HMOs Impact the Gut Microbiome of Children and Adults Starting from Low Predicted Daily Doses.

Recent studies suggest that the dietary intake of human milk oligosaccharides (HMOs) provides health benefits from infancy up to adulthood. Thus far, beneficial changes in the adult gut microbiome have been observed at oral doses of 5-20 g/day of HMOs. Efficacy of lower doses has rarely been tested. We assessed four HMO molecular species-2'Fucosyllactose (2'FL), Lacto-N-neotetraose (LNnT), 3'Sialyllactose (3'SL), and 6'Sialyllactose (6'SL)-at predicted doses from 0.3 to 5 g/day for 6-year-old children and adults (n = 6 each), using ex vivo SIFR® technology (Cryptobiotix, Ghent, Belgium). This technology employing bioreactor fermentation on fecal samples enables us to investigate microbial fermentation products that are intractable in vivo given their rapid absorption/consumption in the human gut. We found that HMOs significantly increased short-chain fatty acids (SCFAs), acetate, propionate (in children/adults), and butyrate (in adults) from predicted doses of 0.3-0.5 g/day onwards, with stronger effects as dosing increased. The fermentation of 6'SL had the greatest effect on propionate, LNnT most strongly increased butyrate, and 2'FL and 3'SL most strongly increased acetate. An untargeted metabolomic analysis revealed that HMOs enhanced immune-related metabolites beyond SCFAs, such as aromatic lactic acids (indole-3-lactic acid/3-phenyllactic acid) and 2-hydroxyisocaproic acid, as well as gut-brain-axis-related metabolites (γ-aminobutyric acid/3-hydroxybutyric acid/acetylcholine) and vitamins. The effects of low doses of HMOs potentially originate from the highly specific stimulation of keystone species belonging to, for example, the Bifidobacteriaceae family, which had already significantly increased at doses of only 0.5 g/day LNnT (adults) and 1 g/day 2'FL (children/adults).

Bridging preclinical and clinical gut microbiota research using the ex vivo SIFR® technology.

Introduction: While modulation of the human adult gut microbiota is a trending strategy to improve health, the underlying mechanisms are poorly understood. Methods: This study aimed to assess the predictive value of the ex vivo, reactor-based, high-throughput SIFR® (Systemic Intestinal Fermentation Research) technology for clinical findings using three structurally different prebiotics [inulin (IN), resistant dextrin (RD) and 2'-fucosyllactose (2'FL)]. Results: The key finding was that data obtained within 1-2 days were predictive for clinical findings upon repeated prebiotic intake over weeks: among hundreds of microbes, IN stimulated Bifidobacteriaceae, RD boosted Parabacteroides distasonis, while 2'FL specifically increased Bifidobacterium adolescentis and Anaerobutyricum hallii. In line with metabolic capabilities of these taxa, specific SCFA (short-chain fatty acids) were produced thus providing insights that cannot be obtained in vivo where such metabolites are rapidly absorbed. Further, in contrast to using single or pooled fecal microbiota (approaches used to circumvent low throughput of conventional models), working with 6 individual fecal microbiota enabled correlations that support mechanistic insights. Moreover, quantitative sequencing removed the noise caused by markedly increased cell densities upon prebiotic treatment, thus allowing to even rectify conclusions of previous clinical trials related to the tentative selectivity by which prebiotics modulate the gut microbiota. Counterintuitively, not the high but rather the low selectivity of IN caused only a limited number of taxa to be significantly affected. Finally, while a mucosal microbiota (enriched with Lachnospiraceae) can be integrated, other technical aspects of the SIFR® technology are a high technical reproducibility, and most importantly, a sustained similarity between the ex vivo and original in vivo microbiota. Discussion: By accurately predicting in vivo results within days, the SIFR® technology can help bridge the so-called "Valley of Death" between preclinical and clinical research. Facilitating development of test products with better understanding of their mode of action could dramatically increase success rate of microbiome modulating clinical trials.Graphical Abstract.

HMOs Exert Marked Bifidogenic Effects on Children's Gut Microbiota Ex Vivo, Due to Age-Related Bifidobacterium Species Composition.

Prebiotics are substrates that are selectively utilized by host microorganisms, thus conferring a health benefit. There is a growing awareness that interpersonal and age-dependent differences in gut microbiota composition impact prebiotic effects. Due to the interest in using human milk oligosaccharides (HMOs) beyond infancy, this study evaluated how HMOs [2'Fucosyllactose (2'FL), Lacto-N-neotetraose (LNnT), 3'Sialyllactose (3'SL), 6'Sialyllactose (6'SL)] and blends thereof affect the microbiota of 6-year-old children (n = 6) and adults (n = 6), compared to prebiotics inulin (IN) and fructooligosaccharides (FOS). The ex vivo SIFR® technology was used, given its demonstrated predictivity in clinical findings. First, HMOs and HMO blends seemed to maintain a higher α-diversity compared to FOS/IN. Further, while 2'FL/LNnT were bifidogenic for both age groups, 3'SL/6'SL and FOS/IN were exclusively bifidogenic for children and adults, respectively. This originated from age-related differences in microbiota composition because while 3'SL/6'SL stimulated B. pseudocatenulatum (abundant in children), FOS/IN enhanced B. adolescentis (abundant in adults). Moreover, all treatments significantly increased acetate, propionate and butyrate (only in adults) with product- and age-dependent differences. Among the HMOs, 6'SL specifically stimulated propionate (linked to Bacteroides fragilis in children and Phocaeicola massiliensis in adults), while LNnT stimulated butyrate (linked to Anaerobutyricum hallii in adults). Indole-3-lactic acid and 3-phenyllactic acid (linked to immune health) and gamma-aminobutyric acid (linked to gut-brain axis) were most profoundly stimulated by 2'FL and HMO blends in both children and adults, correlating with specific Bifidobacteriaceae. Finally, 2'FL/LNnT increased melatonin in children, while 3'SL remarkably increased folic acid in adults. Overall, age-dependent differences in microbiota composition greatly impacted prebiotic outcomes, advocating for the development of age-specific nutritional supplements. HMOs were shown to be promising modulators in the adult, and particularly the children's microbiota. The observed HMO-specific effects, likely originating from their structural heterogeneity, suggest that blends of different HMOs could maximize treatment effects.

B-vitamins and cognitive function - what is the evidence? / Vitaminas del grupo B y la función cognitiva - ¿cuál es la evidencia?

Nutrition and micronutrients such as B-vitamins influence both mental and physical performance. It is well established that even mild micronutrient deficiencies can lead to reduced cognitive and physical capabilities. This is corroborated by strong epidemiological evidence indicating that micronutrient status can affect cognitive function at all ages. However, intervention studies with single or restricted vitamin ranges have yielded mixed results. On the other hand trials with multivitamins suggest efficacy in terms of cognitive and psychological functioning. A high-dose vitamin B supplement (Berocca) is one of the rare vitamin and mineral supplements being supported by multiple double-blind, randomized and placebo-controlled clinical trials as outlined in this review. This neurotropic unique vitamin combination containing water-soluble vitamins of the B complex, vitamin C and the minerals calcium, magnesium and zinc is backed up by extensive scientific evidence showing positive effects of supplementation in terms of brain function and mental performance and improvement of some aspects of physical fitness or performance. Given that a large section of the population is unable or unwilling to eat an adequately balanced diet that would satisfy micronutrient requirements it seems that supplementation with multi-vitamins/minerals may be a useful and possibly necessary option to improve their mental and physical performance (AU)

La nutrición y los micronutrientes, como las vitaminas del grupo B, influyen tanto en el rendimiento físico como en el mental. Está bien establecido que incluso deficiencias marginales de micronutrientes pueden afectar el rendimiento físico y cognitivo. Claras evidencias epidemiológicas lo corroboran, indicando que las concentraciones de micronutrientes pueden afectar la función cognitiva a cualquier edad. Sin embargo, los estudios de intervención con una única vitamina o con un número limitado de ellas han mostrado resultados contradictorios. Por otra parte estudios realizados con multivitamínicos sugieren eficacia en términos de función fisiológica y cognitiva. El complemento alimenticio con dosis altas de vitaminas del grupo B (Berocca) es uno de los pocos complementos vitamínicos y minerales soportados con múltiples estudios clínicos, doble ciego, randomizados y controlados con placebo, como se destaca en esta revisión. Esta combinación única de vitaminas neurotrópicas que incorpora todas las vitaminas hidrosolubles, el complejo B y la vitamina C y los minerales calcio, magnesio y zinc, tiene detrás una extensa evidencia científica que muestra los efectos positivos de la complementación, en términos de mejora del rendimiento mental y físico. Dado que para un amplio sector de la población puede ser difícil seguir una dieta equilibrada y completa que satisfaga todos los requerimientos de micronutrientes, parece que la complementación con multivitamínicos puede ser una opción para mejorar el rendimiento físico y mental (AU)

Higher accuracy of self-monitoring of blood glucose in insulin-treated patients in Germany: clinical and economical aspects.

BACKGROUND: Accuracy standards of blood glucose (BG) meters are currently under review. Revised standards are expected to tighten accuracy requirements. Regarding clinical and financial impact of BG meter accuracy, very little data are available. The aim of this study was to analyze potential cost savings related to higher accuracy of glucose meters in Germany. METHODS: As a model for calculation, a reduction of meter error from 20% to 5% was applied. The health economic analysis was based on four main pillars: (1) number of insulin-treated patients; (2) costs for glucose monitoring in Germany; (3) data of a modeling analysis on the impact on hypoglycemic episodes, glycosylated hemoglobin (HbA1c), and, subsequently, myocardial infarctions; and (4) costs of diabetes-related complications in Germany. A reduction of meter error from 20% to 5% was identified to be associated with a 10% reduction in severe hypoglycemic episodes and a 0.39% reduction in HbA1c, which translates into a 0.5% reduction of myocardial infarctions. RESULTS: According to the health economic analysis, the reduction in severe hypoglycemic episodes and myocardial infarctions led to cost savings of €24.14 per patient per year. Considering 390,000 type 1 diabetes patients or 2.3 million insulin-treated patients in Germany, these savings could be equal to a reduction in health care expenditures of more than €9.4 million and €55.5 million, respectively. CONCLUSIONS: Potential cost savings and clinical effects due to higher accuracy of BG meters should provide an impetus to implementation of tighter accuracy standards and development of glucose meters that provide highest possible accuracy.

Active assistance technology reduces glycosylated hemoglobin and weight in individuals with type 2 diabetes: results of a theory-based randomized trial.

BACKGROUND: Type 2 diabetes is an individual health challenge requiring ongoing self-management. Remote patient reporting of relevant health parameters and linked automated feedback via mobile telephone have potential to strengthen self-management and improve outcomes. This research involved development and evaluation of a mobile telephone-based remote patient reporting and automated telephone feedback system, guided by health behavior change theory, aimed at improving self-management and health status in individuals with type 2 diabetes. SUBJECTS AND METHODS: This research comprised a randomized controlled trial. Inclusion criteria were diagnosis of type 2 diabetes, elevated glycosylated hemoglobin (HbA1c) levels (range, 6.5-11%) or use of oral diabetes medication, and 30-70 years of age. Intervention subjects (n=24) participated in remote patient reporting of health status parameters and linked health behavior change feedback. Control participants (n=24) received standard of care including diabetes education and healthcare provider counseling. Patients were followed for approximately 10 months. RESULTS: Intervention participants achieved, compared with controls and controlling for baseline, a significantly greater mean reduction in HbA1c of -0.40% (95% confidence interval [CI] -0.67% to -0.14%) versus 0.036% (95% CI -0.23% to 0.30%) (P<0.03) and significantly greater weight reduction of -2.1 kg (95% CI -3.6 to -0.6 kg) versus 0.4 kg (95% CI -1.1 to 1.9 kg). Nonsignificant trends for greater intervention compared with control improvement in systolic and diastolic blood pressure were observed. CONCLUSIONS: Sophisticated information technology platforms for remote patient reporting linked with theory-based health behavior change automated feedback have potential to improve patient outcomes in type 2 diabetes and merit scaled-up research efforts.

A pediatric diabetes toolbox for creating centres of reference.

INTRODUCTION: ISPAD guidelines recommend age appropriate diabetes education concepts for young patients and their families as well as tools for nutritional management, psychosocial assessment, and psychological advice but their implementation in Europe is presently unknown. METHODS: On the basis of a structured survey among the European SWEET members information on established tools and programs in national languages were analyzed using an extensive literature and desk search. These were differentiated according to five age-groups and five target groups (young people with diabetes, parents, and other close relations, carers in school and nursery, and healthcare professionals). RESULTS: Responses and original tools were received from 11 SWEET countries reflecting the European status in 2011. More or less structured information for parents, close relations, and carers in school or nursery are available in all 11 participating countries. However, only two countries followed the recommendations of having published a structured, curriculum lead, and evaluated program for different age-groups and carers. One of these was evaluated nationwide and funded by the respective National Health Care System after accreditation. In addition a huge variety of creative tools, e.g., booklets, leaflets, games, videos, and material for educating children of different age-groups and their parents are available - but most of them are not linked to a structured education program. CONCLUSIONS: Harmonizing and integrating these materials into quality assured structured holistic national education programs will be an important future task for the ongoing SWEET project. A comprehensive European diabetes educational toolbox is aimed to be published and continuously updated on the SWEET website.

Supplementation with a multivitamin containing 800 microg of folic acid shortens the time to reach the preventive red blood cell folate concentration in healthy women.

BACKGROUND: The lowest risk of having a child with a neural tube defect (NTD) was related to red blood cell (RBC) folate concentrations of >906 nmol/L. For NTD prevention, it is recommended that women use periconceptional supplementation of 400 microg/day folic acid. Using this dose previous studies indicate that RBC folate >906 nmol/L was not reached within four weeks of supplementation. OBJECTIVE: The effectiveness of a multivitamin/multimineral supplement containing 800 microg folic acid (verum) was evaluated using RBC folate concentration exceeding 906 nmol/L as primary endpoint. In addition, the time frame of achieving the threshold level was established as well as the effect of supplementation of other B vitamins on folate metabolism. SUBJECTS AND METHODS: 46 healthy females received 800 microg/day of folic acid or placebo for 16 weeks. Blood samples were collected in four-week intervals. Plasma and RBC folate were measured with the microbiological method. RESULTS: Mean (+/-SED) RBC folate increased over time to 1430+/-53 nmol/L, but did not reach a steady state after 16 weeks of intervention. Mean time to reach the target level was 4.2 +/- 3.5 weeks in the verum group. Intake of verum also led to an increase over time of plasma folate. CONCLUSIONS: Preventive RBC folate concentration of more than 906 nmol/L can be reached within four weeks of supplementation with daily intake of 800 microg folic acid. With respect to NTD prevention, we suggest the re-evaluation of the current recommendation of folic acid supplementation.

Selected vitamins and trace elements support immune function by strengthening epithelial barriers and cellular and humoral immune responses.

Adequate intakes of micronutrients are required for the immune system to function efficiently. Micronutrient deficiency suppresses immunity by affecting innate, T cell mediated and adaptive antibody responses, leading to dysregulation of the balanced host response. This situation increases susceptibility to infections, with increased morbidity and mortality. In turn, infections aggravate micronutrient deficiencies by reducing nutrient intake, increasing losses, and interfering with utilization by altering metabolic pathways. Insufficient intake of micronutrients occurs in people with eating disorders, in smokers (active and passive), in individuals with chronic alcohol abuse, in certain diseases, during pregnancy and lactation, and in the elderly. This paper summarises the roles of selected vitamins and trace elements in immune function. Micronutrients contribute to the body's natural defences on three levels by supporting physical barriers (skin/mucosa), cellular immunity and antibody production. Vitamins A, C, E and the trace element zinc assist in enhancing the skin barrier function. The vitamins A, B6, B12, C, D, E and folic acid and the trace elements iron, zinc, copper and selenium work in synergy to support the protective activities of the immune cells. Finally, all these micronutrients, with the exception of vitamin C and iron, are essential for antibody production. Overall, inadequate intake and status of these vitamins and trace elements may lead to suppressed immunity, which predisposes to infections and aggravates malnutrition. Therefore, supplementation with these selected micronutrients can support the body's natural defence system by enhancing all three levels of immunity.

Contribution of selected vitamins and trace elements to immune function.

Adequate intakes of vitamins and trace elements are required for the immune system to function efficiently. Micronutrient deficiency suppresses immune functions by affecting the innate T-cell-mediated immune response and adaptive antibody response, and leads to dysregulation of the balanced host response. This increases the susceptibility to infections, with increased morbidity and mortality. In turn, infections aggravate micronutrient deficiencies by reducing nutrient intake, increasing losses, and interfering with utilization by altering metabolic pathways. Insufficient intake of micronutrients occurs in people with eating disorders, in smokers (both active and passive), in individuals with chronic alcohol abuse, in patients with certain diseases, during pregnancy and lactation, and in the elderly. With aging a variety of changes are observed in the immune system, which translate into less effective innate and adaptive immune responses and increased susceptibility to infections. Antioxidant vitamins and trace elements (vitamins C, E, selenium, copper, and zinc) counteract potential damage caused by reactive oxygen species to cellular tissues and modulate immune cell function through regulation of redox-sensitive transcription factors and affect production of cytokines and prostaglandins. Adequate intake of vitamins B(6), folate, B(12), C, E, and of selenium, zinc, copper, and iron supports a Th1 cytokine-mediated immune response with sufficient production of proinflammatory cytokines, which maintains an effective immune response and avoids a shift to an anti-inflammatory Th2 cell-mediated immune response and an increased risk of extracellular infections. Supplementation with these micronutrients reverses the Th2 cell-mediated immune response to a proinflammatory Th1 cytokine-regulated response with enhanced innate immunity. Vitamins A and D play important roles in both cell-mediated and humoral antibody response and support a Th2-mediated anti-inflammatory cytokine profile. Vitamin A deficiency impairs both innate immunity (mucosal epithelial regeneration) and adaptive immune response to infection resulting in an impaired ability to counteract extracellular pathogens. Vitamin D deficiency is correlated with a higher susceptibility to infections due to impaired localized innate immunity and defects in antigen-specific cellular immune response. Overall, inadequate intake and status of these vitamins and minerals may lead to suppressed immunity, which predisposes to infections and aggravates malnutrition.

Immune-enhancing role of vitamin C and zinc and effect on clinical conditions.

Vitamin C concentrations in the plasma and leukocytes rapidly decline during infections and stress. Supplementation of vitamin C was found to improve components of the human immune system such as antimicrobial and natural killer cell activities, lymphocyte proliferation, chemotaxis, and delayed-type hypersensitivity. Vitamin C contributes to maintaining the redox integrity of cells and thereby protects them against reactive oxygen species generated during the respiratory burst and in the inflammatory response. Likewise, zinc undernutrition or deficiency was shown to impair cellular mediators of innate immunity such as phagocytosis, natural killer cell activity, and the generation of oxidative burst. Therefore, both nutrients play important roles in immune function and the modulation of host resistance to infectious agents, reducing the risk, severity, and duration of infectious diseases. This is of special importance in populations in which insufficient intake of these nutrients is prevalent. In the developing world, this is the case in low- and middle-income countries, but also in subpopulations in industrialized countries, e.g. in the elderly. A large number of randomized controlled intervention trials with intakes of up to 1 g of vitamin C and up to 30 mg of zinc are available. These trials document that adequate intakes of vitamin C and zinc ameliorate symptoms and shorten the duration of respiratory tract infections including the common cold. Furthermore, vitamin C and zinc reduce the incidence and improve the outcome of pneumonia, malaria, and diarrhea infections, especially in children in developing countries.