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    • 专利摘要:
    The present invention seeks to implement a new use of probiotics, in particular the strain Leuconostoc mesenteroides subsp. mesenteroides SD23, for consumption by an obese mother during pregnancy and breastfeeding, to partially or totally prevent metabolic changes caused by a high-fat diet, in both the mother and the baby.
    公开号:ES2820874A2
    申请号:ES202090069
    申请日:2019-07-11
    公开日:2021-04-22
    发明作者:Rodriguez Diana Catalina Castro；Gonzalez Elena Zambrano
    申请人:Instituto Nac De Ciencias Medicas Y Nutricion Salvador Zubiran；
    IPC主号:
    专利说明:

    [0002] Use of Leuconostoc mesenteroides subsp. SD23 mesenteroids for maternal-fetal metabolic programming
    [0006] The present invention is in the field of compositions with nutraceutical or therapeutic properties, specifically that of compositions for use in the treatment or prevention of obesity and overweight in the progeny of mothers with obesity, where the composition that is administered during the pregnancy comprises a strain of Leuconostoc mesentedamientos subsp. mesenteroids SD23 as active ingredient.
    [0010] Obesity is a public health problem in Mexico that affects various groups of people to a greater or lesser degree. Although the main cause of this disease is undoubtedly an imbalance between energy intake and expenditure, there is current evidence indicating that a combination of dietary, environmental and genetic factors are also causes of this type of pathology [1-3]. These studies suggest that the composition of the microbiota of each individual is a determining factor that favors obesity or a poor phenotype.
    [0012] Within the sectors of the population that suffer from obesity, are women of reproductive age, as well as children of school age. Various investigations on childhood obesity indicate that this disease can also be the result, not only of sedentary lifestyle, lifestyle and eating conditions, but also of the mother's nutritional and metabolic conditions. Maternal obesity has been observed to predispose the growing fetus and neonate to the development of metabolic diseases from childhood which persist into adult life. Among the adverse effects caused by maternal obesity in the progeny, there are characteristics of the metabolic syndrome, such as insulin resistance, hyperglycemia, increased inflammatory process, increased oxidative stress, and changes in the intestinal microbiota [3-5]. Based on the evidence of the effects of the mother on the child, the hypothesis of "the origins in the development of health and disease", DOHaD, for its acronym in English, has arisen, which proposes that fetal and neonatal physiology and metabolism can be altered by changes during a critical time window of development, that is, in gestation and lactation. These alterations generate a physiological response in the fetus, which is associated with the development of diseases in the adult [6, 7]. The metabolically programmed fetus and neonate present permanent modifications in the structure and physiology of organs, as well as in the expression of genes involved in their own metabolism [8]. Therefore, the adult phenotype is the sum of genetic factors, as well as the influence of the fetal and postnatal environment. The development of obesity prior to and during pregnancy has been reported to be a factor responsible for the adverse effects of developmental programming in progeny, such as predisposition to diabetes, increased abdominal adipose tissue, obesity and cardiovascular disease [9 -12].
    [0014] As mentioned above, the microbiota is a factor involved in obesity and associated diseases, due to its influence on the metabolic and immunological functions of the host. In their first days of life, newborns are rapidly colonized by different bacteria, which are attributed the initiation of the defense system, ensuring good physical and immune development [13]. This invasion of the newborn's digestive tract occurs through the placenta, the amniotic fluid, the birth and lactation routes, which determine a healthy or altered microbiota from which different diseases derive. Several studies have reported that maternal immune cells and bacteria from the mother's intestinal tract cross the placenta and modulate immune responses in the fetus [8, 14]. It has also been shown that the microbiota of the mammary gland is unique and beneficial bacteria are found that access the gland through an internal route and are transferred to the neonate once lactation has begun, generating protective factors for its future life [8 ].
    [0016] Although pregnancy is a period of vulnerability for predisposition to diseases in postnatal life, it is also a window of opportunity to implement interventions that seek to improve the health of pregnant women and, consequently, that of their offspring. Several studies in animal models show that nutritional intervention or exercise in the pregnant obese mother totally or partially prevents the adverse effects of scheduling in the offspring [7, 15, 16].
    [0018] Another type of therapeutic intervention explored in recent years is the use of probiotics as supplements to nutritional diets. Studies have concentrated mainly in the Lactobacillus and Bifidobacterium genera, these effects are summarized in Table 1.
    [0020] Evidence of the use of probiotics for the treatment of various pathologies has shown that the effects are dependent on the bacterial strain and the characteristics of the host such as age and nutritional status [17].
    [0022] Although there are not many studies that report the use of isolated probiotics in the treatment and / or prevention of complications in pregnancy, lactation and the health of the progeny of mothers with metabolic alterations, as with the other therapeutic uses of the probiotics, it is impossible to predict that a specific effect of a previously known strain will be the same in another strain of the same genus, but with no known effects, for the treatment of the same disease.
    [0024] In other words, an expert with average knowledge in the field of probiotics knows that there are specific effects of the different bacterial strains even within the same species, therefore it is important that the studies are conducted at the bacterial strain level and never transpolate them. effects obtained from strain to strain within the same species [18].
    [0026] In addition to the previous complications, it is added that many of the controlled interventions carried out in adults are not feasible during pregnancy, which adds a greater degree of uncertainty to the use of a strain in mothers and their offspring.
    [0028] The evidence related to maternal probiotic interventions, which is summarized in Table 1, shows that at the moment there is no evidence in the state of the art of the use of the bacterial genus Leuconostoc in the pregnant mother or in her progeny.
    [0030] In fact, there are few patent documents that demonstrate specific effects of Leuconostoc mesenteroides on the metabolism in adult individuals, since Leuconostoc mesenteroides is usually administered as a mixture together with other strains and even bacterial genera as in US20140079676 (Olmstead, 2014); or as a mixture to generate a prebiotic composition whose inoculant among other various bacterial genera includes Leuconostoc mesentedamientos as in US20080064657 (Day et al, 2008) and WO2017146213 (Kimura, 2017); or even the use of Leuconostoc mesentedamientos is mentioned only as part of the inoculum to ferment foods such as kimichi KR20120021349 (Sang Kyu, 2012), where said fermentation is directly responsible for the therapeutic effects disclosed in said document.
    [0032]
    [0034] Table 1. Beneficial effects of known probiotic strains during pregnancy and lactation.
    [0035] As described above, the consumption of probiotics plays a significant role in the maintenance of the intestinal ecosystem and in the stimulation of the immune system, improving or preventing certain pathologies, including pathologies related to pregnancy and lactation and their effects on the progeny. That is why the present invention proposes the novel use of a probiotic strain of Leuconostoc mesenteroides, to be consumed during pregnancy and lactation in the obese mother and to partially or totally prevent the metabolic alterations caused by a high-fat diet, both in the mother as well as offspring.
    [0039] The present invention seeks to implement a new use of probiotics, especially of the strain Leuconostoc mesenteroides subsp. mesenteroids SD23 to be consumed during pregnancy and lactation in the obese mother and to partially or totally prevent metabolic alterations caused by a high-fat diet, both in the mother and in the offspring.
    [0041] In one embodiment of the invention it is shown that the administration of the strain Leuconostoc mesenteroides subsp. SD23 mesenteroids improves the fertility rate of female rats fed a high-fat diet.
    [0043] In another form of the invention the administration of the strain Leuconostoc mesenteroides subsp. mesenteroids SD23 decreased the serum concentration of glucose, cholesterol, and triglycerides in female rats that consumed a high-fat diet during the gestation and lactation periods.
    [0045] The administration of the strain Leuconostoc mesenteroides subsp. SD23 mesenteroids to decrease the length of the villi of the small intestine, which are altered by the high-fat diet.
    [0047] In one embodiment of the invention it is shown that maternal intervention with the strain Leuconostoc mesenteroides subsp. mesenteroids SD23 prevents the accumulation of fat in the offspring of obese mothers.
    [0048] In a last embodiment it is shown that maternal intervention with the strain Leuconostoc mesenteroides subsp. mesenteroids SD23 reduces triglyceride levels in male offspring of obese mothers.
    [0052] Figure 1. Effect of probiotic consumption on fertility rate.
    [0053] Figure 2. Weight prior to pregnancy, and maternal weight during pregnancy and lactation in the presence and in the absence of the probiotic.
    [0054] Figure 3. Effect of probiotic consumption on the biochemical parameters of mothers with 21 days of lactation.
    [0055] Figure 4. Effect of probiotic consumption on the small intestine histology of mothers with 21 days of lactation.
    [0056] Figure 5. Effect of probiotic consumption on the weight of the pups at puberty (36 days postnatal).
    [0057] Figure 6. Effect of probiotic consumption on the biochemical parameters of the offspring at puberty (36 days postnatal).
    [0058] Figure 7. Effect of probiotic consumption on the body composition of the offspring in young adulthood (110 days postnatal).
    [0059] Figure 8. Effect of probiotic consumption on the biochemical parameters of the offspring in the young adult age (110 days postnatal).
    [0060] Figure 9. Effect of probiotic consumption on body composition by magnetic resonance imaging in offspring at mature adult age (350 postnatal days).
    [0064] The strain SD23, belonging to the genus and species Leuconostoc mesenteroidos, exhibits probiotic properties that are comparably more favorable than other strains of the same Leuconostoc species and other genera of Lactobacillus and Bifidobacterium strains, bacteria considered commercially probiotic. The present invention addresses a way to intervene favorably in metabolic disorders caused by maternal obesity in offspring throughout their lives. This study has not been described for any strain of the genus Leuconostoc known to date. The most interesting fact is that none of the known strains of this genus or species has been shown to be useful for the simultaneous and effective treatment of metabolic dysfunctions associated with obesity. mother and her offspring. Therefore, the present invention provides a new strain of the Leuconostoc mesentedamientos species of high value for the treatment of maternal obesity.
    [0066] Next, it is described why the strain Leuconostoc mesenteroides subsp. mesenteroids SD23 is of great interest to address a solution to metabolic disorders caused by obesity:
    [0068] 1. The administration of the strain Leuconostoc mesenteroides subsp. SD23 mesenteroids improves the fertility rate of female rats fed a high-fat diet. This finding is of great importance, since one of the problems faced by an obese woman of reproductive age is the low fertility rate, due to the disorders presented by high-fat diets.
    [0069] 2. The administration of the strain Leuconostoc mesenteroides subsp. mesenteroids SD23 decreases serum glucose, cholesterol, and triglyceride concentrations in female rats that consumed a high-fat diet during the gestation and lactation periods.
    [0070] 3. The strain Leuconostoc mesenteroides subsp. mesenteroids SD23 decreases the length of the villi of the small intestine, which are altered by the high-fat diet, indicating in this way that it can reduce the absorption of fat from the diet, and may be a mechanism by which this strain exerts a positive effect on lowering cholesterol and triglyceride concentrations. Another benefit of this strain in the intestine is to avoid hyperplasia of goblet cells, which are affected by obesity.
    [0071] 4. Maternal intervention with the strain Leuconostoc mesenteroides subsp.
    [0072] mesenteroids SD23 prevents in the offspring of obese mothers that are in puberty (36 postnatal days), in young adults (110 postnatal days) and in mature adults (350 postnatal days) in both males and females, the accumulation of fat, being observed in a decrease in weight, total fat and adiposity index. The decrease in total fat is clearly observed in the reduction of gonadal fat, which allows us to infer that it will help the reproductive system of males.
    [0073] 5. Maternal intervention with the strain Leuconostoc mesenteroides subsp.
    [0074] mesenteroids SD23 reduces triglyceride concentrations in male offspring of obese mothers at young adult age.
    [0075] It is important to highlight that the intervention with the strain Leuconostoc mesenteroides subsp. mesenteroids SD23 does not generate any alteration on the health of the control mother rats during the gestation and lactation periods, that is to say, no adverse effects are observed, such as abdominal inflammation and diarrhea, for which the administration of the strain Leuconostoc mesentedamientos subsp. SD23 mesenteroids is not dangerous, even when the administration is in high-risk windows for the development of the offspring, pregnancy and lactation.
    [0077] Characteristics of the microorganism:
    [0079] • The 16S rRNA molecular sequence is stored in the GenBank database under the accession number KR476473.
    [0080] • The scientific classification of the SD23 strain of the present invention is: Kingdom: Bacterium / Phylum: Firmicutes / Order: Lactobacillales / Family: Leuconostocaceae / Genus: Leuconostoc / Species: mesenteroids / Subspecies: mesenteroids.
    [0081] • The substrates that the SD23 bacteria oxidize or ferment are: L-Arabinose; D-Ribose; D-Xylose; D-Galactose; D-Glucose; D-Fructose; D-Mannose; D-Mannitol; Methyl-aD-Glucopyranoside; N-Acetylglucosamine; Amygdalin; Arbutin; Ferric citrate esculin; Salicin; D-Cellobiose; D-Maltose; D-Lactose (bovine origin); D-Melibiosa; D-Sucrose; D-trehalose; D-Raffinose; Gentiobiosa; D-Turanose; 2-Potassium ketogluconate.
    [0082] • The strain grows in a temperature range between 28-37 ° C, with an optimum at 30 ° C.
    [0083] • The strain grows in a pH range between 5 and 7, with an optimum pH of 6.5
    [0084] • Furthermore, the strain is viable under gastrointestinal conditions (acid pH and high bile concentration). Its viability under stomach conditions (pepsin 3g / l at pH 2 and for 2h) is 46.51% and under intestinal conditions (bile salts 0.5%, pH 6.5 and pancreatin 1.9 g / l) is 89.36%. It is also resistant to the conditions of preservation processes (freezing, lyophilization).
    [0085] • The strain is isolated from an autochthonous source of Mexico, the Agave salmiana mead.
    [0087] To give greater clarity to the present invention, the following definitions will be given: It is understood as a "probiotic" living microorganism, more specifically probiotic bacteria, in specific quantities, which have been scientifically studied in relation to the beneficial effects on human health when consumed, even more specifically said beneficial effects are due to an improvement in the balance of the intestinal microbiota.
    [0089] "Prebiotics" are understood to be non-digestible polysaccharides that promote the selective stimulation of the growth and / or activity (s) of one or more microbial species in a specific and limited way of the intestinal microbiota that confers a benefit to the host. Thus, prebiotics refer to any non-viable food component that is specifically fermented in the colon by indigenous bacteria that are thought to be of positive value, eg, bifidobacteria, lactobacilli, etc.
    [0091] A "symbiotic" is understood as the combined administration of a probiotic strain with one or more prebiotic compounds, which can enhance the growth of the administrative probiotic in vivo resulting in a more pronounced health benefit and is called symbiotic.
    [0093] "Gut microbiota" is understood as the set of microorganisms (bacteria, archaea, yeasts, single cell eukaryotic cells, as well as helminths and viruses) that are found throughout the gastrointestinal system of a host.
    [0095] It is understood as "BMI" or "Body Mass Index", a measure of a person's weight scaled with height, more specific to the individual's body weight divided by the square of their height (average weight in kilograms, height in meters). The formula universally used in medicine produces a unit of measurement of kg / m2. According to the US Department of Health & Human Services a BMI below 18.5 indicates thinness, 18.5-24.9 normal weight, 25-29.9 overweight and a BMI of 30 or higher indicates obesity.
    [0097] It is understood as "overweight" as a BMI of 25-29.9.
    [0099] Obesity is understood as a BMI of 30 or higher.
    [0101] "Weight gain" is understood as weight gain resulting from excessive dietary intake, comprising excessive dietary intake of fats, in particular unsaturated fats and, optionally, excessive dietary intake of simple carbohydrates.
    [0102] For a given experimental subject, an excessive dietary intake, particularly of fats, and as an option of simple carbohydrates, greater than the amount necessary to satisfy the physiological needs and maintain the energy balance of the experimental subject. The effect of a treatment on the reduction, or prevention, of body weight gain and metabolic parameters related to obesity, widely described in the scientific literature, induced by diet in an experimental subject can be evaluated by comparing the body weight gain observed in an experimental subject who receives the treatment, with those parameters observed in the same experimental subject who is not given the treatment and who receives the same diet and has the same activity level physical.
    [0104] It is understood as "reducing weight gain" to limit lowering or reducing, in a more specific subject in an experimental subject, the improvement in body weight induced by a treatment compared to the improvement in body weight induced by diet in the subject. of experimentation, but did not consume the treatment.
    [0106] It is understood as "treatment" for obesity or weight gain or "treating" obesity or weight gain of the present invention as the purpose of reducing or maintaining the body weight of a subject.
    [0108] "Prevention" is understood as the administration of the composition against obesity of the present invention for the purpose of reducing or maintaining the body weight of a subject at risk of obesity. In a characterization, prevention involves maintaining the subject's body weight immediately before from the start of administration of the anti-obesity composition.
    [0110] A "food supplement" is understood as a product made from compounds that are commonly used in food, but that is in the form of tablets, powders, capsules, potion or in any other form that is not generally associated with food, and that has beneficial effects on the health of a person.
    [0112] By "functional food" is understood a food that also has beneficial effects on the health of a person. More specifically, functional foods have a beneficial physiological effect on a chronic disease.
    [0113] A "nutraceutical" is understood to be a standardized nutrient of pharmaceutical grade, more specifically they are products derived from food sources that aim to provide extra healthy benefits to the nutritional values found in food. Said nutraceuticals, depending on the jurisdiction, may have properties for the prevention of chronic diseases or for improving health.
    [0115] Preferred forms of the invention, but not limiting, are described below:
    [0117] In a characterization the composition of the present invention can be composed only of the strain Leuconostoc mesenteroides subsp. SD23 mesenteroids or it can be a food composition or pharmaceutical composition containing said strain and other optional components. There are no particular limitations on these optional components as long as they are pharmaceutical or food grade and that they comply with the health standards set by the corresponding authorities.
    [0119] In a characterization of the composition of the invention, the strain of the present invention can be used in the form of whole bacteria, more specifically in the form of a bacterial lysate, preferably the bacterial strain can be in the form of living cells.
    [0121] When the strain Leuconostoc mesenteroides subsp. mesenteroids SD23 is found alone or in composition with prebiotics or other strains of bacterial species is in the form of live bacteria, the composition can count from 1x105 to 1x1013 colony forming units (CFU), preferably a minimum 1x106 CFU, more preferably of at least 1x107 CFU; even higher preferably of at least 1x108 CFU; and most preferably of at least 1x1010 CFU per gram of dry weight of the composition. In the case of the liquid composition, this corresponds, in general, to 1x104 to 1x1012 CFU / ml, preferably at least 1x105 CFU / ml, more preferably a minimum of 1x106 CFU / ml, even more preferably at least 1x107 CFU / ml and most preferably a minimum of 1x1010 CFU / ml. Said mentioned amounts can be supplied in a daily intake, or in more than one, during the consumption of a high fat diet.
    [0123] The determination of an effective amount applicable in humans could be deduced to one skilled in this art, especially in light of the detailed disclosure set forth in the present disclosure.
    [0124] Examples of the dosage form of the strain Leuconostoc mesenteroides subsp. SD23 mesenteroids of the composition of the present invention, in the case of oral administration, include solid formulations such as powders, granules, tablets and capsules and liquid formulations such as syrups, suspensions and emulsions without excluding semi-solid forms or powders. Furthermore, in the case of parenteral administration, examples of doses include suppositories, ointments, sprays or nebulizers.
    [0126] In one embodiment of the present invention it can be administered orally, colposcopically or rectally via suppositories. Oral delivery of the composition consisting of the bacterial strain according to the present invention is preferred, more preferably in the form of capsules, tablets, powders, granules or solutions or suspensions for the oral route.
    [0128] The production of these formulations can be carried out using conventional methods, according to the dosage form.
    [0130] During the production of these formulations they can be composed only of the active ingredient, or they can also include an appropriate pharmaceutical carrier.
    [0132] In those cases where a pharmaceutical carrier is added, there are no particular limitations on the mixing amount of the active ingredient ie the strain Leuconostoc mesenteroides subsp. SD23 mesenteroids of the present invention, where said amount can be appropriately determined according to the dosage form, such as powder, tablet or capsule, as long as the bacterial content is within the range of 1x106 to 1x1012 CFU / g, most preferably a minimum of 1x1010 CFU / ml.
    [0134] As the pharmaceutical carrier it can be any conventional acceptable organic or inorganic carrier, depending on the dosage form. In the case of solid formulations, examples of the carrier include excipients, binders, disintegrants, lubricants, stabilizers and corrective agents and the like.
    [0136] The composition of the present invention comprises food products, food supplements, nutraceuticals, nutritional supplements, medical foods or functional foods.
    [0137] The anti-obesity food or drink of the present invention can be produced using the strain Leuconostoc mesenteroides subsp. SD23 anti-obesity mesenteroids and other components acceptable for inclusion in food or beverages as raw materials, or can be produced by adding the strain Leuconostoc mesentedamientos subsp. SD23 anti-obesity mesenteroids of the present invention to an existing food or drink containing other components.
    [0139] The composition of the invention can be a dairy product, preferably a fermented dairy product, the fermented product can be present in the form of a liquid or present in the form of a dry powder that is obtained by drying the fermented liquid, more specific it can be in the form of dairy products including fermented milk and / or curdled, whipped, drinkable fermented milk, such as cheese or yogurt.
    [0141] The fermented product can also be a vegetable, vegetable, such as soybeans, tubers, cereals or fruits.
    [0143] The composition may be in the form of a product derived from milk, in particular fermented milk, comprising at least the strain Leuconostoc mesenteroides subsp. mesenteroids SD23, as a combined option, as previously mentioned, with other bacteria of the genus Lactobacillus, for example, in the form of fermented foods.
    [0145] There are no particular limitations on the other components included within the food or beverage, as long as the components have been tested for addition to foods and beverages in accordance with food regulations such as the Food Sanitation Act or the federal commission for the protection against sanitary risks (COFEPRIS) or the regulations corresponding to the territory in turn and does not deteriorate the effect on the reduction of weight gain in subjects with a diet rich in fats of said composition.
    [0147] There are no particular limitations on the form of the food or drink, which includes any form of edible composition of the Leuconostoc mesenteroides subsp . SD23 mesenteroids and a carrier that is acceptable for inclusion into food and beverages. Specific examples include all forms of food or drink including solid foods such as bread, gum, cookies, chocolate, confectionery and cereals, jelly-based, cream-based and gel-based foods such as jelly, ice cream, yogurt and gelatin, and beverages such as juices, coffee, and cocoa. In addition, flavorings and food additives and the like can be added.
    [0149] The anti-obesity food or drink containing the strain Leuconostoc mesenteroides subsp. SD23 mesenteroids according to the dose of the present invention, preferably it is marketed as a food or drink that indicates its use for anti-obesity applications, it should be noted that the expression used for the type of indications described above is not limited to the The phrase "anti-obesity", and needless to say, any other expressions indicating an anti-obesity effect are also included within the scope of the present invention. In addition, similarly, the food or drink may also be marketed as a food or beverage that indicates its use to prevent or improve lifestyle conditions for which obesity is a known cause or risk factor, such as hyperlipidemia, high blood pressure, and diabetes.
    [0151] The present invention can be understood more clearly from the following additional description with examples that allow to understand more clearly but do not limit any other embodiment of the invention.
    [0153] Methodology
    [0154] Maternal obesity model: A state of obesity (OM) was induced in recently weaned female rats of the Wistar strain (F0), with an obesogenic diet which contains 23.5% protein, 20.0% lard, 5.0% corn oil, 20.2% polysaccharides, 20.2% simple sugars, 5.0% fiber, 5.0% mineral mix and 1.0% vitamin mix (w / w), the energy value is 4.9 kcal / g; which was provided from weaning, during growth and until mating (120 days), gestation and lactation. The control group (C) was fed during the same period with a commercial diet for rodents (Zeigler Rodent RQ22-5), which contains 22.0% protein, 5.0% vegetable fat, 31.0% polysaccharides, 31.0% simple sugars, 4.0% fiber, 6.0% minerals and 1.0% vitamins (w / w), the energy value is 4.0 kcal / g.
    [0156] Maternal interventions: Half of the F0 females were intervened from 90 days (that is, one month prior to gestation), until mating and throughout pregnancy and lactation, with the probiotic bacterium Leuconostoc mesenteroides subsp. mesenteroids SD23. The groups were identified as CP and MOP. The control group (C) and the obese group (MO) continued with the commercial diet and the high-fat diet respectively throughout the study.
    [0158] The groups used and the intervention of the probiotic strain are shown in detail below:
    [0160] • Control group (C): the females were fed the commercial rodent diet and a daily volume of 0.1mL of 10% milk was administered.
    [0161] • Probiotic control group (PC): the females were fed with the commercial rodent diet and a daily volume of 0.1mL was administered at a concentration of 1x1010 CFU / mL of L. mesenteroides SD23.
    [0162] • Obese group (OM): females were fed a high-fat diet and a daily volume of 0.1mL of 10% milk was administered.
    [0163] • Probiotic obese group (MOP): females were fed a high-fat diet and a daily volume of 0.1mL was administered at a concentration of 1x1010 CFU / mL of L. mesenteroides SD23.
    [0165] Female mating (F0): At 120 days of age, females were mated with non-experimental males of the same lineage. The rats had natural births.
    [0167] Obtention of biological samples: From the mothers (21 days of lactation) and from the pups at 36 and 110 days postnatal, the fat of the sternum, pancreatic, retroperitoneal, mesenteric and gonadal, were collected and weighed individually to calculate the adiposity index (total adipose tissue (g) / body weight (g)). The length of the intestinal villi in the mothers was analyzed as an effect of the high-fat diet and the intervention with the probiotic.
    [0169] Analysis of biochemical parameters: The serum concentrations of glucose, triglycerides and cholesterol were analyzed by an enzymatic method, using the automatic Synchron CX analyzer.
    [0171] Statistical analysis: All data were reported as mean ± SE The results were analyzed by one-way ANOVA with the Tukey test, p <0.05.
    [0172] Results
    [0174] Previous, pregnancy and lactation:
    [0175] Obesity decreased the fertility rate in the OM group, but the intervention with the probiotic in the MOP increased the fertility rate by 35% compared to the OM. In mothers C and CP, the fertility percentage was 80% (Figure 1). The weights of the rats used for the maternal obesity model, 21 days after starting the experiment were similar in group C and MO, but on day 55, 34 days after starting the high-fat diet, it was observed that the weight is significantly different between C and MO. At 90 days the intervention with the probiotic began (Figure 2A). This intervention was continued during pregnancy and lactation (Figure 2B). Maternal weight was not affected by the intervention with the probiotic, and during all stages the control groups (C and CP) presented lower weight compared to the groups that were fed a high-fat diet (OM and MOP). At the end of gestation and from the seventh day of lactation, the weights of the four groups did not show significant differences.
    [0177] Maternal biochemical parameters at the end of lactation: Figure 3 shows the concentrations of glucose, cholesterol and TGS of the four experimental groups (C, CP, MO and MOP). MO presented the highest values of glucose and TGS in serum compared to C and MOP, observing the problems of a high-fat diet. While the administration of the Leuconostoc mesentemides subsp. mesenteroids SD23 prevents increased glucose and TGS concentrations in MOP. Cholesterol concentrations were similar in C, CP and MO, in MOP they remained below the control.
    [0179] Maternal analysis in the small intestine at the end of infancy: The histological analysis of the intestine allowed us to observe the effect of the administration of the strain Leuconostoc mesenteroides subsp. SD23 mesenteroids in maternal obesity. In Figure 4, the length of the villi in the intestine is appreciated, observing a reduction in the length of the villi in CP and MOP. Feeding a high-fat diet alters intestinal morphology, resulting in an increase in the length of intestinal villi, as well as the expression and release of intestinal peptides that control food intake (Covasa 2010; Mao et al. ., 2013). On the other hand, changes in the intestine may be the result of increased fat absorption. A high-fat diet can also cause hyperplasia in the goblet cells present in the intestinal wall (Covasa 2010). The main function of intestinal goblet cells is the formation of mucin that serves as a host defense mechanism (Kim and Ho, 2010). Mucin synthesis in intestinal goblet cells occurs in response to a series of stimuli, hormonal influence, inflammatory factors, bacterial toxins, as well as chemical factors (Specian et al., 1991). Goblet cell hyperplasia is accompanied by defective mucin synthesis, allowing pathogens to invade and attach to the intestinal surface. Therefore, the present invention shows that the administration of the strain Leuconostoc mesentemides subsp. mesenteroids SD23 has an effective effect in decreasing the absorption of fat at the intestinal level.
    [0181] Results in 36- and 110-day-old pups
    [0182] Maternal obesity programs the offspring to develop obesity during their postnatal life, this is observed in Figure 5, where it can be seen that the offspring at puberty (36 days postnatal), descendants of obese mothers (OM) presented higher body weight compared with the offspring of mothers intervened with the probiotic (MOP). It can also be seen that total fat in females does not present a significant difference between the four experimental groups. Regarding the biochemical parameters, the offspring at 36 days did not show significant differences between the four experimental groups (Figure 6).
    [0184] The type of programming that the pups are exposed to during the gestation and lactation period affects their development at young age (110 postnatal days), as seen in Figure 7, despite the fact that the pups have the same body weight , its composition in total fat shows once again that the offspring at 110 days descended from OM presented higher fat and adiposity index compared to C, CP and MOP. A greater effect is observed in male offspring. In Figure 8 you can see the concentrations of glucose, cholesterol and TGS, in the female offspring at 110 days they did not show significant differences between the four experimental groups, on the other hand, in the male offspring the TGS concentrations are increased when they are descendants of obese mothers (OM), but maternal intervention with the probiotic reduces TGS concentrations in their offspring (MOP). The type of diet and intervention that the mother underwent during the gestation and lactation periods, programmed her offspring to develop obesity or metabolic problems during their postnatal life. In Figure 9, it is observed that the offspring at a mature adult age (350 postnatal days) continue to present effects of diet or maternal intervention. The offspring of obese mothers (OM) have a higher percentage of fat compared to the offspring of mothers intervened with the probiotic (MOP). The results obtained by the maternal intervention with the probiotic Leuconostoc mesenteroides subsp. mesenteroids SD23 has beneficial effects on both maternal and offspring metabolism at different postnatal ages. This intervention is an opportunity to prevent or improve the problems caused by negative programming, due to the type of diet that the mother has been exposed to during pregnancy and lactation.
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    [0217] Figure 1. Fertility rate expressed as the number of pregnant women / number of animals in the group. Where: C control diet (n = 12/15); CP control diet 1x1010 CFU / mL L. mesenteroids SD23 (n = 12/15); OM high-fat diet (n = 7/19); MOP high fat diet 1x1010 CFU / mL L. mesenteroids SD23 (n = 18/25).
    [0218] "*" Significant difference in the effect of diet between C and MO, Different letters indicate statistically significant differences between groups C and CP or MO and MOP, chi square test, p <0.05.
    [0220] Figure 2. A) Weight prior to pregnancy, the arrow indicates the days (90) where the intervention with the probiotic begins and B) Maternal weight during pregnancy and lactation. Where: (•) = C control diet (n = 12); (o) = CP control diet 1x1010 CFU / mL L. mesenteroids SD23 (n = 12); (▼) = MO high fat diet (n = 7); (A) = MOP high fat diet 1x1010 CFU / mL L. mesenteroids SD23 (n = 15).
    [0221] "*" Statistically significant difference during pregnancy or lactation between C, CP vs MO, MOP. Mean ± SE; p <0.05. One-way ANOVA, Tukey test.
    [0223] Figure 3. Biochemical parameters of the mother at the end of lactation: A) Glucose. B) Cholesterol. C) Triglycerides (TGS). Where: C control diet (n = 12); CP control diet 1x1010 CFU / mL L. mesenteroids SD23 (n = 12); OM high-fat diet (n = 7); MOP high fat diet 1x1010 CFU / mL L. mesenteroids SD23 (n = 15). Different letters indicate statistically significant differences between groups. Mean ± SE; p <0.05. One-way ANOVA, Tukey test.
    [0225] Figure 4. Histology of the small intestine of mothers at the end of lactation: length of the villi. Where: C control diet (n = 8); PC control diet 1x1010 CFU / mL L. mesenteroids SD23 (n = 8); OM high-fat diet (n = 7); MOP High Fat Diet 1x1010 CFU / mL L. mesenteroids SD23 (n = 8). Different letters indicate statistically significant differences between groups. Mean ± SE; p <0.05. One-way ANOVA, Tukey test. Histological sections stained in H&E observed at 10x in the villi of the small intestine.
    [0227] Figure 5. A) Weight of male offspring at 36 days postnatal; B) Total fat of male offspring at 36 days postnatal; C) Weight of female pups at 36 days postnatal and D) Total fat of female pups at 36 days postnatal. Where: C offspring from dams with a control diet; CP offspring of dams treated with a control diet 1x1010 CFU / mL L. mesenteroids SD23; MO offspring of mothers with a high-fat diet; MOP offspring of mothers treated with a high-fat diet 1x1010 CFU / mL L. mesenteroids SD23. C (n = 8), CP (n = 8), MO (n = 7) and MOP (n = 8) from different litters. Different letters indicate statistically significant differences between groups. Mean ± SE; p <0.05. One-way ANOVA, Tukey test.
    [0229] Figure 6. Biochemical parameters of the offspring at 36 days postnatal: Male offspring: A) Glucose; B) Cholesterol; C) Triglycerides (TGS); Female offspring: D) Glucose; E) Cholesterol and F) Triglycerides (TGS). Where: C offspring from dams with a control diet; CP offspring of dams treated with a control diet 1x1010 CFU / mL L. mesenteroids SD23; MO offspring of mothers with a high-fat diet; MOP offspring of mothers treated with a high-fat diet 1x1010 CFU / mL L. mesenteroids SD23. C (n = 8), CP (n = 8), MO (n = 7) and MOP (n = 8) from different litters. Different letters indicate statistically significant differences between groups. Mean ± SE; p <0.05. One-way ANOVA, Tukey test.
    [0231] Figure 7. A) Weight of male offspring at 110 postnatal days; B) Total fat of male offspring at 110 days postnatal; C) Adiposity index of male offspring at 110 postnatal days; D) Weight of female offspring at 110 days postnatal; E) Total fat of female offspring at 110 postnatal days and F) Adiposity index of female offspring at 110 postnatal days. Where: C offspring from dams with a control diet; CP offspring of dams treated with a control diet 1x1010 CFU / mL L. mesenteroids SD23; MO offspring of mothers with a high-fat diet; MOP offspring of mothers treated with a high-fat diet 1x1010 CFU / mL L. mesenteroids SD23. C (n = 12), CP (n = 11), MO (n = 7) and MOP (n = 15) from different litters. Different letters indicate statistically significant differences between groups. Mean ± SE; p <0.05. One-way ANOVA, Tukey test.
    [0232] Figure 8. Biochemical parameters of the offspring at 110 postnatal days: Male offspring: A) Glucose; B) Cholesterol; C) Triglycerides (TGS); Female offspring: D) Glucose; E) Cholesterol and F) Triglycerides (TGS). Where: C offspring from dams with a control diet; CP offspring of dams treated with a control diet 1x1010 CFU / mL L. mesenteroids SD23; MO offspring of mothers with a high-fat diet; MOP offspring of mothers treated with a high-fat diet 1x1010 CFU / mL L. mesenteroids SD23. C (n = 11), CP (n = 10), MO (n = 7) and MOP (n = 9) from different litters. Different letters indicate statistically significant differences between groups. Mean ± SE; p <0.05. One-way ANOVA, Tukey test.
    [0234] Figure 9. Body composition of the pups at 350 postnatal days: Male pups: A) Percentage of fat with respect to body weight; B) Percentage of lean mass with respect to body weight; C) Weight of female pups: D) Percentage of fat with respect to body weight; E) Percentage of lean mass with respect to body weight and F) Weight. Where: C offspring from dams with a control diet; CP offspring of dams treated with a control diet 1x1010 CFU / mL L. mesenteroids SD23; MO offspring of mothers with a high-fat diet; MOP offspring of mothers treated with a high-fat diet 1x1010 CFU / mL L. mesenteroids SD23. n = 7 for all groups and correspond to different litters. Different letters indicate statistically significant differences between groups. Mean ± SE; p <0.05. One-way ANOVA, Tukey test.
    权利要求:
    Claims (22)
    [1]
    1. A composition for use to treat or prevent weight gain in the offspring of mothers on a high fat diet, wherein the composition comprises the strain Leuconostoc mesenteroides subsp. mesenteroids SD23.
    [2]
    2. The composition according to claim 1 which is a pharmaceutical product.
    [3]
    3. The composition according to claim 2, wherein said pharmaceutical product is suitable to be administered in solid formulations, liquid formulations, OR semi-solid forms or powders.
    [4]
    4. The composition according to claims 1 and 2, wherein said composition is suitable to be administered parenterally, orally, colposcopically or rectally.
    [5]
    The composition according to claim 1 which is a food or a food additive.
    [6]
    6. The composition according to claim 1, wherein said composition is suitable to be administered in animals, preferably in humans.
    [7]
    7. A composition for use to treat or prevent obesity in the offspring of mothers on a high fat diet, wherein the composition comprises the strain Leuconostoc mesentedamientos subsp. mesenteroids SD23.
    [8]
    8. The composition according to claim 7 which is a pharmaceutical product.
    [9]
    The composition according to claim 8, wherein said pharmaceutical product is suitable to be administered in solid formulations, liquid formulations, semi-solid forms or powders.
    [10]
    10. The composition according to claims 7 and 8, wherein said composition is suitable to be administered parenterally, orally, colposcopically or rectally.
    [11]
    The composition according to claim 7 which is a food or a food additive.
    [12]
    12. The composition according to claim 7, wherein said composition is suitable to be administered in animals, preferably in humans.
    [13]
    13. A composition for use to correct fertility problems in female rats fed a high fat diet, wherein the composition comprises the strain Leuconostoc mesentedamientos subsp. mesenteroids SD23.
    [14]
    14. The composition according to claim 13 which is a pharmaceutical product.
    [15]
    15. The composition according to claim 14, wherein said pharmaceutical product is suitable to be administered in solid formulations, liquid formulations, semi-solid forms or powders.
    [16]
    16. The composition according to claims 13 and 14, wherein said composition is suitable to be administered parenterally, orally, colposcopically or rectally.
    [17]
    17. The composition according to claim 13 which is a food or a food additive.
    [18]
    18. A composition for use to lower or regulate serum glucose, cholesterol and triglyceride concentrations of female rats consuming a high fat diet during the gestation and lactation periods, wherein the composition comprises the strain Leuconostoc mesentedamientos subsp. mesenteroids SD23.
    [19]
    19. The composition according to claim 18 which is a pharmaceutical product.
    [20]
    20. The composition according to claim 19, wherein said pharmaceutical product is suitable to be administered in solid formulations, liquid formulations, semi-solid forms or powders.
    [21]
    21. The composition according to claims 18 and 19, wherein said composition is suitable for parental, oral, colposcopic or rectal administration.
    [22]
    22. The composition according to claim 18 which is a food or a food additive.
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    同族专利:
    公开号 | 公开日
    WO2020012412A2|2020-01-16|
    ES2820874R2|2021-09-22|
    MX2018008663A|2018-11-09|
    GB202100170D0|2021-02-24|
    US20210268039A1|2021-09-02|
    WO2020012412A3|2020-03-19|
    GB2590202A|2021-06-23|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    CA2467695C|2003-05-20|2010-03-16|Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College|Isomaltooligosaccharides from leuconostoc as neutraceuticals|
    DK2898061T3|2012-09-20|2020-02-10|Prothera Inc|PROBIOTIC COMPOSITIONS FOR THE TREATMENT OF OBESIS AND OBESE-RELATED CONDITIONS|
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    MX2018008663A|MX2018008663A|2018-07-13|2018-07-13|Use of leuconostoc mesenteroides subsp. sd23 mesenteroides for fetal-maternal metabolic programming.|
    PCT/IB2019/055932|WO2020012412A2|2018-07-13|2019-07-11|Use of leuconostoc mesenteroides subsp. mesenteroides sd23 for maternofetal metabolic programming|
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