Search Results (20)

Group A rotavirus continues to be a leading global etiological agent of severe gastroenteritis in young children under 5 years of age. The replication of this virus in the host is associated with the occurrence of Lewis antigens and the secretor condition. Moreover, histo-blood group antigens (HBGAs) act as attachment factors to the outer viral protein of VP4 for rotavirus. Therefore, in this study, we employed a metabolomic approach to reveal potential signature metabolic molecules and metabolic pathways specific to rotavirus P[8] strain infection (VP4 genotype), which is associated with the expression of HBGA combined secretor and Lewis (Le) phenotypes, specifically secretor/Le^(a+b+). Further integration of the achieved metabolomics results with lipidomic and proteomics metadata analyses was performed. Saliva samples were collected from children diagnosed as negative or positive for rotavirus P[8] strain infection (VP4 genotype), which is associated with the HBGA combined secretor/Le^(a+b+). A total of 22 signature metabolic molecules that were downregulated include butyrate, putrescine, lactic acid, and 7 analytes. The upregulated metabolic molecule was 2,3-Butanediol. Significant pathway alterations were also specifically observed in various metabolism processes, including galactose and butanoate metabolisms. Butyrate played a significant role in viral infection and was revealed to exhibit different reactions with glycerolipids, glycerophospholipids, sphingolipids, sterol lipids, and fatty acyls. Moreover, butyrate might interact with protein receptors of free fatty acid receptor 2 (FFAR2) and free fatty acid receptor 3 (FFAR3). The revealed metabolic pathways and molecule might provide fundamental insight into the status of rotavirus P[8] strain infection for monitoring its effects on humans. Full article

Human milk, the gold standard in infant nutrition, is a unique fluid that provides essential nutrients such as lactose, lipids, proteins, and free oligosaccharides. While its primary role is nutritional, it also protects against pathogens. This protection mainly comes from immunoglobulins, with human milk oligosaccharides (HMOs) providing additional support by inhibiting pathogen binding to host cell ligands. The prebiotic and immune-modulatory activity of HMOs strongly depends on their structure. Over 200 individual structures have been identified so far, with the composition varying significantly among women. The structure and composition of HMOs are influenced by factors such as the Lewis blood group, secretor status, and the duration of nursing. HMO profiles are heavily influenced by maternal phenotypes, which are defined based on the expression of two specific fucosyltransferases. However, recent data have shown that HMO content can be modified by various factors, both changeable and unchangeable, including diet, maternal age, gestational age, mode of delivery, breastfeeding frequency, and race. The first part of this overview presents the historical background of these sugars and the efforts by scientists to extract them using the latest chromatography methods. The second part is divided into subchapters that examine modifiable and non-modifiable factors, reviewing the most recent articles on HMO composition variations due to specific reasons and summarizing potential future challenges in conducting these types of studies. Full article

Human milk oligosaccharides (HMOs) are complexes that play a crucial role in shaping the early-life gut microbiota. This study intends to explore whether HMO patterns are associated with the gut microbiota of infants. We included 96 Chinese breastfeeding mother–infant dyads. Breast milk and infant faecal samples were collected and tested. With milk 2′-fucosyllactose, difucosyllactose, and lacto-N-fucopentaose-I as biomarkers, we divided the mothers into secretor and non-secretor groups. HMO patterns were extracted using principal component analysis. The majority (70.7%) of mothers were categorised as secretor and five different HMO patterns were identified. After adjustment, the infants of secretor mothers exhibited a lower relative abundance of Bifidobacterium bifidum (β = −0.245, 95%CI: −0.465~−0.025). An HMO pattern characterised by high levels of 3-fucosyllactose, lacto-N-fucopentaose-III, and lacto-N-neodifucohexaose-II was positively associated with the relative abundance of Bifidobacterium breve (p = 0.014), while the pattern characterised by lacto-N-neotetraose, 6′-sialyllactose, and sialyllacto-N-tetraose-b was negatively associated with Bifidobacterium breve (p = 0.027). The pattern characterised by high levels of monofucosyl-lacto-N-hexaose-III and monofucosyl-lacto-N-neohexaose was positively associated with Bifidobacterium dentium (p = 0.025) and Bifidobacterium bifidum (p < 0.001), respectively. This study suggests that HMO patterns from mature breast milk were associated with certain gut microbiota of breastfed infants. Full article

The ABO blood groups, Lewis antigens, and secretor systems are important components of transfusion medicine. These interconnected systems have been also shown to be associated with differing susceptibility to bacterial and viral infections, likely as the result of selection over the course of evolution and the constant tug of war between humans and infectious microbes. This comprehensive narrative review aimed to explore the literature and to present the current state of knowledge on reported associations of the ABO, Lewis, and secretor blood groups with SARS-CoV-2 infection and COVID-19 severity. Our main finding was that the A blood group may be associated with increased susceptibility to SARS-CoV-2 infection, and possibly also with increased disease severity and overall mortality. The proposed pathophysiological pathways explaining this potential association include antibody-mediated mechanisms and increased thrombotic risk amongst blood group A individuals, in addition to altered inflammatory cytokine expression profiles. Preliminary evidence does not support the association between ABO blood groups and COVID-19 vaccine response, or the risk of developing long COVID. Even though the emergency state of the pandemic is over, further research is needed especially in this area since tens of millions of people worldwide suffer from lingering COVID-19 symptoms. Full article

The infant non-secretor histoblood group antigen phenotype is associated with reduced risk of symptomatic rotavirus diarrhea, one of the leading global causes of severe pediatric diarrheal disease and mortality. However, little is known regarding the role of secretor status in asymptomatic rotavirus infections. Therefore, we performed a nested case–control study within a birth cohort study previously conducted in Dhaka, Bangladesh, to determine the association between infant secretor phenotype and the odds of asymptomatic rotavirus infection, in addition to the risk of rotavirus diarrhea, in unvaccinated infants. In the parent cohort, infants were enrolled in the first week of life and followed through the first two years of life with multiple clinic visits and active surveillance for diarrheal illness. Secretor phenotyping was performed on saliva. Eleven surveillance stools collected over the first year of life were tested for rotavirus by real-time RT-PCR, followed by conventional PCR and amplicon sequencing to identify the infecting P-type of positive specimens. Similar to findings for symptomatic diarrhea, infant non-secretors experienced significantly fewer primary episodes of asymptomatic rotavirus infection through the first year of life in a likely rotavirus P-genotype-dependent manner. These data suggest that non-secretors experienced reduced risk from rotavirus due to decreased susceptibility to infection rather than reduced infection severity. Full article

Live-attenuated, oral rotavirus vaccines have significantly reduced rotavirus-associated diarrhoea morbidity and infant mortality. However, vaccine immunogenicity is diminished in low-income countries. We investigated whether maternal and infant intrinsic susceptibility to rotavirus infection via histo-blood group antigen (HBGA) profiles influenced rotavirus (ROTARIX^®) vaccine-induced responses in Zambia. We studied 135 mother–infant pairs under a rotavirus vaccine clinical trial, with infants aged 6 to 12 weeks at pre-vaccination up to 12 months old. We determined maternal and infant ABO/H, Lewis, and secretor HBGA phenotypes, and infant FUT2 HBGA genotypes. Vaccine immunogenicity was measured as anti-rotavirus IgA antibody titres. Overall, 34 (31.3%) children were seroconverted at 14 weeks, and no statistically significant difference in seroconversion was observed across the various HBGA profiles in early infant life. We also observed a statistically significant difference in rotavirus-IgA titres across infant HBGA profiles at 12 months, though no statistically significant difference was observed between the study arms. There was no association between maternal HBGA profiles and infant vaccine immunogenicity. Overall, infant HBGAs were associated with RV vaccine immunogenicity at 12 months as opposed to in early infant life. Further investigation into the low efficacy of ROTARIX^® and appropriate intervention is key to unlocking the full vaccine benefits for U5 children. Full article

A major polymorphism in the fucosyltransferase2 (FUT2) gene influences risk of multiple gut diseases, but its impact on the microbiome of breastfed infants was unknown. In individuals with an active FUT2 enzyme (“secretors”), the intestinal mucosa is abundantly fucosylated, providing mutualist bacteria with a rich endogenous source of fucose. Non-secretors comprise approximately one-fifth of the population, and they lack the ability to create this enzyme. Similarly, maternal secretor status influences the abundance of a breastfeeding mother’s fucosylated milk oligosaccharides. We compared the impact of maternal secretor status, measured by FUT2 genotype, and infant secretor status, measured by FUT2 genotype and phenotype, on early infant fecal microbiome samples collected from 2-month-old exclusively breastfed infants (n = 59). Infant secretor status (19% non-secretor, 25% low-secretor, and 56% full-secretor) was more strongly associated with the infant microbiome than it was with the maternal FUT2 genotype. Alpha diversity was greater in the full-secretors than in the low- or non-secretor infants (p = 0.049). Three distinct microbial enterotypes corresponded to infant secretor phenotype (p = 0.022) and to the dominance of Bifidobacterium breve, B. longum, or neither (p < 0.001). Infant secretor status was also associated with microbial metabolic capacity, specifically, bioenergetics pathways. We concluded that in exclusively breastfed infants, infant—but not maternal—secretor status is associated with infant microbial colonization and metabolic capacity. Full article

Objectives: Recently, histo-blood group antigens (HBGAs) have been identified as receptors or attachment factors of several viral pathogens. Among rotaviruses, HBGAs interact with the outer viral protein, VP4, which has been identified as a potential susceptibility factor, although the findings are inconsistent throughout populations due to HBGA polymorphisms. We investigated the association between HBGA phenotypes and rotavirus infection in children with acute gastroenteritis in northern Pretoria, South Africa. Methods: Paired diarrheal stool and saliva samples were collected from children aged ≤ 59 months (n = 342) with acute moderate to severe diarrhea, attending two health care facilities. Rotaviruses in the stool samples were detected by commercial EIA and the rotavirus strains were characterized by RT-PCR targeting the outer capsid VP7 (G-type) and VP4 (P-type) antigens for genotyping. Saliva-based ELISAs were performed to determine A, B, H, and Lewis antigens for blood group typing. Results: Blood type O was the most common blood group (62.5%) in this population, followed by groups A (26.0%), B (9.3%), and AB (2.2%). The H1-based secretors were common (82.7%) compared to the non-secretors (17.3%), and the Lewis antigen positive phenotypes (Le^(a+b+)) were predominant (54.5%). Blood type A children were more likely to be infected by rotavirus (38.8%) than any other blood types. P[4] rotaviruses (21/49; 42.9%) infected only secretor individuals, whereas P[6] rotaviruses (3/49; 6.1%) only infected Le^(a−b−), although the numbers were very low. On the contrary, P[8] rotaviruses infected children with a wide range of blood group phenotypes, including Le^(a−b−) and non-secretors. Conclusions: Our findings demonstrated that Lewis antigens, or the lack thereof, may serve as susceptibility factors to rotaviral infection by specific VP4 genotypes as observed elsewhere. Potentially, the P[8] strains remain the predominant human VP4 genotype due to their ability to bind to a variety of HBGA phenotypes. Full article

Norovirus is the most common cause of acute non-bacterial gastroenteritis. Immunocompromised patients can become chronically infected, with or without symptoms. In Europe, common variable immunodeficiency (CVID) is one of the most common inborn errors of immunity. A potentially severe complication is CVID-associated enteropathy, a disorder with similar histopathology to celiac disease. Studies suggest that chronic norovirus infection may be a contributor to CVID enteropathy, and that the antiviral drug ribavirin can be effective against norovirus. Here, a patient with CVID-like disease with combined B- and T-cell deficiency, had chronic norovirus infection and enteropathy. The patient was routinely administered subcutaneous and intravenous immunoglobulin replacement therapy (SCIg and IVIg). The patient was also administered ribavirin for ~7.5 months to clear the infection. Stool samples (collected 2013–2016) and archived paraffin embedded duodenal biopsies were screened for norovirus by qPCR, confirming a chronic infection. Norovirus genotyping was done in 25 stool samples. For evolutionary analysis, the capsid (VP1) and polymerase (RdRp) genes were sequenced in 10 and 12 stool samples, respectively, collected before, during, and after ribavirin treatment. Secretor phenotyping was done in saliva, and serum was analyzed for histo-blood group antigen (HBGA) blocking titers. The chronic norovirus strain formed a unique variant subcluster, with GII.4 Den Haag [P4] variant, circulating around 2009, as the most recent common ancestor. This corresponded to the documented debut of symptoms. The patient was a secretor and had HBGA blocking titers associated with protection in immunocompetent individuals. Several unique amino acid substitutions were detected in immunodominant epitopes of VP1. However, HBGA binding sites were conserved. Ribavirin failed in treating the infection and no clear association between ribavirin-levels and quantity of norovirus shedding was observed. In conclusion, long term infection with norovirus in a patient with severe CVID led to the evolution of a unique norovirus strain with amino acid substitutions in immunodominant epitopes, but conservation within HBGA binding pockets. Regularly administered SCIg, IVIg, and ~7.5-month ribavirin treatment failed to clear the infection. Full article

Human milk oligosaccharides (HMOs) are the third most represented component in breast milk. They serve not only as prebiotics but they exert a protective role against some significant neonatal pathologies such as necrotizing enterocolitis. Furthermore, they can program the immune system and consequently reduce allergies and autoimmune diseases’ incidence. HMOs also play a crucial role in brain development and in the gut barrier’s maturation. Moreover, the maternal genetic factors influencing different HMO patterns and their modulation by the interaction and the competition between active enzymes have been widely investigated in the literature, but there are few studies concerning the role of other factors such as maternal health, nutrition, and environmental influence. In this context, metabolomics, one of the newest “omics” sciences that provides a snapshot of the metabolites present in bio-fluids, such as breast milk, could be useful to investigate the HMO content in human milk. The authors performed a review, from 2012 to the beginning of 2021, concerning the application of metabolomics to investigate the HMOs, by using Pubmed, Researchgate and Scopus as source databases. Through this technology, it is possible to know in real-time whether a mother produces a specific oligosaccharide, keeping into consideration that there are other modifiable and unmodifiable factors that influence HMO production from a qualitative and a quantitative point of view. Although further studies are needed to provide clinical substantiation, in the future, thanks to metabolomics, this could be possible by using a dipstick and adding the eventual missing oligosaccharide to the breast milk or formula in order to give the best and the most personalized nutritional regimen for each newborn, adjusting to different necessities. Full article

Among the human milk oligosaccharides (HMOS), the galactosyllactoses (GLs) are only limitedly studied. This study aims to describe the presence and relative levels of HMOS, including GLs, in human milk (HM) according to maternal Secretor and Lewis (SeLe) phenotype and lactation stage. Relative levels of 19 HMOS were measured in 715 HM samples collected in the first 4 months postpartum from 371 donors participating in the PreventCD study. From a subset of 24 Dutch women (171 HM samples), samples were collected monthly up to 12 months postpartum and were additionally analyzed for relative and absolute levels of β6′-GL, β3′-GL and α3′-GL. Maternal SeLe phenotype or HM group was assigned based on the presence of specific fucosylated HMOS. Most HMOS, including β6′- and β3′-GL, were present in the vast majority (≥75%) of HM samples, whereas others (e.g., LNDFH II, 2′-F-LNH and α3′-GL) only occurred in a low number (<25%) of samples. Clear differences were observed between the presence and relative levels of the HMOS according to the maternal phenotype and lactation stage. Absolute concentrations of β6′-GL and β3′-GL were higher in HM group IV samples compared to samples of the other three HM groups. β3′-GL was also higher in HM group II samples compared to HM group I samples. β3′-GL and β6′-GL were stable over lactation stages. In conclusion, presence and levels of HMOS vary according to HM group and lactation stage. Not all HMOS behave similarly: some HMOS depend strongly on maternal phenotype and/or lactation stage, whereas others do not. β3′-GL and β6′-GL were present in low concentrations in over 75% of the analyzed HM samples and showed differences between HM groups, but not between the lactation stages. Full article

Histo-blood group antigens, which are present on gut epithelial surfaces, function as receptors or attachment factors and mediate susceptibility to rotavirus infection. The major determinant for susceptibility is a functional FUT2 enzyme which mediates the presence of α-1,2 fucosylated blood group antigens in mucosa and secretions, yielding the secretor-positive phenotype. Secretors are more susceptible to infection with predominant rotavirus genotypes, as well as to the commonly used live rotavirus vaccines. Difference in susceptibility to the vaccines is one proposed factor for the varying degree of efficacy observed between countries. Besides infection susceptibility, secretor status has been found to modulate rotavirus specific antibody levels in adults, as well as composition of breastmilk in mothers and microbiota of the infant, which are other proposed factors affecting rotavirus vaccine take. Here, the known and possible effects of secretor status in both infant and mother on rotavirus vaccine take are reviewed and discussed. Full article

Host susceptibility according to human histo-blood group antigens (HBGAs) is widely known for norovirus infection, but is less described for rotavirus. Due to the variable HBGA polymorphism among populations, we aimed to evaluate the association between HBGA phenotypes (ABH, Lewis and secretor status) and susceptibility to rotavirus and norovirus symptomatic infection, and the polymorphisms of FUT2 and FUT3, of children from southeastern Brazil. Paired fecal-buccal specimens from 272 children with acute diarrhea were used to determine rotavirus/norovirus genotypes and HBGAs phenotypes/genotypes, respectively. Altogether, 100 (36.8%) children were infected with rotavirus and norovirus. The rotavirus P[8] genotype predominates (85.7%). Most of the noroviruses (93.8%) belonged to genogroup II (GII). GII.4 Sydney represented 76% (35/46) amongst five other genotypes. Rotavirus and noroviruses infected predominantly children with secretor status (97% and 98.5%, respectively). However, fewer rotavirus-infected children were Lewis-negative (8.6%) than the norovirus-infected ones (18.5%). FUT3 single nucleotide polymorphisms (SNP) occurred mostly at the T59G > G508A > T202C > C314T positions. Our results reinforce the current knowledge that secretors are more susceptible to infection by both rotavirus and norovirus than non-secretors. The high rate for Lewis negative (17.1%) and the combination of SNPs, beyond the secretor status, may reflect the highly mixed population in Brazil. Full article

Human milk oligosaccharides (HMOs) are bioactive molecules in human milk that play a critical role in infant health. Obesity and associated metabolic aberrations can negatively impact lactation and alter milk composition. Here, the relationship between maternal glucose homeostasis and HMO composition from 136 healthy women was examined. Maternal glucose homeostasis (fasting plasma glucose and insulin, homeostatic model assessment for insulin resistance, and insulin sensitivity index) was evaluated at 30 weeks of gestation in healthy women (body mass index = 18.5–35 kg/m²). Human milk samples were collected at two months postpartum. HMO concentrations were measured via high performance liquid chromatography. Women were categorized into “secretor” and “non-secretor” groups based on 2′-Fucosyllactose concentrations (<100 nmol/mL, non-secretor). Pearson’s correlation analysis and linear models were used to assess the relationships between maternal glucose homeostasis and HMO concentrations. In non-secretors, third trimester fasting plasma glucose and insulin were negatively associated with total HMO-bound sialic acid and concentrations of the sialylated HMOs 3′-sialyllactose and disialylacto-N-tetraose. In secretors, difucosyllactose and lacto-N-fucopentaose-II concentrations increased and sialyllacto-N-tetraose c and sialyllacto-N-tetraose b decreased as insulin sensitivity increased. This study is the first to demonstrate a relationship between obesity-associated maternal factors and HMO composition in both secretor and non-secretor populations. Full article

We aimed to identify if maternal and infant factors were associated with neutral human milk oligosaccharides (HMOs) variability and examined the associations between HMOs concentration and infant growth and disease status in healthy Chinese mothers over a 6-month lactation period. We recruited mothers and their full-term infants as our subjects. At 1–5 days, 8–14 days, 4 weeks, and 6 months postpartum, all participants were interviewed to collect breast milk samples, obtain follow-up data and measure infant length and weight at their local hospital. A total of 23 neutral HMOs were analyzed by high performance liquid chromatography (HPLC)- mass spectrometer (MS). Secretor and Lewis phenotype were determined by the concentration of 2′-fucosyllactose (2′-FL) and Lacto-N-fucopentaose (LNFP)-II. The associations between maternal and infant factors with HMOs concentrations were investigated. A total of 464 human breast milk samples were collected from 116 mothers at four different time points. In total, 76.7% mothers were found to be Secretor and Lewis positive phenotype (Se+Le+), 17.2% were Se-Le+, 4.3% were Se+Le-, and 1.7% were Se-Le-. Several individual HMOs, including 2′-FL, Lactodifucotetraose (LDFT), LNFP-I were determined by Secretor phenotype. Most individual HMOs decreased at the later stage of lactation, except 3′-FL. We suggest that Secretor phenotype and lactation stage could influence most of the neutral HMOs. Concentrations of specific HMOs may be associated with maternal age, allergic history, pre-pregnancy body mass index (BMI), parity, delivery mode, infant gestational age and gender. Full article