Note: Descriptions are shown in the official language in which they were submitted.
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DESCRIPTION
NUTRITIONAL COMPOSITIONS COMPRISING A CASEIN HYDROLYSATE, AS WELL AS DIETARY
BUTYRATE AND/OR A COMPOUND FOR STIMULATING FORMATION OF ENDOGENOUS BUTYRATE
TECHNICAL FIELD
[0001] The present disclosure relates generally to nutritional compositions
comprising
dietary butyrate and a component, which can stimulate the production of
endogenous
butyrate. The nutritional compositions are suitable for administration to
pediatric subjects.
Additionally, the disclosure relates to nutritional compositions including a
prebiotic
comprising polydextrose and galacto-oligosaccharides, dietary butyrate, and a
protein
equivalent source. Further, disclosed are methods for reducing the incidence
of allergy
and/or improving tolerance to cow's milk allergy in target subjects. The
disclosed nutritional
compositions may provide additive and or/synergistic beneficial health
effects.
BACKGROUND ART
[0002] Administration of nutritional compositions or other compositions
including butyrate or
butyrate derivatives often suffer from difficulties regarding the
bioavailability of butyrate
upon administration. For example, certain butyrate derivatives undergo
degradation or
oxidation, which ultimate affect the bioavailability of the butyrate
derivative upon ingestion.
As such, compositions including butyrate derivatives may not provide
therapeutic efficacy
upon ingestion given the degradation of the butyrate derivative.
[0003] Additionally, nutritional compositions including butyrate may suffer
from poor
palatability. The unpleasant taste and odor of compositions including butyrate
can make the
oral administration of certain nutritional compositions including butyrate
difficult, especially
in the pediatric population. For example, certain butyric acid derivatives at
room
temperature are present as a dense liquid having an unpleasant taste and
intense odor.
[0004] Accordingly, it would be beneficial to provide a nutritional
composition that includes
endogenous butyrate to avoid the palatability issues sometimes found with
dietary butyrate.
Further, there is a need for palatable, safe, yet effective, nutritional
compositions that
include a combination of one or more prebiotics, a protein equivalent source,
and butyrate to
reduce incidence of allergy and increase tolerance to cow's milk allergy in
certain subjects.
DISCLOSURE OF THE INVENTION
[0005] Briefly, the present disclosure is directed, in an embodiment, to a
nutritional
composition that includes dietary butyrate and a component which can stimulate
the
production of endogenous butyrate in the human gut. In some embodiments, the
dietary
butyrate may be encapsulated. In some embodiments, the endogenous butyrate may
be
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provided by stimulating short chain fatty acid ("SCFA") production by the gut
microbiota and
the dietary butyrate may be provided by an enriched lipid fraction derived
from milk.
[0006] It is to be understood that both the foregoing general description and
the following
detailed description present embodiments of the disclosure and are intended to
provide an
overview or framework for understanding the nature and character of the
disclosure as it is
claimed. The description serves to explain the principles and operations of
the claimed
subject matter. Other and further features and advantages of the present
disclosure will be
readily apparent to those skilled in the art upon a reading of the following
disclosure.
BEST MODE FOR CARRYING OUT THE INVENTION
[0007] Reference now will be made in detail to the embodiments of the present
disclosure,
one or more examples of which are set forth hereinbelow. Each example is
provided by way
of explanation of the nutritional composition of the present disclosure and is
not a limitation.
In fact, it will be apparent to those skilled in the art that various
modifications and variations
can be made to the teachings of the present disclosure without departing from
the scope of
the disclosure. For instance, features illustrated or described as part of one
embodiment,
can be used with another embodiment to yield a still further embodiment.
[0008] Thus, it is intended that the present disclosure covers such
modifications and
variations as come within the scope of the appended claims and their
equivalents. Other
objects, features and aspects of the present disclosure are disclosed in or
are apparent from
the following detailed description. It is to be understood by one of ordinary
skill in the art
that the present discussion is a description of exemplary embodiments only and
is not
intended as limiting the broader aspects of the present disclosure.
[0009] The present disclosure relates generally to nutritional compositions
comprising
dietary butyrate and a component for stimulating the production of endogenous
butyrate.
Additionally, the disclosure relates to methods for improving the shelf
stability and/or
organoleptic properties of nutritional compositions including butyrate.
[0010] "Nutritional composition" means a substance or formulation that
satisfies at least a
portion of a subject's nutrient requirements. The terms "nutritional(s)",
"nutritional
formula(s)", "enteral nutritional(s)", and "nutritional supplement(s)" are
used as non-limiting
examples of nutritional composition(s) throughout the present disclosure.
Moreover,
"nutritional composition(s)" may refer to liquids, powders, gels, pastes,
solids, concentrates,
suspensions, or ready-to-use forms of enteral formulas, oral formulas,
formulas for infants,
formulas for pediatric subjects, formulas for children, growing-up milks
and/or formulas for
adults.
[0011] "Pediatric subject" means a human less than 13 years of age. In some
embodiments,
a pediatric subject refers to a human subject that is between birth and 8
years old. In other
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embodiments, a pediatric subject refers to a human subject between 1 and 6
years of age. In
still further embodiments, a pediatric subject refers to a human subject
between 6 and 12
years of age. The term "pediatric subject" may refer to infants (preterm or
fullterm) and/or
children, as described below.
[0012] "Infant" means a human subject ranging in age from birth to not more
than one year
and includes infants from 0 to 12 months corrected age. The phrase "corrected
age" means
an infant's chronological age minus the amount of time that the infant was
born premature.
Therefore, the corrected age is the age of the infant if it had been carried
to full term. The
term infant includes low birth weight infants, very low birth weight infants,
and preterm
infants. "Preterm" means an infant born before the end of the 37th week of
gestation. "Full
term" means an infant born after the end of the 37th week of gestation.
[0013] "Child" means a subject ranging in age from 12 months to about 13
years. In some
embodiments, a child is a subject between the ages of 1 and 12 years old. In
other
embodiments, the terms "children" or "child" refer to subjects that are
between one and
about six years old, or between about seven and about 12 years old. In other
embodiments,
the terms "children" or "child" refer to any range of ages between 12 months
and about 13
years.
[0014] "Infant formula" means a composition that satisfies at least a portion
of the nutrient
requirements of an infant. In the United States, the content of an infant
formula is dictated
by the federal regulations set forth at 21 C.F.R. Sections 100, 106, and 107.
[0015] The term "medical food" refers enteral compositions that are formulated
or intended
for the dietary management of a disease or disorder. A medical food may be a
food for oral
ingestion or tube feeding (nasogastric tube), may be labeled for the dietary
management of
a specific medical disorder, disease or condition for which there are
distinctive nutritional
requirements, and may be intended to be used under medical supervision.
[0016] The term "peptide" as used herein describes linear molecular chains of
amino acids,
including single chain molecules or their fragments. The peptides described
herein include
no more than 50 total amino acids. Peptides may further form oligomers or
multimers
consisting of at least two identical or different molecules. Furthermore,
peptidomimetics of
such peptides where amino acid(s) and/or peptide bond(s) have been replaced by
functional
analogs are also encompassed by the term "peptide". Such functional analogues
may
include, but are not limited to, all known amino acids other than the 20 gene-
encoded amino
acids such as selenocysteine.
[0017] The term "peptide" may also refer to naturally modified peptides where
the
modification is effected, for example, by glycosylation, acetylation,
phosphorylation and
similar modification which are well known in the art. In some embodiments, the
peptide
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component is distinguished from a protein source also disclosed herein.
Further, peptides
may, for example, be produced recombinantly, semi-synthetically,
synthetically, or obtained
from natural sources such as after hydrolysation of proteins, including but
not limited to
casein, all according to methods known in the art.
[0018] The term "molar mass distribution" when used in reference to a
hydrolyzed protein or
protein hydrolysate pertains to the molar mass of each peptide present in the
protein
hydrolysate. For example, a protein hydrolysate having a molar mass
distribution of greater
than 500 DaItons means that each peptide included in the protein hydrolysate
has a molar
mass of at least 500 Daltons. Accordingly, in some embodiments, the peptides
disclosed in
Table 1 and Table 2 are derived from a protein hydrolysate having a molar mass
distribution
of greater than 500 Da!tons. To produce a protein hydrolysate having a molar
mass
distribution of greater than 500 Da!tons, a protein hydrolysate may be
subjected to certain
filtering procedures or any other procedure known in the art for removing
peptides, amino
acids, and/or other proteinaceous material having a molar mass of less than
500 Da[tons. For
the purposes of this disclosure, any method known in the art may be used to
produce the
protein hydrolysate having a molar mass distribution of greater than 500
Dalton.
[0019] The term "protein equivalent" or "protein equivalent source" includes
any protein
source, such as soy, egg, whey, or casein, as well as non-protein sources,
such as peptides or
amino acids. Further, the protein equivalent source can be any used in the
art, e.g., nonfat
milk, whey protein, casein, soy protein, hydrolyzed protein, peptides, amino
acids, and the
like. 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), soy bean proteins, and any
combinations
thereof. The protein equivalent source can, in some embodiments comprise
hydrolyzed
protein, including partially hydrolyzed protein and extensively hydrolyzed
protein. The
protein equivalent source may, in some embodiments, include intact protein.
More
particularly, the protein source may include a) about 20% to about 80% of the
peptide
component described herein, and b) about 20% to about 80 % of an intact
protein, a
hydrolyzed protein, or a combination thereof.
[0020] The term "protein equivalent source" also encompasses free amino acids.
In some
embodiments, the amino acids may comprise, but are not limited to, histidine,
isoleucine,
leucine, lysine, methionine, cysteine, phenylalanine, tyrosine, threonine,
tryptophan, valine,
alanine, arginine, asparagine, aspartic acid, glutamic acid, glutamine,
glycine, proline, serine,
carnitine, taurine and mixtures thereof. In some embodiments, the amino acids
may be
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branched chain amino acids. In certain other embodiments, small amino acid
peptides may
be included as the protein component of the nutritional composition. Such
small amino acid
peptides may be naturally occurring or synthesized.
[0021] "Fractionation procedure" includes any process in which a certain
quantity of a
mixture is divided up into a number of smaller quantities known as fractions.
The fractions
may be different in composition from both the mixture and other fractions.
Examples of
fractionation procedures include but are not limited to, melt fractionation,
solvent
fractionation, supercritical fluid fractionation and/or combinations thereof.
[0022] The term "essential amino acid" as used herein refers to an amino acid
that cannot be
synthesized de nova by the organism being considered or that is produced in an
insufficient
amount, and therefore must be supplied by diet. For example, in some
embodiments, where
the target subject is a human, an essential amino acid is one that cannot be
synthesized de
nova by a human.
[0023] The term "non-essential amino acid" as used herein refers to an amino
acid that can
be synthesized by the organism or derived by the organism from essential amino
acids. For
example, in some embodiments, where the target subject is a human, a non-
essential amino
acid is one that can be synthesized in the human body or derived in the human
body from
essential amino acids.
[0024] "Milk fat globule membrane" includes components found in the milk fat
globule
membrane including but not limited to milk fat globule membrane proteins such
as Mucin 1,
Butyrophilin, Adipophilin, CD36, CD14, Lactadherin (PAS6/7), Xanthine oxidase
and Fatty
Acid binding proteins etc.
[0025] The term "growing-up milk" refers to a broad category of nutritional
compositions
intended to be used as a part of a diverse diet in order to support the normal
growth and
development of a child between the ages of about 1 and about 6 years of age.
[0026] "Milk" means a component that has been drawn or extracted from the
mammary
gland of a mammal. In some embodiments, the nutritional composition comprises
components of milk that are derived from domesticated ungulates, ruminants or
other
mammals or any combination thereof.
[0027] "Nutritionally complete" means a composition that may be used as the
sole source of
nutrition, which would supply essentially all of the required daily amounts of
vitamins,
minerals, and/or trace elements in combination with proteins, carbohydrates,
and lipids.
Indeed, "nutritionally complete" describes a nutritional composition that
provides adequate
amounts of carbohydrates, lipids, essential fatty acids, proteins, essential
amino acids,
conditionally essential amino acids, vitamins, minerals and energy required to
support normal
growth and development of a subject.
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[0028] A nutritional composition that is "nutritionally complete" for a full
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 full term
infant.
[0029] A nutritional composition that is "nutritionally complete" for a child
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 a child.
[0030] "Exogenous butyrate" or "dietary butyrate" each refer to butyrate or
butyrate
derivatives which are intentionally included in the nutritional composition of
the present
disclosure itself, rather than generated in the gut.
[0031] "Endogenous butyrate" or "butyrate from endogenous sources" each refer
to
butyrate present in the gut as a result of ingestion of the disclosed
composition that is not
added as such, but is present as a result of other components or ingredients
of the
composition; the presence of such other components or ingredients of the
composition
stimulates butyrate production in the gut.
[0032] The term "cow's milk allergy" describes a food allergy, i.e. an immune
adverse
reaction to one or more of the proteins contained in cow's milk in a human
subject. The
principal symptoms are gastrointestinal, dermatological, and respiratory
symptoms. These
can translate into skin rashes, hives, vomiting, diarrhea, constipation and
distress. The clinical
spectrum extends to diverse disorders: anaphylactic reactions, atopic
dermatitis, wheeze,
infantile colic, gastro esophageal reflux disease (GERD), esophagitis, colitis
gastroenteritis,
headache/migraine and constipation.
[0033] The nutritional composition of the present disclosure may be
substantially free of any
optional or selected ingredients described herein, provided that the remaining
nutritional
composition still contains all of the required ingredients or features
described herein. In this
context, and unless otherwise specified, the term "substantially free" means
that the
selected composition may contain less than a functional amount of the optional
ingredient,
typically less than 0.1% by weight, and also, including zero percent by weight
of such
optional or selected ingredient.
[0034] All percentages, parts and ratios as used herein are by weight of the
total
composition, unless otherwise specified.
[0035] All references to singular characteristics or limitations of the
present disclosure shall
include the corresponding plural characteristic or limitation, and vice versa,
unless otherwise
specified or clearly implied to the contrary by the context in which the
reference is made.
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[0036] All combinations of method or process steps as used herein can be
performed in any
order, unless otherwise specified or clearly implied to the contrary by the
context in which
the referenced combination is made.
[0037] The methods and compositions of the present disclosure, including
components
thereof, can comprise, consist of, or consist essentially of the essential
elements and
limitations of the embodiments described herein, as well as any additional or
optional
ingredients, components or limitations described herein or otherwise useful in
nutritional
compositions.
[0038] As used herein, the term "about" should be construed to refer to both
of the
numbers specified as the endpoint(s) of any range. Any reference to a range
should be
considered as providing support for any subset within that range.
[0039] The present disclosure is directed to nutritional compositions
including butyrate and
LGG. Non-limiting examples of butyrate for use herein include butyric acid,
butyrate salts,
and glycerol esters of butyric acid. The nutritional compositions may further
include a
carbohydrate source, a protein source, and a fat or lipid source. In some
embodiments, the
nutritional compositions may include a component capable of stimulating
endogenous
butyrate production; in other embodiments, the nutritional compositions may
include both
dietary and endogenous butyrate.
[0040] The benefit to providing both exogenous and endogenous butyrate is
accelerated
tolerance acquisition towards cow's milk. Additionally, the benefit to
providing both
exogenous and endogenous butyrate together with Lactobacillus rhamnoses GG
("LGG") is
accelerated tolerance acquisition toward cow's milk. Conventional dietary
management of
cow's milk allergy includes the use of formulations containing protein
hydrolysates and amino
acids rather than intact proteins, and certain probiotics such as
Lactobacillus rhamnoses GG
("LGG"), which contribute to accelerated tolerance acquisition towards cow's
milk. The
inclusion of a component to stimulate endogenous butyrate production by the
gut
microbiota may further accelerate tolerance acquisition and/or may be applied
as a functional
replacement of LGG in a nutritional composition. Further, the inclusion of
certain probiotics,
such as LGG in combination with butyrate, either endogenous or exogenous
butyrate, can
contribute to accelerated tolerance acquisition towards cow's milk.
[0041] In an embodiment, the component for stimulating endogenous buyrate is a
prebiotic
comprising both polydextrose ("PDX") and galacto-oligosaccharides ("GOS"). A
prebiotic
component including PDX and GOS can enhance endogenous butyrate production by
microbiota. Butyrate has epigenetic (histone deacetylase inhibition activity)
that results in
regulatory responses such as generation of regulatory T-cells. In the context
of cow s milk
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allergy, these regulatory responses may result in accelerated tolerance
acquisition to cow's
milk protein.
[0042] In addition to PDX and GOS, the nutritional composition may also
contain one or
more other prebiotics which can exert additional health benefits, which may
include, but are
not limited to, selective stimulation of the growth and/or activity of one or
a limited number
of beneficial gut bacteria, stimulation of the growth and/or activity of
ingested probiotic
microorganisms, selective reduction in gut pathogens, and favorable influence
on gut short
chain fatty acid profile. 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. Prebiotics useful in the present disclosure may
include
oligosaccharides, polysaccharides, and other prebiotics that contain fructose,
xylose, soya,
galactose, glucose and mannose.
[0043] More specifically, prebiotics useful in the present disclosure include
PDX and GOS,
and can, in some embodiments, also include, polydextrose powder, lactulose,
lactosucrose,
raffinose, gluco-oligosaccharide, inulin, fructo-oligosaccharide (FOS),
isomalto-
oligosaccharide, soybean oligosaccharides, lactosucrose, xylo-oligosaccharide
(X0S), chito-
oligosaccharide, manno-oligosaccharide, aribino-oligosaccharide, siallyl-
oligosaccharide, fuco-
oligosaccharide, and gentio-oligosaccharides.
[0044] In an embodiment, 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 cornposition.
More
preferably, 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. In some embodiments, the
total amount
of prebiotics present in the nutritional composition may be from about 0.01
g/100 Kcal to
about 1.5 g/100 Kcal. In certain embodiments, the total amount of prebiotics
present in the
nutritional composition may be from about 0.15 g/100 Kcal to about 1.5 g/100
Kcal. In some
embodiments, the prebiotic component comprises at least 20% w/w PDX and GOS.
[0045] The amount of PDX in the nutritional composition may, in an embodiment,
be within
the range of from about 0.015 g/100 Kcal to about 1.5 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
9/100 Kcal. In some embodiments, PDX may be included in the nutritional
composition in an
amount sufficient to provide between about 1.0 g/L and 10.0 g/L. In another
embodiment,
the nutritional composition contains an amount of PDX that is between about
2.0 g/L and 8.0
g/L. And in still other embodiments, the amount of PDX in the nutritional
composition may
be from about 0.05 g/100 Kcal to about 1.5 g/100 Kcal.
[0046] The prebiotic component also comprises GOS. The amount of GOS in the
nutritional
composition may, in an embodiment, be from about 0.015 g/100 Kcal to about 1.0
g/100
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Kcal. In another embodiment, the amount of GOS in the nutritional composition
may be
from about 0.2 g/100 Kcal to about 0.5 g/100 Kcal.
[0047] In a particular embodiment, GOS and PDX are supplemented into the
nutritional
composition in a total amount of at least about 0.015 g/100 Kcal or about
0.015 g/100 Kcal
to about 1.5 g/100 Kcal. In some embodiments, the nutritional composition may
comprise
GOS and PDX in a total amount of from about 0.1 to about 1.0 g/100 Kcal.
[0048] In some embodiments, the nutritional composition includes a source of
dietary
butyrate that is present in an amount of from about 5 g/100 Kcal to about 500
g/100 kcal. In
some embodiments, the nutritional composition includes a source of dietary
butyrate that is
present in an amount of from about 15 g/100 Kcal to about 450 g/100 kcal. In
some
embodiments, the nutritional composition includes a source of dietary butyrate
that is
present in an amount of from about 20 9/100 Kcal to about 400 g/100 kcal. In
some
embodiments, the nutritional composition includes a source of dietary butyrate
that is
present in an amount of from about 25 g/100 Kcal to about 350 g/100 kcal. In
some
embodiments, the nutritional composition includes a source of dietary butyrate
that is
present in an amount of from about 30 9/100 Kcal to about 280 g/100 kcal.
[0049] In some embodiments, the nutritional composition includes from about
0.01 g to
about 10 g of dietary butyrate per 100 g of total fat in the nutritional
composition. In some
embodiments, the nutritional composition includes from about 0.1 g to about 8
g of dietary
butyrate per 100 g of total fat in the nutritional composition. In some
embodiments, the
nutritional composition includes from about 0.4 g to about 7 g of dietary
butyrate per 100 g
of total fat in the nutritional composition. In some embodiments, the
nutritional composition
includes from about 0.7 g to about 6.5 g of dietary butyrate per 100 g of
total fat in the
nutritional composition. In some embodiments, the nutritional composition
includes from
about 1.2 g to about 5.1 g of dietary butyrate per 100 g of total fat in the
nutritional
composition.
[0050] In some embodiments the dietary butyrate is provided by one or more of
the
following: butyric acid; butyrate salts, including sodium butyrate, potassium
butyrate, calcium
butyrate, and/or magnesium butyrate; glycerol esters of butyric acid; and/or
corresponding
mixtures and corresponding salts of pharmaceutically acceptable bases or
acids, pure
diastereoisomeric forms and enantiomeric forms or mixtures thereof.
[0051] The dietary butyrate can be supplied by any suitable source known in
the art. Non-
limiting sources of dietary butyrate includes animal source fats and derived
products, such as
but not limited to milk, milk fat, butter, buttermilk, butter serum, cream;
microbial
fermentation derived products, such as but not limited to yogurt and fermented
buttermilk;
and plant source derived seed oil products, such as pineapple and/or pineapple
oil, apricot
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and/or apricot oil, barley, oats, brown rice, bran, green beans, legumes,
leafy greens, apples,
kiwi, oranges. In some embodiments, the dietary butyrate is synthetically
produced. In
embodiments where the dietary butyrate is synthetically produced, the chemical
structure of
the dietary butyrate may be modified as necessary. Further, the dietary
butyrate produced
synthetically can be purified by any means known in the art to produce a
purified dietary
butyrate additive that can be incorporated into the nutritional compositions
disclosed herein.
The dietary butyrate may be provided by dairy lipids and/or triglyceride bound
forms of
butyrate.
[0052] In some embodiments, the dietary butyrate may be provided in an
encapsulated form.
In certain embodiments, the encapsulation of the dietary butyrate may provide
for longer
shelf-stability and may provide for improved organoleptic properties of the
nutritional
composition. For example, in some embodiments, the dietary butyrate may be
encapsulated
or coated by the use of, or combination of, fat derived materials, such as
mono- and di-
glycerides; sugar and acid esters of glycerides; phospholipids; plant, animal
and microbial
derived proteins and hydrocolloids, such as starches, maltodextrins, gelatin,
pectins, glucans,
caseins, soy proteins, and/or whey proteins.
[0053] The dietary butyric acid may also be provided in a coated form. For
example, coating
certain glycerol esters of butyric acids and/or amide derivatives of butyric
acids with fat
derived materials, such as mono- and di-glycerides; sugar and acid esters of
glycerides;
phospholipids; plant, animal and microbial derived proteins and hydrocolloids,
such as
starches, rnaltodextrins, gelatin, pectins, glucans, caseins, soy proteins,
and/or whey proteins
may improve the shelf-stability of the dietary butyrate and may further
improve the overall
organoleptic properties of the nutritional composition.
[0054] In certain embodiments, the dietary butyrate comprises glycerol esters
of butyric
acid. Glycerol esters of butyric acid may offer minimal complexity when
formulated and
processed in the nutritional composition. Additionally, glycerol esters of
butyric acid may
improve the shelf life of the nutritional composition including dietary
butyrate an may further
have a low impact on the sensory attributes of the finished product.
[0055] In some embodiments, the dietary butyrate may comprise butyrate salts,
for example,
sodium butyrate, potassium butyrate, calcium butyrate, magnesium butyrate, and
combinations thereof. In some embodiments, the use of selected dietary
butyrate salts may
improve intestinal health when provided to target subjects. In certain
embodiments, dietary
butyrate comprises a suitable butyrate salt that has been coated with one or
more fats or
lipids. In certain embodiments wherein the dietary butyrate comprises a fat
coated butyrate
salt, the nutritional composition may be a dry-powdered composition into which
the dietary
butyrate is incorporated.
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[0056] In some embodiments, the dietary butyrate may comprise any of the
butyrate
compounds disclosed herein that are formulated to be in complex form with
chitosan or one
or cyclodextrins. For example, cyclodextrins are cyclic oligosaccharides
composed of six (a-
cyclodextrin), seven (B-cyclodextrin), or eight (gamma-cyclodextrin) units of
a-1,4-
glucopyranose. Cyclodextrins are further characterized by a hydrophilic
exterior surface and
a hydrophobic core. Without being bound by any particular theory, the
aliphatic butyrate
chain would form a complex with the cyclodextrin core, thus increasing its
molecular weight
and, thus, reducing the volatility of the butyrate compound. Accordingly, the
bioavailability
of dietary butyrate may be improved when the dietary butyrate includes
butyrate
compounds in complex form with one or more cyclodextrins. Further,
cyclodextrins are
bulky hydrophobic molecules that are resistant to stomach acid as well as
gastrointestinal
enzymes, thus administration of the butyrate-cyclodextrin complex as described
herein
would promote absorption of the dietary butyrate in the small intestines.
[0057] In some embodiments the dietary butyrate is provided from an enriched
lipid fraction
derived from milk. For example, bovine milk fat has a butyric acid content
that may be 20
times higher than the butyric acid content in human milk fat. Furthermore,
among the short
chain fatty acids ("SCFAs") present in human milk, i.e. fatty acids having a
carbon chain
length from 4 to 12, butyric acid (C4) is one of the most predominant in
bovine milk. As such,
bovine milk fat and/or enriched fractions of bovine milk fat may be included
in a nutritional
composition to provide dietary butyrate.
[0058] In embodiments where the dietary butyrate is provided by an enriched
lipid fraction
derived from milk the enriched lipid fraction derived from milk may be
produced by any
number of fractionation techniques. These techniques include but are not
limited to melting
point fractionation, organic solvent fractionation, super critical fluid
fractionation, and any
variants and combinations thereof.
[0059] Furthermore, mixtures that may be subjected to the fractionation
procedures to
produce the enriched lipid fraction include, but are not limited to, bovine
whole milk, bovine
cream, caprine milk, ovine milk, yak milk, and/or mixtures thereof. In a
preferred
embodiment the milk mixture used to create the enriched lipid fraction is
bovine milk.
[0060] In addition to providing dietary butyrate, the enriched lipid fraction
may comprise an
one of the following ingredients: saturated fatty acids; trans-fatty acids;
branched-chain fatty
acids ("BCFAs"), including odd-branched chain fatty acids ("OBCFAs");
conjugated linoleic
acid ("CLA"); monounsaturated fatty acids; polyunsaturated fatty acids;
cholesterol;
phospholipids; and milk fat globule membrane, including milk fat globule
membrane protein.
[0061] In some embodiments the enriched lipid fraction includes, per 100 Kcal,
one or more
of the following:
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from about 0.1 g to 8.0 g of saturated fatty acids;
from about 0.2 g to 7.0 g trans-fatty acids;
from about 0.003 g to about 6.1 g branched-chain fatty acids;
from about 0.026 g to about 2.5 g conjugated linoleic acid;
from about 0.8 g to about 2.5 g monounsaturated fatty acids;
from about 2.3 g to about 4.4 g polyunsaturated fatty acids;
from about 100 mg to about 400 mg of cholesterol;
from about 50 mg to about 400 mg of phospholipids; and/or
from about 10 mg to about 500 mg of milk fat globule membrane.
[0062] The following example illustrates a milk fat fraction having an
enriched concentration
of butyric acid (C4) that may be produced by a fractionation procedure.
Example 1
[0063] Illustrated below is a lipid profile of fractionated milk fat produced
by super critical
carbon extraction fractionation procedure and by melt-fractionation.
Milk Fat composition (g fatty acid /100 g TOTAL fatty acids)
MeltFrac
AMF SCCO2
10C
C 4:0 3.9 6.0 4.7
C 6:0 2.5 3.3 2.9
C 8:0 1.4 1.9 1.8
C 10:0 3.1 3.9 3.8
C 12:0 4.2 4.1 4.8
C 14:0 11.4 12.2 10.9
C 14:1 1.1 1.0 1.3
C 15:0 1.1 1.0 0.9
C 16:0 29.4 29.6 22.3
C 16:1 1.9 1.4 2.2
C 17:0 0.6 0.5 0.4
C 18:0 11.4 8.2 6.1
C 18:1, cis, P 21.9 16.5 25.3
C 18:1, trans, w9 0.3 1.6 1.9
C 18:2, g6 1.9 2.2 1.9
C 18:3, g 3, 0.6 0.4 0.6
C 20:0 0.0 0.1 0.1
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C 20:1, g9 0.1 0.1 0.2 1
Saturated 68.7 70.7 58.6
Unsaturated 27.8 23.1 33.3
AMF = anhydrous milk fat; SCCO2 = super-critical carbon dioxide fraction
(super olein).
MeltFrac = melt crystallization fraction separated at 10 C.
[0064] In certain embodiments, the PDX- and GOS-containing prebiotic and
dietary butyrate
is incorporated into a nutritional composition that is an infant formula.
Currently, many infant
formulas are not formulated with dietary butyrate. One reason that infant
formulas include
little to no dietary butyrate is due to the unpleasant organoleptic properties
exhibited by the
nutritional composition when butyrate compounds are incorporated into the
nutritional
composition. For example, many butyrate compounds exhibit an odor that makes
consuming
the nutritional composition in which they are incorporated an unpleasant
experience.
Furthermore, the pediatric and infant population will not readily consume
nutritional
products having an unpleasant odor, taste, and/or mouthf eel. Accordingly,
there exists a
need for a nutritional composition formulated for administration to a
pediatric subject or an
infant that provides butyrate in the gut yet does not have diminished
organoleptic
properties. The incorporation of a prebiotic to stimulate butyrate production
by gut
microbiota and certain dietary butyrate compounds disclosed herein, i.e.
glycerol esters of
butyric acid and amide derivatives of amino acids, into pediatric and infant
nutritional
compositions will provide butyrate while still providing a pleasant sensory
experience.
[0065] In some embodiments, the nutritional composition includes a protein
equivalent
source, wherein the protein equivalent source includes a peptide component
comprising
SEQ ID NO 4, SEQ ID NO 13, SEQ ID NO 17, SEQ ID NO 21, SEQ ID NO 24, SEQ ID NO
30,
SEQ ID NO 31, SEQ ID NO 32, SEQ ID NO 51, SEQ ID NO 57, SEQ ID NO 60, and SEQ
ID
NO 63. In some embodiments, the peptide component may comprise additional
peptides
disclosed in Table 1. For example, the composition may include at least 10
additional
peptides disclosed in Table 1. In some embodiments, 20% to 80% of the protein
equivalent
source comprises the peptide component, and 20% to 80% of the protein
equivalent source
comprises an intact protein, a partially hydrolyzed protein, and combinations
thereof. In
some embodiments, the term additional means selecting different peptides than
those
enumerated.
[0066] In another embodiment 1% to 99% of the protein equivalent source
includes a
peptide component comprising at least 3 peptides selected from the group
consisting of
SEQ ID NO 4, SEQ ID NO 13, SEQ ID NO 17, SEQ ID NO 21, SEQ ID NO 24, SEQ ID NO
30,
SEQ ID NO 31, SEQ ID NO 32, SEQ ID NO 51, SEQ ID NO 57, SEQ ID NO 60, and SEQ
ID
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NO 63, and at least 5 additional peptides selected from Table 1; and wherein
1% to 99% of
the protein equivalent source comprises an intact protein, a partially
hydrolyzed protein, or
combinations thereof. In some embodiments 2% to 80% of the protein equivalent
source
includes a peptide component comprising at least 3 peptides selected from the
group
consisting of SEQ ID NO 4, SEQ ID NO 13, SEQ ID NO 17, SEQ ID NO 21, SEQ ID NO
24,
SEQ ID NO 30, SEQ ID NO 31, SEQ ID NO 32, SEQ ID NO 51, SEQ. ID NO 57, SEQ ID
NO
60, and SEQ ID NO 63, and at least 5 additional peptides selected from Table
1; and wherein
2% to 80% of the protein equivalent source comprises an intact protein, a
partially
hydrolyzed protein, or combinations thereof. In some embodiments 20% to 80% of
the
protein equivalent source includes a peptide component comprising at least 3
peptides
selected from the group consisting of SEQ ID NO 4, SEQ ID NO 13, SEC). ID NO
17, SEQ ID
NO 21, SEQ ID NO 24, SEQ ID NO 30, SEQ ID NO 31, SEQ ID NO 32, SEQ ID NO 51,
SEQ
ID NO 57, SEQ ID NO 60, and SEQ ID NO 63, and at least 5 additional peptides
selected
from Table 1; and wherein 20% to 80% of the protein equivalent source
comprises an intact
protein, a partially hydrolyzed protein, or combinations thereof.
[0067] Table 1 below identifies the amino acid sequences of the peptides that
may be
included in the peptide component of the present nutritional compositions.
TABLE 1
Seq. ID
Number Amino Acid Sequence
(aa)
1 Ala Ile Asn Pro Ser Lys Glu Asn
8
2 Ala Pro Phe Pro Glu
5
3 Asp Ile Gly Ser Glu Ser
6
4 Asp Lys Thr Glu Ile Pro Thr
7
Asp Met Glu Ser Thr 5
6 Asp Met Pro Ile
4
7 Asp Val Pro Ser
4
n/a Glu Asp Ile
3
n/a Glu Leu Phe
3
n/a Glu Met Pro
3
8 Glu Thr Ala Pro Val Pro Leu
7
9 Phe Pro Gly Pro Ile Pro
6
Phe Pro Gly Pro Ile Pro Asn 7
11 Gly Pro Phe Pro
4
12 Gly Pro Ile Val
4
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13 Ile Gly Ser Glu Ser Thr Glu Asp Gin 9
14 Ile Gly Ser Ser Ser Glu Glu Ser 8
15 Ile Gly Ser Ser Ser Glu Glu Ser Ala 9
16 Ile Asn Pro Ser Lys Glu 6
17 Ile Pro Asn Pro Ile 5
18 Ile Pro Asn Pro Ile Gly 6
19 Ile Pro Pro Leu Thr Gin Thr Pro Val 9
Ile Thr Ala Pro 4
21 Ile Val Pro Asn 4
22 Lys His Gin Gly Leu Pro Gin 7
23 Leu Asp Val Thr Pro 5
24 Leu Glu Asp Ser Pro Glu 6
Leu Pro Leu Pro Leu 5
26 Met Glu Ser Thr Glu Val 6
27 Met His Gin
Pro His Gin Pro Leu Pro Pro Thr 11
28 Asn Ala Val Pro Ile 5
29 Asn Glu Val Glu Ala 5
n/a Asn Leu Leu 3
Asn Gin Glu Gin Pro Ile 6
31 Asn Val Pro Gly Glu 5
32 Pro Phe Pro gly Pro Ile 6
33 Pro Gly Pro Ile Pro Asn
34 Pro His Gin Pro Leu Pro Pro Thr 8
Pro Ile Thr Pro Thr 5
36 Pro Asn Pro Ile 4
37 Pro Asn Ser Leu Pro Gin 6
38 Pro Gin Leu Glu Ile Val Pro Asn 8
39 Pro Gin Mn Ile Pro Pro Leu 7
Pro Val Leu Gly Pro Val 6
41 Pro Val Pro Gln 4
42 Pro Val Val Val Pro 5
43 Pro Val Val Val Pro Pro 6
44
Ser Ile Gly Ser Ser Ser Glu Glu Ser Ala Glu 11
Ser Ile Ser Ser Ser Glu Glu 7
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46 Ser Ile Ser
Ser Ser Glu Glu Ile Val Pro Asn 11
47 Ser Lys Asp Ile Gly Ser Glu
7
48 Ser Pro Pro Glu Ile Asn
6
49 Ser Pro Pro Glu Ile Asn Thr
7
50 Thr Asp Ala Pro Ser Phe Ser
7
51 Thr Glu Asp Glu Leu
5
52 Val Ala Thr Glu Glu Val
6
53 Val Leu Pro Val Pro
5
54 Val Pro Gly Glu
4
55 Val Pro Gly Glu Ile Val
6
56 Val Pro Ile Thr Pro Thr
6
57 Val Pro Ser Glu
4
58 Val Val Pro Pro Phe Leu Girt Pro Glu
9
59 Val Val Val Pro Pro
5
60 Tyr Pro Phe Pro Gly Pro
6
61 Tyr Pro Phe Pro Gly Pro Ile Pro
8
62 Tyr Pro Phe Pro Gly Pro Ile Pro Asn
9
63 Tyr Pro Ser Gly Ala
5
64 Tyr Pro Val Glu Pro
5
[0068] Table 2 below further identifies a subset of amino acid sequences from
Table 1 that
may be included in the peptide component disclosed herein.
TABLE 2
Seq ID
Number Amino Acid Sequence (aa)
4 Asp Lys Thr Glu Ile Pro Thr 7
13 Ile Gly Ser Glu Ser Thr Glu Asp Gin 9
17 Ile Pro Asn Pro Ile Gly 6
21 Ile Val Pro Asn 4
24 Leu Glu Asp Ser Pro Glu 6
30 Asn Gin Glu Gin Pro Ile 6
31 Asn Val Pro Gly Glu 5
32 Pro Phe Pro Gly Pro Ile 6
51 Thr Glu Asp Glu Leu 5
57 Val Pro Ser Glu 4
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60 Tyr Pro Phe Pro Gly Pro 6
63 Tyr Pro Ser Gly Ala 5
[0069] In some embodiments, the peptide component may be present in the
nutritional
composition in an amount from about 0.2 g/100 Kcal to about 5.6 g/100 Kcal. In
other
embodiments the peptide component may be present in the nutritional
composition in an
amount from about 1 g/100 Kcal to about 4 g/100 Kcal. In still other
embodiments, the
peptide component may be present in the nutritional composition in an amount
from about 2
g/100 Kcal to about 3 g/100 Kcal.
[0070] The peptide component disclosed herein may be formulated with other
ingredients in
the nutritional composition to provide appropriate nutrient levels for the
target subject. In
some embodiments, the peptide component is included in a nutritionally
complete formula
that is suitable to support normal growth.
[0071] The peptide component may be provided as an element of a protein
equivalent
source. In some embodiments, the peptides identified in Tables 1 and 2, may be
provided by
a protein equivalent source obtained from cow's milk proteins, including but
not limited to
bovine casein and bovine whey. In some embodiments, the protein equivalent
source
comprises hydrolyzed bovine casein or hydrolyzed bovine whey. Accordingly, in
some
embodiments, the peptides identified in Table 1 and Table 2 may be provided by
a casein
hydrolysate. Such peptides may be obtained by hydrolysis or may be synthesized
in vitro by
methods know to the skilled person.
[0072] A non-limiting example of a method of hydrolysis is disclosed herein.
In some
embodiments, this method may be used to obtain the protein hydrolysate and
peptides of
the present disclosure. The proteins are hydrolyzed using a proteolytic
enzyme, Protease N.
Protease N "Amano" is commercially available from Arnano Enzyme U.S.A. Co.,
Ltd., Elgin,
Ill. Protease N is a proteolytic enzyme preparation that is derived from the
bacterial species
Bacillus subtilis. The protease powder is specified as "not less than 150,000
units/g",
meaning that one unit of Protease N is the amount of enzyme which produces an
amino acid
equivalent to 100 micrograms of tyrosine for 60 minutes at a pH of 7Ø To
produce the infant
formula of the present disclosure, Protease N can be used at levels of about
0.5% to about
1.0% by weight of the total protein being hydrolyzed.
[0073] The protein hydrolysis by Protease N is typically conducted at a
temperature of about
50 C. to about 60 C. The hydrolysis occurs for a period of time so as to
obtain a degree of
hydrolysis between about 4% and 10%. In a particular embodiment, hydrolysis
occurs for a
period of time so as to obtain a degree of hydrolysis between about 6% and 9%.
In another
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embodiment, hydrolysis occurs for a period of time so as to obtain a degree of
hydrolysis of
about 7.5%. This level of hydrolysis may take between about one half hour to
about 3 hours.
[0074] A constant pH should be maintained during hydrolysis. In the method of
the present
disclosure, the pH is adjusted to and maintained between about 6.5 and 8. In a
particular
embodiment, the pH is maintained at about 7Ø
[0075] In order to maintain the optimal pH of the solution of whey protein,
casein, water and
Protease N, a caustic solution of sodium hydroxide and/or potassium hydroxide
can be used
to adjust the pH during hydrolysis. If sodium hydroxide is used to adjust the
pH, the amount
of sodium hydroxide added to the solution should be controlled to the level
that it comprises
less than about 0.3% of the total solid in the finished protein hydrolysate. A
10% potassium
hydroxide solution can also be used to adjust the pH of the solution to the
desired value,
either before the enzyme is added or during the hydrolysis process in order to
maintain the
optimal pH.
[0076] The amount of caustic solution added to the solution during the protein
hydrolysis can
be controlled by a pH-stat or by adding the caustic solution continuously and
proportionally.
The hydrolysate can be manufactured by standard batch processes or by
continuous
processes.
[0077] To better ensure the consistent quality of the protein partial
hydrolysate, the
hydrolysate is subjected to enzyme deactivation to end the hydrolysis process.
The enzyme
deactivation step may consist include at heat treatment at a temperature of
about 82 C. for
about 10 minutes. Alternatively, the enzyme can be deactivated by heating the
solution to a
temperature of about 92 C. for about 5 seconds. After enzyme deactivation is
complete, the
hydrolysate can be stored in a liquid state at a temperature lower than 10 C.
[0078] In some embodiments, the protein equivalent source comprises a
hydrolyzed protein,
which includes partially hydrolyzed protein and extensively hydrolyzed
protein, such as
casein. In some embodiments, the protein equivalent source comprises a
hydrolyzed protein
including peptides having a molar mass distribution of greater than 500
Daltons. In some
embodiments, the hydrolyzed protein comprises peptides having a molar mass
distribution in
the range of from about 500 Daltons to about 1,500 Daltons. Still, in some
embodiments the
hydrolyzed protein may comprise peptides having a molar mass distribution
range of from
about 500 Daltons to about 2,000 Daltons.
[0079] In some embodiments, the protein equivalent source may comprise the
peptide
component, intact protein, hydrolyzed protein, including partially hydrolyzed
protein and/or
extensively hydrolyzed protein, and combinations thereof. In some embodiments,
20% to
80% of the protein equivalent source comprises the peptide component disclosed
herein. In
some embodiments, 30% to 60% of the protein equivalent source comprises the
peptide
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component disclosed herein. In still other embodiments, 40% to 50% of the
protein
equivalent source comprises the peptide component.
[0080] In some embodiments, 20% to 80% of the protein equivalent source
comprises intact
protein, partially hydrolyzed protein, extensively hydrolyzed protein, or
combinations
thereof. In some embodiments, 40% to 70% of the protein equivalent source
comprises
intact proteins, partially hydrolyzed proteins, extensively hydrolyzed
protein, or a
combination thereof. In still further embodiments, 50% to 60% of the protein
equivalent
source may comprise intact proteins, partially hydrolyzed protein, extensively
hydrolyzed
protein, or a combination thereof.
[0081] In some embodiments the protein equivalent source comprises partially
hydrolyzed
protein having a degree of hydrolysis of less than 40%. In still other
embodiments, the
protein equivalent source may comprise partially hydrolyzed protein having a
degree of
hydrolysis of less than 25%, or less than 15%.
[0082] In some embodiments, the nutritional composition comprises between
about 1 g and
about 7 g of a protein equivalent source per 100 Kcal. In other embodiments,
the nutritional
composition comprises between about 3.5 g and about 4.5 g of protein
equivalent source
per 100 Kcal.
[0083] Without being bound by any particular theory, the administration of a
nutritional
composition as disclosed herein may reduce allergic response and may improve
tolerance to
cow's milk allergy in certain subjects. In some embodiments, the combination
of prebiotic,
dietary butyrate, and the protein equivalent source provide synergistic health
benefits.
[0084] The nutritional composition may be protein-free in some embodiments and
comprise
free amino acids as an element of the protein equivalent source. In some
embodiments, the
amino acids may be branched chain amino acids. In certain other embodiments,
small amino
acid peptides may be included as the protein component of the nutritional
composition.
Such small amino acid peptides may be naturally occurring or synthesized. In
some
embodiments, the amount of free amino acids in the nutritional composition may
vary from
about 1 g/100 Kcal to about 5 g/100 Kcal.
[0085] In certain embodiments, the protein equivalent source comprises amino
acids and is
substantially free of whole, intact protein. Further in certain embodiments,
the protein
equivalent source comprises amino acids and is substantially free of peptides.
In certain
embodiments, the protein equivalent source includes from about 10% to about
90% w/w of
essential amino acids based on the total amino acids included in the protein
equivalent
source. In certain embodiments, the protein equivalent source includes from
about 25% to
about 75% w/w of essential amino acids based on the total amino acids included
in the
protein equivalent source. In some embodiments, the protein equivalent source
includes
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from about 40% to about 60% of essential amino acids based on the total amino
acids
included in the protein equivalent source.
[0086] In some embodiments, the protein equivalent source includes non-
essential amino
acids. In certain embodiments, the protein equivalent source includes from
about 10% to
about 90% w/w of non-essential amino acids based on the total amino acids
included in the
protein equivalent source. In certain embodiments, the protein equivalent
source includes
from about 25% to about 75% w/w of non-essential amino acids based on the
total amino
acids included in the protein equivalent source. In some embodiments, the
protein equivalent
source includes from about 40% to about 60% w/w of non-essential amino acids
based on
the total amino acids included in the protein equivalent source.
[0087] In some embodiments, the protein equivalent source includes leucine. In
some
embodiments, the protein equivalent source includes from about 2% to about 15%
w/w
leucine per the total amount of amino acids included in the protein equivalent
source. In
some embodiments, the protein equivalent source includes from about 4% to
about 10%
w/w leucine per the total amount of amino acids included in the protein
equivalent source.
[0088] In some embodiments, the protein equivalent source includes lysine. In
some
embodiments, the protein equivalent source includes from about 2% to about 10%
w/w
lysine per the total amino acids included in the protein equivalent source. In
some
embodiments, the protein equivalent source includes from about 4% to about 8%
w/w lysine
per the total amino acids in the protein equivalent source.
[0089] In some embodiments, the protein equivalent source includes valine. In
some
embodiments, the protein equivalent source includes from about 2% to about 15%
w/w
valine per the total amino acids included in the protein equivalent source. In
some
embodiments, the protein equivalent source includes from about 4% to about 10%
w/w
valine per the total amino acids in the protein equivalent source.
[0090] In some embodiments, the protein equivalent source includes isoleucine.
In some
embodiments, the protein equivalent source includes from about 1% to about 8%
w/w
isoleucine per the total amino acids included in the protein equivalent
source. In some
embodiments, the protein equivalent source includes from about 3% to about 7%
w/w
isoleucine per the total amino acids in the protein equivalent source.
[0091] In some embodiments, the protein equivalent source includes threonine.
In some
embodiments, the protein equivalent source includes from about 1% to about 8%
w/w
threonine per the total amino acids included in the protein equivalent source.
In some
embodiments, the protein equivalent source includes from about 3% to about 7%
w/w
threonine per the total amino acids in the protein equivalent source.
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[0092] In some embodiments, the protein equivalent source includes tyrosine.
In some
embodiments, the protein equivalent source includes from about 1% to about 8%
w/w
tyrosine per the total amino acids included in the protein equivalent source.
In some
embodiments, the protein equivalent source includes from about 3% to about 7%
w/w
tyrosine per the total amino acids in the protein equivalent source.
[0093] In some embodiments, the protein equivalent source includes
phenylalanine. In some
embodiments, the protein equivalent source includes from about 1% to about 8%
w/w
phenylalanine per the total amino acids included in the protein equivalent
source. In some
embodiments, the protein equivalent source includes from about 3% to about 7%
w/w
phenylalanine per the total amino acids in the protein equivalent source.
[0094] In some embodiments, the protein equivalent source includes histidine.
In some
embodiments, the protein equivalent source includes from about 0.5% to about
4% w/w
histidine per the total amino acids included in the protein equivalent source.
In some
embodiments, the protein equivalent source includes from about 1.5% to about
3.5% w/w
histidine per the total amino acids in the protein equivalent source.
[0095] In some embodiments, the protein equivalent source includes cystine. In
some
embodiments, the protein equivalent source includes from about 0.5% to about
4% w/w
cystine per the total amino acids included in the protein equivalent source.
In some
embodiments, the protein equivalent source includes from about 1.5% to about
3.5% w/w
cystine per the total amino acids in the protein equivalent source.
[0096] In some embodiments, the protein equivalent source includes tryptophan.
In some
embodiments, the protein equivalent source includes from about 0.5% to about
4% w/w
tryptophan per the total amino acids included in the protein equivalent
source. In some
embodiments, the protein equivalent source includes from about 1.5% to about
3.5% w/w
tryptophan per the total amino acids in the protein equivalent source.
[0097] In some embodiments, the protein equivalent source includes methionine.
In some
embodiments, the protein equivalent source includes from about 0.5% to about
4% w/w
methionine per the total amino acids included in the protein equivalent
source. In some
embodiments, the protein equivalent source includes from about 1.5% to about
3.5% w/w
methionine per the total amino acids in the protein equivalent source.
[0098] In some embodiments, the protein equivalent source includes aspartic
acid. In some
embodiments, the protein equivalent source includes from about 7% to about 20%
w/w
aspartic acid per the total amino acids included in the protein equivalent
source. In some
embodiments, the protein equivalent source includes from about 10% to about
17% w/w
aspartic acid per the total amino acids in the protein equivalent source.
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[0099] In some embodiments, the protein equivalent source includes proline. In
some
embodiments, the protein equivalent source includes from about 5% to about 12%
w/w
proline per the total amino acids included in the protein equivalent source.
In some
embodiments, the protein equivalent source includes from about 7% to about 10%
w/w
proline per the total amino acids in the protein equivalent source.
[0100] In some embodiments, the protein equivalent source includes alanine. In
some
embodiments, the protein equivalent source includes from about 3% to about 10%
w/w
alanine per the total amino acids included in the protein equivalent source.
In some
embodiments, the protein equivalent source includes from about 5% to about 8%
w/w
alanine per the total amino acids in the protein equivalent source.
[0101] In some embodiments, the protein equivalent source includes glutamate.
In some
embodiments, the protein equivalent source includes from about 1.5% to about
8% w/w
glutamate per the total amino acids included in the protein equivalent source.
In some
embodiments, the protein equivalent source includes from about 3% to about 6%
w/w
glutamate per the total amino acids in the protein equivalent source.
[0102] In some embodiments, the protein equivalent source includes serine. In
some
embodiments, the protein equivalent source includes from about 1.5% to about
8% w/w
serine per the total amino acids included in the protein equivalent source. In
some
embodiments, the protein equivalent source includes from about 3% to about 5%
w/w serine
per the total amino acids in the protein equivalent source.
[0103] In some embodiments, the protein equivalent source includes arginine.
In some
embodiments, the protein equivalent source includes from about 2% to about 8%
w/w
arginine per the total amino acids included in the protein equivalent source.
In some
embodiments, the protein equivalent source includes from about 3.5% to about
6% w/w
arginine per the total amino acids in the protein equivalent source.
[0104] In some embodiments, the protein equivalent source includes glycine. In
some
embodiments, the protein equivalent source includes from about 0.5% to about
6% w/w
glycine per the total amino acids included in the protein equivalent source.
In some
embodiments, the protein equivalent source includes from about 1.5% to about
3.5% w/w
glycine per the total amino acids in the protein equivalent source.
[0105] In some embodiments, the nutritional composition comprises between
about 1 g and
about 7 g of a protein equivalent source per 100 Kcal. In other embodiments,
the nutritional
composition comprises between about 3.5 g and about 4.5 g of protein
equivalent source
per 100 Kcal.
[0106] In some embodiments, the nutritional composition comprises between
about 0.5
g/100 Kcal and about 2.5 g/100 Kcal of essential amino acids. In certain
embodiments, the
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nutritional composition comprises between about 1.3 g/100 Kcal to about 1.6
Kcal of
essential amino acids.
[0107] In some embodiments, the nutritional composition comprises between
about 0.5
g/100 Kcal and about 2.5 g/100 Kcal of essential amino acids. In certain
embodiments, the
nutritional composition comprises between about 1.3 g/100 Kcal to about 1.6
Kcal of non-
essential amino acids.
[0108] In some embodiments, the nutritional composition comprises from about
0.2 g/100
Kcal to about 0.5 g/100 Kcal of leucine. In some embodiments, the nutritional
composition
comprises from about 0.1 g/100 Kcal to about 0.4 g/100 Kcal of lysine. In some
embodiments, the nutritional composition comprises from about 0.1 g/100 Kcal
to about 0.4
g/100 Kcal of valine. In some embodiments, the nutritional composition
comprises from
about 0.08 g/100 Kcal to about 0.23 g/100 Kcal of isoleucine. In some
embodiments, the
nutritional composition comprises from about 0.08 g/100 Kcal to about 0.20
g/100 Kcal of
threonine. In some embodiments, the nutritional composition comprises from
about 0.10
g/100 Kcal to about 0.15 g/100 Kcal of tyrosine. In some embodiments, the
nutritional
composition comprises from about 0.05 g/100 Kcal to about 0.15 g/100 Kcal of
phenylalanine. In some embodiments, the nutritional composition comprises from
about 0.01
g/100 Kcal to about 0.09 g/100 Kcal of histidine. In some embodiments, the
nutritional
composition comprises from about 0.02 9/100 Kcal to about 0.08 g/100 Kcal of
cystine. In
some embodiments, the nutritional composition comprises from about 0.02 g/100
Kcal to
about 0.08 g/100 Kcal of tryptophan. In some embodiments, the nutritional
composition
comprises from about 0.02 g/100 Kcal to about 0.08 g/100 Kcal of methionine.
[0109] In some embodiments, the nutritional composition comprises from about
0.2 g/100
Kcal to about 0.7 g/100 Kcal of aspartic acid. In some embodiments, the
nutritional
composition comprises from about 0.1 g/100 Kcal to about 0.4 g/100 Kcal of
proline. In some
embodiments, the nutritional composition comprises from about 0.1 g/100 Kcal
to about 0.3
g/100 Kcal of alanine. In some embodiments, the nutritional composition
comprises from
about 0.08 g/100 Kcal to about 0.25 g/100 Kcal of glutamate. In some
embodiments, the
nutritional composition comprises from about 0.08 g/100 Kcal to about 0.2
g/100 Kcal of
serine. In some embodiments, the nutritional composition comprises from about
0.08 g/100
Kcal to about 0.15 g/100 Kcal of arginine. In some embodiments, the
nutritional composition
comprises from about 0.02 g/100 Kcal to about 0.08 g/100 Kcal of glycine.
[0110] The nutritional composition(s) of the present disclosure including the
protein
equivalent source, may be administered in one or more doses daily. Any orally
acceptable
dosage form is contemplated by the present disclosure. Examples of such dosage
forms
include, but are not limited to pills, tablets, capsules, soft-gels, liquids,
liquid concentrates,
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powders, elixirs, solutions, suspensions, emulsions, lozenges, beads, cachets,
and
combinations thereof.
[0111] In some embodiments, the protein equivalent source may provide from
about 5% to
about 20% of the total calories for the nutritional composition. In some
embodiments, the
protein equivalent source may provide from about 8% to about 12 % of the total
calories for
the nutritional composition.
[0112] In some embodiments, without being bound by any particular theory, the
nutritional
compositions including dietary butyrate, prebiotic, and the protein equivalent
source
disclosed herein, may reduce the incidence of allergic reactions in human
subjects when
administered. For example, in certain embodiments the nutritional compositions
may include
dietary butyrate, prebiotic, and a protein equivalent source, where the
protein equivalent
source is substantially free of whole and/or intact protein. As such, the
protein equivalent
source provides amino acids in addition to dietary butyrate, which, in
combination, may
further prevent allergic reaction and decrease inflammation when administered.
[0113] The nutritional composition(s) of the present disclosure may also
comprise a
carbohydrate source. Carbohydrate sources can be any used in the art, e.g.,
lactose, glucose,
fructose, corn syrup solids, maltodextrins, sucrose, starch, rice syrup
solids, and the like.
The amount of carbohydrate in the nutritional composition typically can vary
from between
about 5 g and about 25 g/100 Kcal. In some embodiments, the amount of
carbohydrate is
between about 6 g and about 22 9/100 Kcal. In other embodiments, the amount of
carbohydrate is between about 12 g and about 14 9/100 Kcal. In some
embodiments, corn
syrup solids are preferred. Moreover, hydrolyzed, partially hydrolyzed, and/or
extensively
hydrolyzed carbohydrates may be desirable for inclusion in the nutritional
composition due
to their easy digestibility. Specifically, hydrolyzed carbohydrates are less
likely to contain
allergenic epitopes.
[0114] Non-limiting examples of carbohydrate materials suitable for use herein
include
hydrolyzed or intact, naturally or chemically modified, starches sourced from
corn, tapioca,
rice or potato, in waxy or non-waxy forms. Non-limiting examples of suitable
carbohydrates
include various hydrolyzed starches characterized as hydrolyzed cornstarch,
maltodextrin,
maltose, corn syrup, dextrose, corn syrup solids, glucose, and various other
glucose
polymers and combinations thereof. Non-limiting examples of other suitable
carbohydrates
include those often referred to as sucrose, lactose, fructose, high fructose
corn syrup,
indigestible oligosaccharides such as fructooligosaccharides and combinations
thereof.
[0115] The nutritional composition(s) of the disclosure may also comprise a
protein source.
The protein source can be any used in the art, e.g., nonfat milk, whey
protein, casein, soy
protein, hydrolyzed protein, amino acids, and the like. Bovine milk protein
sources useful in
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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.
[0116] In one embodiment, the proteins of the nutritional composition 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 certain other embodiments, the proteins are more completely
hydrolyzed. In
still other embodiments, the protein source comprises amino acids. In yet
another
embodiment, the protein source may be supplemented with glutamine-containing
peptides.
[0117] In a particular embodiment of the nutritional composition, the
whey:casein ratio of the
protein source is similar to that found in human breast milk. In an
embodiment, the protein
source comprises from about 40% to about 80% whey protein and from about 20%
to about
60% casein.
[0118] In some embodiments, the nutritional composition comprises between
about 1 g and
about 7 g of a protein source per 100 Kcal. In other embodiments, the
nutritional
composition comprises between about 3.5 g and about 4.5 g of protein per 100
Kcal.
[0119] In some embodiments, the nutritional composition described herein
comprises a fat
source. The enriched lipid fraction described herein may be the sole fat
source or may be
used in combination with any other suitable fat or lipid source for the
nutritional composition
as known in the art. In certain embodiments, appropriate fat sources include,
but are 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, palm olein oil, 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.
[0120] In some embodiment the nutritional composition comprises between about
1 g/100
Kcal to about 10 g/100 Kcal of a fat or lipid source. In some embodiments, the
nutritional
composition comprises between about 2 g/100 Kcal to about 7 g/100 Kcal of a
fat source. In
other embodiments the fat source may be present in an amount from about 2.5
g/100 Kcal
to about 6 g/100 Kcal. In still other embodiments, the fat source may be
present in the
nutritional composition in an amount from about 3 g/100 Kcal to about 4 g/100
Kcal.
[0121] In some embodiments, the fat or lipid source comprises from about 10%
to about
35% palm oil per the total amount of fat or lipid. In some embodiments, the
fat or lipid
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source comprises from about 15% to about 30% palm oil per the total amount of
fat or lipid.
Yet in other embodiments, the fat or lipid source may comprise from about 18%
to about 25
% palm oil per the total amount of fat or lipid.
[0122] In certain embodiments, the fat or lipid source may be formulated to
include from
about 2% to about 16% soybean oil based on the total amount of fat or lipid.
In some
embodiments, the fat or lipid source may be formulated to include from about
4% to about
12% soybean oil based on the total amount of fat or lipid. In some
embodiments, the fat or
lipid source may be formulated to include from about 6% to about 10% soybean
oil based on
the total amount of fat or lipid.
[0123] In certain embodiments, the fat or lipid source may be formulated to
include from
about 2% to about 16% coconut oil based on the total amount of fat or lipid.
In some
embodiments, the fat or lipid source may be formulated to include from about
4% to about
12% coconut oil based on the total amount of fat or lipid. In some
embodiments, the fat or
lipid source may be formulated to include from about 6% to about 10% coconut
oil based on
the total amount of fat or lipid.
[0124] In certain embodiments, the fat or lipid source may be formulated to
include from
about 2% to about 16% sunflower oil based on the total amount of fat or lipid.
In some
embodiments, the fat or lipid source may be formulated to include from about
4% to about
12% sunflower oil based on the total amount of fat or lipid. In some
embodiments, the fat or
lipid source may be formulated to include from about 6% to about 10% sunflower
oil based
on the total amount of fat or lipid.
[0125] In some embodiments, the oils, ie. sunflower oil, soybean oil,
sunflower oil, palm oil,
etc. are meant to cover fortified versions of such oils known in the art. For
example, in
certain embodiments, the use of sunflower oil may include high oleic sunflower
oil. In other
examples, the use of such oils may be fortified with certain fatty acids, as
known in the art,
and may be used in the fat or lipid source disclosed herein.
[0126] In some embodiments, the fat or lipid source includes an oil blend
including sunflower
oil, medium chain triglyceride oil, and soybean oil. In some embodiments, the
fat or lipid
source includes a ratio of sunflower oil to medium chain triglyceride oil of
about 1:1 to about
2:1. In certain other embodiments, the fat or lipid source includes a ratio of
sunflower oil to
soybean oil of from about 1:1 to about 2:1. In still other embodiments, the
fat or lipid source
may include a ratio of medium chain triglyceride oil to soybean oil of from
about 1:1 to about
2:1.
[0127] In certain embodiments the fat or lipid source may comprise from about
15% to about
50% w/w sunflower oil based on the total fat or lipid content. In certain
embodiments, the fat
or lipid source includes from about 25% to about 40% w/w sunflower oil based
on the total
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fat or lipid content. In some embodiments, the fat or lipid source comprises
from about 30%
to about 35% w/w sunflower oil based on the total fat or lipid content.
[0128] In certain embodiments the fat or lipid source may comprise from about
15% to about
50% w/w medium chain triglyceride oil based on the total fat or lipid content.
In certain
embodiments, the fat or lipid source includes from about 25% to about 40% w/w
medium
chain triglyceride oil based on the total fat or lipid content. In some
embodiments, the fat or
lipid source comprises from about 30% to about 35% w/w medium chain
triglyceride oil
based on the total fat or lipid content.
[0129] In certain embodiments the fat or lipid source may comprise from about
15% to about
50% w/w soybean oil based on the total fat or lipid content. In certain
embodiments, the fat
or lipid source includes from about 25% to about 40% w/w soybean oil based on
the total fat
or lipid content. In some embodiments, the fat or lipid source comprises from
about 30% to
about 35% w/w soybean oil based on the total fat or lipid content.
[0130] In some embodiments, the nutritional composition comprises from about 1
g/100 Kcal
to about 3 g/100 Kcal of sunflower oil. In some embodiments, the nutritional
composition
comprises from about 1.3 g/100 Kcal to about 2.5 9/100 Kcal of sunflower oil.
In still other
embodiments, the nutritional composition comprises from about 1.7 g/100 Kcal
to about 2.1
g/100 Kcal of sunflower oil. The sunflower oil as described herein may, in
some
embodiments, include high oleic sunflower oil.
[0131] In certain embodiments, the nutritional composition if formulated to
include from
about 1 g/100 Kcal to about 2.5 9/100 Kcal of medium chain triglyceride oil.
In other
embodiments, the nutritional composition includes from about 1.3 g/100 Kcal to
about 2.1
9/100 Kcal of medium chain triglyceride oil. Still in further embodiments, the
nutritional
composition includes from about 1.6 9/100 Kcal to about 1.9 g/100 Kcal of
medium chain
triglyceride oil.
[0132] In some embodiments, the nutritional composition may be formulated to
include from
about 1 g/100 Kcal to about 2.3 g/100 Kcal of soybean oil. In certain
embodiments, the
nutritional composition may be formulated to include from about 1.2 g/100 Kcal
to about 2
9/100 Kcal of soybean oil. Still in certain embodiments, the nutritional
composition may be
formulated to include from about 1.5 g/100 Kcal to about 1.8 9/100 Kcal of
soybean oil.
[0133] In some embodiments, the term "sunflower oil", "medium chain
triglyceride oil", and
"soybean oil" are meant to cover fortified versions of such oils known in the
art. For
example, in certain embodiments, the use of sunflower oil may include high
oleic sunflower
oil. In other examples, the use of such oils may be fortified with certain
fatty acids, as known
in the art, and may be used in the fat or lipid source disclosed herein.
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[0134] In some embodiments, the fat or lipid source provides from about 35% to
about 55%
of the total calories of the nutritional composition. In other embodiments,
the fat or lipid
source provides from about 40% to about 47% of the total calories of the
nutritional
composition.
[0135] In certain embodiments the nutritional composition may be formulated,
in some
embodiments, such that from about 10% to about 23 % of the total calories of
the nutritional
composition are provided by sunflower oil. In other embodiments, from about
13% to about
20% of the total calories in the nutritional composition may be provided by
sunflower oil.
Still, in other embodiments, from about 15 % to about 18% of the total
calories of the
nutritional composition may be provided by sunflower oil.
[0136] In some embodiments, the nutritional composition may be formulated such
that from
about 10% to about 20% of the total calories are provided by MCT oil. In
certain
embodiments, from about 12% to about 18% of the total calories in the
nutritional
composition may be provided by MCT oil. Still , in certain embodiments, from
about 14% to
about 17% of the calories of the nutritional composition may be provided by
MCT oil.
[0137] In some embodiments, the nutritional composition may be formulated such
that from
about 10% to 20% of the total calories of the nutritional composition are
provided by
soybean oil. In certain embodiments, from about 12% to about 18% of the total
calories of
the nutritional composition may be provided by soybean oil. In certain
embodiments, from
about 13% to about 16% of the total calories may be provided by soybean oil.
[0138] In some embodiments the nutritional composition may also include a
source of
LCPUFAs. In one embodiment the amount of LCPUFA in the nutritional composition
is
advantageously at least about 5 mg/100 Kcal, and 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. Non-limiting examples of LCPUFAs include, but are not limited to, DHA,
ARA, linoleic
(18:2 n-6), y-linolenic (18:3 n-6), dihomo- y-linolenic (20:3 n-6) acids in
the n-6 pathway, a-
linolenic (18:3 n-3), stearidonic (18:4 n-3), eicosatetraenoic (20:4 n-3),
eicosapentaenoic (20:5
n-3), and docosapentaenoic (22:6 n-3).
[0139] In some embodiments, the LCPUFA included in the nutritional composition
may
comprise DHA. In one embodiment the amount of DHA in the nutritional
composition is
advantageously at least about 17 mg/100 Kcal, and may vary from about 5 mg/100
Kcal to
about 75 mg/100 Kcal, more preferably from about 10 mg/100 Kcal to about 50
mg/100
Kcal.
[0140] In another embodiment, especially if the nutritional composition is an
infant formula,
the nutritional composition is supplemented with both DHA and ARA. In this
embodiment,
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the weight ratio of ARA:DHA may be between about 1:3 and about 9:1. In a
particular
embodiment, the ratio of ARA:DHA is from about 1:2 to about 4:1.
[0141] 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.
Alternatively, the
DHA and ARA can be used in refined form.
[0142] The disclosed nutritional composition described herein can, in some
embodiments,
also comprise a source of B-glucan. Glucans are polysaccharides, specifically
polymers of
glucose, which are naturally occurring and may be found in cell walls of
bacteria, yeast, fungi,
and plants. Beta glucans (13-glucans) are themselves a diverse subset of
glucose polymers,
which are made up of chains of glucose monomers linked together via beta-type
glycosidic
bonds to form complex carbohydrates.
[0143113-1,3-glucans are carbohydrate polymers purified from, for example,
yeast,
mushroom, bacteria, algae, or cereals. (Stone BA, Clarke AE. Chemistry and
Biology of (1-3)-
Beta-Glucans. London:Portland Press Ltd; 1993. ) The chemical structure of 13-
1,3-glucan
depends on the source of the 13-1,3-glucan. Moreover, various physiochemical
parameters,
such as solubility, primary structure, molecular weight, and branching, play a
role in biological
activities of 13-1,3-glucans. (Yadomae T., Structure and biological activities
of fungal beta-1,3-
glucans. Yakugaku Zasshi. 2000;120:413-431.)
[0144] 8-1,3-glucans are naturally occurring polysaccharides, with or without
13-1,6-glucose
side chains that are found in the cell walls of a variety of plants, yeasts,
fungi and bacteria. 13-
1,3;1,6-glucans are those containing glucose units with (1,3) links having
side chains attached
at the (1,6) position(s). 8-1,3;1,6 glucans are a heterogeneous group of
glucose polymers
that share structural commonalities, including a backbone of straight chain
glucose units
linked by a 13-1,3 bond with 13-1,6-linked glucose branches extending from
this backbone.
While this is the basic structure for the presently described class of 13-
glucans, some
variations may exist. For example, certain yeast 8-glucans have additional
regions of 8(1,3)
branching extending from the 13(1,6) branches, which add further complexity to
their
respective structures.
[0145] 13-glucans derived from baker's yeast, Saccharomyces cerevislae, are
made up of
chains of D-glucose molecules connected at the 1 and 3 positions, having side
chains of
glucose attached at the 1 and 6 positions. Yeast-derived 13-glucan is an
insoluble, fiber-like,
complex sugar having the general structure of a linear chain of glucose units
with a 13-1,3
backbone interspersed with 13-1,6 side chains that are generally 6-8 glucose
units in length.
More specifically, 13-glucan derived from baker's yeast is poly-(1,6)-13-D-
glucopyranosyl-(1,3)-
8-D-glucopyranose.
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[0146] Furthermore, P-glucans are well tolerated and do not produce or cause
excess gas,
abdominal distension, bloating or diarrhea in pediatric subjects. Addition of
13-glucan to a
nutritional composition for a pediatric subject, such as an infant formula, a
growing-up milk
or another children's nutritional product, will improve the subject's immune
response by
increasing resistance against invading pathogens and therefore maintaining or
improving
overall health.
[0147] In some embodiments, the i3-glucan is 13-1,31,6-glucan. In some
embodiments, the 3-
1,3;1,6-glucan is derived from baker's yeast. The nutritional composition may
comprise
whole glucan particle13-glucan, particulatep-glucan, PGG-glucan (poly-1,6-13-D-
glucopyranosy1-1,3-13-D-glucopyranose) or any mixture thereof.
[0148] In some embodiments, the amount of P-glucan in the nutritional
composition is
between about 3 mg and about 17 mg per 100 Kcal. In another embodiment the
amount of
P-glucan is between about 6 mg and about 17 mg per 100 Kcal.
[0149] The disclosed nutritional composition described herein can, in some
embodiments,
also comprise a source of probiotic. The term "probiotic" means a
microorganism that exerts
beneficial effects on the health of the host. Any probiotic known in the art
may be
acceptable in this embodiment. In a particular embodiment, the probiotic may
be selected
from any Lactobacillus species, Lactobacillus rhamnosus GG (ATCC number
53103),
Bifidobacterium species, Bifidobacterium longum BB536 (BL999, ATCC: BAA-999),
Bifidobacterium longum AH1206 (NCI MB: 41382), Bitidobacterium breve AH1205
(NCI MB:
41387), Bifidobacterium infantis 35624 (NCIMB: 41003), and Bifidobacterium
animalis subsp.
lactis BB-12 (DSM No. 10140) or any combination thereof.
[0150] If included, the nutritional composition may comprise between about 1 x
104 to about
1.5 x 1010 du of probiotics per 100 Kcal, more preferably from about 1 x 106
to about 1 x 109
cfu of probiotics per 100 Kcal.
[0151] In an embodiment, the probiotic(s) may be viable or non-viable. As used
herein, the
term "viable", refers to live microorganisms. The term "non-viable" or "non-
viable
probiotic" means non-living probiotic microorganisms, their cellular
components and/or
metabolites thereof. Such non-viable probiotics may have been heat-killed or
otherwise
inactivated, but they 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 manipulation of organisms, whether such new source is now
known or
later developed.
[0152] The disclosed nutritional composition described herein, can, in some
embodiments
also comprise an effective amount of iron. The iron may comprise encapsulated
iron forms,
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such as encapsulated ferrous fumarate or encapsulated ferrous sulfate or less
reactive iron
forms, such as ferric pyrophosphate or ferric orthophosphate.
[0153] One or more vitamins and/or minerals may also be added in to the
nutritional
composition in amounts sufficient to supply the daily nutritional requirements
of a subject. It
is to be understood by one of ordinary skill in the art that vitamin and
mineral requirements
will vary, for example, based on the age of the child. For instance, an infant
may have
different vitamin and mineral requirements than a child between the ages of
one and thirteen
years. Thus, the embodiments are not intended to limit the nutritional
composition to a
particular age group but, rather, to provide a range of acceptable vitamin and
mineral
components.
[0154] In embodiments providing a nutritional composition for a child, the
composition may
optionally include, but is not limited to, one or more of the following
vitamins or derivations
thereof: vitamin B1 (thiamin, thiamin pyrophosphate, TPP, thiamin
triphosphate, UP, thiamin
hydrochloride, thiamin mononitrate), vitamin B2 (riboflavin, flavin
mononucleotide, FMN,
flavin adenine dinucleotide, FAD, lactoflavin, ovoflavin), vitamin B3 (niacin,
nicotinic acid,
nicotinamide, niacinamide, nicotinamide adenine dinucleotide, NAD, nicotinic
acid
mononucleotide, NicMN, pyridine-3-carboxylic acid), vitamin B3-precursor
tryptophan,
vitamin B6 (pyridoxine, pyridoxal, pyridoxamine, pyridoxine hydrochloride),
pantothenic acid
(pantothenate, panthenol), folate (folic acid, folacin, pteroylglutamic acid),
vitamin B12
(cobalamin, methylcobalamin, deoxyadenosylcobalamin, cyanocobalamin,
hydroxycobalarnin,
adenosylcobalamin), biotin, vitamin C (ascorbic acid), vitamin A (retinol,
retinyl acetate, retinyl
palmitate, retinyl esters with other long-chain fatty acids, retinal, retinoic
acid, retinol esters),
vitamin D (calciferol, cholecalciferol, vitamin D3, 1,25,-dihydroxyvitamin D),
vitamin E (a-
tocopherol, a-tocopherol acetate, a-tocopherol succinate, ct-tocopherol
nicotinate, a-
tocopherol), vitamin K (vitamin Kl, phylloquinone, naphthoquinone, vitamin
1(2, menaquinone-
7, vitamin K3, menaquinone-4, menadione, menaquinone-8, menaquinone-8H,
menaquinone-
9, rnenaquinone-9H, menaquinone-10, menaquinone-11, menaquinone-12,
menaquinone-13),
choline, inositol, 13-carotene and any combinations thereof.
[0155] In embodiments providing a children's nutritional product, such as a
growing-up milk,
the composition may optionally include, but is not limited to, one or more of
the following
minerals or derivations thereof: boron, calcium, calcium acetate, calcium
gluconate, calcium
chloride, calcium lactate, calcium phosphate, calcium sulfate, chloride,
chromium, chromium
chloride, chromium picolonate, copper, copper sulfate, copper gluconate,
cupric sulfate,
fluoride, iron, carbonyl iron, ferric iron, ferrous fumarate, ferric
orthophosphate, iron
trituration, polysaccharide iron, iodide, iodine, magnesium, magnesium
carbonate,
magnesium hydroxide, magnesium oxide, magnesium stearate, magnesium sulfate,
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manganese, molybdenum, phosphorus, potassium, potassium phosphate, potassium
iodide,
potassium chloride, potassium acetate, selenium, sulfur, sodium, docusate
sodium, sodium
chloride, sodium selenate, sodium molybdate, zinc, zinc oxide, zinc sulfate
and mixtures
thereof. Non-limiting exemplary derivatives of mineral compounds include
salts, alkaline
salts, esters and chelates of any mineral compound.
[0156] The minerals can be added to growing-up milks or to other children's
nutritional
compositions in the form of salts such as calcium phosphate, calcium glycerol
phosphate,
sodium citrate, potassium chloride, potassium phosphate, magnesium phosphate,
ferrous
sulfate, zinc sulfate, cupric sulfate, manganese sulfate, and sodium selenite.
Additional
vitamins and minerals can be added as known within the art.
[0157] The nutritional compositions of the present disclosure may optionally
include one or
more of the following flavoring agents, including, but not limited to,
flavored extracts,
volatile oils, cocoa or chocolate flavorings, peanut butter flavoring, cookie
crumbs, vanilla or
any commercially available flavoring. Examples of useful flavorings include,
but are not
limited to, pure anise extract, imitation banana extract, imitation cherry
extract, chocolate
extract, pure lemon extract, pure orange extract, pure peppermint extract,
honey, imitation
pineapple extract, imitation rum extract, imitation strawberry extract, or
vanilla extract; or
volatile oils, such as balm oil, bay oil, bergamot oil, cedarwood oil, cherry
oil, cinnamon oil,
clove oil, or peppermint oil; peanut butter, chocolate flavoring, vanilla
cookie crumb,
butterscotch, toffee, and mixtures thereof. The amounts of flavoring agent can
vary greatly
depending upon the flavoring agent used. The type and amount of flavoring
agent can be
selected as is known in the art.
[0158] The nutritional compositions of the present disclosure may optionally
include one or
more emulsifiers that may be added for stability of the final product.
Examples of suitable
emulsifiers include, but are not limited to, lecithin (e.g., from egg or soy),
alpha lactalbumin
and/or mono- and di-glycerides, and mixtures thereof. Other emulsifiers are
readily
apparent to the skilled artisan and selection of suitable emulsifier(s) will
depend, in part,
upon the formulation and final product.
[0159] The nutritional compositions of the present disclosure may optionally
include one or
more preservatives that may also be added to extend product shelf life.
Suitable
preservatives include, but are not limited to, potassium sorbate, sodium
sorbate, potassium
benzoate, sodium benzoate, calcium disodium EDTA, and mixtures thereof.
[0160] The nutritional compositions of the present disclosure may optionally
include one or
more stabilizers. Suitable stabilizers for use in practicing the nutritional
composition of the
present disclosure include, but are not limited to, gum arabic, gum ghatti,
gum karaya, gum
tragacanth, agar, furcellaran, guar gum, gellan gum, locust bean gum, pectin,
low methoxyl
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pectin, gelatin, microcrystalline cellulose, CMC (sodium
carboxymethylcellulose),
methylcellulose hydroxypropyl methyl cellulose, hydroxypropyl cellulose, DATEM
(diacetyl
tartaric acid esters of mono- and diglycerides), dextran, carrageenans, and
mixtures thereof.
[0161] The nutritional compositions of the disclosure may provide minimal,
partial or total
nutritional support. The compositions may be nutritional supplements or meal
replacements.
The compositions may, but need not, be nutritionally complete. In an
embodiment, the
nutritional composition of the disclosure is nutritionally complete and
contains suitable types
and amounts of lipid, carbohydrate, protein, vitamins and minerals. The amount
of lipid or fat
typically can vary from about 1 to about 25 g/100 Kcal. The amount of protein
typically can
vary from about 1 to about 7 g/100 Kcal. The amount of carbohydrate typically
can vary from
about 6 to about 22 g/100 Kcal.
[0162] In an embodiment, the children's nutritional composition may contain
between about
and about 50% of the maximum dietary recommendation for any given country, or
between about 10 and about 50% of the average dietary recommendation for a
group of
countries, per serving of vitamins A, C, and E, zinc, iron, iodine, selenium,
and choline. In
another embodiment, the children's nutritional composition may supply about 10
¨ 30% of
the maximum dietary recommendation for any given country, or about 10¨ 30% of
the
average dietary recommendation for a group of countries, per serving of B-
vitamins. In yet
another embodiment, the levels of vitamin D, calcium, magnesium, phosphorus,
and
potassium in the children's nutritional product may correspond with the
average levels found
in milk. In other embodiments, other nutrients in the children's nutritional
composition may
be present at about 20% of the maximum dietary recommendation for any given
country, or
about 20% of the average dietary recommendation for a group of countries, per
serving.
[0163] In some embodiments the nutritional composition is an infant formula.
Infant
formulas are fortified nutritional compositions for an infant. The content of
an infant formula
is dictated by federal regulations, which define macronutrient, vitamin,
mineral, and other
ingredient levels in an effort to simulate the nutritional and other
properties of human breast
milk. Infant formulas are designed to support overall health and development
in a pediatric
human subject, such as an infant or a child.
[0164] In some embodiments, the nutritional composition of the present
disclosure is a
growing-up milk. Growing-up milks are fortified milk-based beverages intended
for children
over 1 year of age (typically from 1-3 years of age, from 4-6 years of age or
from 1-6 years of
age). They are not medical foods and are not intended as a meal replacement or
a
supplement to address a particular nutritional deficiency. Instead, growing-up
milks are
designed with the intent to serve as a complement to a diverse diet to provide
additional
insurance that a child achieves continual, daily intake of all essential
vitamins and minerals,
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macronutrients plus additional functional dietary components, such as non-
essential nutrients
that have purported health-promoting properties.
[0165] The exact composition of a growing-up milk or other nutritional
composition
according to the present disclosure can vary from market-to-market, depending
on local
regulations and dietary intake information of the population of interest. In
some
embodiments, nutritional compositions according to the disclosure consist of a
milk protein
source, such as whole or skim milk, plus added sugar and sweeteners to achieve
desired
sensory properties, and added vitamins and minerals. The fat composition
includes an
enriched lipid fraction derived from milk. Total protein can be targeted to
match that of
human milk, cow milk or a lower value. Total carbohydrate is usually targeted
to provide as
little added sugar, such as sucrose or fructose, as possible to achieve an
acceptable taste.
Typically, Vitamin A, calcium and Vitamin D are added at levels to match the
nutrient
contribution of regional cow milk. Otherwise, in some embodiments, vitamins
and minerals
can be added at levels that provide approximately 20% of the dietary reference
intake (DRI)
or 20% of the Daily Value (DV) per serving. Moreover, nutrient values can vary
between
markets depending on the identified nutritional needs of the intended
population, raw
material contributions and regional regulations.
[0166] The disclosed nutritional composition(s) may be provided in any form
known in the
art, such as a powder, a gel, a suspension, a paste, a solid, a liquid, a
liquid concentrate, a
reconstituteable powdered milk substitute or a ready-to-use product. The
nutritional
composition may, in certain embodiments, comprise a nutritional supplement,
children's
nutritional product, infant formula, human milk fortifier, growing-up milk or
any other
nutritional composition designed for an infant or a pediatric subject.
Nutritional
compositions of the present disclosure include, for example, orally-
ingestible, health-
promoting substances including, for example, foods, beverages, tablets,
capsules and
powders. Moreover, the nutritional composition of the present disclosure may
be
standardized to a specific caloric content, it may be provided as a ready-to-
use product, or it
may be provided in a concentrated form. In some embodiments, the nutritional
composition
is in powder form with a particle size in the range of 5 pm to 1500 pm, more
preferably in the
range of 10 pm to 300pm.
[0167] The nutritional compositions of the present disclosure may be provided
in a suitable
container system. For example, non-limiting examples of suitable container
systems include
plastic containers, metal containers, foil pouches, plastic pouches, multi-
layered pouches, and
combinations thereof. In certain embodiments, the nutritional composition may
be a
powdered composition that is contained within a plastic container. In certain
other
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embodiments, the nutritional composition may be contained within a plastic
pouch located
inside a plastic container.
[0168] The nutritional compositions described herein, in some embodiments,
advantageously
reduce the incidence of allergic reaction and improve tolerance to cow's milk
allergy in a
subject. Further, in some embodiments, the nutritional compositions
advantageously reduce
the inflammatory response caused by allergy in a subject. Accordingly, the
disclosure relates
to methods of improving tolerance to cow's milk allergy in a subject. Further,
the disclosure
relates to methods of reducing the incidence of allergic reaction and reducing
the
inflammatory response caused by allergy in a subject via administration of the
nutritional
compositions including PDX/GOS and dietary butyrate as disclosed herein.
[0169] In some embodiments, the method comprises the step of subjecting the
target
subject to cow's milk and then providing the nutritional composition disclosed
herein
including PDX/GOS and dietary butyrate to the target subject. In certain
embodiments, after
the target subject has been subjected to cow's milk, the target subject may be
provided with
a nutritional composition that includes PDX/GOS and dietary butyrate and a
protein
equivalent source as disclosed herein. In certain embodiments, the target
subject, after being
exposed to cow's milk or other allergen, may be administered a nutritional
composition
comprising PDX/GOS and dietary butyrate, and a protein equivalent source. In
certain
embodiments, the protein equivalent source may be substantially free of whole
and/or intact
protein. In certain other embodiments, the protein equivalent source may
comprise
hydrolyzed protein, amino acids, the peptide component disclosed herein, and
combinations
thereof. In some embodiments, the nutritional composition includes a protein
equivalent
source includes amino acids and no hydrolyzed or whole/intact protein.
[0170] In some embodiments, the target subject is not subjected to cow's milk
or an allergen
prior to administration of the nutritional composition. Thus, in some
embodiments, the
method is directed to reducing allergic response in a target subject via
providing the
nutritional compositions disclosed herein including dietary butyrate to the
target subject, and
subsequently exposing the target subject to cow's milk or other allergen.
[0171] The nutritional compositions described herein, in some embodiments,
advantageously
reduce the inflammatory response in a subject. Accordingly, the disclosure
relates to
methods of reducing a proinflammatory response in a subject by administering
to a subject a
nutritional composition containing the protein equivalent source described
herein in
combination with PDX/GOS and dietary butyrate. For example, the present
methods may
reduce the production of proinflammatory cytokines in a subject.
[0172] In some embodiments, the method for reducing an inflammatory response
in a
subject comprises administering to a subject a nutritional composition
comprising a
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carbohydrate source, a protein equivalent source, fat source, PDX/GOS and
dietary butryate,
wherein the protein equivalent source includes a peptide component comprising
SEQ ID NO
4, SEQ ID NO 13, SEQ ID NO 17, SEQ ID NO 21, SEQ ID NO 24, SEQ ID NO 30, SEQ
ID NO
31, SEQ ID NO 32, SEQ ID NO 51, SEQ ID NO 57, SEQ ID NO 60, and SEQ ID NO 63.
In
some embodiments, the peptide component may comprise additional peptides
disclosed in
Table 1. For example, the composition may include at least 10 additional
peptides disclosed
in Table 1. In some embodiments, 20% to 80% of the protein equivalent source
comprises
the peptide component, and 20% to 80% of the protein equivalent source
comprises an
intact protein, a partially hydrolyzed protein, and combinations thereof.
[0173] In another embodiment, the method comprises administering to a subject
a
nutritional composition, wherein 20% to 80% of the protein equivalent source
includes a
peptide component comprising at least 3 peptides selected from the group
consisting of
SEQ ID NO 4, SEQ ID NO 13, SEQ ID NO 17, SEQ ID NO 21, SEQ ID NO 24, SEQ ID NO
30,
SEQ ID NO 31, SEQ ID NO 32, SEQ ID NO 51, SEQ ID NO 57, SEQ ID NO 60, and SEQ
ID
NO 63, and at least 5 additional peptides selected from Table 1; and wherein
20% to 80% of
the protein equivalent source comprises an intact protein, a partially
hydrolyzed protein, or
combinations thereof.
[0174] In yet other embodiments, the method for reducing the inflammatory
response
includes providing a nutritional composition comprising a peptide component
from Table 1,
wherein the peptide component is derived from a casein hydrolysate having a
molar mass
distribution of greater than 500 Daltons. In some embodiments, the molar mass
distribution
of the casein hydrolysate is in a range of 500 to 2000 Da!tons. In other
embodiments, the
method for reducing the inflammatory response includes providing a nutritional
composition
comprising the peptide component described herein, wherein the peptide
component is
derived from a casein hydrolysate that does not include peptides having a
molar mass
distribution of less than 200 Da!tons.
[0175] In some embodiments the target subject may be a pediatric subject.
Further, in one
embodiment, the nutritional composition provided to the pediatric subject may
be an infant
formula. The peptide component identified herein, PDX/GOS and dietary butyrate
as
disclosed herein may be added to the infant formula and, further, each may be
selected from
a specific source and concentrations thereof may be adjusted to maximize
health benefits. In
another embodiment of this method, the nutritional composition comprising the
peptide
component disclosed herein, PDX/GOS and dietary butyrate is a growing up milk.
[0176] In embodiments when the nutritional composition is an infant formula,
the
composition may advantageously reduce a pro-inflammatory response in the
infant, and
thereby reduce the incidence of inflammatory disease. Moreover, the reduction
in
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inflammatory disease may last throughout childhood and into adulthood.
Similarly, when the
nutritional composition is a growing-up milk, a child who ingests the growing-
up milk may
experience a reduction in the incidence of inflammatory disease in adulthood,
as well as
during childhood.
[0177] In certain embodiments, the disclosure is directed to a method for
improving the
absorption of butyrate in a target subject by providing or administering the
nutritional
compositions disclosed herein including PDX/GOS and dietary butyrate to the
target subject.
In some embodiments, the target subject is a pediatric subject or an infant.
In some
embodiments, the nutritional composition is an infant formula or a growing-up
milk.
[0178] All combinations of method or process steps as used herein can be
performed in any
order, unless otherwise specified or clearly implied to the contrary by the
context in which
the referenced combination is made.
[0179] The methods and compositions of the present disclosure, including
components
thereof, can comprise, consist of, or consist essentially of the essential
elements and
limitations of the embodiments described herein, as well as any additional or
optional
ingredients, components or limitations described herein or otherwise useful in
nutritional
compositions.
[0180] Formulation examples are provided to illustrate some embodiments of the
nutritional
composition of the present disclosure but should not be interpreted as any
limitation
thereon. Other embodiments within the scope of the claims herein will be
apparent to one
skilled in the art from the consideration of the specification or practice of
the nutritional
composition or methods disclosed herein. It is intended that the
specification, together with
the example, be considered to be exemplary only, with the scope and spirit of
the disclosure
being indicated by the claims which follow the example.
FORMULATION EXAMPLES
[0181] Table 3 provides an example embodiment of a peptide component including
8
peptides from Table1.
Table 3. Example peptide component
Example of Selected Peptides
for Peptide Component
SEQ ID NO 5
SEQ ID NO 24
SEQ ID NO 33
SEQ ID NO 56
SEQ ID NO 64
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SEQ ID NO 13
SEQ ID NO 24
SEQ ID NO 60
[0182] Table 4 provides an example embodiment of a peptide component including
certain
peptides from Table 1.
Table 4. Example peptide component
Example of Selected Peptides
for Peptide Component
SEQ ID NO 13
SEQ ID NO 24
SEQ ID NO 60
SEQ ID NO 5
SEQ ID NO 11
SEQ ID NO 22
SEQ ID NO 25
SEQ ID NO 33
SEQ ID NO 45
SEQ ID NO 46
SEQ ID NO 47
SEQ ID NO 48
SEQ ID NO 52
SEQ ID NO 34
SEQ ID NO 36
SEQ ID NO 61
SEQ ID NO 62
SEQ ID NO 64
[0183] Table 2 provides an example embodiment of a protein equivalent source
that may be
included in the nutritional compositions disclosed herein. The amounts of
amino acids
disclosed in Table 2 are based on a weight-to-weight percentage based on the
total amino
acids in the protein equivalent source.
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Table 2. Example protein equivalent source
w/w % amount based on total
Amino Acid amino acids
L-Ieucine 9.94
L-lysine 7.93
L-valine 9.21
L-isoleucine 5.48
L-threonine 4.95
L-tyrosine 4.38
L-phenylalanine 4.05
L-histidine 2.12
L-cystine 2.12
L-tryptophan 1.93
L-methionine 1.87
[0184] Table 3 provides an example embodiment of a protein equivalent source
that may be
included in the nutritional compositions disclosed herein. The amounts of
amino acids
disclosed in Table 3 are based on a weight-to-weight percentage based on the
total amino
acids in the protein equivalent source.
Table 3. Example protein equivalent source
w/w % amount based on total
Amino Acid amino acids
L-aspartic acid 16.16
L-proline 8.05
L-alanine 7.87
Monosodium glutamate 5.54
L-serine 4.95
L-arginine 4.27
glycine 2.12
[0185] Table 4 provides an example embodiment of a protein equivalent source
that may be
included in the nutritional compositions disclosed herein. The amounts of
amino acids
disclosed in Table 4 are based on grams per 100 Kcal of the nutritional
composition.
Table 4. Example protein equivalent source
Amino Acid (g) per 100 Kcal
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L-Ieucine 0.25
L-lysine 0.20
L-valine 0.23
L-isoleucine 0.14
L-threonine 0.12
L-tyrosine 0.11
L-phenylalanine 0.10
L-histidine 0.053
L-cystine 0.053
L-tryptophan 0.049
L-methionine 0.047
[0186] Table 5 provides an example embodiment of a protein equivalent source
that may be
included in the nutritional compositions disclosed herein. The amounts of
amino acids
disclosed in Table 5 are based on grams per 100 Kcal of the nutritional
composition.
Table 5. Example protein equivalent source
Amino Acid (g) per 100 Kcal
L-leucine 0.31
L-lysine 0.24
L-valine 0.28
L-isoleucine 0.17
L-threonine 0.15
L-tyrosine 0.13
L-phenylalanine 0.12
L-histidine 0.07
L-cystine 0.07
L-tryptophan 0.06
L-methionine 0.06
[0187] Table 6 provides an example embodiment of a protein equivalent source
that may be
included in the nutritional compositions disclosed herein. The amounts of
amino acids
disclosed in Table 6 are based on grams per 100 Kcal of the nutritional
composition.
Table 6. Example protein equivalent source
Amino Acid (g) per 100 Kcal
L-aspartic acid 0.41
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L-proline 0.20
L-alanine 0.20
Monosodium glutamate 0.14
L-serine 0.13
L-arginine 0.11
Glycine 0.05
[0188] Table 7 provides an example embodiment of a protein equivalent source
that may be
included in the nutritional compositions disclosed herein. The amounts of
amino acids
disclosed in Table 7 are based on grams per 100 Kcal of the nutritional
composition.
Table 7. Example protein equivalent source
Amino Acid (g) per 100 Kcal
L-aspartic acid 0.50
L-proline 0.28
L-alanine 0.24
Monosodium glutamate 0.17
L-serine 0.15
L-arginine 0.13
Glycine 0.07
[0189] Table 8, illustrated below, provides an example embodiment of the
nutritional profile
of a nutritional composition including PDX/GOS and dietary butyrate and
describes the
amount of each ingredient to be included per 100 Kcal serving of nutritional
composition.
Table 8. Nutrition profile of an example nutritional composition including
dietary
butyrate
per 100 Kcal
Nutrient
Minimum Maximum
Protein Equivalent Source (g) 1.0 7.0
Dietary butyrate (mg) 22 280
Lactobacillus rhamnosus GG (cfu) lx1 04 1.5x1012
Carbohydrates (g) 6 22
Fat (g) 1.3 7.2
Prebiotic (g) 0.3 1.2
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DHA (g) 4 22
Beta glucan (mg) 2.9 17
Probiotics (du) 0.5 5.0
Vitamin A (IU) 9.60 x 108 3.80 x 108
Vitamin D (IU) 134 921
Vitamin E (IU) 22 126
Vitamin K (mcg) 0.8 5.4
Thiamin (mcg) 2.9 18
Riboflavin (mcg) 63 328
Vitamin B6 (mcg) 68 420
Vitamin B12 (mcg) 52 397
Niacin (mcg) 0.2 0.9
Folic acid (mcg) 690 5881
Panthothenic acid (mcg) 8 66
Biotin (mcg) 232 1211
Vitamin C (mg) 1.4 5.5
Choline (mg) 4.9 24
Calcium (mg) 4.9 43
Phosphorus (mg) 68 297
Magnesium (mg) 54 210
Sodium (mg) 4.9 34
Potassium (mg) 24 88
Chloride (mg) 82 346
Iodine (mcg) 53 237
Iron (mg) 8.9 79
Zinc (mg) 0.7 2.8
Manganese (mcg) 0.7 2.4
Copper (mcg) 7.2 41
[0190] All references cited in this specification, including without
limitation, all papers,
publications, patents, patent applications, presentations, texts, reports,
manuscripts,
brochures, books, internet postings, journal articles, periodicals, and the
like, are hereby
incorporated by reference into this specification in their entireties. The
discussion of the
references herein is intended merely to summarize the assertions made by their
authors and
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no admission is made that any reference constitutes prior art. Applicants
reserve the right to
challenge the accuracy and pertinence of the cited references.
[0191] Although embodiments of the disclosure have been described using
specific terms,
devices, and methods, such description is for illustrative purposes only. The
words used are
words of description rather than of limitation. It is to be understood that
changes and
variations may be made by those of ordinary skill in the art without departing
from the spirit
or the scope of the present disclosure, which is set forth in the following
claims. In addition,
it should be understood that aspects of the various embodiments may be
interchanged in
whole or in part. Therefore, the spirit and scope of the appended claims
should not be
limited to the description of the versions contained therein.
