Probiotic composition for improving the immune system and gut function of infants and for treating patent ductus arteriosus

Abstract

This invention relates to compositions for treating or preventing patent ductus arteriosus in infants, particularly premature newborns, comprising Lactobacillus fermentum (… Lactobacillus fermentum ) and Bifidobacterium breve ( Bifidobacterium breve The present invention also relates to compositions for treating or preventing sepsis, improving the immune system and intestinal function.

Description

Technical Field

[0001] This invention relates to methods for improving an infant's immune system and intestinal function, as well as methods for treating or preventing infant immune system diseases, sepsis, necrotizing enterocolitis, and other intestinal diseases and patent ductus arteriosus. Background Technology

[0002] Probiotics are live microorganisms that, when administered in adequate amounts, can provide health benefits to the host. Probiotics can be administered via enteral feeding, such as as a dietary supplement.

[0003] Infants are at risk of developing immune system disorders, such as allergies, asthma, autoimmune diseases, and immunodeficiency diseases. Therefore, there is a need to find alternative and better methods to treat and prevent these immune system disorders in infants.

[0004] Infants also face the risk of intestinal diseases such as infantile colic, functional constipation, functional diarrhea, necrotizing enterocolitis, and gastroenteritis. Therefore, alternative and better methods are needed to treat and prevent infantile intestinal diseases.

[0005] Necrotizing enterocolitis (NUC) is a devastating intestinal disease affecting premature or very low birth weight infants. Symptoms of NUC can include feeding difficulties, abdominal distension, reduced activity, bloody stools, bile vomiting, multiple organ failure, and even death. Therefore, alternative and improved methods are needed to treat and prevent NUC in infants.

[0006] Sepsis is a potentially life-threatening condition that occurs when the body's response to infection damages its own tissues and organs. Therefore, alternative and improved methods are needed to treat and prevent infantile sepsis.

[0007] The ductus arteriosus (DAU) is a vascular structure that connects the two main arteries originating from the heart, linking the proximal descending aorta to the pulmonary artery near the origin of a branch of the left pulmonary artery. The DAU is a vital component of the fetal circulation, diverting cardiac output from the lungs to the placenta to support systemic oxygenation. At birth, placental circulation is clamped and removed, resistance in the pulmonary vascular bed decreases, and the lungs become the source of oxygenation and gas exchange; therefore, the DAU is no longer necessary. In normal full-term infants, the DAU closes in over 90% of cases within 48 hours and reaches 100% within 96 hours. In preterm infants, structural and physiological immaturity of the DAU is associated with delayed closure and an increased likelihood of the DAU remaining open at the equivalent of full-term pregnancy.

[0008] Patent ductus arteriosus (PDA) is a medical condition in which the ductus arteriosus fails to close after birth. Diseases associated with PDA include intraventricular hemorrhage, pulmonary hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis (NEC), and acute kidney injury.

[0009] Patent ductus arteriosus (PDA) closure involves two closely related steps: a functional step (vasoconstriction) and an anatomical step (remodeling). Two molecules play crucial roles in this process: prostaglandin E2 (PGE2) and nitric oxide (NO). During fetal development, the vasodilatory activity of these molecules keeps the PDA open. After delivery, the levels and sensitivity of these molecules decrease in full-term infants, favoring PDA contraction and closure. However, preterm infants are more sensitive to PGE2 and NO than full-term infants, causing a balance to shift towards reduced contraction, leading to patent ductus arteriosus (PDA) in preterm infants. Cyclooxygenase inhibitors, which inhibit PGE2 synthesis, are the most commonly used drugs to promote early closure of the PDA in preterm infants. However, alternative and improved methods are still needed for the treatment and prevention of PDA in infants.

[0010] The following description is intended to illustrate certain features of the invention and is not intended to limit the scope of the invention in any way. Any feature or embodiment of the invention not discussed in the summary section, or the inclusion of one or more features in the summary section, should not be construed as limiting any of the claims.

[0011] It should also be understood that the present invention is not limited to the specific compositions, methods, and experimental conditions described herein, as these compositions, methods, and conditions may vary. It should also be understood that the terminology used herein is for describing specific embodiments only and is not intended to be limiting, as the scope will be defined only by the appended claims.

[0012] Unless the context clearly specifies otherwise, the singular forms “a,” “an,” and “the” as used in this specification and the appended claims include plural references. Thus, for example, a reference to “excipient” includes an excipient known in the art, which will become apparent to those skilled in the art upon reading this invention, etc.

[0013] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Any methods and materials similar to or equivalent to those described herein may be used in the practice or testing of this invention, as it should be understood that modifications and variations are included within the spirit and scope of this invention.

[0014] Any range will be understood to include and disclose every discrete point and subrange within that range. In other words, a range in this disclosure is equivalent to a subset of every possible combination of these discrete values, presented in a concise and easily understood format (i.e., a range). The upper or lower bound of any numerical range can also be replaced by the upper or lower bound of another numerical range, respectively. The upper and lower bounds of a numerical range can also be replaced by the upper and lower bounds described in the embodiments below.

[0015] As used herein, the terms “approximately,” “roughly,” “substantially,” and “significantly” will be understood by those skilled in the art and will vary to some extent depending on the context in which they are used. Where the use of a term is unclear to those skilled in the art given the context in which it is used, “approximately” and “roughly” will mean ±<10% of a particular term, and “substantially” and “significantly” will mean ±>10% of a particular term. “Comprising,” “mainly composed of,” and “consisting of” have their conventional meanings in the art.

[0016] As used herein, the term *Lactobacillus fermentum* (… Lactobacillus fermentum ), fermenting lactobacillus ( Limosilactobacillus fermentum ) and Lactobacillus fermentum ( L. fermentum ) are synonyms. Similarly, the terms *Lactobacillus fermentum* CECT5716, *Lactobacillus fermentum* CECT5716, and *Lactobacillus fermentum* (…) are synonyms. L. fermentum CECT5716 is a synonym. *Lactobacillus fermentatus* is a new name for a bacterial species formerly known as *Lactobacillus fermentatus*, and at the time of writing, both names coexist in the technical field.

[0017] As used herein, the term "Lactobacillus fermentum CECT5716 ( L. fermentum "CECT5716", "CECT5714", "LC40" and "Lc40" all refer to Lactobacillus fermentum CECT5716 ( Lactobacillus fermentum CECT5716), which is synonymous with Lactobacillus fermentum CECT5716.

[0018] As used herein, the term "Bifidobacterium breve CECT7263 ( B. breve "CECT7263", "CECT7267", "BFM26", and "BfM26" all refer to Bifidobacterium breve CECT7263 ( Bifidobacterium breve CECT7263).

[0019] As used in this article, the terms “persistent ductus arteriosus”, “PDA”, “persistent ductus”, and “ductus” are synonyms.

[0020] As used in this article, the term "NEC" refers to necrotizing enterocolitis. Summary of the Invention

[0021] This article provides information containing or including Lactobacillus fermentum ( Limosilactobacillus fermentum (also known as Lactobacillus fermentum) Lactobacillus fermentum ) or Lactobacillus fermentum ( L. fermentum )) and / or Bifidobacterium breve ( B. breve A composition is provided. A method for using said composition to improve, for example, an infant's immune system and intestinal function is also provided. A method for treating, for example, an infant's immune system and intestinal disorders by administering said composition is also provided. In some respects, the infant may be premature. A method for treating patent ductus arteriosus in an infant is also provided. In some respects, the infant may be a newborn. In some respects, the infant may be premature.

[0022] In some aspects, the compositions of the present invention comprise, contain, or are composed of *Lactobacillus fermentum* and / or *Bifidobacterium breve*. In some aspects, the compositions comprise, contain, or are composed of *Lactobacillus fermentum* CECT5716 and / or *Bifidobacterium breve* CECT7263.

[0023] Optionally, *Lactobacillus fermentum* CECT 5716 is a bacterial strain deposited as biological material on June 11, 2002, pursuant to the provisions of the Treaty of Budapest; the depositary institution is the Spanish Center for the Preservation of Type Cultures (COLECCIÓN ESPAÑOLADE CULTIVOS TIPO, CECT), located at Edificio 3 CUE, Parc Científic Universitat de Valencia, Catedrático Agustín Escardino, 9, 46980 Paterna (Valencia), ESPAÑA; the accession number is CECT 5716. The biological material with accession number CECT 5716 is deposited by Biosearch, SAU, CaminoPurchil, 66, 18004 Granada, España. According to the new classification, accession number CECT 5716 refers to a bacterial strain of the genus *Lactobacillus* fermentum (the earlier classification was *Lactobacillus* genus and *Lactobacillus fermentum* species).

[0024] Optionally, *Bifidobacterium breve* CECT 7263 is a bacterial strain deposited as biological material on April 17, 2007, pursuant to the provisions of the Treaty of Budapest; the depositary institution is the Spanish Center for the Preservation of Type Cultures (COLECCIÓN ESPAÑOLADE CULTIVOS TIPO, CECT), located at Universitat de Valencia, Campus de Burjassot, 46100 Burjassot (Valencia) Spain; the accession number is CECT 7263. The biological material with accession number CECT 7263 is deposited by Jesús Jiménez López on behalf of PULEVA BIOTECH, SA, Camino de Purchil, 66, 18004 Granada, Spain. The depositor, PULEVA BIOTECH, SA, is now renamed BIOSEARCH SAU. Accession number 7263 refers to a bacterial strain of the species *Bifidobacterium breve* within the genus *Bifidobacterium*.

[0025] The bacteria may be present either in total quantity or independently in the amount of each strain, wherein the amount of each strain is 1 x 10⁻⁶. 3 CFU up to 1x10 12 CFU, 1x10 4 CFU up to 1x10 10 CFU, 1x 10 5 CFU up to 1x 10 9 CFU, 1x10 6 CFU up to 1x10 8 CFU, 1x10 7 CFU up to 1x10 8 CFU, approximately 1x10 3 CFU, approximately 1x10 4 CFU, approximately 1x10 5 CFU, approximately 1x10 6 CFU, approximately 1x10 7 CFU, approximately 1x10 8 CFU, approximately 1x10 9 CFU, approximately 1x10 10 CFU, approximately 1x10 11 CFU or approximately 1x10 12 CFU. In some embodiments, the composition comprises Lactobacillus fermentum, optionally Lactobacillus fermentum CECT5716, in an amount of 1 x 10⁻⁶. 3 CFU up to 1x10 12 CFU, 1x10 4CFU up to 1x10 10 CFU, 1x 10 5 CFU up to 1x 10 9 CFU, 1x10 6 CFU up to 1x10 8 CFU, 1x10 7 CFU up to 1x10 8 CFU, approximately 1x10 3 CFU, approximately 1x10 4 CFU, approximately 1x10 5 CFU, approximately 1x10 6 CFU, approximately 1x10 7 CFU, approximately 1x10 8 CFU, approximately 1x10 9 CFU, approximately 1x10 10 CFU, approximately 1x10 11 CFU or approximately 1x10 12 CFU. In some embodiments, the composition comprises Bifidobacterium breve, optionally Bifidobacterium breve CECT7263, in an amount of 1 x 10⁻⁶. 3 CFU up to 1x10 12 CFU, 1x10 4 CFU up to 1x10 10 CFU, 1x 10 5 CFU up to 1x10 9 CFU, 1x10 6 CFU up to 1x10 8 CFU, 1x10 7 CFU up to 1x10 8 CFU, approximately 1x10 3 CFU, approximately 1x10 4 CFU, approximately 1x10 5 CFU, approximately 1x10 6 CFU, approximately 1x10 7 CFU, approximately 1x10 8 CFU, approximately 1x10 9 CFU, approximately 1x10 10 CFU, approximately 1x10 11 CFU or approximately 1x10 12 CFU. In some embodiments, the composition comprises Lactobacillus fermentum, optionally Lactobacillus fermentum CECT5716, and Bifidobacterium breve, optionally Bifidobacterium breve CECT7263, in a total amount of 1 x 10⁻⁶ CFU. 3 CFU up to 1x10 12 CFU, 1x10 4 CFU up to 1x10 10CFU, 1x 10 5 CFU up to 1x 10 9 CFU, 1x10 6 CFU up to 1x10 8 CFU, 1x10 7 CFU up to 1x10 8 CFU, approximately 1x10 3 CFU, approximately 1x10 4 CFU, approximately 1x10 5 CFU, approximately 1x10 6 CFU, approximately 1x10 7 CFU, approximately 1x10 8 CFU, approximately 1x10 9 CFU, approximately 1x10 10 CFU, approximately 1x10 11 CFU or approximately 1x10 12 CFU.

[0026] The amounts of Lactobacillus fermentum and Bifidobacterium breve in the composition may be the same or different. In some embodiments, the composition effectively contains only one of Lactobacillus fermentum or Bifidobacterium breve.

[0027] In some embodiments, the composition comprises Lactobacillus fermentum, optionally Lactobacillus fermentum CECT5716, at a concentration of 1 x 10⁻⁶. 3 CFU / ml up to 1x10 12 CFU / ml, 1x10 4 CFU / ml up to 1x10 10 CFU / ml, 1x 10 5 CFU / ml to 1x 10 9 CFU / ml, 1x10 6 CFU / ml up to 1x10 8 CFU / ml, 1x10 7 CFU / ml up to 1x10 8 CFU / ml, approximately 1x10 3 CFU / ml, approximately 1x10 4 CFU / ml, approximately 1x10 5 CFU / ml, approximately 1x10 6 CFU / ml, approximately 1x10 7 CFU / ml, approximately 1x10 8 CFU / ml, approximately 1x10 9 CFU / ml, approximately 1x10 10 CFU / ml, approximately 1x10 11 CFU / ml or approximately 1x10 12CFU / ml. In some embodiments, the composition comprises Bifidobacterium breve, optionally Bifidobacterium breve CECT7263, at a concentration of 1x10⁻⁶. 3 CFU / ml up to 1x10 12 CFU / ml, 1x10 4 CFU / ml up to 1x10 10 CFU / ml, 1x 10 5 CFU / ml to 1x 10 9 CFU / ml, 1x10 6 CFU / ml up to 1x10 8 CFU / ml, 1x10 7 CFU / ml up to 1x10 8 CFU / ml, approximately 1x10 3 CFU / ml, approximately 1x10 4 CFU / ml, approximately 1x10 5 CFU / ml, approximately 1x10 6 CFU / ml, approximately 1x10 7 CFU / ml, approximately 1x10 8 CFU / ml, approximately 1x10 9 CFU / ml, approximately 1x10 10 CFU / ml, approximately 1x10 11 CFU / ml or approximately 1x10 12 CFU / ml. In some embodiments, the composition comprises *Lactobacillus fermentum*, optionally *Lactobacillus fermentum* CECT5716, and *Bifidobacterium breve*, optionally *Bifidobacterium breve* CECT7263, at a total concentration of 1 x 10⁻⁶ CFU / ml. 3 CFU / ml up to 1x10 12 CFU / ml, 1x10 4 CFU / ml up to 1x10 10 CFU / ml, 1x 10 5 CFU / ml to 1x 10 9 CFU / ml, 1x10 6 CFU / ml up to 1x10 8 CFU / ml, 1x10 7 CFU / ml up to 1x10 8 CFU / ml, approximately 1x10 3 CFU / ml, approximately 1x10 4 CFU / ml, approximately 1x10 5 CFU / ml, approximately 1x10 6 CFU / ml, approximately 1x10 7 CFU / ml, approximately 1x10 8CFU / ml, approximately 1x10 9 CFU / ml, approximately 1x10 10 CFU / ml, approximately 1x10 11 CFU / ml or approximately 1x10 12 CFU / ml.

[0028] The concentrations of Lactobacillus fermentum and Bifidobacterium breve in the composition may be the same or different from each other. In some embodiments, the composition effectively contains only one of Lactobacillus fermentum or Bifidobacterium breve.

[0029] For example, the composition may contain or include suitable carriers, excipients, additives, flavoring agents, nutritional additives, and other ingredients. In some embodiments, the composition contains maltodextrin. Optionally, the composition contains maltodextrin in amounts of 100 mg to 500 mg, 150 mg to 450 mg, 200 mg to 400 mg, 250 mg to 350 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg. Preferably, the composition contains about 300 mg of maltodextrin. In some embodiments, the composition comprises maltodextrin at concentrations of 100 mg / ml to 500 mg / ml, 150 mg / ml to 450 mg / ml, 200 mg / ml to 400 mg / ml, 250 mg / ml to 350 mg / ml, about 100 mg / ml, about 150 mg / ml, about 200 mg / ml, about 250 mg / ml, about 300 mg / ml, about 350 mg / ml, about 400 mg / ml, about 450 mg / ml, or about 500 mg / ml. Preferably, the composition comprises about 300 mg / ml of maltodextrin.

[0030] In some embodiments, bacteria may be included in the nutrient composition. In some embodiments, the composition may contain or include one or more additional bacterial strains.

[0031] For example, the composition may be in the form of a liquid, dispersion, suspension, or emulsion. For example, the composition may be in a solid form, such as a powder, granules, capsule, tablet, etc.

[0032] For example, the composition can be administered in combination or mixed with breast milk or infant formula or other forms suitable for the administration of probiotics to infants. In some aspects, the composition can be administered, for example, via enteral feeding, such as through a nasogastric tube or orally.

[0033] In some aspects, the compositions of the present invention can be administered, for example, to infants to improve one or both of the immune system and / or intestinal function, and / or the compositions can be used to treat one or both of immune system disorders and / or intestinal disorders. In some aspects, for example, the compositions of the present invention can be administered to treat patent ductus arteriosus.

[0034] For example, the infant disclosed herein can be 1 year old or a newborn. The infant can also be a premature infant. In some embodiments, the gestational age of the premature newborn is less than or equal to about 32 weeks. In some embodiments, the infant's birth weight can be, for example, about 1500 grams (g) or less. In some embodiments, the infant's birth weight can be in the range of about 700 grams to about 1500 grams. Optionally, the infant's birth weight can be in the range of 300 grams to 5000 grams, 400 grams to 4000 grams, 500 grams to 3000 grams, 600 grams to 2000 grams, 700 grams to 1500 grams, 800 grams to 1200 grams, or 900 grams to 1000 grams. Optionally, the infant's birth weight is about 300 grams, about 400 grams, about 500 grams, about 600 grams, about 700 grams, about 800 grams, about 900 grams, about 1000 grams, about 1100 grams, about 1200 grams, about 1300 grams, about 1400 grams, about 1500 grams, about 1600 grams, about 2000 grams, about 3000 grams, about 4000 grams, or about 5000 grams. Preferably, the infant's birth weight is in the range of about 700 grams to about 1500 grams.

[0035] In one aspect, the compositions of the present invention can be administered, for example, to infants to achieve intestinal colonization of the bacterial strains or compositions of the present invention. For example, the compositions can be administered to infants whose gastrointestinal tract contains insufficient or determined amounts of Lactobacillus fermentum or Bifidobacterium breve.

[0036] In some respects, for example, each bacterial strain can be applied independently at a rate of at least 1 x 10⁻⁶ per day. 7 CFU, at least 1x10 daily 8 CFU, at least 1x10 daily 9 CFU, at least 1x10 daily 10 CFU, at least 1x10 daily 11 CFU, at least 1x10 daily 12 CFU, approximately 1x10 per day 7 CFU, approximately 1x10 per day 8 CFU, approximately 1x10 per day 9 CFU, approximately 1x10 per day 10 CFU, approximately 1x10 per day 11 CFU, approximately 1x10 per day 12 CFU.

[0037] For example, the compositions of the present invention can be administered with each feeding of the infant, or according to other suitable protocols, such as once or more daily, or several times a week. A suitable frequency of administration of the composition can be determined, and the frequency of administration can be varied to achieve, for example, optimal improvement of the immune system and / or intestinal function, and / or symptom improvement, and / or tolerability and other factors.

[0038] For example, the compositions of the present invention can be used in infants exhibiting necrotizing enterocolitis (NEC), sepsis, or patent ductus arteriosus (also referred to herein as a persistent duct). For example, the compositions of the present invention can be administered to reduce the need for treatment with one or more positive inotropic drugs (also referred to herein as inotropics).

[0039] Some embodiments of the present invention include a composition comprising Lactobacillus fermentum ( L. fermentum ) and / or Bifidobacterium breve ( B. breve Optionally, *Lactobacillus fermentum* is *Lactobacillus fermentum* strain CECT5716, and / or *Bifidobacterium breve* is *Bifidobacterium breve* strain CECT7263. Optionally, the composition contains at least 1 x 10⁻⁶. 3 CFU Lactobacillus fermentum CECT5716 and / or the composition comprising at least 1x10 3 CFU (Bifidobacterium breve) CECT7263. Optionally, the composition contains at least 1 x 10⁻⁶ CFU / mL. 6 CFU Lactobacillus fermentum CECT5716 and / or the composition comprising at least 1x10 6 CFU (Bifidobacterium breve) CECT7263. Optionally, the composition contains at least 1 x 10⁻⁶ CFU / mL. 9 CFU Lactobacillus fermentum CECT5716 and / or the composition comprising at least 1x10 9 CFU (Bifidobacterium breve) CECT7263. Optionally, the composition contains at least 1 x 10⁻⁶ CFU / mL. 12 CFU Lactobacillus fermentum CECT5716 and / or the composition comprising at least 1x10 12 CFU of Bifidobacterium breve CECT7263. Optionally, the composition comprises a total amount of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the total amount is at least 1 x 10⁻⁶. 3 CFU. Optionally, the composition comprises a total amount of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the total amount is at least 1 x 10⁻⁶ CFU. 6CFU. Optionally, the composition comprises a total amount of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the total amount is at least 2 x 10⁻⁶ CFU. 6 CFU. Optionally, the composition comprises a total amount of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the total amount is at least 1 x 10⁻⁶ CFU. 9 CFU. Optionally, the composition comprises a total amount of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the total amount is at least 2 x 10⁻⁶ CFU. 9 CFU. Optionally, the composition comprises a total amount of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the total amount is at least 1 x 10⁻⁶ CFU. 12 CFU. Optionally, the composition comprises a total amount of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the total amount is at least 2 x 10⁻⁶ CFU. 12 CFU. Optionally, the volume of the composition is 1 ml. Optionally, the composition contains at least 1 x 10 CFU. 3 Lactobacillus fermentum CECT5716 at a concentration of CFU / ml and / or the composition thereof contains at least 1 x 10 3 CFU / ml concentration of Bifidobacterium breve CECT7263. Optionally, the composition contains at least 1 x 10 6 Lactobacillus fermentum CECT5716 at a concentration of CFU / ml and / or the composition thereof contains at least 1 x 10 6 CFU / ml concentration of Bifidobacterium breve CECT7263. Optionally, the composition contains at least 1 x 10 9 Lactobacillus fermentum CECT5716 at a concentration of CFU / ml and / or the composition thereof contains at least 1 x 10 9 CFU / ml concentration of Bifidobacterium breve CECT7263. Optionally, the composition contains at least 1 x 10 12 Lactobacillus fermentum CECT5716 at a concentration of CFU / ml and / or the composition thereof contains at least 1 x 10 12 CFU / ml concentration of Bifidobacterium breve CECT7263. Optionally, the composition comprises a combined total concentration of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the combined total concentration is at least 1 x 10⁻⁶ CFU / ml. 3 CFU / ml. Optionally, the composition comprises a combined total concentration of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the combined total concentration is at least 2 x 10⁻⁶ CFU / ml. 3CFU / ml. Optionally, the composition comprises a combined total concentration of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the combined total concentration is at least 1 x 10⁻⁶ CFU / ml. 6 CFU / ml. Optionally, the composition comprises a combined total concentration of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the combined total concentration is at least 2 x 10⁻⁶ CFU / ml. 6 CFU / ml. Optionally, the composition comprises a combined total concentration of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the combined total concentration is at least 1 x 10⁻⁶ CFU / ml. 9 CFU / ml. Optionally, the composition comprises a combined total concentration of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the combined total concentration is at least 2 x 10⁻⁶ CFU / ml. 9 CFU / ml. Optionally, the composition comprises a combined total concentration of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the combined total concentration is at least 1 x 10⁻⁶ CFU / ml. 12 CFU / ml. Optionally, the composition comprises a combined total concentration of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the combined total concentration is at least 2 x 10⁻⁶ CFU / ml. 12 CFU / ml. Optionally, the composition is in a form that is nutritionally acceptable for infants. Optionally, the composition is in a form suitable for enteral feeding of infants, such as via nasogastric tube or oral administration.

[0040] Some embodiments of the present invention include a composition for a method of treating or preventing patent ductus arteriosus in an infant, wherein the method includes applying the composition to the infant, and wherein the composition is any composition of the present invention. For example, in some embodiments, the composition comprises *Lactobacillus fermentum*, optionally *Lactobacillus fermentum* CECT5716, and / or *Bifidobacterium breve*, optionally *Bifidobacterium breve* CECT7263. Optionally, the composition contains at least 1 x 10⁻⁶. 3 CFU, optional, at least 1x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 1x10 12 The CFU of Lactobacillus fermentum CECT5716 and / or the composition comprises at least 1 x 10 3 CFU, optional, at least 1x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 1x10 12CFU of Bifidobacterium breve CECT7263. Optionally, the composition comprises a combined total amount of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the combined total amount is at least 1 x 10⁻⁶. 3 CFU, optional, at least 2x10 3 CFU, optional, at least 1x10 6 CFU, optional, at least 2x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 2x10 9 CFU, optional, at least 1x10 12 CFU, optional, at least 2x10 12 CFU. Optionally, the volume of the composition is 1 ml. Optionally, the composition contains a concentration of at least 1 x 10⁻⁶ CFU. 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 1x10 12 CFU / ml of Lactobacillus fermentum CECT5716; and / or the composition contains at least 1 x 10 .... 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 1x10 12 CFU / ml of Bifidobacterium breve CECT7263. Optionally, the composition comprises a mixed total concentration of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the mixed total concentration is at least 1 x 10⁻⁶ CFU / ml. 3 CFU / ml, optionally at least 2 x 10 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 2 x 10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 2 x 10 9 CFU / ml, optionally at least 1x10 12 CFU / ml, optionally at least 2 x 10 12CFU / ml. Optionally, the composition is in a form nutritionally acceptable to the infant. Optionally, the composition is in a form suitable for enteral feeding (e.g., via nasogastric tube or oral administration). Optionally, the composition for the treatment or prevention of patent ductus arteriosus is used for an infant with sepsis. Optionally, the infant is a newborn. Optionally, the infant is a preterm infant. Further, optionally, or additionally, the method comprises administering the composition to the infant once daily. Optionally, the method comprises administering the composition to the infant via enteral feeding, such as via nasogastric tube or oral administration. Optionally, the method comprises administering the composition to the infant along with food; for example, breast milk, milk bank donation milk, infant formula or formula milk, and / or artificial formula for preterm infants. Preferably, the method comprises administering the infant a constant daily volume of the composition and a volume of food varying according to the infant's weight. Most preferably, the method comprises administering 1 ml of the composition and an equivalent volume of food of 5 ml per 1 kg of infant body weight daily to the infant. Optionally, the method includes applying the composition to the infant in a composition:food ratio of 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:9, 1:10, 1:15, 1:20 and / or 1:25.

[0041] A preferred embodiment of the present invention includes a composition for a method of treating or preventing patent ductus arteriosus in preterm infants; wherein the method comprises administering the composition once daily via enteral feeding to the infant together with food such as breast milk, milk bank donation milk, infant formula or formula milk powder and / or artificial formula for preterm infants; wherein the composition contains at least 1 x 10 9 CFU (Cytobacterium fermentum) CECT5716, and the composition comprises at least 1 x 10 9 CFU Bifidobacterium breve CECT7263.

[0042] Some embodiments of the present invention include a composition for a method of treating or preventing necrotizing enterocolitis in infants, wherein the method includes administering the composition to an infant, and wherein the composition is any composition of the present invention. For example, in some embodiments, the composition comprises *Lactobacillus fermentum*, optionally *Lactobacillus fermentum* CECT5716, and / or *Bifidobacterium breve*, optionally *Bifidobacterium breve* CECT7263. Optionally, the composition contains at least 1 x 10⁻⁶. 3 CFU, optional, at least 1x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 1x10 12The CFU of Lactobacillus fermentum CECT5716 and / or the composition comprises at least 1 x 10 3 CFU, optional, at least 1x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 1x10 12 CFU of Bifidobacterium breve CECT7263. Optionally, the composition comprises a combined total amount of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the combined total amount is at least 1 x 10⁻⁶. 3 CFU, optional, at least 2x10 3 CFU, optional, at least 1x10 6 CFU, optional, at least 2x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 2x10 9 CFU, optional, at least 1x10 12 CFU, optional, at least 2x10 12 CFU. Optionally, the volume of the composition is 1 ml. Optionally, the composition contains a concentration of at least 1 x 10⁻⁶ CFU. 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 1x10 12 CFU / ml of Lactobacillus fermentum CECT5716; and / or the composition contains at least 1 x 10 .... 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 1x10 12 CFU / ml of Bifidobacterium breve CECT7263. Optionally, the composition comprises a mixed total concentration of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the mixed total concentration is at least 1 x 10⁻⁶ CFU / ml. 3 CFU / ml, optionally at least 2 x 10 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 2 x 10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 2 x 10 9 CFU / ml, optionally at least 1x10 12 CFU / ml, optionally at least 2 x 10 12CFU / ml. Optionally, the composition is in a form nutritionally acceptable to the infant. Optionally, the composition is in a form suitable for enteral feeding of the infant (e.g., via nasogastric tube or oral administration). Optionally, the infant is a newborn. Optionally, the infant is a preterm infant. Further, optionally, or additionally, the method includes administering the composition to the infant once daily. Optionally, the method includes administering the composition to the infant via enteral feeding, such as via nasogastric tube or oral administration. Optionally, the method includes administering the composition to the infant along with food; for example, breast milk, milk bank donation milk, infant formula or formula milk, and / or artificial formula for preterm infants. Preferably, the method includes administering a constant daily volume of the composition and a volume of food varying according to the infant's weight. Most preferably, the method includes administering 1 ml of the composition and an equivalent volume of food of 5 ml per 1 kg of infant body weight to the infant daily. Optionally, the method includes applying the composition to the infant in a composition:food ratio of 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:9, 1:10, 1:15, 1:20 and / or 1:25.

[0043] Some embodiments of the present invention include compositions for methods of treating or preventing infantile sepsis, wherein the method includes administering the composition to an infant, and wherein the composition is any composition of the present invention. For example, in some embodiments, the composition comprises *Lactobacillus fermentum*, optionally *Lactobacillus fermentum* CECT5716, and / or *Bifidobacterium breve*, optionally *Bifidobacterium breve* CECT7263. Optionally, the composition contains at least 1 x 10⁻⁶. 3 CFU, optional, at least 1x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 1x10 12 The CFU of Lactobacillus fermentum CECT5716 and / or the composition comprises at least 1 x 10 3 CFU, optional, at least 1x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 1x10 12 CFU of Bifidobacterium breve CECT7263. Optionally, the composition comprises a combined total amount of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the combined total amount is at least 1 x 10⁻⁶. 3 CFU, optional, at least 2x10 3 CFU, optional, at least 1x10 6 CFU, optional, at least 2x106 CFU, optional, at least 1x10 9 CFU, optional, at least 2x10 9 CFU, optional, at least 1x10 12 CFU, optional, at least 2x10 12 CFU. Optionally, the volume of the composition is 1 ml. Optionally, the composition contains a concentration of at least 1 x 10⁻⁶ CFU. 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 1x10 12 CFU / ml of Lactobacillus fermentum CECT5716; and / or the composition contains at least 1 x 10 .... 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 1x10 12 CFU / ml of Bifidobacterium breve CECT7263. Optionally, the composition comprises a mixed total concentration of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the mixed total concentration is at least 1 x 10⁻⁶ CFU / ml. 3 CFU / ml, optionally at least 2 x 10 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 2 x 10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 2 x 10 9 CFU / ml, optionally at least 1x10 12 CFU / ml, optionally at least 2 x 10 12CFU / ml. Optionally, the composition is in a nutritionally acceptable form for an infant. Optionally, the composition is in a form suitable for enteral feeding of an infant (e.g., via nasogastric tube or oral administration). Optionally, the infant is a newborn. Optionally, the infant is a preterm infant. Further, optionally, or additionally, the method comprises administering the composition to the infant once daily. Optionally, the method comprises administering the composition to the infant via enteral feeding, such as via nasogastric tube or oral administration. Optionally, the method comprises administering the composition to the infant along with food; such as breast milk, milk bank donation milk, infant formula or formula milk, and / or artificial formula for preterm infants. Preferably, the method comprises administering the infant a constant daily volume of the composition and a volume of food varying according to the infant's weight. Most preferably, the method comprises administering 1 ml of the composition and an equivalent volume of food of 5 ml per 1 kg of infant body weight daily to the infant. Optionally, the method includes applying the composition to the infant in a composition:food ratio of 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:9, 1:10, 1:15, 1:20 and / or 1:25.

[0044] Some embodiments of the present invention include a composition for a method of treating or preventing infantile immune system diseases, wherein the method includes administering the composition to an infant, and wherein the composition is any composition of the present invention. For example, in some embodiments, the composition comprises *Lactobacillus fermentum*, optionally *Lactobacillus fermentum* CECT5716, and / or *Bifidobacterium breve*, optionally *Bifidobacterium breve* CECT7263. Optionally, the composition contains at least 1 x 10⁻⁶. 3 CFU, optional, at least 1x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 1x10 12 The CFU of Lactobacillus fermentum CECT5716 and / or the composition comprises at least 1 x 10 3 CFU, optional, at least 1x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 1x10 12 CFU of Bifidobacterium breve CECT7263. Optionally, the composition comprises a combined total amount of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the combined total amount is at least 1 x 10⁻⁶. 3 CFU, optional, at least 2x10 3 CFU, optional, at least 1x10 6 CFU, optional, at least 2x106 CFU, optional, at least 1x10 9 CFU, optional, at least 2x10 9 CFU, optional, at least 1x10 12 CFU, optional, at least 2x10 12 CFU. Optionally, the volume of the composition is 1 ml. Optionally, the composition contains a concentration of at least 1 x 10⁻⁶ CFU. 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 1x10 12 CFU / ml of Lactobacillus fermentum CECT5716; and / or the composition contains at least 1 x 10 .... 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 1x10 12 CFU / ml of Bifidobacterium breve CECT7263. Optionally, the composition comprises a mixed total concentration of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the mixed total concentration is at least 1 x 10⁻⁶ CFU / ml. 3 CFU / ml, optionally at least 2 x 10 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 2 x 10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 2 x 10 9 CFU / ml, optionally at least 1x10 12 CFU / ml, optionally at least 2 x 10 12CFU / ml. Optionally, the composition is in a nutritionally acceptable form for an infant. Optionally, the composition is in a form suitable for enteral feeding of an infant (e.g., via nasogastric tube or oral administration). Optionally, the infant is a newborn. Optionally, the infant is a preterm infant. Further, optionally, or additionally, the method comprises administering the composition to the infant once daily. Optionally, the method comprises administering the composition to the infant via enteral feeding, such as via nasogastric tube or oral administration. Optionally, the method comprises administering the composition to the infant along with food; such as breast milk, milk bank donation milk, infant formula or formula milk, and / or artificial formula for preterm infants. Preferably, the method comprises administering the infant a constant daily volume of the composition and a volume of food varying according to the infant's weight. Most preferably, the method comprises administering 1 ml of the composition and an equivalent volume of food of 5 ml per 1 kg of infant body weight daily to the infant. Optionally, the method includes applying the composition to the infant in a composition:food ratio of 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:9, 1:10, 1:15, 1:20 and / or 1:25.

[0045] Some embodiments of the present invention include compositions for methods of treating or preventing intestinal diseases in infants, wherein the method includes applying the composition to an infant, and wherein the composition is any composition of the present invention. For example, in some embodiments, the composition comprises *Lactobacillus fermentum*, optionally *Lactobacillus fermentum* CECT5716, and / or *Bifidobacterium breve*, optionally *Bifidobacterium breve* CECT7263. Optionally, the composition contains at least 1 x 10⁻⁶. 3 CFU, optional, at least 1x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 1x10 12 The CFU of Lactobacillus fermentum CECT5716 and / or the composition comprises at least 1 x 10 3 CFU, optional, at least 1x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 1x10 12 CFU of Bifidobacterium breve CECT7263. Optionally, the composition comprises a combined total amount of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the combined total amount is at least 1 x 10⁻⁶. 3 CFU, optional, at least 2x10 3 CFU, optional, at least 1x10 6 CFU, optional, at least 2x106 CFU, optional, at least 1x10 9 CFU, optional, at least 2x10 9 CFU, optional, at least 1x10 12 CFU, optional, at least 2x10 12 CFU. Optionally, the volume of the composition is 1 ml. Optionally, the composition contains a concentration of at least 1 x 10⁻⁶ CFU. 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 1x10 12 CFU / ml of Lactobacillus fermentum CECT5716; and / or the composition contains at least 1 x 10 .... 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 1x10 12 CFU / ml of Bifidobacterium breve CECT7263. Optionally, the composition comprises a mixed total concentration of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the mixed total concentration is at least 1 x 10⁻⁶ CFU / ml. 3 CFU / ml, optionally at least 2 x 10 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 2 x 10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 2 x 10 9 CFU / ml, optionally at least 1x10 12 CFU / ml, optionally at least 2 x 10 12CFU / ml. Optionally, the composition is in a nutritionally acceptable form for an infant. Optionally, the composition is in a form suitable for enteral feeding of an infant (e.g., via nasogastric tube or oral administration). Optionally, the infant is a newborn. Optionally, the infant is a preterm infant. Further, optionally, or additionally, the method comprises administering the composition to the infant once daily. Optionally, the method comprises administering the composition to the infant via enteral feeding, such as via nasogastric tube or oral administration. Optionally, the method comprises administering the composition to the infant along with food; such as breast milk, milk bank donation milk, infant formula or formula milk, and / or artificial formula for preterm infants. Preferably, the method comprises administering the infant a constant daily volume of the composition and a volume of food varying according to the infant's weight. Most preferably, the method comprises administering 1 ml of the composition and an equivalent volume of food of 5 ml per 1 kg of infant body weight daily to the infant. Optionally, the method includes applying the composition to the infant in a composition:food ratio of 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:9, 1:10, 1:15, 1:20 and / or 1:25.

[0046] Some embodiments of the present invention include a method for treating or preventing patent ductus arteriosus in an infant, wherein the method includes administering the composition to the infant, and wherein the composition is any composition of the present invention. For example, in some embodiments, the composition comprises *Lactobacillus fermentum*, optionally *Lactobacillus fermentum* CECT5716, and / or *Bifidobacterium breve*, optionally *Bifidobacterium breve* CECT7263. Optionally, the composition comprises at least 1 x 10⁻⁶. 3 CFU, optional, at least 1x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 1x10 12 The CFU of Lactobacillus fermentum CECT5716 and / or the composition comprises at least 1 x 10 3 CFU, optional, at least 1x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 1x10 12 CFU of Bifidobacterium breve CECT7263. Optionally, the composition comprises a combined total amount of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the combined total amount is at least 1 x 10⁻⁶. 3 CFU, optional, at least 2x10 3 CFU, optional, at least 1x10 6 CFU, optional, at least 2x10 6CFU, optional, at least 1x10 9 CFU, optional, at least 2x10 9 CFU, optional, at least 1x10 12 CFU, optional, at least 2x10 12 CFU. Optionally, the volume of the composition is 1 ml. Optionally, the composition contains a concentration of at least 1 x 10⁻⁶ CFU. 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 1x10 12 CFU / ml of Lactobacillus fermentum CECT5716; and / or the composition contains at least 1 x 10 .... 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 1x10 12 CFU / ml of Bifidobacterium breve CECT7263. Optionally, the composition comprises a mixed total concentration of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the mixed total concentration is at least 1 x 10⁻⁶ CFU / ml. 3 CFU / ml, optionally at least 2 x 10 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 2 x 10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 2 x 10 9 CFU / ml, optionally at least 1x10 12 CFU / ml, optionally at least 2 x 10 12CFU / ml. Optionally, the composition is in a form nutritionally acceptable to the infant. Optionally, the composition is in a form suitable for enteral feeding (e.g., via nasogastric feeding or oral administration). Optionally, the method of treating or preventing patent ductus arteriosus in an infant is used for an infant with sepsis. Optionally, the infant is a newborn. Optionally, the infant is a preterm infant. Further, optionally, or additionally, the method comprises administering the composition to the infant once daily. Optionally, the method comprises administering the composition to the infant via enteral feeding, such as via nasogastric tube feeding or oral administration. Optionally, the method comprises administering the composition to the infant along with food; for example, breast milk, milk bank donation milk, infant formula or formula milk, and / or artificial formula for preterm infants. Preferably, the method comprises administering the infant a constant daily volume of the composition and a volume of food varying according to the infant's weight. Most preferably, the method comprises administering 1 ml of the composition and an equivalent volume of food of 5 ml per 1 kg of infant body weight daily to the infant. Optionally, the method includes applying the composition to the infant in a composition:food ratio of 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:9, 1:10, 1:15, 1:20 and / or 1:25.

[0047] Some embodiments of the present invention include a method for treating or preventing necrotizing enterocolitis in infants, wherein the method includes administering the composition to the infant, and wherein the composition is any composition of the present invention. For example, in some embodiments, the composition comprises *Lactobacillus fermentum*, optionally *Lactobacillus fermentum* CECT5716, and / or *Bifidobacterium breve*, optionally *Bifidobacterium breve* CECT7263. Optionally, the composition contains at least 1 x 10⁻⁶. 3 CFU, optional, at least 1x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 1x10 12 The CFU of Lactobacillus fermentum CECT5716 and / or the composition comprises at least 1 x 10 3 CFU, optional, at least 1x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 1x10 12 CFU of Bifidobacterium breve CECT7263. Optionally, the composition comprises a combined total amount of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the combined total amount is at least 1 x 10⁻⁶. 3 CFU, optional, at least 2x10 3 CFU, optional, at least 1x106 CFU, optional, at least 2x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 2x10 9 CFU, optional, at least 1x10 12 CFU, optional, at least 2x10 12 CFU. Optionally, the volume of the composition is 1 ml. Optionally, the composition contains a concentration of at least 1 x 10⁻⁶ CFU. 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 1x10 12 CFU / ml of Lactobacillus fermentum CECT5716; and / or the composition contains at least 1 x 10 .... 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 1x10 12 CFU / ml of Bifidobacterium breve CECT7263. Optionally, the composition comprises a mixed total concentration of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the mixed total concentration is at least 1 x 10⁻⁶ CFU / ml. 3 CFU / ml, optionally at least 2 x 10 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 2 x 10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 2 x 10 9 CFU / ml, optionally at least 1x10 12 CFU / ml, optionally at least 2 x 10 12CFU / ml. Optionally, the composition is in a nutritionally acceptable form for an infant. Optionally, the composition is in a form suitable for enteral feeding of an infant (e.g., via nasogastric tube or oral administration). Optionally, the infant is a newborn. Optionally, the infant is a preterm infant. Further, optionally, or additionally, the method comprises administering the composition to the infant once daily. Optionally, the method comprises administering the composition to the infant via enteral feeding, such as via nasogastric tube or oral administration. Optionally, the method comprises administering the composition to the infant along with food; such as breast milk, milk bank donation milk, infant formula or formula milk, and / or artificial formula for preterm infants. Preferably, the method comprises administering the infant a constant daily volume of the composition and a volume of food varying according to the infant's weight. Most preferably, the method comprises administering 1 ml of the composition and an equivalent volume of food of 5 ml per 1 kg of infant body weight daily to the infant. Optionally, the method includes applying the composition to the infant in a composition:food ratio of 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:9, 1:10, 1:15, 1:20 and / or 1:25.

[0048] Some embodiments of the present invention include a method for treating or preventing infantile sepsis, wherein the method includes administering the composition to an infant, and wherein the composition is any composition of the present invention. For example, in some embodiments, the composition comprises *Lactobacillus fermentum*, optionally *Lactobacillus fermentum* CECT5716, and / or *Bifidobacterium breve*, optionally *Bifidobacterium breve* CECT7263. Optionally, the composition contains at least 1 x 10⁻⁶ units. 3 CFU, optional, at least 1x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 1x10 12 The CFU of Lactobacillus fermentum CECT5716 and / or the composition comprises at least 1 x 10 3 CFU, optional, at least 1x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 1x10 12 CFU of Bifidobacterium breve CECT7263. Optionally, the composition comprises a combined total amount of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the combined total amount is at least 1 x 10⁻⁶. 3 CFU, optional, at least 2x10 3 CFU, optional, at least 1x10 6 CFU, optional, at least 2x10 6CFU, optional, at least 1x10 9 CFU, optional, at least 2x10 9 CFU, optional, at least 1x10 12 CFU, optional, at least 2x10 12 CFU. Optionally, the volume of the composition is 1 ml. Optionally, the composition contains a concentration of at least 1 x 10⁻⁶ CFU. 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 1x10 12 CFU / ml of Lactobacillus fermentum CECT5716; and / or the composition contains at least 1 x 10 .... 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 1x10 12 CFU / ml of Bifidobacterium breve CECT7263. Optionally, the composition comprises a mixed total concentration of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the mixed total concentration is at least 1 x 10⁻⁶ CFU / ml. 3 CFU / ml, optionally at least 2 x 10 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 2 x 10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 2 x 10 9 CFU / ml, optionally at least 1x10 12 CFU / ml, optionally at least 2 x 10 12CFU / ml. Optionally, the composition is in a nutritionally acceptable form for an infant. Optionally, the composition is in a form suitable for enteral feeding of an infant (e.g., via nasogastric tube or oral administration). Optionally, the infant is a newborn. Optionally, the infant is a preterm infant. Further, optionally, or additionally, the method comprises administering the composition to the infant once daily. Optionally, the method comprises administering the composition to the infant via enteral feeding, such as via nasogastric tube or oral administration. Optionally, the method comprises administering the composition to the infant along with food; such as breast milk, milk bank donation milk, infant formula or formula milk, and / or artificial formula for preterm infants. Preferably, the method comprises administering the infant a constant daily volume of the composition and a volume of food varying according to the infant's weight. Most preferably, the method comprises administering 1 ml of the composition and an equivalent volume of food of 5 ml per 1 kg of infant body weight daily to the infant. Optionally, the method includes applying the composition to the infant in a composition:food ratio of 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:9, 1:10, 1:15, 1:20 and / or 1:25.

[0049] Some embodiments of the present invention include a method for treating or preventing infantile immune system disorders, wherein the method includes administering the composition to the infant, and wherein the composition is any composition of the present invention. For example, in some embodiments, the composition comprises *Lactobacillus fermentum*, optionally *Lactobacillus fermentum* CECT5716, and / or *Bifidobacterium breve*, optionally *Bifidobacterium breve* CECT7263. Optionally, the composition contains at least 1 x 10⁻⁶ units. 3 CFU, optional, at least 1x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 1x10 12 The CFU of Lactobacillus fermentum CECT5716 and / or the composition comprises at least 1 x 10 3 CFU, optional, at least 1x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 1x10 12 CFU of Bifidobacterium breve CECT7263. Optionally, the composition comprises a combined total amount of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the combined total amount is at least 1 x 10⁻⁶. 3 CFU, optional, at least 2x10 3 CFU, optional, at least 1x10 6 CFU, optional, at least 2x10 6CFU, optional, at least 1x10 9 CFU, optional, at least 2x10 9 CFU, optional, at least 1x10 12 CFU, optional, at least 2x10 12 CFU. Optionally, the volume of the composition is 1 ml. Optionally, the composition contains a concentration of at least 1 x 10⁻⁶ CFU. 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 1x10 12 CFU / ml of Lactobacillus fermentum CECT5716; and / or the composition contains at least 1 x 10 .... 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 1x10 12 CFU / ml of Bifidobacterium breve CECT7263. Optionally, the composition comprises a mixed total concentration of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the mixed total concentration is at least 1 x 10⁻⁶ CFU / ml. 3 CFU / ml, optionally at least 2 x 10 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 2 x 10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 2 x 10 9 CFU / ml, optionally at least 1x10 12 CFU / ml, optionally at least 2 x 10 12CFU / ml. Optionally, the composition is in a nutritionally acceptable form for an infant. Optionally, the composition is in a form suitable for enteral feeding of an infant (e.g., via nasogastric tube or oral administration). Optionally, the infant is a newborn. Optionally, the infant is a preterm infant. Further, optionally, or additionally, the method comprises administering the composition to the infant once daily. Optionally, the method comprises administering the composition to the infant via enteral feeding, such as via nasogastric tube or oral administration. Optionally, the method comprises administering the composition to the infant along with food; such as breast milk, milk bank donation milk, infant formula or formula milk, and / or artificial formula for preterm infants. Preferably, the method comprises administering the infant a constant daily volume of the composition and a volume of food varying according to the infant's weight. Most preferably, the method comprises administering 1 ml of the composition and an equivalent volume of food of 5 ml per 1 kg of infant body weight daily to the infant. Optionally, the method includes applying the composition to the infant in a composition:food ratio of 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:9, 1:10, 1:15, 1:20 and / or 1:25.

[0050] Some embodiments of the present invention include a method for treating or preventing intestinal diseases in infants, wherein the method includes administering the composition to the infant, and wherein the composition is any composition of the present invention. For example, in some embodiments, the composition comprises *Lactobacillus fermentum*, optionally *Lactobacillus fermentum* CECT5716, and / or *Bifidobacterium breve*, optionally *Bifidobacterium breve* CECT7263. Optionally, the composition comprises at least 1 x 10⁻⁶. 3 CFU, optional, at least 1x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 1x10 12 The CFU of Lactobacillus fermentum CECT5716 and / or the composition comprises at least 1 x 10 3 CFU, optional, at least 1x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 1x10 12 CFU of Bifidobacterium breve CECT7263. Optionally, the composition comprises a combined total amount of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the combined total amount is at least 1 x 10⁻⁶. 3 CFU, optional, at least 2x10 3 CFU, optional, at least 1x10 6 CFU, optional, at least 2x10 6CFU, optional, at least 1x10 9 CFU, optional, at least 2x10 9 CFU, optional, at least 1x10 12 CFU, optional, at least 2x10 12 CFU. Optionally, the volume of the composition is 1 ml. Optionally, the composition contains a concentration of at least 1 x 10⁻⁶ CFU. 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 1x10 12 CFU / ml of Lactobacillus fermentum CECT5716; and / or the composition contains at least 1 x 10 .... 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 1x10 12 CFU / ml of Bifidobacterium breve CECT7263. Optionally, the composition comprises a mixed total concentration of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the mixed total concentration is at least 1 x 10⁻⁶ CFU / ml. 3 CFU / ml, optionally at least 2 x 10 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 2 x 10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 2 x 10 9 CFU / ml, optionally at least 1x10 12 CFU / ml, optionally at least 2 x 10 12CFU / ml. Optionally, the composition is in a nutritionally acceptable form for an infant. Optionally, the composition is in a form suitable for enteral feeding of an infant (e.g., via nasogastric tube or oral administration). Optionally, the infant is a newborn. Optionally, the infant is a preterm infant. Further, optionally, or additionally, the method comprises administering the composition to the infant once daily. Optionally, the method comprises administering the composition to the infant via enteral feeding, such as via nasogastric tube or oral administration. Optionally, the method comprises administering the composition to the infant along with food; such as breast milk, milk bank donation milk, infant formula or formula milk, and / or artificial formula for preterm infants. Preferably, the method comprises administering the infant a constant daily volume of the composition and a volume of food varying according to the infant's weight. Most preferably, the method comprises administering 1 ml of the composition and an equivalent volume of food of 5 ml per 1 kg of infant body weight daily to the infant. Optionally, the method includes applying the composition to the infant in a composition:food ratio of 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:9, 1:10, 1:15, 1:20 and / or 1:25.

[0051] Some embodiments of the present invention include the use of the composition in the preparation of a medicament for treating or preventing patent ductus arteriosus in infants, wherein said composition is any composition of the present invention. For example, in some embodiments, the composition comprises *Lactobacillus fermentum*, optionally *Lactobacillus fermentum* CECT5716, and / or *Bifidobacterium breve*, optionally *Bifidobacterium breve* CECT7263. Optionally, the composition comprises at least 1 x 10⁻⁶. 3 CFU, optional, at least 1x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 1x10 12 The CFU of Lactobacillus fermentum CECT5716 and / or the composition comprises at least 1 x 10 3 CFU, optional, at least 1x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 1x10 12 CFU of Bifidobacterium breve CECT7263. Optionally, the composition comprises a combined total amount of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the combined total amount is at least 1 x 10⁻⁶. 3 CFU, optional, at least 2x10 3 CFU, optional, at least 1x10 6 CFU, optional, at least 2x10 6CFU, optional, at least 1x10 9 CFU, optional, at least 2x10 9 CFU, optional, at least 1x10 12 CFU, optional, at least 2x10 12 CFU. Optionally, the volume of the composition is 1 ml. Optionally, the composition contains a concentration of at least 1 x 10⁻⁶ CFU. 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 1x10 12 CFU / ml of Lactobacillus fermentum CECT5716; and / or the composition contains at least 1 x 10 .... 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 1x10 12 CFU / ml of Bifidobacterium breve CECT7263. Optionally, the composition comprises a mixed total concentration of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the mixed total concentration is at least 1 x 10⁻⁶ CFU / ml. 3 CFU / ml, optionally at least 2 x 10 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 2 x 10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 2 x 10 9 CFU / ml, optionally at least 1x10 12 CFU / ml, optionally at least 2 x 10 12CFU / ml. Optionally, the composition and / or drug is in a nutritionally acceptable form for the infant. Optionally, the composition and / or drug is in a form suitable for enteral feeding (e.g., via nasogastric feeding or oral administration). Optionally, the infant is a newborn. Optionally, the infant is a preterm infant. Further, optionally, or additionally, the method comprises administering the drug to the infant once daily. Optionally, the drug is administered to the infant via enteral feeding, such as via nasogastric tube feeding or oral administration. Optionally, the drug is administered to the infant with food; for example, breast milk, milk bank donation milk, infant formula or formula milk, and / or artificial formula for preterm infants. Preferably, the drug is administered to the infant with a constant daily volume of drug and a volume of food varying according to the infant's weight. Most preferably, the drug is administered to the infant with a daily volume of 1 ml of drug and a food volume equivalent to 5 ml per 1 kg of infant weight. Optionally, the method includes administering the drug to the infant in a composition:food ratio of 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:9, 1:10, 1:15, 1:20 and / or 1:25.

[0052] Some embodiments of the present invention include the use of the composition in the preparation of a medicament for treating or preventing necrotizing enterocolitis in infants, wherein said composition is any composition of the present invention. For example, in some embodiments, the composition comprises *Lactobacillus fermentum*, optionally *Lactobacillus fermentum* CECT5716, and / or *Bifidobacterium breve*, optionally *Bifidobacterium breve* CECT7263. Optionally, the composition comprises at least 1 x 10⁻⁶. 3 CFU, optional, at least 1x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 1x10 12 The CFU of Lactobacillus fermentum CECT5716 and / or the composition comprises at least 1 x 10 3 CFU, optional, at least 1x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 1x10 12 CFU of Bifidobacterium breve CECT7263. Optionally, the composition comprises a combined total amount of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the combined total amount is at least 1 x 10⁻⁶. 3 CFU, optional, at least 2x10 3 CFU, optional, at least 1x10 6 CFU, optional, at least 2x10 6CFU, optional, at least 1x10 9 CFU, optional, at least 2x10 9 CFU, optional, at least 1x10 12 CFU, optional, at least 2x10 12 CFU. Optionally, the volume of the composition is 1 ml. Optionally, the composition contains a concentration of at least 1 x 10⁻⁶ CFU. 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 1x10 12 CFU / ml of Lactobacillus fermentum CECT5716; and / or the composition contains at least 1 x 10 .... 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 1x10 12 CFU / ml of Bifidobacterium breve CECT7263. Optionally, the composition comprises a mixed total concentration of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the mixed total concentration is at least 1 x 10⁻⁶ CFU / ml. 3 CFU / ml, optionally at least 2 x 10 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 2 x 10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 2 x 10 9 CFU / ml, optionally at least 1x10 12 CFU / ml, optionally at least 2 x 10 12CFU / ml. Optionally, the composition and / or drug is in a nutritionally acceptable form for the infant. Optionally, the composition and / or drug is in a form suitable for enteral feeding (e.g., via nasogastric feeding or oral administration). Optionally, the infant is a newborn. Optionally, the infant is a preterm infant. Further, optionally, or additionally, the method comprises administering the drug to the infant once daily. Optionally, the drug is administered to the infant via enteral feeding, such as via nasogastric tube feeding or oral administration. Optionally, the drug is administered to the infant with food; for example, breast milk, milk bank donation milk, infant formula or formula milk, and / or artificial formula for preterm infants. Preferably, the drug is administered to the infant with a constant daily volume of drug and a volume of food varying according to the infant's weight. Most preferably, the drug is administered to the infant with a daily volume of 1 ml of drug and a food volume equivalent to 5 ml per 1 kg of infant weight. Optionally, the method includes administering the drug to the infant in a composition:food ratio of 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:9, 1:10, 1:15, 1:20 and / or 1:25.

[0053] Some embodiments of the present invention include the use of the composition in the preparation of a medicament for treating or preventing infantile sepsis, wherein said composition is any composition of the present invention. For example, in some embodiments, the composition comprises *Lactobacillus fermentum*, optionally *Lactobacillus fermentum* CECT5716, and / or *Bifidobacterium breve*, optionally *Bifidobacterium breve* CECT7263. Optionally, the composition comprises at least 1 x 10⁻⁶. 3 CFU, optional, at least 1x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 1x10 12 The CFU of Lactobacillus fermentum CECT5716 and / or the composition comprises at least 1 x 10 3 CFU, optional, at least 1x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 1x10 12 CFU of Bifidobacterium breve CECT7263. Optionally, the composition comprises a combined total amount of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the combined total amount is at least 1 x 10⁻⁶. 3 CFU, optional, at least 2x10 3 CFU, optional, at least 1x10 6 CFU, optional, at least 2x10 6CFU, optional, at least 1x10 9 CFU, optional, at least 2x10 9 CFU, optional, at least 1x10 12 CFU, optional, at least 2x10 12 CFU. Optionally, the volume of the composition is 1 ml. Optionally, the composition contains a concentration of at least 1 x 10⁻⁶ CFU. 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 1x10 12 CFU / ml of Lactobacillus fermentum CECT5716; and / or the composition contains at least 1 x 10 .... 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 1x10 12 CFU / ml of Bifidobacterium breve CECT7263. Optionally, the composition comprises a mixed total concentration of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the mixed total concentration is at least 1 x 10⁻⁶ CFU / ml. 3 CFU / ml, optionally at least 2 x 10 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 2 x 10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 2 x 10 9 CFU / ml, optionally at least 1x10 12 CFU / ml, optionally at least 2 x 10 12CFU / ml. Optionally, the composition and / or drug is in a nutritionally acceptable form for the infant. Optionally, the composition and / or drug is in a form suitable for enteral feeding (e.g., via nasogastric feeding or oral administration). Optionally, the infant is a newborn. Optionally, the infant is a preterm infant. Further, optionally, or additionally, the method comprises administering the drug to the infant once daily. Optionally, the drug is administered to the infant via enteral feeding, such as via nasogastric tube feeding or oral administration. Optionally, the drug is administered to the infant with food; for example, breast milk, milk bank donation milk, infant formula or formula milk, and / or artificial formula for preterm infants. Preferably, the drug is administered to the infant with a constant daily volume of drug and a volume of food varying according to the infant's weight. Most preferably, the drug is administered to the infant with a daily volume of 1 ml of drug and a food volume equivalent to 5 ml per 1 kg of infant weight. Optionally, the method includes administering the drug to the infant in a composition:food ratio of 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:9, 1:10, 1:15, 1:20 and / or 1:25.

[0054] Some embodiments of the present invention include the use of the composition in the preparation of a medicament for treating or preventing infantile immune system disorders, wherein said composition is any composition of the present invention. For example, in some embodiments, the composition comprises *Lactobacillus fermentum*, optionally *Lactobacillus fermentum* CECT5716, and / or *Bifidobacterium breve*, optionally *Bifidobacterium breve* CECT7263. Optionally, the composition comprises at least 1 x 10⁻⁶. 3 CFU, optional, at least 1x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 1x10 12 The CFU of Lactobacillus fermentum CECT5716 and / or the composition comprises at least 1 x 10 3 CFU, optional, at least 1x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 1x10 12 CFU of Bifidobacterium breve CECT7263. Optionally, the composition comprises a combined total amount of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the combined total amount is at least 1 x 10⁻⁶. 3 CFU, optional, at least 2x10 3 CFU, optional, at least 1x10 6 CFU, optional, at least 2x10 6CFU, optional, at least 1x10 9 CFU, optional, at least 2x10 9 CFU, optional, at least 1x10 12 CFU, optional, at least 2x10 12 CFU. Optionally, the volume of the composition is 1 ml. Optionally, the composition contains a concentration of at least 1 x 10⁻⁶ CFU. 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 1x10 12 CFU / ml of Lactobacillus fermentum CECT5716; and / or the composition contains at least 1 x 10 .... 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 1x10 12 CFU / ml of Bifidobacterium breve CECT7263. Optionally, the composition comprises a mixed total concentration of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the mixed total concentration is at least 1 x 10⁻⁶ CFU / ml. 3 CFU / ml, optionally at least 2 x 10 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 2 x 10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 2 x 10 9 CFU / ml, optionally at least 1x10 12 CFU / ml, optionally at least 2 x 10 12CFU / ml. Optionally, the composition and / or drug is in a nutritionally acceptable form for the infant. Optionally, the composition and / or drug is in a form suitable for enteral feeding (e.g., via nasogastric feeding or oral administration). Optionally, the infant is a newborn. Optionally, the infant is a preterm infant. Further, optionally, or additionally, the method comprises administering the drug to the infant once daily. Optionally, the drug is administered to the infant via enteral feeding, such as via nasogastric tube feeding or oral administration. Optionally, the drug is administered to the infant with food; for example, breast milk, milk bank donation milk, infant formula or formula milk, and / or artificial formula for preterm infants. Preferably, the drug is administered to the infant with a constant daily volume of drug and a volume of food varying according to the infant's weight. Most preferably, the drug is administered to the infant with a daily volume of 1 ml of drug and a food volume equivalent to 5 ml per 1 kg of infant weight. Optionally, the method includes administering the drug to the infant in a composition:food ratio of 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:9, 1:10, 1:15, 1:20 and / or 1:25.

[0055] Some embodiments of the present invention include the use of the composition in the preparation of a medicament for treating or preventing intestinal diseases in infants, wherein said composition is any composition of the present invention. For example, in some embodiments, the composition comprises *Lactobacillus fermentum*, optionally *Lactobacillus fermentum* CECT5716, and / or *Bifidobacterium breve*, optionally *Bifidobacterium breve* CECT7263. Optionally, the composition comprises at least 1 x 10⁻⁶. 3 CFU, optional, at least 1x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 1x10 12 The CFU of Lactobacillus fermentum CECT5716 and / or the composition comprises at least 1 x 10 3 CFU, optional, at least 1x10 6 CFU, optional, at least 1x10 9 CFU, optional, at least 1x10 12 CFU of Bifidobacterium breve CECT7263. Optionally, the composition comprises a combined total amount of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the combined total amount is at least 1 x 10⁻⁶. 3 CFU, optional, at least 2x10 3 CFU, optional, at least 1x10 6 CFU, optional, at least 2x10 6CFU, optional, at least 1x10 9 CFU, optional, at least 2x10 9 CFU, optional, at least 1x10 12 CFU, optional, at least 2x10 12 CFU. Optionally, the volume of the composition is 1 ml. Optionally, the composition contains a concentration of at least 1 x 10⁻⁶ CFU. 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 1x10 12 CFU / ml of Lactobacillus fermentum CECT5716; and / or the composition contains at least 1 x 10 .... 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 1x10 12 CFU / ml of Bifidobacterium breve CECT7263. Optionally, the composition comprises a mixed total concentration of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the mixed total concentration is at least 1 x 10⁻⁶ CFU / ml. 3 CFU / ml, optionally at least 2 x 10 3 CFU / ml, optionally at least 1x10 6 CFU / ml, optionally at least 2 x 10 6 CFU / ml, optionally at least 1x10 9 CFU / ml, optionally at least 2 x 10 9 CFU / ml, optionally at least 1x10 12 CFU / ml, optionally at least 2 x 10 12CFU / ml. Optionally, the composition and / or drug is in a nutritionally acceptable form for the infant. Optionally, the composition and / or drug is in a form suitable for enteral feeding (e.g., via nasogastric feeding or oral administration). Optionally, the infant is a newborn. Optionally, the infant is a preterm infant. Further, optionally, or additionally, the method comprises administering the drug to the infant once daily. Optionally, the drug is administered to the infant via enteral feeding, such as via nasogastric tube feeding or oral administration. Optionally, the drug is administered to the infant with food; for example, breast milk, milk bank donation milk, infant formula or formula milk, and / or artificial formula for preterm infants. Preferably, the drug is administered to the infant with a constant daily volume of drug and a volume of food varying according to the infant's weight. Most preferably, the drug is administered to the infant with a daily volume of 1 ml of drug and a food volume equivalent to 5 ml per 1 kg of infant weight. Optionally, the method includes administering the drug to the infant in a composition:food ratio of 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:9, 1:10, 1:15, 1:20 and / or 1:25.

[0056] statement

[0057] Certain embodiments of the present invention are described by the following numbered groups of statements:

[0058] Statement 1: A composition comprising Lactobacillus fermentum ( L. fermentum CECT5716 and Bifidobacterium breve ( B. breve CECT7263.

[0059] Statement 2: In the composition according to Statement 1, each of Lactobacillus fermentum and Bifidobacterium breve contains at least 1 x 10 3 An independent quantity of CFU exists.

[0060] Statement 3: In the composition according to Statement 1, the total amount of Lactobacillus fermentum and Bifidobacterium breve is at least 1 x 10⁻⁶. 3 CFU.

[0061] Statement 4: The composition according to any one of Statements 1-3, wherein the composition is in a form acceptable for infant nutrition.

[0062] Statement 5: The composition according to any one of Statements 1-3, wherein the composition is in a form suitable for enteral feeding of infants.

[0063] Statement 6: The composition according to any one of Statements 4 or 5 is used to improve the immune system or intestinal function of an infant.

[0064] Statement 7: The composition according to any one of Statements 4 or 5 is used to treat an infant’s immune system or intestinal disease.

[0065] Statement 8: The composition according to any one of Statements 4 or 5 is used to treat patent ductus arteriosus in infants.

[0066] Statement 9: In accordance with the use described in Statement 8, the infant suffers from sepsis.

[0067] Statement 10: The use according to any one of statements 6-9, wherein the infant is a newborn.

[0068] Statement 11: The use according to any one of Statements 6 or 10, wherein the infant is a premature infant.

[0069] Statement 12: The use according to any one of statements 6-11, wherein the composition is administered via enteral feeding.

[0070] Statement 13: The use according to any one of statements 6-12, wherein Lactobacillus fermentum and Bifidobacterium breve each contain at least 1 x 10 9 Independent administration of CFU.

[0071] Statement 14: A method for improving an infant’s immune system or gut function, comprising administering to the infant a composition comprising Lactobacillus fermentum and Bifidobacterium breve.

[0072] Statement 15: The method described in Statement 14, wherein Lactobacillus fermentum is strain CECT5716 and Bifidobacterium breve is strain CECT7263.

[0073] Statement 16: A method of treating an infant’s immune system or intestinal disease, comprising administering to the infant a composition comprising Lactobacillus fermentum and Bifidobacterium breve.

[0074] Statement 17: The method as described in Statement 16, wherein Lactobacillus fermentum is strain CECT5716 and Bifidobacterium breve is strain CECT7263.

[0075] Statement 18: A method for treating patent ductus arteriosus in an infant, comprising administering to the infant a composition comprising Lactobacillus fermentum and Bifidobacterium breve.

[0076] Statement 19: The method as described in Statement 18, wherein Lactobacillus fermentum is strain CECT5716 and Bifidobacterium breve is strain CECT7263.

[0077] Statement 20: The method as described in Statement 18, wherein the infant is a newborn.

[0078] Statement 21: The method is as described in Statement 20, wherein the newborn is a premature infant.

[0079] Statement 22: The method as described in Statement 21, wherein the composition is administered via enteral feeding.

[0080] Statement 23: The method as described in Statement 22, wherein Lactobacillus fermentum and Bifidobacterium breve are each administered at a dose of at least 1 x 10⁻⁶ per day. 9 Independent administration of CFU.

[0081] Statement 24: The composition according to the embodiments described herein.

[0082] Statement 25: The treatment method described in the implementation plan herein. Attached Figure Description

[0083] By combining the attached figures ( Figure 1 The embodiments of the present invention will be more clearly understood from the following detailed description up to Figure 4. These figures are for illustrative purposes only and are not intended to limit the scope of the invention.

[0084] Figure 1

[0085] Figure 1 A simplified diagram of the time points used in the study described in the examples below is shown. The study population consisted of 581 preterm infants (n=581) (gestational age less than or equal to 32 weeks) with a birth weight less than 1500 grams. The LD group received 1x10 6 CFU / day of Lactobacillus fermentum CECT5716 and 1x10 6 CFU / day of Bifidobacterium breve CECT7263. HD group administered 1x10 9 CFU / day of Lactobacillus fermentum CECT5716 and 1x10 9 CFU / day of Bifidobacterium breve CECT7263. Weeks (e.g., “32 weeks,” “34 weeks,” and “37 weeks”) indicate the week after birth. Randomization was performed within 72 hours of birth. The arrow between “birth” and “32 weeks” indicates weekly follow-up at week 32. Measured outcomes included: safety, NEC incidence, sepsis incidence, health parameters, and fecal microbiota.

[0086] Figure 2

[0087] Figure 2 The clinical results were shown. Figure 2 The incidence (%) of necrotizing enterocolitis (NEC), sepsis, and patent ductus arteriosus (PDA) (persistent ductus arteriosus) in each group of infants is shown, along with the reference incidence level for each disease. The high-dose group received 1x10 9 CFU / day of Lactobacillus fermentum CECT5716 and 1x109 CFU / day of Bifidobacterium breve CECT7263. Low-dose group administered 1x10 6 CFU / day of Lactobacillus fermentum CECT5716 and 1x10 6 CFU / day of Bifidobacterium breve CECT7263. For patent ductus arteriosus, the incidence was significantly lower in the high-dose group. For NEC and sepsis, there was no significant difference between the high-dose and low-dose groups. Reference incidence levels (indicated by dashed lines) were obtained from the official Spanish database (SENEO–Redes Neonatales), which includes data from 10 participating hospitals. Data from preterm infants weighing 700–1500 grams between 2016 and 2020 were included to calculate reference values.

[0088] Figure 3

[0089] Figure 3A The positive inotropic drug treatment was demonstrated. Figure 3A The incidence rate (%) of infants receiving positive inotropic drugs in each group is shown, along with a reference incidence level. The high-dose group received 1x10... 9 CFU / day of Lactobacillus fermentum CECT5716 and 1x10 9 CFU / day of Bifidobacterium breve CECT7263. Low-dose group administered 1x10 6 CFU / day of Lactobacillus fermentum CECT5716 and 1x10 6 CFU / day of Bifidobacterium breve CECT7263. The high-dose group had a significantly lower need for positive inotropic agents. The reference incidence level (15%, indicated by the dashed line) was obtained from the official Spanish database (SENEO–Redes Neonatales), which includes data from 10 participating hospitals. Data from preterm infants weighing 700–1500 grams between 2016 and 2020 were included to calculate the reference value.

[0090] Figure 3B This is a graph showing the risk of sepsis from patent ductus arteriosus. Figure 3B The incidence (%) of patent ductus arteriosus is shown in each group of infants with or without sepsis. "Without sepsis" refers to infants who do not have sepsis, while "sepsis" refers to infants with sepsis. The low-dose group refers to those given 1x10... 6 CFU / day of Lactobacillus fermentum CECT5716 and 1x10 6 Infants receiving CFU / Bifidobacterium breve CECT7263. The high-dose group refers to those given 1x10... 9 CFU / day of Lactobacillus fermentum CECT5716 and 1x10 9Infants receiving CFU / Bifidobacterium breve CECT7263. "No duct" refers to the incidence (%) in infants without patent ductus arteriosus (PDA), while "duct" refers to the incidence (%) in infants with PDA. An asterisk (*) indicates a statistically significant difference in the incidence of PDA between infants with and without sepsis in the low-dose group (p<0.005). Sepsis is a recognized risk factor for PDA. In the low-dose group, infants with sepsis had a significantly higher incidence of PDA compared to infants without sepsis (i.e., 1 x 10^6 mmol / L). 6 CFU / day of Lactobacillus fermentum CECT5716 and 1x10 6 CFU / Bifidobacterium breve CECT7263), which supports this. High probiotic dosage (i.e., 1x10) 9 CFU / day of Lactobacillus fermentum CECT5716 and 1x10 9 The administration of CFU / Bifidobacterium breve CECT7263 can prevent this associated risk.

[0091] Figure 4

[0092] Figure 4A Colony diagrams of LC40 (i.e. CECT5716) and BfM26 (i.e. CECT 7263) are shown. Figure 4A This shows the percentage (%) of infants whose stool samples contained different bacteria two weeks after birth. *Lactobacillus fermentum* CECT5716 and *Bifidobacterium breve* CECT7263 were not detected. LC40 indicates the presence of *Lactobacillus fermentum* CECT5716 but not *Bifidobacterium breve* CECT7263. BfM26 indicates the presence of *Bifidobacterium breve* CECT7263 but not *Lactobacillus fermentum* CECT5716. LC40+BfM26 indicates the presence of both *Bifidobacterium breve* CECT7263 and *Lactobacillus fermentum* CECT5716. LC40+BfM26 (HD) refers to a daily intake of 1x10... 9 CFU (Cytobacterium fermentum) CECT5716 and 1x10 9 Infants taking CFU / Bifidobacterium breve CECT7263. This group included 158 infants (n=158). LC40+BfM26 (LD) refers to a daily dose of 1x10 6 CFU (Cytobacterium fermentum) CECT5716 and 1x10 6Infants treated with CFU / day of Bifidobacterium breve CECT7263. This group included 179 infants (n=179). Infant percentage (%) values ​​are shown in the chart above each bar, with decimal points marked with decimal commas in these labels. Two weeks after the intervention, approximately 65% ​​(66.5% specifically) of the infants had Bifidobacterium breve CECT7263 and Lactobacillus fermentum CECT5716 in their stool.

[0093] Figure 4B The presence of LC40 (i.e., CECT5716) and / or BFM26 (i.e., CECT7263) at 2 weeks of age is shown. Figure 4B Showing the relationship in a simplified form Figure 4A Same data. "Not detected" means neither *Lactobacillus fermentum* CECT5716 nor *Bifidobacterium breve* CECT7263 was detected. LC40 indicates *Lactobacillus fermentum* CECT5716 was detected. BfM26 indicates *Bifidobacterium breve* CECT7263 was detected. Low dose refers to an administration of 1x10... 6 CFU / day of Lactobacillus fermentum CECT5716 and 1x10 6 Infants taking CFU / Bifidobacterium breve CECT7263. A high dose refers to 1x10g per day. 9 CFU (Cytobacterium fermentum) CECT5716 and 1x10 9 Infants with CFU / Bifidobacterium breve CECT7263. Detailed Implementation

[0094] The inventors have unexpectedly discovered that compositions comprising *Lactobacillus fermentum* CECT5716 and *Bifidobacterium breve* CECT7263 can treat or prevent patent ductus arteriosus (PDA) in infants. Furthermore, the inventors have unexpectedly discovered that compositions comprising *Lactobacillus fermentum* CECT5716 and *Bifidobacterium breve* CECT7263 can treat or prevent PDA in infants with sepsis and prevent a higher risk of developing persistent ductus arteriosus associated with sepsis. Compositions comprising *Lactobacillus fermentum* CECT5716 and *Bifidobacterium breve* CECT7263 can be advantageously used for the treatment or prevention (e.g., prevention) of PDA in infants (e.g., newborns), particularly in cases where the infant has sepsis or is at risk of sepsis or at risk of developing persistent ductus arteriosus, for example, if the infant is preterm. The composition is preferably administered to the infant via enteral feeding, such as through a nasogastric tube or orally. Preferably, the composition is administered to the infant with food; for example, breast milk, milk bank donation milk, infant formula or formula milk, and / or artificial formula for preterm infants. Preferably, the composition is administered to the infant in a constant daily volume together with a volume of food that varies according to the infant's weight; for example, 1 ml of the composition is given to the infant daily, along with a food volume equivalent to 5 ml per 1 kg of infant body weight. The composition can be administered to the infant with food in a composition:food ratio of 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:9, 1:10, 1:15, 1:20, and / or 1:25. The composition is preferably administered to the infant at a daily dose of 1 ml.

[0095] Advantageously, administering the compositions of the present invention to infants can reduce the need for positive inotropic drugs or other drugs or treatments that may be poorly tolerated by infants or contraindicated due to, for example, other required drugs or treatments. Advantageously, administering the compositions of the present invention to infants can reduce polydrug use. Advantageously, the compositions of the present invention may be considered a dietary intervention and may be more preferred (e.g., by infant caregivers) compared to other treatments considered more chemical or medical.

[0096] As shown in the example below, compared to a lower daily dose of 1x10 6 CFU (Cytobacterium fermentum) CECT5716 and 1x10 6 Compared to CFU-Bifidobacterium breve CECT7263, a daily dose of 1x10 9 CFU (Cytobacterium fermentum) CECT5716 and 1x10 9 CFU-Bifidobacterium breve CECT7263 significantly reduced the incidence of patent ductus arteriosus in infants. Furthermore, in infants with sepsis, daily administration of 1x109 CFU (Cytobacterium fermentum) CECT5716 and 1x10 9 CFU of Bifidobacterium breve CECT7263 prevented the significant negative correlation between sepsis and patent ductus arteriosus. Similar effects can be expected with other doses of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263. For example, a daily dose of approximately 1 x 10⁻⁶ compared to zero dose. 3 CFU, approximately 1x10 4 CFU, approximately 1x10 5 CFU, 1x10 6 CFU, 1x 10 7 CFU, 1x10 8 CFU, 1x10 10 CFU, 1 x 10 11 CFU and / or 1x10 12 CFU of Lactobacillus ferment 5716 and approximately 1x10 3 CFU, approximately 1x10 4 CFU, approximately 1x10 5 CFU, 1x10 6 CFU, 1x10 7 CFU, 1x10 8 CFU, 1x10 10 CFU, 1 x 10 11 CFU and / or 1 x 10 12 CFU of Bifidobacterium breve CECT7263 may reduce the incidence of patent ductus arteriosus (PDA) in infants and / or prevent a significant negative correlation between sepsis and PDA. Similarly, administration of either Lactobacillus fermentum CECT5716 or Bifidobacterium breve CECT7263 (e.g., at a daily dose of approximately 1 x 10⁻⁶) may reduce the incidence of PDA in infants and / or prevent a significant negative correlation between sepsis and PDA. 3 CFU, 1x10 4 CFU, 1x10 5 CFU, 1x 10 6 CFU, 1X 10 7 CFU, 1x10 8 CFU, 1x10 10 CFU, 1x10 11 and / or 1x10 12 CFU (Chronic Fusion) can also produce similar effects.

[0097] Higher doses or amounts of Lactobacillus fermentum (optionally Lactobacillus fermentum CECT5716) and / or Bifidobacterium breve (optionally Bifidobacterium breve CECT7263) produce greater therapeutic and / or preventive (e.g., prophylactic) effects. For example, with approximately 1x10 6CFU of Lactobacillus fermentum (optionally Lactobacillus fermentum CECT5716) and / or approximately 1 x 10 6 Compared to the dosage or amount of CFU Bifidobacterium breve (optionally Bifidobacterium breve CECT7263), approximately 1 x 10 9 CFU of Lactobacillus fermentum (optionally Lactobacillus fermentum CECT5716) and / or approximately 1 x 10 9 CFU-Bifidobacterium breve (optional Bifidobacterium breve CECT7263) has greater therapeutic and / or preventative (e.g., prophylactic) effects. Similarly, approximately 1x10 12 The dose or ratio of CFU is approximately 1x10. 11 CFU dosage or amount has a greater effect, approximately 1x10 11 The dose or ratio of CFU is approximately 1x10. 10 CFU dosage or amount has a greater effect, while approximately 1x10 10 The dose or ratio of CFU is approximately 1x10. 9 CFU dosage or amount has a greater effect, while approximately 1x10 9 The dose or ratio of CFU is approximately 1x10. 8 CFU dosage or amount has a greater effect, while approximately 1x10 8 The dose or ratio of CFU is approximately 1x10. 7 CFU dosage or amount has a greater effect, while approximately 1x10 7 The dose or ratio of CFU is approximately 1x10. 6 CFU dosage or amount has a greater effect, while approximately 1x10 6 The dose or ratio of CFU is approximately 1x10. 5 CFU dosage or amount has a greater effect, while approximately 1x10 5 The dose or ratio of CFU is approximately 1x10. 4 CFU dosage or amount has a greater effect, while approximately 1x10 4 The dose or ratio of CFU is approximately 1x10. 3 CFU dosage or amount has a greater effect, while approximately 1x10 3 The dose or ratio of CFU is approximately 1x10. 2 A dose or amount of CFU has a greater effect than a negligible or zero dose or content. Most preferably, the composition contains about 1 x 10 9 CFU of Lactobacillus fermentum (optionally Lactobacillus fermentum CECT5716) and / or approximately 1 x 10 9 The dosage or amount of CFU Bifidobacterium breve (optionally Bifidobacterium breve CECT7263).

[0098] It is reasonable to expect that administration of other strains of Lactobacillus fermentum and / or Bifidobacterium breve to infants may also reduce the incidence of patent ductus arteriosus and / or prevent a significant negative correlation between sepsis and persistent arterial duct.

[0099] As illustrated in the examples below, the application of Lactobacillus fermentum (e.g., Lactobacillus fermentum CECT5716) and / or Bifidobacterium breve (e.g., Bifidobacterium breve CECT7263) can reduce the risk of sepsis. See Table 2 below for details.

[0100] Reasonably, the application of Lactobacillus fermentum (e.g., Lactobacillus fermentum CECT5716) and / or Bifidobacterium breve (e.g., Bifidobacterium breve CECT7263) can also be effective in treating and / or preventing necrotizing enterocolitis, immune system disorders, and / or intestinal diseases in infants.

[0101] Example

[0102] Research Design

[0103] This multicenter, prospective, randomized, double-blind phase 3 study aims to compare the efficacy and safety of different doses of probiotic mixtures in preventing severe enterocolitis or death in preterm infants.

[0104] Within the first 72 hours after birth, patients were randomly assigned to receive one of two proposed doses of the probiotic mixture involved in the study. Newborns were enrolled consecutively. Once they met the inclusion criteria and their parents consented to participate in the study, they were assigned to one of the two intervention groups.

[0105] - Group 1: Daily dose of probiotic product Lactobacillus fermentum CECT5716 1x10 6 CFU and Bifidobacterium breve CECT7263 1x10 6 CFU.

[0106] - Group 2: Daily dose of probiotic product Lactobacillus fermentum CECT5716 1x10 9 CFU and Bifidobacterium breve CECT7263 1x10 9 CFU.

[0107] Each administration was given concurrently with enteral feeding. The intervention continued until postmenopausal age at week 36.

[0108] Meconium samples were collected from the patients before the intervention began.

[0109] After the intervention began, stool samples were collected weekly until the subjects reached 32, 34 and 37 weeks of gestation, which coincided with the end of the intervention (36+6 weeks of gestation or PCA). Stool samples were then collected at 40 weeks of gestation and 3 months of corrected gestational age.

[0110] The intervention involves administering 1 ml of a probiotic blend product daily until the end of 36 weeks of pregnancy (36+6 PCA).

[0111] After collection, all fecal samples were stored at -18°C and then maintained at -80°C until processing. The levels of gut microbiota and the administered probiotics were investigated. Polymerase chain reaction (PCR) technology was used for the detection and quantitative analysis of microorganisms in the biopharmaceuticals.

[0112] The intervention was administered as long as subjects received enteral feeding of ≥5 ml / kg / day. The researchers considered the intervention to be temporarily suspended during any clinical / analytical period of enteral feeding interruption. The intervention was resumed once subjects were able to receive enteral feeding again, unless the researchers explicitly stated that the intervention was to be permanently suspended.

[0113] The assessment of necrotizing enterocolitis (NEC) was conducted by the neonatal nursing team responsible for the newborns included in the study. The modified Bell staging criteria, which are shown in Table 1 below and have been reported in Walsh and Kliegman. Pediatr ClinNorth Am. 1986 Feb; 33(1): 179–201, were used for the assessment and diagnosis of NEC. Inclusion and exclusion criteria: Inclusion criteria:

[0114] - Premature infants with a gestational age of 32 weeks or less and a birth weight of ≤1500g admitted to the neonatal department.

[0115] - Premature infants who meet any of the above criteria and are receiving enteral feeding: breast milk, milk bank donation milk and / or premature infant formula, starting at 5 ml / kg / day. Exclusion criteria:

[0116] - Any clinical condition that prevents the initiation of enteral nutrition within the first 72 hours after birth.

[0117] - Chromosomal disorders and complex fetal malformations make it impossible to provide enteral nutrition within the first 72 hours after birth.

[0118] - The newborn's parents or legal guardians do not accept informed consent for participation in the study. result: Main results:

[0119] The primary efficacy variable was the absence of NEC and / or hospital-acquired sepsis in preterm infants during hospitalization. Secondary results:

[0120] - Colonization of beneficial bacteria in the gut of premature infants.

[0121] - Gastrointestinal infection manifestations directly related to the administration of probiotics

[0122] - Daily weight gain (g)

[0123] - Weekly body length increase (cm)

[0124] - Weekly increase in head circumference (cm)

[0125] - Shorten hospital stay for premature infants

[0126] - Digestive tolerance

[0127] NEC incidence rate:

[0128] No significant differences were found between the two doses in terms of NEC morbidity or sepsis. NEC assessment was performed by the neonatal nursing team responsible for the newborns in the study. For this purpose, the modified Bell staging criteria for NEC were considered according to Table 1. Evaluation criteria:

[0129] 1. NEC ≥ Modified Bell Stage IIA occurs.

[0130] 2. Hospital-acquired sepsis occurs.

[0131] 3. Number of sepsis episodes during hospitalization

[0132] 4. Death.

[0133] 5. Digestive tolerance

[0134] The diagnosis of NEC is based on the BellNEC staging criteria in Table 1.

[0135] The hospital's diagnosis of sepsis was in line with the recommendations of the Castrillo Hospital team.

[0136] Probiotic colonization:

[0137] Two weeks after the high-dose intervention, more than 60% of the infants had both strains in their stool (see Figure 4).

[0138] Patent ductus arteriosus: result:

[0139] A significant difference in the incidence of patent ductus arteriosus was observed between the two groups receiving high-dose and low-dose probiotic combinations of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263 (17.9% in the high-dose probiotic group and 25.1% in the low-dose group; p=0.046).

[0140] like Figure 2 As shown, when applying 1x10 9 CFU / day of Lactobacillus fermentum CECT5716 and 1x10 9 In the group treated with CFU / Bifidobacterium breve CECT7263, a significantly lower incidence of patent ductus arteriosus was observed.

[0141] Therefore, 4.8% of preterm infants in the high-dose probiotic group required the administration of positive inotropic drugs, compared to 10.5% in the low-dose probiotic group (p=0.014).

[0142] like Figure 3A As shown, when applying 1x10 9 CFU / day of Lactobacillus fermentum CECT5716 and 1x10 9 In the group receiving CFU / Bifidobacterium breve CECT7263, the need for positive inotropic drugs was significantly reduced.

[0143] It is worth noting that the reported use of positive inotropic drugs in the region is 15% (Spanish Neonatal Network Database SEN1500), so even lower doses of probiotics appear to be beneficial by reducing the proportion of preterm infants who need to be given positive inotropic drugs.

[0144] In the low-dose probiotic group, a significant interaction between sepsis and patent ductus arteriosus (PDA) was observed (40.4% of preterm infants with sepsis had persistent PDA, compared to 21.5% of preterm infants without sepsis (p < 0.005)). However, this interaction was not observed in the high-dose probiotic group, where the percentage of PDA was similar in both populations (22.7% in the sepsis group, compared to 16.9% in the preterm infants without sepsis (p < 0.238)).

[0145] The finding that no significant negative interaction was observed between sepsis and patent ductus arteriosus when infants were given high doses of the tested probiotics was unexpected.

[0146] like Figure 3B As shown, high doses of probiotics (i.e., 1x10) 9CFU / day of Lactobacillus fermentum CECT5716 and 1x10 9 Administration of CFU / Bifidobacterium breve CECT7263 can protect patients from the risk of patent ductus arteriosus associated with sepsis.

[0147] Sepsis is widely recognized as a risk factor for re-opening and persistent patency of the ductus arteriosus (PDA) in preterm infants. This is supported by the significantly higher incidence of PDA in infants with sepsis compared to those without sepsis in the low-dose group (see [link to article]). Figure 3B Elevated PG (such as PGE2) levels during sepsis or necrotizing enterocolitis may mediate the reopening of the ductus arteriosus in preterm infants.

[0148] However, in the group receiving high-dose probiotics, sepsis did not affect the incidence of patent ductus arteriosus, demonstrating the protective effect of high-dose probiotics (see [link to article]). Figure 3B Elevated PGE2 levels during sepsis have been identified as a mediator of ductus arteriosus reopening or persistent patency; therefore, the ability of probiotic products to reduce PGE2 may be the reason for the protective effect observed in the group receiving high doses of probiotics.

[0149] As shown in Figure 4, about 65% of the infants' stool samples showed the presence of Bifidobacterium breve CECT7263 and Lactobacillus fermentum CECT5716 two weeks after the intervention.

[0150] Table 2: Subgroup analysis – hospital sepsis events classified by colonization status at 2 weeks of age after birth.

[0151] Data is n (%), *adjusted for sex and gestational age at birth, OR = odds ratio, CI = confidence interval, Ref = reference group used to calculate the odds ratio.

[0152] As shown in Table 2, the presence of Bifidobacterium breve CECT7263 in infant feces is associated with a reduced risk of sepsis. Effects on the ductus arteriosus and its interaction with sepsis

[0153] The combination of these two probiotics appears to have some effect on the maturation of the cardiovascular system:

[0154] - The incidence of patent ductus arteriosus was significantly lower in infants who received high doses of medication.

[0155] Infants taking high doses of medication have a lower need for positive inotropic drugs.

[0156] - Patent ductus arteriosus is associated with sepsis: Infants taking high doses of probiotics are protected from the associated risk of persistent patent ductus arteriosus and sepsis.

[0157] Surprisingly, the inventors discovered that administering *Lactobacillus fermentum* CECT5716 and *Bifidobacterium breve* CECT7263 to premature infants reduced the incidence of patent ductus arteriosus (PDA). Administering higher doses of *Lactobacillus fermentum* CECT5716 and *Bifidobacterium breve* CECT7263 to premature infants further reduced the incidence of PDA. This was compared to administering 1x10... 6 CFU / day of Lactobacillus fermentum CECT5716 and 1x10 6 Compared to CFU / day of Bifidobacterium breve CECT7263, 1x10 CFU / day is used for preterm infants. 9 CFU / day of Lactobacillus fermentum CECT5716 and 1x10 9 CFU / day of Bifidobacterium breve CECT7263 reduces the incidence of patent ductus arteriosus (PDA) in infants. Similarly, daily administration of any dose of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263 to preterm infants is expected to reduce the incidence of PDA. It is possible to see the same technical effect in any infant at risk of persistent PDA and / or any infant with persistent PDA. Therefore, administration of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263 has a technical effect in treating or preventing PDA in infants (optionally preterm infants).

[0158] Surprisingly, the inventors discovered that administering *Lactobacillus fermentum* CECT5716 and *Bifidobacterium breve* CECT7263 to preterm infants can reduce the need for positive inotropic drugs. Administering higher doses of *Lactobacillus fermentum* CECT5716 and *Bifidobacterium breve* CECT7263 to preterm infants can further reduce the need for positive inotropic drugs. Compared to administering 1x10... 6 CFU / day of Lactobacillus fermentum CECT5716 and 1x10 6 Compared to CFU / day of Bifidobacterium breve CECT7263, 1x10 CFU / day is used for preterm infants. 9 CFU / day of Lactobacillus fermentum CECT5716 and 1x10 9 CFU / day of Bifidobacterium breve CECT7263 can reduce the need for positive inotropic drugs in infants. Similarly, administering any dose of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263 daily to preterm infants is expected to reduce the need for positive inotropic drugs. The same technical effect can be observed in any infant. Therefore, administration of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263 has the technical effect of reducing the need for positive inotropic drugs in infants (optionally preterm infants).

[0159] Surprisingly, the inventors discovered that administering higher doses of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263 to premature infants reduced the incidence of patent ductus arteriosus (PDA) in infants with sepsis, a risk factor for persistent PDA. This was compared to administering 1x10... 6 CFU / day of Lactobacillus fermentum CECT5716 and 1x10 6 Compared to CFU / day of Bifidobacterium breve CECT7263, 1x10 CFU / day is used for preterm infants. 9 CFU / day of Lactobacillus fermentum CECT5716 and 1x10 9 CFU / day of Bifidobacterium breve CECT7263 reduces the incidence of patent ductus arteriosus (PDA) in infants with sepsis. It is possible to see the same technical effect in any infant with PDA and / or risk of sepsis and / or with sepsis. Therefore, administration of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263 has a technical effect in protecting infants (optionally preterm infants) from the increased risk of sepsis-related PDA.

[0160] This invention is readily adaptable to various modifications and alternatives, specific examples of which are described in detail herein. However, it should be understood that this invention is not limited to the specific examples or methods disclosed; rather, it encompasses all modifications, equivalents, and alternatives falling within the spirit and scope of the claims.

Claims

1. A composition comprising Lactobacillus fermentum ( L. fermentum ) and Bifidobacterium breve ( B. breve ).

2. The composition according to claim 1, wherein the Lactobacillus fermentum is Lactobacillus fermentum strain CECT5716, and wherein the Bifidobacterium breve is Bifidobacterium breve strain CECT7263.

3. The composition according to claim 1 or 2, wherein the composition comprises at least 1 x 10 3 CFU (Cytobacterium fermentum) CECT5716, and wherein the composition contains at least 1 x 10 3 CFU Bifidobacterium breve CECT7263.

4. The composition according to claim 1, 2 or 3, wherein the composition comprises at least 1 x 10 6 CFU Lactobacillus fermentum CECT5716, and wherein the composition comprises at least 1 x 10 6 CFU Bifidobacterium breve CECT7263.

5. The composition according to any one of the preceding claims, wherein the composition comprises at least 1x10 9 CFU (Cytobacterium fermentum) CECT5716, and wherein the composition contains at least 1 x 10 9 CFU Bifidobacterium breve CECT7263.

6. The composition according to any one of the preceding claims, wherein the composition comprises 1x10 9 CFU (Cytobacterium fermentum) CECT5716, and wherein the composition contains 1 x 10 9 CFU Bifidobacterium breve CECT7263.

7. The composition of claim 1 or 2, wherein the composition comprises a combined total amount of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the combined total amount is at least 2 x 10 3 CFU.

8. The composition according to any one of claims 1 to 4 or 7, wherein the composition comprises a combined total amount of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the combined total amount is at least 2x10 6 CFU.

9. The composition according to any one of claims 1 to 4, 7 or 8, wherein the composition comprises a total amount of *Lactobacillus fermentum* CECT5716 and *Bifidobacterium breve* CECT7263, wherein the total amount is 2 x 10⁻⁶. 6 CFU.

10. The composition according to any one of the preceding claims, wherein the composition comprises a combined total amount of Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263, wherein the combined total amount is at least 2x10 9 CFU.

11. The composition according to any one of the preceding claims, wherein the composition comprises a total amount of *Lactobacillus fermentum* CECT5716 and *Bifidobacterium breve* CECT7263, wherein the total amount is 2 x 10⁻⁶. 9 CFU.

12. The composition according to any one of the preceding claims, wherein the composition is in a form that is nutritionally acceptable for infants.

13. The composition according to any one of the preceding claims, wherein the composition is in a form suitable for enteral feeding of an infant.

14. A composition for treating or preventing patent ductus arteriosus in an infant, wherein the method comprises applying the composition to the infant, and wherein the composition is the composition of any of the preceding claims.

15. The composition for use according to claim 14, wherein the infant suffers from sepsis.

16. A composition for a method of treating or preventing necrotizing enterocolitis in infants, wherein the method comprises applying the composition to the infant, and wherein the composition is the composition of any one of claims 1 to 13.

17. A composition for a method of treating or preventing infantile sepsis, wherein the method comprises applying the composition to the infant, and wherein the composition is the composition of any one of claims 1 to 13.

18. A composition for a method of treating or preventing an infant's immune system disease, wherein the method comprises applying the composition to the infant, and wherein the composition is the composition of any one of claims 1 to 13.

19. A composition for a method of treating or preventing intestinal diseases in infants, wherein the method comprises applying the composition to the infant, and wherein the composition is the composition of any one of claims 1 to 13.

20. The composition according to any one of claims 14 to 19, wherein the method comprises administering the composition to the infant once daily.

21. The composition according to any one of claims 14 to 20, wherein the infant is a newborn.

22. The composition according to any one of claims 14 to 21, wherein the infant is a premature infant.

23. The composition according to any one of claims 14 to 22, wherein the method comprises administering the composition to an infant via enteral feeding.

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