Lactobacillus paracasei and combination of microorganisms with lactobacillus paracasei

Abstract

The present application refers to a Lactobacillus paracasei strain which is deposited in the Colección Española de Cultivos Tipo (CECT) under the accession number CECT30660 and combination of microorganisms with said strain. It also discloses bacterial culture comprising said strains and said combinations, a supernatant obtainable from said strain and said combination. Their use in the treatment of dysbiosis and / or infections in the female reproductive tract is also disclosed.

Description

[0001] Lactobacillus paracasei and combination of microorganisms with Lactobacillus paracasei

[0002] This application claims the benefit of European Patent Application 23383310.2 filed December 18th, 2023.

[0003] Technical Field

[0004] Present invention relates to the field of probiotic strains and conditioned media obtained from the same, useful for the balancing of the microbiota in the female reproductive tract. It relates to the use of probiotics and postbiotics to control fungal and bacterial infections, which ultimately may have an effect on the preterm birth and other labor complications.

[0005] Background Art

[0006] Microbiota plays a fundamental role in the animal physiological mechanisms, such as immunity. They form a mutually beneficial relationship with the animal host; the host provides shelter and nutrition, and in return, the microbiota protects the host from a variety of pathogenic microorganisms but also to inflammatory and metabolic disorders. Thus, the structure of the microbial communities is crucial for the health status of an individual. Considering that, microbial dysbiosis impairs the health status by enhancing the susceptibility of the host to a spectrum of risk, such as inflammatory and metabolic disorders or infection.

[0007] In the case of the female reproductive tract, age, hormones, physiologic (gestational status, use of contraceptives, menstrual cycle, sexual activity among other) and pathologic changes (bacterial vaginosis, urinary tract infections, and sexually transmitted diseases, among other), are associated with significant changes in its microbiota. Conventionally, normal vaginal flora has been thought to be dominated by Lactobacilli, and in particular, L. iners, L. crispatus, L. gasseri, and Ljensenii, have been shown to predominate in the vaginal microbiota in healthy women of reproductive age in varied proportions. In these healthy cases, vaginal microbiota protects the host from potentially pathogenic microbes like those causing bacterial vaginosis, urinary tract infections, Candida infections, and sexually transmitted diseases (STDs). Thus, dysbiosis in this environment is closely related to complications such as gynecological diseases and pregnancy complications.

[0008] One important dysbiosis related complication is preterm birth (PTB), which is described as birth before 37th week gestation. It has a worldwide prevalence of about 11.1% of all pregnancies, involving up to 15 million pregnancies each year globally. Being born prematurely can lead to adverse long-term health outcomes, such as neonatal death, a high risk of early-life infections and pre-term-induced disorders later in life. Hence, pre-term birth is a risk factor that has an impact on development in adult life. Although several factors can cause pre-term birth, from endogenous factors (short cervical length, maternal nutrition depletion, etc.) to exogenous factors (air pollution, drugs consumption, etc.), a very relevant and important one is inflammation. It is described that almost half of all preterm births are provoked or triggered by inflammation at the fetal-maternal interface ending in preterm labor or rupture of membranes. An important cause of that is the infection through microorganisms invasion of the uterus via ascending through the vagina or hematogenously via the placenta or often may be originated from the gut.

[0009] In female reproductive tract with a healthy microbiota, this confers a protection as described before. Thus, in a dysbiosis situation preterm birth may be triggered.

[0010] With the aim of treating inflammatory and dysbiosis conditions, several strategies are being tested. Among them antibiotic administration as a strategy to prevent PTB showed ineffective results, promoting resistant bacterial strains and a decrease of Lactobacillus and Bifidobacterium abundance. Other strategies such as the use of probiotics have demonstrated benefits on the host. Some probiotics from Lactobacilli and Bifidobacterium genus showed capacity to modulate immune response and antiinflammatory properties in the neonatal period.

[0011] As a way of example, the document of Vitali, B. , Cruciani, F., Baldassarre, M.E. et al. Dietary supplementation with probiotics during late pregnancy: outcome on vaginal microbiota and cytokine secretion. BMC Microbiol 12, 236 (2012). https: / / doi.org / 10.1186 / 1471-2180-12-236, discloses a mixture of Lactobacillus, Bifidobacterium and Streptococcus strains, which after administration as diet supplement to healthy women during late pregnancy, resulted in the modulation of the vaginal microbiota and cytokine secretion, with potential implications in preventing preterm birth.

[0012] Other authors, such as Yang et al., have shown that the supernatant (conditioned media) of a strain of Lactobacillus rhamnosus was able to reduce the percentage of pre-term birth cases up to 43 % in a model of preterm delivery including the challenge with an LPS injection into the uterus to cause inflammation (see Yang S, Li W, Challis JRG, et al. Probiotic Lactobacillus rhamnosus GR-1 supernatant prevents lipopolysaccharide-induced preterm birth and reduces inflammation in pregnant CD-1 mice. Am J Obstet Gynecol 2014;211 :44.e1-12.).

[0013] In spite of all these efforts, there is still a need of alternative probiotics and strains that finally get the purpose of allowing preventing reproductive female tract dysbiosis and the somehow associated pregnancy complication know as pre-term birth. Summary of the Invention

[0014] During the studies leading to the present invention the inventors investigated different bacterial strains isolated from vaginal exudates samples. The different strains were examined for their capability to treat and / or prevent female reproductive tract dysbiosis and complications thereof, and in particular to prevent preterm birth, and to prevent and / or treat labor and / or pregnancy complications. And, as it is illustrated below in a non-restricted way, the inventors surprisingly found and selected a Lactobacillus paracasei strain, deposited with the Accession Number 30660, which was effective in the prevention and / or treatment of the above-mentioned conditions.

[0015] As shown in the examples, the L. paracasei CECT30660 presents a high production of L-lactic acid, which is in significantly higher proportion than the D-lactic component. L-lactic acid is a common compound of human metabolism, an endogenous compound, whereas D-lactic acid is a harmful enantiomer with neurotoxic effects produced by some strains of microorganism or by some less relevant metabolic pathways.

[0016] Also as shown in the examples, L. paracasei CECT30660 presents an excellent inhibition capacity of the growth of pathogens that promote dysbiosis in the female reproductive tract, such as Streptococcus agalactiae. It was surprisingly better than the inhibition capacity of strains that presented higher capacity of production of L-lactic acid (e.g. ORD0993). Of very important and surprising note is that the inhibition is independent of the effect of the acidification of the medium: the supernatant of L. paracasei CECT30660 remains active when it is neutralized, which means that its effect against the growth of pathogens a is not dependent on the pH decrease. I.e. L. paracasei CECT30660 produces components that inhibit the growth of pathogens such Group B Streptococcus in a superior and surprising manner.

[0017] As will be shown in the examples, the supernatant obtained from a culture of this strain CECT30660, alone or in combination with the supernatant of a culture of other bacterial strains, was able to reduce the preterm birth in an animal model to a percentage of around 71 % in relation to non-treated animals (the delivery on time was about 40 % in relation to 0 % observed with the challenged but non-treated animals). No others have shown or suggested this effect with a strain of L. paracasei.

[0018] This is indeed surprising since the L. paracasei CECT30660 is not a hydrogen peroxide (H2O2) producer, and also surprising because this effect was obtained with neutralized supernatant.

[0019] In addition, and also in a surprising mode, if the supernatant of CECT30660 was combined with the supernatant of a strain of Bifidobacterium longum biovar infantis, this combination reduced preterm deliveries by up to 42.8 % (delivery on time was about 60-65 % in relation to the non-challenged animals), which is more than an additive effect, since the strain of Bifidobacterium longum biovar infantis, in particular the CECT7210 or Bifidobacterium longum biovar infantis IM-1® strain, reduced the preterm delivery to a percentage of around 80 %, which was translated to a delivery on time of around 12 %, while, as indicated, the strain CECT30660 occasioned a delivery on time of around 30-35 %. The use of supernatants instead of the whole bacterial strains was due to the assayed model, but data make the strain of CECT30660, or a combination with other, good tools to provide in a target tissue all those compounds leading to the desired effect (i.e., preterm birth prevention).

[0020] Thus, in a first aspect the present invention provides a strain of Lactobacillus paracasei deposited in the "Coleccion Espanola de Cultivos Tipo (CECT)” under the accession number 30660 and named by the applicant as ORD0998, or a mutant or variant thereof. The strain CECT30660 was deposited on 17 June 2022, and it was declared viable on 23 June 2022 and communicated on 15 July 2022.

[0021] The second aspect of the present invention is a bacterial culture comprising the strain as defined in the first aspect.

[0022] As will be also illustrated in more detail in the examples below, this strain of L. paracasei was able to inhibit the growth of group B Streptococcus in an in-vitro assay. This effect makes of the strain of the invention a very good tool to reduce the amount of this dangerous pathogen in the vaginal tract of a pregnant woman. Advantageously, administering the strain of the first aspect may reduce the dose of the currently administered antibiotics when the labor starts reducing side effects as dysbiosis caused in the mother and the baby by de administration of antibiotics. Moreover, the strain of the first aspect may well be the basis of safe and convenient strategies to control this pathogenic group of bacteria during pregnancy.

[0023] As indicated, the inventors also tested combinations of the strain of the invention with additional microorganisms, finding synergy and increased preventive and / or treatment effects for the above- mentioned conditions for said combinations.

[0024] Thus, in a third aspect the invention relates to a microorganism combination comprising the strain as defined in the first aspect and / or the bacterial culture as defined in the second aspect, in combination with one or more additional microorganism strains and / or bacterial cultures comprising the one or more additional microorganism strains.

[0025] It was also observed, as enunciated, that supernatants obtained from the strain as defined in the first aspect and / or the bacterial culture as defined in the second aspect have the ability to prevent and / or treat female reproductive tract dysbiosis and complications thereof, and in particular the prevention of preterm birth and the prevention and / or treatment of labor and / or pregnancy complications. Thus, a fourth aspect of the invention is a supernatant obtainable from the Lactobacillus paracasei strain CECT30660.

[0026] Following the findings obtained with the combination of different microorganism strains, the inventors also tested and found a synergistic effect in the prevention and treatment of the above-mentioned conditions when combining the supernatant obtained from a bacterial culture comprising the strain of the invention with supernatants obtained from different bacterial cultures comprising different microorganism strains.

[0027] Thus, the fifth aspect of the invention relates to a combination of microorganism supernatants comprising the supernatant as defined in the fourth aspect, and one or more additional supernatants of one or more additional microorganism strains.

[0028] A sixth aspect of the invention is a lysate obtainable from the Lactobacillus paracasei strain CECT30660, in particular a cell-lysate.

[0029] The seventh aspect of the invention relates to a combination of microorganism lysates comprising the lysate as defined in the sixth aspect, and one or more additional lysates of one or more additional microorganism strains.

[0030] In an eighth aspect the invention relates to a pharmaceutical, veterinary, nutritional or food composition, comprising the strain of the invention as defined in the first aspect, and / or the bacterial culture as defined in the second aspect, and / or the microorganism combination as defined in the third aspect, and / or the supernatant as defined in the fourth aspect, and / or the combination of supernatants as defined in the fifth aspect, and / or the lysate as defined in the sixth aspect, and / or the combination of lysates as defined in the seventh aspect.

[0031] A ninth aspect of the invention relates to a medical device comprising the strain of Lactobacillus paracasei as defined in the first aspect, and / or the bacterial culture as defined in the second aspect, and / or the microorganism combination as defined in the third aspect, and / or the supernatant as defined in the fourth aspect, and / or the combination of microorganism supernatants as defined in the fifth aspect, and / or the lysate as defined in the sixth aspect, and / or the combination of lysates as defined in the seventh aspect, and / or the composition as defined in the eighth aspect.

[0032] The invention can also be used as an adjuvant in parallel to the administration of a main treatment in order, for example, to contribute to the inhibition of the growth of the pathogen or to help to reestablish the equilibrium for a healthy vaginal environment. Thus, the invention also contemplates the strain of Lactobacillus paracasei as defined in the first aspect, and / or the bacterial culture as defined the second aspect, and / or the microorganism combination as defined in the third aspect, and / or the supernatant as defined in the fourth aspect, and / or the combination of microorganism supernatants as defined in the fifth aspect, and / or the lysate as defined in the sixth aspect, and / or the combination of lysates as defined in the seventh aspect, and / or the composition as defined in the eighth aspect, and / or the medical device as defined in the ninth aspect for use as an adjuvant.

[0033] The invention can also be used in combination with a further therapeutic agent. Therefore, the invention also contemplates the strain of Lactobacillus paracasei as defined in the first aspect, and / or the bacterial culture as defined the second aspect, and / or the microorganism combination as defined in the third aspect, and / or the supernatant as defined in the fourth aspect, and / or the combination of microorganism supernatants as defined in the fifth aspect, and / or the lysate as defined in the sixth aspect, and / or the combination of lysates as defined in the seventh aspect, and / or the composition as defined in the eighth aspect, and / or the medical device as defined in the ninth aspect for use in combination with a further therapeutic agent.

[0034] A tenth aspect of the invention relates to the strain of Lactobacillus paracasei as defined in the first aspect, and / or the bacterial culture as defined in the second aspect, and / or the microorganism combination as defined in the third aspect, and / or the supernatant as defined in the fourth aspect, and / or the combination of microorganism supernatants as defined in the fifth aspect, and / or the lysate as defined in the sixth aspect, and / or the combination of lysates as defined in the seventh aspect, and / or the composition as defined in the eighth aspect, and / or the medical device as defined in the ninth aspect, for use in therapy. In other words, they are for use as a medicament.

[0035] An eleventh aspect of the invention is the strain of Lactobacillus paracasei as defined in the first aspect, and / or the bacterial culture as defined in the second aspect, and / or the microorganism combination as defined in the third aspect, and / or the supernatant as defined in the fourth aspect, and / or the combination of microorganism supernatants as defined in the fifth aspect, and / or the lysate as defined in the sixth aspect, and / or the combination of lysates as defined in the seventh aspect, and / or the composition as defined in the eighth aspect, and / or the medical device as defined in the ninth aspect, for use in the prevention and / or treatment of female reproductive tract dysbiosis and complications thereof.

[0036] A twelfth aspect of the invention relates to the strain, and / or the bacterial culture, and / or the combination of microorganisms, and / or the composition as respectively defined in the first, second, third, eighth and ninth aspects, for use as a probiotic. And a thirteenth aspect of the invention relates to the supernatant, and / or the combination of supernatants, and / or the composition, and / or the lysate as defined in the sixth aspect, and / or the combination of lysates as defined in the seventh aspect, as respectively defined in the fourth, fifth, sixth, seventh, eighth and ninth aspects, for use as a postbiotic.

[0037] A fourteenth aspect relates to the strain of Lactobacillus paracasei as defined in the first aspect, and / or the bacterial culture as defined in the second aspect, and / or the microorganism combination as defined in the third aspect, and / or the supernatant as defined in the fourth aspect, and / or the combination of microorganism supernatants as defined in the fifth aspect, and / or the lysate as defined in the sixth aspect, and / or the combination of lysates as defined in the seventh aspect, and / or the composition, and / or the medical device, as defined in the eighth aspect, and / or the medical device as defined in the ninth aspect, for use in the prevention and / or treatment of infections, in particular infections of the female reproductive tract.

[0038] Other aspects of the present invention relate to the use of the strain of the invention, and / or the bacterial culture, and / or the combination of microorganisms, and / or the supernatant, and / or the combination of supernatants, and / or the lysate as defined in the sixth aspect, and / or the combination of lysates as defined in the seventh aspect, and / or the composition, and / or the medical device as respectively defined in the first, second, third, fourth, fifth, sixth, seventh, eighth and ninth aspects for the manufacture of a medicament, in particular for the therapeutic and / or preventive treatment of female reproductive tract dysbiosis and complications thereof, or for the prevention and / or treatment of infections, in particular infections of the female reproductive tract, in an animal including a human, or for the manufacture of a food product, or of a nutritional composition.

[0039] The invention may alternatively be formulated as a method for therapeutic and / or preventive treatment of female reproductive tract dysbiosis and complications thereof, or for the prevention and / or treatment of infections, in particular infections of the female reproductive tract, in an animal including a human, comprising administering to said animal in need thereof an effective amount (i.e., therapeutically or nutraceutically effective amount) of the strain, and / or of the bacterial culture, and / or of the combination of microorganisms, and / or of the supernatant, and / or of the combination of supernatants, and / or the lysate as defined in the sixth aspect, and / or the combination of lysates as defined in the seventh aspect, and / or of the composition, and / or of the medical device, as respectively defined in the aspects one to ninth of the invention, together with pharmaceutically or nutraceutically acceptable excipients or carriers, in a subject in need thereof, including a human.

[0040] The invention also relates to a process for the preparation of the bacterial culture as defined in the second aspect, and to a process for the preparation of the supernatant as defined in the fourth aspect, and to a process for the preparation of the combination of microorganism supernatants as defined in the fifth aspect, and to a process for the preparation of the lysate as defined in the sixth aspect, and to a process for the preparation of the combination of lysates as defined in the seventh aspect. The invention also relates to the bacterial culture, the supernatant, the combination of microorganism supernatants, the lysate and the combination of lysates obtainable by such processes.

[0041] The strain of Lactobacillus paracasei of the invention, isolated from vaginal exudate samples, was deposited by the applicant, according to the Budapest Treaty, on 17 June 2022 in the Coleccion Espanola de Cultivos Tipo (CECT), located at Edificio CUE, Parc Cientific Universitat de Valencia, Catedratico Agustin Escardino, 9; 4890 Paterna (Valencia), Spain. The strain was given the access number CECT30660 after it was considered viable.

[0042] These and other objects of the present invention will be further described in the detailed description section that follows, and they are not intended to be limiting of the present invention. Methods and materials similar or equivalent to those described herein can be used in the practice of the present invention.

[0043] Brief Description of Drawings

[0044] FIG. 1: Postbiotic combined treatment reduces percentage deliver preterm (FIG. 1a) and increases deliver on time (FIG. 1b). Representation of term deliveries on time (value = 1) or premature deliveries (value = 0); of the same groups of animals.

[0045] LPS stands for Lipopolysaccharide; MRS stands for De Man, Rogosa and Sharpe selective culture; ORD stands for strain ORD0998 (CECT30660); CECT stands for strain CECT7210; %DP stands for % of delivery preterm; DOT stands for delivery on time.

[0046] FIG. 2: Plasma concentrations of proinflammatory cytokines after treatments.

[0047] LPS stands for Lipopolysaccharide; MRS stands for De Man, Rogosa and Sharpe selective culture;

[0048] ORD stands for strain ORD0998 (CECT30660); CECT stands for strain CECT7210; n.s. refers to nonsignificant.

[0049] FIG. 3: Myometrium concentrations of proinflammatory cytokines after treatments.

[0050] LPS stands for Lipopolysaccharide; ORD stands for strain ORD0998 (CECT30660); CECT stands for strain CECT7210; MIX refers to the mix of ORD0998 (CECT30660) and CECT7210.

[0051] FIG. 4: Placenta concentrations of proinflammatory cytokines after treatments.

[0052] LPS stands for Lipopolysaccharide; ORD stands for strain ORD0998 (CECT30660); CECT stands for strain CECT7210; MIX refers to the mix of ORD0998 (CECT30660) and CECT7210; n.s. refers to nonsignificant. Detailed description of the invention

[0053] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs at the time of filling. However, in the event of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0054] As used herein, the indefinite articles "a” and "an” are synonymous with "at least one” or "one or more.” Unless indicated otherwise, definite articles used herein, such as "the” also include the plural of the noun.

[0055] As it is used in the art, the term "microorganism” refers to organisms that are microscopic, and include bacteria, yeasts, fungi, archaea or protists. The term "bacteria” is used herein as in the art, to designate a unicellular microorganism which is prokaryotic, i.e., that lack a membrane-bound nucleus and organelles. The term "probiotic” refers to bacteria in the context of dietary supplements. Generally, the term probiotic refers to dietary supplements containing potentially beneficial bacteria or yeast, with lactic acid bacteria as the most common microbes used. The term "effective amount” as used herein, means an amount of an active ingredient high enough to deliver the desired benefit, but low enough to avoid serious side effects within the scope of medical judgment. The term "pharmaceutically acceptable” as used herein pertains to compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g. human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. If not indicated to the contrary the terms pharmaceutically effective or acceptable include also veterinary effective or acceptable. Each carrier, excipient, etc. must also be "acceptable” in the sense of being compatible with the other ingredients of the formulation. Suitable carriers, excipients, etc. can be found in standard pharmaceutical texts, the skilled person in the art will extensively know.

[0056] In particular embodiments of the first aspect, the Lactobacillus paracasei CECT30660 strain mutant or variant thereof is a Lactobacillus paracasei strain having a sequence identity of at least 95%, at least 96%, at least 97%, at least 98%, or of at least 99% with the Lactobacillus paracasei CECT30660 strain. In particular embodiments, the sequence identity is at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, or of at least 99.9%. In a more particular embodiment, the sequence identity is at least 99.9%.

[0057] In particular embodiments, the Lactobacillus paracasei CECT30660 mutant or variant thereof is a L. paracasei strain maintaining the group B Streptococcus growth inhibition activity of the L. paracasei CECT30660 strain.

[0058] In particular embodiments of the third, fifth, seventh and additional aspects, the Bifidobacterium longum biovar infantis CECT7210 strain mutant or variant thereof is a Bifidobacterium longum biovar infantis strain having a sequence identity of at least 95%, at least 96%, at least 97%, at least 98%, or of at least 99% with the Bifidobacterium longum biovar infantis CECT7210 strain. In particular embodiments, the sequence identity is at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, or of at least 99.9%. In a more particular embodiment, the sequence identity is at least 99.9%.

[0059] In particular embodiments, the Bifidobacterium longum biovar infantis CECT7210 mutant or variant thereof is a Bifidobacterium longum biovar infantis strain maintaining the preterm birth prevention synergistic effect of the Bifidobacterium longum biovar infantis CECT7210 strain in the present invention.

[0060] In particular embodiments of the first aspect, the Lactobacillus paracasei CECT30660 strain mutant or variant thereof is a Lactobacillus paracasei strain having an Average Nucleotide Identity (ANI) of at least 95%, at least 96%, at least 97%, at least 98%, or of at least 99% with the Lactobacillus paracasei CECT30660 strain. In particular embodiments, the ANI is of at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, or of at least 99.9%. In a more particular embodiment, the ANI is at least 99.9%.

[0061] In more particular embodiments, the L. paracasei CECT30660 mutant or variant thereof is a L. paracasei strain having an Average Nucleotide Identity (ANI) from 95 to 99% with the L. paracasei CECT30660 strain and maintaining the group B Streptococcus growth inhibition activity of the L. paracasei CECT30660 strain. For example, a mutant or variant thereof having an ANI of at least 99.9% with the L. paracasei CECT30660 strain and maintaining the group B Streptococcus growth inhibition activity of the L. paracasei CECT30660 strain.

[0062] In particular embodiments of the third, fifth, seventh and additional aspects, the Bifidobacterium longum biovar infantis CECT7210 strain mutant or variant thereof is a Bifidobacterium longum biovar infantis strain having an Average Nucleotide Identity (ANI) of at least 95%, at least 96%, at least 97%, at least 98%, or of at least 99% with the Bifidobacterium longum biovar infantis CECT7210 strain. In particular embodiments, the ANI is of at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, or of at least 99.9%. In a more particular embodiment, the ANI is at least 99.9%.

[0063] In more particular embodiments, the Bifidobacterium longum biovar infantis CECT7210 mutant or variant thereof is a Bifidobacterium longum biovar infantis strain having an ANI from 95 to 99% with the Bifidobacterium longum biovar infantis CECT7210 strain and maintaining the preterm birth prevention synergistic effect of the Bifidobacterium longum biovar infantis CECT7210 strain in the present invention. For example, a mutant or variant thereof having an ANI of at least 99.9% with the Bifidobacterium longum biovar infantis CECT7210 strain and maintaining the preterm birth prevention synergistic effect of the Bifidobacterium longum biovar infantis CECT7210 strain in the present invention.

[0064] The term "Average Nucleotide Identity (ANI)” is a measure of nucleotide-level genomic similarity between the coding regions of two genomes. Average Nucleotide Identity can be assessed as described here: Yoon SH, Ha SM, Lim J, Kwon S, Chun J. A large-scale evaluation of algorithms to calculate average nucleotide identity. Antonie Van Leeuwenhoek. 2017 Oct;110(10):1281- 1286. In the present invention the strain Lactobacillus paracasei ORD0998 (also known as CECT30660) represents the reference genome to which a Lactobacillus paracasei genome is compared; and the strain Bifidobacterium longum biovar infantis CECT7210 represents the reference genome to which a Bifidobacterium longum biovar infantis genome is compared.

[0065] The term "female reproductive tract” used herein refer to the female reproductive system which is made up of the internal and external sex organs that function in reproduction of new offspring. The internal sex organs are the vagina, uterus, Fallopian tubes, and ovaries. The external sex organs are also known as the genitals and these are the organs of the vulva including the labia, clitoris, and vaginal opening.

[0066] The term "dysbiosis” used herein refers to the condition (also called dysbacteriosis) which is characterized as a disruption to the microbiota homeostasis caused by an imbalance in the microflora, changes in their functional composition and metabolic activities, or a shift in their local distribution. It is a term for a microbial imbalance or maladaptation on or inside the body, such as an impaired microbiota. There are many etiologies that may cause it such as pregnancy, drugs intake (in particular antibiotics), stress, use of contraceptive, or a combination thereof. And the associated term "complications thereof' used herein refers to conditions or events that are induced or conditioned by the female reproductive tract dysbiosis such as infection by sexually transmitted infections (STIs), premature delivery (or preterm birth) and low birth weight, pelvic inflammatory disease in the uterus and fallopian tubes, infection after gynecologic surgery, among other.

[0067] The term "Preterm birth” (PTB) used herein refers, in the context of human species, to the birth of a baby at fewer than 37 weeks gestational age, as opposed to full-term delivery at approximately 40 weeks. Very early preterm birth is before 32 weeks, early preterm birth occurs between 32-36 weeks, late preterm birth is between 34-36 weeks' gestation. It is also known as Premature birth. Although data in this description have been carried out with animal models, thus with the particular definition of PTB in the species used as example, the same are to be understood as extrapolable to human as the skilled person will understand.

[0068] The term "Pregnancy complications” used herein refers to health problems that are related to pregnancy. The following problems originate in the mother, although they may have serious consequences for the fetus as well:

[0069] Gestational diabetes, Hyperemesis gravidarum, Pelvic girdle pain, High blood pressure, Venous thromboembolism, Anemia, Infection, Candidiasis, Bacterial vaginosis, Peripartum cardiomyopathy, Hypothyroiditis. The following problems occur in the fetus or placenta, but may have serious consequences on the mother as well: Ectopic pregnancy, Miscarriage, Placental abruption, Placenta praevia, Placenta accreta, Multiple pregnancies, Vertically transmitted infection, Intrauterine bleeding.

[0070] The relation of altered vaginal microbiota with these complications is explained below:

[0071] Gestational diabetes: women with an altered vaginal microbiota have been found to have an increased risk of developing gestational diabetes, a condition in which blood sugar levels rise during pregnancy. The imbalance in the vaginal microbiota can affect the body's inflammatory response and hormone production, which may contribute to the development of this condition.

[0072] Hyperemesis gravidarum is a severe form of nausea and vomiting during pregnancy. While the exact cause of this condition is not known, it has been found that women with an altered vaginal microbiota may have an increased risk of developing it.

[0073] Pelvic pain during pregnancy can be caused by a number of factors, including an imbalance in the vaginal microbiota. The presence of pathogenic bacteria in the vagina can cause inflammation in the pelvic area and increase the risk of developing pain.

[0074] High blood pressure: women with an altered vaginal microbiota may have an increased risk of developing high blood pressure during pregnancy, known as pre-eclampsia. This is thought to be because the imbalance in the vaginal microbiota may affect endothelial function and the body's inflammatory response.

[0075] Venous thromboembolism is a condition in which blood clots form in the veins. Women with an altered vaginal microbiota may have an increased risk of developing this condition during pregnancy, possibly due to an exaggerated inflammatory response in the body.

[0076] Anemia: imbalance in the vaginal microbiota may also contribute to anemia during pregnancy. Some pathogenic bacteria can interfere with the absorption of iron and other nutrients, which can lead to iron deficiency and anemia.

[0077] Infections: vaginal infections during pregnancy are common and can be caused by a variety of microorganisms. An imbalance in the vaginal microbiota can increase the risk of developing infections, including bacterial vaginosis and vaginal candidiasis. Peripartum cardiomyopathy is a condition in which the heart muscle weakens after childbirth. Women with an altered vaginal microbiota have been found to have an increased risk of developing this condition, possibly due to an exaggerated inflammatory response in the body.

[0078] Hypothyroidism during pregnancy can be caused by a variety of factors, including an imbalance in the vaginal microbiota. Some pathogenic bacteria can affect thyroid function and increase the risk of developing hypothyroidism.

[0079] Ectopic pregnancy occurs when the fertilized egg implants outside the uterus. Women with an imbalance in vaginal microbiota have been found to have an increased risk of developing ectopic pregnancy, possibly due to increased inflammation in the fallopian tube.

[0080] Miscarriage occurs when pregnancy stops before 20 weeks gestation. Women with an imbalance in vaginal microbiota have a higher risk of developing miscarriage, possibly due to increased inflammation in the uterus.

[0081] Placental abruption occurs when the placenta separates from the uterus before delivery. Women with an imbalance in vaginal microbiota are at increased risk of developing this complication, possibly due to increased inflammation in the uterus.

[0082] Placenta previa occurs when the placenta implants in the lower part of the uterus, partially or completely covering the cervix. Women with an imbalance in vaginal microbiota have a higher risk of developing placenta previa, possibly due to increased inflammation in the uterus.

[0083] Placenta accreta occurs when the placenta abnormally attaches to the uterus. Women with an imbalance in vaginal microbiota have an increased risk of developing placenta accreta, possibly due to increased inflammation in the uterus.

[0084] Multiple pregnancies may be associated with an increased risk of pregnancy complications, including preterm delivery and low birth weight. Women with an imbalance in vaginal microbiota have been found to have an increased risk of developing multiple pregnancies, possibly due to increased inflammation in the uterus.

[0085] Vertically transmitted infections are those that are transmitted from mother to fetus during pregnancy. An imbalance in the vaginal microbiota may increase the risk of developing vertically transmitted infections, such as cytomegalovirus infection or human papillomavirus infection.

[0086] Intrauterine bleeding during pregnancy can be caused by a variety of factors, including an imbalance in the vaginal microbiota. Pathogenic bacteria can cause inflammation in the uterus and increase the risk of developing intrauterine bleeding.

[0087] The term "labor complications” used herein refers to complications that occur primarily during childbirth. They are also termed obstetric labor complications and the following types are identified Amniotic fluid embolism, Bleeding, Cord prolapse, Obstructed labour, Placental abruption, Premature labour, Nuchal cord, Perinatal asphyxia, Mechanical fetal injury and Uterine rupture. The relation of altered vaginal microbiota with these complications is explained below:

[0088] Amniotic fluid embolism is a rare but serious complication of childbirth that can be life-threatening to the mother and fetus. It has been found that certain bacteria in the vaginal microbiota may contribute to this complication, although the exact cause is unclear.

[0089] Bleeding during labor: excessive bleeding during labor can be caused by a variety of factors, including an imbalance in the vaginal microbiota. Pathogenic bacteria can cause inflammation in the uterus and increase the risk of developing bleeding during labor.

[0090] Umbilical cord prolapse occurs when the umbilical cord slips out of the uterus before the fetus during delivery. Women with an imbalance in vaginal microbiota have an increased risk of developing cord prolapse, possibly due to increased inflammation in the uterus.

[0091] Obstructive labor occurs when the fetus cannot pass through the mother's pelvis during delivery.

[0092] Women with an imbalance in vaginal microbiota have an increased risk of developing obstructive labor, possibly due to increased inflammation in the uterus.

[0093] Placental abruption during labor may be caused by an imbalance in the vaginal microbiota. Pathogenic bacteria can cause inflammation in the uterus and increase the risk of developing placental abruption. Preterm labor occurs when labor begins before 37 weeks gestation. An imbalance in the vaginal microbiota may increase the risk of developing preterm labor, possibly due to increased inflammation in the uterus.

[0094] Nuchal cord occurs when the umbilical cord wraps around the neck of the fetus during delivery. Women with an imbalance in vaginal microbiota have an increased risk of developing nuchal cord, possibly due to increased inflammation in the uterus.

[0095] Perinatal asphyxia occurs when the fetus does not receive enough oxygen during delivery. An imbalance in the vaginal microbiota may increase the risk of developing perinatal asphyxia, possibly due to increased inflammation in the uterus.

[0096] Mechanical fetal injuries can occur during labor, especially in cases of difficult labor. An imbalance in the vaginal microbiota may increase the risk of developing mechanical fetal injury, possibly due to increased inflammation in the uterus.

[0097] Uterine rupture is a complication determined by an exaggerated and continuous contraction of the uterus, which can overcome the resistance of the lower segment before it allows the product to come out. An imbalance in the vaginal microbiota may increase the risk of developing uterine rupture.

[0098] The term “postbiotic” used herein refers to soluble factors, metabolic products or byproducts, secreted by live bacteria, or released after bacterial lysis providing physiological benefits to the host. They are also termed as metabiotics, biogenics, or simply metabolites. Therefore, postbiotic also refers to nucleic acids (DNA or RNA), proteins, lipids, carbohydrates or other cellular components obtained from bacteria. The term "bacterial culture” used herein refers to a method of multiplying microbial organisms by letting them reproduce in predetermined culture medium under controlled laboratory conditions. There are several types of bacterial culture methods that are selected based on the agent being cultured and the downstream use: Broth cultures; Agar plates; Agar based dipsticks; Stab cultures; Culture collections; Solid plate culture of thermophilic microorganisms. It also refers to the result of such growth itself, which contains cells of the multiplied microorganism(s).

[0099] As used herein, "supernatant” or "conditioned culture media” refers to culture media in which cells of the strain of the invention have been cultured for a suitable period of time and into which the cells have secreted active agent(s) to sufficient levels to provide a desired biological activity. A culture supernatant may contain one or more soluble metabolites of the bacterium useful in the methods described herein. The skilled in the art will know which media is suitable for culturing the bacterium, and for how long it should be cultured in order to obtain a supernatant with enough active metabolites using its common general knowledge. The culture supernatant may be obtained, for example, by settling, precipitating or centrifuging the cells in culture. The supernatant may be filtered. A culture supernatant may contain one or more soluble metabolites and non-consumed compounds initially present in the culture media. The supernatants and its compounds are postbiotics. The supernatant may contain cells of the strain of the invention or may be cell-free or substantially cell-free.

[0100] The term "lysate" as used herein refers to a biological sample obtained through the process of cellular lysis. Cellular lysis involves the deliberate disruption of cells, resulting in the release of their cellular contents into a liquid or semi-liquid medium. The lysate contains a mixture of various intracellular components, such as proteins, nucleic acids, metabolites, and other biomolecules, derived from the lysed cells. The lysate and its compounds are postbiotics.

[0101] "Nutritional compositions” (also termed nutraceuticals or nutraceutical compositions) are edible compositions including dietary supplements, oral rehydration solutions (ORS), food additives, baby cereals and infant formulas. Dietary supplements intend to supply nutrients, (vitamins, minerals, fatty acids or amino acids) that are missing or not consumed in sufficient quantity in a person's diet (infants, pregnant women, elderly people, etc). Infant formulas relate to manufactured food designed and marketed for feeding to babies and infants under 12 months of age, usually prepared for bottle-feeding or cup-feeding from powder (mixed with water) or liquid (with or without additional water). The U.S. Federal Food, Drug, and Cosmetic Act (FFDCA) defines infant formula as "a food which purports to be or is represented for special dietary use solely as a food for infants by reason of its simulation of human milk or its suitability as a complete or partial substitute for human milk.

[0102] The terms "group B Streptococcus” or “B group Streptococcus”, refer to the Streptococcus agalactiae. The genus Lactobacillus was renamed as Lacticasei bacillus by Zheng J, et al. (2020). Therefore, for example, Lactobacillus paracasei has been recently renamed as Lacticaseibacillus paracasei. In the present invention, the old nomenclature is used, and the term “Lactobacillus" is used instead of Lacticaseibacillus.

[0103] The term "food composition” or "food product” is used herein in its broadest meaning, including any type of product, in any form of presentation, which can be ingested by an animal, including humans. In particular it includes food such as a milk product, a yogurt, a curd, a cheese, a fermented milk, a milk powder, a milk based fermented product, an ice-cream, a fermented cereal-based product, a milk-based powder, a beverage, a dressing, and a pet food.

[0104] As above exposed, the inventors propose for the first time a Lactobacillus paracasei strain and said strain for use in the prevention and / or treatment of female reproductive tract dysbiosis and complications thereof, in particular for use in the prevention of preterm birth, and / or the prevention and / or treatment of labor and / or pregnancy complications.

[0105] As previously indicated, a first aspect of the invention provides a strain of Lactobacillus paracasei deposited in the "Coleccion Espanola de Cultivos Tipo (CECT)” under the accession number CECT30660 and named by the applicant as ORD0998, or a mutant or variant thereof.

[0106] The scope of the present invention also encompasses bacteria obtained by mutation, variation or recombination of the strain Lactobacillus paracasei CECT30660. In particular embodiments of the invention, the mutant is a genetically modified mutant obtained by classical mutagenesis (i.e. using chemical or physical agents) or by genetic engineering techniques, for example, directed mutagenesis. In another embodiment, the variant is a naturally occurring variant.

[0107] In one embodiment, it is provided a method to obtain a mutant or variant of Lactobacillus paracasei CECT30660 comprising the step of subjecting the Lactobacillus paracasei CECT30660 to a DNA recombinant technique, for example mutagenesis, or to conditions to generate spontaneous mutations, for example UV light or chemical mutagens.

[0108] In a particular embodiment, the strain or mutant or variant thereof comprise a 16S Ribosomal RNA gene of sequence SEQ ID NO: 3.

[0109] The general use of the strain of the invention is the particular embodiment in which the invention is in the form of viable cells. This means the introduction of the living bacteria in an unfermented composition. However, in another particular embodiment the invention can also be extended to non- viable and / or metabolically inactive cells in compositions comprising beneficial factors expressed by the strain in a previous process.

[0110] The second aspect of the present invention is a bacterial culture comprising the strain as defined in the first aspect. In other words, a bacterial culture obtainable from the strain CECT30660 of the invention. More in particular, a bacterial culture consisting of a pure bacterial culture of the strain CECT30660.

[0111] As previously indicated, the invention also relates to a method for preparing the bacterial culture. Generically, the bacterial pure culture is obtainable from the growth of one or more cells of the strain in a selected media, in particular the media where the specie Lactobacillus paracasei is usually grown. In a more particular embodiment, the media is Man-Rogosa-Sharpe (MRS).

[0112] In a particular embodiment, the method for preparing the bacterial culture comprises the steps of: a) culturing the strain CECT30660 under suitable growth conditions, thereby generating a cell culture.

[0113] In a particular embodiment, the strain CECT30660 is cultured or incubated for a suitable period of time, particularly for at least 15 h, at least 16 h, at least 17 h, at least 18 h, at least 19 h, at least 20 h, at least 21 h, at least 22 h, at least 23 h, or at least 24 h. In an even more particular embodiment, it is cultured of at least 24 h. In another particular embodiment, the incubation lasts for about 24 h.

[0114] In a particular embodiment, it is cultured in MRS medium. In another particular embodiment it is cultured without agitation. In another particular embodiment it is cultured under anaerobic conditions.

[0115] In a more particular embodiment, the strain CECT30660 is cultured for at least 24 h in MRS medium, without agitation and under anaerobic conditions.

[0116] The third aspect of the invention relates to a microorganism combination comprising the strain as defined in the first aspect or the bacterial culture as defined in the second aspect, in combination with one or more additional microorganism strains or cultures obtained comprising the additional microorganism strains.

[0117] In a particular embodiment, the additional microorganism combined with the strain of the invention is a strain of Bifidobacterium longum biovar infantis.

[0118] In a more particular embodiment, the Bifidobacterium longum biovar infantis strain used in combination is the CECT7210, which was isolated from breast-fed infant feces and deposited by the applicant, according to the Budapest Treaty, on 20 November 2006 in the Coleccibn Espanola de Cultivos Tipo (CECT), located at Universidad de Valencia, Edificio de Investigation, Campus de Burjassot, 46100 Burjassot (Valencia), Spain. The strain was given the access number CECT7210 after it was considered viable. A bacterial culture of the CECT7210 is obtainable from the growth of one or more cells of the strain in a selected media, in particular the media where the specie is usually grown. In a more particular embodiment, the media is Man-Rogosa-Sharpe (MRS). In a more particular embodiment, the media further comprises Cysteine-HCI 0.05% w / v.

[0119] In a particular embodiment, the method for preparing the bacterial culture comprises the steps of: a) culturing the strain CECT7210 under suitable growth conditions, thereby generating a cell culture.

[0120] In a particular embodiment, the strain CECT7210 is cultured or incubated for a suitable period of time, particularly for at least 15 h, at least 16 h, at least 17 h, at least 18 h, at least 19 h, at least 20 h, at least 21 h, at least 22 h, at least 23 h, or at least 24 h. In an even more particular embodiment, it is cultured for at least 24 h. In another particular embodiment, the incubation lasts for about 24 h.

[0121] In another particular embodiment it is cultured without agitation.

[0122] In another particular embodiment it is cultured under anaerobic conditions.

[0123] In a more particular embodiment, the strain CECT7210 is cultured for at least 24 h in MRS medium with Cysteine-HCI 0.05% w / v, without agitation and under anaerobic conditions.

[0124] The general use of any of the Bifidobacterium strains of the previous embodiments is the embodiment in which they are in the form of viable cells. This means the introduction of the living bacteria in an unfermented composition. However, in another embodiment they can also be in the form of non-viable cells in compositions comprising beneficial factors expressed by the strains in previous processes.

[0125] Data in examples below demonstrate that the combination with a Bifidobacterium longum are advantageous combinations for the intended uses in the female reproductive tract. Bifidobacterium longum is not usually found in the vagina. Thus, it is noteworthy that a strain of a microorganism with a different tissue tropism can provide so beneficial effects in these other kinds of tissues.

[0126] In another particular embodiment, optionally in combination with the embodiments above or below of the combinations with CECT30660, the one or more additional microorganism strains or cultures thereof are selected from the group consisting of Lactobacillus crispatus, in particular L. crispatus LBV88 (DSM 22566); Lactobacillus rhamnosus, in particular L. rhamnosus LBV96 (DSM 22560); Lactobacillus gasseri, in particular L. gasseri LBV150 (DSM 22583); Lactobacillus jensenii, in particular L. jensenii LBV116 (DSM 22567); Bifidobacterium longum, in particular B. longum biovar infantis CECT7210.

[0127] The fourth aspect of the invention is a supernatant obtainable from the Lactobacillus paracasei strain CECT30660. It is also disclosed here, indeed, a supernatant obtainable from the Lactobacillus paracasei strain CECT30660 or obtainable from a bacterial culture obtainable by and / or comprising the strain as defined in the first aspect. In other words, a supernatant obtained from the strain as defined in the first aspect and / or the bacterial culture as defined in the second aspect.

[0128] As previously indicated, the invention also relates to a method for preparing the supernatant of the fourth aspect. Generically, the supernatant is obtainable from the separation of the one or more cells of the strain from the media where the one or more have been grown.

[0129] In a particular embodiment, the method for preparing the supernatant of CECT30660 culture comprises the steps of: a) culturing the strain under suitable growth conditions as indicated in previous embodiments, thereby generating a cell culture; and b) separating the culture medium from (a), thereby obtaining the cell-free culture supernatant.

[0130] In a particular embodiment, the separation of the culture medium from the cells is carried out by centrifugation and / or filtration. In another particular embodiment, the culture supernatant is further subjected to a step selected from the group consisting of dehydration, filtration, ultra-filtration, centrifugation, ultra-centrifugation, precipitation, chromatography, and combinations thereof.

[0131] In a particular embodiment the supernatant is concentrated and / or freeze-dried. In a more particular embodiment, is reconstituted freeze-dried.

[0132] In a more particular embodiment, the supernatant was obtained by centrifugation of the bacterial culture of the second aspect at 3220 g and neutralized with NaOH 10N. In a more particular embodiment, the supernatant neutralized was sterilized by filtration using a filter of 0.2 micrometers of porous diameter.

[0133] The term "neutralized” refers to the condition in which the supernatant is neither acidic nor alkaline, with a pH value close to 7. In the examples is shown that, since the supernatant of Lactobacillus is initially acidic, sodium hydroxide (NaOH) is added to achieve neutralization. This process is relevant for studying the effects of the supernatant independently of any influence an acidic pH might exert. For instance, it is well-documented that the growth of certain bacteria can be inhibited by the acidification of the medium caused by Lactobacillus. By neutralizing the supernatant, it can be determined whether it inhibits bacterial growth due to factors other than medium acidification.

[0134] The fifth aspect of the invention relates to a combination of microorganism supernatants comprising the supernatant as defined in the fourth aspect, and one or more additional supernatants of one or more additional microorganism strains. In a particular embodiment, the additional supernatant is obtained from a strain of a Bifidobacterium longum biovar infantis, or a mutant, obtained by classical mutagenesis (i.e., using chemical or physical agents) or by genetic engineering techniques, or a naturally occurring variant thereof.

[0135] As previously indicated, the additional supernatant can also be obtained from a bacterial culture comprising a strain of Bifidobacterium longum biovar infantis, or a mutant, said mutant in particular obtained by classical mutagenesis (i.e., using chemical or physical agents) or by genetic engineering techniques, or a naturally occurring variant thereof.

[0136] In a more particular embodiment, the additional supernatant is from a strain or culture of Bifidobacterium longum biovar infantis deposited in the Coleccion Espanola de Cultivos Tipo (CECT) under the accession number CECT7210, or a mutant, obtained by classical mutagenesis (i.e., using chemical or physical agents) or by genetic engineering techniques, or a naturally occurring variant thereof.

[0137] In a more particular embodiment, the CECT7210 supernatant is obtained by centrifugation of the bacterial culture of the CECT7210, obtained as defined above, at 3220 g and neutralized with NaOH 10N. In a more particular embodiment, the CECT7210 supernatant neutralized is sterilized by filtration using a filter of 0.2 micrometers of porous diameter.

[0138] As previously indicated, the invention also relates to a method for preparing the combination of microorganism supernatants of the fifth aspect. Generically, the combination of supernatants of microorganisms is obtained by mixing the supernatants obtained from each of the bacterial cultures. In a particular, the combination of microorganism supernatants is obtained by mixing supernatants in the same proportion (e.g., if two supernatants are combined, each supernatant is mixed at 50% v / v).

[0139] In a more particular embodiment, the combination of supernatants is obtained by mixing the CECT30660 supernatant of the second aspect and the CECT7210 supernatant obtained as indicated above in 50% v / v proportion.

[0140] The sixth aspect of the invention is a lysate obtainable from the Lactobacillus paracasei strain CECT30660.

[0141] It is also disclosed here, indeed, a lysate obtainable from the Lactobacillus paracasei strain CECT30660 or obtainable from a bacterial culture obtainable by and / or comprising the strain as defined in the first aspect. In other words, a lysate obtained from the strain as defined in the first aspect and / or the bacterial culture as defined in the second aspect.

[0142] As previously indicated, the invention also relates to a method for preparing the lysate of the sixth aspect. Generically, the lysate is obtainable from lysing a cell culture of the strain. In a particular embodiment, the method for preparing the lysate of CECT30660 culture comprises the steps of: a) culturing the strain under suitable growth conditions as indicated in previous embodiments, thereby generating a cell culture; b) optionally separating the cells from the supernatant as indicated in previous embodiments; and c) lysing the fraction containing the cells thereby obtaining the lysate.

[0143] In a particular embodiment the lysate is obtained by mechanical, chemical, enzymatic, or physical means. In a more particular embodiment, the lysate is obtained by a chemical disruption method comprising the use of a chemical agent selected from an alkali, an acid, a detergent or a combination thereof.

[0144] In particular embodiment the lysate is obtained by a mechanical disruption method selected from shear forces or ultrasounds.

[0145] In a particular embodiment the lysate is concentrated and / or freeze-dried. In a more particular embodiment, is reconstituted freeze-dried.

[0146] The seventh aspect of the invention relates to a combination of microorganism lysates comprising the lysate as defined in the sixth aspect, and one or more additional lysates of one or more additional microorganism strains.

[0147] In a particular embodiment, the additional lysate is obtained from a strain of a Bifidobacterium longum biovar infantis, or a mutant, obtained by classical mutagenesis (i.e., using chemical or physical agents) or by genetic engineering techniques, or a naturally occurring variant thereof.

[0148] As previously indicated, the additional lysate can also be obtained from a bacterial culture comprising a strain of Bifidobacterium longum biovar infantis, or a mutant, said mutant in particular obtained by classical mutagenesis (i.e., using chemical or physical agents) or by genetic engineering techniques, or a naturally occurring variant thereof.

[0149] In a more particular embodiment, the additional lysate is from a strain or culture of Bifidobacterium longum biovar infantis deposited in the Coleccion Espanola de Cultivos Tipo (CECT) under the accession number CECT7210, or a mutant, obtained by classical mutagenesis (i.e., using chemical or physical agents) or by genetic engineering techniques, or a naturally occurring variant thereof.

[0150] In a more particular embodiment, the CECT7210 lysate is obtained by lysing the cell containing fraction obtained from the bacterial culture of the CECT7210, obtained as defined above.

[0151] As previously indicated, the invention also relates to a method for preparing the combination of microorganism lysates of the seventh aspect. Generically, the combination of lysates of microorganisms is obtained by mixing the lysates obtained from each of the bacterial cultures.

[0152] In a particular, the combination of microorganism lysates is obtained by mixing lysates in the same proportion (e.g. if two lysates are combined, each lysate is mixed at 50% v / v).

[0153] In a more particular embodiment, the combination of lysates is obtained by mixing the CECT30660 lysate of the sixth aspect and the CECT7210 lysate obtained as indicated above in 50% v / v proportion.

[0154] Thus, according to the third, fifth and seventh aspect, in a further aspect the invention refers to a combination of

[0155] - the Lactobacillus paracasei strain as defined in the first aspect, and / or the bacterial culture as defined in the second aspect, and / or the supernatant as defined in the third aspect; with

[0156] - a Bifidobacterium longum biovar infantis strain deposited in the Coleccion Espanola de Cultivos Tipo (CECT) under the accession number CECT7210 or a strain with a sequence identity of at least 98% with the Bifidobacterium longum biovar infantis CECT7210, and / or a bacterial culture comprising a Bifidobacterium longum biovar infantis CECT7210 or a strain with a sequence identity of at least 98% with the Bifidobacterium longum biovar infantis CECT7210, and / or a supernatant obtainable by a method comprising the steps of: a) culturing a Bifidobacterium longum biovar infantis CECT7210 or a strain with a sequence identity of at least 98% with the Bifidobacterium longum biovar infantis CECT7210 in a culture medium under suitable growth conditions, particularly with MRS culture media, without agitation and under anaerobic conditions; and b) separating the culture medium from the Bifidobacterium longum biovar infantis CECT7210 or a strain with a sequence identity of at least 98% with the Bifidobacterium longum biovar infantis CECT7210, thereby obtaining the culture supernatant.

[0157] In particular, wherein the combination is of the Lactobacillus paracasei strain as defined in the first aspect with the Bifidobacterium longum biovar infantis CECT7210 strain, or a strain with a sequence identity of at least 98% with the Bifidobacterium longum biovar infantis CECT7210.

[0158] More in particular, wherein the combination is of the Lactobacillus paracasei CECT30660 with the Bifidobacterium longum biovar infantis CECT7210.

[0159] The eighth aspect of the invention relates to a pharmaceutical, veterinary, nutritional or food composition, comprising the strain of the invention as defined in the first aspect, and / or the bacterial culture as defined in the second aspect, and / or the microorganism combination as defined in the third aspect, and / or the supernatant as defined in the fourth aspect, and / or the combination of supernatants as defined in the fifth aspect, and / or the lysate as defined in the sixth aspect, and / or the combination of lysates as defined in the seventh aspect. In a particular embodiment, the composition comprises two, three, four or five of the strain of the invention as defined in the first aspect, the bacterial culture as defined in the second aspect; the microorganism combination as defined in the third aspect, the supernatant as defined in the fourth aspect, the combination of supernatants as defined in the fifth aspect, the lysate as defined in the sixth aspect, and the combination of lysates as defined in the seventh aspect.

[0160] In a particular embodiment, the composition is a pharmaceutical composition comprising therapeutically and / or prophy lactically effective amounts of the strain of the invention as defined in the first aspect, and / or of the bacterial culture as defined in the second aspect, and / or of the microorganism combination as defined in the third aspect, and / or of the supernatant as defined in the fourth aspect, and / or of the combination of supernatants as defined in the fifth aspect, and / or the lysate as defined in the sixth aspect, and / or the combination of lysates as defined in the seventh aspect, together with pharmaceutical acceptable excipients and / or carriers.

[0161] In another particular embodiment the pharmaceutical composition comprises the strain as defined in the first aspect and embodiments thereof in an amount from about 104cfu / g of the composition to about 1011cfu / g of the composition. More in particular in an amount from about 105cfu / g of the composition to about 1010cfu / g of the composition. More in particular in an amount from 106cfu / g of the composition to about 1010cfu / g of the composition. More in particular in an amount from about 107cfu / g of the composition to about 1010cfu / g of the composition. Even more in particular in an amount from about 108cfu / g of the composition to about 1010cfu / g of the composition.

[0162] In a more particular embodiment, the pharmaceutical composition comprises the strain as defined in the first aspect and embodiments thereof in an amount of 109cfu / g of the composition.

[0163] In a particular embodiment, the composition is a veterinary composition comprising therapeutically and / or prophy lactically effective amounts of the strain of the invention as defined in the first aspect, and / or of the bacterial culture as defined in the second aspect, and / or of the microorganism combination as defined in the third aspect, and / or of the supernatant as defined in the fourth aspect, and / or of the combination of supernatants as defined in the fifth aspect, and / or the lysate as defined in the sixth aspect, and / or the combination of lysates as defined in the seventh aspect, together with veterinary acceptable excipients and / or carriers.

[0164] In another particular embodiment the veterinary composition comprises the strain as defined in the first aspect and embodiments thereof in an amount from about 107cfu / g of the composition to about 1011cfu / g of the composition. In a more particular embodiment, the veterinary composition comprises the strain as defined in the first aspect and embodiments thereof in an amount of 109cfu / g of the composition.

[0165] In another particular embodiment, the composition is a nutritional composition and it comprises nutritionally effective amounts of the strain of the invention as defined in the first aspect, and / or of the bacterial culture as defined in the second aspect, and / or of the microorganism combination as defined in the third aspect, and / or of the supernatant as defined in the fourth aspect, and / or of the combination of supernatants as defined in the fifth aspect, and / or the lysate as defined in the sixth aspect, and / or the combination of lysates as defined in the seventh aspect, together with nutraceutical acceptable excipients, carriers and / or edible ingredients. In a more particular embodiment, the nutritional composition is selected from the group consisting of a dietary supplement, and additive, and an infant formula.

[0166] In another particular embodiment the nutritional composition comprises the strain as defined in the first aspect and embodiments thereof in an amount from 105cfu / g of the composition to 109cfu / g of the composition.

[0167] In a more particular embodiment, the nutritional composition comprises the strain as defined in the first aspect and embodiments thereof in an amount of 107cfu / g of the composition.

[0168] In a more particular embodiment, the composition is a food composition or food product that comprises nutritionally effective amounts of the strain of the invention as defined in the first aspect, and / or of the bacterial culture as defined in the second aspect, and / or of the microorganism combination as defined in the third aspect, and / or of the supernatant as defined in the fourth aspect, and / or of the combination of supernatants as defined in the fifth aspect, and / or the lysate as defined in the sixth aspect, and / or the combination of lysates as defined in the seventh aspect, together with appropriate amounts of other edible ingredients.

[0169] In a more particular embodiment, the food product or composition is selected from the group consisting of a milk product, a yogurt, a curd, a cheese, a fermented milk, a milk powder, a milk based fermented product, an ice-cream, a fermented cereal-based product, a milk-based powder, a beverage, a dressing, and a pet food.

[0170] In another particular embodiment, the food product comprises the strain as defined in the first aspect and embodiments thereof in an amount from 105cfu / g of the composition to 109cfu / g of the composition. In a more particular embodiment, the food composition comprises the strain as defined in the first aspect and embodiments thereof in an amount of 107cfu / g of the composition.

[0171] In another particular embodiment of any of the pharmaceutical, veterinary, nutraceutical or food compositions as previously disclosed, they further comprise one or more of a non-digestible saccharide. In a particular embodiment, the non-digestible saccharide is selected from the group consisting of a human milk oligosaccharide (HMO), a galactooligosaccharide (GOS), a fructooligosaccharide (FOS), and combinations thereof. More in particular they further comprise a fructooligosaccharide (FOS).

[0172] Also, in another particular embodiment of the compositions of the invention, they are in a form selected from the group consisting of supplements, solutions, tablets, capsules, ovules, suppositories, granules, suspensions, dispersions, powders, lozenge, chewable candy, candy bar, concentrate, drops, elixir, emulsion, film, gel, granule, chewing gum, jelly, oil, paste, pastille, pellet, soap, sponge, suppository, syrup, chewable gelatin form, or chewable tablet. In particular, the composition is in a form selected from the group consisting of supplement, cream, solution, tablet, capsule, suspension, dispersion, powder, foam, lozenge, chewable candy, candy bar, concentrate, drops, elixir, emulsion, film, gel, granule, chewing gum, jelly, oil, paste, pastille, soap, sponge, suppository, syrup, chewable gelatin, and chewable tablet.

[0173] In a more particular embodiment of the compositions of the invention, they further comprise one or more of a coating agent. In a particular embodiment the coating agent is hydroxypropyl methylcellulose.

[0174] In a more particular embodiment of the compositions of the invention, they further comprise corn starch.

[0175] In a more particular embodiment of the compositions of the invention, they further comprise one or more of an anti-caking agent. In another particular embodiment the anti-caking agent is selected from magnesium stearate, silicon dioxide or a combination thereof.

[0176] In a particular embodiment, the compositions of the invention comprise a L. paracasei strain as defined in the first aspect and embodiments thereof, one or more of a non-digestible saccharide, one or more of a coating agent, corn starch, a L. crispatus strain, a L. rhamnosus strain, a L. gasseri strain, a L. jensenii strain, and one or more of an anti-caking agent.

[0177] In a more particular embodiment, the compositions of the invention comprise a L. paracasei strain as defined in the first aspect and embodiments thereof, one or more of a fructooligosaccharide, hydroxypropyl methylcellulose, corn starch, a L. crispatus LBV88 (DSM 22566) strain, a L. rhamnosus LBV96 (DSM 22560) strain, a L gasseri LBV150N (DSM 22583) strain, a L. jensenii LBV116 (DSM 22567) strain, magnesium stearate, and silicon dioxide.

[0178] In a more particular embodiment, the compositions of the invention comprise a L. paracasei strain as defined in the first aspect and embodiments thereof, one or more of a fructooligosaccharide, hydroxypropyl methylcellulose, corn starch, a L. crispatus LBV88 (DSM 22566) strain, a L. rhamnosus LBV96 (DSM 22560) strain, a L gasseri LBV150N (DSM 22583) strain, a Ljensenii LBV116 (DSM 22567) strain, a B. longum biovar infantis (CECT7210) strain, magnesium stearate, and silicon dioxide.

[0179] The present invention also contemplates medical devices including the strain of Lactobacillus paracasei as defined in the first aspect, and / or the bacterial culture as defined in the second aspect, and / or the microorganism combination as defined in the third aspect, and / or the supernatant as defined in the fourth aspect, and / or the combination of microorganism supernatants as defined in the fifth aspect, and / or the lysate as defined in the sixth aspect, and / or the combination of lysates as defined in the seventh aspect, and / or the composition as defined in the eighth aspect.

[0180] Examples of pharmaceutical composition and / or medical devices according to the invention are:

[0181] - Vaginal creams: these creams contain medications that are applied internally into the vagina. They are commonly used to treat infections and conditions such as vaginal atrophy.

[0182] - Vaginal ovules or suppositories: these are small solid forms that are inserted into the vagina, where they dissolve or melt at body temperature, releasing the medication.

[0183] - Vaginal tablets: they are similar to suppositories, but in tablet form. They are inserted into the vagina and dissolve to release the medication.

[0184] - Vaginal gels: these gels contain medication and are applied to the vagina. They are used to treat infections and other conditions, as well as for lubrication.

[0185] - Vaginal rings: these are flexible devices that are inserted into the vagina and release medication steadily over an extended period of time. A common example is the contraceptive ring.

[0186] - Foams: these preparations contain medications and are applied to the vagina, often as spermicides or for other therapeutic purposes.

[0187] - Subdermal Implants: although not delivered directly into the vaginal tissue, subdermal implants are inserted under the skin and release hormones to prevent pregnancy.

[0188] - Intrauterine Hormone Release Systems: similar to traditional IUDs, these devices release hormones into the uterus. Example: Mirena system

[0189] - Contraceptive patches: Although not applied directly to the vaginal tissue, contraceptive patches release hormones through the skin to prevent pregnancy.

[0190] - Contraceptive sponges: These sponges contain spermicide and are inserted into the vagina before intercourse to prevent pregnancy.

[0191] - Hormone pellets: these are small capsules or "pellets" containing hormones. They are typically inserted under the skin in areas such as the hip or abdomen. They release hormones steadily for a period that can vary from 3 to 6 months, and even up to a year. Commonly used for hormone replacement therapy, especially in the management of menopausal symptoms.

[0192] - Aerosols.

[0193] - Applicators with cannula.

[0194] - Intrauterine infusion systems.

[0195] - Intrauterine Devices (IUD type).

[0196] - Vaginal systems.

[0197] - Cervical systems.

[0198] Therefore, the ninth aspect of the invention relates to a medical device comprising the strain of Lactobacillus paracasei as defined in the first aspect, and / or the bacterial culture as defined in the second aspect, and / or the microorganism combination as defined in the third aspect, and / or the supernatant as defined in the fourth aspect, and / or the combination of microorganism supernatants as defined in the fifth aspect, and / or the lysate as defined in the sixth aspect, and / or the combination of lysates as defined in the seventh aspect, and / or the composition as defined in the eighth aspect. In a more particular embodiment, the medical device is selected from the group consisting of vaginal creams, vaginal ovules, suppositories, vaginal tablets, vaginal gels, vaginal rings, foams, aerosols, applicators with cannula, intrauterine infusion systems, intrauterine devices (e.g. IUD type), vaginal systems, cervical systems, subdermal implants, intrauterine hormone release systems, contraceptive patches, contraceptive sponges and hormone pellets. In particular, the medical device is selected from the group consisting of vaginal ovules, vaginal rings, aerosol, applicators with cannula, intrauterine infusion systems, intrauterine devices (e.g. IUD type), vaginal systems, cervical systems, subdermal implants, intrauterine hormone release systems, contraceptive patches, contraceptive sponges and hormone pellets.

[0199] In a particular embodiment of the ninth aspect, the general use of any of the bacterial strain / s of its embodiments is in the form of non-viable cells or postbiotics.

[0200] The tenth aspect of the invention relates to the strain of Lactobacillus paracasei as defined in the first aspect, and / or the bacterial culture as defined the second aspect, and / or the microorganism combination as defined in the third aspect, and / or the supernatant as defined in the fourth aspect, and / or the combination of microorganism supernatants as defined in the fifth aspect, and / or the lysate as defined in the sixth aspect, and / or the combination of lysates as defined in the seventh aspect, and / or the composition as defined in the eighth aspect, and / or the medical device as defined in the ninth aspect for use in therapy. In other words, they are for use as a medicament. The invention can also be used as an adjuvant. For example, in a treatment against bacterial or fungal vaginosis the invention can be administered in parallel to the administration of the respective antibiotic or antifungal used as main treatment.

[0201] The effect of the adjuvant would be to contribute to the inhibition of the growth of the pathogen, but also to help to reestablish the equilibrium for a healthy vaginal environment, e.g. to help in the recolonization of a healthy microbiota in the vagina.

[0202] Therefore, the invention also contemplates the strain of Lactobacillus paracasei as defined in the first aspect, and / or the bacterial culture as defined the second aspect, and / or the microorganism combination as defined in the third aspect, and / or the supernatant as defined in the fourth aspect, and / or the combination of microorganism supernatants as defined in the fifth aspect, and / or the lysate as defined in the sixth aspect, and / or the combination of lysates as defined in the seventh aspect, and / or the composition as defined in the eighth aspect, and / or the medical device as defined in the ninth aspect for use as an adjuvant.

[0203] The invention can also be used in combination with a further therapeutic agent. Therefore, the invention also contemplates the strain of Lactobacillus paracasei as defined in the first aspect, and / or the bacterial culture as defined the second aspect, and / or the microorganism combination as defined in the third aspect, and / or the supernatant as defined in the fourth aspect, and / or the combination of microorganism supernatants as defined in the fifth aspect, and / or the lysate as defined in the sixth aspect, and / or the combination of lysates as defined in the seventh aspect, and / or the composition as defined in the eighth aspect, and / or the medical device as defined in the ninth aspect for use in combination with a further therapeutic agent. In other words, the invention also contemplates the strain of Lactobacillus paracasei as defined in the first aspect; and / or the bacterial culture as defined the second aspect; and / or the microorganism combination as defined in the third aspect; and / or the supernatant as defined in the fourth aspect; and / or the combination of microorganism supernatants as defined in the fifth aspect; and / or the lysate as defined in the sixth aspect; and / or the combination of lysates as defined in the seventh aspect; and / or the composition as defined in the eighth aspect; and / or the medical device as defined in the ninth aspect; in combination with a further therapeutic agent.

[0204] In a more particular embodiment, the further therapeutic agent is selected from the group consisting of an antibiotic, an antifungal, an anti-viral drug, a hormonal treatment, an anti-inflammatory, a fertility treatment, an antibody, a vaccine, and a combination thereof.

[0205] The eleventh aspect of the invention relates to the strain of Lactobacillus paracasei as defined in the first aspect, and / or the bacterial culture as defined the second aspect, and / or the microorganism combination as defined in the third aspect, and / or the supernatant as defined in the fourth aspect, and / or the combination of microorganism supernatants as defined in the fifth aspect, and / or the lysate as defined in the sixth aspect, and / or the combination of lysates as defined in the seventh aspect, and / or the composition as defined in the eighth aspect, and / or the medical device as defined in the ninth aspect, for use in the prevention and / or treatment of female reproductive tract dysbiosis and / or complications thereof.

[0206] As shown in the examples, the strain shows and improved efficacy at a pH close to neutrality. This is of interest in situations where pH reduction is not feasible, and / or where further pH reduction effect is not sufficiently effective.

[0207] Thus, in particular embodiments of the tenth aspect, they are for use when the pH of the reproductive tract is of at least 6.5, at least 7, at least 7.5, or at least 8. In particular the pH is of at least 6.5. In particular the pH is of at least 7. In particular the pH is of around 7.

[0208] It happens that certain dysbiosis and / or infections are not under control even when probiotics are administered, and the pH may fluctuate. In such cases, the invention is beneficial. Thus, in particular embodiments of the tenth aspect, they are for use in recurrent reproductive tract dysbiosis and / or infections and / or complications thereof.

[0209] In a particular embodiment of the eleventh aspect, the dysbiosis cause or etiology is selected from the group consisting of a microorganism infection, pregnancy, drugs and / or antibiotics intake, use of contraceptive, stress, or a combination thereof.

[0210] In another particular embodiment, optionally in combination with any of the embodiments above or below, the dysbiosis is caused by an infection selected from a bacterial infection, a fungal (yeast) infection, a parasite infection, a viral infection, and combinations thereof.

[0211] In another particular embodiment, optionally in combination with any of the embodiments above or below, the dysbiosis is caused by an infection by one or more microorganisms or parasites selected from de genus Gardnerella spp., Streptococcus spp., Candida spp., Trichomonas, Prevotella spp., Mobiluncus spp., Bacteroides spp., Peptostreptococcus spp., Megasphaera spp., Atopobium spp., Dialisterspp., Sneathia spp., Ureaplasma spp., Mycoplasma spp., and Porphyromonas spp.. More in particular, the one or more infective microorganisms or parasites are selected from Gardnerella vaginalis, B group Streptococcus, Candida albicans, Atopobium vaginale Sneathia amnii, Sneathia sanguinegens, Ureaplasma urealyticum, Mycoplasma hominis and Trichomonas vaginalis. More in particular, the infective microorganism is B group Streptococcus.

[0212] In also another particular embodiment, optionally in combination with any of the embodiments above or below, the dysbiosis is coursing with a colonization of female reproductive tract tissue over the levels commonly accepted as healthy of one or more of the following genus of microorganisms Gardnerella spp., Streptococcus spp., Candida spp., Trichomonas, Prevotella spp., Mobiluncus spp., Bacteroides spp., Peptostreptococcus spp., Megasphaera spp., Atopobium spp., Dialisterspp., Sneathia spp., Ureaplasma spp., Mycoplasma spp., and Porphyromonas spp.. More in particular, the one or more microorganisms are selected from Gardnerella vaginalis, B group Streptococcus, Candida albicans, Atopobium vaginale Sneathia amnii, Sneathia sanguinegens, Ureaplasma urealyticum, Mycoplasma hominis and Trichomonas vaginalis. More in particular, the microorganism is B group Streptococcus.

[0213] The skilled person may determine the dysbiosis is coursing with a colonization of female reproductive tract tissue over levels accepted as healthy according to diagnostic methods well known in the state of the art. For example, this may be done, or this is achieved, by using the Nugent score or the Amsel criteria.

[0214] In another particular embodiment of the eleventh aspect, the prevention and / or treatment of female reproductive tract dysbiosis and complications thereof, is for the prevention of recurrences after a previous infection or imbalance of certain microorganisms of the microbiota of the reproductive tract. In a more particular embodiment, it is for the prevention of a recurrence after an infection caused by a bacterium, a virus, a parasite, a fungus, and combinations thereof.

[0215] It is widely known that the microbiota in any tissue in conditions of health is acting in symbiosis or as commensal with the said tissue of the animal in the case of the description, and it also plays a role in avoiding the colonization of pathogenic microorganisms. In the particular case of vaginal microbiota, the amount and type of bacteria present have significant implications for an individual's overall health. In a dysbiosis of any cause, the female reproductive tract is colonized with certain microorganisms that alter these health conditions. Restoration of the microbiota is of huge importance and it is one of the effects of any of the for use in therapy of the strain of Lactobacillus paracasei as defined in the first aspect, and / or the bacterial culture as defined the second aspect, and / or the microorganism combination as defined in the third aspect, and / or the supernatant as defined in the fourth aspect, and / or the combination of microorganism supernatants as defined in the fifth aspect, and / or the lysate as defined in the sixth aspect, and / or the combination of lysates as defined in the seventh aspect, and / or the composition as defined in the eighth aspect, and / or the medical device as defined in the ninth aspect.

[0216] Thus, in another particular embodiment of the eleventh aspect, the prevention and / or treatment of female reproductive tract dysbiosis and complications thereof, is for the restoration of the microbiota of the female reproductive tract. Due to all these effects, the different strains, cultures, combinations, compositions, and supernatants of the aspects first to ninth, and its corresponding embodiments are for use in the prevention and / or treatment of the commonly associated to dysbiosis symptomatology including itching, pain and burning of certain areas, such as the vagina and the vulva.

[0217] In another particular embodiment of the eleventh aspect, the dysbiosis is selected from dysbiosis of the female reproductive tract in pregnant animals, including human; and dysbiosis of the female reproductive tract in non-pregnant animals, including human.

[0218] In a more particular embodiment of the eleventh aspect, the complications of dysbiosis are selected from the group consisting of preterm birth, low birth weight, labor complications, pregnancy complications, infection by sexually transmitted infections (STIs), pelvic inflammatory disease in the uterus and fallopian tubes, infection after gynecologic surgery, and combinations thereof.

[0219] In a more particular embodiment of the eleventh aspect, dysbiosis complications are labor complications, and they are selected from the group consisting of Amniotic fluid embolism, Bleeding, Cord prolapse, Obstructed labour, Placental abruption, Premature labour, Nuchal cord, Perinatal asphyxia, Mechanical fetal injury and Uterine rupture, and combinations thereof.

[0220] In another particular embodiment of the eleventh aspect, dysbiosis complications are pregnancy complications, which are selected from the group consisting of Gestational diabetes, Hyperemesis gravidarum, Pelvic girdle pain, High blood pressure, Venous thromboembolism, Anemia, Infection, Candidiasis, Bacterial vaginosis, Peripartum cardiomyopathy, Hypothyroiditis, Ectopic pregnancy, Miscarriage, Placental abruption, Placenta praevia, Placenta accreta, Multiple pregnancies, Vertically transmitted infection, Intrauterine bleeding, and combinations thereof.

[0221] In a particular embodiment of the strain of Lactobacillus paracasei as defined in the first aspect, and / or the bacterial culture as defined in the second aspect, and / or the microorganism combination as defined in the third aspect, and / or the supernatant as defined in the fourth aspect, and / or the combination of microorganism supernatants as defined in the fifth aspect, and / or the lysate as defined in the sixth aspect, and / or the combination of lysates as defined in the seventh aspect, and / or the composition as defined in the eighth aspect, and / or the medical device as defined in the ninth aspect, for use in the prevention and / or treatment of female reproductive tract dysbiosis and complications thereof, they are for use in the prevention of preterm birth.

[0222] As indicated in the examples, the supernatant of this specie contained compounds (postbiotics) that were able to reduce the preterm birth rate in an animal model. A particular useful combination of supernatants includes the supernatant of the fourth aspect with the supernatant of the strain of Bifidobacterium longum biovar infantis CECT7210.

[0223] The examples below show that a combination of supernatants of these two species of microorganisms were able to reduce the preterm birth percentage at a high extent in an animal model.

[0224] In another particular embodiment of the eleventh aspect, the dysbiosis is in any tissue or organ of the female reproductive tract and selected from the group consisting of the vagina, uterus, Fallopian tubes, ovaries, vulva including the labia, clitoris, and vaginal opening. In a more particular embodiment, the dysbiosis is in the vagina and / or in the vulva.

[0225] The twelfth aspect of the invention relates to the strain, and / or the bacterial culture, and / or the combination of microorganisms, and / or the composition, and / or the medical device, as respectively defined in the first, second, third, eighth and ninth aspects, for use as a probiotic.

[0226] The thirteenth aspect of the invention relates to a supernatant, a combination of supernatants, and / or the lysate as defined in the sixth aspect, and / or the combination of lysates as defined in the seventh aspect, and / or a composition, and / or the medical device, as respectively defined in the first, second, third, fourth, fifth, sixth, seventh, and ninth aspects, for use as a postbiotic.

[0227] The invention also contemplates, as described in the fourteenth aspect, the strain of Lactobacillus paracasei as defined in the first aspect, and / or the bacterial culture as defined the second aspect, and / or the microorganism combination as defined in the third aspect, and / or the supernatant as defined in the fourth aspect, and / or the combination of microorganism supernatants as defined in the fifth aspect, and / or the composition as defined in the eighth aspect, and / or the medical device as defined in the ninth aspect, for use in the prevention and / or treatment of infections, in particular infections of the female reproductive tract, more in particular in any tissue or organ of the female reproductive tract and selected from the group consisting of the vagina, uterus, Fallopian tubes, ovaries, vulva including the labia, clitoris, and vaginal opening. In a more particular embodiment, the infection is in the vagina and / or in the vulva. All embodiments described in the eleventh aspect also apply to this fourteenth aspect. In particular, all embodiments described above regarding infective microorganisms also apply to this fourteenth aspect. In particular, the infection to be prevented or treated is caused by B group Streptococcus.

[0228] According to the eleventh and fourteenth aspects, the strain of Lactobacillus paracasei as defined in the first aspect, and / or the bacterial culture as defined the second aspect, and / or the microorganism combination as defined in the third aspect, and / or the supernatant as defined in the fourth aspect, and / or the combination of microorganism supernatants as defined in the fifth aspect, and / or the composition as defined in the eighth aspect, and / or the medical device as defined in the ninth aspect, for use in the prevention and / or treatment of female reproductive tract dysbiosis, and / or an infection of the female reproductive tract.

[0229] As it is also for use in the prevention of certain events induced by dysbiosis and / or infection of the female reproductive tract: In particular, for use in the prevention of Amniotic fluid embolism, Bleeding, Cord prolapse, Obstructed labour, Placental abruption, Preterm birth, Nuchal cord, Perinatal asphyxia, Mechanical fetal injury, Uterine rupture, and / or combinations thereof. More in particular for use in the prevention of Preterm birth.

[0230] As it is also for use in the treatment and / or prevention of certain conditions conditioned by dysbiosis and / or infection of the female reproductive tract: In particular, it is for use in the prevention and / or treatment of Inflammation in the female reproductive tract, Gestational diabetes, Hyperemesis gravidarum, Pelvic girdle pain, High blood pressure, Venous thromboembolism, Anemia, Infection, Candidiasis, Bacterial vaginosis, Peripartum cardiomyopathy, Hypothyroiditis, Ectopic pregnancy, Miscarriage, Placental abruption, Placenta praevia, Placenta accreta, Multiple pregnancies, Vertically transmitted infection, Intrauterine bleeding, and / or combinations thereof. More in particular, it is for use in the prevention and / or treatment of Inflammation in the female reproductive tract, bacterial vaginosis and / or candidiasis. In particular, Inflammation in the uterus and / or the fallopian tubes. More in particular, it is for use in the prevention and / or treatment of bacterial vaginosis and / or candidiasis. More in particular, it is for use in the prevention and / or treatment of bacterial vaginosis.

[0231] In particular embodiments, wherein the dysbiosis and / or infection cause is B group Streptococcus. In particular embodiments, when the pH of the female reproductive tract is of at least 6.5.

[0232] Throughout the description and claims the word "comprise" and variations of the word, are not intended to exclude other technical features, additives, components, or steps. Furthermore, the word "comprise” encompasses the case of "consisting of'. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples are provided by way of illustration, and they are not intended to be limiting of the present invention. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein.

[0233] For completeness, the present description is also disclosed in the following numbered embodiments: 1 . A Lactobacillus paracasei strain which is deposited in the Coleccion Espanola de Cultivos Tipo (CECT) under the accession number CECT30660, or a mutant or variant thereof.

[0234] 2. A bacterial culture comprising the strain as defined in embodiment 1.

[0235] 3. A microorganism combination comprising the strain of Lactobacillus paracasei as defined in embodiment 1 or the bacterial culture as defined in embodiment 2, in combination with one or more additional microorganism strains or bacterial cultures comprising the additional microorganism strain.

[0236] 4. A supernatant obtainable from the Lactobacillus paracasei strain CECT30660.

[0237] 5. The supernatant according to embodiment 4, which is obtainable by a method comprising the steps of: a) culturing the Lactobacillus paracasei strain CECT30660 in a culture medium under suitable growth conditions, particularly with MRS culture media, without agitation and under anaerobic conditions; and b) separating the culture medium from the Lactobacillus paracasei strain CECT30660, thereby obtaining the culture supernatant.

[0238] 6.- A combination of microorganism supernatants comprising the supernatant as defined in any one of embodiments 4-5, and one or more additional supernatants of one or more additional microorganism strains.

[0239] 7.- The microorganism combination according to embodiment 3 or the combination of microorganism supernatants according to embodiment 6, wherein the one or more additional microorganism strains comprise a strain of Bifidobacterium longum biovar infantis.

[0240] 8.- The microorganism combination or the combination of microorganism supernatants according to embodiment 7, wherein the strain of Bifidobacterium longum biovar infantis is the one deposited in the Coleccion Espanola de Cultivos Tipo (CECT) under the accession number CECT7210, or a mutant or variant thereof.

[0241] 9.- A pharmaceutical, veterinary, nutritional or food composition, comprising a strain of Lactobacillus paracasei as defined in embodiment 1; and / or a bacterial culture as defined in embodiment 2; and / or a microorganism combination as defined in any one of embodiments 3 or 7-8; and / or a supernatant as defined in any one of embodiments 4-5; and / or the combination of microorganism supernatants as defined in any one of embodiments 6-8. 10.- A medical device, comprising a strain of Lactobacillus paracasei as defined in embodiment 1; and / or a bacterial culture as defined in embodiment 2; and / or a microorganism combination as defined in any one of embodiments 3 or 7-8; and / or a supernatant as defined in any one of embodiments 4-5; and / or the combination of microorganism supernatants as defined in any one of embodiments 6-8; and / or the composition as defined in embodiment 9.

[0242] 11 .- A strain of Lactobacillus paracasei as defined in embodiment 1 ; and / or a bacterial culture as defined in embodiment 2; and / or a microorganism combination as defined in any one of embodiments 3 or 7-8; and / or a supernatant as defined in any one of embodiments 4-5; and / or the combination of microorganism supernatants as defined in any one of embodiments 6-8; and / or the composition as defined in embodiment 9; and / or the medical device as defined in embodiment 10; for use as an adjuvant or in combination with a further therapeutic agent.

[0243] 12.- A strain of Lactobacillus paracasei as defined in embodiment 1; and / or a bacterial culture as defined in embodiment 2; and / or a microorganism combination as defined in any one of embodiments 3 or 7-8; and / or a supernatant as defined in any one of embodiments 4-5; and / or the combination of microorganism supernatants as defined in any one of embodiments 6-8; and / or the composition as defined in embodiment 9; and / or the medical device as defined in embodiment 10; for use in therapy.

[0244] 13.- A strain of Lactobacillus paracasei as defined in embodiment 1; and / or a bacterial culture as defined in embodiment 2; and / or a microorganism combination as defined in any one of embodiments 3 or 7-8; and / or a supernatant as defined in any one of embodiments 4-5; and / or the combination of microorganism supernatants as defined in any one of embodiments 6-8; and / or the composition as defined in embodiment 9; and / or the medical device as defined in embodiment 10; for use in the prevention and / or treatment of female reproductive tract dysbiosis and / or complications thereof.

[0245] 14.- A strain of Lactobacillus paracasei as defined in embodiment 1; and / or a bacterial culture as defined in embodiment 2; and / or a microorganism combination as defined in any one of embodiments 3 or 7-8; and / or a supernatant as defined in any one of embodiments 4-5; and / or the combination of microorganism supernatants as defined in any one of embodiments 6-8; and / or the composition as defined in embodiment 9; and / or the medical device as defined in embodiment 10; for use in the prevention and / or treatment of infections of the female reproductive tract and / or complications thereof, particularly caused by Group B Streptococcus.

[0246] 15.- The strain, bacterial culture, microorganism combination, supernatant, combination of microorganism supernatants, or composition, for use according to any one of embodiments 13-14, wherein the dysbiosis or infection or complication thereof is selected from the group consisting of: - dysbiosis or infection or complication thereof of the female reproductive tract in pregnant animals, including human; and

[0247] - dysbiosis or complication thereof of female reproductive tract in non- pregnant animals, including human.

[0248] 16.- The strain, bacterial culture, microorganism combination, supernatant, combination of microorganism supernatants, or composition, for use according to embodiment 15, wherein the complication of dysbiosis or infection is selected from the group consisting of pre-term birth, labor complications, pregnancy complications, and combinations thereof.

[0249] 17. A method to obtain a mutant or variant of Lactobacillus paracasei CECT30660 as defined in embodiment 1, comprising the step of subjecting the Lactobacillus paracasei CECT30660 to a DNA recombinant technique, for example mutagenesis, or to conditions to generate spontaneous mutations, for example UV light or chemical mutagens.

[0250] Examples

[0251] Example 1 . Isolation and characterization of the strain of Lactobacillus paracasei CECT30660 and its strong inhibition of group B Streptococcus.

[0252] From vaginal exudate samples collected with sterile swabs, bacterial colonies were isolated under sterile conditions by seeding them on plates of different culture media (MRS, Tomato and Rogosa Agar). The colonies were selected for the different morphologies observed taking into account shape, surface and edge. The selected colonies were assigned a colony number and incubated at 37°C for 24h. In the event that there was not enough growth, they were allowed to incubate longer, a maximum of 72h.

[0253] With the grown colonies, a gram staining was performed where the gram of the bacteria and the cellular morphology of the bacteria were determined, selecting those colonies that presented morphology of elongated bacilli, with Gram positive.

[0254] DNA was extracted from these colonies and the 16S rRNA gene was amplified using the oligonucleotides:

[0255] 1a (forward): 5’- AATACATGCAAGTCGAACGA-3' (SEQ ID NO: 1)

[0256] 1b (reverse): 5’-TTAACCCAACATCTCACGAC-3’ (SEQ ID NO: 2)

[0257] The sequencing of each amplified fragment allowed the identification of each colony at the genus and species level using the BLASTn bioinformatics application against the NCBI 16S Ribosomal RNA sequences database. The ability of the identified vaginal Lactobacillus to produce L or D-Lactic acid was determined. The determinations of the two lactic acid isomers were performed using the R-Biopharm D-lactic acid / L- lactic acid kit (Boehringer Ingelheim), and UV-method for the determination of D- and L-lactic acid in Food, following the manufacturer's instructions. The obtained results are those of table 1.

[0258] Table 1.

[0259] Lactic acid production data after 18h incubation. Within the same column, the letters represent sets where there are no significant differences between the data according to the Conover-Iman test. Correction p-value = fdr.

[0260] In particular, the CRD0998 (CECT7210) has a 16S Ribosomal RNA gene which is of sequence

[0261] TATGAGAGTTTGATCCTGGCTCAGGATGAACGCTGGCGGCGTGCCTAATACATGCAAGTCGAACGA

[0262] GTTCTCGTTGATGATCGGTGCTTGCACCGAGATTCAACATGGAACGAGTGGCGGACGGGTGAGTA

[0263] ACACGTGGGTAACCTGCCCTTAAGTGGGGGATAACATTTGGAAACAGATGCTAATACCGCATAGAT

[0264] CCAAGAACCGCATGGTTCTTGGCTGAAAGATGGCGTAAGCTATCGCTTTTGGATGGACCCGCGGC

[0265] GTATTAGCTAGTTGGTGAGGTAATGGCTCACCAAGGCGATGATACGTAGCCGAACTGAGAGGTTGA

[0266] TCGGCCACATTGGGACTGAGACACGGCCCAAACTCCTACGGGAGGCAGCAGTAGGGAATCTTCCA

[0267] CAATGGACGCAAGTCTGATGGAGCAACGCCGCGTGAGTGAAGAAGGCTTTCGGGTCGTAAAACTC

[0268] TGTTGTTGGAGAAGAATGGTCGGCAGAGTAACTGTTGTCGGCGTGACGGTATCCAACCAGAAAGC

[0269] CACGGCTAACTACGTGCCAGCAGCCGCGGTAATACGTAGGTGGCAAGCGTTATCCGGATTTATTG

[0270] GGCGTAAAGCGAGCGCAGGCGGTTTTTTAAGTCTGATGTGAAAGCCCTCGGCTTAACCGAGGAAG

[0271] CGCATCGGAAACTGGGAAACTTGAGTGCAGAAGAGGACAGTGGAACTCCATGTGTAGCGGTGAAA

[0272] TGCGTAGATATATGGAAGAACACCAGTGGCGAAGGCGGCTGTCTGGTCTGTAACTGACGCTGAGG

[0273] CTCGAAAGCATGGGTAGCGAACAGGATTAGATACCCTGGTAGTCCATGCCGTAAACGATGAATGCT

[0274] AGGTGTTGGAGGGTTTCCGCCCTTCAGTGCCGCAGCTAACGCATTAAGCATTCCGCCTGGGGAGT ACGACCGCAAGGTTGAAACTCAAAGGAATTGACGGGGGCCCGCACAAGCGGTGGAGCATGTGGTT TAATTCGAAGCAACGCGAAGAACCTTACCAGGTCTTGACATCTTTTGATCACCTGAGAGATCAGGTT TCCCCTTCGGGGGCAAAATGACAGGTGGTGCATGGTTGTCGTCAGCTCGTGTCGTGAGATGTTGG GTTAAGTCCCGCAACGAGCGCAACCCTTATGACTAGTTGCCAGCATTTAGTTGGGCACTCTAGTAA GACTGCCGGTGACAAACCGGAGGAAGGTGGGGATGACGTCAAATCATCATGCCCCTTATGACCTG GGCTACACACGTGCTACAATGGATGGTACAACGAGTTGCGAGACCGCGAGGTCAAGCTAATCTCTT AAAGCCATTCTCAGTTCGGACTGTAGGCTGCAACTCGCCTACACGAAGTCGGAATCGCTAGTAATC GCGGATCAGCACGCCGCGGTGAATACGTTCCCGGGCCTTGTACACACCGCCCGTCACACCATGAG AGTTTGTAACACCCGAAGCCGGTGGCGTAACCCTTTTAGGGAGCGAGCCGTCTAAGGTGGGACAA ATGATTAGGGTGAAGTCGTAACAAGGTAGCCGTAGGAGAACCTGCGGCTGGATCACCTCCTT (SEQ ID NO: 3)

[0275] The lactobacilli of vaginal origin identified were screened to identify those that were capable of inhibiting the growth of Streptococcus agalactiae, for which the pathogen Streptococcus agalactiae was grown in the presence of a small amount of culture supernatant of each of the lactobacilli (grown in MRS medium) previously neutralized to determine the effect of the possible substances produced by the lactobacilli present in each of these supernatants on the growth of the pathogen. The effect of each of the supernatants tested was compared with a control culture of S. agalactiae to which the same amount of MRS was added, also neutralized. The control S. agalactiae growth curves and the S. agalactiae growth curves with each of the neutralized supernatants obtained after the growth of each of the Lactobacillus were performed in 96-well microtiter plates in an EPOCH 2 Biotek spectrophotometer, each growth was carried out in triplicate within each microtiter plate, and 3 independent experiments were carried out for each supernatant obtained. The growth curves of S. agalactiae were obtained by taking OD readings at 600nm of each of the cultures that were in the wells of the microtiter plate every 2h for 32h in a row. The three parameters of the growth of the pathogen in culture were determined with the supernatants of the different lactobacilli as well as the control using the package for R Grofit. growth velocity (pi), lag phase length (A) and maximum cell growth (A) were evaluated. The results obtained are those of table 2.

[0276] Table 2

[0277] Growth velocity (pi) and maximum cell growth (A) standardized regarding control. *: p <0.05. **: p'<0.05 where p’= p / n°Ho Dunn Test (Bonferroni's Correction)

[0278] Example 2. Bacterial culture and supernatant preparations.

[0279] CECT30660 was incubated at 37°C for at least 24 h in MRS medium, without agitation, and under anaerobic conditions. Supernatant was obtained by centrifugation at 3220 g and neutralized with NaOH 10N. Supernatant neutralized was sterilized by filtration using a filter of 0.2 micrometers of porous diameter.

[0280] CECT7210 was incubated at 37°C for at least 24 h in MRS medium with Cystine-HCI 0.05% w / v, without agitation, and under anaerobic conditions. Supernatant was obtained by centrifugation at 3220 g and neutralized with NaOH 10N. Supernatant neutralized was sterilized by filtration using a filter of 0.2 micrometers of porous diameter.

[0281] Example 3. A combination of CECT30660 and CECT7210 postbiotics reduces LPS-induced preterm birth and reduce systemic inflammation in pregnant mice.

[0282] 35 female HSD:ICR (CD-1) outbred mice (8-12 weeks old), were randomly group-housed in cages with 5 mice each; under a temperature-controlled environment (22 ± 2°C); relative humidity (55 ± 10%) and on a 12-hour light / dark cycle with free access to standard food and water. Female CD-1 mice were mated with males during 24h (2 female mice per one male mice in every cage). The morning of vaginal plug detection was designated gestational day 1 (gestational length, 19-20 days) and pregnant CD-1 mice weight was monitored.

[0283] Intrauterine injection of LPS was given by minilaparotomy on gestational day 15, as previously described in different studies. Isoflurane anesthetized mice were given analgesic buprenorphine (0.1 mg / kg), and an incision (approximately 1 cm) was made to expose the lower segments of the uterine horns. Saline solution (100 mL) or 25 pig of LPS {Escherichia coli 055:B5; Sigma-Aldrich, St. Louis, MO) dissolved in 100-mL saline solution was injected between the two lowest gestational sacs of either the left or right uterine horn. Fascia and skin were closed with 4.0 Vicryl sutures and staples, respectively. Mice were housed in individual cages. PTB was defined as the delivery of at least 1 pup within 48 hours of LPS injection. Mice were distributed randomly to receive the treatments at 24h and 30 minutes before the surgery. Mice were injected intraperitoneally with 200 pil saline solution or postbiotic treatment (CECT7210, CECT30660 or MIX of 50 % CECT7210 and 50 % CECT30660; n=10 per group). Mice were checked at 2-hour intervals for signs of PTB (vaginal bleeding, bloody bleeding, or presence of pups) for up to 12 hours after surgery, and every 12 hours thereafter. Animals were monitored until term for the delivery of pups, and the time of delivery was recorded. Before death, maternal blood was collected from anesthetized mice by cardiac puncture, and plasma was obtained by centrifugation at 5000g for 15 min at 40C. The animals were sacrificed with carbon dioxide 8 hours after LPS or NaCI solution intrauterine injection for the collection of amniotic fluid, placental and myometrial tissues. Amniotic fluid was pooled from all gestational sacs and centrifuged to remove any cellular debris. Placental tissue was divided from decidua and fetal membranes in ice-cold phosphate-buffered saline solution and pooled from all fetuses. Myometrium was separated from decidua and endometrium by scraping. All samples were flash-frozen in liquid nitrogen and stored at -80°C.

[0284] Cytokine's concentrations were determined with a mouse cytokine Th17 Panel A 6-plex assay (Bio-Rad Laboratories Inc, Mississauga, Ontario, Canada) on a Luminex 200 cytometer and Bioplex HTF (BioRad Laboratories Inc). This assay measured concentrations of interleukin (IL)-1|3, IL-6, IL-10, IL-17A; I nterferon-y (IFN- y); tumor necrosis alpha a (TNF-a). Data analysis was performed with Bio-Plex Manager software (version 5.0; Bio-Rad Laboratories Inc. Tissues were smashed and homogenized in ethylenediaminetetraacetic acid-free protease inhibitor that contained RIPA lysis buffer (1 ml per 0.5 g of tissue, Thermo Fisher Scientific Inc, Rockford, IL). Homogenized samples were left on ice for 45 minutes before being centrifuged at 12000g for 15 minutes at 4°C to finally collect the supernatant. Protein concentration was measured by Bradford assay kit (Bio-Rad Laboratories Inc.) with BSA as standard. 250 pig of total protein was used for the measurement of cytokines in myometrium and placenta tissues. Cytokines were also analyzed in maternal plasma and amniotic fluid. Maternal plasma progesterone was measured with an Enzyme Immunoassay kit (Cayman Chemical Co, Ann Arbor, Ml). Maternal plasma and amniotic oxytocin were measured with ELISA kit (Cusabio, MD, USA).

[0285] Statistical analyses were performed with IBM SPSS Statistics v26 (IBM Corp., Armonk, NY, USA), using Chi-square test, with one-sided Fisher's exact test for comparison of PTB rate; Cytokines, progesterone and oxytocin concentrations in multiple groups were analyzed with GraphPad Prism 9 software (Graph- Pad Software, La Jolla, CA, USA), using two-way analysis of variance (ANOVA) and Fisher's exact tests for categoric variables. Data are presented as mean ± SEM. Results were expressed as mean of values ± SEM and differences between groups were set up as statistically significant when P value was lower than 0.05. Results

[0286] The combination of CECT7210 and CECT30660 postbiotic supernatants reduced LPS-induced PTB. The effect of the different treatments on PTB was analyzed through percentage of deliver preterm and deliveries on time (FIG. 1). Preterm labor was not induced in animals treated intrauterine and intraperitoneally with saline. On the contrary, animals treated intrauterine with LPS and intraperitoneally with saline produced 100% of premature deliveries (FIG. 1a). Similar results were obtained with the animals treated with the bacterial growth medium MRS by IP and treated intrauterine (NaCI (20%) vs. LPS (85.6%)). MRS+LPS, and CECT7210+LPS reduced slightly the % of preterm delivery. Animals treated by intrauterine with LPS and individually by IP with CECT30660 or CECT7210 presented an effect on preterm deliveries of 71.4% and 85.6%, respectively. Surprisingly, the combination of both postbiotics administered intraperitoneally reduced preterm deliveries by up to 42.8% (FIG. 1a), thus, the deliver on time was of about 60-65 %, more than the addition of observed delivery on time of the treatment with the supernatants of the individual strains. The results of percentage of preterm delivery were contrasted with the results of deliver on time, which were negatively correlated (FIG. 1b).

[0287] Analysis of cytokine inflammation levels and other hormones were performed in a new group of animals treated intrauterine with saline or LPS and injected intraperitoneally with saline or the postbiotic MIX.

[0288] The combination of CECT7210 and CECT30660 postbiotics attenuated LPS-induced plasma cytokines levels.

[0289] The analysis of cytokines levels in the maternal plasma showed that LPS intrauterine injection plus saline IP injection group (LPS group) resulted in a significant increase of the proinflammatory cytokines IL-6 and IL-10 (FIG. 2). Animals treated with intrauterine LPS injection that were treated previously with the mix of postbiotics (MIX+LPS group), both showed an important decrease in levels of IL-6 and TNF- ci. No differences were observed in the IFN- y and IL-17a levels.

[0290] The combination of CECT7210 and CECT30660 postbiotics do not affects the amnionic liquid cytokines levels.

[0291] In the case of amniotic fluid, no significant changes were found in the analysis of cytokines between groups (data not shown).

[0292] The combination of CECT7210 and CECT30660 postbiotics reduces the LPS-induced myometrium cytokines levels.

[0293] The analysis of cytokines levels in the myometrium showed some significant changes in their concentrations (FIG. 3). The MIX group showed an important decrease of IFN-y levels. Treatment with the postbiotic MIX caused a significant decrease on the myometrium cytokine levels of IL-113, IL-6, TNFo, IL-17a compared to LPS group (FIG. 3). The combination of CECT7210 and CECT30660 postbiotics reduces the LPS-induced myometrium cytokines levels.

[0294] The analysis of cytokines levels in the placenta, showed an increased level of IL-1 p and IL-6 after intrauterine LPS treatment (data not shown). However, treatment with MIX injection did not affect IL-1 p and IL-6 placental levels. No significant changes were observed in placental TNF-a levels after different treatments.

[0295] Effect of the combination of CECT7210 and CECT30660 postbiotic supernatants on maternal plasma progesterone concentration.

[0296] Maternal plasma progesterone level was analyzed after different treatments (data not shown). LPS treatment significantly reduced maternal progesterone concentration. Saline group that received CECT7210 and CECT30660 supernatants MIX maintained high concentrations of plasma progesterone in comparison with the saline group without IP treatment. To confirm that these concentrations are identical between groups or the mix supernatant IP injection may cause any effect, a powerful analysis test should be required to demonstrate differences.

[0297] Effect of the combination of CECT7210 and CECT30660 postbiotic supernatants on maternal plasma and amniotic liquid oxytocin concentration.

[0298] Maternal plasma oxytocin and amniotic oxytocin concentration were analyzed after different treatments. MIX+LPS group presented a significant decrease compared to MIX group in maternal plasma oxytocin levels (data not shown). However, no other significant changes were observed between other groups in maternal plasma oxytocin concentration or amniotic oxytocin levels.

[0299] Citation List

[0300] Non-patent literature

[0301] Yang S., Li W., Challis J.R.G., et al. Probiotic Lactobacillus rhamnosus GR-1 supernatant prevents lipopolysaccharide-induced preterm birth and reduces inflammation in pregnant CD-1 mice. American Journal of Obstetrics and Gynecology. 2014;211 :44.e1-44.e12. DOI: https: / / doi.Org / 10.1016 / j.ajog.2014.01.029

[0302] Vitali B., Cruciani F., Baldassarre M.E., et al. Dietary supplementation with probiotics during late pregnancy: outcome on vaginal microbiota and cytokine secretion. BMC Microbiology. 2012; 12:236. DOI: https: / / doi.org / 10.1186 / 1471-2180-12-236

[0303] Zheng J., et al. A taxonomic note on the genus Lactobacillus: Description of 23 novel genera, emended description of the genus Lactobacillus Beijerinck 1901, and union of Lactobacillaceae and Leuconostocaceae. International Journal of Systematic and Evolutionary Microbiology. 2020;70(4). DOI: https: / / doi.Org / 10.1099 / ijsem.0.004107 Yoon S.H., Ha S.M., Lim J., Kwon S. , Chun J. A large-scale evaluation of algorithms to calculate average nucleotide identity. Antonie Van Leeuwenhoek. 2017;110(10):1281— 1286. DOI: https: / / doi.Org / 10.1007 / s 10482-017-0844-4

Claims

Claims1 . A Lactobacillus paracasei strain which is deposited in the Coleccion Espanola de Cultivos Tipo (CECT) under the accession number CECT30660, or a Lactobacillus paracasei strain having a sequence identity of at least 98% with the Lactobactillus paracasei CECT30660.

2. The Lactobacillus paracasei strain according to claim 1, wherein the strain has a Nucleotide Average Identity (ANI) of at least 99.9% with the Lactobactillus paracasei CECT30660.

3. The Lactobacillus paracasei strain according to any one of claims 1-2, wherein the strain is the Lactobacillus paracasei CECT30660 strain.

4. A bacterial culture comprising the strain of Lactobacillus paracasei as defined in any one of claims 1- 3.

5. A supernatant obtainable by a method comprising the steps of: a) culturing the strain of Lactobacillus paracasei as defined in any one of claims 1-3 in a culture medium under suitable growth conditions, particularly with MRS culture media, without agitation and under anaerobic conditions; and b) separating the culture medium from the strain, thereby obtaining the culture supernatant.6.- A combination of- the Lactobacillus paracasei strain as defined in any one of claims 1-3, and / or the bacterial culture as defined in claim 4, and / or the supernatant as defined in claim 5; with- a Bifidobacterium longum biovar infantis strain deposited in the Coleccion Espanola de Cultivos Tipo (CECT) under the accession number CECT7210 or a strain with a sequence identity of at least 98% with the Bifidobacterium longum biovar infantis CECT7210, and / or a bacterial culture comprising a Bifidobacterium longum biovar infantis CECT7210 or a strain with a sequence identity of at least 98% with the Bifidobacterium longum biovar infantis CECT7210, and / or a supernatant obtainable by a method comprising the steps of: a) culturing a Bifidobacterium longum biovar infantis CECT7210 or a strain with a sequence identity of at least 98% with the Bifidobacterium longum biovar infantis CECT7210 in a culture medium under suitable growth conditions, particularly with MRS culture media, without agitation and under anaerobic conditions; and b) separating the culture medium from the Bifidobacterium longum biovar infantis CECT7210 or a strain with a sequence identity of at least 98% with the Bifidobacterium longum biovar infantis CECT7210, thereby obtaining the culture supernatant.7.- The combination according to claim 6, wherein the combination is of the Lactobacillus paracasei strain as defined in any one of claims 1-3 with the Bifidobacterium longum biovar infantis CECT7210 strain, or a strain with a sequence identity of at least 98% with the Bifidobacterium longum biovar infantis CECT7210.8.- The combination according to any one of claims 6-7, wherein the combination is of the Lactobacillus paracasei CECT30660 with the Bifidobacterium longum biovar infantis CECT7210.9.- A pharmaceutical, veterinary, nutritional or food composition, comprising a strain of Lactobacillus paracasei as defined in any one of claims 1-3; and / or a bacterial culture as defined in claim 4; and / or a supernatant as defined in claim 5; and / or the combination as defined in any one of claims 6-8.10.- The composition according to claim 9, wherein the composition further comprises a Bifidobacterium longum biovar infantis CECT7210 or a strain with a sequence identity of at least 98% with the Bifidobacterium longum biovar infantis CECT7210.11 .- The composition according to any one of claims 9-10, wherein the composition is in a form selected from the group consisting of supplement, cream, solution, tablet, capsule, suspension, dispersion, powder, foam, lozenge, chewable candy, candy bar, concentrate, drops, elixir, emulsion, film, gel, granule, chewing gum, jelly, oil, paste, pastille, soap, sponge, suppository, syrup, chewable gelatin, and chewable tablet.12.- A medical device, comprising a strain of Lactobacillus paracasei as defined in any one of claims 1- 3; and / or a bacterial culture as defined in claim 4; and / or a supernatant as defined in claim 5; and / or the combination as defined in any one of claims 6-8; and / or the composition as defined in any one of claims 9-11.13.- The medical device according to claim 12, wherein the medical device is selected from the group consisting of vaginal ovules, vaginal rings, aerosol, applicators with cannula, intrauterine infusion systems, intrauterine devices, vaginal systems, cervical systems, subdermal implants, intrauterine hormone release systems, contraceptive patches, contraceptive sponges and hormone pellets.14.- A strain of Lactobacillus paracasei as defined in any one of claims 1-3; and / or a bacterial culture as defined in claim 4; and / or a supernatant as defined in claim 5; and / or a combination as defined in any one of claims 6-8; and / or a composition as defined in any one of claims 9-11 ; for use in therapy.15.- A strain of Lactobacillus paracasei as defined in any one of claims 1-3; and / or a bacterial culture as defined in claim 4; and / or a supernatant as defined in claim 5; and / or a combination as defined in any one of claims 6-8; and / or a composition as defined in any one of claims 9-11; for use in the prevention and / or treatment of female reproductive tract dysbiosis and / or an infection of the female reproductive tract.16.- The strain, the bacterial culture, the supernatant, the combination, and / or the composition, for use according to claim 15, which is for use in the prevention of Amniotic fluid embolism, Bleeding, Cord prolapse, Obstructed labour, Placental abruption, Preterm birth, Nuchal cord, Perinatal asphyxia, Mechanical fetal injury, Uterine rupture, and / or combinations thereof.17.- The strain, the bacterial culture, the supernatant, the combination, and / or the composition, for use according to claim 16, which is for use in the prevention of Preterm birth.18.- The strain, the bacterial culture, the supernatant, the combination, and / or the composition, for use according to claim 15, which is for use in the prevention and / or treatment of Gestational diabetes, Hyperemesis gravidarum, Pelvic girdle pain, High blood pressure, Venous thromboembolism, Anemia, Infection, Candidiasis, Bacterial vaginosis, Peripartum cardiomyopathy, Hypothyroiditis, Ectopic pregnancy, Miscarriage, Placental abruption, Placenta praevia, Placenta accreta, Multiple pregnancies, Vertically transmitted infection, Intrauterine bleeding, and / or combinations thereof.19.- The strain, the bacterial culture, the supernatant, the combination and / or the composition, for use according to claim 18, which is for use in the prevention and / or treatment of bacterial vaginosis; candidiasis; and / or inflammation of the female reproductive tract, in particular inflammation in the uterus and / or fallopian tubes.20.- The strain, the bacterial culture, the supernatant, the combination and / or the composition, for use according to claim 19, which is for use in the prevention and / or treatment of bacterial vaginosis or candidiasis.21.- The strain, the bacterial culture, the supernatant, the combination, and / or the composition, for use according to claim 20, which is for use in the prevention and / or treatment of bacterial vaginosis.22.- The strain, the bacterial culture, the supernatant, the combination, and / or the composition; for use according to any one of claims 15-21, wherein the dysbiosis and / or infection cause is B group Streptococcus.23.- The strain, the bacterial culture, the supernatant, the combination, or the composition, for use according to any one of claims 15-22, when the pH of the female reproductive tract is of at least 6.5.24.- A strain of Lactobacillus paracasei as defined in any one of claims 1-3; and / or a bacterial culture as defined in claim 4; and / or a supernatant as defined in claim 5; and / or a combination as defined in any one of claims 6-8; and / or a composition as defined in any one of claims 9-11; and / or for use as defined in claim 14; and / or for use as defined in any one of claims 15-23, in combination with a further therapeutic agent.

25. The strain, the bacterial culture, the supernatant, the combination, and / or the composition, in combination according to claim 24, wherein the further therapeutic agent is selected from the group consisting of an antibiotic, an antifungal, an anti-viral drug, a hormonal treatment, an anti-inflammatory, a fertility treatment, an antibody, a vaccine, and a combination thereof.26.- A method to obtain a mutant or variant of Lactobacillus paracasei strain as defined in any one of claims 1-3, comprising the step of subjecting the Lactobacillus paracasei strain to a DNA recombinant technique, for example mutagenesis, or to conditions to generate spontaneous mutations, for example UV light or chemical mutagens.

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