EP2658388A2 - Method for inhibiting pathogens using a nutritional composition - Google Patents
Method for inhibiting pathogens using a nutritional compositionInfo
- Publication number
- EP2658388A2 EP2658388A2 EP11809005.9A EP11809005A EP2658388A2 EP 2658388 A2 EP2658388 A2 EP 2658388A2 EP 11809005 A EP11809005 A EP 11809005A EP 2658388 A2 EP2658388 A2 EP 2658388A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- lactoferrin
- kcal
- human
- source
- nutritional composition
- Prior art date
- Legal status (The legal status 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 status listed.)
- Ceased
Links
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- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- 229940080237 sodium caseinate Drugs 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000000153 supplemental effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 244000052613 viral pathogen Species 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 235000019163 vitamin B12 Nutrition 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000010497 wheat germ oil Substances 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/40—Transferrins, e.g. lactoferrins, ovotransferrins
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23J—PROTEIN COMPOSITIONS FOR FOODSTUFFS; WORKING-UP PROTEINS FOR FOODSTUFFS; PHOSPHATIDE COMPOSITIONS FOR FOODSTUFFS
- A23J1/00—Obtaining protein compositions for foodstuffs; Bulk opening of eggs and separation of yolks from whites
- A23J1/20—Obtaining protein compositions for foodstuffs; Bulk opening of eggs and separation of yolks from whites from milk, e.g. casein; from whey
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/115—Fatty acids or derivatives thereof; Fats or oils
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/17—Amino acids, peptides or proteins
- A23L33/19—Dairy proteins
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/20—Reducing nutritive value; Dietetic products with reduced nutritive value
- A23L33/21—Addition of substantially indigestible substances, e.g. dietary fibres
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/40—Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- This disclosure relates generally to the field of nutritional
- compositions such as infant formulas, human milk fortifiers, children's dietary supplements, and the like, having lactoferrin compositions therein. More particularly, the disclosure relates to a method for inhibiting the invasive mechanisms of harmful bacterial pathogens and/or inhibiting the adhesion of at least one pathogen in a human gastrointestinal tract by administering to the human a nutritional composition including lactoferrin produced by a non-human source.
- compositions for humans there are currently a variety of dietary compositions for humans, especially young humans, to provide supplemental or primary nutrition at certain stages in life.
- commercial dietary compositions for infants seek to mimic to the extent possible the composition and associated functionality of human milk.
- proteins some of which have physiological activity, and blended fat ingredients
- dietary compositions are formulated such that they simulate human milk for use as a complete or partial substitute.
- Other ingredients often utilized in dietary compositions for infants may include a carbohydrate source such as lactose as well as other vitamins, minerals and elements believed to be present in human milk for the absorption by the infant.
- proteins present within human milk provide for a defense against pathogens to prevent and inhibit infection while additionally promoting an immunological response within the infant.
- Proteins including haptocorrin and lactoferrin are understood to help infants defend against a variety of bacterial pathogens via bacteriostatic and bactericidal activity.
- Lactoferrin is one of the primary proteins in human milk and is considered a glycoprotein having an average molecular weight of approximately 80 kilodaltons. It is an iron binding protein having the capacity to bind two molecules of iron in a reversible fashion and can facilitate the uptake of iron within the intestines for the human. Functionally, lactoferrin regulates iron absorption and as such can bind iron-based free radicals as well as donate iron for an
- lactoferrin An additional role of lactoferrin is its anti- microbial activity in guarding against intestinal infections in humans generally, but especially in infants. Lactoferrin has been known to be both bacteriostatic and bactericidal in inhibiting the growth of specific bacteria while also killing microbes prior to a successful invasion of intestinal cells.
- lactoferrin In obtaining a commercially viable dietary composition, the addition of lactoferrin has generally been limited due to predicted losses of activity during processing. For example, generally, the temperature and pH requirements in processing infant formulas and other products such as human milk fortifiers and various children's products reduce specific functions of the lactoferrin, causing lactoferrin not to be included within a final formulation. In addition, lactoferrin is often considered only for its iron binding qualities; thus, lactoferrin may generally be excluded from a formulation where such properties are thought to be diminished by processing conditions.
- human breast milk is relatively low in iron, containing about 0.3 milligrams of iron per liter of breast milk. While this quantity is low, human infants have high absorption rate, absorbing about half of the iron from the breast milk.
- human infants are fed prior art formulas with high levels of iron fortification, e.g. from about 10 mg to about 12 milligrams per liter, the infants absorb less than about 5% of the total iron. With such increased levels of iron within the prior art formulas, virtually all of the lactoferrin iron binding sites would be expected to be occupied, as lactoferrin is a known iron transport protein.
- Additional complications of the prior art formulas include the inability of providing a bacteriostatic effect. This is partially due to the use of lactoferrin with blocked or damaged binding sites as the bacteriostatic effect is at least partially related to the degree of binding to iron of the lactoferrin present within the formula.
- composition such as an infant formula, human milk fortifier, children's dietary supplement, and the like, which contains lactoferrin, in particular, lactoferrin produced by a non-human source.
- lactoferrin included in the compositions has a bacteriostatic effect even after processing under conditions of high temperature and low pH.
- a combination of characteristics including the maintenance of the anti-invasion or anti-adhesion mechanisms of lactoferrin through either high or low pH or high temperature conditions, such as during pasteurization, provide for a dietary composition that may at least partially protect against harmful bacterial pathogens.
- the present disclosure is directed, in an embodiment, to a method for inhibiting one or more of the invasive mechanisms of a bacterial pathogen and/or the adhesion of at least one pathogen using a nutritional composition comprising a lipid or fat, a protein source, a prebiotic composition, and lactoferrin from a non-human source, where the composition provides active anti- invasion and anti-adhesion mechanisms against strains of undesirable bacteria found in the human gastrointestinal tract, even after processing which includes exposure to harsh environmental conditions.
- the disclosure is directed to a nutritional product comprising:
- the nutritional composition comprises about 0.3 g/100 kcal to about 0.7 g/100 kcal of a prebiotic composition which comprises a combination of polydextrose and galactooligosaccharide .
- the lactoferrin is non-human lactoferrin and/or human lactoferrin produced by a genetically modified organism.
- organism refers to any contiguous living system, such as animal, plant, fungus or micro-organism.
- the lactoferrin used is such that an effective amount of a nutritional composition containing lactoferrin may be administered to inhibit at least one of the invasive mechanisms of at least one pathogen in the gastrointestinal tract of a human, even if, during processing, the nutritional composition has been exposed to pH and temperature fluctuations typical of certain processing conditions like pasteurization.
- the lactoferrin includes anti-invasion mechanisms which may destruct the attachment factors and injection needle used by certain bacteria on human cells.
- the lactoferrin used is such that an effective amount of a nutritional composition containing lactoferrin may be administered to inhibit the adhesion of at least one pathogen in the gastrointestinal tract of a human, even if, during processing, the nutritional composition has been exposed to pH and temperature fluctuations typical of certain processing conditions like
- ETEC Enterotoxigenic E. coli
- EPEC Enteropathogenic E. coli
- SEOC Shigatoxin producing E. coli
- EAEC Enteroaggregative E. coli
- Salmonella ser Salmonella ser.
- a nutritional composition comprises a lipid or fat, a protein source, a prebiotic composition having at least 20% of an oligosaccharide, especially one which comprises galacto- oligosaccharide (GOS), and lactoferrin which provides active anti-invasion or anti-adhesion mechanisms against strains of undesirable bacteria found in the human
- the lactoferrin included in the compositions is produced by a non-human source.
- the prebiotic comprises a
- composition disclosed herein comprises: a. up to about 7 g/100 kcal of a fat or lipid, more preferably about 3 to about 7 g/100 kcal of a fat or lipid;
- the nutritional composition comprises about 0.3 g/100 kcal to about 0.7 g/100 kcal of a prebiotic composition which comprises a combination of polydextrose and galactooligosaccharide;
- prebiotic means a non- digestible food ingredient that beneficially affects the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon that can improve the health of the host.
- probiotic means a microorganism with low or no
- infant is generally defined as a human from about birth to 12 months of age.
- a "preterm infant” is an infant born after less than 37 weeks gestation.
- a "full term infant” as used herein, means an infant born after at least 37 weeks gestation.
- Children are defined as humans from the age of 12 months to about
- an "anti-bacterially effective amount,” as used herein is generally defined as an amount of lactoferrin that provides at least one anti-invasion mechanism against strains of bacteria.
- lactoferrin produced by a non-human source means lactoferrin which is produced by or obtained from a source other than human breast milk.
- lactoferrin for use in the present disclosure includes human lactoferrin produced by a genetically modified organism as well as non-human lactoferrin.
- Bioly active lactoferrin means lactoferrin which possesses at least one anti-invasion or anti-adhesion mechanism against pathogens.
- non-human lactoferrin refers to lactoferrin having an amino acid sequence that is different from the amino acid sequence of human lactoferrin.
- organism refers to any contiguous living system, such as animal, plant, fungus or micro-organism.
- the nutritional product may be an infant formula.
- infant formula applies to a composition in liquid or powdered form that satisfies the nutrient requirements of an infant by being a substitute for human milk. In the United States, the content of an infant formula is dictated by the federal regulations set forth at 21 C.F.R. ⁇ 100, 106 and 107.
- the nutritional product may be a human milk fortifier, meaning it is a composition which is added to human milk in order to enhance the nutritional value of human milk.
- the disclosed composition may be in powder or liquid form.
- the disclosed nutritional product may be a children's nutritional composition.
- the nutritional products of the disclosure may provide minimal, partial, or total nutritional support.
- the compositions may be nutritional supplements or meal replacements.
- the compositions may be administered in conjunction with a food or nutritional composition.
- the compositions can either be intermixed with the food or other nutritional compositions prior to ingestion by the subject or can be administered to the subject either before or after ingestion of a food or nutritional composition.
- the compositions may be administered to preterm infants receiving infant formula, breast milk, a human milk fortifier, or combinations thereof.
- the compositions may, but need not, be nutritionally complete.
- nutrients to vary depending on a number of factors including, but not limited to, age, clinical condition, and dietary intake of the subject to whom the term is being applied.
- nutritional composition of the present disclosure provides adequate amounts of all carbohydrates, lipids, essential fatty acids, proteins, essential amino acids, conditionally essential amino acids, vitamins, minerals, and energy required for normal growth.
- essential refers to any nutrient which cannot be synthesized by the body in amounts sufficient for normal growth and to maintain health and which therefore must be supplied by the diet.
- conditionally essential as applied to nutrients means that the nutrient must be supplied by the diet under conditions when adequate amounts of the precursor compound is unavailable to the body for endogenous synthesis to occur.
- composition which is "nutritionally complete” for the preterm infant will, by definition, provide qualitatively and quantitatively adequate amounts of all carbohydrates, lipids, essential fatty acids, proteins, essential amino acids, conditionally essential amino acids, vitamins, minerals, and energy required for growth of the preterm infant.
- the composition which is "nutritionally complete” for the term infant will, by definition, provide qualitatively and quantitatively adequate amounts of all carbohydrates, lipids, essential fatty acids, proteins, essential amino acids, conditionally essential amino acids, vitamins, minerals, and energy required for growth of the term infant.
- the composition which is "nutritionally complete” for the preterm infant will, by definition, provide qualitatively and quantitatively adequate amounts of all carbohydrates, lipids, essential fatty acids, proteins, essential amino acids, conditionally essential amino acids, vitamins, minerals, and energy required for growth of the term infant.
- the nutritional composition may be provided in any form known in the art, including a powder, a gel, a suspension, a paste, a solid, a liquid, a liquid concentrate, or a ready-to-use product.
- the nutritional composition is an infant formula, especially an infant formula adapted for use as sole source nutrition for an infant.
- the nutritional product disclosed herein may be administered enterally.
- enteral means through or within the gastrointestinal, or digestive, tract, and “enteral administration” includes oral feeding, intragastric feeding, transpyloric administration, or any other introduction into the digestive tract.
- Lactoferrins are single chain polypeptides of about 80 kD containing 1
- lactoferrin comprises two homologous lobes, called the N- and C-lobes, referring to the N-terminal and C- terminal part of the molecule, respectively.
- Each lobe further consists of two sub- lobes or domains, which form a cleft where the ferric ion (Fe 3+ ) is tightly bound in synergistic cooperation with a (bi)carbonate anion. These domains are called Nl, N2, Cl and C2, respectively.
- the N-terminus of lactoferrin has strong cationic peptide regions that are responsible for a number of important binding
- Lactoferrin has a very high isoelectric point ( ⁇ pl 9) and its cationic nature plays a major role in its ability to defend against bacterial, viral, and fungal pathogens.
- ⁇ pl 9 isoelectric point
- the N-terminal residues 1- 47 of human lactoferrin (1-48 of bovine lactoferrin) are critical to the iron- independent biological activities of lactoferrin.
- residues 2 to 5 (RRRR) and 28 to 31 (RKVR) are arginine-rich cationic domains in the N- terminus especially critical to the antimicrobial activities of lactoferrin.
- a similar region in the N-terminus is found in bovine lactoferrin (residues 17 to 42;
- lactoferrins from different host species may vary in their amino acid sequences though commonly possess a relatively high isoelectric point with positively charged amino acids at the end terminal region of the internal lobe.
- Suitable lactoferrins for use in the present disclosure include those having at least 48% homology with the amino acid sequence AVGEQELRKCNQWSGL at the HLf (349-364) fragment.
- the lactoferrin has at least 65% homology with the amino acid sequence AVGEQELRKCNQWSGL at the HLf (349- 364) fragment, and, in embodiments, at least 75% homology.
- non- human lactoferrins for use in the present disclosure include, without limitation, bovine lactoferrin, porcine lactoferrin, equine lactoferrin, buffalo lactoferrin, goat lactoferrin, murine lactoferrin and camel lactoferrin.
- lactoferrin included herein maintain relevant activity even if exposed to a low pH (i.e., below 7, and even as low as about 4.6 or lower) and/or high temperatures (i.e., above about 65°C, and as high as about 120°C, conditions which would be expected to destroy or severely limit the stability or activity of human lactoferrin or recombinant human lactoferrin.
- a low pH i.e., below 7, and even as low as about 4.6 or lower
- high temperatures i.e., above about 65°C, and as high as about 120°C, conditions which would be expected to destroy or severely limit the stability or activity of human lactoferrin or recombinant human lactoferrin.
- These low pH and/or high temperature conditions can be expected during certain processing regimen for nutritional compositions of the types described herein, such as pasteurization.
- bovine lactoferrin has an the amino acid composition which has only about a 70% sequence homology to that of human lactoferrin, and is stable and remains active under conditions under which human or recombinant human lactoferrin become unstable or inactive
- bovine lactoferrin has bactericidal activity against undesirable bacterial pathogens found in the human gut.
- lactoferrin is present in the nutritional
- compositions in an amount of at least about 10 mg/100 kCal, especially when the nutritional composition is intended for use by children.
- the upper limit of lactoferrin is about 240 mg/100 kCal.
- lactoferrin is present in the nutritional composition in an amount of from about 70 mg to about 220 mg/100 kCal; in yet another embodiment, lactoferrin is present in an amount of about 90 mg to about 190 mg/100 kCal.
- Nutritional compositions for infants can include lactoferrin in the quantities of from about 0.5 mg to about 1.5 mg per milliliter of formula. In nutritional compositions replacing human milk, lactoferrin may be present in quantities of from about 0.6 mg to about 1.3 mg per milliliter of formula.
- Suitable fat or lipid sources for practicing the present disclosure may be any known or used in the art, including but not limited to, animal sources, e.g., milk fat, butter, butter fat, egg yolk lipid; marine sources, such as fish oils, marine oils, single cell oils; vegetable and plant oils, such as corn oil, canola oil, sunflower oil, soybean oil, palmolein, coconut oil, high oleic sunflower oil, evening primrose oil, rapeseed oil, olive oil, flaxseed (linseed) oil, cottonseed oil, high oleic safflower oil, palm stearin, palm kernel oil, wheat germ oil; medium chain triglyceride oils and emulsions and esters of fatty acids; and any combinations thereof.
- animal sources e.g., milk fat, butter, butter fat, egg yolk lipid
- marine sources such as fish oils, marine oils, single cell oils
- vegetable and plant oils such as corn oil, canola oil, sunflower oil, soybean oil, palmolein, coconut oil
- Bovine milk protein sources useful in practicing the present disclosure include, but are not limited to, milk protein powders, milk protein concentrates, milk protein isolates, nonfat milk solids, nonfat milk, nonfat dry milk, whey protein, whey protein isolates, whey protein concentrates, sweet whey, acid whey, casein, acid casein, caseinate (e.g. sodium caseinate, sodium calcium caseinate, calcium caseinate) and any combinations thereof.
- the proteins are provided as intact proteins. In other embodiments, the proteins are provided as a combination of both intact proteins and partially hydrolyzed proteins, with a degree of hydrolysis of between about 4% and 10%. In yet another embodiment, the protein source may be supplemented with glutamine- containing peptides.
- the whey:casein ratio of the protein source is similar to that found in human breast milk.
- the protein source comprises from about 20% to about 85% whey protein. In another embodiment, the protein source may comprise from about 20% to about 80% casein. In yet another embodiment of the disclosure, the protein source includes about 60% to about 85% whey and about 15% to about 40% casein.
- the nutritional composition may also contain one or more probiotics. Any probiotic known in the art may be acceptable in this embodiment provided it achieves the intended result.
- the probiotic may be selected from Lactobacillus species, Lactobacillus rhamnosus GG, Bifidobacterium species, Bifidobacterium longum, Bifidobacterium brevis and Bifidobacterium animalis subsp. lactis BB-12.
- the amount of the probiotic may vary from about 10 4 to about 10 10 colony forming units (cfu) per kg body weight per day. In another embodiment, the amount of the probiotic may vary from about 10 6 to about 10 9 cfu per kg body weight per day. In yet another embodiment, the amount of the probiotic may be at least about 10 6 cfu per kg body weight per day. Moreover, the disclosed composition may also include probiotic-conditioned media
- the probiotic(s) may be viable or non-viable.
- viable refers to live microorganisms.
- nonviable or non-viable probiotic means non-living probiotic microorganisms, their cellular components and metabolites thereof. Such non-viable probiotics may have been heat-killed or otherwise inactivated but retain the ability to favorably influence the health of the host.
- the probiotics useful in the present disclosure may be naturally- occurring, synthetic or developed through the genetic
- the nutritional composition contains one or more prebiotics.
- Such prebiotics may be naturally- occurring, synthetic, or developed through the genetic manipulation of organisms and/or plants, whether such new source is now known or developed later.
- the prebiotic included in the prebiotics may be naturally- occurring, synthetic, or developed through the genetic manipulation of organisms and/or plants, whether such new source is now known or developed later.
- the prebiotic included in the prebiotics may be naturally- occurring, synthetic, or developed through the genetic manipulation of organisms and/or plants, whether such new source is now known or developed later.
- compositions of the present disclosure include those taught by U.S. Patent No. 7,572,474, the disclosure of which is incorporated herein by reference.
- Prebiotics useful in the present disclosure may include
- prebiotics useful in the present disclosure may include lactulose, lactosucrose, raffinose, gluco- oligosaccharide, inulin, polydextrose, polydextrose powder, galacto-oligosaccharide, fructo-oligosaccharide, isomalto-oligosaccharide, soybean oligosaccharides, lactosucrose, xylo-oligosacchairde, chito-oligosaccharide, manno-oligosaccharide, aribino-oligosaccharide, siallyl-oligosaccharide, fuco-oligosaccharide, and gentio- oligosaccharides.
- the total amount of prebiotics present in the nutritional composition may be from about 1.0 g/L to about 10.0 g/L of the composition.
- the total amount of prebiotics present in the nutritional composition may be from about 2.0 g/L and about 8.0 g/L of the composition.
- At least 20% of the prebiotics should comprise galacto-oligosaccharide (GOS), polydextrose, or a mixture thereof.
- the nutritional compositions comprise polydextrose and galactooligosaccaharide.
- the nutritional compositions comprise one or more additional prebiotics.
- the amount of each of galacto-oligosaccharide and/or polydextrose in the nutritional composition may, in an embodiment, be within the range of from about 1.0 g/L to about 4.0 g/L.
- the total amount of prebiotics present in the nutritional composition may be from about 0.1 g/100 kcal to about 1 g/100 kcal. More preferably, the total amount of prebiotics present in the nutritional composition may be from about 0.3 g/100 kcal to about 0.7 g/100 kcal. At least 20% of the prebiotics should comprise galactooligosaccharide (GOS) and/or polydextrose (PDX).
- GOS galactooligosaccharide
- PDX polydextrose
- the amount of galacto-oligosaccharide in the nutritional composition may, in an embodiment, be from about 0.2 g/100 Kcal to about 1.0 g/100 Kcal. In another embodiment, the amount of galacto-oligosaccharide in the nutritional composition may be from about 0.1 g/100 Kcal to about 0.5 g/100 Kcal. In yet another embodiment, the amount of galactooligsaccharide is within the range of from about 0.2 g/100 kcal to about 0.6 g/100 kcal.
- the amount of polydextrose in the nutritional composition may, in an embodiment, be within the range of from about 0.1 g/100 kcal to about 1 g/100 kcal. In another embodiment, the amount of polydextrose is within the range of from about 0.2 g/100 kcal to about 0.6 g/100 kcal. In yet another embodiment, if polydextrose is used in the prebiotic composition, the amount of polydextrose in the nutritional composition may, in an embodiment, be within the range of from about 0.1 g/100 Kcal to about 0.5 g/100 Kcal.
- the ratio of polydextrose to galactooligosaccharide in the prebiotic composition is between about 9:1 and about 1:9.
- the prebiotic composition in combination with lactoferrin, inhibits the adhesion of one or more pathogens in the gastrointestinal tract when the nutritional compositions are provided to humans.
- An example of one such pathogen is Enterobacter sakazakii (otherwise known as Cronobacter sakazakii).
- Another pathogen for which adhesion is inhibited by the combination of lactoferrin with the prebiotic composition is E. coli.
- the nutritional formulation of the disclosure may also contain a source of long chain polyunsaturated fatty acids (LCPUFAs) which comprise docosahexanoic acid (DHA).
- LCPUFAs long chain polyunsaturated fatty acids
- DHA docosahexanoic acid
- suitable LCPUFAs include, but are not limited to, a-linoleic acid, ⁇ -linoleic acid, linoleic acid, linolenic acid, eicosapentanoic acid (EPA) and arachidonic acid (ARA).
- the nutritional composition is supplemented with both DHA and ARA.
- the weight ratio of ARA:DHA may be from about 1:3 to about 9:1. In one embodiment of the present disclosure, this ratio is from about 1:2 to about 4:1.
- the amount of long chain polyunsaturated fatty acids in the nutritional composition may vary from about 5 mg/100 kcal to about 100 mg/100 kcal, more preferably from about 10 mg/100 kcal to about 50 mg/100 kcal.
- the nutritional composition may be supplemented with oils containing
- DHA and ARA using standard techniques known in the art.
- DHA and ARA may be added to the formula by replacing an equivalent amount of an oil, such as high oleic sunflower oil, normally present in the formula.
- the oils containing DHA and ARA may be added to the formula by replacing an equivalent amount of the rest of the overall fat blend normally present in the formula without DHA and ARA.
- the source of DHA and ARA may be any source known in the art such as marine oil, fish oil, single cell oil, egg yolk lipid, and brain lipid.
- the DHA and ARA are sourced from the single cell Martek oil, DHASCO® and ARASCO® respectively, or variations thereof.
- the DHA and ARA can be in natural form, provided that the remainder of the LCPUFA source does not result in any substantial deleterious effect on the infant.
- the DHA and ARA can be used in refined form.
- sources of DHA and ARA are single cell oils as taught in U.S. Pat. Nos. 5,374,567; 5,550, 156; and 5,397,591, the disclosures of which are incorporated herein in their entirety by reference.
- the nutritional compositions comprise from about 0.5 mg/100 kcal to about 5 mg/100 kcal of iron, including iron bound to lactoferrin.
- lactoferrin as used in embodiments of the present disclosure is its anti-invasion and anti-adhesion mechanism in the human gastrointestinal tract. Specifically, lactoferrin may destroy the injection needle used by certain bacteria to invade and cause pathogenesis. Likewise, lactoferrin inhibits the adhesion of pathogens in the gastrointestinal tract of humans.
- a bacterium known to cause pathogenesis is Escherichia coli which may cause diarrhea in infants, children and adults and is realized as an agent for pediatric diarrhea. The E. coli produces and translocates bacterial protein through a needle complex via a type III secretory system.
- the secretory system of many gram-negative pathogenic bacteria is a type III secretion including the following bacteria: Shigella, Salmonella,
- the type III secretory system functions through use of a needle for the transport of virulent proteins from the bacterial cytoplasm through the needle directly into the host cell's cytoplasm.
- the use of the needle provides for a passage through the multiple membranes including the double membranes of the gram-negative bacterium and the eukaryotic membrane of the human cell.
- the needle complex is comprised of E. coli secretion component F (EscF) with E. coli secreted protein A (EspA) attaching to the tip of the needle, forming a generally hollow structure for the passage of components from the bacteria to the host human cell.
- bacterial proteins such as EspB may be introduced into the host cell through this tube. While the physiology of EspB may not be fully understood in the article "The Enter opatho genie E. coli effector EspB facilitates microvillus effacing and
- EspB Antiphagocytosis by Inhibiting Myosin Function
- myosin proteins interact with actin filaments to participate in cellular processes such as phagocytosis in eliminating potential bacterial pathogens. Harmful symptoms occur where EspB emitted by the E. coli inhibits the interaction between various myosin proteins and actin filaments in suppressing phagocytosis, leading to diarrhea or other gastric distress in infants, children and adults.
- One of the anti-invasion mechanisms of lactoferrin is in inhibiting the translocation of EspB into human cells. Specifically, one mechanism may include the inhibition of the formation of the necessary secretory structures for
- Lactoferrin is capable of degrading EspA, the protein responsible for the tube like structure for translocating Esp B into the host cell. As EspA may be degraded by lactoferrin, the portal through the human cell membrane would not be created thus alleviating pathogenesis created from Esp B entering into the human cell's cytoplasm. Furthermore, lactoferrin may also possess proteolytic activity resulting in the degrading EspB. Ultimately, lactoferrin effectively disrupts the needle complex associated with the pathogen's secretion system while simultaneously degrading proteins responsible for symptoms including gastrointestinal distress and diarrhea.
- This Example exemplifies the inhibition of pathogens, namely E. sakazakii 4603 and 29004 and E. coli E2348/69, by lactoferrin alone and in combination with polydextrose and galactooligosaccharide.
- E. sakazakii 4603 and 29004 give the highest adherence rates to HEp-2 cells.
- HEp-2 cells obtained from the ATTC are grown in 75 cm 2 tissue culture flasks containing 25 ml of MEM supplemented with 10% FBS in a CO2 incubator at tissue culture conditions. Confluent HEp-2 cells are harvested by adding 0.5 ml of 0.25% Trypsin-EDTA Solution (Sigma) and incubating for 15 minutes at tissue culture conditions.
- Trypsin is inactivated with 0.5 ml of FBS, and the cells are seeded onto 12-mm diameter glass coverslips in 24-well tissue culture plates at approximately 3.6 x 10 5 viable cells per well. Plates are incubated under tissue culture conditions for two days prior to the start of each experiment, or until confluency is reached.
- lactoferrin at final concentrations of 0.1 mg/ml, 0.6 mg/ml, and 1 mg/ml, alone and in combination with a 1:1 blend of galactooligosaccharide (obtained from DOMO) and polydextrose (obtained from DMV) at final concentrations of 4 mg/ml and 16 mg/ml of, is added to the HEp-2 cells. Control wells containing no lactoferrin are also prepared.
- E. coli or E. sakazakii culture containing ca. 10 7 cells
- Tissue culture plates are then incubated at 37°C in a CO2 incubator for three hours.
- the wells are then washed five times to remove non-adherent cells, and adhered bacteria are enumerated by microscopic
- coverslips are mounted on microscope slides and observed under a phase contrast microscope with the lOOx objective. Fifteen photomicrographs of each coverslip are taken using Motic Image software following an established geometric pattern throughout the entire coverslip. The number of cells and bacteria in each image is counted using Image J image analysis software. Adherence is calculated as the number of adhered bacteria per HEp-2 cell.
- adhered cells are also enumerated by quantitative real-time PCR (qRT-PCR), as described in Humphries et al., Interactions of enteropathogenic Escherichia coli with pediatric and adult intestinal biopsy specimens during early adherence, Infect. Immun., 77, 4463-4468 (2009). Briefly, genomic DNA are extracted from the infected HEp-2 cells and quantified by qRT-PCR using oligonucleotide primers that amplify the 16s rRNA region of E sakazakii 4603 and 29004 or E. coli 2348/69.
- qRT-PCR quantitative real-time PCR
- PCR mixture consists of 11.25 ⁇ 1 SYBR solution, 2.5 MasterMix, 1 ⁇ of each primer, and 5 ⁇ of DNA template.
- the PCR reactions are performed using an Eppendorf Mastercycler Realplex2.
- This example illustrates an embodiment of a nutritional product according to the present disclosure.
- This example illustrates another embodiment of a nutritional product according to the present disclosure.
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Application Number | Priority Date | Filing Date | Title |
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US12/980,813 US8648036B2 (en) | 2010-12-29 | 2010-12-29 | Use of nutritional compositions including lactoferrin and one or more prebiotics in inhibiting adhesion of pathogens in the gastrointestinal tract |
US12/980,808 US20120171163A1 (en) | 2010-12-29 | 2010-12-29 | Method for inhibiting a bacterial invasive mechanism using a nutritional composition |
PCT/US2011/065231 WO2012091946A2 (en) | 2010-12-29 | 2011-12-15 | Method for inhibiting pathogens using a nutritional composition |
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EP11809005.9A Ceased EP2658388A2 (en) | 2010-12-29 | 2011-12-15 | Method for inhibiting pathogens using a nutritional composition |
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EP (1) | EP2658388A2 (en) |
CN (1) | CN103327828B (en) |
BR (1) | BR112013011642B1 (en) |
CA (1) | CA2822892C (en) |
EC (1) | ECSP13012798A (en) |
HK (1) | HK1189456A1 (en) |
MX (1) | MX2013006094A (en) |
MY (1) | MY174494A (en) |
PE (1) | PE20141192A1 (en) |
RU (1) | RU2013128920A (en) |
SG (2) | SG10201508194RA (en) |
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US8968722B2 (en) | 2010-12-29 | 2015-03-03 | Mead Johnson Nutrition Company | Milk-based nutritional compositions containing lactoferrin and uses thereof |
EP2934188B1 (en) * | 2012-12-18 | 2018-04-11 | MJN U.S. Holdings LLC | Milk-based nutritional compositions containing lactoferrin and uses thereof |
US20140271978A1 (en) * | 2013-03-15 | 2014-09-18 | Mead Johnson Nutrition Company | Low-buffer nutritional compositions and uses thereof |
US9609888B2 (en) * | 2013-07-31 | 2017-04-04 | Mead Johnson Nutrition Company | Nutritional compositions containing synergistic combination and uses thereof |
WO2019049157A1 (en) * | 2017-09-10 | 2019-03-14 | Technion Research & Development Foundation Limited | Composition and method for a prebiotic delivery system targeted to probiotic bacteria |
GB2618609A (en) * | 2022-05-13 | 2023-11-15 | Lintbells Ltd | Methods and processes for manufacture of a topically adherent selective bactericide |
WO2024056786A1 (en) | 2022-09-14 | 2024-03-21 | N.V. Nutricia | Nutritional composition |
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US20100316619A1 (en) * | 2009-02-12 | 2010-12-16 | Anja Wittke | Nutritional composition with prebiotic component |
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IE61701B1 (en) | 1986-07-17 | 1994-11-30 | Morinaga Milk Industry Co Ltd | Process for producing bovine lactoferrin in high purity |
US4977137B1 (en) * | 1987-06-03 | 1994-06-28 | Baylor College Medicine | Lactoferrin as a dietary ingredient promoting the growth of the gastrointestinal tract |
US5407957A (en) | 1990-02-13 | 1995-04-18 | Martek Corporation | Production of docosahexaenoic acid by dinoflagellates |
ZA92452B (en) | 1991-01-24 | 1992-10-28 | Martek Corp | Microbial oil mixtures and uses thereof |
US5374567A (en) | 1993-05-20 | 1994-12-20 | The United States Of America As Represented By The Secretary Of The Navy | Operational amplifier using bipolar junction transistors in silicon-on-sapphire |
ATE209862T1 (en) | 1994-02-16 | 2001-12-15 | Pharming Intellectual Pty Bv | ISOLATION OF LACTOFERRIN FROM MILK |
WO2003073866A1 (en) | 2002-03-07 | 2003-09-12 | Upfront Chromatography A/S | A process of isolating lactoferrin |
CN101247823A (en) * | 2005-05-05 | 2008-08-20 | 布里斯托尔-迈尔斯斯奎布公司 | Use of bovine lactoferrin in the manufacture of a medicament for inhibiting the growth of bacteria |
US20070191264A1 (en) * | 2005-05-05 | 2007-08-16 | Bristol-Myers Squibb Company, A Delaware Corporation | Methods for inhibiting the growth of bacteria |
US7572474B2 (en) * | 2005-06-01 | 2009-08-11 | Mead Johnson Nutrition Company | Method for simulating the functional attributes of human milk oligosaccharides in formula-fed infants |
US20080003329A1 (en) * | 2006-06-30 | 2008-01-03 | Ricardo Rueda | Enriched infant formulas |
WO2008047391A1 (en) * | 2006-10-17 | 2008-04-24 | S.I.F.Fr.A. Farmaceutici Srl | Nutriceutic composition comprising lactoferrin and proteasic probiotics |
EP2476322A3 (en) * | 2007-11-26 | 2015-02-25 | Nestec S.A. | Age-tailored nutrition system for infants |
ITRM20080163A1 (en) * | 2008-03-26 | 2009-09-27 | Maurizio Acri | USE OF LATTOFERRINA FOR THE PREVENTION OF NEONATAL SEPSIS IN PREMATURED NEWBORNS |
RU2543815C2 (en) * | 2009-10-29 | 2015-03-10 | Нестек С.А. | Nutritional compositions containing lactoferrin and probiotics and sets of their parts |
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DATABASE GNPD Mintel; January 2010 (2010-01-01), ANONYMOUS: "New birth formula", XP002754399 * |
DATABASE GNPD Mintel; June 2010 (2010-06-01), ANONYMOUS: "Infant formula milk powder (stage 1)", XP002754398 * |
DATABASE GNPD Mintel; September 2010 (2010-09-01), ANONYMOUS: "Stage 1 Baby formula powder", XP002754397 * |
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RU2013128920A (en) | 2015-02-10 |
SG190781A1 (en) | 2013-07-31 |
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PE20141192A1 (en) | 2014-10-01 |
TW201238503A (en) | 2012-10-01 |
CN103327828A (en) | 2013-09-25 |
HK1189456A1 (en) | 2014-06-13 |
TWI626893B (en) | 2018-06-21 |
MX2013006094A (en) | 2013-07-03 |
SG10201508194RA (en) | 2015-11-27 |
CA2822892C (en) | 2020-04-28 |
CA2822892A1 (en) | 2012-07-05 |
MY174494A (en) | 2020-04-23 |
BR112013011642A2 (en) | 2016-07-12 |
CN103327828B (en) | 2016-05-11 |
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WO2012091946A3 (en) | 2012-09-07 |
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