WO2017037105A1 - Procédés et compositions utilisant bifidobacterium longum pour optimiser l'allaitement - Google Patents

Procédés et compositions utilisant bifidobacterium longum pour optimiser l'allaitement Download PDF

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Publication number
WO2017037105A1
WO2017037105A1 PCT/EP2016/070496 EP2016070496W WO2017037105A1 WO 2017037105 A1 WO2017037105 A1 WO 2017037105A1 EP 2016070496 W EP2016070496 W EP 2016070496W WO 2017037105 A1 WO2017037105 A1 WO 2017037105A1
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WIPO (PCT)
Prior art keywords
atcc baa
longum atcc
composition
peripartum
longum
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PCT/EP2016/070496
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English (en)
Inventor
Florence Rochat
Gabriela Bergonzelli Degonda
Jonas HAUSER
Jeroen Antonius Johannes Schmitt
Tiago ALVES NUNES
Valerie MARQUARDT
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Nestec S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by Nestec S.A. filed Critical Nestec S.A.
Priority to CA2994352A priority Critical patent/CA2994352A1/fr
Priority to BR112018001179A priority patent/BR112018001179A2/pt
Priority to CN201680049601.9A priority patent/CN107980002A/zh
Priority to MX2018002032A priority patent/MX2018002032A/es
Priority to EP16759752.5A priority patent/EP3344269A1/fr
Publication of WO2017037105A1 publication Critical patent/WO2017037105A1/fr
Priority to PH12018500117A priority patent/PH12018500117A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/745—Bifidobacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • Medications such as antidepressants, anti-anxiety drugs, or beta-blockers may be used as treatments for peripartum emotional distress. However, these may have side effects and many may not be safe for use or desirable to use perinatally. Accordingly, there is a need to prevent or treat peripartum emotional distress and to support breastfeeding initiation and optimise breastfeeding duration. In particular, there is a need for new ingredients that do not suffer from side effects of known ingredients.
  • Bifidobacterium longum NCC3001 (ATCC BAA-999) to an individual may improve anxiety and depressive symptoms, may down regulate activity in brain centers involved in the control of emotions and mood (limbic regions such as the amygdala), and may down regulate the expression of Corticotropin Releasing Hormone (hereinafter CRH) in the hypothalamus.
  • CRH Corticotropin Releasing Hormone
  • the present invention encompasses B. longum ATCC BAA-999, or a composition comprising B. longum ATCC BAA-999 for use in an individual to; support breastfeeding initiation and/or to optimise breastfeeding duration and/or to optimize the quality and/or quantity of breast milk and/or to prevent or treat peripartum emotional distress and/or to regulate amygdala activity and/or to regulate the HPA axis.
  • Said individual may be a mammal and in particular may be a human trying to get pregnant, pregnant or lactating.
  • the HPA axis may be regulated for example by regulating it's activity which may be regulated for example by regulating the release of CRH.
  • Peripartum emotional distress may be a condition selected from the group consisting of: peripartum low mood , peripartum anxiety, peripartum depression and peripartum traumatic stress disorder.
  • the B. longum ATCC BAA-999, or composition comprising B. longum ATCC BAA-999 may be particularly effective for use as specified above if administered to the individual for at least 3 weeks or at least 6 weeks. Said administration may be daily.
  • the B. longum ATCC BAA-999, or composition comprising B. longum ATCC BAA-999 may be administered at any time during the perinatal period e.g. pre-pregnancy to an individual trying to get pregnant, to a pregnant individual or to an individual that has had a baby e.g. a lactating individual.
  • At least a portion of the B. longum ATCC BAA-999 or B. longum ATCC BAA-999 comprises in the composition may be alive.
  • At least a portion of the B. longum ATCC BAA-999 or B. longum ATCC BAA-999 comprises in the composition may be non-replicating.
  • the B. longum ATCC BAA-999 or composition comprising B. longum ATCC BAA-999 may be administered to an individual in any therapeutically effective dose.
  • Particularly useful doses may be daily doses comprising between 10 4 and 10 12 cfu of the B. longum ATCC BAA-999, more particularly between 10 9 and 10 12 for example 10 10 .
  • composition comprising B. longum ATCC BAA-999 may further comprises an ingredient selected from the group consisting of a fat, a protein, a prebiotic, a carbohydrate, a vitamin, myoinositol, another probiotic, and combinations thereof.
  • the prebiotic may be selected from the group consisting of an oligosaccharide, a dietary fiber, and a combination thereof.
  • dietary fiber include but are not restricted to pectins, mucilages, gums, galacto-oligosaccharides, oligofructan, inulin, polyfructoses, arabinoglactans, hemicellulose, oligosaccharides or mixtures of thereof.
  • the fat may be selected from the group consisting of DHA, EPA, DP A, and a combination thereof.
  • composition comprising B. longum ATCC BAA-999 may be any type of composition suitable for perinatal consumption and in particular may be a maternal supplement.
  • the B. longum ATCC BAA-999 or composition comprising B. longum ATCC BAA-999 may be simultaneously, sequentially or separately administered to another ingredient e.g. a pharmaceutical, that may; support breastfeeding initiation and/or optimise breastfeeding duration and/or optimize the quality and/or quantity of breast milk and/or prevent or treat peripartum emotional distress and/or regulate amygdala activity and/or to regulate HPA axis e.g. the release of CRH, in an individual.
  • a pharmaceutical e.g. a pharmaceutical, that may; support breastfeeding initiation and/or optimise breastfeeding duration and/or optimize the quality and/or quantity of breast milk and/or prevent or treat peripartum emotional distress and/or regulate amygdala activity and/or to regulate HPA axis e.g. the release of CRH, in an individual.
  • B. longum ATCC BAA-999 or composition comprising B. longum ATCC BAA-999, optionally simultaneously sequentially or separately administered to said another ingredient, may also be administered in combination with a psychosocial or psychological intervention e.g. cognitive behavioural therapy, interpersonal therapy, parent training programs, and/or alternative therapy and/or complementary therapy e.g. yoga therapy, music therapy, art therapy.
  • longum ATCC BAA-999 may also be used in a method of supporting breastfeeding initiation and/or optimising breastfeeding duration and/or optimising the quality and/or quantity of breast milk and/or preventing or treating peripartum emotional distress and/or regulating amygdala activity and/or regulating the HPA axis e.g. the release of CRH, in an individual, said method comprising administering B. longum ATCC BAA-999 or a composition comprising B. longum ATCC BAA-999 to said individual. Said method may be a natural therapy.
  • B. longum ATCC BAA-999 or a composition comprising B. longum ATCC BAA-999 may also be used in the manufacture of a composition for use in an individual to; support breastfeeding initiation and/or to optimise breastfeeding duration and/or to optimize the quality and/or quantity of breast milk and/or to prevent or treat peripartum emotional distress and/or to regulate amygdala activity and/or to regulate the HPA axis e.g. the release of CRH.
  • B. longum ATCC BAA-999 or a composition comprising B. longum ATCC BAA-999 may also be used in an individual to; to support breastfeeding initiation and/or to optimise breastfeeding duration and/or to optimize the quality and/or quantity of breast milk and/or to prevent or treat peripartum emotional distress and/or to regulate amygdala activity and/or to regulate the HPA axis e.g. the release of CRH. Said use may be non-therapeutic.
  • B. longum ATCC BAA-999, or a composition comprising B. longum ATCC BAA-999 may also be used to prevent or treat the negative effects of peripartum emotional distress in the offspring of individuals.
  • An advantage of the present invention is that B. longum ATCC BAA-999 is effective, readily available, low-priced, and safe to administer perinatally without unwanted side effects.
  • Another advantage of one or more embodiments provided by the present disclosure is to provide a better safety profile relative to known mood-regulating compounds.
  • a further advantage of one or more embodiments provided by the present disclosure is to minimize or avoid completely the side effects from known mood-regulating compounds.
  • An additional advantage of one or more embodiments provided by the present disclosure is to improve the effect of and/or reduce the dose of one or more known mood-regulating compounds which are co-administered with the composition disclosed herein i.e. exert an adjuvant effect.
  • Yet another advantage of one or more embodiments provided by the present disclosure is to minimize or avoid completely unnecessary costs related to healthcare assistance.
  • a further advantage of one or more embodiments provided by the present disclosure is to use a bacterial strain that provides other health benefits as well.
  • FIG. 1 shows the design of the clinical trial disclosed herein.
  • FIG. 2 shows graphs demonstrating the primary outcome from administration of B. longum ATCC BAA-999, improvement in depression and anxiety dichomotous scores.
  • FIG. 3 shows graphs demonstrating the secondary outcome from administration of B. longum ATCC BAA-999, improvement in depression and anxiety continuous scores.
  • FIGS. 4 and 5 respectively show graphs and a table demonstrating that administration of B. longum ATCC BAA-999 significantly improved the physical global domain as well as general physical health (physical functioning) and problems with work of other daily activities (role physical) and resulted in an improvement trend in the mental subdomains of vitality and role emotional.
  • FIG. 6 shows fMRI images demonstrating greater engagement of the visual association and parietal cortices in the group administered B. longum ATCC BAA-999 relative to the placebo group and lesser engagement of brain centers involved in emotion and mood (amygdala and fronto-limbic region) in the group administered B. longum ATCC BAA-999 relative to the placebo group.
  • FIG. 7 shows a graph demonstrating the effect of the administration of B. longum ATCC BAA- 999 on CRH in the hypothalamus. DETAILED DESCRIPTION
  • compositions disclosed herein may lack any element that is not specifically disclosed.
  • a disclosure of an embodiment using the term “comprising” includes a disclosure of embodiments “consisting essentially of and “consisting of the components identified.
  • the methods disclosed herein may lack any step that is not specifically disclosed herein.
  • a disclosure of an embodiment using the term “comprising” includes a disclosure of embodiments “consisting essentially of and “consisting of the steps identified.
  • Animal includes, but is not limited to, mammals, which includes but is not limited to, rodents, aquatic mammals, domestic animals such as dogs and cats, farm animals such as sheep, pigs, cows and horses, and humans. Where “animal,” “mammal” or a plural thereof is used, these terms also apply to any animal that is capable of the effect exhibited or intended to be exhibited by the context of the passage.
  • the terms “individual” and “patient” are understood to include an animal, especially a mammal trying to get pregnant, pregnant or lactating, and more especially a human trying to get pregnant, a pregnant human or a human that has given birth e.g. a lactating human.
  • a person at risk of peripartum emotional distress may be a person that has previously suffered from peripartum emotional distress, has a family history of peripartum emotional stress or has previously suffered from emotional distress e.g. anxiety or depression.
  • the terms “individual” and “patient” are often used herein to refer to a human, the present disclosure is not so limited. Accordingly, the terms “individual” and “patient” refer to any animal, mammal that can benefit from the treatment.
  • treatment and “treating” include any effect that results in the improvement of the condition or disorder, for example lessening/ameliorating, reducing, modulating, or eliminating the condition or disorder.
  • the term does not necessarily imply that a subject is treated until total recovery.
  • Non-limiting examples of “treating” or “treatment of a condition or disorder include: (1) inhibiting the condition or disorder, i.e. arresting the development of the condition or disorder or its clinical symptoms and (2) relieving the condition or disorder, i.e. causing the temporary or permanent regression of the condition or disorder or its clinical symptoms.
  • a treatment can be patient- or doctor-related.
  • prevention or “preventing” mean causing the clinical symptoms of the referenced condition or disorder to not develop or reducing the risk of their development in an individual.
  • condition or disorder The individual may be exposed or predisposed to the condition or disorder but does not yet experience or display symptoms of the condition or disorder.
  • condition and disorder mean any disease, condition, symptom, or indication but more particularly mean any peripartum emotional distress condition or disorder.
  • optimise mean to improve, increase, or enhance.
  • the term can mean to increase the chance that an individual will breastfeed for the period they desire without needing to stop breastfeeding or excusive breastfeeding e.g. because of emotional distress e.g. to minimise the risk of early cessation of breastfeeding because of peripartum emotional distress.
  • the term optimise can mean to increase the amount of breastmilk produced by an individual.
  • the term optimise can mean to improve the composition of breastmilk and for example to bring it in line or closer to the composition of breastmilk produced by an individual that is not or has not suffered from peripartum emotional distress. It may for example mean to reduce or modulate the concentration of stress hormones e.g. Cortisol, in breastmilk and in particular to bring the concentration of these ingredients in line or closer to the concentration found in breastmilk produced by an individual that is not or has not suffered from peripartum emotional distress and more particularly the medium or mean of the concentration of a stress hormone e.g. Cortisol, found in the breastmilk of individuals not suffering from perinatal emotional distress.
  • stress hormones e.g. Cortisol
  • support means to facilitate, enable, or to remove barriers. With respect to supporting the initiation of breastfeeding, the term support can mean to increase the chance that an individual will successfully initiate breastfeeding.
  • the terms “regulate” and “modulate” as used herein mean to bring back into balance or to maintain balance or homeostatis e.g. to normalize acitivity or the concentration of a compound and bring it in-line with that seen in a healthy or optimally functioning individual.
  • the term “maternal supplement” means a supplement that can be administered to a mammal in the perinatal period.
  • compositions mean a product or composition that is intended for ingestion by an individual such as a human and provides at least one nutrient to the individual.
  • compositions of the present disclosure can comprise, consist of, or consist essentially of the essential elements and limitations described herein, as well as any additional or optional ingredients, components, or limitations described herein or otherwise useful in a diet.
  • complete nutrition contains sufficient types and levels of macronutrients (protein, fats and carbohydrates) and micronutrients to be sufficient to be a sole source of nutrition for the animal to which the composition is administered. Individuals can receive 100% of their nutritional requirements from such complete nutritional compositions.
  • perinatal or peripartum period refers to the period before pregnancy when an individual is trying to get pregnant, to the pregnancy period, and to the post pregnancy period following birth including the lactation period.
  • B. longum ATCC BAA-999 or a composition comprising B. longum ATCC BAA-999 for use in an individual to; support breastfeeding initiation and/or to optimise breastfeeding duration and/or to optimize the quality and/or quantity of breast milk and/or to prevent or treat peripartum emotional distress and/or to regulate amygdala activity and/or to regulate the HPA axis e.g. the release of CRH.
  • the individual is a mammal trying to get pregnant, a pregnant mammal or a mammal that has given birth e.g. a lactating mammal.
  • the individual is a human trying to get pregnant, a pregnant human or a human that has given birth e.g. a lactating human.
  • peripartum emotional distress refers to any emotional distress occurring in the peripartum period.
  • the emotional distress can be mild e.g. the baby blues to severe.
  • Non limiting examples of conditions encompassed by the term peripartum emotional distress are, peripartum low mood, peripartum anxiety, peripartum depression and peripartum traumatic stress disorder.
  • the peripartum emotional distress is selected from the group consisting of peripartum low mood, peripartum anxiety, peripartum depression and peripartum traumatic stress disorder.
  • B. longum ATCC BAA-999 may prevent or treat peripartum emotional distress, support breastfeeding initiation and/or, optimise breastfeeding duration, and/or to optimize the quality and/or quantity of breast milk in an individual by modulating activity in the in brain centers involved in the control of emotions and mood (limbic regions such as the amygdala), and/or by regulating hypothalamic-pituitary adrenal axis (hereinafter HPA) activity by modulating the release of CRH e.g. in the hypothalamus, and thereby regulating Cortisol levels.
  • HPA hypothalamic-pituitary adrenal axis
  • B. longum ATCC BAA-999 is also known as BL999 and NCC3001 and may be obtained commercially from specialist suppliers, for example from Morinaga Milk Industry Co. Ltd. of Japan under the trademark BB536.
  • the term "B. longum ATCC BAA-999" includes the bacterium, parts of the bacterium, and/or a growth medium fermented by the bacterium.
  • the B. longum ATCC BAA-999 may be cultured according to any suitable method.
  • B. longum ATCC BAA-999 may be added to a composition in any technically feasible form e.g. a freeze- dried or spray-dried form.
  • the B. longum ATCC BAA-999 or composition comprising B. longum ATCC BAA-999 may be administered for any time period. However, administration daily for a time period of at least 3, 4, 5 or 6 weeks may be particularly effective. Accordingly, in an embodiment, the B. longum ATCC BAA-999 or composition comprising B. longum ATCC BAA-999 can be administered to the individual daily for a time period that is at least three weeks, at least four weeks in some embodiments, at least five weeks in other embodiments, and at least six weeks in yet other embodiments.
  • the B. longum ATCC BAA-999, or composition comprising B. longum ATCC BAA-999 may be administered at any time during the perinatal period e.g.
  • pre-pregnancy to an individual trying to get pregnant, to a pregnant individual or to an individual post birth (postnatally) e.g. during the lactating period in a lactating individual.
  • Administration to an individual desiring to get pregnant may be at any time during which an individual is trying to become pregnant however, ordinarily administration will be during at least the 12 months preceeding the pregnancy or desired pregnancy and more particularly 1, 2, 3 or 4 months preceding the pregnancy or desired pregnancy.
  • Administration during pregnancy may be at any point e.g. during the 1st, 2nd and/or 3rd trimester.
  • Administration after an individual has given birth may be at any point in particular may be for 2 years, lyear or 6months following birth (postpartum) and in particular for the time period when an individual is lactating.
  • treatment in early pregnancy and mid pregnancy may be particularly beneficial as it may prevent or minimise said accelerated increase in CRH.
  • B. longum ATCC BAA-999 or composition comprising B. longum ATCC BAA-999 as a prophylactic treatment.
  • the B. longum ATCC BAA-999, or composition comprising B. longum ATCC BAA-999 is administered during pregnancy and post pregnancy e.g. during the lactation period.
  • B. longum ATCC BAA-999, or composition comprising B. longum ATCC BAA-999 is administered for the 2nd and/or 3rd trimester of a pregnancy and during the lactation period of an individual, in particular an individual at risk of peripartum emotional distress.
  • the B. longum ATCC BAA-999 or composition can be administered to treat or prevent peripartum emotional distress.
  • longum ATCC BAA-999 can do this is by stabilising and/or improving mood of an individual in the peripartum period.
  • the term "mood” refers to a state or quality of feeling (an emotional state) at a particular time. Moods differ from simple emotions in that they are less specific, less intense, and less likely to be triggered by a particular stimulus or event. Moods generally have either a positive or negative valence.
  • An improved mood may comprise one or more of a decreased depressive level, a decreased anxiety level, a decreased stress level, an increased perceived energy level ("vitality"), a more positive emotional state, an increased self-esteem, a reduced amount and/or a reduced intensity of negative thoughts and/or negative tensions, a reduced risk of mood swings, or retention of a positive mood.
  • the B. longum ATCC BAA-999 or composition comprising B. longum ATCC BAA-999 may be administered orally and/or enterally
  • At least a portion of the B. longum ATCC BAA-999 may be living bacterium. Additionally or alternatively, at least a portion of the B. longum ATCC BAA-999 may be inactivated non- replicating bacterium.
  • Non-replicating means that no viable cells and/or colony forming units can be detected by classical plating methods. Such classical plating methods are summarized in the microbiology book: James Monroe Jay, Martin J. Loessner, David A. Golden. 2005. Modern food microbiology. 7th edition, Springer Science, New York, N.Y. 790 p. Typically, the absence of viable cells can be shown as follows: no visible colony on agar plates or no turbidity in liquid growth medium after inoculation with different concentrations of bacterial preparations ("non-replicating" samples) and incubation under appropriate conditions (aerobic and/or anaerobic atmosphere for at least 24 h).
  • a non-replicating form of the B. longum ATCC BAA-999 may be preferable.
  • at least 80%, preferably at least 90%, more preferably at least 95% of the B. longum ATCC BAA-999 can be non-replicating in the composition.
  • at least a part of the B. longum ATCC BAA-999 are alive and preferably arrive alive in the intestine.
  • at least 5%, preferably at least 10%, more preferably at least longum ATCC BAA-999 can persist in the intestine and may increase their effectiveness by multiplication.
  • the alive B. longum ATCC BAA-999 may also be effective by interacting with the commensal bacteria and/or the host.
  • the B. longum ATCC BAA-999 or composition comprising B. longum ATCC BAA-999 may be administered in any amount that is effective in achieving the objective of the present invention.
  • An amount adequate to accomplish this purpose is defined as "a therapeutically effective dose”. Amounts effective for this purpose will depend on a number of factors known to those of skill in the art, such as the severity of the condition and the weight and general state of the patient.
  • the composition can be administered to a patient susceptible to or otherwise at risk of peripartum emotional distress in an amount that is sufficient to at least partially reduce the risk of developing said condition.
  • an amount is "a prophylactically effective dose.”
  • the precise amounts depend on a number of patient-specific factors, such as the patient's state of health and weight.
  • An individual at risk of peripartum emotional distress may be a person that has previously suffered from peripartum emotional distress, has a family history of peripartum emotional stress or has previously suffered from emotional distress e.g. anxiety or depression.
  • the B. longum ATCC BAA-999 or composition comprising B. longum ATCC BAA-999 is preferably administered in an amount that provides a therapeutically effective dose and/or in a prophylactic effective dose of the B. longum ATCC BAA-999. If at least a portion of the B. longum ATCC BAA-999 is present in a viable form, the B. longum ATCC BAA-999 is theoretically effective in any concentration because the B. longum ATCC BAA-999 can colonize the gut and multiply therein. Nevertheless, a daily dose of the B. longum ATCC BAA-999 or composition comprising B. longum ATCC BAA-999 preferably provides between 10 4 and 10 12 cfu (colony forming units) of the B.
  • the composition may comprise between 10 2 and 10 10 cfu, preferably 10 2 to 10 9 cfu, more preferably 10 2 to 10 8 cfu of the B. longum ATCC BAA-999 per gram dry weight of the composition.
  • the B. longum ATCC BAA-999 or composition comprising B. longum ATCC BAA-999 can be administered in a dose comprising between 10 2 and 10 10 non-replicating cells of the B. longum ATCC BAA-999 per gram of dry weight of the composition, preferably 10 3 to 10 10 non-replicating cells per gram of dry weight of the composition, more preferably 10 5 to 10 10 non-replicating cells per gram of dry weight of the composition.
  • Non-replicating micro-organisms do not form colonies, so the term "cells" indicates the amount of non-replicating micro-organisms obtained from the specified amount of replicating bacterial cells. This amount includes micro-organisms that are inactivated, non-viable or dead, or present as fragments such as DNA or cell wall materials.
  • the B. longum ATCC BAA-999 or composition comprising B. longum ATCC BAA-999 may be administered or employed in any form suitable for ingestion by an individual.
  • the composition will be a maternal supplement in the form of a powdered nutritional composition to be consumed directly or to be reconstituted in for example milk, juice or water, or sprinkled on food before consumption, a food product, a drink, a tablet or pill for example a soft gel capsule.
  • composition comprising B. longum ATCC BAA-999 is a powder it may be a powder having a water activity less than 0.2, preferably less than 0.15.
  • the composition may be a shelf- stable powder.
  • the low water activity can provide this shelf stability and can ensure that the B. longum ATCC BAA-999 and any additional probiotic micro-organism will remain viable even after long storage times.
  • Water activity (aw) is a measurement of the energy status of the water in a system and is defined as the vapor pressure of water divided by that of pure water at the same temperature; therefore, pure distilled water has a water activity of exactly one.
  • composition comprising B. longum ATCC BAA-999 may comprise a protein.
  • suitable proteins include animal proteins (such as milk protein, meat protein or egg protein), a vegetable protein (such as soy protein, wheat protein, rice protein, or pea protein); mixtures of free amino acids; or combinations thereof. Milk proteins such as casein and whey, and soy proteins are particularly preferred.
  • the proteins may be intact, hydrolyzed, or a mixture of intact and hydrolyzed proteins.
  • Partially hydrolyzed proteins degree of hydrolysis between 2 and 20%
  • pre-hydrolyzed protein sources are generally easier digested and absorbed by an impaired gastro -intestinal tract.
  • hydrolysis process may be carried out as desired and as known in the art.
  • a whey protein hydrolysate may be prepared by enzymatically hydro lyzing the whey fraction in one or more steps. If the whey fraction used as the starting material is substantially lactose-free, the protein can suffer much less lysine blockage during the hydrolysis process. This enables the extent of lysine blockage to be reduced from about 15% by weight of total lysine to less than about 10% by weight of lysine; for example about 7% by weight of lysine which greatly improves the nutritional quality of the protein source.
  • the composition comprising B. longum ATCC BAA-999 may comprise a carbohydrate and/or a fat.
  • the fat may for example be a long chain polyunsaturated fatty acids, such as arachidonic acid (ARA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and/or docosapentaenoic acid (DP A).
  • ARA arachidonic acid
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • DP A docosapentaenoic acid
  • Non-limiting examples of suitable carbohydrates include sucrose, lactose, glucose, fructose, corn syrup solids, maltodextrins, and mixtures thereof. Additionally or alternatively, a dietary fiber may be added. Dietary fiber passes through the small intestine undigested by enzymes and functions as a natural bulking agent and laxative. Dietary fiber may be soluble or insoluble and generally a blend of the two types is preferred.
  • Non-limiting examples of suitable dietary fibers include soy, pea, oat, pectin, guar gum, partially hydrolyzed guar gum, gum Arabic, fructo- oligosaccharides, acidic oligosaccharides, galacto-oligosaccharides, sialyl-lactose and oligosaccharides derived from animal milks.
  • a preferred fiber blend is a mixture of inulin with shorter chain fructo-oligosaccharides.
  • the fiber content is between 2 and 40 g/L of the composition, for example between 4 and 10 g/L.
  • the composition comprising B. longum ATCC BAA-999 may comprise minerals and/or micronutrients such as trace elements and vitamins in accordance with the recommendations of Government bodies such as the USRDA.
  • the composition may comprise, per daily dose, one or more of the following micronutrients, preferably in the ranges given: 300 to 500 mg calcium, 50 to 100 mg magnesium, 150 to 250 mg phosphorus, 5 to 20 mg iron, 1 to 7 mg zinc, 0.1 to 0.3 mg copper, 50 to 200 ⁇ g iodine, 5 to 15 ⁇ g selenium, 1000 to 3000 ⁇ g beta carotene, 10 to 80 mg Vitamin C, 1 to 2 mg Vitamin Bl, 0.5 to 1.5 mg Vitamin B6, 0.5 to 2 mg Vitamin B2, 5 to 18 mg niacin, 0.5 to 2.0 ⁇ g Vitamin B12, 100 to 800 ⁇ g folic acid, 30 to 70 ⁇ g biotin, 1 to 5 ⁇ g Vitamin D, and/or 3 to 10 ⁇ g Vitamin E.
  • the composition comprising B. longum ATCC BAA-999 may also comprise an additional food grade micro-organism (i.e., in addition to the B. longum ATCC BAA-999).
  • Food grade microorganisms are micro-organisms that are safe for use in food.
  • the food grade micro-organisms can comprise food-grade yeast.
  • the food grade bacteria may be selected from the group consisting of lactic acid bacteria, bifidobacteria, propionibacteria and mixtures thereof.
  • suitable food grade yeast include Saccharomyces cerevisiae and/or
  • the food grade bacteria can comprise another/additional probiotic bacteria, although in some embodiments the B. longum ATCC BAA-999 is the only probiotic bacteria in the composition.
  • Probiotic means microbial cell preparations or components of microbial cells with a beneficial effect on the health or well-being of the host. (Salminen S., Ouwehand A., Benno Y. et al "Probiotics: how should they be defined” Trends Food Sci. Technol. 1999: 10 107-10).
  • Probiotic bacteria are preferably selected from the group consisting of lactic acid bacteria, bifidobacteria, propionibacteria and mixtures thereof.
  • Probiotic bacteria may be any lactic acid bacteria or bifidobacteria with established probiotic characteristics.
  • probiotic bacteria may be capable of promoting the development of a bifidogenic intestinal microbiota.
  • Non-limiting examples of suitable probiotic bacteria include Bifidobacterium, Lactobacillus, Streptococcus, Saccharomyces and mixtures thereof, in particular selected from the group consisting of Bifidobacterium longum, Bifidobacterium lactis, Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus paracasei, Lactobacillus johnsonii, Lactobacillus plantarum, Lactobacillus salivarius, Enterococcus faecium, Saccharomyces boulardii and and mixtures thereof, preferably selected from the group consisting of Lactobacillus johnsonii (NCC533; CNCM 1-1225), Bifidobacterium longum (NCC490; CNCM 1-2170),
  • Bifidobacterium longum NCC2705; CNCM 1-26178
  • Bifidobacterium lactis 2818; CNCM 1- 3446
  • Lactobacillus paracasei NCC2461 ; CNCM 1-2116
  • B. longum ATCC BAA-999 and any additional probiotic micro-organism may be provided or comprised in the composition comprising B. longum ATCC BAA-999 in an encapsulated form.
  • Encapsulation of the bacteria can have therapeutical and technical advantages. For example, encapsulation can increase the survival of the bacteria and thus the number of live bacteria which arrive in the intestine. Furthermore, the bacteria can be gradually released, allowing a prolonged action of the bacteria on the health of the subject. For example, the bacteria may be freeze or spray dried and incorporated into a gel.
  • the composition comprising B. longum ATCC BAA-999 may comprise at least one prebiotic.
  • Prebiotic means a food substance intended to promote the growth of probiotic bacteria in the intestines.
  • a prebiotic can promote the growth of certain food grade bacteria, in particular growth of probiotic bacteria, in the intestines and can thus enhance the effect of B. longum ATCC BAA-999 and any additional probiotic bacteria.
  • the prebiotic is selected from the group consisting of oligosaccharides and optionally fructose, galactose, mannose, soy and/or inulin; dietary fibers; or mixtures thereof.
  • the composition may further contain one or more of the following: a protective hydrocolloid (such as a gum, a protein, a modified starch), a binder, a film- forming agent, an encapsulating agent, a wall/shell material, a matrix compound, a coating, an emulsifier, a surface active agent, a solubilizing agent (such as an oil, a fat, a wax, a lecithin), an adsorbent, a carrier, a filler, a co- compound, a dispersing agent, a wetting agent, a processing aid (such as a solvent), a flowing agent, a taste masking agent, a weighting agent, a jellifying agent, a gel forming agent, an antioxidant or an antimicrobial.
  • a protective hydrocolloid such as a gum, a protein, a modified starch
  • a binder such as a gum, a protein, a modified starch
  • a film- forming agent such as
  • composition is a nutritionally complete formula.
  • B. longum ATCC BAA-999 or a composition comprising B. longum ATCC BAA-999 may be simultaneously, sequentially or separately administered to another ingredient that may; support breastfeeding initiation and/or optimise breastfeeding duration and/or optimize the quality and/or quantity of breast milk and/or prevent or treat peripartum emotional distress and/or regulate amygdala activity and/or to regulate the HPA axis e.g. the release of CRH, in an individual.
  • Non limiting examples of such other ingredients include: anti-depressants, anti-anxiety drugs, beta and herbal remedies for emotional distress such as St. John's wart, extracts of passion flower, valerian, kali phos.
  • the B. longum ATCC BAA-999 or composition comprising B. longum ATCC BAA-999, optionally simultaneously sequentially or separately administered to said another ingredient, may also be administered in combination with a form of psychosocial or psychological intervention e.g. cognitive behavioural therapy, interpersonal therapy, parent training programs, and/or alternative therapy and/or complementary therapy e.g. yoga therapy, music therapy, art therapy.
  • a form of psychosocial or psychological intervention e.g. cognitive behavioural therapy, interpersonal therapy, parent training programs, and/or alternative therapy and/or complementary therapy e.g. yoga therapy, music therapy, art therapy.
  • longum ATCC BAA-999 for use in the manufacture of a composition for use in an individual to; support breastfeeding initiation and/or to optimise breastfeeding duration and/or to optimize the quality and/or quantity of breast milk and/or to prevent or treat peripartum emotional distress and/or to regulate amygdala activity and/or to regulate the HPA axis e.g. the release of CRH.
  • B. longum ATCC BAA-999 or a composition comprising B. longum ATCC BAA-999 to; support breastfeeding initiation and/or to optimise breastfeeding duration and/or to optimize the quality and/or quantity of breast milk and/or to prevent or treat peripartum emotional distress and/or to regulate amygdala activity and/or to regulate the HPA axis e.g. the release of CRH, in an individual.
  • Said use may be non- therapeutic.
  • B. longum ATCC BAA-999 or a composition comprising B. longum ATCC BAA-999, for use to prevent or treat the negative effects of peripartum emotional distress in the offspring of individuals.
  • Said negative effects may for example be caused by over exposure to stress hormones e.g. Cortisol, in-utero or in breastmilk
  • stress hormones refers to one or more hormones secreted in response to stress.
  • Non limiting examples of stress hormones are: Cortisol, noradrenaline, CRH, adrenocorticotrophine (ACTH), and glucocorticoids.
  • Over exposure to stress hormones e.g. Cortisol refers to an exposure e.g. intake of stress hormones such as Cortisol in breastmilk, that is above an optimum amount.
  • An optimum amount may be an amount falling within a range found in the breastmilk of individuals not suffering from perinatal emotional distress and more particularly the medium or mean of the concentration of a stress hormone e.g. Cortisol, found in the breastmilk of individuals not suffering from perinatal emotional distress.
  • Over exposure to stress hormones, such as Cortisol, in-utero and/or through breastmilk has been linked to neurobehavioural changes and to an increased risk of the development of one or more of the following conditions: attachment insecurity, emotional dysregulation, poor self-control, internalizing and externalizing problems, difficulties in cognitive functioning and in social interactions with parents and peers, impaired adaptive functioning and psychopathology including conduct disorders, affective disorders and anxiety and depressive disorders including a reduced to tolerance to stressful situations and increased sensitivity to anxiety . It has also been linked to an increased risk of the development of ADHD and learning disabilities.
  • the overexposure of offspring to stress hormones such as Cortisol e.g. concentrations in breastmilk, may be prevented and/or minimized and one or more of these conditions may be prevented or treated e.g. The risk of them occurring may be reduced or their severity may be mitigated.
  • HPA activity plays a critical part not only in stress regulation but also in sleep, feeding, emotions, emotion-regulation, and in the equilibrium of the gut microbiota.
  • Offspring of individuals suffering from peripartum emotional distress are at an increased risk of overexposure to stress and stress hormines such as Cortisol in-utero and through breastmilk.
  • said individual is an individual suffering from peripartum emotional distress.
  • the individual is a lactating human, and even more particularly a lactating human suffering from peripartum emotional distress.
  • Example 1 The following non-limiting example is a randomized, double blind, placebo-controlled trial illustrative of B. longum ATCC BAA-999 reducing brain emotional reactivity.
  • the present inventors assessed brain activation patterns using the backward masked fear paradigm (fMRI), cognitive function (memory and concentration), serum BDNF and
  • the fMRI paradigm utilized Blood Oxygenation Level Dependent (BOLD) activation in response to the presentation of emotional stimuli (fear and happy faces) that were masked by a neutral face, measured over four consecutive fMRI scan acquisitions in the scanner.
  • BOLD Blood Oxygenation Level Dependent
  • FIG. 2 shows that treatment with B. longum ATCC BAA-999 improved depression scores both by intention-to-treat analysis (ITT) and per protocol analysis (PP).
  • ITT intention-to-treat analysis
  • PP per protocol analysis
  • Treatment with B. longum ATCC BAA-999 did not improve anxiety scores when analyzed as continuous variables.
  • FIGS. 4 and 5 show that there was a statistically significant improvement in SF-36 physical global domain, as well as in general physical health (Physical functioning) and problems with work or other daily activities (Role physical), in the B. longum ATCC BAA-999 compared to placebo. Non-significant differences between treatment groups were observed in SF-36 mental global domain. However, when analyzing the mental subdomains, non-statistically significant trends for improvement in Vitality and Role emotional were observed in the B. longum ATCC BAA-999 treated group.
  • FIG. 6 shows that functional MRI revealed significant reductions from baseline in response to negative emotional stimuli in multiple brain areas involved in emotion processing, including amygdala, frontal and temporal brain regions (p ⁇ 0.001), in patients treated with B. longum ATCC BAA-999 compared with placebo. Specifically, before treatment, there was no major difference in response to fear stimuli vs fixation between placebo and B. longum groups, except for greater engagement of the visual association and parietal cortices in B. longum group.
  • mice chronically infected with the parasite Trichuris muris showed an increase in the content of CRH mRNA in the paraventricular nucleus of the hypothalamus in comparison to uninfected mice (Fig. 7).
  • Treatment of infected mice with B. longum ATCC BAA-999 resulted in a reduction in the content of CRH (Fig. 7).
  • mice Male BALB/c or AKR mice (Harlan, Canada) were purchases at age of 6-8 wks and housed in a conventional specific pathogen free unit at McMaster University Central Animal Facility. All experiments were conducted with approval from the McMaster University Animal Care Committee.
  • CRH in hypothalamus was assessed by in situ hybridizations using 35S-labeled RNA probes on frozen brain sections (Whitfield et al, 1990; Foster et al, 2002). Briefly, brains were removed and rapidly frozen by immersion in 2-methylbutane at -60°C, and stored at -70°C. Cryostat-cut 12-mm-thick coronal sections were thaw-mounted onto gelatin- coated slides, dried, and stored at -35°C. Tissue sections were fixed with 4% formaldehyde, acetylated with 0.25% acetic anhydride in 0.1 M triethanolamine-HCl, pH 8.0, dehydrated, and delipidated with chloroform.
  • Anti-sense CRH ribonucleotide probe (gift of Dr. James Herman, University of Cincinnati) was transcribed from linearized plasmid using the Riboprobe System (Promega Biotech, Burlington, ON) with a-35S-UTP (specific activity > 1000 Ci/ mmol; Perkin- Elmer, Boston, MA) and T3 and T7 polymerases respectively.
  • Radiolabeled probes were diluted in a hybridization buffer (0.6 M NaCl, 10 mM Tris pH 8.0, 1 mM EDTA pH 8.0, 10% Dextran sulfate, 0.01% sheared salmon sperm DNA, 0.05% total yeast RNA, type XI, 0.01% yeast tRNA, IX Denhardt's solution) and applied to brain sections (approximately 500,000 CPM/section). Slides were incubated overnight at 55°C in a humidified chamber. To reduce nonspecific binding of the probe, slides were washed in 20 mg/ml RNase solution for 30 min at room temperature, followed by 1 h each in 2XSSC at 50°C, 0.2XSSC at 55° and 60°C.
  • a hybridization buffer 0.6 M NaCl, 10 mM Tris pH 8.0, 1 mM EDTA pH 8.0, 10% Dextran sulfate, 0.01% sheared salmon sperm DNA, 0.05% total yeast RNA
  • FIG. 7 shows the effect of the administration of B. longum ATCC BAA-999 on CRH in the hypothalamus.
  • composition comprising Bifidobacterium lactis BB122) further combined within vitamins, minerals and myo-inositol is set out in table 1.
  • the composition in table I is for a nutritional supplement in a powder form, intended to be sprinkled on food.

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Abstract

La présente invention concerne B longum ATCC BAA-999, ou une composition comprenant B longum ATCC BAA-999, pour utilisation chez un individu pour : faciliter l'initiation de l'allaitement et/ou optimiser la durée de l'allaitement et/ou pour optimiser la qualité et/ou la quantité du lait maternel et/ou prévenir ou traiter la détresse émotionnelle périnatale et/ou pour réguler l'activité amygdalienne et/ou pour réguler la libération de CRH, et pour prévenir ou traiter les effets négatifs de la détresse émotionnelle périnatale dans la progéniture d'individus.
PCT/EP2016/070496 2015-08-31 2016-08-31 Procédés et compositions utilisant bifidobacterium longum pour optimiser l'allaitement WO2017037105A1 (fr)

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CA2994352A CA2994352A1 (fr) 2015-08-31 2016-08-31 Procedes et compositions utilisant bifidobacterium longum pour optimiser l'allaitement
BR112018001179A BR112018001179A2 (pt) 2015-08-31 2016-08-31 métodos e composições usando bifidobacterium longum para otimizar a amamentação
CN201680049601.9A CN107980002A (zh) 2015-08-31 2016-08-31 使用长双岐杆菌优化母乳喂养的方法和组合物
MX2018002032A MX2018002032A (es) 2015-08-31 2016-08-31 Metodos y composiciones que usan bifidobacterium longum para optimizar la lactancia materna.
EP16759752.5A EP3344269A1 (fr) 2015-08-31 2016-08-31 Procédés et compositions utilisant bifidobacterium longum pour optimiser l'allaitement
PH12018500117A PH12018500117A1 (en) 2015-08-31 2018-01-15 Methods and compositions using bifidobacterium longum to optimize breastfeeding

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