2 Program in Glycobiology, Shriver Center, University of Massachusetts Medical School, Waltham, MA 02452; 3 Departamento de Infectologia, Instituto Nacional de Ciencias Medicas y Nutricion, Mexico City 14000, Mexico; and 4 Center for Epidemiology and Biostatistics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
Received on September 12, 2003; revised on September 26, 2003; accepted on October 23, 2003
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: diarrhea / fucosyltransferases / Lewis blood groups / secretor / stable toxin of E. coli
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
Polymorphisms of the secretor and Lewis genes also control expression of the Lewis blood group type (Erney et al., 2000; Henry et al., 1995
). The different histo-blood group types in humans are associated with heterogeneous expression of glycoconjugates in erythrocytes and other tissues. Varying expression of these glycoconjugates can be associated with differential risk of infectious diseases (Blackwell et al., 1986a
,b
,c
; Kallenius et al., 1980
; Lomberg et al., 1983
; Newburg, 1997
; Newburg et al., 1993
). For example, differential expression of Lewis or ABO histo-blood group types can be associated with varying risks of infection and diseases of the gastrointestinal tract (Glass et al., 1985
; Huang et al., 2003
; Ikehara et al., 2001
; Ruiz-Palacios et al., 2003
), presumably through differential expression of cell surface glycoconjugates that are used as receptors for pathogens of the intestinal mucosa.
The many human milk oligosaccharides and their related glycoconjugates include some that are bioactive. Milk glycoconjugates that have structural homology to the glycan moieties of intestinal mucosal cell surface may act as competitive inhibitors of pathogen binding to their glycoconjugate receptors. Examples include human milk oligosaccharides containing 1,2-linked fucose that inhibit the stable toxin-producing Escherichia coli in vitro and its toxin-induced secretory diarrhea in vitro and in vivo (Crane et al., 1994
; Newburg et al., 1990
). Glycoconjugates found in human milk also inhibit binding by campylobacter in vitro, ex vivo, and in vivo (Cervantes et al., 1995
; Ruiz-Palacios et al., 2003
), and inhibit binding by caliciviruses in vitro (Huang et al., 2003
; Jiang et al., forthcoming
; Marionneau et al., 2002
). Thus specific fucosyloligosaccharides of human milk have been observed to inhibit specific pathogens, but the clinical relevance of their presence in human milk, that is, the relationship between these milk oligosaccharides and risk of disease in a breastfeeding population, had not been tested.
We previously reported highly heterogeneous expression of milk fucosyloligosaccharides among individual mothers. Milk fucosyloligosaccharide expression also changes qualitatively and quantitatively over the course of lactation (Chaturvedi et al., 2001). The ratio of the
1,2-linked fucosyloligosaccharides to those that contain only
1,3- and
1,4-linked fucose declines exponentially over the first year of lactation. This pattern suggests coordinated reciprocal control of the synthesis of fucosyloligosaccharides, although the biological basis of this change over lactation is unknown. Individual lactating mothers exhibit similar exponential changes in this oligosaccharide ratio over the course of lactation, but at any given stage of lactation absolute values of this ratio often differ among mothers. This heterogeneous expression of human milk fucosyloligosaccharides among individual lactating mothers provides an opportunity to study both the basis of this variation and the role of milk oligosaccharides in protecting infants from enteric pathogens.
The current study was designed to test the hypothesis that fucosyloligosaccharides are part of a milk-borne innate immune system; if true, this necessitates that (1) fucosyloligosaccharide expression in human milk be constituative and, therefore, depend on maternal genotype; and (2) fucosyloligosacchride expression in milk be relevant to protection of breastfed infants against infectious disease. To test whether expression of human milk fucosyloligosaccharides is innate, we examined covariation of milk fucosyloligosaccharides of mothers in relation to their Lewis blood group type, which implies control by the same fucosyltransferase genes. To test whether fucosyloligosaccharide variation in maternal milk is clinically relevant, we examined the effect of predominance of 2-linked over non-2-linked fucosyloligosaccharides in milk in relation to protection of breastfed infants against diarrhea associated with stable toxin (ST)-E. coli and diarrhea in general.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
In other tissues, Lewis structural moieties are based on a lactosamine backbone (Gal-GlcNAc); however, the most prevalent type 2 fucosyloligosaccharides in human milk are synthesized from lactose (Gal-Glc) and therefore are defined as the glucose analogs to the type 2 Lewis structures. For both type 1 and type 2 pathways, the 2-fucosyltransferase and the 3- and 4-fucosyltransferases compete for the same substrates. Thus the relative activities of these fucosyltransferases are reflected in the combined content of 2-linked fucosyloligosaccharides relative to the combined content of fucosyloligosaccharides whose fucose is not 2-linked. Differences in these fucosyltransferase activities can be a result of differences in the expression of their respective genes; thus distinct genotypes could result in characteristically distinct patterns of oligosaccharide expression in milk. A single, sensitive phenotypic biomarker of the relative activities of these fucosyltransferases may be the ratio of the 2-linked to non-2-linked fucosyloligosaccharides.
Lewis blood group type
The bloods of the mothers in our cohort were typed for Lewis blood group by hemagglutination of the erythrocytes. Differences in maternal blood group type reflect expression of polymorphisms in maternal Lewis and secretor genotypes. The Lewis blood group distribution in study mothers was as follows: 67 were Lea-b+, 24 were Lea-b-, and the serologic classification for 2 mothers was Lea+b-. However, because the milk of the two Lea+b- mothers contained 2-linked fucosylated oligosaccharide, a finding inconsistent with being an obligate nonsecretor, the discrepancy between milk and blood group phenotypes was resolved by classifying the blood group as indeterminant and excluding these two mothers when calculating the distribution of Lewis blood group phenotypes.
Red cells adsorb fucosylated glycolipids (primarily type 1) from serum and therefore exhibit serological phenotypes that reflect the genotypes shown in Table II: the phenotype Lea-b- is a manifestation of the lele genotype (i.e., homozygous recessive for the Lewis gene); Lea-b- individuals express much less 3-linked fucose than the Lea-b+ phenotype individuals. The phenotype Lea-b+ is a manifestation of the four genotypes that contain at least one dominant Lewis gene and at least one dominant secretor gene. In Lea-b+ individuals, the Lewis fucosyltransferase (Le, or FucT-III) utilizes and depletes 2-linked fucosylated structures to produce the combined 2-, 3-, and 4-linked fucosylated structures, for example, Leb for type 1 and Ley for type 2; thus the Lea-b+ erythrocyte phenotype is negative for Lea but positive for Leb antigens.
|
|
|
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The distribution of blood group types in a given population are manifestations of polymorphisms in genes whose products control glycoconjugate expression on the surface of red blood cells, generally at the nonreducing terminus of the glycan moiety. These same genetic polymorphisms are expressed in other tissues as variation in the production of cell surface carbohydrates, some of which are used as receptors by various pathogens. Associations have been reported previously between blood group type and susceptibility to specific diseases, especially those of mucosal surfaces. For example, individuals of O blood group type have greater susceptibility to cholera (Glass et al., 1985) and certain strains of noroviruses (Huang et al., 2003
). P blood group types have been associated with different susceptibilities to hemolytic uremic syndrome (Newburg et al., 1993
). These genetic polymorphisms can also be expressed as variable production of glycoconjugates in secretions; the glycans of secreted glycoconjugates can bind to pathogens, inhibit binding by pathogens to their host, and thereby protect the host. For example, secretors, that is, those whose secretions contain glycoconjugates with
1,2-linked fucose moieties, appear to be less susceptible to urinary tract infections and infection by Candida albicans and Haemophilus influenzae than nonsecretors (Blackwell et al., 1986a
,b
,c
).
The distribution of Lewis blood group phenotypes in our study population differs from typical U.S. or European populations (Erney et al., 2000) in that the Mexican mestizo population has a much lower prevalence of Lewisa+b- (obligate nonsecretors) and a higher prevalence of Lewisa-b-. We calculated a Hardy-Weinberg distribution of genotypes in this population (Table II), such that the distribution of Lewis and secretor genes predict erythrocyte phenotypes that match the observed phenotypes. The gene frequency of 0.9 for Se, the dominant secretor gene, fits well with the observation that most of these mothers are secretors. The frequency of 0.5 for Le (FUT3), the dominant Lewis gene, fits well with our finding a 3:1 ratio of Lea-b+ to Lea-b-. This cohort appears to contain no true nonsecretors, based on the presence of measurable 2-linked fucosyloligosaccharides in the milk of each of the 93 nursing Mexican mothers.
We used this Hardy-Weinberg distribution of genotypes as a basis for interpreting the distribution of milk fucosyloligosaccharide phenotypes in this population. The milk of 67 Lea-b+ mothers contained significantly more 1,3- or
1,4-linked oligosaccharides, that is, LNF-II (Lea) and 3-FL (Lex), whereas the milk of the 24 Lea-b- mothers contained more
1,2-linked oligosaccharides, that is, LNF-I (H-1) and 2'-FL (H-2). However, the amounts of oligosaccharides, even within each blood group type, had a wide distribution of patterns, with few discrete clustered groupings. Note that the milks of women with Lea-b- blood group phenotypes had much lower concentrations of
1,4-linked oligosaccharides relative to the milk of women with Lea-b+ blood group phenotypes, consistent with our analysis; but our proposed synthetic scheme cannot account for the presence of any
1,4-linked structures in the milk of Lea-b- mothers. The lack of a precise correspondence between the calculated Hardy-Weinberg distribution and observed milk oligosaccharide phenotypes could be due to several reasons. For example, there is the possibility that there are other missense mutations of the FUT2 or FUT3 genes not yet identified in this Mexican population that significantly lowered the
1,2-fucosyltransferase activity or
1,3/4-transferase activity. Other enzymes may make significant contribution to fucosyloligosaccharide synthesis in milk as compared to erythrocytes, such as FucT-I (H) as an alternative 2-fucosyltransferase, and FucT-IV, -V, -VI, -VII, or -IX as alternative 3-fucosyltransferases. The multimodal distribution of milk oligosaccharides, even within Lewis blood group types, suggests that several genotypes that express as one phenotype in erythrocytes could express as multiple phenotypes in milk. This may be due to a greater sensitivity of the HPLC of milk oligosaccharides relative to the serology used in Lewis blood group typing or may represent a true biological difference between glycan expression in milk oligosaccharides relative to that in erythrocyte glycolipids.
This continuum of oligosaccharide amounts and patterns in milk, which we presume contains the phenotypes for many possible genotypes, was expressed as a ratio of 2-linked to non-2-linked fucosyloligosaccharides in each milk sample. This ratio reflects the competition between the Lewis (FucT-III [Le]) and secretor (FucT-II [Se]) fucosyltransferases described in Figure 1 that underlie the differential phenotypic expression of Lewis moieties. Consistent with these observations, these oligosaccharide ratios distributed differently in milk of mothers of different Lewis blood group type. The highest fucosyloligosaccharide ratios were found primarily in the milks of Lea-b- mothers, whereas milk with the lowest ratios was produced exclusively by Lea-b+ mothers. These ratios were also significantly related to protection of breastfeeding infants from disease.
Enterotoxigenic E.coli produce an ST that causes diarrhea. ST-induced diarrhea in mice can be inhibited by human milk (Cleary et al., 1983). This inhibitory activity is due to an
1,2-linked fucosylated oligosaccharide (Newburg et al., 1990
). These fucosyloligosaccharides inhibit binding of stable toxin of E. coli to its host cell receptor in vitro (Newburg et al., 1995
). If such inhibition of stable toxin were to also take place in the intestine of nursing infants, one would expect suppression of the symptoms of diarrhea in nursing children infected by ST-E. coli due to the presence of the specific
1,2-linked fucosyloligosaccharide inhibitor. If the same 2-fucosyltranferase that synthesizes the ST inhibitor also synthesizes the smaller 2-linked sugars measured in this study, there should be a direct relationship between a high ratio of 2-linked fucosyloligosaccharides and protection from ST-induced diarrhea. The four nursing infants in our cohort who were infected by ST-E. coli and developed diarrhea were consuming milk with significantly lower fucosylated oligosaccharide ratios than the milk consumed by those infants who were also infected but asymptomatic. This is consistent with
1,2-linked fucosyloligosaccharides of human milk playing a major role in providing significant protection to breastfed infants against ST of E. coli.
However, diarrhea associated with ST-E. coli accounts for less than 2% of total diarrhea cases in our population. Other more common enteric pathogens include campylobacter and noroviruses. Campylobacter binds to 2-linked fucosyl moieties of intestinal glycoconjugates, and its binding and infection are inhibited in vitro and in vivo by human milk fucosyloligosaccharides that have a 2-linked moiety, specifically the H-2 epitope (Ruiz-Palacios et al., 2003). Norovirus binding is also inhibited by fucosylated
1,2-linked glycans (Huang et al., 2003
; Marionneau et al., 2002
). Thus we investigated whether fucosylated oligosaccharides of human milk were also associated with protection of nursing infants against diarrhea due to pathogens other than ST. Infants who contracted one or more episodes of moderate to severe diarrhea while breastfeeding were consuming milk whose ratios were significantly lower than the milk consumed by infants who remained free of diarrheal symptoms while breastfeeding. Thus milk with higher 2-linked to non-2-linked fucosyloligosaccharide ratios affords greater protection against infant diarrhea due to all causes in this cohort. This suggests the presence of a family of oligosaccharides and/or glycoconjugates in milk, defined by their
1,2-linked fucose, that protect against several major enteric pathogens.
Our study population consisted only of secretors whose innate variation in the expression of 2-linked fucose is much less than that between secretors and nonsecretors. Nonetheless, we still found significant variation in the expression of 1,2-linked fucosyloligosaccharides in human milk, and found that this variation was significantly related to the incidence of diarrheal disease among breastfed infants. One might predict that protection against ST afforded by human milk might show even greater variation in a population that has greater differences in fucosyloligosaccharide expression, such as populations of European origin, which typically have 20% nonsecretors.
Some important enteric pathogens, for example, rotavirus, are inhibited by human milk oligosaccharides or glycoconjugates that are not fucosylated (Newburg et al., 1998; Smith et al., 1987
). Thus the association we described in this study addresses only one possible set of enteric pathogens that may be inhibited by one family of milk oligosaccharides; other oligosaccharides that inhibit other pathogens are probable. We conclude that the family of
1,2-linked fucosylated oligosaccharides, probably in conjunction with other families of oligosaccharides, constitute a powerful innate immune system of human milk.
A general hypothesis is that individual variation in oligosaccharide or glycoconjugate expression underlies varying susceptibility to different pathogens. The highly heterogeneous expression of glycoconjugates on cell surfaces would ensure that human populations are heterogeneous in their susceptibility to a given pathogen. Thus a major survival strategy for human populations periodically confronted with newly emergent, virulent, deadly pathogens would be that some proportion of the population is innately resistant by virtue of the heterogenous expression of glycoconjugates. Our data support a related hypothesis: oligosaccharides and glycoconjugates of milk protect infants from enteric pathogens because they contain epitopes homologous with intestinal receptors for pathogens, but expression of specific protective glycan epitopes vary among mothers of different genotype, providing a basis for selection of a population whose genotype provides the most protection in milk against pathogens. However, the hypothesis is confounded, as the genotypes of mothers with the highest innate protection to a given pathogen in their milk might also be expected to have infants with genotypes that have high probability of expression of the pathogen-binding epitope in their intestine, assuming both are mediated by the same genes. The expression of protective glycans in milk may be the stronger force for selection of traits in human populations. Milks containing the highest relative amount of epitopes with 1,2-linked fucose are most strongly associated with protection against ST, described herein, and campylobacter and some noroviruses, described elsewhere (Morrow et al., 2002
). This phenomenon may help explain the prevalence of specific blood group types in regions where specific pathogens are endemic. For example, the low incidence of nonsecretors in the indigenous population of Mexico could be a consequence of the greater vulnerability of infants receiving milk containing less protective
1,2-linked glycans.
Despite the strong relationship, maternal blood group phenotype does not fully explain phenotype expression of fucosylated oligosaccharides in milk, but does support the conclusion that the expression of milk oligosaccharides is determined by maternal genetics. Genotyping of individual maternal fucosyltransferase genes is necessary to better understand variation in oligosaccharide expression in human milk. This study was limited to measurement of maternal phenotype and was not designed to provide genotype information for mother or infant, nor the infant's histo-blood group phenotype. Future studies are needed to clarify the genotypephenotype relationship for breastfeeding motherinfant pairs and to relate this information to risk of diarrheal disease in children.
That notwithstanding, the strong relationship between the milk oligosaccharide phenotypes and the Lewis blood group phenotypes implies a common genetic basis of control: polymorphisms of the Lewis and secretor genes that underlie Lewis blood group phenotypes may also contribute to variation in the relative quantities of 2- to 3/4-linked fucosyloligosaccharides in human milk. Variation in expression of 2-linked fucosyloligosaccharides in human milk is significantly associated with variation in risk of disease in breastfed infants, supporting the conclusion that fucosylated oligosaccharides are a fundamental and potent mechanism of protection by human milk against infectious disease. Thus oligosaccharides may represent a significant component of an innate immune system of human milk whereby the lactating mother protects her nursing infant from environmental pathogens. The active moieties of these protective milk oligosaccharides may provide a basis for designing novel therapeutic agents for the prophylaxis and treatment of disease.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Infant illness and feeding history were collected weekly. Stool samples were collected weekly with additional samples obtained whenever diarrhea occurred. Study outcomes included all diarrhea episodes, moderate to severe diarrhea using a standardized scoring system (Ruuska and Vesikari, 1990; Velazquez et al., 1996
), and diarrhea due to ST-associated E. coli. Diarrhea episodes were defined as three or more watery stools within a 24-h period or loose to watery bowel movements that exceeded the child's usual daily stool frequency by two or more stools as determined by a study physician. Diarrhea due to ST-E. coli was defined as its detection in a stool sample collected during an episode of diarrhea. Testing for ST-E. coli was performed in the laboratory in Mexico using previously published methods (Lopez-Vidal et al., 1990
). Maternal blood group typing was performed in the clinical laboratory in Mexico using postpartum blood samples.
Study population
The 93 motherinfant pairs in this study were monitored for up to 2 years postpartum. The analysis presented in this article was restricted to the duration of breastfeeding. The median duration of any breastfeeding was 9 months (range, 2 weeks to 24 months). Mothers' median age was 23 years; 22% completed a secondary or higher education; a median of five individuals lived in study households; and 33% of infants were the first-born child. The demographic profile and infant feeding practices of this study population has been detailed elsewhere (Guerrero et al., 1999). The ABO distribution in study mothers was 18 (19%) A, 1 (1%) AB, 12 (13%) B, and 62 (67%) O blood group type. The Lewis blood group distribution in study mothers was 67 (72%) Lea-b+ and 24 (26%) Lea-b-. The serologic classification for two of the mothers was Lea+b-, which indicates obligate nonsecretors. However, because the milk of these two mothers contained 2-linked fucosylated oligosaccharide, inconsistent with being a nonsecretor, the discrepancy between milk and blood group phenotypes was resolved by classifying the blood group as indeterminant and excluding these two from further analysis related to Lewis blood group type.
Incidence of diarrhea
A total of 234 diarrhea episodes were identified in study children during 857 months of breastfeeding; the overall incidence of diarrhea was 28.8 cases per 100 child-months of follow-up ([number of episodes/months of follow-up]x 100). There were 77 (33%) episodes of moderate to severe diarrhea; the incidence of moderate to severe diarrhea was 9.3 cases per 100 child-months of follow-up. Over the course of breastfeeding, a median of two episodes of diarrhea occurred per child (range, 012 episodes), including a median of one moderate to severe diarrhea episode (range, 012 episodes). Symptomatic infection with ST-producing E. coli was identified in 4 (4%) of the 93 study children at some time during the follow-up period.
Milk samples were collected in the homes of study mothers by an experienced study nurse using an Egnell electric breast pump. Samples were transported on ice from the study household to the laboratory, where they were stored at -70°C. Milk samples were later transported to Boston, and oligosaccharide content was analyzed as described previously (Chaturvedi et al., 1997). Briefly, the human milk samples were centrifuged at 4,000 x g to separate the cream; the skimmed milk was made 67% with ethanol, stored overnight at 4°C, and recentrifuged; and the clear liquid was lyophilized to yield the crude oligosaccharide fraction. A 500-µg aliquot of the oligosaccharides from each sample was dried in vacuo for 46 h over phosphorus pentoxide. To each sample, 0.5 mL perbenzoylation reagent (benzoic anhydride [50 mg/mL] and 4-dimethylaminopyridine [25 mg/mL] in dry pyridine) was added (pyridine was predried over three sequential treatments of 4Ð molecular sieves that had been freshly baked in an oven at 450°C overnight and cooled in a desiccator before use). After mixing, incubation was for 16 h at 37°C. Water (4.5 mL) was added to each sample, and the resulting solution was passed twice over a C-18 Bond-Elut column (3 mL, 0.5 mg; Varian, Sunnyvale, CA). The C-18 columns had previously been wetted with HPLC acetonitrile (5 mL) and equilibrated with 5 mL 1% pyridine in water and fitted onto a vacuum manifold with adequate vacuum to achieve a flow rate of 0.5 mL/min. After washing the column with 5 mL 10% pyridine and 5 mL HPLC water, the perbenzoylated oligosaccharides were eluted with 5 mL HPLC acetonitrile; the eluate was dried under N2 and taken up in 100 µL HPLC acetonitrile.
The resulting perbenzoylated oligosaccharides were resolved by reversed-phase HPLC (C-8 column, 3 µ; 4.6 mm x 10 cm) at 1 mL/min with a 15-min linear gradient from acetonitrile:water (4:1) to 100% acetonitrile, with holding at the final condition for an additional 10 min. The perbenzoylated oligosaccharides were detected at 229 nm, and their peaks were integrated on a Macintosh computer with Rainin Dynamax software (Emeryville, CA). All of the major milk oligosaccharides produced a peak that was fully resolved and in the linear range of detection, except that LNF-II and LNF-III coelute in this system.
Statistical analysis
Incidence rates of diarrhea were calculated as the total number of cases per 100 child-months at risk (i.e., birth to the end of breastfeeding or termination from study). The major milk oligosaccharide Lewis antigen homologs were measured in individual milk samples as concentrations (mmol/L). These oligosaccharide values were then used to calculate a fucosyloligosaccharide ratio for each milk sample. The fucosyloligosaccharide ratio was defined as the ratio of 2-linked to non-2-linked fucosyloligosaccharides in the milk sample of each individual. We examined the association between maternal milk ratios in relation to maternal Lewis blood group type (i.e., Lea-b+ versus Lea-b-); the association between infants who developed and did not develop ST-associated diarrhea; and the association between milk oligosaccharide ratios and diarrhea episodes classified into three categories by severity of diarrhea: infants who had moderate to severe, mild, and no episodes of diarrhea while breastfeeding. Analysis of variance, general linear model, two-sample t-tests, and median test were used where appropriate to evaluate these comparisons. Potential confounding and interaction effects were assessed by general linear model for any affects of maternal sociodemographic factors and of ABO blood group type on the relationship between milk oligosaccharides and risk of diarrhea and on the relationship between Lewis blood group type and oligosaccharide expression.
![]() |
Acknowledgements |
---|
![]() |
Footnotes |
---|
![]() |
Abbreviations |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Blackwell, C.C., May, S.J., Brettle, R.P., MacCallum, C.J., and Weir, D.M. (1986b) Host-parasite interactions underlying non-secretion of blood group antigens and susceptibility to recurrent urinary tract infections. In Lark, D.L. (Ed.), Protein-carbohydrate interactions in biological systems. Academic Press, London, pp. 229230.
Blackwell, C.C., Thom, S.M., Weir, D.M., Kinane, D.F., and Johnstone, F.D. (1986c) Host-parasite interactions underlying non-secretion of blood group antigens and susceptibility to infections by Candida albicans. In Lark, D.L. (Ed.), Protein-carbohydrate interactions in biological systems. Academic Press, London, pp. 231233.
Cervantes, L.E., Newburg, D.S., and Ruiz-Palacios, G.M. (1995) 1-2 Fucosylated chains (H-2 and Lewisb) are the main human milk receptor analogs for Campylobacter. Pediatr. Res., 37, 171A.
Chaturvedi, P., Warren, C.D., Ruiz-Palacios, G.M., Pickering, L.K., and Newburg, D.S. (1997) Milk oligosaccharide profiles by reversed-phase HPLC of their perbenzoylated derivatives. Anal. Biochem., 251, 8997.[CrossRef][ISI][Medline]
Chaturvedi, P., Warren, C.D., Altaye, M., Morrow, A.L., Ruiz-Palacios, G., Pickering, L.K., and Newburg, D.S. (2001) Fucosylated human milk oligosaccharides vary between individuals and over the course of lactation. Glycobiology, 11, 365372.
Cleary, T.G., Chambers, J.P., and Pickering, L.K. (1983) Protection of suckling mice from heat-stable enterotoxin of Escherichia coli by human milk. J. Infect. Dis., 148, 11141119.[ISI][Medline]
Crane, J.K., Azar, S.S., Stam, A., and Newburg, D.S. (1994) Oligosaccharides from human milk block binding and activity of the Escherichia coli heat-stable enterotoxin (STa) in T84 intestinal cells. J. Nutr., 124, 23582364.[ISI]
Erney, R., Hilty, M., Pickering, L., Ruiz-Palacios, G., and Prieto, P. (2001) Human milk oligosaccharides: a novel method provides insight into human genetics. Adv. Exp. Med. Biol., 501, 285297.[ISI][Medline]
Erney, R.M., Malone, W.T., Skelding, M.B., Marcon, A.A., Kleman-Leyer, K.M., O'Ryan, M.L., Ruiz-Palacios, G., Hilty, M.D., Pickering, L.K., and Prieto, P.A. (2000) Variability of human milk neutral oligosaccharides in a diverse population. J. Pediatr. Gastroenterol. Nutr., 30, 181192.[CrossRef][ISI][Medline]
Glass, R.I., Holmgren, J., Haley, C.E., Khan, M.R., Svennerholm, A.M., Stoll, B.J., Belayet-Hossain, K.M., Black, R.E., Yunus, M., and Barua, D. (1985) Predisposition for cholera of individuals with O blood group. Possible evolutionary significance. Am. J. Epidemiol., 121, 791796.[Abstract]
Guerrero, M.L., Morrow, R.C., Calva, J.J., Ortega-Gallegos, H., Weller, S.C., Ruiz-Palacios, G.M., and Morrow, A.L. (1999) Rapid ethnographic assessment of breastfeeding practices in periurban Mexico City. Bull. World Health Org., 77, 323330.[ISI][Medline]
Henry, S., Oriol, R., and Samuelsson, B. (1995) Lewis histo-blood group system and associated secretory phenotypes. Vox Sang., 69, 166182.[ISI][Medline]
Huang, P., Farkas, T., Marionneau, S., Zhong, W., Ruvoen-Clouet, D.V.M., Morrow, A.L., Altaye, M., Pickering, L.K., Newburg, D.S., LePendu, J., and Jiang, X. (2003) Noroviruses bind to human ABO, Lewis and secretor histo-blood group antigens: identification of 4 distinct strain-specific patterns. J. Infect. Dis., 188, 1931.[CrossRef][ISI][Medline]
Ikehara, Y., Nishihara, S., Yasutomi, H., Kitamura, T., Matsuo, K., Shimizu, N., Inada, K., Kodera, Y., Yamamura, Y., Narimatsu, H., and others. (2001) Polymorphisms of two fucosyltransferase genes (Lewis and Secretor genes) involving type I Lewis antigens are associated with the presence of anti-Helicobacter pylori IgG antibody. Cancer Epidemiol. Biomarkers Prev., 10, 971977.
Jiang, X., P, H., Zong, W., Morrow, A.L., Ruiz-Palacios, G.M., and Pickering, L.K. (forthcoming) Human milk contains elements that block Norwalk-like viruses binding to histo-blood group antigens in saliva. Adv. Exp. Med. Biol.
Kallenius, G., Mollby, R., Svensson, S.B., Winberg, J., Lundblad, A., Svensson, S., and Cedergren, B. (1980) The Pk antigen as receptor for the haemagglutinin of pyelonephritogenic Escherichia coli. FEMS Microbiol. Lett., 7, 297.[CrossRef][ISI]
Lomberg, H., Hanson, L.A., Jacobsson, B., Jodal, U., Leffler, H., and Svanborg-Eden, C. (1983) Correlation of P blood group vesicoureteral reflux and bactgerial attachment in patients with recurrent pyelonephritis. N. Engl. J. Med., 308, 11891192.[Abstract]
Lopez-Vidal, Y., Calva, J.J., Trujillo, A., Ponce de Leon, A., Ramos, A., Svennerholm, A.M., and Ruiz-Palacios, G.M. (1990) Enterotoxins and adhesins of enterotoxigenic Escherichia coli: are they risk factors for acute diarrhea in the community? J. Infect. Dis., 162, 442447.[ISI][Medline]
Marionneau, S., Ruvoen, N., Le Moullac-Vaidye, B., Clement, M., Cailleau-Thomas, A., Ruiz-Palacois, G., Huang, P., Jiang, X., and Le Pendu, J. (2002) Norwalk virus binds to histo-blood group antigens present on gastroduodenal epithelial cells of secretor individuals. Gastroenterology, 122, 19671977.[ISI][Medline]
Morrow, A.L., Reves, R.R., West, M.S., Guerrero, M.L., Ruiz-Palacios, G.M., and Pickering, L.K. (1992) Protection against infection with Giardia lamblia by breast-feeding in a cohort of Mexican infants. J. Pediatr., 121, 363370.[ISI][Medline]
Morrow, A.L., Ruiz-Palacios, G.M., Altaye, M., Jiang, X., Guerrero, M.L., Meinzen-Derr, J.K., Farkas, T., Chaturvedi, P., Pickering, L.K., Newburg, D.S. (2002) Human milk oligosaccharide homologs of Lewis blood group epitopes and protection against diarrhea in breastfed infants. Glycobiology, 12, 648.
Newburg, D.S. (1997) Do the binding properties of oligosaccharides in milk protect human infants from gastrointestinal bacteria? J. Nutr., 127, 980S984S.[Medline]
Newburg, D.S., Pickering, L.K., McCluer, R.H., and Cleary, T.G. (1990) Fucosylated oligosaccharides of human milk protect suckling mice from heat-stabile enterotoxin of Escherichia coli. J. Infect. Dis., 162, 10751080.[ISI][Medline]
Newburg, D.S., Chaturvedi, P., Lopez, E.L., Devoto, S., Gayad, A., and Cleary, T.G. (1993) Susceptibility to hemolytic-uremic syndrome relates to erythrocyte glycosphingolipid patterns. J. Infect. Dis., 168, 476479.[ISI][Medline]
Newburg, D.S., Chaturvedi, P., Crane, J.K., Cleary, T.G., and Pickering, L.K. (1995) Fucosylated oligosaccharide(s) of human milk inhibits stable toxin of Escherichia coli. In Agrawal, V.P., Sharma, C.B., Sah, A., and Zingde, M.D. (Eds.), Complex carbohydrates and advances in biosciences. Society of Biosciences, Muzaffarnagar, India, pp. 199226.
Newburg, D., Peterson, J., Ruiz-Palacios, G., Matson, D., Morrow, A., Shults, J., Guerrero, M., Chaturvedi, P., Newburg, S., Scallan, C., and others. (1998) Role of human-milk lactadherin in protection against symptomatic rotavirus infection. Lancet, 351, 11601164.[CrossRef][ISI][Medline]
Oriol, R., Mollicone, R., Cailleau, A., Balanzino, L., and Breton, C. (1999) Divergent evolution of fucosyltransferase genes from vertebrates, invertebrates, and bacteria. Glycobiology, 9, 323334.
Ruiz-Palacios, G.M., Cervantes, L.E., Ramos, P., Chavez-Munguia, B., and Newburg, D.S. (2003) Campylobacter jejuni binds intestinal H(O) antigen (Fuc1,2Gal ß1,4GlcNAc), and fucosyloligosaccharides of human milk inhibit its binding and infection. J. Biol. Chem., 278, 1411214120.
Ruuska, T. and Vesikari, T. (1990) Rotavirus disease in Finnish children: use of numerical scores for clinical severity of diarrhoeal episodes. Scand. J. Infect. Dis., 22, 259267.[ISI][Medline]
Smith, D.F., Prieto, P.A., McCrumb, D.K., and Wang, W.-C. (1987) A novel sialylfucopentaose in human milk. Presence of this oligosaccharide is not dependent on expression of the secretor or Lewis fucosyltransferases. J. Biol. Chem., 262, 1204012047.
Thurl, S., Henker, J., Siegel, M., Tovar, K., and Sawatzki, G. (1997) Detection of four human milk groups with respect to Lewis blood group dependent oligosaccharides. Glycoconj. J., 14, 795799.[CrossRef][ISI][Medline]
Velazquez, F.R., Matson, D.O., Calva, J.J., Guerrero, L., Morrow, A.L., Carter-Campbell, S., Glass, R.I., Estes, M.K., Pickering, L.K., and Ruiz-Palacios, G.M. (1996) Rotavirus infections in infants as protection against subsequent infections. N. Engl. J. Med., 335, 10221028.
Viverge, D., Grimmonprez, L., Cassanas, G., Bardet, L., Bonnet, H., and Solere, M. (1985) Variations of lactose and oligosaccharides in milk from women of blood types secretor A or H, secretor Lewis, and secretor H/nonsecretor Lewis during the course of lactation. Ann. Nutr. Metab., 29, 111.[ISI]
Viverge, D., Grimmonprez, L., Cassanas, G., Bardet, L., and Solere, M. (1990) Discriminant carbohydrate components of human milk according to donor secretor types. J. Pediatr. Gastroenterol. Nutr., 11, 365370.[ISI][Medline]