Probiotic compositions to improve immune system and gut function and to treat persistent ductus arteriosus in infants

Abstract

The invention relates to compositions comprising Lactobacillus fermentum and Bifidobacterium breve for treating or preventing persistent ductus arteriosus in infants, in particular neonates who were born preterm. The invention also relates to compositions for treating or preventing sepsis, improving the immune system and gut function.

Description

[0001] PROBIOTIC COMPOSITIONS TO IMPROVE IMMUNE SYSTEM AND GUT FUNCTION AND TO TREAT PERSISTENT DUCTUS ARTERIOSUS IN INFANTS

[0002] Field of the invention

[0003] The present invention relates to methods for improving the immune system and gut function in an infant, and method for treating or preventing in an infant: immune system disorders, sepsis, gut disorders such as necrotizing enterocolitis, and persistent ductus arteriosus.

[0004] Background

[0005] Probiotics are live microorganisms which when administered in adequate amounts confer a health benefit on the host. A probiotic can be administered by enteric feeding, for example as a dietary supplement.

[0006] Infants are at risk of immune system disorders, such as allergies, asthma, autoimmune diseases and immunodeficiency diseases. There is a need for alternative and improved methods for the treatment and prevention of disorders of the immune system in infants.

[0007] Infants are also at risk of gut disorders, such as infantile colic, functional constipation, functional diarrhoea, necrotizing enterocolitis, and gastroenteritis. There is a need for alternative and improved methods for the treatment and prevention of gut disorders in infants.

[0008] Necrotizing enterocolitis is a devastating intestinal disease that affects premature or very low birth weight infants. Symptoms of necrotizing enterocolitis may include poor feeding, bloating, decreased activity, blood in the stool, vomiting of bile, multi-organ failure, and even death. There is a need for alternative and improved methods for the treatment and prevention of necrotizing enterocolitis in infants.

[0009] Sepsis is a potentially life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. There is a need for alternative and improved methods for the treatment and prevention of sepsis in infants.

[0010] The ductus arteriosus is a vascular structure that bridges the 2 major arteries leading from the heart, connecting the proximal descending aorta to the pulmonary artery near the origin of the left branch pulmonary artery. The ductus arteriosus is an essential component of fetal circulation, diverting cardiac output away from the lungs toward the placenta to support systemic oxygenation. At birth, the placental circulation is clamped and removed, resistance in the pulmonary vascular bed decreases, and the lungs become the source of oxygenation and gas exchange; thus, the ductus arteriosus is no longer necessary. In normal term infants, the ductus arteriosus closes in >90% by 48 hours and in 100% by 96 hours of age. In preterm infants, structural and physiological immaturity of the ductus arteriosus is associated with later closure of the ductus arteriosus and increasing the probability that the ductus arteriosus will remain open at the equivalent of term gestation.

[0011] Persistent ductus arteriosus (also called patent ductus arteriosus or PDA) is a medical condition in which the ductus arteriosus fails to close after birth. Morbidities such as intraventricular hemorrhage, pulmonary hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis (NEC) and acute kidney injury are related to persistent ductus arteriosus. Closure of the ductus arteriosus occurs in two steps that are closely related: The functional step (vasoconstriction) and the anatomical step (remodelling). Two molecules play a key role in this process: Prostaglandin E2 (PGE2) and Nitric Oxide (NO). During the fetal period, the vasodilatory activity of these molecules keeps the ductus arteriosus open. After delivery, in a term infant the level and sensitivity to these molecules decreases, favouring contraction and closure of the ductus arteriosus. However, a preterm infant is more sensitive to both PGE2 and NO compared to a term infant, thus pushing the balance toward less constriction favouring persistent ductus arteriosus in preterm infants. Cyclooxygenase inhibitors, which inhibit PGE2 synthesis, have been the most common medications used to facilitate earlier closure of patent ductus arteriosus in preterm infants. However, there is a need for alternative and improved methods for the treatment and prevention of persistent ductus arteriosus in infants.

[0012] The following illustrates certain features of the invention, and is not meant to limit the scope of the invention in any way. The failure to discuss a specific feature or embodiment of the invention, or the inclusion of one or more features in this summary section, should not be construed to limit any claims.

[0013] It is also to be understood that the invention is not limited to particular compositions, methods, and experimental conditions described, as such compositions, methods, and conditions may vary. It is also to be understood that the terminology used herein is for purposes of describing particular embodiments only, and is not intended to be limiting, since the scope will be limited only by the appended claims.

[0014] As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, references to "an excipient" includes one excipient known in the art which will become apparent to those persons skilled in the art upon reading this invention and so forth.

[0015] Unless defined otherwise, 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 belongs. Any methods and materials similar or equivalent to those described herein may be used in the practice or testing of the invention, as it will be understood that modifications and variations are encompassed within the spirit and scope of the instant invention.

[0016] Any range will be understood to encompass and be a disclosure of each discrete point and subrange within the range. Stated differently, the ranges in the present disclosure are equivalent to a subset of the unwieldy and lengthy description of every possible combination of these discrete values, presented in an easily understood shorthand format (i.e., a range). The upper or lower value of any numerical range may also be replaced with the upper or lower value of another numerical range, respectively. The upper and lower value of a numerical range may also be replaced with the upper and lower value described in Examples below.

[0017] As used herein, "about," "approximately," "substantially," and "significantly" will be understood by a person of ordinary skill in the art and will vary in some extent depending on the context in which they are used. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, "about" and "approximately" will mean plus or minus <10% of particular term, and "substantially" and "significantly" will mean plus or minus >10% of the particular term. "Comprising," "consisting essentially of," and "consisting of have their customary meaning in the art.

[0018] As used herein, the terms Lactobacillus fermentum, Limosilactobacillus fermentum, and L. fermentum are synonymous. Similarly, the terms Lactobacillus fermentum CECT5716, Limosilactobacillus fermentum CECT5716, and L. fermentum CECT5716 are synonymous. Limosilactobacillus fermentum is a new name for the bacterial species previously referred to as Lactobacillus fermentum, at the time of writing both names coexist in the technical field.

[0019] As used herein, the terms “L. fermentum CECT5716”, “CECT5716”, “LC40”, and “Lc40” each referto Lactobacillus fermentum CECT5716, which is synonymous with Limosilactobacillus fermentum CECT5716.

[0020] As used herein, the terms “8. breve CECT7263”, “CECT7263”, “BFM26”, and “BfM26” each refer to Bifidobacterium breve CECT7263.

[0021] As used herein, the terms “persistent ductus arteriosus”, “patent ductus arteriosus”, “PDA”, “persistent ductus” and “ductus” are used synonymously.

[0022] As used herein, the term “NEC” refers to necrotizing enterocolitis.

[0023] Summary of the invention

[0024] Provided herein are compositions containing or comprising Limosilactobacillus fermentum (also called Lactobacillus fermentum or L. fermentum) and / or Bifidobacterium breve (B. breve). Also provided are methods of use of said compositions to improve, for example, immune system and gut function in infants. Also provided are methods for treatment, for example, of immune system and gut disorders in infants by administering said compositions. In some aspects, infants may be born preterm. Also provided are methods for treatment, for example, of persistent ductus arteriosus in infants. In some aspects, infants may be neonates. In some aspects, infants may be born preterm. In some aspects, the composition of the present invention comprises, contains, or consists of L. fermentum and / or 8. breve. In some aspects, the composition comprises, contains, or consists of L. fermentum CECT5716 and / or 8. breve CECT7263.

[0025] Optionally, L. fermentum CECT5716 is the bacterial strain deposited as biological material under the terms of the Budapest Treaty on 11 June 2002; at the COLECCION ESPANOLA DE CULTIVOS TIPO (CECT), Edificio 3 CUE, Parc Cientffic Universitat de Valencia, Catedratico Agustin Escardino, 9, 46980 Paterna (Valencia), ESPANA; and accorded accession number CECT 5716. This biological material accorded accession number CECT 5716 was deposited by Biosearch, S.A.U., Camino Purchil, 66, 18004 Granada, Espana. Accession number CECT 5716 refers to a bacterial strain which, under the new classification, has genus Limosilactobacillus and species Limosilactobacillus fermentum (an earlier classification was genus Lactobacillus, species Lactobacillus fermentum). Optionally, 8. breve CECT7263 is the bacterial strain deposited as biological material under the terms of the Budapest Treaty on 17 April 2007; at the COLECCION ESPANOLA DE CULTIVOS TIPO (CECT), Universitat de Valencia, Campus de Burjassot, 46100 Burjassot (Valencia) Spain; and accorded accession number 7263. This biological material accorded accession number 7263 was deposited by Jesus Jimenez Lopez on behalf of PULEVA BIOTECH, S.A., Camino de Purchil, 66, 18004 Granada, Spain. The depositor PULEVA BIOTECH, S.A. is now known as BIOSEARCH S.A.U. Accession number 7263 refers to a bacterial strain which has genus Bifidobacterium and species Bifidobacterium breve.

[0026] Said bacteria may be present in a total amount or independently in an amount of each strain of from 1x103CFU to 1x1012CFU, 1x104CFU to 1x101° CFU, 1x105CFU to 1x109CFU, 1x106CFU to 1x108CFU, 1x107CFU to 1x108CFU, about 1x103CFU, about 1x104CFU, about 1x105CFU, about 1x106CFU, about 1x107CFU, about 1x108CFU, about 1x109CFU, about 1x101° CFU, about 1x1011CFU, or about 1x1012CFU. In some embodiments, the composition comprises L. fermentum, optionally L. fermentum CECT5716, in an amount of from 1x103CFU to 1x1012CFU, 1x104CFU to 1x101° CFU, 1x105CFU to 1x109CFU, 1x106CFU to 1x108CFU, 1x107CFU to 1x108CFU, about 1x103CFU, about 1x104CFU, about 1x105CFU, about 1x106CFU, about 1x107CFU, about 1x108CFU, about 1x109CFU, about 1x101° CFU, about 1x1011CFU, or about 1x1012CFU. In some embodiments, the composition comprises B. breve, optionally B. breve CECT7263, in an amount of from 1x103CFU to 1x1012CFU, 1x104CFU to 1x101° CFU, 1x105CFU to 1x109CFU, 1x106CFU to 1x108CFU, 1x107CFU to 1x108CFU, about 1x103CFU, about 1x104CFU, about 1x105CFU, about 1x106CFU, about 1x107CFU, about 1x108CFU, about 1x109CFU, about 1x1010CFU, about 1x1011CFU, or about 1x1012CFU. In some embodiments, the composition comprises L. fermentum, optionally L. fermentum CECT5716, and B. breve, optionally B. breve CECT7263, in a total amount of from 1x103CFU to 1x1012CFU, 1x104CFU to 1x101° CFU, 1x105CFU to 1x109CFU, 1x106CFU to 1x108CFU, 1x107CFU to 1x108CFU, about 1x103CFU, about 1x104CFU, about 1x105CFU, about 1x106CFU, about 1x107CFU, about 1x108CFU, about 1x109CFU, about 1x1010CFU, about 1x1011CFU, or about 1x1012CFU.

[0027] The amount of L. fermentum and B. breve in the composition may be the same or different from each other. In some embodiments, the composition effectively comprises only one of L. fermentum or B. breve.

[0028] In some embodiments, the composition comprises L. fermentum, optionally L. fermentum CECT5716, at a concentration of from 1x103CFU / ml to 1x1012CFU / ml, 1x104CFU / ml to 1x101° CFU / ml, 1x105CFU / ml to 1x109CFU / ml, 1x106CFU / ml to 1x108CFU / ml, 1x107CFU / ml to 1x108CFU / ml, about 1x103CFU / ml, about 1x104CFU / ml, about 1x105CFU / ml, about 1x106CFU / ml, about 1x107CFU / ml, about 1x108CFU / ml, about 1x109CFU / ml, about 1x101° CFU / ml, about 1x1011CFU / ml, or about 1x1012CFU / ml. In some embodiments, the composition comprises B. breve, optionally B. breve CECT7263, at a concentration of from 1x103CFU / ml to 1x1012CFU / ml, 1x104CFU / ml to 1x101° CFU / ml, 1x105CFU / ml to 1x109CFU / ml, 1x106CFU / ml to 1x108CFU / ml, 1x107CFU / ml to 1x108CFU / ml, about 1x103CFU / ml, about 1x104CFU / ml, about 1x105CFU / ml, about 1x106CFU / ml, about 1x107CFU / ml, about 1x108CFU / ml, about 1x109CFU / ml, about 1x101° CFU / ml, about 1x1011CFU / ml, or about 1x1012CFU / ml. In some embodiments, the composition comprises L. fermentum, optionally L. fermentum CECT5716, and B. breve, optionally B. breve CECT7263, at a total concentration of from 1x103CFU / ml to 1x1012CFU / ml, 1x104CFU / ml to 1x101° CFU / ml, 1x105CFU / ml to 1x109CFU / ml, 1x106CFU / ml to 1x108CFU / ml, 1x107CFU / ml to 1x108CFU / ml, about 1x103CFU / ml, about 1x104CFU / ml, about 1x105CFU / ml, about 1x106CFU / ml, about 1x107CFU / ml, about 1x108CFU / ml, about 1x109CFU / ml, about 1x1010CFU / ml, about 1x1011CFU / ml, or about 1x1012CFU / ml.

[0029] The concentration of L. fermentum and B. breve in the composition may be the same or different from each other. In some embodiments, the composition effectively comprises only one of L. fermentum or B. breve.

[0030] The composition may, for example, contain or comprise suitable carriers, excipients, additives, flavours, nutritional additives and other ingredients. In some embodiments, the composition comprises maltodextrin. Optionally, the composition comprises maltodextrin in an amount of from 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 200mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg. Preferably, the composition comprises about 300 mg maltodextrin. In some embodiments, the composition comprises maltodextrin at a concentration of from 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 maltodextrin.

[0031] In some embodiments, the bacteria may be contained in a nutritional composition. In some embodiments, the composition may contain or comprise one or more additional bacterial strains. The composition may, for example, be in the form of a liquid, dispersion, suspension, or emulsion. The composition may, for example, be in solid form, such as, for example, a powder, granules, capsules, tablets and others.

[0032] The composition may, for example, be administered in combination with or mixed in breast milk or baby formula or other forms suitable for administration of probiotics to infants. In some aspects, the composition may, for example, be administered by enteric feeding, for example by nasogastric feeding or by oral administration.

[0033] In some aspects, a composition of the present invention may, for example, be administered to an infant to improve one or both of immune system and / or gut function, and / or the composition may be administered to treat one or both of disorders of the immune system and / or gut disorders. In some aspects, a composition of the present invention may, for example, be administered to treat persistent ductus arteriosus.

[0034] An infant of the present disclosure may, for example, be up to 1 year old or may be a neonate. The infant may also be preterm. In some embodiments, a preterm neonate is of a gestational age less than or equal to about 32 weeks. In some embodiments, the infant may, for example, have a birth weight of about 1500 grams (g) or less. In some embodiments, the infant may have a birth weight in the range of about 700 grams to about 1500 grams. Optionally, the infant may have a birth weight 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 has a birth weight of 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 has a birth weight in the range of about 700 grams to about 1500 grams.

[0035] In one aspect, a composition of the present invention may, for example, be administered to an infant to achieve intestinal colonization with the bacterial strain(s) or composition(s) of the present invention. The composition may, for example, be administered to an infant who has, or has been determined to have, an insufficient amount of L. fermentum or B. breve in the Gl tract.

[0036] In some aspects, each bacterial strain may, for example, be independently administered in the amount of at least 1x107CFU per day, at least 1x108CFU per day, at least 1x109CFU per day, at least 1x101° CFU per day, at least 1x1011CFU per day, at least 1x1012CFU per day, about 1x107CFU per day, about 1x108CFU per day, about 1x109CFU per day, about 1x101° CFU per day, about 1x1011CFU per day, about 1x1012CFU per day.

[0037] A composition of the present invention may, for example, be administered with every feeding of an infant or according to another suitable schedule, for example, one or more times a day, or several times a week. Suitable frequency of administration of the composition may be determined and may be varied to achieve, for example, optimal improvement of immune system and / or gut function, and / or improvement of symptoms, and / or tolerability and other factors.

[0038] The composition of the present invention may, for example, be administered to an infant exhibiting necrotizing enterocolitis (NEC), sepsis or persistent ductus arteriosus (also referred to herein as persistent ductus). The compositions of the present invention may, for example, be administered to reduce the need for treatment with one or more inotropic drug(s) [also referred to herein as inotropics].

[0039] Some embodiments of the present invention comprise a composition comprising Lactobacillus fermentum (L. fermentum) and / or Bifidobacterium breve (B. breve). Optionally, the L. fermentum is strain L. fermentum CECT5716, and / or the B. breve is strain B. breve CECT7263. Optionally, the composition comprises at least 1x103CFU L. fermentum CECT5716 and / or the composition comprises at least 1x103CFU B. breve CECT7263. Optionally, the composition comprises at least 1x106CFU L. fermentum CECT5716 and / or the composition comprises at least 1x106CFU B. breve CECT7263. Optionally, the composition comprises at least 1x109CFU L. fermentum CECT5716 and / or the composition comprises at least 1x109CFU B. breve CECT7263. Optionally, the composition comprises at least 1x1012CFU L. fermentum CECT5716 and / or the composition comprises at least 1x1012CFU B. breve CECT7263. Optionally, the composition comprises a combined total amount of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total amount is at least 1x103CFU. Optionally, the composition comprises a combined total amount of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total amount is at least 1x106CFU. Optionally, the composition comprises a combined total amount of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total amount is at least 2x106CFU. Optionally, the composition comprises a combined total amount of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total amount is at least 1x109CFU. Optionally, the composition comprises a combined total amount of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total amount is at least 2x109CFU. Optionally, the composition comprises a combined total amount of L. fermentum CECT5716 and 8. breve CECT7263, wherein the combined total amount is at least 1x1012CFU. Optionally, the composition comprises a combined total amount of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total amount is at least 2x1012CFU. Optionally, the composition has a volume of one millilitre (1 ml). Optionally, the composition comprises a concentration of at least 1x103CFU / ml L. fermentum CECT5716 and / or the composition comprises a concentration of at least 1x103CFU / ml B. breve CECT7263. Optionally, the composition comprises a concentration of at least 1x106CFU / ml L. fermentum CECT5716 and / or the composition comprises a concentration of at least 1x106CFU / ml 8. breve CECT7263. Optionally, the composition comprises a concentration of at least 1x109CFU / ml L. fermentum CECT5716 and / or the composition comprises a concentration of at least 1x109CFU / ml 8. breve CECT7263. Optionally, the composition comprises a concentration of at least 1x1012CFU / ml L. fermentum CECT5716 and / or the composition comprises a concentration of at least 1x1012CFU / ml 8. breve CECT7263. Optionally, the composition comprises a combined total concentration of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total concentration is at least 1x103CFU / ml. Optionally, the composition comprises a combined total concentration of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total concentration is at least 2x103CFU / ml. Optionally, the composition comprises a combined total concentration of L. fermentum CECT5716 and 8. breve CECT7263, wherein the combined total concentration is at least 1x106CFU / ml. Optionally, the composition comprises a combined total concentration of L. fermentum CECT5716 and 8. breve CECT7263, wherein the combined total concentration is at least 2x106CFU / ml. Optionally, the composition comprises a combined total concentration of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total concentration is at least 1x109CFU / ml. Optionally, the composition comprises a combined total concentration of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total concentration is at least 2x109CFU / ml. Optionally, the composition comprises a combined total concentration of L. fermentum CECT5716 and 8. breve CECT7263, wherein the combined total concentration is at least 1x1012CFU / ml. Optionally, the composition comprises a combined total concentration of L. fermentum CECT5716 and 8. breve CECT7263, wherein the combined total concentration is at least 2x1012CFU / ml. Optionally, the composition is in a form nutritionally acceptable for an infant. Optionally, the composition is in a form suitable for enteric feeding of an infant, for example by nasogastric feeding or by oral administration.

[0040] Some embodiments of the present invention comprise a composition for use in a method for treating or preventing persistent ductus arteriosus in an infant, wherein the method comprises administering the composition to the infant, and wherein the composition is any composition according to the present invention. For example, in some embodiments the composition comprises L. fermentum, optionally L. fermentum CECT5716, and / or B. breve, optionally B. breve CECT7263. Optionally, the composition comprises L. fermentum CECT5716 in an amount of at least 1x103CFU, optionally at least 1x106CFU, optionally at least 1x109CFU, optionally at least 1x1012CFU and / or the composition comprises 8. breve CECT7263 in an amount of at least 1x103CFU, optionally at least 1x106CFU, optionally at least 1x109CFU, optionally at least 1x1012CFU. Optionally, the composition comprises a combined total amount of L. fermentum CECT5716 and 8. breve CECT7263, wherein the combined total amount is at least 1x103CFU, optionally at least 2x103CFU, optionally at least 1x106CFU, optionally at least 2x106CFU, optionally at least 1x109CFU, optionally at least 2x109CFU, optionally at least 1x1012CFU, optionally at least 2x1012CFU. Optionally, the composition has a volume of one millilitre (1 ml). Optionally, the composition comprises L. fermentum CECT5716 at a concentration of at least 1x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 1x109CFU / ml, optionally at least 1x1012CFU / ml, and / or the composition comprises B. breve CECT7263 at a concentration of at least 1x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 1x109CFU / ml, optionally at least 1x1012CFU / ml. Optionally, the composition comprises a combined total concentration of L. fermentum CECT5716 and 8. breve CECT7263, wherein the combined total concentration is at least 1x103CFU / ml, optionally at least 2x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 2x106CFU / ml, optionally at least 1x109CFU / ml, optionally at least 2x109CFU / ml, optionally at least 1x1012CFU / ml, optionally at least 2x1012CFU / ml. Optionally, the composition is in a form nutritionally acceptable for an infant. Optionally, the composition is in a form suitable for enteric feeding (e.g. by nasogastric feeding or by oral administration) to an infant.

[0041] Optionally, the composition for use in a method for treating or preventing persistent ductus arteriosus is for use in an infant who has sepsis. Optionally, the infant is a neonate. Optionally, the infant was born preterm. Further optionally, or additionally, the method comprises administering the composition to the infant once per day. Optionally, the method comprises administering the composition to the infant by enteric feeding, for example by nasogastric feeding or by oral administration. Optionally, the method comprises administering the composition to the infant with food; such as breast milk, milk from the Donated Breast Milk Bank, baby formula or formula milk, and / or artificial formula for premature babies. Preferably, the method comprises administering a constant daily volume of the composition to the infant with a volume of food that varies depending on the weight of the infant. Most preferably, the method comprises daily administration to the infant of 1 ml composition and a food volume equal to 5 ml food per 1 kg infant weight. Optionally, the method comprises administering the composition to the infant with food in a ratio of composition:food 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.

[0042] A preferred embodiment of the present invention comprises a composition for use in a method for treating or preventing persistent ductus arteriosus in an infant who was born preterm; wherein the method comprises administering the composition to the infant once per day by enteric feeding together with food such as breast milk, milk from the Donated Breast Milk Bank, baby formula or formula milk, and / or artificial formula for premature babies; wherein the composition comprises at least 1x109CFU L. fermentum CECT5716 and the composition comprises at least 1x109CFU 8. breve CECT7263.

[0043] Some embodiments of the present invention comprise a composition for use in a method for treating or preventing necrotizing enterocolitis in an infant, wherein the method comprises administering the composition to the infant, and wherein the composition is any composition according to the present invention. For example, in some embodiments the composition comprises L. fermentum, optionally L. fermentum CECT5716, and / or 8. breve, optionally 8. breve CECT7263. Optionally, the composition comprises L. fermentum CECT5716 in an amount of at least 1x103CFU, optionally at least 1x106CFU, optionally at least 1x109CFU, optionally at least 1x1012CFU and / or the composition comprises 8. breve CECT7263 in an amount of at least 1x103CFU, optionally at least 1x106CFU, optionally at least 1x109CFU, optionally at least 1x1012CFU. Optionally, the composition comprises a combined total amount of L. fermentum CECT5716 and 8. breve CECT7263, wherein the combined total amount is at least 1x103CFU, optionally at least 2x103CFU, optionally at least 1x106CFU, optionally at least 2x106CFU, optionally at least 1x109CFU, optionally at least 2x109CFU, optionally at least 1x1012CFU, optionally at least 2x1012CFU. Optionally, the composition has a volume of one millilitre (1 ml). Optionally, the composition comprises L. fermentum CECT5716 at a concentration of at least 1x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 1x109CFU / ml optionally at least 1x1012CFU / ml and / or the composition comprises 8. breve CECT7263 at a concentration of at least 1x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 1x109CFU / ml, optionally at least 1x1012CFU / ml. Optionally, the composition comprises a combined total concentration of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total concentration is at least 1x103CFU / ml, optionally at least 2x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 2x106CFU / ml, optionally at least 1x109CFU / ml, optionally at least 2x109CFU / ml, optionally at least 1x1012CFU / ml, optionally at least 2x1012CFU / ml. Optionally, the composition is in a form nutritionally acceptable for an infant. Optionally, the composition is in a form suitable for enteric feeding (e.g. by nasogastric feeding or by oral administration) to an infant. Optionally, the infant is a neonate. Optionally, the infant was born preterm. Further optionally, or additionally, the method comprises administering the composition to the infant once per day. Optionally, the method comprises administering the composition to the infant by enteric feeding, for example by nasogastric feeding or by oral administration. Optionally, the method comprises administering the composition to the infant with food; such as breast milk, milk from the Donated Breast Milk Bank, baby formula or formula milk, and / or artificial formula for premature babies. Preferably, the method comprises administering a constant daily volume of the composition to the infant with a volume of food that varies depending on the weight of the infant. Most preferably, the method comprises daily administration to the infant of 1 ml composition and a food volume equal to 5 ml food per 1 kg infant weight. Optionally, the method comprises administering the composition to the infant with food in a ratio composition :food 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 comprise a composition for use in a method for treating or preventing sepsis in an infant, wherein the method comprises administering the composition to the infant, and wherein the composition is any composition according to the present invention. For example, in some embodiments the composition comprises L. fermentum, optionally L. fermentum CECT5716, and / or 8. breve, optionally B. breve CECT7263. Optionally, the composition comprises L. fermentum CECT5716 in an amount of at least 1x103CFU, optionally at least 1x106CFU, optionally at least 1x109CFU, optionally at least 1x1012CFU and / or the composition comprises B. breve CECT7263 in an amount of at least 1x103CFU, optionally at least 1x106CFU, optionally at least 1x109CFU, optionally at least 1x1012CFU. Optionally, the composition comprises a combined total amount of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total amount is at least 1x103CFU, optionally at least 2x103CFU, optionally at least 1x106CFU, optionally at least 2x106CFU, optionally at least 1x109CFU, optionally at least 2x109CFU, optionally at least 1x1012CFU, optionally at least 2x1012CFU. Optionally, the composition has a volume of one millilitre (1 ml). Optionally, the composition comprises L. fermentum CECT5716 at a concentration of at least 1x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 1x109CFU / ml optionally at least 1x1012CFU / ml and / or the composition comprises B. breve CECT7263 at a concentration of at least 1x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 1x109CFU / ml, optionally at least 1x1012CFU / ml. Optionally, the composition comprises a combined total concentration of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total concentration is at least 1x103CFU / ml, optionally at least 2x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 2x106CFU / ml, optionally at least 1x109CFU / ml, optionally at least 2x109CFU / ml, optionally at least 1x1012CFU / ml, optionally at least 2x1012CFU / ml. Optionally, the composition is in a form nutritionally acceptable for an infant. Optionally, the composition is in a form suitable for enteric feeding (e.g. by nasogastric feeding or by oral administration) to an infant. Optionally, the infant is a neonate. Optionally, the infant was born preterm. Further optionally, or additionally, the method comprises administering the composition to the infant once per day. Optionally, the method comprises administering the composition to the infant by enteric feeding, for example by nasogastric feeding or by oral administration. Optionally, the method comprises administering the composition to the infant with food; such as breast milk, milk from the Donated Breast Milk Bank, baby formula or formula milk, and / or artificial formula for premature babies. Preferably, the method comprises administering a constant daily volume of the composition to the infant with a volume of food that varies depending on the weight of the infant. Most preferably, the method comprises daily administration to the infant of 1 ml composition and a food volume equal to 5 ml food per 1 kg infant weight. Optionally, the method comprises administering the composition to the infant with food in a ratio composition :food 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 comprise a composition for use in a method for treating or preventing an immune system disorder in an infant, wherein the method comprises administering the composition to the infant, and wherein the composition is any composition according to the present invention. For example, in some embodiments the composition comprises L. fermentum, optionally L. fermentum CECT5716, and / or B. breve, optionally B. breve CECT7263. Optionally, the composition comprises L. fermentum CECT5716 in an amount of at least 1x103CFU, optionally at least 1x106CFU, optionally at least 1x109CFU, optionally at least 1x1012CFU and / or the composition comprises B. breve CECT7263 in an amount of at least 1x103CFU, optionally at least 1x106CFU, optionally at least 1x109CFU, optionally at least 1x1012CFU. Optionally, the composition comprises a combined total amount of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total amount is at least 1x103CFU, optionally at least 2x103CFU, optionally at least 1x106CFU, optionally at least 2x106CFU, optionally at least 1x109CFU, optionally at least 2x109 CFU, optionally at least 1x1012CFU, optionally at least 2x1012CFU. Optionally, the composition has a volume of one millilitre (1 ml). Optionally, the composition comprises L. fermentum CECT5716 at a concentration of at least 1x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 1x109CFU / ml optionally at least 1x1012CFU / ml and / or the composition comprises B. breve CECT7263 at a concentration of at least 1x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 1x109CFU / ml, optionally at least 1x1012CFU / ml. Optionally, the composition comprises a combined total concentration of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total concentration is at least 1x103CFU / ml, optionally at least 2x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 2x106CFU / ml, optionally at least 1x109CFU / ml, optionally at least 2x109CFU / ml, optionally at least 1x1012CFU / ml, optionally at least 2x1012CFU / ml. Optionally, the composition is in a form nutritionally acceptable for an infant. Optionally, the composition is in a form suitable for enteric feeding (e.g. by nasogastric feeding or by oral administration) to an infant. Optionally, the infant is a neonate. Optionally, the infant was born preterm. Further optionally, or additionally, the method comprises administering the composition to the infant once per day. Optionally, the method comprises administering the composition to the infant by enteric feeding, for example by nasogastric feeding or by oral administration. Optionally, the method comprises administering the composition to the infant with food; such as breast milk, milk from the Donated Breast Milk Bank, baby formula or formula milk, and / or artificial formula for premature babies.

[0046] Preferably, the method comprises administering a constant daily volume of the composition to the infant with a volume of food that varies depending on the weight of the infant. Most preferably, the method comprises daily administration to the infant of 1 ml composition and a food volume equal to 5 ml food per 1 kg infant weight. Optionally, the method comprises administering the composition to the infant with food in a ratio composition:food 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 comprise a composition for use in a method for treating or preventing a gut disorder in an infant, wherein the method comprises administering the composition to the infant, and wherein the composition is any composition according to the present invention. For example, in some embodiments the composition comprises L. fermentum, optionally L. fermentum CECT5716, and / or B. breve, optionally B. breve CECT7263. Optionally, the composition comprises L. fermentum CECT5716 in an amount of at least 1x103CFU, optionally at least 1x106CFU, optionally at least 1x109CFU, optionally at least 1x1012CFU and / or the composition comprises B. breve CECT7263 in an amount of at least 1x103CFU, optionally at least 1x106CFU, optionally at least 1x109CFU, optionally at least 1x1012CFU. Optionally, the composition comprises a combined total amount of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total amount is at least 1x103CFU, optionally at least 2x103CFU, optionally at least 1x106CFU, optionally at least 2x106CFU, optionally at least 1x109CFU, optionally at least 2x109CFU, optionally at least 1x1012CFU, optionally at least 2x1012CFU. Optionally, the composition has a volume of one millilitre (1 ml). Optionally, the composition comprises L. fermentum CECT5716 at a concentration of at least 1x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 1x109CFU / ml optionally at least 1x1012CFU / ml and / or the composition comprises B. breve CECT7263 at a concentration of at least 1x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 1x109CFU / ml, optionally at least 1x1012CFU / ml. Optionally, the composition comprises a combined total concentration of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total concentration is at least 1x103CFU / ml, optionally at least 2x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 2x106CFU / ml, optionally at least 1x109CFU / ml, optionally at least 2x109CFU / ml, optionally at least 1x1012CFU / ml, optionally at least 2x1012CFU / ml. Optionally, the composition is in a form nutritionally acceptable for an infant. Optionally, the composition is in a form suitable for enteric feeding (e.g. by nasogastric feeding or by oral administration) to an infant. Optionally, the infant is a neonate. Optionally, the infant was born preterm. Further optionally, or additionally, the method comprises administering the composition to the infant once per day. Optionally, the method comprises administering the composition to the infant by enteric feeding, for example by nasogastric feeding or by oral administration. Optionally, the method comprises administering the composition to the infant with food; such as breast milk, milk from the Donated Breast Milk Bank, baby formula or formula milk, and / or artificial formula for premature babies. Preferably, the method comprises administering a constant daily volume of the composition to the infant with a volume of food that varies depending on the weight of the infant. Most preferably, the method comprises daily administration to the infant of 1 ml composition and a food volume equal to 5 ml food per 1 kg infant weight. Optionally, the method comprises administering the composition to the infant with food in a ratio composition :food 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 comprise a method for treating or preventing persistent ductus arteriosus in an infant, wherein the method comprises administering the composition to the infant, and wherein the composition is any composition according to the present invention. For example, in some embodiments the composition comprises L. fermentum, optionally L. fermentum CECT5716, and / or B. breve, optionally B. breve CECT7263. Optionally, the composition comprises L. fermentum CECT5716 in an amount of at least 1x103CFU, optionally at least 1x106CFU, optionally at least 1x109CFU, optionally at least 1x1012CFU and / or the composition comprises B. breve CECT7263 in an amount of at least 1x103CFU, optionally at least 1x106CFU, optionally at least 1x109CFU, optionally at least 1x1012CFU. Optionally, the composition comprises a combined total amount of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total amount is at least 1x103CFU, optionally at least 2x103CFU, optionally at least 1x106CFU, optionally at least 2x106CFU, optionally at least 1x109CFU, optionally at least 2x109CFU, optionally at least 1x1012CFU, optionally at least 2x1012CFU. Optionally, the composition has a volume of one millilitre (1 ml). Optionally, the composition comprises L. fermentum CECT5716 at a concentration of at least 1x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 1x109CFU / ml optionally at least 1x1012CFU / ml and / or the composition comprises B. breve CECT7263 at a concentration of at least 1x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 1x109CFU / ml, optionally at least 1x1012CFU / ml. Optionally, the composition comprises a combined total concentration of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total concentration is at least 1x103CFU / ml, optionally at least 2x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 2x106CFU / ml, optionally at least 1x109CFU / ml, optionally at least 2x109CFU / ml, optionally at least 1x1012CFU / ml, optionally at least 2x1012CFU / ml. Optionally, the composition is in a form nutritionally acceptable for an infant. Optionally, the composition is in a form suitable for enteric feeding (e.g. by nasogastric feeding or by oral administration) to an infant. Optionally, the method for treating or preventing persistent ductus arteriosus is for use in an infant who has sepsis. Optionally, the infant is a neonate. Optionally, the infant was born preterm. Further optionally, or additionally, the method comprises administering the composition to the infant once per day. Optionally, the method comprises administering the composition to the infant by enteric feeding, for example by nasogastric feeding or by oral administration. Optionally, the method comprises administering the composition to the infant with food; such as breast milk, milk from the Donated Breast Milk Bank, baby formula or formula milk, and / or artificial formula for premature babies. Preferably, the method comprises administering a constant daily volume of the composition to the infant with a volume of food that varies depending on the weight of the infant. Most preferably, the method comprises daily administration to the infant of 1 ml composition and a food volume equal to 5 ml food per 1 kg infant weight. Optionally, the method comprises administering the composition to the infant with food in a ratio composition :food 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 comprise a method for treating or preventing necrotizing enterocolitis in an infant, wherein the method comprises administering the composition to the infant, and wherein the composition is any composition according to the present invention. For example, in some embodiments the composition comprises L. fermentum, optionally L. fermentum CECT5716, and / or B. breve, optionally B. breve CECT7263. Optionally, the composition comprises L. fermentum CECT5716 in an amount of at least 1x103CFU, optionally at least 1x106CFU, optionally at least 1x109CFU, optionally at least 1x1012CFU and / or the composition comprises B. breve CECT7263 in an amount of at least 1x103CFU, optionally at least 1x106CFU, optionally at least 1x109CFU, optionally at least 1x1012CFU. Optionally, the composition comprises a combined total amount of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total amount is at least 1x103CFU, optionally at least 2x103CFU, optionally at least 1x106CFU, optionally at least 2x106CFU, optionally at least 1x109CFU, optionally at least 2x109CFU, optionally at least 1x1012CFU, optionally at least 2x1012CFU. Optionally, the composition has a volume of one millilitre (1 ml). Optionally, the composition comprises L. fermentum CECT5716 at a concentration of at least 1x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 1x109CFU / ml optionally at least 1x1012CFU / ml and / or the composition comprises B. breve CECT7263 at a concentration of at least 1x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 1x109CFU / ml, optionally at least 1x1012CFU / ml. Optionally, the composition comprises a combined total concentration of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total concentration is at least 1x103CFU / ml, optionally at least 2x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 2x106CFU / ml, optionally at least 1x109CFU / ml, optionally at least 2x109CFU / ml, optionally at least 1x1012CFU / ml, optionally at least 2x1012CFU / ml. Optionally, the composition is in a form nutritionally acceptable for an infant. Optionally, the composition is in a form suitable for enteric feeding (e.g. by nasogastric feeding or by oral administration) to an infant. Optionally, the infant is a neonate. Optionally, the infant was born preterm. Further optionally, or additionally, the method comprises administering the composition to the infant once per day. Optionally, the method comprises administering the composition to the infant by enteric feeding, for example by nasogastric feeding or by oral administration. Optionally, the method comprises administering the composition to the infant with food; such as breast milk, milk from the Donated Breast Milk Bank, baby formula or formula milk, and / or artificial formula for premature babies. Preferably, the method comprises administering a constant daily volume of the composition to the infant with a volume of food that varies depending on the weight of the infant. Most preferably, the method comprises daily administration to the infant of 1 ml composition and a food volume equal to 5 ml food per 1 kg infant weight. Optionally, the method comprises administering the composition to the infant with food in a ratio composition:food 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 comprise a method for treating or preventing sepsis in an infant, wherein the method comprises administering the composition to the infant, and wherein the composition is any composition according to the present invention. For example, in some embodiments the composition comprises L. fermentum, optionally L. fermentum CECT5716, and / or B. breve, optionally B. breve CECT7263. Optionally, the composition comprises L. fermentum CECT5716 in an amount of at least 1x103CFU, optionally at least 1x106CFU, optionally at least 1x109CFU, optionally at least 1x1012CFU and / or the composition comprises B. breve CECT7263 in an amount of at least 1x103CFU, optionally at least 1x106CFU, optionally at least 1x109CFU, optionally at least 1x1012CFU. Optionally, the composition comprises a combined total amount of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total amount is at least 1x103CFU, optionally at least 2x103CFU, optionally at least 1x106CFU, optionally at least 2x106CFU, optionally at least 1x109CFU, optionally at least 2x109CFU, optionally at least 1x1012CFU, optionally at least 2x1012CFU. Optionally, the composition has a volume of one millilitre (1 ml). Optionally, the composition comprises L. fermentum CECT5716 at a concentration of at least 1x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 1x109CFU / ml optionally at least 1x1012CFU / ml and / or the composition comprises B. breve CECT7263 at a concentration of at least 1x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 1x109CFU / ml, optionally at least 1x1012CFU / ml. Optionally, the composition comprises a combined total concentration of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total concentration is at least 1x103CFU / ml, optionally at least 2x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 2x106CFU / ml, optionally at least 1x109CFU / ml, optionally at least 2x109CFU / ml, optionally at least 1x1012CFU / ml, optionally at least 2x1012CFU / ml. Optionally, the composition is in a form nutritionally acceptable for an infant. Optionally, the composition is in a form suitable for enteric feeding (e.g. by nasogastric feeding or by oral administration) to an infant. Optionally, the infant is a neonate. Optionally, the infant was born preterm. Further optionally, or additionally, the method comprises administering the composition to the infant once per day. Optionally, the method comprises administering the composition to the infant by enteric feeding, for example by nasogastric feeding or by oral administration. Optionally, the method comprises administering the composition to the infant with food; such as breast milk, milk from the Donated Breast Milk Bank, baby formula or formula milk, and / or artificial formula for premature babies. Preferably, the method comprises administering a constant daily volume of the composition to the infant with a volume of food that varies depending on the weight of the infant. Most preferably, the method comprises daily administration to the infant of 1 ml composition and a food volume equal to 5 ml food per 1 kg infant weight. Optionally, the method comprises administering the composition to the infant with food in a ratio composition:food 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 comprise a method for treating or preventing an immune system disorder in an infant, wherein the method comprises administering the composition to the infant, and wherein the composition is any composition according to the present invention. For example, in some embodiments the composition comprises L. fermentum, optionally L. fermentum CECT5716, and / or B. breve, optionally B. breve CECT7263. Optionally, the composition comprises L. fermentum CECT5716 in an amount of at least 1x103CFU, optionally at least 1x106CFU, optionally at least 1x109CFU, optionally at least 1x1012CFU and / or the composition comprises B. breve CECT7263 in an amount of at least 1x103CFU, optionally at least 1x106CFU, optionally at least 1x109CFU, optionally at least 1x1012CFU. Optionally, the composition comprises a combined total amount of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total amount is at least 1x103CFU, optionally at least 2x103CFU, optionally at least 1x106CFU, optionally at least 2x106CFU, optionally at least 1x109CFU, optionally at least 2x109CFU, optionally at least 1x1012CFU, optionally at least 2x1012CFU. Optionally, the composition has a volume of one millilitre (1 ml). Optionally, the composition comprises L. fermentum CECT5716 at a concentration of at least 1x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 1x109CFU / ml optionally at least 1x1012CFU / ml and / or the composition comprises B. breve CECT7263 at a concentration of at least 1x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 1x109CFU / ml, optionally at least 1x1012CFU / ml. Optionally, the composition comprises a combined total concentration of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total concentration is at least 1x103CFU / ml, optionally at least 2x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 2x106CFU / ml, optionally at least 1x109CFU / ml, optionally at least 2x109CFU / ml, optionally at least 1x1012CFU / ml, optionally at least 2x1012CFU / ml. Optionally, the composition is in a form nutritionally acceptable for an infant. Optionally, the composition is in a form suitable for enteric feeding (e.g. by nasogastric feeding or by oral administration) to an infant. Optionally, the infant is a neonate. Optionally, the infant was born preterm. Further optionally, or additionally, the method comprises administering the composition to the infant once per day. Optionally, the method comprises administering the composition to the infant by enteric feeding, for example by nasogastric feeding or by oral administration. Optionally, the method comprises administering the composition to the infant with food; such as breast milk, milk from the Donated Breast Milk Bank, baby formula or formula milk, and / or artificial formula for premature babies. Preferably, the method comprises administering a constant daily volume of the composition to the infant with a volume of food that varies depending on the weight of the infant. Most preferably, the method comprises daily administration to the infant of 1 ml composition and a food volume equal to 5 ml food per 1 kg infant weight. Optionally, the method comprises administering the composition to the infant with food in a ratio composition :food 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 comprise a method for treating or preventing a gut disorder in an infant, wherein the method comprises administering the composition to the infant, and wherein the composition is any composition according to the present invention. For example, in some embodiments the composition comprises L. fermentum, optionally L. fermentum CECT5716, and / or B. breve, optionally B. breve CECT7263. Optionally, the composition comprises L. fermentum CECT5716 in an amount of at least 1x103CFU, optionally at least 1x106CFU, optionally at least 1x109CFU, optionally at least 1x1012CFU and / or the composition comprises B. breve CECT7263 in an amount of at least 1x103CFU, optionally at least 1x106CFU, optionally at least 1x109CFU, optionally at least 1x1012CFU. Optionally, the composition comprises a combined total amount of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total amount is at least 1x103CFU, optionally at least 2x103CFU, optionally at least 1x106CFU, optionally at least 2x106CFU, optionally at least 1x109CFU, optionally at least 2x109CFU, optionally at least 1x1012CFU, optionally at least 2x1012CFU. Optionally, the composition has a volume of one millilitre (1 ml). Optionally, the composition comprises L. fermentum CECT5716 at a concentration of at least 1x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 1x109CFU / ml optionally at least 1x1012CFU / ml and / or the composition comprises B. breve CECT7263 at a concentration of at least 1x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 1x109CFU / ml, optionally at least 1x1012CFU / ml. Optionally, the composition comprises a combined total concentration of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total concentration is at least 1x103CFU / ml, optionally at least 2x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 2x106CFU / ml, optionally at least 1x109CFU / ml, optionally at least 2x109CFU / ml, optionally at least 1x1012CFU / ml, optionally at least 2x1012CFU / ml. Optionally, the composition is in a form nutritionally acceptable for an infant. Optionally, the composition is in a form suitable for enteric feeding (e.g. by nasogastric feeding or by oral administration) to an infant. Optionally, the infant is a neonate.

[0053] Optionally, the infant was born preterm. Further optionally, or additionally, the method comprises administering the composition to the infant once per day. Optionally, the method comprises administering the composition to the infant by enteric feeding, for example by nasogastric feeding or by oral administration. Optionally, the method comprises administering the composition to the infant with food; such as breast milk, milk from the Donated Breast Milk Bank, baby formula or formula milk, and / or artificial formula for premature babies. Preferably, the method comprises administering a constant daily volume of the composition to the infant with a volume of food that varies depending on the weight of the infant. Most preferably, the method comprises daily administration to the infant of 1 ml composition and a food volume equal to 5 ml food per 1 kg infant weight. Optionally, the method comprises administering the composition to the infant with food in a ratio composition:food 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 comprise use of a composition in the manufacture of a medicament for treating or preventing persistent ductus arteriosus in an infant, wherein the composition is any composition according to the present invention. For example, in some embodiments the composition comprises L. fermentum, optionally L. fermentum CECT5716, and / or B. breve, optionally B. breve CECT7263. Optionally, the composition comprises L. fermentum CECT5716 in an amount of at least 1x103CFU, optionally at least 1x106CFU, optionally at least 1x109CFU, optionally at least 1x1012CFU and / or the composition comprises B. breve CECT7263 in an amount of at least 1x103CFU, optionally at least 1x106CFU, optionally at least 1x109CFU, optionally at least 1x1012CFU. Optionally, the composition comprises a combined total amount of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total amount is at least 1x103CFU, optionally at least 2x103CFU, optionally at least 1x106CFU, optionally at least 2x106CFU, optionally at least 1x109CFU, optionally at least 2x109CFU, optionally at least 1x1012CFU, optionally at least 2x1012CFU. Optionally, the composition has a volume of one millilitre (1 ml). Optionally, the composition comprises L. fermentum CECT5716 at a concentration of at least 1x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 1x109CFU / ml optionally at least 1x1012CFU / ml and / or the composition comprises B. breve CECT7263 at a concentration of at least 1x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 1x109CFU / ml, optionally at least 1x1012CFU / ml. Optionally, the composition comprises a combined total concentration of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total concentration is at least 1x103CFU / ml, optionally at least 2x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 2x106CFU / ml, optionally at least 1x109CFU / ml, optionally at least 2x109CFU / ml, optionally at least 1x1012CFU / ml, optionally at least 2x1012CFU / ml. Optionally, the composition and / or the medicament is in a form nutritionally acceptable for an infant. Optionally, the composition and / or the medicament is in a form suitable for enteric feeding (e.g. by nasogastric feeding or by oral administration) to an infant. Optionally, the medicament is for use in an infant who has sepsis. Optionally, the infant is a neonate. Optionally, the infant was born preterm. Further optionally, or additionally, the medicament is to be administered to the infant once per day. Optionally, the medicament is to be administered to the infant by enteric feeding, for example by nasogastric feeding or by oral administration. Optionally, the medicament is to be administered to the infant with food; such as breast milk, milk from the Donated Breast Milk Bank, baby formula or formula milk, and / or artificial formula for premature babies. Preferably, the medicament is to be administered to the infant as a constant daily volume of medicament with a volume of food that varies depending on the weight of the infant. Most preferably, the medicament is to be administered to the infant as a daily volume of 1 ml medicament with a food volume equal to 5 ml food per 1 kg infant weight. Optionally, the medicament is to be administered to the infant with food in a ratio composition:food 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. Some embodiments of the present invention comprise use of a composition in the manufacture of a medicament for treating or preventing necrotizing enterocolitis in an infant, wherein the composition is any composition according to the present invention. For example, in some embodiments the composition comprises L. fermentum, optionally L. fermentum CECT5716, and / or B. breve, optionally B. breve CECT7263. Optionally, the composition comprises L. fermentum CECT5716 in an amount of at least 1x103CFU, optionally at least 1x106CFU, optionally at least 1x109CFU, optionally at least 1x1012CFU and / or the composition comprises B. breve CECT7263 in an amount of at least 1x103CFU, optionally at least 1x106CFU, optionally at least 1x109CFU, optionally at least 1x1012CFU. Optionally, the composition comprises a combined total amount of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total amount is at least 1x103CFU, optionally at least 2x103CFU, optionally at least 1x106CFU, optionally at least 2x106CFU, optionally at least 1x109CFU, optionally at least 2x109CFU, optionally at least 1x1012CFU, optionally at least 2x1012CFU. Optionally, the composition has a volume of one millilitre (1 ml). Optionally, the composition comprises L. fermentum CECT5716 at a concentration of at least 1x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 1x109CFU / ml optionally at least 1x1012CFU / ml and / or the composition comprises B. breve CECT7263 at a concentration of at least 1x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 1x109CFU / ml, optionally at least 1x1012CFU / ml. Optionally, the composition comprises a combined total concentration of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total concentration is at least 1x103CFU / ml, optionally at least 2x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 2x106CFU / ml, optionally at least 1x109CFU / ml, optionally at least 2x109CFU / ml, optionally at least 1x1012CFU / ml, optionally at least 2x1012CFU / ml. Optionally, the composition and / or the medicament is in a form nutritionally acceptable for an infant. Optionally, the composition and / or the medicament is in a form suitable for enteric feeding (e.g. by nasogastric feeding or by oral administration) to an infant. Optionally, the infant is a neonate. Optionally, the infant was born preterm. Further optionally, or additionally, the medicament is to be administered to the infant once per day. Optionally, the medicament is to be administered to the infant by enteric feeding, for example by nasogastric feeding or by oral administration. Optionally, the medicament is to be administered to the infant with food; such as breast milk, milk from the Donated Breast Milk Bank, baby formula or formula milk, and / or artificial formula for premature babies. Preferably, the medicament is to be administered to the infant as a constant daily volume of medicament with a volume of food that varies depending on the weight of the infant. Most preferably, the medicament is to be administered to the infant as a daily volume of 1 ml medicament with a food volume equal to 5 ml food per 1 kg infant weight. Optionally, the medicament is to be administered to the infant with food in a ratio composition:food 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 comprise use of a composition in the manufacture of a medicament for treating or preventing sepsis in an infant, wherein the composition is any composition according to the present invention. For example, in some embodiments the composition comprises L. fermentum, optionally L. fermentum CECT5716, and / or B. breve, optionally B. breve CECT7263. Optionally, the composition comprises L. fermentum CECT5716 in an amount of at least 1x103CFU, optionally at least 1x106CFU, optionally at least 1x109CFU, optionally at least 1x1012CFU and / or the composition comprises B. breve CECT7263 in an amount of at least 1x103CFU, optionally at least 1x106CFU, optionally at least 1x109CFU, optionally at least 1x1012CFU. Optionally, the composition comprises a combined total amount of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total amount is at least 1x103CFU, optionally at least 2x103CFU, optionally at least 1x106CFU, optionally at least 2x106CFU, optionally at least 1x109CFU, optionally at least 2x109CFU, optionally at least 1x1012CFU, optionally at least 2x1012CFU. Optionally, the composition has a volume of one millilitre (1 ml). Optionally, the composition comprises L. fermentum CECT5716 at a concentration of at least 1x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 1x109CFU / ml optionally at least 1x1012CFU / ml and / or the composition comprises B. breve CECT7263 at a concentration of at least 1x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 1x109CFU / ml, optionally at least 1x1012CFU / ml. Optionally, the composition comprises a combined total concentration of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total concentration is at least 1x103CFU / ml, optionally at least 2x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 2x106CFU / ml, optionally at least 1x109CFU / ml, optionally at least 2x109CFU / ml, optionally at least 1x1012CFU / ml, optionally at least 2x1012CFU / ml. Optionally, the composition and / or the medicament is in a form nutritionally acceptable for an infant. Optionally, the composition and / or the medicament is in a form suitable for enteric feeding (e.g. by nasogastric feeding or by oral administration) to an infant. Optionally, the infant is a neonate. Optionally, the infant was born preterm. Further optionally, or additionally, the medicament is to be administered to the infant once per day. Optionally, the medicament is to be administered to the infant by enteric feeding, for example by nasogastric feeding or by oral administration. Optionally, the medicament is to be administered to the infant with food; such as breast milk, milk from the Donated Breast Milk Bank, baby formula or formula milk, and / or artificial formula for premature babies. Preferably, the medicament is to be administered to the infant as a constant daily volume of medicament with a volume of food that varies depending on the weight of the infant. Most preferably, the medicament is to be administered to the infant as a daily volume of 1 ml medicament with a food volume equal to 5 ml food per 1 kg infant weight. Optionally, the medicament is to be administered to the infant with food in a ratio composition:food 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. Some embodiments of the present invention comprise use of a composition in the manufacture of a medicament for treating or preventing an immune system disorder in an infant, wherein the composition is any composition according to the present invention. For example, in some embodiments the composition comprises L. fermentum, optionally L. fermentum CECT5716, and / or B. breve, optionally B. breve CECT7263. Optionally, the composition comprises L. fermentum CECT5716 in an amount of at least 1x103CFU, optionally at least 1x106CFU, optionally at least 1x109CFU, optionally at least 1x1012CFU and / or the composition comprises B. breve CECT7263 in an amount of at least 1x103CFU, optionally at least 1x106CFU, optionally at least 1x109CFU, optionally at least 1x1012CFU. Optionally, the composition comprises a combined total amount of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total amount is at least 1x103 CFU, optionally at least 2x103CFU, optionally at least 1x106CFU, optionally at least 2x106CFU, optionally at least 1x109CFU, optionally at least 2x109CFU, optionally at least 1x1012CFU, optionally at least 2x1012CFU. Optionally, the composition has a volume of one millilitre (1 ml). Optionally, the composition comprises L. fermentum CECT5716 at a concentration of at least 1x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 1x109CFU / ml optionally at least 1x1012CFU / ml and / or the composition comprises B. breve CECT7263 at a concentration of at least 1x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 1x109CFU / ml, optionally at least 1x1012CFU / ml. Optionally, the composition comprises a combined total concentration of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total concentration is at least 1x103CFU / ml, optionally at least 2x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 2x106CFU / ml, optionally at least 1x109CFU / ml, optionally at least 2x109CFU / ml, optionally at least 1x1012CFU / ml, optionally at least 2x1012CFU / ml. Optionally, the composition and / or the medicament is in a form nutritionally acceptable for an infant. Optionally, the composition and / or the medicament is in a form suitable for enteric feeding (e.g. by nasogastric feeding or by oral administration) to an infant. Optionally, the infant is a neonate. Optionally, the infant was born preterm. Further optionally, or additionally, the medicament is to be administered to the infant once per day. Optionally, the medicament is to be administered to the infant by enteric feeding, for example by nasogastric feeding or by oral administration. Optionally, the medicament is to be administered to the infant with food; such as breast milk, milk from the Donated Breast Milk Bank, baby formula or formula milk, and / or artificial formula for premature babies. Preferably, the medicament is to be administered to the infant as a constant daily volume of medicament with a volume of food that varies depending on the weight of the infant. Most preferably, the medicament is to be administered to the infant as a daily volume of 1 ml medicament with a food volume equal to 5 ml food per 1 kg infant weight.

[0056] Optionally, the medicament is to be administered to the infant with food in a ratio composition:food 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.

[0057] Some embodiments of the present invention comprise use of a composition in the manufacture of a medicament for treating or preventing a gut disorder in an infant, wherein the composition is any composition according to the present invention. For example, in some embodiments the composition comprises L. fermentum, optionally L. fermentum CECT5716, and / or B. breve, optionally B. breve CECT7263. Optionally, the composition comprises L. fermentum CECT5716 in an amount of at least 1x103CFU, optionally at least 1x106CFU, optionally at least 1x109CFU, optionally at least 1x1012CFU and / or the composition comprises B. breve CECT7263 in an amount of at least 1x103CFU, optionally at least 1x106CFU, optionally at least 1x109CFU, optionally at least 1x1012CFU. Optionally, the composition comprises a combined total amount of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total amount is at least 1x103CFU, optionally at least 2x103CFU, optionally at least 1x106CFU, optionally at least 2x106CFU, optionally at least 1x109CFU, optionally at least 2x109CFU, optionally at least 1x1012CFU, optionally at least 2x1012CFU. Optionally, the composition has a volume of one millilitre (1 ml). Optionally, the composition comprises L. fermentum CECT5716 at a concentration of at least 1x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 1x109CFU / ml optionally at least 1x1012CFU / ml and / or the composition comprises B. breve CECT7263 at a concentration of at least 1x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 1x109CFU / ml, optionally at least 1x1012CFU / ml. Optionally, the composition comprises a combined total concentration of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total concentration is at least 1x103CFU / ml, optionally at least 2x103CFU / ml, optionally at least 1x106CFU / ml, optionally at least 2x106CFU / ml, optionally at least 1x109CFU / ml, optionally at least 2x109CFU / ml, optionally at least 1x1012CFU / ml, optionally at least 2x1012CFU / ml. Optionally, the composition and / or the medicament is in a form nutritionally acceptable for an infant. Optionally, the composition and / or the medicament is in a form suitable for enteric feeding (e.g. by nasogastric feeding or by oral administration) to an infant. Optionally, the infant is a neonate. Optionally, the infant was born preterm. Further optionally, or additionally, the medicament is to be administered to the infant once per day. Optionally, the medicament is to be administered to the infant by enteric feeding, for example by nasogastric feeding or by oral administration. Optionally, the medicament is to be administered to the infant with food; such as breast milk, milk from the Donated Breast Milk Bank, baby formula or formula milk, and / or artificial formula for premature babies. Preferably, the medicament is to be administered to the infant as a constant daily volume of medicament with a volume of food that varies depending on the weight of the infant. Most preferably, the medicament is to be administered to the infant as a daily volume of 1 ml medicament with a food volume equal to 5 ml food per 1 kg infant weight. Optionally, the medicament is to be administered to the infant with food in a ratio composition:food 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.

[0058] Statements

[0059] Some embodiments of the invention are described by the following set of numbered statements: Statement 1 : A composition comprising Lactobacillus fermentum (L. fermentum) CECT5716 and Bifidobacterium breve (B. breve) CECT7263.

[0060] Statement 2: The composition of statement 1 , wherein each of L. fermentum and B. breve is present in an independent amount of at least 1x103CFU.

[0061] Statement 3: The composition of statement 1 , wherein the combined total amount of L. fermentum and B. breve is at least 1x103CFU.

[0062] Statement 4: The compositions of any one of statement s 1-3, wherein the composition is in a form nutritionally acceptable for an infant.

[0063] Statement 5: The composition of any one of statements 1-3, wherein the composition is in a form suitable for enteric feeding of an infant.

[0064] Statement 6: The composition of any one of statement s 4 or 5 for use in the improvement of immune system or gut function of the infant.

[0065] Statement 7: The composition of any one of statement s 4 or 5 for use in the treatment of immune system or gut disorders in the infant.

[0066] Statement 8: The composition of any one of statement s 4 or 5 for use in the treatment of persistent ductus arteriosus in the infant.

[0067] Statement 9: The use of statement 8, wherein the infant has sepsis. Statement 10: The use of any one of statements 6-9, wherein the infant is a neonate.

[0068] Statement 11 : The use of any one of statements 6 or 10, wherein the infant was born preterm.

[0069] Statement 12: The use of any one of statements 6-11 , wherein the composition is administered by enteric feeding.

[0070] Statement 13: The use of any one of statements 6-12, wherein each of L. fermentum and B. breve is administered in an independent amount of at least 1x109cfu per day.

[0071] Statement 14: A method for improving immune system or gut function in an infant comprising administering to said infant a composition comprising L. fermentum and B. breve.

[0072] Statement 15: The method of statement 14, wherein L. fermentum is strain CECT5716 and B. breve is strain CECT7263.

[0073] Statement 16: A method for treating an immune system or gut disorder in an infant comprising administering to said infant a composition comprising L. fermentum and B. breve.

[0074] Statement 17: The method of statement 16, wherein L. fermentum is strain CECT5716 and B. breve is strain CECT7263.

[0075] Statement 18: A method for treating a persistent ductus arteriosus in an infant comprising administering to said infant a composition comprising L. fermentum and B. breve.

[0076] Statement 19: The method of statement 18, wherein L. fermentum is strain CECT5716 and B. breve is strain CECT7263.

[0077] Statement 20: The method of statement 18, wherein the infant is a neonate.

[0078] Statement 21 : The method of statement 20, wherein the neonate was born preterm.

[0079] Statement 22: The method of statement 21 , wherein the composition is administered by enteric feeding.

[0080] Statement 23: The method of claim 22, wherein L. fermentum and B. breve are each administered in an independent amount of at least 1x109cfu per day.

[0081] Statement 24: A composition according to an embodiment herein.

[0082] Statement 25: A method of treatment according to an embodiment herein.

[0083] Brief Description of the Drawings

[0084] Embodiments of the present invention will be more clearly understood from the following detailed description taken in conjunction with the accompanying drawings, Figures 1 to 4. The figures are provided only by way of example and not by way of limitation.

[0085] Figure 1

[0086] Figure 1 is a simplified diagram showing the time-points used in the study described below in the examples. The study population was 581 infants (n=581) born premature (at less than or equal to 32 weeks of gestation) and with a birth weight of less than 1500 g. Group LD were administered 1x106CFU / day L. fermentum CECT5716 and 1x106CFU / day B. breve CECT7263. Group HD were administered 1x109CFU / day L. fermentum CECT5716 and 1x109CFU / day B. breve CECT7263. The numbers of weeks (e.g. “32 weeks”, “34 weeks”, and “37 weeks” represent the number of weeks after birth. Randomization was within 72 hours of birth. The arrows between “Birth” and “32 weeks” represent weekly follow-up until week 32 after birth. The outcomes measured were: safety, NEC incidence, sepsis incidence, health parameters, and faecal microbiota.

[0087] Figure 2

[0088] Figure 2 is a chart showing clinical outcomes. Figure 2 shows the incidence (%) of the respective conditions necrotizing enterocolitis (NEC), sepsis and persistent ductus arteriosus (persistent ductus) in infants from each group, as well as a reference incidence level for each condition. Group High dose were administered 1x109CFU / day L. fermentum CECT5716 and 1x109CFU / day B. breve CECT7263. Group Low dose were administered 1x106CFU / day L. fermentum CECT5716 and 1x106CFU / day B. breve CECT7263. For persistent ductus arteriosus a significantly lower incidence was observed in the Group High dose. For each of NEC and sepsis there were no significant differences between the Group High dose and Group Low dose. The reference incidence levels (represented by the dotted lines) were obtained from an official Spanish database (SENEO - Redes Neonatales) which includes data of 10 of the hospitals participating in the study. Data from 2016-2020 from infants born prematurely with a weight of 700-1500 g were included to calculate the reference.

[0089] Figure 3

[0090] Figure 3A is a chart showing treatment with inotropics. Figure 3A shows the incidence (%) of treatment with inotropics in infants from each group, as well as a reference incidence level. High Dose Group were administered 1x109CFU / day L. fermentum CECT5716 and 1x109CFU / day B. breve CECT7263. Low Dose Group were administered 1x106CFU / day L. fermentum CECT5716 and 1x106CFU / day B. breve CECT7263. The need for inotropics was significantly lower in the High Dose Group. The reference incidence level (15%, represented by the dotted line) was obtained from an official Spanish database (SENEO - Redes Neonatales) which includes data of 10 of the hospitals participating in the study. Data from 2016-2020 from infants born prematurely with a weight of 700- 1500 g were included to calculate the reference.

[0091] Figure 3B is a chart showing persistent ductus arteriosus risk sepsis associated. Figure 3B shows the incidence (%) of persistent ductus arteriosus (Ductus) in infants from each group with or without sepsis. No Sepsis refers to infants who did not have sepsis, while Sepsis refers to infants who had sepsis. Low Dose Group refers to infants who were administered 1x106CFU / day L. fermentum CECT5716 and 1x106CFU / day B. breve CECT7263. High Dose Group refers to infants who were administered 1x109CFU / day L. fermentum CECT5716 and 1x109CFU / day B. breve CECT7263. No Ductus refers to the incidence (%) of infants who did not have persistent ductus arteriosus, while Ductus refers to the incidence (%) of infants who had persistent ductus arteriosus. The asterisk (*) indicates a statistically significant (p<0.005) difference in the incidence of persistent ductus arteriosus between infants who had sepsis and infants who did not have sepsis, in the Low Dose Group. Sepsis is a recognised risk factor for persistent ductus arteriosus. This is supported by the significantly higher incidence of persistent ductus arteriosus in the infants who had sepsis, compared to the infants who did not have sepsis, in the Low Dose Group (i.e. 1x106CFU / day L. fermentum CECT5716 and 1x106CFU / day B. breve CECT7263). The administration of the high probiotic dose (i.e. 1x109CFU / day L. fermentum CECT5716 and 1x109CFU / day B. breve CECT7263) protected from this associated risk.

[0092] Figure 4

[0093] Figure 4A is a chart showing LC40 (i.e. CECT5716) and BfM26 (i.e. CECT7263) colonization.

[0094] Figure 4A shows the proportion (%) of infants in whose faeces different bacteria were detected at two weeks postnatal age. None means neither L. fermentum CECT5716 nor B. breve CECT7263 were detected. LC40 means L. fermentum CECT5716 was detected but not B. breve CECT7263.

[0095] BfM26 means B. breve CECT7263 was detected but not L. fermentum CECT5716. LC40 + BfM26 means both B. breve CECT7263 and L. fermentum CECT5716 were detected. LC40+ BfM26 (HD) refers to infants who were administered 1x109CFU / day L. fermentum CECT5716 and 1x109CFU / day B. breve CECT7263. This group included 158 infants (n=158). LC40+ BfM26 (LD) refers to infants who were administered 1x106CFU / day L. fermentum CECT5716 and 1x106CFU / day B. breve CECT7263. This group included 179 infants (n=179). The proportion of infants (%) values are indicated on the chart above each bar, in these labels the decimal separator is a decimal comma. Around 65% (specifically 66.5%) of infants showed B. breve CECT7263 and L. fermentum CECT5716 in their faeces after two weeks of intervention.

[0096] Figure 4B is a chart showing the presence of LC40 (i.e. CECT5716) and / or BFM26 (i.e. CECT7263) at 2 weeks postnatal age. Figure 4B shows the same data as Figure 4A in a simplified representation. No detection means neither L. fermentum CECT5716 nor B. breve CECT7263 were detected. LC40 means L. fermentum CECT5716 was detected. BfM26 means B. breve CECT7263 was detected. Low dose refers to infants who were administered 1x106CFU / day L. fermentum CECT5716 and 1x106CFU / day B. breve CECT7263. High Dose refers to infants who were administered 1x109CFU / day L. fermentum CECT5716 and 1x109CFU / day B. breve CECT7263.

[0097] Detailed description

[0098] The inventors have unexpectedly found that a composition comprising Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263 can treat or prevent persistent ductus arteriosus in an infant. Furthermore, the inventors have unexpectedly found that a composition comprising Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263 can treat or prevent persistent ductus arteriosus in an infant who has sepsis, and protect against the higher risk of developing persistent ductus arteriosus associated with sepsis. A composition comprising Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263 can be advantageously used as a treatment or preventative (e.g. prophylactic) against persistent ductus arteriosus in an infant (e.g. a neonate), especially where the infant has sepsis or is at risk of sepsis or otherwise at risk of developing persistent ductus arteriosus - for example if the infant was born preterm. The composition is preferably administered to the infant by enteric feeding, for example by nasogastric feeding or by oral administration. Preferably, the composition is administered to the infant together with food; such as breast milk, milk from the Donated Breast Milk Bank, baby formula or formula milk, and / or artificial formula for premature babies. Preferably, a constant daily volume of the composition is administered to the infant with a volume of food that varies depending on the weight of the infant; for example daily administration to the infant of 1 ml composition and a food volume equal to 5 ml food per 1 kg infant weight. The composition can be administered to the infant with food, for example in a ratio composition:food 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 in a daily dose of 1 ml per day.

[0099] Advantageously, administering the composition of the present invention to an infant can reduce the need for treatment with inotropics or other medicines or treatments that might be less well tolerated by the infant or contra-indicated due to e.g. other required medications or treatments.

[0100] Advantageously, administering the composition of the present invention to an infant can reduce polypharmacy. Advantageously, the composition of the present invention might be perceived as a dietary intervention and might be preferred (e.g. by the infant’s guardian(s)) compared to other treatments perceived as more chemical or medical.

[0101] As shown in the examples described below, a daily dose of 1x109CFU L. fermentum CECT5716 and 1x109CFU B. breve CECT7263 significantly lowered the incidence of persistent ductus arteriosus in infants, compared to a lower daily dose of 1x106CFU L. fermentum CECT5716 and 1x106CFU B. breve CECT7263. Furthermore, in infants with sepsis, a daily dose of 1x109CFU L. fermentum CECT5716 and 1x109CFU B. breve CECT7263 protected against the significant negative association between sepsis and persistent ductus arteriosus. It might be expected that other dose amounts of L. fermentum CECT5716 and B. breve CECT7263 would also have a similar effect. For example, compared to a zero dose, it is likely that a daily dose of about 1x103CFU, about 1x104CFU, about 1x105CFU, about 1x106CFU, about 1x107CFU, about 1x108CFU, about 1x1010CFU, about 1x1011, and / or about CFU 1x1012CFU L. fermentum CECT5716 and about 1x103CFU, about 1x104CFU, about 1x105CFU, about 1x106CFU, about 1x107CFU, about 1x108CFU, about 1x1010CFU, about 1x1011, and / or about CFU 1x1012CFU B. breve CECT7263 would lower the incidence of persistent ductus arteriosus in infants, and / or protect against the significant negative association between sepsis and persistent ductus arteriosus. Similarly, it is plausible that administering only one of L. fermentum CECT5716 or B. breve CECT7263 (for example either bacterial strain at a daily dose of about 1x103CFU, about 1x104CFU, about 1x105CFU, about 1x106CFU, about 1x107CFU, about 1x108CFU, about 1x101° CFU, about 1x1011, and / or about CFU 1x1012CFU) would also lead to a similar effect.

[0102] A higher dose or amount of L. fermentum (optionally L. fermentum CECT5716) and / or B. breve (optionally B. breve CECT7263) leads to a greater treatment effect and / or preventative (e.g. prophylactic) effect. For example, a dose or amount of about 1x109CFU L. fermentum (optionally L. fermentum CECT5716) and / or about 1x109CFU B. breve (optionally B. breve CECT7263) has a greater treatment effect and / or preventative (e.g. prophylactic) effect than a dose or amount of about 1x106CFU L. fermentum (optionally L. fermentum CECT5716) and / or about 1x106CFU B. breve (optionally B. breve CECT7263). Similarly, it is expected that a dose or amount of about 1x1012CFU has a greater effect than a dose or amount of about 1x1011CFU, which has a greater effect than a dose or amount of about 1x1010CFU, which has a greater effect than a dose or amount of about 1x109CFU, which has a greater effect than a dose or amount of about 1x108CFU, which has a greater effect than a dose or amount of about 1x107CFU, which has a greater effect than a dose or amount of about 1x106CFU, which has a greater effect than a dose or amount of about 1x105CFU, which has a greater effect than a dose or amount of about 1x104CFU, which has a greater effect than a dose or amount of about 1x103CFU, which has a greater effect than a dose or amount of about 1x102CFU, which has a greater effect than a negligible or zero dose or amount. Most preferably, the composition comprises a dose or amount of about 1x109CFU L. fermentum (optionally L. fermentum CECT5716) and / or about 1x109CFU B. breve (optionally B. breve CECT7263).

[0103] It is plausible, and reasonable to expect, that administering other strains of L. fermentum and / or B. breve to an infant might also lower the incidence of persistent ductus arteriosus, and / or protect against the significant negative association between sepsis and persistent ductus arteriosus.

[0104] As shown in the examples described below, administering L. fermentum (for example L. fermentum CECT5716 and / or B. breve (for example B. breve CECT7263) reduces the risk of sepsis. See in particular Table 2 below.

[0105] It is plausible that administering L. fermentum (for example L. fermentum CECT5716 and / or B. breve (for example B. breve CECT7263) also effectively treats and / or prevents necrotizing enterocolitis, immune system disorder(s), and / or gut disorder(s) in an infant.

[0106] Examples

[0107] Study design

[0108] This multicenter, prospective, randomized, double-blind phase 3 study was designed to compare the efficacy and safety of the prophylactic use of probiotic mixtures at different doses, administered enterally, in the prevention of severe enterocolitis or death in premature infants.

[0109] In the first 72 hours of life, patients were randomized to receive one of the two proposed doses of the probiotic mixture that was the object for the study. Neonates were included in the study continuously. When it was verified that they met the inclusion criteria, and the parents gave their consent to participate in the study, they were assigned to one of the two intervention groups.

[0110] Group I: daily dose of probiotic products L. fermentum CECT5716 1x106CFU and B. breve CECT7263 1x106CFU.

[0111] Group II: daily dose of probiotic products L. fermentum CECT5716 1x109CFU and B. breve CECT7263 1x109CFU.

[0112] Each dose was administered coinciding with the intake of enteral feeding. The intervention was carried out until completing the 36th week of postmenstrual age.

[0113] A meconium sample was collected from patients before the start of the intervention.

[0114] Once the intervention began, weekly stool samples were collected until the subjects reached 32 weeks of postconceptional age, at week 34 and at 37 weeks postconception, coinciding with the end of the intervention (36+6 postconceptional age or PCA), and subsequently stool samples were collected at 40 weeks postconceptional age and at 3 months corrected age.

[0115] The intervention, administration of 1 ml of probiotic mixture product, was continued daily until the end of 36 weeks of postconceptional age (36+6 PCA).

[0116] All stool samples were stored at -18°C after collection and then kept at -80°C until processing. A study of the intestinal flora content and detection of administered probiotics was carried out. Polymerase chain reaction (PCR) techniques were used for the detection and quantitative analysis of microorganisms in biological products.

[0117] The intervention was performed whenever the subject was receiving enteral feeding of > 5 ml / kg / day food. The intervention was temporarily suspended during interruptions of enteral feeding on the occasion of any clinical / analytical process that, in the opinion of the Investigator, so indicated. The intervention was resumed once the subject was able to receive enteral feeding again, unless the researcher expressly indicated the definitive suspension of the intervention.

[0118] The assessment of necrotizing enterocolitis (NEC) was carried out by the care team of neonatologists responsible for the neonates included in the study. For NEC assessment and diagnosis, the Modified Bell’s Staging Criteria for NEC shown in Table 1 below and reported in Walsh and Kliegman. Pediatr Clin North Am. 1986 Feb; 33(1): 179-201 were taken into account.

[0119] Table 1 : Modified Bell’s Staging Criteria for NEC (adapted from Table 3 of Walsh and Kliegman. Pediatr Clin North Am. 1986 Feb; 33(1): 179-201)

[0120] Inclusion and exclusion criteria:

[0121] Inclusion criteria:

[0122] Premature newborns of gestational age less than or equal to 32 weeks of gestation with birth weight < 1500g, admitted to the Neonatology Unit.

[0123] Premature newborns who meet any of the above criteria and received enteral feeding: breast milk, milk from the Donated Breast Milk Bank and / or artificial formula for premature babies, starting at an amount of 5 ml / kg / day.

[0124] Exclusion criteria:

[0125] Any clinical circumstance that prevented the start of enteral nutrition in the first 72 hours of life.

[0126] Chromosomopathies and complex fetal malformations, incompatible with the enteral nutrition in the first 72 hours of life.

[0127] Non-acceptance of informed consent to participate in the study by the parents or legal guardians of the newborn.

[0128] Outcomes:

[0129] Primary outcome:

[0130] The main efficacy variable is the absence of NEC and / or nosocomial sepsis during the period of hospital stay of the premature infant.

[0131] Secondary outcomes:

[0132] Intestinal probiotic colonization of premature newborns.

[0133] Infectious manifestations of the gastrointestinal tract directly related with probiotics administered

[0134] Body weight gain (g) daily

[0135] Body length increase (cm) weekly

[0136] Weekly head circumference (cm) increase

[0137] Reduction in duration of hospital stay of the premature infant

[0138] Digestive tolerance

[0139] NEC incidence:

[0140] No significant differences were detected between both doses regarding the NEC incidence or sepsis. The assessment of NEC was carried out by the care team of neonatologists responsible for the neonates included in the study. For this, the Modified Bell’s Staging Criteria for NEC according to Table 1 was taken into account.

[0141] Evaluation criteria:

[0142] 1 . Development of NEC > stage IIA modified Bell’s Staging Criteria for NEC.

[0143] 2. Development of nosocomial sepsis

[0144] 3. Number of episodes of nosocomial sepsis during admission

[0145] 4. Death.

[0146] 5. Digestive tolerance

[0147] NEC was diagnosed based on the Bell’s Staging Criteria for NEC according to Table 1 .

[0148] The diagnosis of nosocomial sepsis was made in compliance with the recommendations of the Castrillo Hospital Group. Probiotic colonization:

[0149] At two weeks of intervention at the high dose, more than 60% of the infants presented both strains in feces (see Fig. 4).

[0150] Persistent ductus arteriosus:

[0151] Results:

[0152] Significant differences were observed between groups receiving high and low dose of the probiotic combination of L. fermentum CECT5716 + B. breve CECT7263 in the incidence of persistent ductus arteriosus (17.9% in group receiving high probiotic dose vs 25.1% in group receiving low dose; p- value 0,046).

[0153] As shown in Figure 2, a significantly lower incidence of persistent ductus arteriosus was observed in the group administered 1x109CFU / day L. fermentum CECT5716 and 1x109CFU / day B. breve CECT7263.

[0154] Accordingly, 4.8% of preterm infants in the group receiving high probiotic dose required administration of inotropes in contrast to 10.5% of preterm infants in the group receiving low dose (p- value 0.014).

[0155] As shown in Figure 3A, the need for inotropics was significantly lower in the group administered 1x109CFU / day L. fermentum CECT5716 and 1x109CFU / day B. breve CECT7263.

[0156] It is important to mention that the reported use of inotropes in the region is 15% (Spanish neonatal network database SEN1500) so even the lower dose of probiotic seemed to induce a benefit by reducing the proportion of the preterm infants who required administration of inotropes.

[0157] Significant interaction between sepsis and persistent ductus arteriosus was observed in the group receiving low probiotic dose (40.4% of preterm infants who experienced sepsis had persistent ductus arteriosus versus 21 .5% of preterm infants who did not experience sepsis (p value 0.005)). However, such interaction was not observed in the group receiving high probiotic dose in which the percentage of persistent ductus arteriosus was similar in both populations (22.7% in the population who experienced sepsis versus 16.9% of preterm infants who did not experience sepsis (p value 0.238)). The finding that the negative significant interaction between sepsis and persistent ductus arteriosus is not observed when infants get the high dose of the tested probiotics is unexpected.

[0158] As shown in Figure 3B, the administration of the high probiotic dose (i.e. 1x109CFU / day

[0159] L. fermentum CECT5716 and 1x109CFU / day B. breve CECT7263) protected from the risk of persistent ductus arteriosus associated with sepsis.

[0160] Sepsis has been recognized as a risk factor for re-opening and persistence of the ductus arteriosus in preterm infants. This is supported by the significantly higher incidence of persistent ductus arteriosus in the infants with sepsis compared to no sepsis, in the Low dose group (see Fig. 3B). Elevated levels of PGs (e.g. PGE2) during sepsis or necrotizing enterocolitis may mediate the reopening of the ductus arteriosus in preterm infants.

[0161] However, in the group receiving the high dose of probiotic, sepsis did not affect the incidence of persistent ductus arteriosus - evidencing a protective role of the high dose of probiotic (see Fig. 3B). Elevated levels of PGE2 during sepsis has been identified as a mediator factor of re-opening or persistence of open ductus arteriosus, so, the capability of the probiotic product to reduce PGE2 might be responsible for the protective effect observed in the group receiving the high probiotic dose. As shown in Figure 4, around 65% of infants showed B. breve CECT7263 and L. fermentum CECT5716 in their faeces after two weeks of intervention.

[0162] Table 2: Subgroup analysis - Nosocomial sepsis events by colonization status at 2 weeks’ postnatal age

[0163] Data are n (%), * Adjusted for sex and gestational age at birth, OR = odds ratio, Cl = confidence interval, Ref = reference group for calculation of odds ratio.

[0164] As shown in Table 2, the presence of B. breve CECT7263 in an infant’s faeces is related to a reduction in the risk of sepsis.

[0165] The effects on the ductus arteriosus and the interaction with sepsis

[0166] The combination of the two probiotics appears to have some effects on the maturation of cardiovascular system:

[0167] The infants that took the high dose had a significantly lower incidence of persistent ductus arteriosus.

[0168] The infants that took the high dose had a lower necessary need for treatment with inotropics. Persistent ductus arteriosus is associated with sepsis: The infants that took the high probiotic dose were protected from this associated risk between persistent ductus arteriosus and sepsis.

[0169] Unexpectedly, the inventors have found that administering L. fermentum CECT5716 and B. breve CECT7263 to infants who were born preterm reduced the incidence of persistent ductus arteriosus in the infants. Administering a higher dose of L. fermentum CECT5716 and B. breve CECT7263 to infants who were born preterm reduced the incidence of persistent ductus arteriosus in the infants. Administering 1x109CFU / day L. fermentum CECT5716 and 1x109CFU / day B. breve CECT7263 to infants who were born preterm reduced the incidence of persistent ductus arteriosus in the infants, compared to administering 1x106CFU / day L. fermentum CECT5716 and 1x106CFU / day B. breve CECT7263. Similarly, compared to no dose, administering any daily dose of L. fermentum CECT5716 and B. breve CECT7263 to infants who were born preterm is expected to reduce the incidence of persistent ductus arteriosus in the infants. It is plausible that the same technical effect would be seen in any infant at risk of persistent ductus arteriosus and / or any infant suffering from persistent ductus arteriosus. Therefore, administering L. fermentum CECT5716 and 8. breve CECT7263 has the technical effect of treating or preventing persistent ductus arteriosus in an infant, optionally an infant who was born preterm.

[0170] Unexpectedly, the inventors have found that that administering L. fermentum CECT5716 and 8. breve CECT7263 to infants who were born preterm reduced the need for treatment of the infants with inotropics. Administering a higher dose of L. fermentum CECT5716 and 8. breve CECT7263 to infants who were born preterm reduced the need for treatment of the infants with inotropics. Administering 1x109CFU / day L. fermentum CECT5716 and 1x109CFU / day 8. breve CECT7263 to infants who were born preterm reduced the need for treatment of the infants with inotropics, compared to administering 1x106CFU / day L. fermentum CECT5716 and 1x106CFU / day 8. breve CECT7263. Similarly, compared to no dose, administering any daily dose of L. fermentum CECT5716 and B. breve CECT7263 to infants who were born preterm is expected to reduce the need for treatment of the infants with inotropics. It is plausible that the same technical effect would be seen in any infant. Therefore, administering L. fermentum CECT5716 and B. breve CECT7263 has the technical effect of reducing the need for treatment of an infant with inotropics, optionally an infant who was born preterm.

[0171] Unexpectedly, the inventors have found that administering a higher dose of L. fermentum CECT5716 and 8. breve CECT7263 to infants who were born preterm reduced the incidence of persistent ductus arteriosus in the infants who had sepsis, which is a risk-factor for persistent ductus arteriosus. Administering 1x109CFU / day L. fermentum CECT5716 and 1x109CFU / day 8. breve CECT7263 to infants who were born preterm reduced the incidence of persistent ductus arteriosus in the infants who had sepsis, compared to administering 1x106CFU / day L. fermentum CECT5716 and 1x106CFU / day B. breve CECT7263. It is plausible that the same technical effect would be seen in any infant at risk of persistent ductus arteriosus and / or at risk of sepsis and / or suffering from sepsis. Therefore, administering L. fermentum CECT5716 and B. breve CECT7263 has the technical effect of protecting an infant (optionally an infant who was born preterm) from the increased risk of persistent ductus arteriosus associated with sepsis.

[0172] The invention is susceptible to various modifications and alternative means, and specific examples thereof are herein described in detail. It should be understood, however, that the invention is not to be limited to the particular examples or methods disclosed, but to the contrary, the invention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the claims.

Claims

ClaimsWhat is claimed is:1 . A composition comprising Lactobacillus fermentum (L. fermentum) and Bifidobacterium breve (B. breve).

2. The composition of claim 1 , wherein the L. fermentum is strain L. fermentum CECT5716, and wherein the B. breve is strain B. breve CECT7263.

3. The composition of claim 1 or 2, wherein the composition comprises at least 1x103CFU L. fermentum CECT5716 and wherein the composition comprises at least 1x103CFU B. breve CECT7263.

4. The composition of claim 1 , 2 or 3, wherein the composition comprises at least 1x106CFU L. fermentum CECT5716 and wherein the composition comprises at least 1x106CFUB. breve CECT7263.

5. The composition of any preceding claim, wherein the composition comprises at least 1x109CFU L. fermentum CECT5716 and wherein the composition comprises at least 1x109CFU B. breve CECT7263.

6. The composition of any preceding claim, wherein the composition comprises 1x109CFU L. fermentum CECT5716 and wherein the composition comprises 1x109CFU B. breve CECT7263.

7. The composition of claim 1 or 2, wherein the composition comprises a combined total amount of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total amount is at least 2x103CFU.

8. The composition of any one of claims 1 to 4 or 7, wherein the composition comprises a combined total amount of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total amount is at least 2x106CFU.

9. The composition of any one of claims 1 to 4, 7 or 8, wherein the composition comprises a combined total amount of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total amount is 2x106CFU.

10. The composition of any preceding claim, wherein the composition comprises a combined total amount of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total amount is at least 2x109CFU.11 . The composition of any preceding claim, wherein the composition comprises a combined total amount of L. fermentum CECT5716 and B. breve CECT7263, wherein the combined total amount is 2x109CFU.

12. The composition of any preceding claim, wherein the composition is in a form nutritionally acceptable for an infant.

13. The composition of any preceding claim, wherein the composition is in a form suitable for enteric feeding of an infant.

14. A composition for use in a method for treating or preventing persistent ductus arteriosus in an infant, wherein the method comprises administering the composition to the infant, and wherein the composition is the composition of any preceding claim.

15. The composition for use of claim 14, wherein the infant has sepsis.

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

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

18. A composition for use in a method for treating or preventing an immune system disorder in an infant, wherein the method comprises administering the composition to the infant, and wherein the composition is the composition of any one of claims 1 to 13.

19. A composition for use in a method for treating or preventing a gut disorder in an infant, wherein the method comprises administering the composition to the infant, and wherein the composition is the composition of any one of claims 1 to 13.

20. The composition for use of any one of claims 14 to 19, wherein the method comprises administering the composition to the infant once per day.21 . The composition for use of any one of claims 14 to 20, wherein the infant is a neonate.

22. The composition for use of any one of claims 14 to 21 , wherein the infant was born preterm.

23. The composition for use of any one of claims 14 to 22, wherein the method comprises administering the composition to the infant by enteric feeding.

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