breast cancer.
  • the ER+ breast cancer is luminal B breast cancer.
  • the breast cancer is a human epidermal growth factor receptor 2-positive (HER2+) breast cancer.
  • the breast cancer is a human epidermal growth factor receptor 2-negative (HER2-) breast cancer.
  • the breast cancer is a cancer with a combined expression of receptors, e.g., hormone receptor-positive and HER2 negative (HR+ HER2 ⁇ ).
  • the breast cancer is a cancer of Group 1 (luminal A), Group 2 (luminal B), Group 3 (HER2+) or Group 4 (basal-like).
  • Group 1 includes tumors that are ER+ and progesterone- receptor-positive (PR+) positive, but negative for HER2 (HR+ HER2 ⁇ ).
  • Group 2 includes tumors that are ER+, PR-and HER2+.
  • Group 3 includes tumors that are ER- and PR-, but HER2+.
  • the breast cancer is a HER2+ breast cancer or a triple negative breast cancer (TNBC).
  • TNBC triple negative breast cancer
  • the breast cancer is HER2+ breast cancer, preferably HER2+ breast adenocarcinoma.
  • the breast cancer is a triple negative breast cancer (TNBC).
  • the breast cancer is a non-invasive breast cancer, in particular a ductal carcinoma in situ or a lobular carcinoma in situ.
  • the breast cancer is an invasive breast cancer, in particular selected in the group comprising or consisting of invasive ductal carcinoma, invasive lobular carcinoma, Paget’s disease of the nipple, inflammatory breast cancer, Phyllodes tumor of the breast, locally advanced breast cancer and metastatic breast cancer.
  • the type of tissue where breast cancer arises is milk ducts, milk-productive lobules or connective tissues.
  • the breast cancer is a metastatic or a locally advanced breast cancer.
  • the term “locally advanced breast cancer” refers to cancer that has spread from where it started in the breast to nearby tissue or lymph nodes, but not to other parts of the body.
  • the cancer is a metastatic cancer or a cancer susceptible to undergo metastasis, in particular a metastatic breast cancer or a breast cancer susceptible to undergo metastasis.
  • the term “metastatic breast cancer” refers to a cancer that has spread from the breast to other parts of the body, such as the bones, liver, lungs, or brain. Metastatic breast cancer may also be referred to as stage IV breast cancer.
  • cancer susceptible to undergo metastasis refers to an invasive cancer for which cancer cells may detach from the primary tumor and propagate in other organs, where they can grow to form secondary tumors, also referred to as metastases.
  • metastases also referred to as metastases.
  • pathophysiological factors that can influence tumor growth such as, inter alia, conditions related to diet, obesity, glucose and lipid metabolism, and inflammation. These conditions are relevant within the scope of the present invention because of the ability of commensal bacteria, including bacteria from the genus Dysosmobacter, to influence these conditions.
  • the subject further suffers from one or more disease or condition that accelerates tumor growth selected from the group comprising or consisting of obesity-related disorders, liver diseases, metabolic disorders, adipokine-related disorders and inflammatory diseases, and combinations thereof.
  • the one or more disease or condition that accelerates tumor growth is selected from the group comprising or consisting of obesity-related disorders, metabolic disorders, and inflammatory diseases, and combinations thereof.
  • the one or more disease or condition that accelerates tumor growth is selected from the group comprising or consisting of obesity-related disorders and metabolic disorders.
  • the subject further suffers from obesity-related disorders.
  • the subject further suffers from liver diseases.
  • the subject further suffers from metabolic disorders. In some embodiments, the subject further suffers from adipokine-related disorders. In some embodiments, the subject further suffers from inflammatory diseases. [0112] In some embodiment, the subject is not suffering from obesity-related disorders. In some embodiments, the subject has a normal BMI index.
  • the subject further suffers from one or more disease or condition that accelerates tumor growth selected from the group comprising or consisting of obesity, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver (NAFL), cirrhosis, diabetes mellitus, glucose intolerance, hyperglycemia, abnormal lipid metabolism, dyslipidemia, high cholesterol, elevated LDL-cholesterol, decreased HDL- cholesterol, elevated triglycerides and intestinal inflammation, and combinations thereof.
  • the subject further suffers from obesity.
  • the subject further suffers from NASH.
  • the subject further suffers from NAFL.
  • the subject further suffers from cirrhosis.
  • the subject further suffers from diabetes mellitus. In some embodiments, the subject further suffers from glucose intolerance. In some embodiments, the subject further suffers from hyperglycemia. In some embodiments, the subject further suffers from abnormal lipid metabolism. In some embodiments, the subject further suffers from dyslipidemia. In some embodiments, the subject further suffers from high cholesterol. In some embodiments, the subject further suffers from elevated LDL-cholesterol. In some embodiments, the subject further suffers from decreased HDL-cholesterol. In some embodiments, the subject further suffers from elevated triglycerides. In some embodiments, the subject further suffers from intestinal inflammation. [0115] In some embodiments, the subject suffers from gut microbiota imbalance.
  • gut microbiota imbalance refers to the overrepresentation or the underrepresentation of at least one microbial species, preferably at least one bacterial species.
  • the population of bacteria from the genus Dysosmobacter are underrepresented.
  • the population of Dysosmobacter welbionis is underrepresented.
  • the population of Dysosmobacter welbionis is decreased in subjects suffering from obesity and/or obesity-related disorders. [0116]
  • the population of Dysosmobacter welbionis negatively correlates with the body mass index of the subject.
  • the composition for use according to the invention comprises a therapeutically effective amount of said bacteria, preferably from about 1 ⁇ 10 2 to about 1 ⁇ 10 15 CFU.
  • CFU means “colony forming unit”.
  • the composition for use according to the invention comprises a therapeutically effective amount of said bacteria, preferably from about 1 ⁇ 10 4 to about 1 ⁇ 10 12 CFU, more preferably from about 1 ⁇ 10 5 to about 1 ⁇ 10 10 CFU, even more preferably from about 1 ⁇ 10 6 to about 5 ⁇ 10 9 CFU.
  • the composition for use according to the invention comprises a therapeutically effective amount of said bacteria, preferably from about 1 ⁇ 10 2 to about 1 ⁇ 10 15 CFU, from about 1 ⁇ 10 4 to about 1 ⁇ 10 12 CFU, from about 1 ⁇ 10 5 to about 1 ⁇ 10 10 CFU, from about 1 ⁇ 10 6 to about 5 ⁇ 10 9 CFU.
  • the composition for use according to the invention comprises a therapeutically effective amount of said bacteria, preferably from about 1 ⁇ 10 4 to about 1 ⁇ 10 14 CFU, from about 1 ⁇ 10 5 to about 1 ⁇ 10 13 CFU, from about 1 ⁇ 10 6 to about 1 ⁇ 10 12 CFU, from about 1 ⁇ 10 7 to about 1 ⁇ 10 11 CFU, from about 1 ⁇ 10 8 to about 1 ⁇ 10 10 CFU, from about 2 ⁇ 10 8 to about 6 ⁇ 10 9 CFU.
  • the composition for use according to the invention comprises a therapeutically effective amount of said bacteria, preferably from about 1 ⁇ 10 4 to about 1 ⁇ 10 12 CFU/mL, more preferably from about 1 ⁇ 10 5 to about 1 ⁇ 10 10 CFU/mL, even more preferably from about 1 ⁇ 10 6 to about 5 ⁇ 10 9 CFU/mL.
  • the composition for use according to the invention comprises a therapeutically effective amount of said bacteria, preferably from about 1 ⁇ 10 4 to about 1 ⁇ 10 14 CFU/mL, preferably from about 1 ⁇ 10 5 to about 1 ⁇ 10 13 CFU/mL, more preferably from about 1 ⁇ 10 6 to about 1 ⁇ 10 12 CFU/mL, even more preferably from about 1 ⁇ 10 7 to about 1 ⁇ 10 11 CFU/mL, 1 ⁇ 10 8 to about 1 ⁇ 10 10 CFU/mL, and even more preferably from about 2 ⁇ 10 8 to about 6 ⁇ 10 9 CFU/mL.
  • the composition for use according to the invention comprises a therapeutically effective amount of said bacteria, preferably from about 1 ⁇ 10 2 to about 1 ⁇ 10 15 CFU/g, preferably from about 1 ⁇ 10 4 to about 1 ⁇ 10 12 CFU/g, more preferably from about 1 ⁇ 10 5 to about 1 ⁇ 10 10 CFU/g and even more preferably from about 1 ⁇ 10 6 to about 5.10 9 CFU/g.
  • the composition for use according to the invention comprises a therapeutically effective amount of said bacteria, preferably from about 1 ⁇ 10 4 to about 1 ⁇ 10 14 CFU/g, preferably from about 1 ⁇ 10 5 to about 1 ⁇ 10 13 CFU/g, more preferably from about 1 ⁇ 10 6 to about 1 ⁇ 10 12 CFU/g, even more preferably from about 1 ⁇ 10 7 to about 1 ⁇ 10 11 CFU/g, from about 1 ⁇ 10 8 to about 1 ⁇ 10 10 CFU/g, and even more preferably from about 2 ⁇ 10 8 to about 6 ⁇ 10 9 CFU/g.
  • the composition for use according to the invention comprises a therapeutically effective amount of said bacteria, preferably from about 1 ⁇ 10 6 to about 1 ⁇ 10 10 CFU/g or CFU/mL, preferably from about 1 ⁇ 10 8 to about 1 ⁇ 10 10 CFU/g or CFU/mL, more preferably from about 1 ⁇ 10 9 to about 1 ⁇ 10 10 CFU/g or CFU/mL.
  • the composition for use according to the invention comprises a therapeutically effective amount of said bacteria, preferably from about 1 ⁇ 10 6 to about 1 ⁇ 10 11 CFU/g or CFU/mL, preferably from about 1 ⁇ 10 8 to about 1 ⁇ 10 11 CFU/g or CFU/mL, more preferably from about 1 ⁇ 10 10 to about 1 ⁇ 10 11 CFU/g or CFU/mL.
  • the composition for use according to the invention comprises an amount of fragment of the bacteria and/or variant thereof corresponding to an amount of bacteria and/or variant thereof ranging from about 1 ⁇ 10 2 to about 1 ⁇ 10 15 cells/g, preferably from about 1 ⁇ 10 4 to about 1 ⁇ 10 12 cells/g, more preferably from about 1 ⁇ 10 5 to about 1 ⁇ 10 10 cells/g and even more preferably from about 1 ⁇ 10 6 to about 1 ⁇ 10 9 cells/g.
  • the composition for use according to the invention comprises an amount of fragment of the bacteria and/or variant thereof corresponding to an amount of bacteria and/or variant thereof ranging from about 1 ⁇ 10 4 to about 1 ⁇ 10 14 cells/g, preferably from about 1 ⁇ 10 5 to about 1 ⁇ 10 13 cells/g, more preferably from about 1 ⁇ 10 6 to about 1 ⁇ 10 12 cells/g, even more preferably from about 1 ⁇ 10 7 to about 1 ⁇ 10 11 cells/g.
  • the composition for use according to the invention comprises an amount of fragment of the bacteria and/or variant thereof corresponding to an amount of bacteria and/or variant thereof ranging from about 1 ⁇ 10 8 to about 1 ⁇ 10 10 cells/g, preferably from about 1 ⁇ 10 9 to about 1 ⁇ 10 10 cells/g.
  • the composition for use according to the invention comprises an amount of fragment of the bacteria and/or variant thereof corresponding to an amount of bacteria and/or variant thereof ranging from about 1 ⁇ 10 2 to about 1 ⁇ 10 15 cells/mL, preferably from about 1 ⁇ 10 4 to about 1 ⁇ 10 12 cells/mL, more preferably from about 1 ⁇ 10 5 to about 1 ⁇ 10 10 cells/mL and even more preferably from about 1 ⁇ 10 6 to about 1 ⁇ 10 9 cells/mL.
  • the composition for use according to the invention comprises an amount of fragment of the bacteria and/or variant thereof corresponding to an amount of bacteria and/or variant thereof ranging from about 1 ⁇ 10 4 to about 1 ⁇ 10 14 cells/mL, preferably from about 1 ⁇ 10 5 to about 1 ⁇ 10 13 cells/mL, more preferably from about 1 ⁇ 10 6 to about 1 ⁇ 10 12 cells/mL, even more preferably from about 1 ⁇ 10 7 to about 1 ⁇ 10 11 cells/mL.
  • the composition for use according to the invention comprises an amount of fragment of the bacteria and/or variant thereof corresponding to an amount of bacteria and/or variant thereof ranging from about 1 ⁇ 10 8 to about 1 ⁇ 10 10 cells/mL, preferably from about 1 ⁇ 10 9 to about 1 ⁇ 10 10 cells/mL.
  • the composition for use according to the invention comprises an amount of fragment of the bacteria corresponding to an amount of bacteria ranging from about 1 ⁇ 10 6 to about 1 ⁇ 10 10 cells/g or cells/mL, preferably from about 1 ⁇ 10 8 to about 1 ⁇ 10 10 cells/g or cells/mL, more preferably from about 1 ⁇ 10 9 to about 1 ⁇ 10 10 cells/g or cells/mL.
  • the composition for use according to the invention comprises an amount of fragment of the bacteria corresponding to an amount of bacteria ranging from about 1 ⁇ 10 6 to about 1 ⁇ 10 11 cells/g or cells/mL, preferably from about 1 ⁇ 10 8 to about 1 ⁇ 10 11 cells/g or cells/mL, more preferably from about 1 ⁇ 10 10 to about 1 ⁇ 10 11 cells/g or cells/mL.
  • the composition for use according to the invention is in the form of a pharmaceutical composition, further comprising a pharmaceutically acceptable carrier.
  • the carrier must be “acceptable” in the sense of being compatible with the composition for use according to the invention, and not be deleterious upon being administered to an individual.
  • the carrier does not produce an adverse, allergic or other untoward reaction when administered to an individual, preferably a human individual.
  • the composition for use according to the invention or the pharmaceutical composition for use according to the invention further comprises at least another anticancer agent.
  • Anticancer agents are known from the state of the art.
  • Non-limitative examples of anticancer agents include acalabrutinib, alectinib, alemtuzumab, anastrozole, avapritinib, avelumab, belinostat, bevacizumab, bleomycin, blinatumomab, bosutinib, brigatinib, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin copanlisib, cytarabine, daunorubicin, decitabine, dexamethasone, docetaxel, doxorubicin, encorafenib, erdafitinib, etoposide, everolimus, exemestane, fludarabine, 5-fluorouracil, gemcitabine, ifosfamide, imatinib Mesylate, leuprolide, lomustine, mechlorethamine, melphalan
  • the anticancer agent is an anticancer agent suitable to treat a breast cancer.
  • the anticancer agent is to be administered in combination with, concomitantly or sequentially, the composition for use according to the invention or the pharmaceutical composition for use according to the invention.
  • the present invention further relates to a medicament comprising the composition or pharmaceutical composition for use according to the invention. In some embodiments, said medicament is for treating and/or preventing breast cancer.
  • the present invention also relates to a composition
  • a composition comprising at least (a) bacteria from the genus Dysosmobacter, preferably from the species Dysosmobacter welbionis, more preferably from the strain Dysosmobacter welbionis J115 T , and/or variants and/or fragments thereof, and/or (b) a culture supernatant of bacteria from the genus Dysosmobacter, preferably from the species Dysosmobacter welbionis, more preferably from the strain Dysosmobacter welbionis J115 T , and/or variants thereof, for use for the manufacture of a medicament for treating and/or preventing breast cancer in a subject in need thereof.
  • Another object of the present invention is bacteria from the genus Dysosmobacter, preferably from the species Dysosmobacter welbionis, more preferably from the strain Dysosmobacter welbionis J115 T , and/or variants and/or fragments thereof, for use for the manufacture of a medicament for treating and/or preventing breast cancer in a subject in need thereof.
  • Still another object of the present invention is a culture supernatant of bacteria from the genus Dysosmobacter, preferably from the species Dysosmobacter welbionis, more preferably from the strain Dysosmobacter welbionis J115 T , and/or variants thereof, for use for the manufacture of a medicament for treating and/or preventing breast cancer in a subject in need thereof.
  • the composition for use according to the invention is in the form of a nutraceutical or neutraceutical composition, further comprising a nutraceutically acceptable agent.
  • the nutraceutical composition comprises a nutraceutically effective amount of bacteria from the genus Dysosmobacter, and/or variants, extracts or fragments thereof.
  • the nutraceutical composition is intended for ingestion by a human user, and may be useful for their preventative and medicinal qualities.
  • the nutraceutical composition of the invention is for use for preventing and/or treating breast cancer in a subject in need thereof.
  • the nutraceutical composition is in form of a food or dietary supplement. In another embodiment, the nutraceutical composition is in form of a functional food.
  • the nutraceutical composition is formulated as a food additive, beverage, tablet, capsule, caplet, lozenge, syrup, suspension or emulsion.
  • the nutraceutical composition further comprises one or more secondary nutraceutical components, wherein the secondary nutraceutical component is active nutritionally or therapeutically in the prevention and/or treatment of breast cancer.
  • the secondary nutraceutical component(s) is a vitamin, a mineral.
  • the nutraceutically acceptable agent is selected from one or more of the group comprising talc, titanium dioxide, starch, cornstarch, modified cornstarch, kaolin, microcrystalline cellulose and powdered cellulose.
  • the present invention further relates to a prebiotic comprising one or more active ingredients or substances that increase the level of bacteria from the genus Dysosmobacter, preferably from the species Dysosmobacter welbionis, more preferably from the strain Dysosmobacter welbionis J115 T , and/or variants and/or fragments thereof, in the microbiota of a subject in need thereof.
  • the prebiotic is for use in preventing and/or treating breast cancer in said subject.
  • the prebiotic is selected from the group comprising or consisting of myo-inositol, inulin and inulin-type fructans, oligofructose, beta-glucans, xylose, arabinose, arabinoxylan, ribose, phytates, galactose, rhamnose, cellobiose, fructose, lactose, salicin, sucrose, glucose, esculin, tween 80, trehalose, maltose, mannose, mellibiose, mucus or mucins, raffinose, fructooligosaccharides, galacto- oligosaccharides, amino acids, alcohols, fermentable carbohydrates, water-soluble cellulose derivatives (e.g., methylcellulose, methyl ethyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, cationic hydroxyeth
  • the present invention also relates to a therapeutic combination product for its separate, simultaneous or sequential administration.
  • therapeutic combination product that may also be referred to as a therapeutic kit of parts
  • a therapeutic kit of parts refers to a product comprising or consisting of at least the 2 following parts: a first part comprising the composition for use, pharmaceutical composition for use or medicament according to the invention, and a second part comprising the prebiotic.
  • the therapeutic combination product is for treating and/or preventing breast cancer.
  • the prebiotic is comprised in the composition for use, pharmaceutical composition for use or medicament according to the invention.
  • the present invention further relates to a composition
  • a composition comprising at least (a) one bacterium from the genus Dysosmobacter, preferably from the species Dysosmobacter welbionis, more preferably from the strain Dysosmobacter welbionis J115 T , and/or variants, extracts or fragments thereof, and/or (b) a culture supernatant of bacteria from the genus Dysosmobacter, preferably from the species Dysosmobacter welbionis, more preferably from the strain Dysosmobacter welbionis J115 T , and/or variants thereof, for use as an adjuvant to a treatment administered to a subject suffering from breast cancer.
  • an “adjuvant” relates to an agent that potentiates the effect of a treatment, typically a breast cancer treatment. “Potentiates” means that the positive effects of the treatment on the disease or condition, preferably breast cancer, used with the adjuvant account for more than the sum of the effects of the treatment and the adjuvant taken individually.
  • the breast cancer in the subject is treated by methods known in the art, e.g., hormonal therapy, chemotherapy and immunotherapy.
  • the subject further suffers from one or more disease or condition that accelerates tumor growth selected from the group comprising or consisting of obesity-related disorders, liver diseases, metabolic disorders, adipokine-related disorders and inflammatory diseases, and combinations thereof.
  • the subject further suffers from one or more disease or condition that accelerates tumor growth selected from the group comprising or consisting of obesity, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver (NAFL), cirrhosis, diabetes mellitus, glucose intolerance, hyperglycemia, abnormal lipid metabolism, dyslipidemia, high cholesterol, elevated LDL-cholesterol, decreased HDL-cholesterol, elevated triglycerides and intestinal inflammation, and combinations thereof.
  • NASH non-alcoholic steatohepatitis
  • NAFL non-alcoholic fatty liver
  • the subject suffers from an imbalance of gut microbiota.
  • the gut microbiota of the subject comprises a decreased population of bacteria from the genus Dysosmobacter, preferably Dysosmobacter welbionis, compared to a healthy subject.
  • the present invention further relates to a method of treating and/or preventing breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising at least (a) bacteria from the genus Dysosmobacter, preferably from the species Dysosmobacter welbionis, more preferably from the strain Dysosmobacter welbionis J115 T , and/or variants, extracts or fragments thereof, and/or (b) a culture supernatant of bacteria from the genus Dysosmobacter, preferably from the species Dysosmobacter welbionis, more preferably from the strain Dysosmobacter welbionis J115 T , and/or variants thereof.
  • a composition comprising at least (a) bacteria from the genus Dysosmobacter, preferably from the species Dysosmobacter welbionis, more preferably from the strain Dysosmobacter wel
  • the method further comprises administering to the subject a therapeutically effective amount of another anticancer agent.
  • another anticancer agent examples of other anticancer agents have been described hereinabove.
  • the present invention also relates to a method of treating and/or preventing breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising (i) a composition comprising bacteria from the genus Dysosmobacter, and/or variants, extracts or fragments thereof, and (ii) another therapeutic agent, wherein the other therapeutic agent is an anticancer agent.
  • the method is used when the subject suffers from breast cancer, and aims at slowing down or reversing the progression of tumor growth. In another embodiment, the method is used when the subject does not suffer from breast cancer, and aims at preventing the appearance of breast cancer. In one embodiment, the method is used acutely. In another embodiment, the method is used chronically. [0159] In some embodiments, the subject further suffers from one or more disease or condition that accelerates tumor growth selected from the group comprising or consisting of obesity-related disorders, liver diseases, metabolic disorders, adipokine-related disorders and inflammatory diseases, and combinations thereof.
  • the subject further suffers from one or more disease or condition that accelerates tumor growth selected from the group comprising or consisting of obesity, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver (NAFL), cirrhosis, diabetes mellitus, glucose intolerance, hyperglycemia, abnormal lipid metabolism, dyslipidemia, high cholesterol, elevated LDL-cholesterol, decreased HDL-cholesterol, elevated triglycerides and intestinal inflammation, and combinations thereof.
  • the subject suffers from an imbalance of gut microbiota.
  • the gut microbiota of the subject comprises a decreased population of bacteria from the genus Dysosmobacter, preferably Dysosmobacter welbionis, compared to a healthy subject.
  • the present invention further relates to a composition comprising at least (a) bacteria from the genus Dysosmobacter, preferably from the species Dysosmobacter welbionis, more preferably from the strain Dysosmobacter welbionis J115 T , and/or variants thereof, and/or (b) a culture supernatant of bacteria from the genus Dysosmobacter, preferably from the species Dysosmobacter welbionis, more preferably from the strain Dysosmobacter welbionis J115 T , and/or variants thereof, for use as a probiotic.
  • the bacteria comprised in the composition are the strain J115 T , and/or variant thereof, which is beneficial for improving the gastrointestinal environment of a subject.
  • the present invention also relates to a method for increasing the population of bacteria from the genus Dysosmobacter, preferably Dysosmobacter welbionis, more preferably Dysosmobacter welbionis strain J115 T , within the gut microbiota of a subject, comprising administering the bacteria to the subject, wherein the bacteria is comprised in a composition, pharmaceutical composition, or a prebiotic.
  • the subject is at risk of developing breast cancer, or suffers from breast cancer.
  • the present invention also relates to a method for treating gut microbiota imbalance, comprising administering to a subject a composition or a prebiotic comprising at least (a) bacteria from the genus Dysosmobacter, preferably Dysosmobacter welbionis, more preferably Dysosmobacter welbionis strain J115 T , and/or (b) a culture supernatant of bacteria from the genus Dysosmobacter, preferably from the species Dysosmobacter welbionis, more preferably from the strain Dysosmobacter welbionis J115 T , and/or variants thereof.
  • a composition or a prebiotic comprising at least (a) bacteria from the genus Dysosmobacter, preferably Dysosmobacter welbionis, more preferably Dysosmobacter welbionis strain J115 T , and/or variants thereof.
  • Figure 1A-1G is set of graphs showing that Dysosmobacter welbionis J115 T partly alleviates high-fat diet driven tumor growth.
  • Fig.1A shows bodyweight evolution of under normal diet (ND) or high-fat diet (HFD). Arrow indicates the induction of tumors.
  • Fig. 1B shows E0771 tumor volume evolution.
  • Fig. 1C shows tumor volume evolution with focus on ND and HFD groups.
  • Fig. 1D shows tumor volume evolution with focus on HFD groups treated or not with J115 T .
  • Fig. 1E shows survival curve deduced by calculating the time needed for each tumor to reach 300 mm3 from linear regressions.
  • Fig. 1A shows bodyweight evolution of under normal diet (ND) or high-fat diet (HFD). Arrow indicates the induction of tumors.
  • Fig. 1B shows E0771 tumor volume evolution.
  • Fig. 1C shows tumor volume evolution with focus on ND and HFD groups.
  • Fig. 1D shows tumor volume evolution with
  • FIG. 1F shows survival curve focused on the difference between ND and HFD groups.
  • Fig.1G shows survival curve focused on the difference between HFD and HFD J115 T groups.
  • Mice harboring tumors smaller than 100 mm3 were excluded.
  • FIG. 1C, 1D Two-way ANOVA analysis followed by Sidak’s multiple comparison test.
  • FIG.2A-2E is set of graphs showing that Dysosmobacter welbionis J115 T alleviates high-fat diet driven tumor growth and confirms the results of Figure 1.
  • Fig.2A shows bodyweight evolution of under normal diet (ND) or high-fat diet (HFD). Arrow indicates the induction of tumors.
  • Fig.2B shows E0771 tumor volume evolution.
  • Fig.2C shows survival curve deduced by calculating the time needed for each tumor to reach 400 mm3 from linear regressions.
  • FIG. 2D shows survival curve focused on the difference between ND and HFD groups.
  • Fig. 2E shows survival curve focused on the difference between HFD and HFD J115 T groups.
  • FIG.2C, 2D, 2E Log-rank (Mantel-Cox) test. * p ⁇ 0.05.
  • Figure 3A-3B is set of graphs showing that Dysosmobacter welbionis J115 T alleviates high-fat diet driven tumor growth and confirms the results of Figure 1 and 2.
  • Fig.3A shows bodyweight evolution of under high-fat diet (HFD). Arrow indicates the induction of tumors.
  • Fig.3B shows E0771 tumor volume evolution.
  • Statistical analysis Two-way ANOVA followed by Sidak’s multiple comparison test. ** p ⁇ 0.01.
  • Figure 4A-4B is set of graphs showing that Dysosmobacter welbionis J115 alleviates tumor growth in a non-obesity related context.
  • Fig. 4A shows bodyweight evolution of Balb/c mice under normal diet (ND).
  • Fig. 4B shows 4T1 tumor volume evolution.
  • Statistical analysis Two-way ANOVA followed by Sidak’s multiple comparison test. ** p ⁇ 0.01.
  • Figure 5A-5D is a set of histograms showing that Dysosmobacter welbionis J115 T supernatant decreases cell density and proliferation in triple-negative breast cancer (TNBC) models in vitro.
  • TNBC triple-negative breast cancer
  • Fig.5A-5B show cell density (A) and cell proliferation (B) of PY8119 cells after 24h of treatment with either non-fermented bacterial medium, fermented bacterial medium and pH and short-chain fatty acid (SCFA) content-matched (to fermented) phosphate buffered solution (PBS) at indicated concentrations.
  • Fig. 5C- 5D show cell density (C) and cell proliferation (D) of E0771 cells after 24h of treatment with either non-fermented bacterial medium, fermented bacterial medium or pH and short-chain fatty acid (SCFA) content-matched (to fermented medium) phosphate buffered solution (PBS) at indicated concentrations.
  • SCFA short-chain fatty acid
  • Example 1 Materials and Methods Bacteria culture [0170] Dysosmobacter welbionis J115 T was cultured anaerobically in a modified YCFA medium supplemented with 10 g/L inositol.
  • 4T1 cells were derived from the mammary gland of BALB/c mouse strain. E0771 and 4T1 cells were maintained in Dulbecco’s Modified Eagle Medium (GIBCO, Thermo Fisher Scientific) with 25 mM glucose, 4 mM glutamine, and 25 mM HEPES, supplemented with 10% heat-inactivated Fetal Bovine Serum (FBS) (Thermo Fisher Scientific). PY8119 cells were maintained in culture in F-12K medium (GIBCO, Thermo Fisher Scientific) with 7 mM glucose and 2 mM glutamine, supplemented with 5% heat-inactivated FBS (Thermo Fisher Scientific). They were cultured in a humidified atmosphere at 37°C and 5% CO 2 .
  • Dulbecco’s Modified Eagle Medium GIBCO, Thermo Fisher Scientific
  • FBS Fetal Bovine Serum
  • PY8119 cells were maintained in culture in F-12K medium (GIBCO, Thermo Fisher Scientific) with 7 m
  • PrestoBlue reagent ThermoFisher Scientific
  • Cell proliferation was measured by using a 5-bromo-2-deoxyuridine (BrDu) incorporation ELISA-based kit (Roche) following the provider's protocol. After 24 hours of incubation with indicated treatments described above, BrDu was added to the culture medium for 2 hours. Then, after a fixation step of the cells with a solution provided by the manufacturer and binding of anti-BrDu antibody coupled to a peroxidase, cellular proliferation was assessed by measuring the absorbance at 370 nm using a plate reader (SpectraMax M2e, Molecular Devices). All data were normalized to the absorbance of untreated wells and expressed in percent of control.
  • mice [0174] All mouse experiments were approved by the ethical committee for animal care of the Health Sector of the elle Catholique de Louvain, under the specific number 2021/UCL/MD/04 and its amendment 2022/UCL/MD/A10 and performed in accordance with the guidelines of the local ethics committee and in accordance with the Belgian Law of 29 May 2013, regarding the protection of laboratory animals (agreement number LA1230467).
  • ND normal diet
  • HFD high-fat diet
  • D12492 Research Diets
  • Bodyweight was assessed weekly.
  • Oral bacteria administration [0175] Freshly thawed Dysosmobacter welbionis J115 T was administered daily in late post-prandial stage by oral gavage. Each mouse received at least 1.0 ⁇ 10 9 live (cultivable) bacteria in 0.2 mL.
  • ND and HFD control groups were given an oral gavage of an equivalent volume of PBS-carbonate buffer supplemented with 15 % (weight/vol) trehalose.
  • E0771 tumors were induced by subcutaneous injection of 1 ⁇ 10 6 cells in the fifth mammary fat pad of C57Bl/6JRj female mice 6 weeks after the beginning of the HFD treatment.4T1 tumors were induced by subcutaneous injection of 2 ⁇ 10 5 cells in the fifth mammary fat pad of 8 weeks old BALB/c mice. E0771 cells were freshly passaged just before the injection and prepared as a mixture of 1:1 PBS and Matrigel (Corning) and injected within 30 min. 4T1 cells were freshly passaged just before the injection and prepared in a PBS solution and injected within 30 min.
  • mice were treated daily with either a placebo or Dysosmobacter welbionis J115 T .
  • obese mice treated with the placebo exhibited a significantly higher tumor growth with an 80% bigger tumor volume than the lean mice ( Figure 1B and 1C), whereas obese mice treated with Dysosmobacter welbionis J115 T displayed a significantly reduced development of the tumor which was similar to the lean mice ( Figure 1B and 1D).
  • Obese mice are also characterized by a faster tumor growth as shown in Figure 1E and 1F, the time to reach the same volume of tumor is shortened in obese mice versus lean mice, in other words, the tumor of the lean mice will reach a volume of 300 mm3in 27 days when the obese mice have reached this size in only 19 days (Figure 1E and 1F).
  • this effect on the delayed tumor size induced by Dysosmobacter welbionis J115 T strongly extended the time required to reach the same volume as the one observed in the obese mice.
  • Dysosmobacter welbionis J115 T treated mice will reach a volume of 300 mm3 in 27 days, which is similar to the lean mice and much delayed than the obesity (weight) matched mice receiving the placebo ( Figure 1E and 1G).
  • this beneficial effect was not linked to a body weight loss of the Dysosmobacter welbionis J115 T treated mice ( Figure 1A).
  • This first set of data convincingly show that a non-invasive approach such as using Dysosmobacter welbionis J115 T could be linked to such a strong delay in cancer development and that surprisingly this is not due to the anti-obesity effect of Dysosmobacter welbionis J115 T .
  • Dysosmobacter welbionis J115 T was also tested for its ability to reduce or delay the development of cancer in non-obesogenic conditions in vivo.
  • Cells were subcutaneously injected in the fifth mammary fat pad of mice ( Figure 4A). Mice were then treated daily with either a placebo or Dysosmobacter welbionis J115 T .
  • mice treated with Dysosmobacter welbionis J115 T displayed a significantly reduced growth of the tumor compared to the untreated mice ( Figure 4B).

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Abstract

La présente invention concerne une composition comprenant des bactéries du genre Dysosmobacter, et/ou des variants, des extraits ou des fragments associés, pour une utilisation dans la prévention et/ou le traitement du cancer du sein.
PCT/EP2023/071660 2022-08-05 2023-08-04 Dysosmobacter pour le traitement du cancer du sein WO2024028479A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020011856A1 (fr) 2018-07-10 2020-01-16 Université Catholique de Louvain Dysosmobacter, nouveau genre bactérien du microbiote gastro-intestinal et ses utilisations
WO2020202148A1 (fr) * 2019-03-31 2020-10-08 Biomica Consortium microbien et ses utilisations
WO2022061094A1 (fr) * 2020-09-18 2022-03-24 Evelo Biosciences, Inc. Formes galéniques solides de bactéries

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
WO2020011856A1 (fr) 2018-07-10 2020-01-16 Université Catholique de Louvain Dysosmobacter, nouveau genre bactérien du microbiote gastro-intestinal et ses utilisations
WO2020202148A1 (fr) * 2019-03-31 2020-10-08 Biomica Consortium microbien et ses utilisations
WO2022061094A1 (fr) * 2020-09-18 2022-03-24 Evelo Biosciences, Inc. Formes galéniques solides de bactéries

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