U.S. patent application number 14/846120 was filed with the patent office on 2016-03-03 for method for stimulating intestinal barrier integrity after non-natural birth.
This patent application is currently assigned to N.V. NUTRICIA. The applicant listed for this patent is N.V. Nutricia. Invention is credited to Christopher BEERMANN, Gunther BOEHM, Joachim SCHMITT.
Application Number | 20160058806 14/846120 |
Document ID | / |
Family ID | 35809614 |
Filed Date | 2016-03-03 |
United States Patent
Application |
20160058806 |
Kind Code |
A1 |
SCHMITT; Joachim ; et
al. |
March 3, 2016 |
METHOD FOR STIMULATING INTESTINAL BARRIER INTEGRITY AFTER
NON-NATURAL BIRTH
Abstract
The present invention relates to methods for feeding and
stimulating the health of infants delivered via caesarean section
comprising administering long chain polyunsaturated fatty acids
and/or nucleotides.
Inventors: |
SCHMITT; Joachim; (Hoesbach,
DE) ; BOEHM; Gunther; (Lepzig, DE) ; BEERMANN;
Christopher; (Petersburg, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
N.V. Nutricia |
Zoetermeer |
|
NL |
|
|
Assignee: |
N.V. NUTRICIA
Zoetermeer
NL
|
Family ID: |
35809614 |
Appl. No.: |
14/846120 |
Filed: |
September 4, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12091047 |
Sep 26, 2008 |
|
|
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PCT/NL2006/050248 |
Oct 6, 2006 |
|
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14846120 |
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Current U.S.
Class: |
424/93.4 |
Current CPC
Class: |
A23L 33/21 20160801;
A23Y 2220/85 20130101; A61P 1/12 20180101; A61P 11/02 20180101;
A61K 47/36 20130101; A23Y 2300/55 20130101; A23Y 2300/19 20130101;
A23L 33/135 20160801; A23Y 2300/25 20130101; A61P 17/00 20180101;
A61K 31/7076 20130101; A23Y 2300/49 20130101; A23Y 2300/21
20130101; A23Y 2300/31 20130101; A23C 9/206 20130101; A23L 33/40
20160801; A23Y 2300/29 20130101; A61K 31/7068 20130101; A23Y
2300/45 20130101; A61K 35/747 20130101; A23L 33/12 20160801; A23Y
2300/59 20130101; A61K 31/702 20130101; A61K 31/7072 20130101; A23V
2002/00 20130101; A61K 31/202 20130101; A61K 31/708 20130101; Y02A
50/473 20180101; A23L 33/10 20160801; A61K 31/734 20130101; A61P
1/00 20180101; Y02A 50/475 20180101; A23L 33/17 20160801; A61P
27/02 20180101; A23C 9/203 20130101; A61K 31/732 20130101; A61K
35/74 20130101; Y02A 50/30 20180101; A23C 9/1234 20130101; A23L
29/065 20160801; A61P 37/02 20180101; A61P 37/08 20180101; A61K
35/745 20130101; A61P 31/04 20180101; A61K 31/7064 20130101; A61P
11/06 20180101; A23Y 2300/41 20130101; A61P 1/14 20180101; A23Y
2300/65 20130101; A61K 31/7016 20130101; A23V 2002/00 20130101;
A23V 2200/32 20130101; A23V 2200/3204 20130101; A23V 2200/3202
20130101; A23V 2200/30 20130101; A23V 2200/324 20130101; A23V
2250/28 20130101; A61K 35/745 20130101; A61K 2300/00 20130101; A61K
35/747 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 35/745 20060101
A61K035/745; A23L 1/30 20060101 A23L001/30; A61K 31/7064 20060101
A61K031/7064; A23L 1/308 20060101 A23L001/308; A61K 31/702 20060101
A61K031/702; A61K 31/202 20060101 A61K031/202; A23L 1/29 20060101
A23L001/29; A23L 1/305 20060101 A23L001/305 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 21, 2005 |
EP |
05023029.1 |
Claims
1. A method for stimulating development of healthy intestinal flora
in an infant delivered by caesarian section by increasing species
diversity of the Bifidobacteria in the intestines of the infant,
comprising feeding to an infant delivered by caesarian section and
suffering from low intestinal Bifidobacteria counts and/or lacking
adequate species diversity of Bifidobacteria, a composition
comprising: (a) a Bifidobacteria consisting of Bifidobacterium
breve; and (b) at least non-digestible galacto-oligosaccharides;
wherein the composition is not human breast milk, and wherein the
administration increases the amount of intestinal Bifidobacterium
breve and other Bifidobacterium species.
2. The method according to claim 1, wherein the composition further
comprises one or more of the following non-digestible
oligosaccharides: fructan, fructo-oligosaccharide, non-digestible
dextrin, xylo-oligosaccharide, arabino-oligosaccharide,
arabino-galacto-oligosaccharide, gluco-oligosaccharide,
chito-oligosaccharide, gluco-manno-oligosaccharide,
galacto-manno-oligosaccharide, mannan-oligosaccharide,
fuco-oligosaccharide, galacturonic oligosaccharide, guluronic acid
oligosaccharide, mannuronic acid oligosaccharide, iduronic acid
oligosaccharide, riburonic acid oligosaccharide, glucuronic acid or
oligosaccharide.
3. The method according to claim 1, wherein the composition
comprises a trans-galacto-oligosaccharide and/or a
fructooligosaccharide.
4. The method according to claim 2, wherein the composition
comprises at least one of: (i) a nucleotide; and (ii) a nucleotide
precursor selected from the group consisting of nucleosides, purine
bases, pyrimidine bases, ribose and deoxyribose.
5. The method according to claim 11, wherein the LC-PUFA is
selected from the group consisting of eicosapentaenoic acid,
docosahexaenoic acid and arachidonic acid.
6. The method according to claim 11, wherein the LC-PUFA content is
0.1 to 15 wt. % based on weight of total lipid in the
composition.
7. The method according to claim 6, wherein the LC-PUFA content is
less than 3 wt. %, and wherein (a) omega-3 LC-PUFA present in the
composition is below 1 wt. % of total lipid content; (b) omega-6
LC-PUFA present in the composition is below 2 wt. % of the total
lipid content; and (c) arachidonic acid present in the composition
is below 1 wt. % of the total lipid content.
8. The method according to claim 4, wherein the at least one
nucleotide is selected from the group consisting of cytidine
5'-monophosphate, uridine 5'-monophosphate, adenosine
5'-monophosphate, guanosine 5'-monophosphate, inosine
5'-monophosphate, and a sodium salt of any of said nucleotides.
9. The method according to claim 4, wherein the nucleotide is
present at a concentration of 5 to 100 mg per 100 gram dry weight
of the composition.
10. The method according to claim 1 wherein the composition
comprises: (i) a lipid component that provides 5 to 50% of the
total calories of the composition, (ii) a protein component that
provides 5 to 50% of the total calories of the composition, and
(iii) a carbohydrate component that provides 15 to 90% of the total
calories of the composition.
11. The method according to claim 1, wherein the composition
further comprises long-chain polyunsaturated fatty acid
(LC-PUFA).
12. A method for stimulating development of healthy intestinal
flora in an infant delivered by caesarian section by increasing
species diversity of the Bifidobacteria in the intestines of the
infant, comprising: (a) identifying an infant delivered via
caesarean section and suffering from low intestinal Bifidobacteria
counts and/or lacking adequate species diversity of Bifidobacteria;
and (b) feeding the infant, a composition comprising: (i) a
Bifidobacterium consisting of Bifidobacterium breve, and (ii) at
least non-digestible galacto-oligosaccharides; wherein the
composition is not human breast milk, and wherein the
administration increases the amount of intestinal Bifidobacterium
breve and other Bifidobacterium species.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Continuation of patent application
Ser. No. 12/091,047, filed as the National Phase of International
Patent Application No. PCT/NL2006/050248, filed Oct. 6, 2006,
published as WO 2007/046699 A2, which claims priority to European
Application No. 05023029.1, filed Oct. 21, 2005. The contents of
these applications are herein incorporated by reference in their
entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to methods for feeding and
therapy infants delivered via caesarean section.
BACKGROUND OF THE INVENTION
[0003] Infants have an immature intestine at birth. After birth,
the neonatal gastro-intestinal tract undergoes rapid growth and
maturation, including mucus formation and maturation and closing of
tight junctions to allergens, toxins and pathogenic
micro-organisms. In human milk several factors are present which
improve gut maturation.
[0004] A permeable, immature intestinal barrier plays a role in the
acquirement of intestinal inflammation, infections, diarrhea, and
atopic diseases including food allergy. A properly maturing
intestine, especially in combination with a healthy intestinal
flora, results in a reduced incidence of infections, a strengthened
immune system, a reduced incidence of food allergy and/or other
atopic diseases, and/or a reduced incidence of diarrhea,
constipation and/or intestinal inflammation.
[0005] Intestinal permeability decreases faster in breast-fed
babies than in formula-fed infants. However, not always is
breast-feeding realizable.
[0006] W02004112509 describes a composition for inducing a pattern
of intestinal barrier maturation similar to that observed with
breast-feeding and able to improve intestinal barrier maturation,
e.g. during neonatal stress.
[0007] W02005122790 describes a method for stimulating barrier
integrity in a mammal by administering to a mammal a composition
comprising: cicosapentacnoic acid (EPA), docosahexaenoic acid (DHA)
and arachidonic acid (ARA), and at least two distinct
oligosaccharides.
[0008] EP1549158 describes infant formula compositions which
comprise 3.2 mg/L to 15.4 mg/L of CMP; 1.8 mg/L to 11.0 mg/L of
UMP; 1.8 mg/L to 8.0 mg/L of GMP; 0.1 mg/L to 2.2 mg/L of IMP; and
2.5 mg/L to 13.2 mg/L of AMP
[0009] W003043445 describes processed baby foods which are
formulated with a) oils, b) nucleotides, c) oils and
nucleotides.
[0010] Natren.RTM. produces the probiotic product Life Start.RTM.
which is designed specifically for infants and suitable for infants
delivered via caesarean section. Life Start.RTM. is made with
Bifidobacterium infantis. Because the Life Start.RTM. product
contains only one single Bifidobacteria species, the benefits for
the infant will be very limited.
SUMMARY OF THE INVENTION
[0011] The present inventors have found that infants delivered via
caesarean section have an intestinal flora which is different from
the intestinal flora of infants born via the vaginal route.
Particularly, infants born via caesarean section have a reduced
rate of intestinal colonization by Bifidobacteria and have a less
diverse Bifidobacterium intestinal flora regarding species than
infants born via the vaginal route, particularly missing
Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium
infantis and Bifidobacterium bifidum. It was further found that the
intestinal flora of infants delivered via caesarean section have a
lower content of Bifidobacteria compared to the intestinal flora of
infants delivered vaginally. Additionally it was found that the
intestinal flora of infants born via caesarean section has a high
content of (undesirable) Escherichia coli 6 weeks after
delivery.
[0012] A healthy and fully developed gastrointestinal flora has
important physiological effects. One important aspect is that it
reduces the occurrence of (gastrointestinal) infections. Because
infants delivered via a caesarean section lack a healthy flora,
preventing infection is particularly important for these infants.
These infants are normally delivered in a hospital environment,
which is a risk for pathogenic infection due to the occurrence of
nosocomial bacteria. Additionally, the impaired development of a
healthy intestinal flora results in faster colonization of
pathogenic bacteria compared to a situation where the infants
intestinal tract is inoculated by maternal bacteria originating
from the mother's vaginal and fecal flora. In order to prevent
bacterial trans location or translocation of bacterial (eno- or
exo) toxins across the intestinal barrier of these (nosocomial)
pathogens, it is of utmost importance to improve and/or accelerate
intestinal maturation in caesarean section delivered infants.
[0013] Improvement of the intestinal barrier maturation and/or
barrier integrity in caesarean section delivered infants
furthermore reduces the incidence of intestinal inflammation, food
allergy and/or other atopic diseases.
[0014] The inventors have recognized that the barrier function of
babies born via caesarean section is impaired and found that
long-chain polyunsaturated fatty acids (LC-PUFA) and/or nucleotides
improve the maturation and integrity of the intestinal barrier,
and/or have an anti-inflammatory effect in babies delivered via
caesarean section. LC-PUFA furthermore promote the adhesion of
lactic acid producing bacteria to mucosal surfaces. Hence, the
present invention concerns the use of compositions comprising
LC-PUFA and/or nucleotide that particularly aim to a) decrease the
incidence of infections by increasing intestinal barrier integrity
and/or maturation, b) decrease the incidence of (food) allergy
and/or atopic diseases by increasing intestinal barrier integrity
and/or maturation, c) dampen or subdue intestinal inflammatory
processes that otherwise would further increase intestinal barrier
permeability, and/or d) improve the flora by increasing
colonization of lactic acid producing bacteria to mucosal surfaces
in infants delivered by caesarean section.
[0015] In a further aspect the present invention can be suitably
brought to practice by incorporation of the present active
ingredients in a nutritional composition. Such composition can be
administered to the infant without posing a heavy burden on the
infant delivered via caesarean section.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0016] The present invention provides the use of a composition
comprising (i) long chain polyunsaturated fatty acid (LC-PUFA);
and/or (ii) at least one selected from the group consisting of (a)
nucleotide and (b) nucleotide precursor selected from the group
consisting of nucleosides, purine bases, pyridine bases, ribose and
deoxyribose for the manufacture of a composition for administration
to an infant delivered via caesarean section. In a further aspect
the present method provides the use of a composition comprising (i)
long chain polyunsaturated fatty acid (LC-PUFA); and/or (ii) at
least one selected from the group consisting of (a) nucleotide and
(b) nucleotide precursor selected from the group consisting of
nucleosides, purine bases, pyridine bases, ribose and deoxyribose
for the manufacture of a composition for i) treatment and/or
prevention of disorders in infants delivered via caesarean section
and/or ii) the stimulation of health in infants delivered via
caesarean section.
[0017] The present invention also provides a method for feeding an
infant delivered via caesarean section, said method comprising
administering to said infant a composition comprising (i) long
chain polyunsaturated fatty acid (LC-PUFA) and/or (ii) at least one
selected from the group consisting of (a) nucleotide and (b)
nucleotide precursor selected from the group consisting of
nucleosides, purine bases, pyridine bases, ribose and
deoxyribose.
Caesarean Section
[0018] A caesarean section (c-section) is a surgical procedure
where an infant is delivered through an incision made in the
mother's abdominal wall, and then through the wall of the uterus. A
caesarean section is usually performed when it is safer for the
mother or the infant than a vaginal delivery. Other times, a woman
may choose to have a caesarean section rather than deliver her
infant vaginally.
Long-Chain Polyunsaturated Fatty Acids
[0019] Throughout this description, the composition as used in the
method according to the present invention is often referred to as
the "present composition". The present composition preferably
comprises long chain polyunsaturated fatty acids (LC-PUFA).
LC-Pl.JFA are fatty acids wherein the acyl chain has a length of 20
to 24 carbon atoms (preferably 20 or 22 carbon atoms) and wherein
the acyl chain comprises at least two unsaturated bonds between
said carbon atoms in the acyl chain. More preferably the present
composition comprises at least one LC-PUFA selected from the group
consisting of eicosapentaenoic acid (EPA, 20:5 n3), docosahexaenoic
acid (DHA, 22:6 n3), arachidonic acid (ARA, 20:4 n6) and
docosapentaenoic acid (DPA, 22:5 n3). EPA, DHA and ARA were found
to effectively reduce intestinal tight junction permeability (see
example 2). Reduced tight junction permeability reduces the
occurrence of infection and/or reduces passage of allergens and/or
reduces passage of bacterial (endo- or exo) toxins. Hence
incorporation of LC-PUFA, preferably EPA, DHA, DPA and/or ARA, in
the present composition improves intestinal barrier integrity,
which is of utmost important for babies delivered via a caesarean
section since these babies have a less developed intestinal flora
and hence a slower maturing intestinal barrier. LC-PUFA further
have anti-inflammatory effects and promote the adhesion of lactic
acid producing bacteria to mucosal surfaces, thereby stimulating
the development of a healthy flora, which are further advantages
for use in caesarean section delivered infants.
[0020] Since a low concentration of ARA, DHA, DPA and/or EPA is
already effective in reducing tight junction permeability, the
content of LC-PUFA in the present composition, which is preferably
a nutritional composition, preferably does not exceed 15 wt. % of
the total fat content, preferably does not exceed 10 wt. %, even
more preferably does not exceed 5 wt. %. Preferably the present
composition comprises at least 0.1 wt. %, preferably at least 0.25
wt. %, more preferably at least 0.5 wt. %, even more preferably at
least 0.75 wt. % LC-PUFA of the total fat content. For the same
reason, the EPA content preferably does not exceed 5 wt. % of the
total fat, more preferably does not exceed 1 wt. %, but is
preferably at least 0.025 wt. %, more preferably at least 0.05 wt.
% of the total fat. The DHA content preferably does not exceed 5
wt. %, more preferably does not exceed 1 wt. %, but is at least 0.1
wt. % of the total fat. As ARA was found to be particularly
effective in reducing tight junction permeability, the present
composition comprises relatively high amounts, preferably at least
0.1 wt. %, even more preferably at least 0.25 wt. %, most
preferably at least 0.35 wt. % ARA of the total fat. The ARA
content preferably does not exceed 5 wt. %, more preferably does
not exceed 1 wt. % of the total fat. When the present enteral
composition comprises ARA, EPA and DHA are advantageously added to
balance the action of ARA, e.g. reduce the potential
pro-inflammatory action of ARA metabolites. Excess metabolites from
ARA may cause inflammation. Hence, the present composition
preferably comprises ARA, EPA and DHA, wherein the weight ratio
ARA/DHA preferably is above 0.25, preferably above 0.5, even more
preferably above 1. The ratio ARA/DHA is preferably below 25, more
preferably below 15. The weight ratio ARA/EPA is preferably between
1 and 100, more preferably between 5 and 20.
[0021] In order to mimic human breast milk as closely as possible
and to reduce side effects of high dosages of LC-PUFA, in the
present composition the content of LC-PUFA, preferably does not
exceed 3 wt. % of the total fat content. The content of n3 (omega
3) LC-PUFA preferably is below 1 wt. % of the total fat content.
The n6 (omega 6) LC-PUFA preferably is preferably below 2 wt. % of
the total fat content. The ARA content is preferably below 1 wt. %
of the total fat content. The weight ratio EPA!DHA preferably is 1
or below.
[0022] The LC-PUFA may be provided as free fatty acids, in
triglyceride form, in diglyceride form, in monoglyceride form, in
phospholipid form, or as a mixture of one of more of the above,
preferably in triglyceride form. The present composition preferably
comprises at least one of ARA and DHA in phospholipid form.
Nucleotides
[0023] In a preferred embodiment the present composition comprises
nucleotide and/or nucleotide precursors selected from the group
consisting of nucleoside, purine base, pyridine base, ribose and
deoxyribose. More preferably the composition comprises nucleotide.
The nucleotide is preferably in the monophosphate, diphosphate or
triphosphate form, more preferably a nucleotide monophosphate. The
nucleotide preferably is a ribonucleotide or a deoxyribonucleotide,
more preferably a ribonucleotide. The nucleotides can be monomeric,
dimeric or polymeric (including RNA and DNA). The nucleotides
preferably are present as a free acid or in the form of a salt,
more preferably monosodium salt. Incorporation of nucleotide in the
present composition improves intestinal barrier integrity and/or
maturation, which is of utmost importance for babies delivered via
a caesarean section since these babies have a less developed
intestinal flora and hence a slower maturing intestinal barrier.
Preferably, the composition comprises one or more selected form the
group consisting of cytidine 5'-monophospate (CMP), uridine
5'-monophospate (UMP), adenosine 5'-monophospate (AMP), guanosine
5'-monophospate (GMP), and inosine 5'-monophospate (IMP) and/or
salts thereof, in particular monosodium salts thereof, more
preferably at least 3 selected form the group consisting of CMP,
UMP, AMP, GMP and IMP and/or salts thereof, in particular
monosodium salts thereof. An increased diversity of nucleotides can
further improve barrier integrity.
[0024] Preferably the composition comprises 5 to 100 mg, more
preferably 5 to 50 mg, most preferably 10 to 25 mg nucleotides per
100 gram dry weight of the present composition. The nucleotides
further stimulate the immune system thereby enhancing protection
against a high load of intestinal pathogens such as E. coli.
[0025] Preferably the present composition comprises 1 to 20 mg,
more preferably 3 to 12.5 mg CMP per 100 g dry weight of the
composition. Preferably the composition comprises 1 to 20 mg, more
preferably 2 to 9 mg UMP per 100 g dry weight of the composition.
Preferably the present composition comprises 0.5 to 15 mg, more
preferably 1.5 to 8 mg AMP per 100 g dry weight of the present
composition. Preferably the composition comprises 0.2 to 10 mg,
more preferably 0.6 to 3 mg GMP per 1 00 g dry weight of the
composition. Preferably the present composition comprises 0.5 to 10
mg, more preferably 1.3 to 5 mg IMP per 100 g dry weight of the
composition.
[0026] Preferably the present composition comprises both (i)
LC-PUFA and (ii) nucleotide and/or nucleotide precursor selected
from the group consisting of nucleosides, purine bases, pyridine
bases, ribose and deoxyribose, since a combination of these
components unexpectedly improve gut barrier function, immune system
and/or intestinal flora, e.g. a synergistic effect is
envisaged.
Non-Digestible Oligosaccharides
[0027] The present composition preferably comprises non-digestible
oligosaccharides which are fermented into organic acids (preferably
lactic acid, butyrate, propionate and/or acetate) and stimulate the
growth of the intestinal lactic acid producing bacteria
(hereinafter referred to as "non-digestible saccharides").
Preferably the growth Bifidobacteria and/or Lactobacilli is
stimulated. An increased content of Bifidobacteria and/or
Lactobacilli stimulate the formation of a healthy intestinal flora.
Additionally, the formed organic acids stimulate mucus production
and therefore further decrease intestinal barrier permeability in
infants delivered by caesarean section (see Example 3, below). The
non-digestible oligosaccharides also enhance the effectiveness of
the LC-PUFA and/or nucleotide in the present composition, as
co-administration of the non-digestible oligosaccharides with the
LC-PUFA and/or nucleotide causes a delay in absorption of the
LC-PUFA and/or nucleotide in the small intestine, thereby
prolonging and/or increasing the effects of the LC-PUFA and/or
nucleotide in the colon. Advantageously, the present composition
comprises non-digestible oligosaccharides preferably with a degree
of polymerization (DP) of 2 to 250, more preferably 2 to 100, more
preferably 2 to 10.
[0028] The present composition preferably contains non-digestible
oligosaccharide with a degree of polymerization (DP) below 60, more
preferably below 40, even more preferably below 20, most preferably
below 10. Short chain non-digestible oligosaccharides provide an
improved lactate and/or acetate production, stimulating the barrier
integrity in the infant born via caesarean section. The
non-digestible oligosaccharides are preferably not or only
partially digested in the intestine by the action of acids or
digestive enzymes present in the human upper digestive tract (small
intestine and stomach) and arc fermented by the human intestinal
flora. For example, sucrose, lactose, maltose and the maltodextrins
are considered digestible.
[0029] Preferably the present composition comprises at least one
non-digestible oligosaccharide selected from the group consisting
of fructo-oligosaccharides (including inulins), non-digestible
dextrins, galacto-oligosaccharides (including
transgalacto-oligosaccharides), xylo-oligosaccharidcs,
arabino-oligosaccharidcs, arabinogalacto-oligosaccharides,
gluco-oligosaccharides (including cyclodextrins and
gentio-oligosaccharides), chito-oligosaccharides,
glucomanno-oligosaccharides, galactomanno-oligosaccharidcs,
mannan-oligosaccharides, fuco-oligosaccharides, galacturonic acid
oligosaccharides, guluronic acid oligosaccharides, mannuronic acid
oligosaccharides, iduronic acid oligosaccharides, riburonic acid
oligosaccharides, glucuronic acid oligosaccharides and mixtures
thereof, more preferably fructo-oligosaccharides,
galacto-oligosaccharides (including transgalacto-oligosaccharides),
fuco-oligosaccharidcs and galacturonic acid oligosaccharides and
mixtures thereof, even more preferably galacto-oligosaccharides
and/or inulin, most preferably transgalacto-oligosaccharides.
[0030] The present non-digestible oligosaccharide is preferably
selected from the group consisting of galacto-oligosaccharides and
fructo-oligosaccharides (e.g. inulin).
[0031] Preferably at least 50 wt. % of the present non-digestible
oligosaccharides have a degree of polymerization of 2 to 60. In a
particular preferred embodiment the present composition comprises
at least galacto-oligosaccharides and fructo-oligosaccharides. The
galacto-oligosaccharides preferably comprise saccharides with a DP
of 2 to 10. The fructo-oligosaccharides preferably comprise
saccharides with a DP of 2 to 60. Preferably, the
galacto-oligosaccharide comprises beta bonds, as is the case in
human milk oligosaccharides.
[0032] In a preferred embodiment the present composition comprises
galacturonic acid oligosaccharides. The galacturonic acid
oligosaccharides of the invention advantageously reduce the
adhesion of pathogenic micro-organisms to the intestinal epithelial
cells, thereby reducing colonization of (nosocomial) pathogenic
bacteria in the colon of the infant delivered by caesarean section.
Furthermore, the galacturonic acid oligosaccharides of the present
invention stimulate the formation of a healthy intestinal flora and
arc fermented, resulting in a production of intestinal organic
acids and a reduction of intestinal pH, which inhibit the growth of
(nosocomial) pathogenic bacteria. The co-administration of
galacturonic acid oligosaccharides therefore further improves
protection for the infant delivered via caesarean section from
infections due to the underdeveloped barrier function and/or
underdeveloped intestinal bacterial flora.
[0033] The term galacturonic acid oligosaccharide as used in the
present invention preferably refers to an oligosaccharide wherein
at least 50% of the monosaccharide units present in the
oligosaccharide are galacturonic acid. The present composition
preferably comprises galacturonic acid oligosaccharide with a DP
between 2 and 250, preferably 2 and 50, more preferably 2 and 20.
The galacturonic acid oligosaccharides used in the invention are
preferably prepared from pectin, pectate, and/or polygalacturonic
acid. The galacturonic acid oligosaccharide is preferably derived
from pectin. Preferably the pectin oligosaccharide is prepared by
hydrolysis and/or beta-elimination of fruit pectin and/or vegetable
pectin, more preferably from apple, citrus and/or sugar beet
pectin, more preferably the apple, citrus and/or sugar beet pectin
has been treated by at least a lyase. Preferably the pectin lysate
and/or the galacturonic acid oligosaccharide is prepared from
bacterial production.
[0034] In a preferred embodiment, at least one of the terminal
hexuronic acid units of the galacturonic acid oligosaccharide has a
double bond, which is preferably situated between the C4 and Cs
position of the terminal hexuronic acid unit. The double bond
effectively protects against attachment of pathogenic bacteria to
intestinal epithelial cells. This is advantageous for infants
delivered by caesarean section. Preferably at least 5%, more
preferably at least 10%, even more preferably at least 25% of the
terminal hexuronic acid units of the galacturonic acid
oligosaccharide is an unsaturated hexuronic acid unit As each
individual galacturonic acid oligosaccharide preferably comprises
only one unsaturated terminal hexuronic acid unit, preferably less
than 50% of the terminal hexuronic acid units is an unsaturated
hexuronic acid unit (i.e. comprises a double bond).
[0035] The present composition preferably comprises between 0.01
and 10 grams galacturonic acid oligosaccharide with a DP of 2 to
250 per 100 gram dry weight of the composition, more preferably
between 0.05 and 6 gram, even more preferably 0.2 to 2 gram.
Preferably the present composition comprises between 0.01 and 10
grams galacturonic acid oligosaccharide with a DP of 2 to 25 per
100 gram dry weight of the nutritional composition, more preferably
between 0.05 and 6 gram, even more preferably 0.2 to 2 gram. The
short chain galacturonic acid oligosaccharides are more effective
and/or better suitable for inclusion in the present
composition.
[0036] Preferably, the composition comprises (i)
galacto-oligosaccharides, (ii) fructo-oligosaccarides and (iii)
galacturonic acid oligosaccharidcs. This combination is
particularly suitable for protection the infants delivered via
caesarean section as it provides an optimal stimulation of the
Bifodobacteria and/or Lactobacilli and reduces adherence of
pathogenic organisms and reduces colonization by and/or adherence
of potential pathogenic bacteria such as E. coli.
Lactic Acid Producing Bacteria
[0037] The present composition preferably comprises lactic acid
producing bacteria, either living or dead. Dead bacteria can for
example be prepared by inactivating living bacteria by heat
treatment and/or sonication. Living lactic acid bacteria are
advantageously incorporated to stimulate fast colonization of the
infant's intestinal tract. Lactic acid producing bacteria are
preferably provided as a mono- or mixed culture of live
microorganisms. The present composition preferably comprises
10.sup.2 to 10.sup.13 colony forming units (cfu) of lactic acid
producing bacteria per gram dry weight of the present composition,
preferably 10.sup.2 to 10.sup.12 cfu, more preferably 10.sup.5 to
10.sup.10 cfu, most preferably from 10.sup.4 to 5.times.10.sup.9
cfu.
[0038] Preferably the present composition comprises bacteria of the
genus Lactobacillus and/or Bifidobacterium. Preferably the
composition comprises at least one Bifidobacterium selected from
the group consisting of B. longum, B. breve, B. infantis, B.
catenulatum, B. pseudocatenulatum, B. adolescentis, B. animalis, B.
gallicum, B. lactis and B. bifidum, more preferably at least one
Bifidobacterium selected from the group consisting of B. breve, B.
infantis, B. bifidum, B. catenulatum, B. longum, even more
preferably at least one Bifidobacterium selected from the group
consisting of B. breve and B. longum, most preferably B. breve.
Preferably the composition comprises at least two different
Bifidobacterium species, subspecies or strains. The present
composition preferably comprises at least one, more preferably at
least two, even more preferably at least three, most preferably at
least four different Bifidobacterium species. The present
composition preferably comprises at least one, more preferably at
least two, even more preferably at least three, most preferably at
least four different Bifidobacterium strains. The above-mentioned
combinations commonly aim to increase the diversity and/or the
quantity of microorganisms in the intestine of the caesarean
section delivered infant. This beneficially affects the infant,
providing various health benefits.
[0039] Preferably the present composition contains a Lactobacillus
selected from the group consisting of L. casei, L. reuteri, L
paracasei, L. rhamnosus, L. acidophilus, L. johnsonii, L. lactis,
L. salivarius, L. crispatus, L. gasseri, L. zeae, L. fermentum and
L. plantarum, more preferably L. casei, L. paracasei, L. rhamnosus,
L. johnsonii, L. acidophilus, L. fennentum and most preferably L.
paracasei. Even more preferably the present composition comprises
Bifidobacterium breve and/or Lactobacillus paracasei, because the
growth of these bacteria in impaired in the intestine of cesarean
delivered infants. The further increased biodiversity will have a
stimulatory effect on health of the newborn delivered by caesarean
section.
Formulae
[0040] The present composition is preferably enterally
administered, more preferably orally. The present composition is
preferably an infant formula. The present composition is preferably
a synthetic formula, prepared by admixing different ingredients.
The present composition is not a naturally (non-treated) occurring
mammalian milk, e.g. not human breast milk. The present composition
can be advantageously used as a complete nutrition for infants. The
present composition preferably comprises lipid, protein and
carbohydrate and is preferably administered as a liquid food. The
term "liquid food" as used in the present invention includes dry
food (e.g. powders) which are accompanied with instructions so as
to admix said dry food mixture with a suitable liquid (e.g.
water).
[0041] The present composition preferably provides nutrition to the
infant, and comprises a lipid component, a protein component and a
carbohydrate component. The lipid component preferably provides 5
to 50% of the total calories, the protein component preferably
provides 5 to 50% of the total calories, and the carbohydrate
component preferably provides 15 to 90% of the total calories. The
present composition is preferably used as an infant formula,
wherein the lipid component provides 35 to 50% of the total
calories, the protein component provides 7.5 to 12.5% of the total
calories, and the carbohydrate component provides 40 to 55% of the
total calories. For calculation of the % of total calories for the
protein component, the total of energy provided by the proteins,
peptides and amino acids needs to be taken.
[0042] Preferably the lipid component comprises a combination of at
least one lipid selected from the group consisting of vegetable
lipids and animal lipids and at least one oil selected from the
group consisting of fish, animal, vegetable, algae, fungal and
bacterial oil. Preferably, the lipid comprises at least 12 mg/100
kcal .alpha..-linolenic acid (ALA). Preferably the lipid
composition has a wt/wt ratio of linoleic acid (LA) and ALA between
5 and 15, more preferably 5 to 10. Preferably the amount of trans
fatty acids is below 4 wt. % based on total lipid. A high content
of trans fatty acids compromises the intestinal barrier.
[0043] The protein component used in the present composition
preferably comprises at least one selected from the group
consisting of non-human animal proteins (such as milk proteins,
meat proteins and egg proteins), vegetable proteins (such as soy
protein, wheat protein, rice protein, potato protein and pea
protein), free amino acids and mixtures thereof. Cow's milk derived
nitrogen source, particularly cow milk protein proteins such as
casein and whey proteins are particularly preferred. Preferably the
protein component comprises intact proteins, more preferably intact
bovine whey proteins and/or intact bovine casein proteins. As the
present composition is suitably used to reduce the allergic
reaction in an infant, the protein of the infant formula is
preferably selected from the group consisting of hydrolyzed milk
protein (e.g. hydrolyzed casein and/or hydrolyzed whey protein),
vegetable protein and/or amino acids. The use of these hydrolyzed
proteins further reduces the allergic reactions of the infant. The
use of these hydrolyzed proteins advantageously improves the
absorption of the dietary protein component by the immature
intestine of caesarean delivered infants.
[0044] Preferably the composition comprises digestible
carbohydrates. The digestible carbohydrates used in the present
composition arc preferably selected from the group consisting of
sucrose, lactose, glucose, fructose, corn syrup solids, starch and
maltodextrins, and mixtures thereof, more preferably lactose.
[0045] Stool irregularities (e.g. hard stools, insufficient stool
volume, diarrhea) are a major problem in many babies, including
especially caesarean section delivered infants. It was found that
stool problems may be reduced by administering the present LC-PUFA
in liquid food. The present composition preferably has an
osmolality between 50 and 500 mOsm/kg, more preferably between 100
and 400 mOsm/kg. In view of the above, it is also important that
the liquid food does not have an excessive caloric density, however
still provides sufficient calories to feed the subject. Hence, the
liquid food preferably has a caloric density between 0.1 and 2.5
kcal/ml, even more preferably a caloric density of between 0.5 and
1.5 kcal/ml, most preferably between 0.6 and 0.8 kcal/ml.
Application
[0046] The present invention provides a method for feeding an
infant delivered via caesarean section, said method comprising
administering the present composition comprising (i) LC-PUFA;
and/or (ii) nucleotide and/or nucleotide precursor selected from
the group consisting of nucleosides, purine bases, pyridine bases,
ribose and deoxyribose to said infant.
[0047] The present invention also provides a method for i)
stimulating the health of an infant delivered via caesarean
section, and/or ii) treatment and/or prevention of a disorder in
infants delivered via caesarean section comprising administering
the present composition to the infant. The disorders are preferably
selected from the group consisting of intestinal disorders caused
by a flora low in bifidobacteria content. Preferably the disorder
is selected from the group consisting of infection and atopic
disease. The present composition is preferably administered to the
infant delivered via caesarean section in the first year of life,
preferably within 3 months after birth, even more preferably within
two weeks after birth, even more preferably within 100 hours, more
preferably within 72 hours, most preferably within 48 hours after
birth.
[0048] The present composition can be advantageously used for
stimulating the maturation of the intestinal barrier; decreasing
intestinal barrier permeability and/or stimulating the immune
system. The present method preferably comprises the steps a)
admixing (i) a nutritionally or pharmaceutically acceptable liquid;
and (ii) a dry composition, wherein the dry composition (ii)
comprises LC-PUFA and/or nucleotides, preferably LC-PUFA and
nucleotides; and step b) administering the composition obtained in
step a) to an infant born via caesarean section.
[0049] Administration of a composition comprising LC-PUFA and/or
nucleotide results in a decreased translocation of (nosocomial)
pathogenic micro-organisms, such as Eschericia coli, other
Gram-negative species belonging to the genera Aeromonas,
Klebsiella, Enterobacter, Pseudomonas, Proteus, and Acinetobacter
and Gram positive species such as Enterococcus, Staphylococcus,
Streptococcus, Bacillus, and Clostridium, viruses and/or fungi,
preferably Escherichia coli (E. coli). Hence, the present
composition is preferably used in a method for treatment and/or
prevention of infection and/or diarrhea in infants delivered by
caesarean section, said method comprising administering the present
composition to an infant delivered by caesarean section. In a
preferred embodiment the present composition is used for the
treatment and/or prevention of infection caused by Eschericia coli,
Aeromonas, Klebsiella, Enterobacter and/or Pseudomonas, more
preferably E. coli.
[0050] Administration of the present composition comprising LC-PUPA
and/or nucleotides and/or nucleotide precursors results in a
decreased translocation of allergens across the intestinal barrier.
Hence, the present composition is preferably used in a method for
treatment or prevention of allergy, preferably food allergy, atopic
eczema (e.g. atopic dermatitis), asthma, allergic rhinitis and/or
allergic conjunctivitis in infants delivered by caesarean section,
said method comprising administering said composition to an infant
delivered by caesarean section. Preferably the present composition
is used for the treatment and/or prevention of atopic
dermatitis.
[0051] Furthermore, administration of the present composition
strengthens the immune system. Hence, the present composition
comprising LC-PUFA and/or nucleotides and/or nucleotide precursors
is advantageously used in a method for treatment and/or prevention
of systemic infections and/or inflammation in infants delivered by
caesarean section. In a preferred method, the present composition
is used for the treatment and/or prevention of, necrotizing
enterocolitis.
[0052] In this document and in its claims, the verb "to comprise"
and its conjugations is used in its non-limiting sense to mean that
items following the word are included, but items not specifically
mentioned are not excluded. In addition, reference to an element by
the indefinite article "a" or "an" does not exclude the possibility
that more than one of the element is present, unless the context
clearly requires that there be one and only one of the elements.
The indefinite article "a" or "an" thus usually means "at least
one".
EXAMPLES
Example 1
Molecular Characterization of Intestinal Microbiota in Infants Born
by Vaginal Delivery Vs. Caesarean Delivery
[0053] In the present study the influence of mode of delivery
(caesarean delivery versus vaginal delivery) on the intestinal
microbial composition at the third day of life was studied using by
PCR amplification with species-specific primers for ten
Bifidobacterium species, three Ruminococcus species and one
Bacteroides species.
[0054] The microbial DNA was extracted and analysed according to
Favier et al, Environ Microbial 2002; 68:219-226 and Satokari et
al, Appl Environ Microbiol 2001; 67:504-513; Satorkari et al System
Appl Microbiol 2003; 26:572-584.
[0055] The results of the Bifidobacterium and other species
detected in faecal samples of 21 newborns after caesarean delivery
obtained at the 3rd day of life are given in Table 1:
[0056] Table 2 gives the Bifidobacterium and other species detected
in faecal samples of 21 newborns after vaginal delivery obtained at
the 3rd day of life. No signal specific for the species B. dentium,
B. angulatum, B. lactis, Ruminococcus bromii, Ruminococcus callidus
and Ruminococcus obeum was observed in the faeces of infants
delivered by caesarean section as well as in the faeces of
vaginally delivered infants.
TABLE-US-00001 TABLE 1 Caesarean secton delivered infants B. B. B.
B. catenu- B. B. B. Bacteroides NEWBORN breve infantis bifidum
latum group adolescentis longum gallicumm fragilis 1 - - - - - - -
- 2 - - - - - ++ - - 3 - - - - - - - - 4 - - - - - - - - 5 - - - -
- - - - 6 - - - - - - - - 7 - - - - - - - - 8 - - - - - - - - 9 - -
- - - - - - 10 - - - - - - ++ - 11 - - - - - - - - 12 - - - - - - -
- 13 - - - - - - - - 14 - - - - - - - - 15 - - - - - - - - 16 - - -
- - - - - 17 - - - - - - - - 18 - - - - - - - - 19 - - - - - - - -
20 - - - - - - - - 21 - - - - - - - - 22 - - - - - - - - 23 - - - -
- - - - (-) = no amplification; (+/-) = weak amplification; (+) =
positive amplification; (++) = strong amplification
[0057] It can be concluded that the microbial flora of an infant
born via caesarean section differs from that or an infant born via
the vaginal route. Not only is the amount of bifidobacieria and
other species quantitatively much lower, also on a species level
the flora of caesarean section delivered infants is less diverse.
Since Bifidobacterium is the dominant genus in infant's flora these
results are generalised to less intestinal bacteria and a less
diverse intestinal flora in caesarean section delivered infants,
leaving the intestine more susceptible to colonisation by
(nocosomial) pathogens.
[0058] These results are indicative for the advantageous use of the
composition and method according to the present invention, e.g. a
method for feeding babies born via caesarean section in order to
decrease effects of intestinal pathogens and stimulate a healthy
intestinal flora and consequently prevent infection, stimulate a
healthy immune system and stimulate intestinal maturation, in
particular in infants delivered by caesarean section.
TABLE-US-00002 TABLE 2 Vaginally delivered infants B. B. B. B.
catenu- B. B. B. Bacteroides NEWBORN breve infantis bifidium latum
group adolescentis longum gallicum fragitis 1a - + - - - ++ - - 2a
+/- - ++ ++ - ++ - - 3a - - - + - - - - 4a +/- - - ++ + + - - 5a
+/- - ++ ++ - ++ ++ - 6a - - +/- ++ - ++ - - 7a - - +/- ++ - - - -
8a ++ ++ - + ++ - - - 9a - - - + ++ + - - 10a ++ - - + ++ - - - 11a
++ - ++ ++ - ++ - + 12a + + + + - ++ - + 13a +/- - - + - + - - 16a
- - - ++ - + - - 17a +/- - + + - + - - 18a +/- - + + - + - - 19a +
- - + - + - - 20a - - - + - + - - 21a - - - + ++ + - - 22a - + - ++
- + - - 23a + - ++ ++ - + - - (-) = no amplification; (+/-) = weak
amplification; (+) = positive amplification; (++) = strong
amplification
Example 2
Effect of LC-PUFA on Barrier Integrity
[0059] Monolayers (MC) of intestinal epithelial cell lines T84 were
incubated in the luminal compartment with different 100 .mu.M
polyunsaturated fatty acids ARA (arachidonic acid;
5,8,11,14-eicosatetraenoic acid), DHA (cis-4,7,10,13,16,19
docosahexaenoic acid), EPA (eicosapentaenoic acid) or control
palmiiic (C 16:0) acid (Palm) (Sigma, St. Louis, USA) for 0, 24, 48
and 72 hr. The epithelial barrier function was determined by
measuring the transepithelial resistance (TER, .OMEGA.cm.sup.2) by
epithelial volt-ohm meter (EVOM; World Precision Instruments,
Germany) and permeability for 4 kD FITC dextran (paracellular
permeability marker, Sigma, USA).
[0060] Results of the effect of fatty acids (100 .mu.M) on
spontaneous barrier integrity after 72 hr incubation are given in
Table 3. Table 3 shows that the LC-PUFA's ARA, EPA and DHA reduce
the molecular flux and improve epithelial resistance. In contrast
the control palmitic acid has the opposite effects, i.e.
compromises barrier integrity. These results are indicative for the
advantageous use of EPA, DHA and ARA, and in particularly ARA in
the composition according to the present invention and for use in a
method according to the present invention, e.g. in a method for
improving barrier integrity in infants delivered by caesarean
section. Also gamma-linolenic acid (GLA) showed a positive effect
on basal barrier integrity resistance and flux.
TABLE-US-00003 TABLE 3 Ingredient (LC-PUFA) Flux Resistance (TER)
Control 79 1090 Palmitic acid 161 831 DHA 72 1574 ARA 28 1816 EPA
65 1493
Example 3
Effect of LC-PUFA on IL-4 Mediated Barrier Disruption
[0061] Monolayers (MC) of intestinal epithelial cell lines T84 were
incubated in the presence of IL-4 (2 ng/ml, scrosal compartment,
Sigma, USA) with or without polyunsaturated fatty acids ARA, DHA,
GLA, EPA, or control palmitic acid (10 .mu.M or 100 .mu.M, mucosal
compartment, Sigma, St. Louis, USA). Cells were pre-incubated with
ARA, DHA, EPA, or palmitic acid for 48 hr prior to the IL-4
incubation. The co-incubation of PUFA's and palmitic acid with IL-4
was continued for another 48 hr, while culture medium and additives
were changed every 24 hr. The epithelial barrier function was
determined by measuring the transepithelial resistance (TER) and
permeability as described in example 2.
[0062] Results of the effect of ARA, DHA, EPA and palmitic acid
(100 .mu.M) on IL-4 mediated barrier disruption are given in Table
4. Table 4 shows that the LC-PUFA's ARA, DHA and EPA inhibit the
increased flux caused by IL-4. In contrast palmitic acid had a
detrimental effect and decreased barrier disruption compared to
control. These results are indicative for the advantageous use of
ARA, DHA, and EPA in clinical and infant nutrition formulations to
prevent or reduce IL-4 mediated barrier disruption, e.g. as occurs
in food or cows milk allergy. These results are indicative for the
advantageous use of EPA, DHA and ARA, and in particularly ARA in
the composition according to the present invention and for use in a
method according to the present invention, particularly in a method
for treatment and/or prevention of allergy, atopic eczema, asthma,
allergic rhinitis, and/or allergic conjunctivitis in infants
delivered by caesarean section.
TABLE-US-00004 TABLE 4 Ingredient (LC-PUFA) IL-4 Flux IL-4 TER
Control 582 374 Palmitic acid 777 321 DHA 271 547 ARA 218 636 EPA
228 539
Example 4
Flora of Caesarean Section Delivered Infants
[0063] The bifidobacterial content in the feces of infants
delivered via caesarean section was determined. The percentage of
the genus Bifidobacterium as a total of total bacteria in the first
week was 4.3% in caesarean section delivered infants (n=44) versus
19.8% in vaginally delivered infants (n=28). The percentage E. coli
was still 11.8% after 6 weeks when the infants were fed an normal
diet. (see Table 5).
TABLE-US-00005 TABLE 5 Bifidobacteria E. coli Infants first week
(%) Week 6 (%) Vaginal delivery 19.8 C-section 4.3 11.8
[0064] These results indicate the desirability of the
administration of the present LC-PUFA's and/or nucleotides and/or
nucleotide precursors to infants born via caesarean section.
Example 6
Method for Feeding Babies Born Via Caesarean Section
[0065] Within two days after the infant is born via caesarean
section, a nutritional composition is administered which contains
(per liter):
[0066] energy 672 Kcal; Protein 14 g; Whey:Casein ratio 60:40; Fat
36 g; Carbohydrate 73 g; Vitamin A 500 .mu.g RE; Mixed natural
carotenoids 35 .mu.g RE; Vitamin D3 12 .mu.g; Vitamin E 12 mg;
Vitamin K1 45.0 .mu.g; Vitamin B.sub.1 (thiamin) 400 .mu.g; Vitamin
B.sub.2 (riboflavin) 1000 .mu.g; Vitamin B.sub.6 (pyridoxine) 400
.mu.g; Vitamin B.sub.12 (cyanacobalmine) 2.0 .mu.g; Niacin 4.1 mg;
Folic Acid 120 .mu.g; Pantothenic Acid 2800 mcg; Biotin 18 .mu.g;
Vitamin C (ascorbic acid) 86 mg; Choline 100 mg; Inositol 33 mg;
Taurine 67 mg, Calcium 510 mg; Phosphorous 290 mg; Magnesium 50 mg;
Iron 7.0 mg; Zinc 4.9 mg; Manganese 84 .mu.g; Copper 330 .mu.g;
Iodine I 00 .mu.g; Sodium 170 mg; Potassium 740 mg; Chloride 460 mg
and Selenium 14 .mu.g; wherein the fat content includes 0.65 wt. %
LC-PUFA based on total fatty acids, including 0.35 wt. % ARA, 0.05
wt. % EPA, and 0.2 wt. % DHA further comprising 3.6 g
transgalacto-oligosaccharides obtained from Elix'or.TM. (Borculo
Dorno Ingredients, Netherlands) and 0.4 g fructo-oligosaccharides
obtained from RaftilineHP.TM. (Orafti Active Food Ingredients,
Belgium) and about 20 mg nucleotides (about 6.4 mg CMP, about 4 mg
UMP, about 6 mg AMP, about 1.4 mg GMP and about 2.4 mg IMP).
* * * * *