ABSTRACT
Breast milk exerts pivotal regulatory functions early in development whereby it contributes to the maturation of brain and associated cognitive functions. However, the specific components of maternal milk mediating this process have remained elusive. Sialylated human milk oligosaccharides (HMOs) represent likely candidates since they constitute the principal neonatal dietary source of sialic acid, which is crucial for brain development and neuronal patterning. We hypothesize that the selective neonatal lactational deprivation of a specific sialylated HMOs, sialyl(alpha2,3)lactose (3'SL), may impair cognitive capabilities (attention, cognitive flexibility, and memory) in adulthood in a preclinical model. To operationalize this hypothesis, we cross-fostered wild-type (WT) mouse pups to B6.129-St3gal4tm1.1Jxm/J dams, knock-out (KO) for the gene synthesizing 3'SL, thereby providing milk with approximately 80% 3'SL content reduction. We thus exposed lactating WT pups to a selective reduction of 3'SL and investigated multiple cognitive domains (including memory and attention) in adulthood. Furthermore, to account for the underlying electrophysiological correlates, we investigated hippocampal long-term potentiation (LTP). Neonatal access to 3'SL-poor milk resulted in decreased attention, spatial and working memory, and altered LTP compared to the control group. These results support the hypothesis that early-life dietary sialylated HMOs exert a long-lasting role in the development of cognitive functions.
Subject(s)
Cognition/drug effects , Milk, Human/chemistry , Oligosaccharides/deficiency , Adult , Animals , Attention/drug effects , Female , Hippocampus/drug effects , Humans , Lactation , Memory, Short-Term/drug effects , Mice , Mice, Knockout , Spatial Navigation/drug effectsABSTRACT
BACKGROUND: Despite the efficacy of a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) for patients with irritable bowel syndrome, many questions remain unanswered with respect to its clinical implementation. AIM: To review literature to identify, synthesise, and provide direction for future research in the implementation and evaluation of the low FODMAP diet. METHODS: Bibliographical searches were performed in Ovid Medline, CINAHL, Scopus and PubMed from database commencement until September 2018, with search terms focused on the population (irritable bowel syndrome) and intervention of interest (FODMAP). RESULTS: Predictors of response to a low FODMAP diet remain under investigation, with preliminary data supporting faecal microbiota or faecal volatile organic compound profiling. Training of clinicians, and standards for the education of patients about the phases of a low FODMAP diet, as well as the role of Apps, require formal evaluation. There are limited data on the longer term efficacy and safety of the low FODMAP diet with respect to sustained symptom control, effect on quality of life and healthcare utilisation, nutritional adequacy, precipitation of disordered eating behaviours, effects on faecal microbiota and metabolomic markers, and subsequent translation to clinical effects. CONCLUSIONS: Many gaps in implementation of the low FODMAP diet in clinical practice, as well as long-term safety and efficacy, remain for further investigation.
Subject(s)
Diet, Carbohydrate-Restricted/methods , Disaccharides/deficiency , Irritable Bowel Syndrome/diet therapy , Monosaccharides/deficiency , Oligosaccharides/deficiency , Polymers , Disaccharides/metabolism , Fermentation/physiology , Gastrointestinal Microbiome/physiology , Humans , Irritable Bowel Syndrome/diagnosis , Irritable Bowel Syndrome/metabolism , Monosaccharides/metabolism , Oligosaccharides/metabolism , Polymers/metabolism , Prospective Studies , Quality of Life , Randomized Controlled Trials as Topic/methodsSubject(s)
ABO Blood-Group System/analysis , Blood Grouping and Crossmatching , Leukemia, Erythroblastic, Acute/immunology , Oligosaccharides/deficiency , Adolescent , Agglutination Tests , Anemia/chemically induced , Anemia/immunology , Anemia/therapy , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Blood Group Incompatibility/prevention & control , Blood Grouping and Crossmatching/methods , Coombs Test , Cytarabine/administration & dosage , Cytarabine/adverse effects , Daunorubicin/administration & dosage , Daunorubicin/adverse effects , Erythrocyte Transfusion , Fatal Outcome , Female , Humans , Leukemia, Erythroblastic, Acute/complications , Leukemia, Erythroblastic, Acute/drug therapy , Oligosaccharides, Branched-Chain , Plant Lectins , Platelet Transfusion , Sepsis/etiologyABSTRACT
Early postnatal development encounters milk as a key environmental variable and yet the sole nutrient source. One evolutionary conserved constituent of milk is sialic acid, which is generally displayed on glycoconjugates and free glycans. During early postnatal development, high sialic acid need was proposed to be unmet by the endogenous sialic acid synthetic capacity. Hence, milk sialic acid was proposed to serve as a conditional nutrient for the newborn. In the elderly, at the other end of ontogeny, decreased sialylation in the brain, saliva, and immune system is observed. Analogous to the neonatal situation, the endogenous synthetic capacity may be unable to keep up with the need in this age group. The data discussed here propose a functional dietary role of sialic acid as a building block for sialylation and beyond.
Subject(s)
Milk, Human/chemistry , Sialic Acids/metabolism , Aged, 80 and over , Animals , Glycoconjugates/analysis , Humans , Infant , Infant Nutritional Physiological Phenomena , Infant, Newborn , Lactose/administration & dosage , Lactose/analogs & derivatives , Lactose/deficiency , Models, Animal , Oligosaccharides/administration & dosage , Oligosaccharides/deficiencyABSTRACT
Many microbial pathogens alter expression and/or posttranslational modifications of their surface proteins in response to dynamics within their host microenvironments to retain optimal interactions with their host cells and/or to evade the humoral immune response. Anaplasma phagocytophilum is an intragranulocytic bacterium that utilizes sialyl Lewis x (sLe(x))-modified P-selectin glycoprotein ligand 1 as a receptor for infecting myeloid cells. Bacterial populations that do not rely on this receptor can be obtained through cultivation in sLe(x)-defective cell lines. A. phagocytophilum major surface protein 2 [Msp2(P44)] is encoded by members of a paralogous gene family and is speculated to play roles in host adaptation. We assessed the complement of Msp2(P44) paralogs expressed by A. phagocytophilum during infection of sLe(x)-competent HL-60 cells and two HL-60 cell lines defective for sLe(x) expression. Multiple Msp2(P44) and N-terminally truncated 25- to 27-kDa isoforms having various isoelectric points and electrophoretic mobilities were expressed in each cell line. The complement of expressed msp2(p44) paralogs and the glycosyl residues modifying Msp2(P44) varied considerably among bacterial populations recovered from sLe(x)-competent and -deficient host cells. Thus, loss of host cell sLe(x) expression coincided with both differential expression and glycosylation of A. phagocytophilum Msp2(P44). This reinforces the hypothesis that this bacterium is able to generate a large variety of surface-exposed molecules that could provide great antigenic diversity and result in multiple binding properties.
Subject(s)
Anaplasma phagocytophilum/physiology , Bacterial Outer Membrane Proteins/biosynthesis , Gene Expression Profiling , Neutrophils/microbiology , Oligosaccharides/deficiency , Anaplasma phagocytophilum/chemistry , Bacterial Outer Membrane Proteins/isolation & purification , Cell Line , Electrophoresis, Gel, Two-Dimensional , Glycosylation , Humans , Proteome/analysis , Sialyl Lewis X AntigenABSTRACT
Galactosialidosis (MIM 256540) is an autosomal recessive lysosomal storage disease caused by a defect of the protective protein/cathepsin A. Increased amounts of urinary sialic acid-rich oligosaccharides are considered to be an essential diagnostic marker of the disease. We here report a patient with atypical clinical features who consistently has excreted normal amounts of sialyloligosaccharides in the urine. The boy started to have attacks of neuropathic pain associated with hyperesthesia around 1(1/2) years of age. From 4 years of age when his vision was first tested, the patient developed progressive visual loss and at the age of 10 years, macular cherry-red spots were found. At this age, he also had a mild learning disability and clinical examination showed mild facial coarsening, increased lumbar lordosis and pyramidal signs in the legs. In conclusion, the clinical and laboratory features of this patient show that galactosialidosis may be considered in patients even in the absence of oligosacchariduria and that galactosialidosis should be regarded as a differential diagnosis in patients with neuropathic pain.
Subject(s)
Lysosomal Storage Diseases/complications , Neuralgia/complications , Oligosaccharides/deficiency , Child , Humans , Lysosomal Storage Diseases/urine , Male , Neuralgia/urine , Oligosaccharides/urineABSTRACT
Anaplasma phagocytophilum, the causative agent of human granulocytic anaplasmosis, is an obligate intracellular bacterium that infects neutrophils and neutrophil precursors. Bacterial recognition of P-selectin glycoprotein ligand-1 (PSGL-1) and the alpha2,3-sialylated- and alpha1,3-fucosylated-moiety sialyl-Lewis x (sLe(x)), which modifies the PSGL-1 N terminus, is important for adhesion to and invasion of myeloid cells. We have previously demonstrated that A. phagocytophilum organisms of the NCH-1 strain that utilize an sLe(x)-modified PSGL-1-independent means of entry can be enriched for by cultivation in undersialylated HL-60 cells that are unable to construct sLe(x). Because it was unknown whether other A. phagocytophilum isolates share this ability, we extended our studies to the geographically diverse strains HZ and HGE1. HL-60 A2 is a clonal cell line that is defective for sialylation and alpha1,3-fucosyltransferase. HL-60 A2 cell surfaces, therefore, not only lack sLe(x) but also are virtually devoid of any other sialic acid- and/or alpha1,3-fucose-modified glycan. By cultivating HZ and HGE1 in HL-60 A2 cells, we enriched for bacterial subpopulations (termed HZA2 and HGE1A2) that bind and/or infect myeloid cells in the absence of sialic acid and alpha1,3-fucose and in the presence of antibody that blocks the N terminus of PSGL-1. Thus, multiple A. phagocytophilum isolates share the ability to use sLe(x)-modified PSGL-1-dependent and -independent routes of entry into myeloid cells. HZA2 and HGE1A2 represent enriched bacterial populations that will aid dissection of the complexities of the interactions between A. phagocytophilum and host myeloid cells.
Subject(s)
Anaplasma phagocytophilum/pathogenicity , Ehrlichiosis/microbiology , Myeloid Cells/immunology , Oligosaccharides/deficiency , Bacterial Adhesion/physiology , Cell Line, Tumor , Ehrlichiosis/immunology , Fucose/chemistry , HL-60 Cells , Humans , Membrane Glycoproteins/immunology , Membrane Glycoproteins/metabolism , Myeloid Cells/microbiology , N-Acetylneuraminic Acid/chemistry , Neutrophils/immunology , Oligosaccharides/blood , Oligosaccharides/metabolism , Sialyl Lewis X AntigenABSTRACT
Knock-out (KO) mice lacking gangliotetraose gangliosides attributable to disruption of the gene for GM2/GD2 synthase [GalNAcT (UDP-N-acetylgalactosamine:GM3/GD3 beta-1,4-N-acetylgalactosaminyltransferase; EC 2.4.1.92 [EC])] are revealing key neural functions for the complex gangliosides of brain. This study has found such animals to be highly susceptible to kainic acid (KA)-induced seizures in terms of both seizure severity and duration. Intraperitoneal injection of 25 mg/kg KA produced status epilepticus for approximately 200 min in normal mice or heterozygotes and more than four times longer in the KO mice. The latter group suffered approximately 30% mortality, which increased to approximately 75% at dosage of 30 mg/kg KA, compared with 10-14% for the other two genotypes at the latter dosage. Nissl staining and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling assay revealed substantial deterioration of pyramidal neurons attributable to apoptosis in the KO hippocampus, especially the CA3 region. Seizure activity in the KO mouse was only moderately diminished by intraperitoneal injection of GM1 ganglioside, whereas LIGA 20, a semisynthetic analog of GM1, substantially reduced both seizure severity and cell damage. The potency of LIGA 20 was correlated with its enhanced membrane permeability (compared with GM1), as seen in the increased uptake of [3H]LIGA 20 into the subcellular fractions of brain including cell nuclei. The latter finding is consonant with LIGA 20-induced restoration of the Na+/Ca2+ exchanger located at the inner membrane of the nuclear envelope in KO mice, an exchanger dependent on tight association with GM1 or its analog for optimal activity. These results point to a neuroprotective role for GM1 and its associated exchanger in the nucleus, based on regulation of Ca2+ flux between nucleoplasm and nuclear envelope.
Subject(s)
Apoptosis , G(M1) Ganglioside/analogs & derivatives , Gangliosides/metabolism , Kainic Acid , Neurons , Neuroprotective Agents/pharmacology , Seizures/mortality , Seizures/physiopathology , Sphingosine/analogs & derivatives , Animals , Apoptosis/drug effects , Brain/metabolism , Disease Susceptibility , G(M1) Ganglioside/deficiency , G(M1) Ganglioside/pharmacokinetics , G(M1) Ganglioside/pharmacology , Gangliosides/deficiency , Hippocampus/physiopathology , Mice , Mice, Inbred C57BL , Mice, Knockout , N-Acetylgalactosaminyltransferases/deficiency , Oligosaccharides/deficiency , Seizures/chemically induced , Sodium-Calcium Exchanger/drug effects , Sodium-Calcium Exchanger/metabolism , Sphingosine/pharmacokinetics , Sphingosine/pharmacology , Status Epilepticus/chemically induced , Status Epilepticus/physiopathology , Time FactorsABSTRACT
The interaction of L-selectin on lymphocytes with sulfated ligands on high endothelial venules leads to rolling and is critical for recruitment of lymphocytes into peripheral lymph nodes. Peripheral node addressin represents a class of L-selectin ligands recognized by the function-blocking monoclonal antibody MECA-79. Its epitope overlaps with sialyl 6-sulfo Lewis X, an L-selectin recognition determinant. Here, mice lacking two N-acetylglucosamine-6-O-sulfotransferases (GlcNAc6ST-1 and GlcNAc6ST-2) demonstrated elimination of both peripheral node addressin and sialyl 6-sulfo Lewis X in high endothelial venules, considerably reduced lymphocyte homing to peripheral lymph nodes and reduced sticking of lymphocytes along high endothelial venules. Our results establish an essential function for the sulfotransferases in L-selectin ligand synthesis and may have relevance for therapy of inflammatory diseases.
Subject(s)
B-Lymphocytes/immunology , Endothelium, Lymphatic/enzymology , L-Selectin/metabolism , Leukocyte Rolling , Membrane Proteins/deficiency , Oligosaccharides/deficiency , Sulfotransferases/deficiency , Acetylglucosamine/analogs & derivatives , Acetylglucosamine/metabolism , Animals , Antigens, Surface , B-Lymphocytes/enzymology , E-Selectin/immunology , Endothelium, Lymphatic/immunology , L-Selectin/immunology , Lewis X Antigen/analogs & derivatives , Ligands , Lymph Nodes/cytology , Lymph Nodes/immunology , Mice , Mice, Knockout , Mutation , Sialyl Lewis X Antigen/analogs & derivatives , Sulfotransferases/genetics , Carbohydrate SulfotransferasesABSTRACT
The plasma and nuclear membranes of neural cells have been shown to express gangliosides to a limited extent before, and at increasing levels during, differentiation. Recent studies employing qualitative cytochemistry have shown that GM1 expression in particular is significantly elevated in both membranes by specific neuritogenic agents. The present study provides a more complete description of ganglioside patterns of the 2 membranes of NG108-15 cells and a mutated form of the latter lacking gangliotetraose gangliosides. Nuclei of wild type NG108-15 cells were found to contain predominantly GM1 and GD1a, whereas whole cells had those in addition to substantial amounts of GM2 and GM3. GM1 and GD1a levels increased 2--3.5-fold in both whole cells and nuclei following axonogenic stimulation, but changed little in response to dendritogenic agents. GM2 expression, limited to the plasma membrane, showed little if any change with axonogenic stimuli but a 1.5--2-fold increase following treatment with dendritogenic agents. GM3 resembled GM2 in being virtually absent from the nuclear membrane, while its presence in the plasma membrane showed only modest change at most with any of the stimuli. The gangliotetraose ganglioside-deficient mutant cell line, NG-CR72, had significantly higher basal levels of GM2 in the plasma membrane compared to wild type NG108-15 cells, and this level increased significantly on treatment with dendritogenic agents. Basal GM3 levels were greatly reduced in the mutant cells and changed little with any of the stimuli. As expected, nuclei of NG-CR72 cells were virtually devoid of gangliosides. These mutant cells were previously shown to extend well defined dendritic neurites but were incapable of forming stable axonal processes. This study thus demonstrates major differences in the ganglioside content of wild type and mutated NG108-15 cells and their nuclei, and in their response to different neuritogenic stimuli.