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    • 专利摘要:
    The subject of the invention is a commensal, heritable, gram negative, strictly anaerobic and non-sporulated bacterium of the family Christensenellaceae, belonging to a UTO (Operational Taxonomic Unit) characterized by a 16S rRNA sequence SEQ ID No. 2, for use as a medicine. The invention also relates to compositions comprising at least one such bacterium.
    公开号:FR3063647A1
    申请号:FR1770822
    申请日:2017-08-02
    公开日:2018-09-14
    发明作者:Claude Vincent
    申请人:International Nutrition Res Co；
    IPC主号:
    专利说明:

    Holder (s): INTERNATIONAL NUTRITION RESEARCH COMPANY Privately Held.
    Extension request (s)
    Agent (s): AQUINOV.
    SPECIFIC BACTERIA FOR THEIR USE AS MEDICINAL PRODUCTS IN PARTICULAR FOR THE FIGHT AGAINST OVERWEIGHT, OBESITY, CARDIOMETABOLIC DISEASES AND INFLAMMATORY DISEASES OF THE BOWEL.
    FR 3 063 647 - A1 (57) The subject of the invention is a commensal, heritable, gram negative, strictly anaerobic and non-spore-forming bacterium from the family of Christensenellaceae, and belonging to an UTO (Operational Taxonomic Unit) characterized by 16S rRNA sequence SEQ ID No. 2, for use as a medicament.
    A subject of the invention is also compositions comprising at least one such bacterium.
    SPECIFIC BACTERIA FOR THEIR USE AS MEDICAMENTS IN PARTICULAR FOR THE FIGHT AGAINST OVERWEIGHT, OBESITY, CARDIOMETABOLIC DISEASES AND INFLAMMATORY BOWEL DISEASES
    The present invention relates to particular bacteria for their use as medicaments, in particular for preventing or combating overweight, obesity, cardiometabolic diseases and inflammatory diseases of the intestine. The invention also relates to compositions including such bacteria.
    Overweight and obesity today affect all populations, both in developed countries and in developing countries. They are at the origin of chronic diseases, such as mainly cardiometabolic diseases in particular diabetes and cardiovascular diseases but also certain cancers, neurodegenerative diseases and inflammatory bowel diseases, which affect a large portion of the world population and become the leading cause of death.
    Modern medicine finds itself helpless in the face of these chronic pathologies, the management of which is more difficult, time-consuming and less dichotomous than acute diseases. In addition, the sustainability of these diseases over time, with the aging of the population, has a considerable impact on public health spending which is becoming unbearable. This is why a first objective of the invention is to propose a simple, effective and economical solution to deal with this major health problem.
    The pandemic of these chronic diseases seems to be linked to a combination of several factors: a poor Western type diet, physical inactivity and factors affecting genetics and epigenetics.
    Research to combat these pathologies initially focused on imbalances in food intake, both quantitative and qualitative (in particular a high consumption of saturated lipids, fructose and carbohydrates) associated or not with sedentary lifestyle , which lead to weight gain. However, it has been found that not everyone is equal before the same food intake and research has been conducted to assess the impact of genetics and epigenetics on weight gain. This research has shown that only a tiny fraction of the problems of overweight and obesity are directly attributed to genetics. On the other hand, the results at the epigenetic level made it possible to reveal an interest in the microbiome which seemed to play an important role in many chronic diseases and in particular obesity and cardiometabolic diseases. It was notably noted that a quantitative but especially functional intestinal dysbiosis could lead to an increase in the absorption and storage of energy in the form of fat, with an equal amount of food intake. This functional dysbiosis is due to the disappearance or marginalization of certain bacteria which have a positive influence on the health of the host. Most of these bacteria are heritable; this explaining the existence of lean or fat lines, or the existence of obese who never have metabolic disturbances, in particular at the level of glycemia and lipids, because they have no functional intestinal dysbiosis , the host genes are not mutated.
    Indeed, if the existence of a microbiome / brain interaction was the first step to understand the action of the microbiome in particular in the context of overweight through satiety receptors in particular, the most important discovery was that of the heritability of bacteria. This notion of heritability has been demonstrated by the study of cohorts of monozygotic twins (Goodrich "Genetic determinant of the gut microbiome in UK twins", CelIPress 2016), and has made it possible to give an explanation for the transmission of obesity or certain chronic diseases. Thus in the context of obesity and cardiovascular disease it was discovered that variations of genes were directly linked to visceral fat explaining epidemics of obesity and metabolic syndrome in particular of diabetes and cardiovascular diseases, and this as well in developed countries than in emerging countries like China and the countries of South America. This new concept of epigenetics has upset the understanding of many chronic diseases and makes it possible to envisage new treatments thanks to bacteria which can palliate genetic changes. This is all the more important since it is now proven that the epigenetics of mother and father can be transmitted to children, particularly in obesity.
    Another objective of the invention is therefore to propose a solution to fight in particular against overweight, obesity, cardiometabolic diseases and inflammatory diseases of the intestine by acting on the intestinal microbiome and in particular on bacteria. heritable.
    The microbiome is a set of microorganisms (bacteria, archaea, viruses and eukaryotes grouped into domains) which are specific to each individual. These microorganisms are found on the skin, in the mouth and the largest number in the digestive system which counts about 3.3 million. This microbiome thus contains more than one hundred and fifty times of genes than the human genome.
    The different levels for classifying bacteria are: domain, phylum, class, order, family, genus, species and strain. The bacteria can also be identified and characterized by UTOs (Operational Taxonomic Units), a UTO corresponding to a grouping of strains of bacteria of the same species whose 16S rRNA sequences have a similarity of more than 97%.
    To know and analyze the bacteria constituting the intestinal microbiome, several methods currently exist:
    Culture: this technique is limited because 80% of the microbiome is not cultivated (currently only a thousand species are cultivated due to the difficulties in practicing this culture),
    Biological labeling using 16S rRNA as a marker
    UTO sequencing either by the SANGER method or by pyrosequencing of rRNA
    16S,
    The fingerprint by electrophoresis, polymorphism and ribosomal DNA chips
    FISH and qPCR methods with group amplification shootgun metagenomic analysis
    Meta analysis with metagenomics (composition and function of all genes), metaproteomics (protein analysis), metabolomics (metabolic profile) and metatranscriptomics (RNA).
    However, currently, among the millions of bacteria constituting the microbiome, very few (about a thousand) are defined, characterized and cultivated.
    Each individual has their own microbiome that comes from their history and roots, but there are species common to many individuals. In particular, we know that more than 85% of the species are common between Europe, the United States and Japan.
    Furthermore, the intestinal microbiome is not homogeneous. It varies in quantity and quality when it comes to the stomach, duodenum, jejunum, ileum and finally the colon where there is the largest number of anaerobic bacteria. We also know that certain bacteria are found in the mucus that lines the intestinal wall.
    In addition, the immune system, the genetic system and the neurotransmitters (in particular those making the connection between intestine and brain) influence the microbiome which makes its study even more complex.
    It is therefore a particularly delicate area by its complexity and the number of inter-reacting factors and it is impossible today to establish a standard microbiome of good health.
    In overweight and obesity, we know that the diversity of the microbiome decreases as well as its richness (61% of obese have a low number of genera). A correlation between certain phyla (in particular firmicutes, bacteriodetes, proteobacteria and actinobacteria) and overweight and / or obesity has been sought. A relationship between the firmicutes ratio on bacteriodetes has been described as increasing with the BMI (body mass index), but with the replication of studies, some scientists have reversed this judgment by demonstrating the opposite. Thus, staying at the level of large complexes such as phyla does not provide a solution to combat overweight and / or obesity and chronic metabolic diseases. Research has been directed towards lower levels in the bacterial classification, at the level of families, genera, species and even strains.
    Many studies have been carried out on the families of bacteria, but again no satisfactory results have been obtained. Indeed, a family can contain dozens of species and even more strains, without the possibility of knowing which bacterium (s) has (s) the action. In addition, some families may harbor dangerous species alongside beneficial species.
    Recently, studies have been carried out on species likely to influence weight loss by their increase in the microbiome, namely Akkermansia muciniphila, Methanobrevibacter smithii, Faecalibacterium prausnitzii, Bifidobacterium longum, Roseburia intestinalis, Eubacterium rectale and Christensenella minuta. However, the studies have been carried out only on mice which does not suggest any activity on humans. Mouse studies are unreliable because these animals have a microbiome different from humans, and mice with humanized microbiomes lose their natural reactions to metabolic markers.
    Regarding cardiometabolic diseases such as diabetes, it has been shown that it can exist in vitro or on animals, a significant decrease in Clostridiales and an increase in Bacteriodetes, as well as a decrease in Roseburia intestinalis and Faecalibacterium pransnitzii, which would regulate glucose and glycemia through the permeability of the intestinal barrier, but here again these observations do not allow to bring a satisfactory solution to fight against overweight, obesity and the cardiometabolic diseases resulting therefrom because the number of different bacteria is too important.
    Three types of bacterial therapies acting on the microbiome have been proposed to date.
    The first was to use prebiotics to increase all bacteria in order to compensate for the decrease induced by obesity. However, this solution is at best a decoy and at worst a danger by increasing unwanted bacteria which is the natural tendency of the microbiome in dysbiosis. Selective growth was also sought in vitro by crossing selected food on selected strain, but this did not work in humans.
    The second was to use probiotics as a "food" for the development of selected bacteria. This solution is also not satisfactory because the probiotics developed have been limited to food bacteria which are used in the first part of the intestine while the bacteria of metabolic interest are in the colon and nestled in the mucus. In addition, it is difficult to demonstrate long-term action on humans because the activity is highly random.
    Finally, the third proposed solution is the fecal implantation of bacteria from normal or lean people to obese people using a technique that works on mice. This technique has the disadvantage of trying to implant foreign strains which can be rejected and there is a possible transmission of carcinogenic signals according to the fears expressed by oncologists.
    There is therefore currently no therapeutic solution acting on the microbiome which is satisfactory for overweight, obese and / or suffering from cardiometabolic diseases and / or inflammatory bowel diseases.
    The invention therefore aims to meet this need, by proposing the use of new specific bacteria which act in a particularly effective manner to combat overweight, obesity, cardiometabolic diseases and inflammatory diseases of the intestine.
    To this end, the invention relates to the use of particular bacteria selected and harvested from the microbiome of overweight or obese people with a metabolic syndrome. In particular, the invention relates to commensal, heritable, gram negative, strictly anaerobic and non-spore-forming bacteria of the Christensenellaceae family and belonging to a UTO characterized by a 16S rRNA sequence SEQID No. 2.
    Bacteria of the Christensenellaceae family, in particular of the genus Christensenella, have already been studied, in particular in application US2017042948. This is the case in particular of Christensenella minuta, Christensenella massiliensis and Christensenella timonensis. We also know that overweight or obese people with dysbiosis in heritable bacteria of the family Christensenellaceae experience a variation rs74331972 of their FIHT gene and a variation rs 1433723 of their TDRG1 gene (Beaumont "Christensenella, heridity and visceral fat heritable components" , Genome biology 2016).
    However, not all bacteria of the Christensenellaceae family play a role in overweight, obesity and / or cardiometabolic and / or inflammatory diseases, and none of the above bacteria has demonstrated a direct link with these pathologies in humans. 'man.
    The bacteria according to the invention are distant (see phylogenetic tree Figure 1) from those already described for their use in the fight against overweight, obesity, cardiometabolic diseases and / or inflammatory diseases of the intestine.
    Advantageously, the bacteria according to the invention have a significantly demonstrated and very important efficacy in combating overweight, obesity, cardiometabolic diseases and inflammatory diseases of the intestine in humans, in particular by reducing the visceral fat of on the one hand and intestinal permeability on the other. They have been specifically selected from a population of overweight or obese people with metabolic syndrome and are therefore perfectly suited for use as an effective medicine in humans with great adaptability for implantation in an inflammatory environment.
    The invention also relates to compositions comprising at least one of these bacteria.
    Other characteristics and advantages of the invention will emerge from the detailed description of the invention which follows, carried out with reference in particular to FIG. 1 which represents the phylogenetic tree of the bacteria according to the invention.
    DEFINITIONS
    By "rRNA" is meant ribosomal ribonucleic acid.
    By “16S rRNA” is meant the rRNA constituting the small subunit of the prokaryotic ribosomes. In bacteria, their sequence makes it possible to identify and characterize operational taxonomic units.
    By "obesity" means a concentration of excessively high fat mass in the body with an increase in the volume of adipose tissue, tissue containing these fats. Obese adult humans have a BMI (body mass index) greater than 30.
    By “cardiometabolic disease” is meant a metabolic and / or cardiovascular disease. These cardiometabolic diseases can be induced by overweight and / or obesity. It can be in particular pre-diabetes, diabetes, vascular and cardiac diseases, atherosclerosis, hyperlipidemia, hyperglycemia, NASH (non-alcoholic fatty liver disease), NAFLD (disease of non-alcoholic fatty liver), infarction, stroke, hypertension.
    By “use as medicine” is meant a use for any curative or preventive effect with regard to human or animal diseases, as well as any use in humans, with a view to establishing a medical diagnosis or restoring, correcting or modifying their organic functions. The use as a medicament within the framework of the present invention notably includes a use as a specific modulator of the microbiome for reconstituting an ecosystem beneficial for the health of the host.
    By “cardiometabolic risk” or “metabolic syndrome” is meant a syndrome which groups together at least three risk factors chosen in particular from: waist circumference, glycemia, HDL cholesterol, triglycerides and blood pressure, and which leads to cardiometabolic diseases.
    By "overweight" means a concentration of excessively high fat mass in the body with an increase in the volume of adipose tissue, tissue containing these fats. Overweight adult humans have a BMI (body mass index) greater than 25.
    By “faecal transplant” is meant stool intended to be transplanted into an individual and coming either from the individual himself taken before treatment and implanted after treatment, or from another individual deemed healthy.
    By “UTO” or “Operational Taxonomic Unit” is meant a grouping of bacteria of the same species whose 16S rRNA sequences have a similarity of more than 97%. Thus, a UTO characterized by a 16S rRNA sequence "X" includes bacteria with a 16S rRNA sequence having a similarity of more than 97.5% with the sequence "X".
    DETAILED DESCRIPTION OF THE INVENTION
    The subject of the invention is a commensal bacteria, inheritable gram negative, strictly anaerobic and non-spore-forming from the family Christensenelloceae, belonging to a UTO characterized by a 16S rRNA sequence SEQ ID No. 2 (called UTO 2 for the present description ), for use as a medicine.
    UTO 2 bacteria are commensal and heritable bacteria found in human intestinal mucus.
    They preferably have a diameter of 0.5 μm.
    They can in particular be cultivated in a pH of between 7 and 8 under strict anaerobic conditions, at a temperature of 37 ° C. for 4 days on yeast with supplementation of nourishing glucose.
    They are small producers of short chain fatty acids, in particular acetic acid, isobutyrate and isovalerate.
    The 16S rRNA sequences which make it possible to identify these bacteria specifically and with certainty are distant from the 16S rRNA sequences of known bacteria of the same family and of the same genus such as Christensenello minuta, Christensenello mossiliensis, Christensenello timonensis. They are below 90% of Christensenello minuta in the phylogenetic tree (see Figure 1) and are well individualized.
    The bacteria according to the invention can be removed and selected from the intestinal microbiome of a population of overweight or obese people with metabolic syndrome. They are correlated with the improvement of many factors characteristic of overweight, obesity, cardiometabolic diseases or inflammatory diseases of the intestine, and in particular with a decrease in visceral fat. The bacteria according to the invention can be harvested in particular by removing faecal material, in particular faecal material from an overweight or obese person and having a metabolic syndrome whose FIHT and TDRGl genes have not undergone genetic variation, and more precisely whose the FIHT gene did not undergo a variation rs74331972 and whose TDRG1 gene did not undergo a variation rs 1433723.
    The bacteria useful according to the invention can be administered to humans by any suitable mode of administration, in particular by oral or rectal route.
    They are particularly useful in the treatment of overweight, obesity and / or in the treatment of cardiometabolic diseases and / or inflammatory bowel diseases, in particular cardiometabolic and / or inflammatory bowel diseases induced by overweight and obesity.
    Advantageously, the bacteria according to the invention are in particular capable of: reducing the weight, and / or decreasing the visceral fat and the subcutaneous fat, and / or preserving the lean mass, and / or decreasing the hepatic fats and blocking the fibrosis of the liver, and / or decrease the waist circumference, and / or normalize the blood pressure, and / or decrease the inflammation of the intestinal barrier, organs and muscular or adipose tissues, in particular of the colon, and / or decrease the permeability of the intestinal barrier by the action on the reconstitution of mucus, the closing of tight junctions, the reactivation of hormonal receptors such as TLR4, GPL2, CCK and / or regulate HDL, LDL and total cholesterol and / or regulate triglycerides, and / or lower blood sugar and / or postprandial blood sugar, and / or insulin resistance and / or insulin sensitivity.
    decrease inflammation of the intestine, in particular in inflammatory bowel diseases and in particular Crohn's disease (Crohn's disease being linked to the metabolic syndrome and therefore to the same microbiome).
    These various factors are characteristics or consequences of cardiometabolic diseases or inflammatory diseases of the intestine, in particular in overweight or obese people, so that the action of the bacteria according to the invention on these factors makes it possible to combat overweight, obesity, cardiometabolic diseases and inflammatory bowel diseases.
    The bacteria according to the invention are therefore particularly useful in the treatment of overweight, obesity, metabolic syndrome, pre-diabetes, diabetes, vascular and cardiac diseases, atherosclerosis, hyperlipidemia, hyperglycemia, NASH (non-alcoholic fatty liver disease) and / or NAFLD (non-alcoholic fatty liver disease) and / or IBD (inflammatory bowel disease in English or IBD "Inflammatory Bowel Disease") in particular the disease from Crohn's. Advantageously, the invention makes it possible to act on the reconstitution of mucus, of the epithelium and the increase in the impermeability of the intestinal barrier for the modulation of tight junctions in order to reduce the endotoxemia and the blood translocation of bacteria and lipopolysaccharide endotoxins (LPS). Indeed, overweight and obese people and those with cardiometabolic diseases and / or inflammatory bowel diseases, have a degraded and thin mucus which is badly renewed. In addition, the inflamed epithelium is deficient with very open tight junctions that allow bacteria and LPS to pass through. This phenomenon is due to inflammation of the intestine and it causes chronic low grade inflammation in the body.
    The bacteria useful according to the invention are particularly suitable for people with a BMI greater than 25 and in particular greater than 30 and / or to people with hypertriglycemia.
    Advantageously, the use of bacteria UTO 2 makes it possible to increase the efficient bacterial population of the family Christensenellaceae without increasing the potentially dangerous bacteria like Catabacter hongkongensis of the same family and close to Christensenella minuta.
    The bacteria according to the invention can be used at the same time as a food rebalancing and / or a calorie restriction. Food rebalancing can consist in particular in eliminating from the diet harmful nutrients for the microbiome: fructose and trans fatty acids. The calorie restriction is preferably slight, around 600 kcal / day. In particular, it modulates glucose homeostasis, protein turnover and lipogenesis.
    The bacteria according to the invention can be used at a daily unit dose of 10 4 to 10 12 (in number of bacteria), preferably between 10 4 to 10 12 .
    Preferably, the bacteria according to the invention are administered at a daily to weekly frequency. Such a frequency makes it possible to keep a colony of bacteria according to the invention sufficient in the microbiome and to prevent the mortality of the bacteria from being higher than the growing bacteria.
    The frequency is determined according to several criteria, in particular the importance of the symptom to be treated, the importance of visceral fat to lose, the importance of hyperglycemia or hypertriglyceremia or the frequency of diarrhea.
    The cure will last until the expected result is obtained; maintenance treatment may be recommended for cases where the implantation of bacteria has been long.
    A stool analysis or a mucus sample to check the UTO 2 content is not compulsory for all patients at the start of treatment, since it is an inheritable bacterium directly linked to visceral fat. However, it may be necessary for patients with very high BMI or high inflammation (CRP us). Similarly, if after several months of treatment the result according to the desired effects (decrease in waist circumference, weight loss, decrease in hyperglycemia etc.) is not achieved, it is preferable to perform a stool analysis to verify that the bacteria have nested well or if strongly disturbed genetic or epigenetic factors require the use of a higher frequency of administration than that initially planned.
    In all cases, a stool analysis or direct removal of mucus is preferable after one year from the end of treatment.
    The advantage of bacteria from the Christensenellaceae family is that they have a good correlation between the presence of these bacteria in the stool and in the mucus, which does not require endoscopic samples to be taken from the colon.
    Advantageously, the bacteria according to the invention can be used in the context of personalized medicine. Indeed, it is possible to adapt the treatment to the genetics of the patient to know to what extent he will respond to the treatment and what is the dose to use. In the context of heritable bacteria of the Christensenellaceae family, the genes which know a variation are known, it is FHIT with the variation rs 74331972 and TDRG1 variant rs 1433723. It is thus possible to use a genetic analysis of the host. in parallel with the genetic analysis of the microbiome to fully personalize the treatment of the patient in severe cases with possible resistance to the treatment in order to adjust the dose to be administered.
    The bacteria according to the invention can be used alone directly, but preferably, they are used within a composition.
    A subject of the invention is therefore also a composition comprising at least one UTO 2, that is to say at least one inheritable gram negative commensal bacterium, strictly anaerobic and not spore-forming from the family of Christensenellaceae, and belonging to a UTO characterized by 16S rRNA sequence SEQ ID No. 2.
    The composition also comprises excipients, known to those skilled in the art and conventionally used in the pharmaceutical industry, to be adapted as a function of the galenical form of the composition.
    According to a particularly suitable embodiment, the composition according to the invention comprises the combination:
    at least one commensal, heritable, gram-negative, strictly anaerobic, non-spore-forming bacterium from the family Christensenellaceae belonging to a UTO characterized by a 16S rRNA sequence SEQ ID No. 1 (UTO 1), and at least minus one inheritable commensal bacterium, gram negative, strictly anaerobic and non-spore-forming from the family of Christensenellaceae and belonging to a UTO characterized by a 16S rRNA sequence SEQ ID No. 2 (UTO 2).
    Advantageously, the combination of bacteria according to the invention belonging to UTO 1 and bacteria according to the invention belonging to UTO 2 makes it possible to obtain a greater effect on the therapeutic applications sought.
    The bacteria UTO 1 and / or UTO 2 can also be associated with other bacteria in the composition.
    The composition can in particular also comprise at least one commensal bacterium, heritable, from the family of Christensenellaceae and belonging to a UTO (called UTO 3 for the present description) characterized by a 16S rRNA sequence SEQ ID No. 3 and / or at least one bacterium belonging to a UTO (designated UTO 4 for the present description) characterized by a 16S rRNA sequence SEQ ID No. 4 and / or at least one bacterium belonging to a UTO (designated UTO 5 for the present description) characterized by a 16S rRNA sequence SEQ ID No. 5 and / or at least one bacterium belonging to a UTO (called UTO 6 for the present description) characterized by a 16S rRNA sequence SEQ ID No. 6 and / or at least a bacterium belonging to a UTO (designated UTO 7 for the present description) characterized by a 16S rRNA sequence SEQ ID No. 7 and / or at least one bacterium belonging to a UTO (designated UTO 8 for the present description) ca characterized by a 16S SEQ ID No.8 rRNA sequence and / or at least one bacterium belonging to a UTO (called UTO 9 for the present description) characterized by a 16S SEQ ID No.9 rRNA sequence, and / or at least one bacterium belonging to a UTO (designated UTO 10 for the present description) characterized by a 16S rRNA sequence SEQ ID No. 10, and / or at least one bacterium belonging to a UTO (designated UTO 11 for the present description ) characterized by a 16S rRNA sequence SEQ ID No.11, and / or at least one bacterium belonging to a UTO (called UTO 12 for the present description) characterized by a 16S rRNA sequence SEQ ID No.12, and / or at least one bacterium belonging to a UTO (designated UTO 13 for the present description) characterized by a 16S rRNA sequence SEQ ID No. 13, and / or at least one bacterium belonging to a UTO (designated UTO 14 for the present description) characterized by a 16S SE rRNA sequence Q ID N ° 14, and / or at least one bacterium belonging to a UTO (called UTO 15 for the present description) characterized by a 16S rRNA sequence SEQ ID N ° 15.
    These bacteria are capable of acting on the same factors as the bacteria useful according to the invention, but can hardly be used alone because they are less frequent in the microbiome and thus their implantation is more random. On the other hand, their use in combination with the bacteria according to the invention makes it possible to improve the effectiveness of the latter and strengthens the ecosystem of the Christensenellocées.
    The composition according to the invention can also comprise one or more methanogenic bacteria of the family of Methanobacteriaceae, of the genus Methanobacterium and / or Methanobrevibacter and / or Methonosphoero and / or Methanothermobacter, in particular Methanothermobacter smithii, Methanogens facilitate the implantation of Christensenellocées en especially in obese people or people with diabetes but on the other hand should be used with caution in inflammatory bowel disease.
    It can also include one or more bacteria of the following species, genera or orders: Marvinbryantia formatexigens and / or Bacteroides thetoiotoomicron and / or Akkermonsio muciniphilo and / or Foecolibocterium prausnitzii and / or Clostridium thermocellum and / or Dehalobacteriaceae and / or Oscilloeiro and / or Ruminococcaceae and / or Ruminococcus and / or Lachinospiraceae and / or Lachinospira and / or Bacteroidaceae and / or Rikenellaceae and / or Clostridium and / or Clostridioles. All these bacteria can be bacteria of known strains currently cultivated or can be new strains, in particular strains harvested from the faeces of an overweight or obese person and in metabolic syndrome to obtain strains resistant to inflammation. characteristic of overweight or obese people. These bacteria are known to have an influence on weight regulation in mice even though most of them are not heritable, therefore with an unknown mode of action. The most likely scientific hypothesis is that they strengthen the ecosystem of the Christensenellaceae family.
    The bacteria useful according to the invention can also be used in combination with at least one other bacterium chosen from Christensenello mossiliensis, Christensenello timonensis, Christensenello minuta. Again, these bacteria can be harvested from the feces of an overweight or obese person and metabolic syndrome to obtain strains resistant to the inflammation characteristic of overweight or obese people. These bacteria are from the Christensenellaceae family with a less convincing action in clinical experience on obese patients with a cardiometabolic risk but they make it possible to create both a synergy but above all a strengthening of the ecosystem of the bacteria of the invention.
    The compositions according to the invention can also comprise other constituents, in particular at least one amino acid and / or at least one peptide. It can in particular be threonine, leucine, serine, proline, alanine, glycine, glutamine, glutamic acid, tryptophan and / or at least one peptide containing at least one of these amino acids. According to a variant, these amino acids can be administered in parallel with the bacteria according to the invention, but in an independent composition. The amount of each of the amino acids or biopeptides is preferably between 500 mg and 1 g per day.
    The presence of amino acid (s) or peptide (s) in addition to the bacteria useful according to the invention makes it possible in particular to strengthen the intestinal mucus and to restore the intestinal barrier by reducing its permeability. These 2 factors are characteristic of obese people and cardiometabolic patients, the mucus is thinner preventing the niche of commensal bacteria such as the bacteria according to the invention; the tight junctions being wide open allowing endotoxemia which causes the chronic inflammation of the organism. The compositions according to the invention can also comprise at least one probiotic and / or at least one prebiotic. It may for example be oligosaccharides in particular RS4 for prebiotics or lactic ferments for probiotics. Probiotics help improve quantitative dysbiosis and the general health of the microbiota. Prebiotics make it possible to increase the food of the bacteria according to the invention which have been implanted. Preferably, the prebiotics and / or the probiotics are administered at the start of the treatment with the bacteria according to the invention.
    The bacteria according to the invention are preferably used alive. In the compositions according to the invention, the bacteria present (UTO 2 and any other bacteria) are preferably for at least 50% of the living bacteria (percentage by number), even more preferably at least 90%.
    The bacteria useful according to the invention and the compositions including them can be in any form. Preferably, the bacteria and / or the composition are in lyophilized form.
    Preferably, the compositions according to the invention are in the form of powder, microencapsulated powder, capsule, capsugel, tablet, or fecal transplant. According to a particularly suitable variant, the compositions according to the invention are in a gastro-resistant form, in particular in a gastro-resistant form intended to be absorbed at the intestinal level, preferably at the colon level, in particular at the level of the terminal ileum or colon entrance.
    The compositions according to the invention are produced by simple mixing of the constituents and / or by conventional methods known to those skilled in the art adapted to the desired dosage forms.
    The compositions according to the invention can be used for all therapeutic applications, in particular all therapeutic applications of bacteria useful according to the invention as described in the present application.
    Preferably, the compositions according to the invention are used at a daily unit dose for each bacteria present in the composition (UTO2 and other bacteria possibly present) from 10 4 to 10 12 . It is possible to adapt the dosage of the bacteria present in the composition as a function of several criteria, in particular as a function of the amount of said bacteria found in the stool collected from the people to be treated.
    The bacteria and the compositions according to the invention can be given both to adults, to the elderly, to children and to adolescents. The dosage can be the same for all patients regardless of age.
    Advantageously, the invention makes it possible to reduce the therapeutic failures which are numerous either by giving up the treatment in progress and more often at the start, or by gaining weight after a few months and with a greater recovery than before. visceral fat mass, either through the continuation of chronic cardiometabolic and / or inflammatory diseases and their acute manifestations.
    The invention is now illustrated by examples of compositions according to the invention and by a clinical study demonstrating the effectiveness and the interest of the bacteria according to the invention.
    EXAMPLES OF COMPOSITIONS ACCORDING TO THE INVENTION
    Example 1
    This example of composition according to the invention is a composition in lyophilized form comprising UTO 1 and at least one suitable excipient.
    Example 2
    This example of composition according to the invention is a composition in lyophilized form comprising UTO 2 and at least one suitable excipient.
    Example 3
    This example of composition according to the invention is a composition in lyophilized form comprising UTO 1 and UTO 2 and at least one suitable excipient.
    Example 4
    This example of composition according to the invention is a composition in lyophilized form comprising UTO 1, UTO 2, UTO3, UTO 4, UTO 5, UTO 6, UTO 7, l 'UTO 8, UTO 9, UTO 10, UTO 11, UTO 12, UTO 13, IOTU14 and IOTU15 and at least one suitable excipient.
    Example 5
    This example of composition according to the invention is a composition in lyophilized form comprising UTO 1, UTO 2 and Akkermansia muciniphali and at least one suitable excipient.
    Example 6
    This example of composition according to the invention is a composition in lyophilized form comprising UTO 1, UTO 2 and Methonobrevibocter smithii and at least one suitable excipient.
    Example 7
    This example of composition according to the invention is a composition in lyophilized form comprising UTO 1, UTO 2, Christensenello mossiliensis, Christensenello timonensis, and Christensenello minuta and at least one suitable excipient.
    Example 8
    This example of composition according to the invention is a composition in lyophilized form comprising UTO 1, UTO 2, Faecalibacterium prousnitzii, Oscillospiro and Lochinospiro and at least one suitable excipient.
    EVALUATION OF THE EFFECT OF THE INVENTION
    An interventional clinical study was carried out in France on a population of 107 obese or overweight people and in metabolic syndrome with abdominal obesity (waist circumference greater than 86cm for women and 94cm for men) and two other risk factors of metabolic syndrome.
    A product known to fight overweight, obesity and metabolic syndrome was administered with a calorie restriction of 600 kcal for a period of 12 weeks.
    The patients' stools were collected at the beginning and at the end of the study after 12 weeks, to detect the impacts on the correlations between the bacteria present in the stools and the evolution of clinical signs. The main criterion retained for the evolution of the metabolic syndrome was visceral fat mass measured by CTScan and weight as a secondary criterion.
    The determination and characterization of the bacteria was carried out by analysis of the 16S rRNA, confirmed by qPCR and a shotgun metagenomics.
    It turned out that only 286 UTOs were significantly linked to the loss of visceral fat (p = 0.002) and weight in humans. These bacteria belong to the Clostridiales order and to the Christensenellaceae family. Among these 286 UTOs, 15 of them had sufficient representativeness in the patients studied and a positive correlation with the loss of visceral fat. It was also noted that the action of these bacteria was greater on patients who initially had hypertriglyceremia. These UTOs are UTOs 1 to 15 as described in the present application.
    The starting quantity of these UTOs and their evolution after treatment is presented in Table 1 below.
    Bacteria Numberofpatientsmodulated %ofnumberofpatients Starting quantity of bacteria(%) Evolution(multipliedby) Pstudent Δ%Weight Pstudent Δ% FatVisceral PStudent Populationtotal 107 - - - -9.4 0.0000 OTU1 21 41 0.00043 5.88 0.0007 -4.8 0.0000 -12.8 0.0003 OTU 2 19 37 0.00013 2.97 0.0002 -4.8 0.0000 -15.4 0.0003 OTU 3 10 20 0.00198 2.16 0.0043 -5.1 0.0008 -19.5 0.0093 OTU4 10 20 0.00019 3.39 0.0354 -5.1 0.0019 -16.4 0.0136 OTU 5 10 20 0.00001 54.78 0.2932 -4.2 0.0125 -17.7 0.0035 OTU 6 12 24 0.00006 5.68 0.0020 -4.4 0.00325 -12.8 0.0043 OTU 7 15 29 0.00005 4.96 0.0000 -5.1 0.0004 -12.9 0.0092 OTU 8 4 8 0.00055 2.84 0.1627 -7.4 0.0510 -27.0 0.0655 OTU 9 7 14 0.00005 11.14 0.0247 -6.0 0.0056 -15.4 0.0797 OTU 10 4 8 0.00018 5.23 0.2216 -5.1 0.0305 -14.1 0.0301 OTU 11 6 12 0.00045 1.52 0.0122 -4.2 0.0018 -11.2 0.0737 OTU 12 3 6 0.00035 4.50 0.2345 -7.0 0.0916 -22.4 0.2086 OTU 13 5 10 0.00052 4.51 0.2760 -6.1 0.0397 -19.9 0.0127 OTU 14 3 6 0.00025 10.04 0.3264 -3.2 0.0147 -9.7 0.0567 OTU 15 2 4 0.00073 5.70 0.4820 -4.2 0.0941 -6.8 0.2463
    Table 1
    In addition, the precise action of each of the UTO 1 and UTO 2 was evaluated based on the results of the study population. The results are presented in Table 2 below.
    Bacteria Results16S BaselineNumber ofdeparture evolvedweX times Δ% evolutionweight % VS.Evolution ofpopulationtotal Δ% evolutionmassoilyvisceral % VS.EvolutionMGV of thepopulationtotal Total population 107 -3.6 -9.4 Population ofstudy without themUTO 1 bacteria andUTO 2 -3.4 -6% -8.9 -5% UTO 1 0.00043 5.9 -4.8 + 33% -12.8 + 36% UTO 2 0.00013 3.0 -4.8 + 33% -15.4 + 64% Total of 2 bacteriaUTO 1 and UTO 2 0.00042 5.1 -4.8 + 33% -13.4 + 43%
    Table 2
    The increase in bacteria according to the invention in the microbiome is directly linked to a reduction in weight and fat mass in humans. The bacteria according to the invention therefore play a key role in the fight against overweight, obesity, cardiometabolic diseases and inflammatory diseases, in particular linked to visceral fat, and can be used for this purpose.
    It has also been found that the best results are obtained with people with a BMI greater than 30.
    It is also noted that the UTOs 1 and 2 according to the invention were already present in sufficient quantity to be detected and individualized in the patients of the study despite their overweight or obesity and the metabolic syndrome. The presence of these bacteria in a highly inflammatory environment means that they have become resistant to inflammation and that the two genes FHIT and TDRG1 have partially resisted the epigenetics of the diet or the epigenetic transmission of the parents.
    权利要求:
    Claims (18)
    [1" id="c-fr-0001]
    1. Commensal bacteria, heritable, gram negative, strictly anaerobic and non-spore-forming from the family Christensenellaceae, and belonging to a UTO (Operational Taxonomic Unit) characterized by a 16S rRNA sequence SEQ ID N ° 2, for use as a medicament .
    [2" id="c-fr-0002]
    2. A bacterium for use according to claim 1, in the treatment of overweight, obesity, cardiometabolic diseases and / or inflammatory bowel diseases.
    [3" id="c-fr-0003]
    3. Bacterium for use according to one of the preceding claims, in the treatment of metabolic syndrome, pre-diabetes, diabetes, vascular and cardiac diseases, atherosclerosis, hyperlipidemia, hyperglycemia , NASH and / or NAFLD, Crohn's disease.
    [4" id="c-fr-0004]
    4. Bacterium for use according to one of the preceding claims, for:
    decrease weight, and / or decrease visceral fat and subcutaneous fat, and / or
    - preserve lean body mass, and / or
    - decrease liver fat and block liver fibrosis, and / or
    - decrease the waist size, and / or
    - normalize blood pressure, and / or
    - decrease inflammation of the intestinal barrier, of organs and of muscle or adipose tissue, and / or
    - regulate HDL, LDL and total cholesterol and / or
    - regulate triglycerides, and / or decrease blood sugar and / or postprandial blood sugar, and / or insulin resistance and / or insulin sensitivity.
    - decrease inflammation of the intestine.
    [5" id="c-fr-0005]
    5. Composition comprising at least one commensal bacterium, heritable, gram negative, strictly anaerobic and non-sporulated from the family of Christensenellaceae, and belonging to a UTO characterized by a 16S rRNA sequence SEQ ID No. 2.
    [6" id="c-fr-0006]
    6. Composition according to claim 5, characterized in that it also comprises a commensal, inheritable bacterium, from the family of Christensenellaceae and belonging to a UTO characterized by a 16S rRNA sequence SEQ ID No. 3 and / or a bacterium belonging to a UTO characterized by a 16S SEQ ID NO: 4 rRNA sequence and / or a bacterium belonging to a UTO characterized by a 16S SEQ ID NO: 5 rRNA sequence and / or a bacteria belonging to a UTO characterized by a 16S rRNA sequence SEQ ID No. 6 and / or a bacterium belonging to a UTO characterized by a 16S rRNA sequence SEQ ID No. 7 and / or a bacterium belonging to a UTO characterized by a 16S rRNA sequence SEQ ID No. 8 and / or a bacterium belonging to a UTO characterized by a 16S rRNA sequence SEQ ID No. 9 and / or a bacterium belonging to a UTO characterized by a 16S rRNA sequence SEQ ID No. 10 and / or a bacterium belonging to a characterized UTO by a 16S SEQ ID NO: 11 rRNA sequence and / or a bacteria belonging to a UTO characterized by a 16S SEQ ID ΝΊ2 rRNA sequence and / or a bacteria belonging to a UTO characterized by a 16S SEQ rRNA sequence ID No. 13 and / or a bacterium belonging to a UTO characterized by a 16S rRNA sequence SEQ ID No. 14 and / or a bacterium belonging to a UTO characterized by a 16S rRNA sequence SEQ ID No. 15.
    [7" id="c-fr-0007]
    7. Composition according to one of claims 5 or 6, characterized in that it also comprises one or more methanogenic bacteria of the family of Methanobacteriaceae, of the genus Methanobacterium and / or Methanobrevibacter and / or Methanosphaera and / or Methanothermobacter, and / or Methanobrevibacter smithii bacteria.
    [8" id="c-fr-0008]
    8. Composition according to one of claims 5 to 7, characterized in that it also comprises one or more bacteria of the following species, genera or orders: Marvinbryantia formatexigens and / or Bacteroides thetaiotaomicron and / or Akkermansia muciniphila and / or Faecalibacterium prausnitzii and / or Clostridium thermocellum and / or Dehafobacteriaceae and / or Oscillospira and / or Mogibacteriaceae and / or Ruminococcaceae and / or Ruminococcus and / or Lachinospiraceae and / or Lachinospira and / or Bacteroidaceae and / or Rikenellaceae and / or Clostridium.
    [9" id="c-fr-0009]
    9. Composition according to one of claims 5 to 8, characterized in that it also comprises at least one other bacterium chosen from Christensenello mossiliensis, Christensenello timonensis and Christensenello minuta.
    [10" id="c-fr-0010]
    10. Composition of claim 5 to 9, characterized in that the bacteria are present in lyophilized form.
    [11" id="c-fr-0011]
    11. Composition according to one of claims 5 to 10, characterized in that the bacteria present are for at least 50% of living bacteria (by number).
    [12" id="c-fr-0012]
    12. Composition according to one of claims 5 to 11, characterized in that the bacteria present are for at least 90% of living bacteria (by number).
    [13" id="c-fr-0013]
    13. Composition according to one of claims 5 to 12, characterized in that it also comprises at least one amino acid and / or at least one peptide.
    [14" id="c-fr-0014]
    14. Composition according to one of claims 5 to 13, characterized in that it also comprises at least one amino acid chosen from threonine, leucine, serine, proline, alanine, glycine, glutamine, glutamic acid, tryptophan and / or at least one peptide containing at least one of these amino acids.
    [15" id="c-fr-0015]
    15. Composition according to one of claims 5 to 14, characterized in that it comprises at least one probiotic and / or at least one prebiotic.
    [16" id="c-fr-0016]
    16. Composition according to one of claims 5 to 15, characterized in that it is in the form of powder, microencapsulated powder, capsule, capsugel, tablet, or fecal transpiant.
    [17" id="c-fr-0017]
    17. Composition according to one of claims 5 to 16, characterized in that it is in an gastro-resistant form.
    [18" id="c-fr-0018]
    18. Composition according to one of claims 5 to 17, for use as a medicament.
    1/1
    100
    78 99
    85 74
    100
    100
    Butyricicoccus pullicaecorum strain 25 3 Ruminococcaceae Intestinimonas butyriciproducens strain AF211 Ruminococcaceae
    UTO2
    Uncultured Clostridia the bacterium clone Rs-J39 R7 group
    A Clostridia clone Rs-J39 Christensenellaceae R7 group
    Metagenome s8 159701 Christensenellaceae R7 group
    Unident rumen bacterium RFN65 Christensenellaceae R7 group A Clostridia bacterium clone Rs L02 Christensenellaceae R7 group
    UT010
    UTO1
    UTO13
    UTO8
    UTO4
    UTO14
    UTO15
    UTO5
    UTO11
    UTO12
    UTO9
    UTO3
    Gracilibacter thermotolerans strain JW YJLS1 Gracilibacteriaceae Clostridium butirycum strain VPI3266 Clostridiaceae 1
    Clostridium butirycum strain CB TO A Clostridiaceae 1
    Clostridium cavendishii strain BL 28 Clostridiaceae 1
    Caloramator australicus strain DF4 Clostridiaceae 1
    Fervidicella metallireducens strain AeB clostridiaceae 1
    Desulfitibacter alkalitolerans strain sk kt5 Peptococcaceae
    Uncultured Firmicutes clone BS B3
    UTO6
    UTO7
    Ch sp Marseille P2436 Christensenellaceae
    A clone RL385 aao81 d07 Christensenellaceae
    A bacterium clone RL385 aao81 d07 Christensenellaceae
    Christensenella minuta YIT 12065 Christensenellaceae
    Ch minuta strain YIT 12065 Christensenellaceae
    Ch minuta strain Marseille P1999 Christensenellaceae
    Organism close ELU0098-T213-S-NI 000250 Christensenellaceae
    Ch sp Marseille P2437 Christensenellaceae
    A bacterium clone RL 181 aah4 lf03 Christensenellaceae
    Catabacter hongkongensis Catabacter Christensenellaceae uncultured clone dgD-165 Christensenellaceae
    Catabacter hongkongensis strain HKU16 Christensenellaceae
    Catabacter hongkongensis strain 88678 Christensenellaceae a Clostridia clone dgD-165 Christensenellaceae
    Catabacter hongkongensis strain JCM 17853 Christensenellaceae
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    同族专利:
    公开号 | 公开日
    WO2018162726A1|2018-09-13|
    ES2884049T3|2021-12-10|
    WO2018162738A1|2018-09-13|
    DK3592869T3|2021-07-26|
    US10681932B2|2020-06-16|
    EP3592869A1|2020-01-15|
    US20180255819A1|2018-09-13|
    EP3592869B1|2021-04-28|
    PT3592869T|2021-07-19|
    US11044933B2|2021-06-29|
    EP3592870A1|2020-01-15|
    FR3063646A1|2018-09-14|
    US20210352946A1|2021-11-18|
    FR3063647B1|2019-06-07|
    FR3063646B1|2021-07-30|
    US20180255821A1|2018-09-13|
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    WO2015164555A1|2014-04-23|2015-10-29|Cornell University|Modulation of fat storage in a subject by altering population levels of christensenellaceae in the gi tract|
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    WO2020182916A1|2019-03-11|2020-09-17|Lnc Therapeutics|Bacterium of the christensenellaceae family for the prevention and/or treatment of chronic inflammatory diseases and/or inflammatory gastrointestinal diseases and/or cancers|
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    FR3097740B1|2019-06-25|2021-06-25|Lnc Therapeutics|Bacteria of the Christensenellaceae family and composition containing it for the prevention and / or treatment of pathological loss of muscle mass or of a disease characterized by pathological loss of muscle mass|
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    法律状态:
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    2021-01-22| TP| Transmission of property|Owner name: LNC THERAPEUTICS, FR Effective date: 20201216 |
    2021-03-05| CA| Change of address|Effective date: 20210126 |
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    优先权:
    申请号 | 申请日 | 专利标题
    FR1770237|2017-03-10|
    FR1770237A|FR3063646B1|2017-03-10|2017-03-10|BACTERIA SPECIFIC FOR THEIR USE AS A MEDICINAL PRODUCT, IN PARTICULAR FOR THE CONTROL OF OVERWEIGHT, OBESITY, CARDIOMETABOLIC DISEASES AND INFLAMMATORY DISEASES OF THE INTESTINE|
    FR1770822A|FR3063647B1|2017-03-10|2017-08-02|SPECIFIC BACTERIA FOR THEIR USE AS A MEDICAMENT ESPECIALLY FOR COMBATING OVERWEIGHT, OBESITY, CARDIOMETABOLIC DISEASES AND INFLAMMATORY BOWEL DISEASES|FR1770237A| FR3063646B1|2017-03-10|2017-03-10|BACTERIA SPECIFIC FOR THEIR USE AS A MEDICINAL PRODUCT, IN PARTICULAR FOR THE CONTROL OF OVERWEIGHT, OBESITY, CARDIOMETABOLIC DISEASES AND INFLAMMATORY DISEASES OF THE INTESTINE|
    FR1770822A| FR3063647B1|2017-03-10|2017-08-02|SPECIFIC BACTERIA FOR THEIR USE AS A MEDICAMENT ESPECIALLY FOR COMBATING OVERWEIGHT, OBESITY, CARDIOMETABOLIC DISEASES AND INFLAMMATORY BOWEL DISEASES|
    ES18714717T| ES2884049T3|2017-03-10|2018-03-09|Bacteria of the christensenellaceae family for use as a medicinal product, in particular to treat overweight, obesity, cardiometabolic diseases and inflammatory bowel diseases|
    EP18714718.6A| EP3592870A1|2017-03-10|2018-03-09|Specific bacteria for use as a drug, in particular to combat overweight, obesity, cardiometabolic diseases and inflammatory bowel diseases|
    EP18714717.8A| EP3592869B1|2017-03-10|2018-03-09|Bacteria of the christensenellaceae for use as a drug, in particular for treating obesity, cardiometabolic diseases and inflammatory bowel diseases|
    PCT/EP2018/055955| WO2018162738A1|2017-03-10|2018-03-09|Specific bacteria for use as a drug, in particular to combat overweight, obesity, cardiometabolic diseases and inflammatory bowel diseases|
    PCT/EP2018/055937| WO2018162726A1|2017-03-10|2018-03-09|Specific bacteria for use as a drug, in particular to combat overweight, obesity, cardiometabolic diseases and inflammatory bowel diseases|
    DK18714717.8T| DK3592869T3|2017-03-10|2018-03-09|BACTERIA FROM CHRISTENSENELLACEAE FOR USE AS A MEDICINAL PRODUCT, NAMELY FOR THE TREATMENT OF OBESITY, CARDIOMETABOLIC DISEASES AND INFLAMMATORY INTESTINAL DISEASES|
    PT187147178T| PT3592869T|2017-03-10|2018-03-09|Specific bacteria for use as a drug, in particular to combat overweight, obesity, cardiometabolic diseases and inflammatory bowel diseases|
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