Stephen Boyd, PhD, MDKathryn Dykman, MD

John Hall, DDSBill McAnalley, PhD

H. Reginald McDaniel, MDBob Ward, PED

Kia Gary, RNEric Moore, DChemJane Ramberg, MS

EXTERNAL EDITORIAL BOARD MANNATECH INCORPORATEDINTERNAL EDITORIAL BOARD

TECHNICAL STAFF

GRAPHIC ARTIST

Tom Gardiner, PhDGlobal Health Safety Environment and Regulatory Affairs CoordinatorShell Chemical Company (Retired)Houston, Texas

James C. Garriott, PhD, D-ABFTProfessor (Clinical Adjunct Faculty) University of Texas Health Science CenterConsulting ToxicologistSan Antonio, Texas

Alice Johnson-Zeiger, PhDProfessor of Biochemistry (Retired) University of Texas Health CenterTyler, Texas

Doris Lefkowitz, PhDAssociate Clinical Professor of MicrobiologyUniversity of South FloridaCollege of MedicineTampa, Florida

Stanley S. Lefkowitz, PhDProfessor of Microbiology and ImmunologyTexas Tech School of MedicineLubbock, Texas

Robert K. Murray, MD, PhDProfessor (Emeritus), BiochemistryUniversity of TorontoToronto, Ontario, Canada

The Benefits Throughout Life of Breastfeedingwith Emphasis on the Role of GlycoconjugatesTom Gardiner, PhD and Jane Ramberg, MS

Bruce Peschel

EDITOR IN CHIEFEileen Vennum, RAC

INTRODUCTIONEarly nutrition can have short- and

long-term effects on health, braindevelopment and behavior. Whencompared with infant formulas, breastmilk is a much richer source of gly-conutritional substances (e.g., oligosac-charides, glycoproteins, and other gly-coconjugates). With emphasis on gly-coconjugates, this paper will discussthe currently known consequences ofbreastfeeding on health, both duringand after breastfeeding. If moredetailed information or scientific refer-ences on this subject are desired, theycan be found in a previously publishedscientific review article.1

GLYCOCONJUGATES IN BREASTMILK

Breast milk is a rich source ofoligosaccharides (complex sugars),which typically contain most of theessential glycoconjugate sugars, includ-ing fucose, sialic acid (N-acetylneu-raminic acid), galactose, mannose,

N-acetylglucosamine, and N-acetyl-galactosamine. Fucose- and sialic acid-containing oligosaccharides appear tobe the most abundant. The oligosaccha-ride content of breast milk can vary. Forexample, in full-term babies’ milk, sialicacid and N-acetylglucosamine decreasesignificantly from weeks 1 to 13 afterbirth. Premature babies’ milk containshigher concentrations of these glyco-conjugate sugars. Such changes suggestthat the composition of milk is alteredaccording to the nutritional needs ofthe infant. Since oligosaccharides arenot easily digested in the small intes-tine, they also provide the "soluble"fiber of breast milk, a structure thatallows them to bind pathogens (bacte-ria, fungi, and viruses) and preventinfection.

Glycoproteins, which contain mostof the eight glycoconjugate sugars, arealso abundant in breast milk. One ofthe most widely recognized and charac-terized glycoproteins found in

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AUGUST 11, 2000 VOL 1, NO 26

PROVIDING SCIENTIFIC INFORMATION RELATED TO NUTRITIONAL SACCHARIDES AND OTHER DIETARY INGREDIENTS.

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The scientific information in this journal is educational and is not to be used as a substitute for a doctor's care or for proven therapy.

Milk is Life

colostrum (the first "milk" secreted after a baby is born) is theantibody (a molecule produced by the body in response tosomething foreign) immunoglobulin A (IgA), which con-tains sialic acid, fucose, galactose, N-acetylglucosamine, andN-acetylgalactosamine. Antibodies are essential for properfunctioning of the immune system: IgA is the most abun-dant antibody. Cytokines (chemical messengers) are otherimportant breast milk glycoproteins. They are involved incell-to-cell communication and immune system activation,and may play a key role in early growth and development,and in protection against infection. The membrane sur-rounding milk fat also contains large glycoproteins thatappear to protect the newborn against infection.

Various other glycoconjugates are present in breast milk.A glycolipid (molecule composed of fat and sugars) found inthe milk fat membrane protects blood and various cellsfrom destruction by the immune system. Other glycoconju-gates affect brain development, anchor either proteins orcomplex sugars to cellular membranes, or have the poten-tial to influence inflammatory processes.

Enzymes and intermediate components involved in themetabolism of glycoconjugates are also present. Bloodgroup-related carbohydrates, which can react with cells lin-ing the stomach and intestines, are found on one humanmilk enzyme. Another enzyme is able to stimulate cell adhe-sion, important in normal cellular function and cell-to-cellcommunication.

The known functions of these components are summa-rized in Table 1.

PROTECTION AGAINST INFECTIONBreastfeeding is now generally recognized as a critical fac-

tor in protecting newborns against infections, particularlyin developing countries. The World Health Organizationhas estimated that increasing breastfeeding by 40% wouldreduce respiratory deaths by 50% and diarrheal deaths by66% worldwide in children less than 18 months of age. Inone study, exclusive breastfeeding decreased the risk ofdying from respiratory infections more than 3-fold andhalved the incidence of diarrhea. This is quite understand-able when one considers the many anti-infection compo-nents in breast milk.

Immunoglobulins, such as IgA, play an important role inprotecting the nursing newborn from potentially deadlyinfections caused by bacteria or viruses. IgA, produced inthe breast following intestinal exposure to a pathogen, isdirected against the bacteria, viruses, fungi, and other for-eign substances to which the mother has been exposed. Thecarbohydrate portion of breast milk IgA binds pathogens toprevent them from reaching mucosal cell membranes,where they might cause infections or deposit toxins (Figure A). Additionally, macrophages, which are a key cel-lular component of the immune system, are believed to beactivated in breast milk by IgA.

Numerous human milk glycoconjugates are known toinhibit several severely infectious pathogens. Of particularsignificance are the pathogens responsible for producingdiarrhea, which can be lethal to newborns. For example, atoxin produced by such pathogens is inhibited by a varietyof human milk glycoconjugates (see Figure C). Protectionfrom pathogen-induced diarrhea also results from the

GlycoScience Vol. 1, No. 26 August 11, 2000 2

Fig A

IgA

cytokines

other glycoproteins

oligosaccharides

glycolipids

other glycoconjugates

enzymes

sialic acid (a component of oligosaccharides, glycoproteins, glycolipids, and gangliosides)

Breast Milk Component Function● protects against infection by

bacteria, viruses, fungi ● activates macrophages● stimulates liver bile duct

development

● protect against infection● activate immune system● support overall growth and

development

● protect against infection ● bind bacterial toxins ● enhance absorption of iron,

copper, zinc, and vitamin B12● encourage growth of "good"

bacteria

● encourage growth of "good" bacteria

● protect against infection

● protect against infection● protect cells from immune

system attack

● support brain development● influence inflammation● anchor proteins or sugars in

cell membranes

● stimulate cell adhesion● metabolism of glycoconjugates

● important for normal brain development

Table 1: Beneficial Effects of Breast Milk Components on Human Development and Function

growth-promoting activity of beneficial intestinal bacteriaby breast milk glycoproteins and oligosaccharides (Figure B).Breast milk glycoconjugates also protect against respiratoryand other viruses.

An important mechanism responsible for the anti-bacter-ial and anti-viral effects of the various glycoconjugates inbreast milk appears to be prevention of pathogen attach-ment to host cell membranes. This occurs because certainglycoconjugates are structurally similar to host cell surfaceglycoconjugates used as receptors by pathogens, and so maybind the pathogen and competitively inhibit attachmentand/or penetration into the host cell (Figure C).

Numerous studies provide evidence to support the impor-tance of this mechanism. For example, in one study it wasshown that an ongoing infection could not be furtherinhibited once a virus penetrates a host cell, suggesting thatany protective effect occurs before viral attachment or pen-etration. Similarly, human milk mucin (a glycoprotein) canbind to a virus and stop the virus from reproducing.

OTHER BIOLOGICAL ACTIVITIES OF BREAST MILKGLYCOCONJUGATES

There are numerous other beneficial biological effects ofbreast milk glycoconjugates. For example, a variety of glycoproteins have been identified that enhance thebioavailability of iron, copper, zinc, and vitamin B12 to theinfant (Figure D).

Breast milk and its glycoconjugates are also important fornormal development and function of the infant’s liver,which affects fat digestion. Breast-fed infants produce moreof the bile acids necessary for fat metabolism and digestion.The concentration of acids necessary for fat metabolism ishigher in infants fed human milk. A human milk enzymeimportant for fat digestion in infants contains fucose, galac-tose, glucosamine, galactosamine, and sialic acid.

LONGER-TERM BENEFITS FROM BREAST MILKGLYCOCONJUGATES

Beneficial biological activities of breast milk glycoconju-gates often extend well beyond the time of breastfeeding.These include normal development and function of thebrain, immune system, and gastrointestinal organs, resist-ance to infection, and improved response to vaccines. Thesebenefits are summarized in Table 2 (next page).

Some of the more beneficial activities relate to braindevelopment and function. Breast milk glycoconjugatescontribute to normal brain development through modula-

Fig C

Fig D

GlycoScience Vol. 1, No. 26 August 11, 2000 3

Fig B

tion of the metabolism of essential components of nervedevelopment and structure. In addition, sialic acid, anessential component of breast milk glycoconjugates, isimportant for the normal development of the brain. In fact,there are reports that supplementary sialic acid can increaseconcentrations of sialicacid in brain glycoconju-gates and improve learningbehavior. In this regard, alarge study tracking chil-dren from birth to age 18showed that scores from IQtests, standardized tests,teacher evaluations, andhigh school performancewere higher in childrenwho were breast-fed com-pared to those who werebottle-fed. Scores were alsohigher the longer breast-feeding was continued(Figure E).

Since formula-fedinfants obtain less than

20% of the amount of sialic acid supplied to breast-fedbabies, these authors suggested that supplementation ofinfant formulas with sialic acid-containing glycoconjugatescould be advisable when breastfeeding is not possible. Itappears that dietary sialic acids, such as those found inhuman milk, are readily absorbed, bioavailable, and maycontribute to higher concentrations of sialic acid in thebody.

Breastfeeding appears to stimulate development of theimmune system, as evidenced by the larger thymus (anorgan that is important in early life for immune function)found in nursing infants at 4 months of age. This effect,coupled with the transference of the mother’s antigens (sub-stances that can stimulate an immune response) and otherimmune system glycoconjugate components to the infantvia breast milk, provides an opportunity for decreased riskof allergies, autoimmune disease, and inflammatory boweldisease. In one study, breastfeeding for more than 1 monthresulted in significant reductions in food allergies at years 1and 3, and in protection against hay fever and asthma up toage 17. In another study, breast-fed children followed until5 years of age had a lower occurrence of eczema, asthma,and food allergies (Figure F). Breastfeeding has also been

GlycoScience Vol. 1, No. 26 August 11, 2000 4

Fig F

Table 2:Health Benefits Throughout Life from Breastfeeding.

Fig E

HealthEffect

TimeDuring

BreastfeedingDuring

Childhood*During

AdulthoodImmune systemfunction

increased thymus size

enhanced vac-cine response

fewer food allergies

less hay fever

less eczema

less asthma

Illnesses (lower incidence)

wheezing bronchitis

rheumatoid arthritis

Crohn’s disease

ulcerative colitis

ear infections

respiratory infections

gastrointestinal infections

diarrhea

Otherimproved school performance

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shown to protect against wheezing bronchitis for 6-7 years,and single investigations provide evidence that the preva-lence of rheumatoid arthritis, Crohn’s disease, and possiblyulcerative colitis among adults is reduced by breastfeedingin infancy. Since glycoconjugates are well-known modula-tors of the immune system and are abundant in breast milk, they undoubtedly play important roles in these long-term processes.

Breastfeeding also appears to improve protection againstvarious infections and enhances vaccine responses afternursing is discontinued. For example, infants who had beensolely breast-fed for at least 4 months had 50% fewer earinfections during their first year of life, when compared withbabies who had never been breast-fed. In another study ofchildren fed human milk and followed from birth to 12months of age, the level in human milk of a higher amountof a particular glycoprotein resulted in fewer acute respirato-ry infections (ARI), suggesting that the glycoprotein provid-ed protection against ARI. In a large study of children fol-lowed for 2 years after birth, breastfeeding during the first 13weeks of life provided significant protection against gas-trointestinal and respiratory infections for up to 1 year. Ininfants immunized with type B flu vaccine at the ages of 2,4, and 6 months, antibody levels measured at 7 and 12

months were significantly higher in breast-fed infants, pro-viding strong evidence that breastfeeding enhances theactive immune response in the first year of life.

CONCLUSIONSIt seems there is little doubt that breastfeeding is benefi-

cial, and, in some instances, even life-sustaining. These ben-efits have been summarized in Tables 1 and 2.

In fact, only one isolated study reported an adverseresponse. In this case, an infant’s diarrhea stopped whenbreastfeeding was discontinued. With all of this availablescientific evidence, the implications for the value of supple-mental glyconutrition for nursing mothers and infants,especially when breastfeeding is not possible, is overwhelm-ing. In fact, the livestock industry has been using glycocon-jugate sugar (e.g., sialic acid) supplementation in diets toenhance growth and development in commercial breedingprograms. Moreover, recent scientific studies of thebioavailability of glycoconjugate sugars (e.g., mannose) sup-plemented in the diet have shown that they are well-absorbed and preferentially utilized in glycoconjugate syn-thesis. This is particularly important, since they are theessential building blocks of glycoconjugates.

GlycoScience Vol. 1, No. 26 August 11, 2000 5

REFERENCE1. Gardiner T. The importance of glycoforms in breastfeeding and early nutrition.

GlycoScience & Nutrition (Official Publication of GlycoScience.com: The Nutrition Science Site). 2000;1(23):1-6.