Night workers with circadian misalignment are susceptible to alcohol-induced intestinal hyperpermeability with social drinking.

Alcohol-induced intestinal hyperpermeability (AIHP) is a known risk factor for alcoholic liver disease (ALD), but only 20-30% of heavy alcoholics develop AIHP and ALD. The hypothesis of this study is that circadian misalignment would promote AIHP. We studied two groups of healthy subjects on a stable work schedule for 3 mo [day workers (DW) and night workers (NW)]. Subjects underwent two circadian phase assessments with sugar challenge to access intestinal permeability between which they drank 0.5 g/kg alcohol daily for 7 days. Sleep architecture by actigraphy did not differ at baseline or after alcohol between either group. After alcohol, the dim light melatonin onset (DLMO) in the DW group did not change significantly, but in the NW group there was a significant 2-h phase delay. Both the NW and DW groups had no change in small bowel permeability with alcohol, but only in the NW group was there an increase in colonic and whole gut permeability. A lower area under the curve of melatonin inversely correlated with increased colonic permeability. Alcohol also altered peripheral clock gene amplitude of peripheral blood mononuclear cells in CLOCK, BMAL, PER1, CRY1, and CRY2 in both groups, and inflammatory markers lipopolysaccharide-binding protein, LPS, and IL-6 had an elevated mesor at baseline in NW vs. DW and became arrhythmic with alcohol consumption. Together, our data suggest that central circadian misalignment is a previously unappreciated risk factor for AIHP and that night workers may be at increased risk for developing liver injury with alcohol consumption.

Immune biomarkers in the spectrum of childhood noncommunicable diseases.

A biomarker is an accurately and reproducibly quantifiable biological characteristic that provides an objective measure of health status or disease. Benefits of biomarkers include identification of therapeutic targets, monitoring of clinical interventions, and development of personalized (or precision) medicine. Challenges to the use of biomarkers include optimizing sample collection, processing and storage, validation, and often the need for sophisticated laboratory and bioinformatics approaches. Biomarkers offer better understanding of disease processes and should benefit the early detection, treatment, and management of multiple noncommunicable diseases (NCDs). This review will consider the utility of biomarkers in patients with allergic and other immune-mediated diseases in childhood. Typically, biomarkers are used currently to provide mechanistic insight or an objective measure of disease severity, with their future role in risk stratification/disease prediction speculative at best. There are many lessons to be learned from the biomarker strategies used for cancer in which biomarkers are in routine clinical use and industry-wide standardized approaches have been developed. Biomarker discovery and validation in children with disease lag behind those in adults; given the early onset and therefore potential lifelong effect of many NCDs, there should be more studies incorporating cohorts of children. Many pediatric biomarkers are at the discovery stage, with a long path to evaluation and clinical implementation. The ultimate challenge will be optimization of prevention strategies that can be implemented in children identified as being at risk of an NCD through the use of biomarkers.

Neurodevelopment of Preterm Infants at 24 Months After Neonatal Supplementation of a Prebiotic Mix: A Randomized Trial.

OBJECTIVES: Fetal brain maturation is disrupted by preterm birth. Inflammation during the neonatal period may further harm neurodevelopmental outcomes. The present study aimed to determine the effect of short-chain galacto-oligosaccharides/long-chain fructo-oligosaccharides/pectin-derived acidic oligosaccharides (scGOS/lcFOS/pAOS) on neurodevelopmental outcomes measured by Bayley Scales of Infant and Toddler Development in preterm infants at 24 months. METHODS: In this randomized controlled trial, scGOS/lcFOS/pAOS or placebo was supplemented between days 3 and 30 of life. Serum samples at day 1, 7, and 14 were analyzed for cytokine levels. Stool samples at day 1, 7, 14, and 30 were measured for bacterial count and bifidobacteria percentage. At 24 months corrected age infants were followed up by a blinded pediatric psychologist for the Bayley Scales of Infant and Toddler Development II or III. RESULTS: Seventy-seven of one hundred one (76%) eligible infants participated in the follow-up study. Neurodevelopmental outcomes were not different in the scGOS/lcFOS/pAOS and placebo group. Infections during the neonatal period, lower percentages of bifidobacteria at day 7 (F = 3.8, P = 0.05) and day 14 (F = 5.0, P = 0.02) and higher levels of Interleukine (IL)-1ß (F = 4.0, P = 0.04) and IL-8 (F = 8.0, P = 0.01) at day 7 are associated with lower mental developmental index. Lower psychomotor outcomes are associated with IL-2 (F = 4.0, P = 0.05), IL-4 (F = 6.0, P = 0.02) at birth, and interferon gamma at day 7 (F = 4.4, P = 0.04). CONCLUSIONS: scGOS/lcFOS/pAOS showed no significant improvement of neurodevelopmental outcomes at 24 months in preterm infants. Infections, lower bifidobacteria counts, and higher serum cytokine levels during the neonatal period were associated with lower neurodevelopmental outcomes at 24 months of age indicating the relevance of microbiome and immune responses in neurodevelopmental processes.

Response on Pneumococcal Vaccine in Preterm Infants After Neutral and Acidic Oligosaccharides Supplementation.

BACKGROUND: Supplementation of oligosaccharides in premature infants was shown to influence the immune system. We determined the effect of combined short-chain galacto-oligosaccharides (scGOS), long-chain fructo-oligosaccharides (lcFOS) and pectin-derived acidic oligosaccharides (pAOS) on antibody concentrations after pneumococcal conjugate vaccination in very preterm infants. METHODS: Very preterm infants with gestational age <32 weeks and/or birth weight <1500 g were randomized to receive enteral supplementation with scGOS/lcFOS/pAOS or placebo between days 3 and 30 of life. Blood samples were collected at birth, 5 and 12 months of age and compared with term samples from a Dutch cross-sectional population-based serosurveillance study. IgG antibody levels to pneumococcal capsular polysaccharides were determined by multiplex immunoassay. RESULTS: In total, 113 preterm infants were included with similar baseline and nutritional characteristics in both groups. After 3 primary pneumococcal vaccinations, the scGOS/lcFOS/pAOS-group had lower GMC antibody concentrations (µg/mL; serotype 4: 1.53, 6B:0.25, 9V: 1.19, 14: 2.39, 18C: 1.88, 19F: 7.42, 23F: 0.72) than the placebo group (serotype 4: 3.29, 6B: 0.79, 9V:2.64, 14: 4.52, 18C: 3.13, 19F: 14.64, 23F: 1.88; all P < 0.05), but comparable with those in the term control group (serotype 4: 0.97, 6B: 0.32, 9V: 1.67, 14: 3.24, 18C: 2.03, 19F: 5.06, 23F: 0.59; all P > 0.05). After the booster vaccination at 11 months, antibody levels were no longer different between the two preterm groups. CONCLUSION: Enteral supplementation of scGOS/lcFOS/pAOS has a regulatory effect on the response to conjugated polysaccharide pneumococcal vaccine with normalization of the enhanced responses in preterm infants toward levels similar to healthy term infants.

Lower transplacental antibody transport for measles, mumps, rubella and varicella zoster in very preterm infants.

BACKGROUND: Maternal antibodies, transported over the placenta during pregnancy, contribute to the protection of infants from infectious diseases during the first months of life. In term infants, this protection does not last until the first recommended measles-mumps-rubella vaccination at 14 months in the Netherlands, while these viruses still circulate. The aim of the study was to investigate the antibody concentration against measles, mumps, rubella and varicella (MMRV) in mothers and preterm infants or healthy term infants at birth. METHODS: Antibody concentrations specific for MMRV were measured in cord blood samples from preterm (gestational age <32 weeks and/or birth weight <1500 g) and term infants, and matched maternal serum samples, using a fluorescent bead-based multiplex immune-assay. RESULTS: Due to lower placental transfer ratios of antibodies against MMRV in 96 preterm infants (range 0.75-0.87) compared to 42 term infants (range 1.39-1.65), the preterm infants showed 1.7-2.5 times lower geometric mean concentrations at birth compared to term infants. Maternal antibody concentration is the most important determinant of infant antibody concentration against MMRV. CONCLUSIONS: Preterm infants benefit to a lesser extent from maternal antibodies against measles, mumps, rubella and varicella than term infants, posing them even earlier at risk for infectious diseases caused by these still circulating viruses.

Neonatal modulation of serum cytokine profiles by a specific mixture of anti-inflammatory neutral and acidic oligosaccharides in preterm infants.

Infections are common in preterm infants and cause differences in cytokine levels. Aim of this study was to measure cytokine levels in preterm infants during the first year of life and to determine the effect of feeding a specific non-digestible carbohydrate mixture (scGOS/lcFOS/pAOS). Furthermore, other perinatal factors in relation to these cytokine levels were analysed. In a randomized controlled trial, preterm infants (GA <32weeks and/or birth weight <1500 g) received a scGOS/lcFOS/pAOS mixture or a placebo (maltodextrin) between days 3 and 30 of life. Cytokine levels (IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-17, IFN-γ, and TNF-α) were analysed at 5 time points during the study: before start of the study, at day 7, at day 14 and at 5 and 12 months after the start of the intervention. In total, 55 preterm infants in the scGOS/lcFOS/pAOS group and 58 in the placebo group were included. During the neonatal period cytokine levels increased, followed by a decrease at 5 months and 12 months. Enteral supplementation of the non-digestible oligosaccharides decreased cytokine levels at day 7 but not at day 14, indicating a temporarily anti-inflammatory effect. In the neonatal period, serious infection before sampling increased all cytokine levels. In conclusion, enteral supplementation of this specific non-digestible oligosaccharide mixture decreased cytokine levels in preterm infants at day 7 of life, although this effect disappeared thereafter.

Neutral and acidic oligosaccharides supplementation does not increase the vaccine antibody response in preterm infants in a randomized clinical trial.

BACKGROUND: In preterm infants, a decreased immunological response and lower serological effectiveness are observed after immunizations due to ineffectiveness of both humoral and cellular immune mechanisms. OBJECTIVE: To determine the effect of 80% neutral oligosaccharides [small-chain galacto-oligosaccharides/long-chain fructo-oligosaccharides (scGOS/lcFOS)] in combination with 20% pectin-derived acidic oligosaccharides (pAOS) on antibody concentrations after DTaP-IPV-Hib immunization in preterm infants. DESIGN: In this randomized clinical trial, preterm infants with gestational age <32 weeks and/or birth weight <1500 g received enteral supplementation with scGOS/lcFOS/pAOS or placebo (maltodextrin) between days 3 and 30 of life. Blood samples were collected at 5 and 12 months of age. RESULTS: In total, 113 infants were included. Baseline and nutritional characteristics were not different in both groups. Geometric mean titers were not different after prebiotic supplementation at 5 months, Ptx (37/44 EU/ml), FHA (78/96 EU/ml), Prn (78/80 EU/ml), Diphtheria (0.40/0.57 IU/ml), Tetanus (0.74/0.99 IU/ml) and Hib (0.35/0.63 µg/ml), and at 12 months Ptx (55/66 EU/ml), FHA (122/119 EU/ml), Prn (116/106 Eu/ml), Diphtheria (0.88/1.11 IU/ml), Tetanus (1.64/1.79 IU/ml) and Hib (2.91/2.55 µg/ml). CONCLUSIONS: Enteral supplementation of neutral (scGOS/lcFOS) and acidic oligosaccharides (pAOS) does not improve the immunization response in preterm infants. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN16211826 ISRCTN16211826.

Transplacental transport of IgG antibodies specific for pertussis, diphtheria, tetanus, haemophilus influenzae type b, and Neisseria meningitidis serogroup C is lower in preterm compared with term infants.

BACKGROUND: Maternal antibodies, transported through the placenta during pregnancy, contribute to the protection of infants from infectious diseases during the first months of life. The aim of this study was to measure the concentration of antibodies against several vaccine-preventable diseases in paired maternal and cord blood serum samples in preterm and term infants and to assess placental transfer ratios and infant antibody concentrations against vaccine-preventable diseases. METHODS: Antibody concentrations specific against pertussis proteins (pertussis toxin, filamentous hemagglutinin, pertactin, and fimbriae), diphtheria and tetanus toxins, and antibody concentrations specific against polysaccharides from Haemophilus influenzae type b and Neisseria meningitidis serogroup C were measured in cord blood samples from preterm (<32 weeks and 1500 g) and term infants and maternal serum samples, using a fluorescent bead-based multiplex immunoassay. RESULTS: A total of 96 preterm and 42 term infants and their mothers were included in the study. Placental transfer ratios of antibodies against all vaccine antigens were significantly lower in preterm infants (medians varied from 0.26 to 0.86) compared with term infants (medians, 0.74-1.89; all antibodies P < 0.05). Furthermore, polysaccharide-vaccine-specific antibodies showed lower transplacental transport ratios than protein-vaccine-specific antibodies. Maternal concentrations are the most important determinants of infant antibody concentrations against vaccine-preventable diseases. CONCLUSIONS: Preterm infants benefit to a lesser extent from maternal antibodies against vaccine-preventable diseases than term infants, posing them at higher risk for infectious diseases in the first months of life.

Neutral and acidic oligosaccharides in preterm infants: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Serious infectious morbidity is high in preterm infants. Enteral supplementation of prebiotics may reduce the incidence of serious infections, especially infections related to the gastrointestinal tract. OBJECTIVE: The objective was to determine the effect of enteral supplementation of a prebiotic mixture consisting of neutral oligosaccharides ((SC)GOS/(LC)FOS) and acidic oligosaccharides (AOS) on serious infectious morbidity in preterm infants. DESIGN: In a randomized controlled trial, preterm infants (gestational age <32 wk and/or birth weight <1500 g) received enteral supplementation of 80% (SC)GOS/(LC)FOS and 20% AOS (1.5 g . kg(-1) . d(-1)) or placebo (maltodextrin) between days 3 and 30 of life. Serious infectious morbidity was defined as a culture positive for sepsis, meningitis, pyelonephritis, or pneumonia. The analysis was performed by intention-to-treat and per-protocol, defined as > or =50% supplementation dose during the study period. RESULTS: In total, 113 preterm infants were included. Baseline and nutritional characteristics were not different between groups. In the intention-to-treat analysis, the incidence of > or =1 serious infection, > or =1 serious endogenous infection, or > or =2 serious infectious episodes was not significantly different in the (SC)GOS/(LC)FOS/AOS-supplemented and placebo groups. In the per-protocol analysis, there was a trend toward a lower incidence of > or =1 serious endogenous infection and > or =2 serious infectious episodes in the (SC)GOS/(LC)FOS/AOS-supplemented group than in the placebo group (P = 0.09 and P = 0.07, respectively). CONCLUSIONS: Enteral supplementation of (SC)GOS/(LC)FOS/AOS does not significantly reduce the risk of serious infectious morbidity in preterm infants. However, there was a trend toward a lower incidence of serious infectious morbidity, especially for infections with endogenous bacteria. This finding suggests a possible beneficial effect that should be evaluated in a larger study. This trial was registered at isrctn.org as ISRCTN16211826.

Design of a randomised controlled trial on immune effects of acidic and neutral oligosaccharides in the nutrition of preterm infants: carrot study.

BACKGROUND: Prevention of serious infections in preterm infants is a challenge, since prematurity and low birth weight often requires many interventions and high utility of devices. Furthermore, the possibility to administer enteral nutrition is limited due to immaturity of the gastrointestinal tract in the presence of a developing immune system. In combination with delayed intestinal bacterial colonisation compared with term infants, this may increase the risk for serious infections. Acidic and neutral oligosaccharides play an important role in the development of the immune system, intestinal bacterial colonisation and functional integrity of the gut. This trial aims to determine the effect of enteral supplementation of acidic and neutral oligosaccharides on infectious morbidity (primary outcome), immune response to immunizations, feeding tolerance and short-term and long-term outcome in preterm infants. In addition, an attempt is made to elucidate the role of acidic and neutral oligosaccharides in postnatal modulation of the immune response and postnatal adaptation of the gut. METHODS/DESIGN: In a double-blind placebo controlled randomised trial, 120 preterm infants (gestational age <32 weeks and/or birth weight <1500 gram) are randomly allocated to receive enteral acidic and neutral oligosaccharides supplementation (20%/80%) or placebo supplementation (maltodextrin) between day 3 and 30 of life. Primary outcome is infectious morbidity (defined as the incidence of serious infections). The role of acidic and neutral oligosaccharides in modulation of the immune response is investigated by determining the immune response to DTaP-IPV-Hib(-HBV)+PCV7 immunizations, plasma cytokine concentrations, faecal Calprotectin and IL-8. The effect of enteral acidic and neutral oligosaccharides supplementation on postnatal adaptation of the gut is investigated by measuring feeding tolerance, intestinal permeability, intestinal viscosity, and determining intestinal microflora. Furthermore, short-term and long-term outcome are evaluated. DISCUSSION: Especially preterm infants, who are at increased risk for serious infections, may benefit from supplementation of prebiotics. Most studies with prebiotics only focus on the colonisation of the intestinal microflora. However, the pathways how prebiotics may influence the immune system are not yet fully understood. Studying the immune modulatory effects is complex because of the multicausal risk of infections in preterm infants. The combination of neutral oligosaccharides with acidic oligosaccharides may have an increased beneficial effect on the immune system. Increased insight in the effects of prebiotics on the developing immune system may help to decrease the (infectious) morbidity and mortality in preterm infants. TRIAL REGISTRATION: Current Controlled Trials ISRCTN16211826.