Micronutrients at Supplemental Levels, Tight Junctions and Epithelial Barrier Function: A Narrative Review.

Disease modifiers, whether from cancer, sepsis, systemic inflammation, or microbial pathogens, all appear to induce epithelial barrier leak, with induced changes of the Tight Junctional (TJ) complex being pivotal to the process. This leak-and the ensuant breakdown of compartmentation-plays a central role in disease morbidity on many levels. Accumulation of lung water in the luminal compartment of airways was a major driver of morbidity and mortality in COVID-19 and is an excellent example of the phenomenon. Increasing awareness of the ability of micronutrients to improve basal barrier function and reduce barrier compromise in pathophysiology may prove to be a low-cost, safe, and easily administered prophylactic and/or therapeutic option amenable to large populations. The growing appreciation of the clinical utility of supplemental doses of Vitamin D in COVID-19 is but one example. This narrative review is intended to propose a general theory on how and why micronutrients-at levels above normal dietary intake-successfully remodel TJs and improve barrier function. It discusses the key difference between dietary/Recommended Daily Allowance (RDA) levels of micronutrients versus supplemental levels, and why the latter are needed in disease situations. It advances a hypothesis for why signal transduction regulation of barrier function may require these higher supplemental doses to achieve the TJ remodeling and other barrier element changes that are clinically beneficial.

Micronutrients, genetics and COVID-19.

PURPOSE OF REVIEW: Marked inter-individual differences in the clinical manifestation of coronavirus disease 2019 (COVID-19) has initiated studies in the field of genetics. This review evaluates recent genetic evidence (predominantly in the last 18 months) related to micronutrients (vitamins and trace elements) and COVID-19. RECENT FINDINGS: In patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), altered circulating levels of micronutrients may serve as prognostic markers of disease severity. Mendelian randomization (MR) studies did not find significant effect of variable genetically predicted levels of micronutrients on COVID-19 phenotypes, however, recent clinical studies on COVID-19 point out to vitamin D and zinc supplementation as a nutritional strategy to reduce disease severity and mortality. Recent evidence also points to variants in vitamin D receptor ( VDR ) gene, most notably rs2228570 (FokI) "f" allele and rs7975232 (ApaI) "aa" genotype as poor prognostic markers. SUMMARY: Since several micronutrients were included in the COVID-19 therapy protocols, research in the field of nutrigenetics of micronutrients is in progress. Recent findings from MR studies prioritize genes involved in biological effect, such as the VDR gene, rather than micronutrient status in future research. Emerging evidence on nutrigenetic markers may improve patient stratification and inform nutritional strategies against severe COVID-19.

The role of maternal choline, folate and one-carbon metabolism in mediating the impact of prenatal alcohol exposure on placental and fetal development.

Prenatal alcohol consumption (PAE) may be associated with a broad spectrum of impacts, ranging from no overt effects, to miscarriage, fetal growth restriction and fetal alcohol spectrum disorder. A major mechanism underlying the effects of PAE is considered to be altered DNA methylation and gene expression. Maternal nutritional status may be an important factor in determining the extent to which PAE impacts pregnancy outcomes, particularly the dietary micronutrients folate and choline because they provide methyl groups for DNA methylation via one carbon metabolism. This review summarises the roles of folate and choline in development of the blastocyst, the placenta and the fetal brain, and examines the evidence that maternal intake of these micronutrients can modify the effects of PAE on development. Studies of folate or choline deficiency have found reduced blastocyst development and implantation, reduced placental invasion, vascularisation and nutrient transport capability, impaired fetal brain development, and abnormal neurodevelopmental outcomes. PAE has been shown to reduce absorption and/or metabolism of folate and choline and to produce similar outcomes to maternal choline/folate deficiency. A few studies have demonstrated that the effects of PAE on brain development can be ameliorated by folate or choline supplementation; however, there is very limited evidence on the effects of supplementation in early pregnancy on the blastocyst and placenta. Further studies are required to support these findings and to determine optimal supplementation parameters.

Alterations in Antioxidant Micronutrient Concentrations in Placental Tissue, Maternal Blood and Urine and the Fetal Circulation in Pre-eclampsia.

Trace elements such as selenium and zinc are vital components of many enzymes, including endogenous antioxidants, and can interact with each other. Women with pre-eclampsia, the hypertensive disease of pregnancy, have been reported as having changes in some individual antioxidant trace elements during pregnancy, which are related to maternal and fetal mortality and morbidity. We hypothesised that examination of the three compartments of (a) maternal plasma and urine, (b) placental tissue and (c) fetal plasma in normotensive and hypertensive pregnant women would allow identification of biologically significant changes and interactions in selenium, zinc, manganese and copper. Furthermore, these would be related to changes in the angiogenic markers, placental growth factor (PlGF) and Soluble Fms-Like Tyrosine Kinase-1 (sFlt-1) concentrations. Venous plasma and urine were collected from healthy non-pregnant women (n = 30), normotensive pregnant controls (n = 60) and women with pre-eclampsia (n = 50) in the third trimester. Where possible, matched placental tissue samples and umbilical venous (fetal) plasma were also collected. Antioxidant micronutrient concentrations were measured by inductively coupled plasma mass-spectrometry. Urinary levels were normalised to creatinine concentration. Plasma active PlGF and sFlt-1 concentrations were measured by ELISA. Maternal plasma selenium, zinc and manganese were all lower in women with pre-eclampsia (p < 0.05), as were fetal plasma selenium and manganese (p < 0.05 for all); maternal urinary concentrations were lower for selenium and zinc (p < 0.05). Conversely, maternal and fetal plasma and urinary copper concentrations were higher in women with pre-eclampsia (p < 0.05). Differences in placental concentrations varied, with lower overall levels of selenium and zinc (p < 0.05) in women with pre-eclampsia. Maternal and fetal PlGF were lower and sFlt-1 higher in women with pre-eclampsia; maternal plasma zinc was positively correlated with maternal plasma sFlt-1 (p < 0.05). Because of perceptions that early- and late-onset pre-eclampsia have differing aetiologies, we subdivided maternal and fetal data accordingly. No major differences were observed, but fetal sample sizes were small following early-onset. Disruption in these antioxidant micronutrients may be responsible for some of the manifestations of pre-eclampsia, including contributing to an antiangiogenic state. The potential benefits of mineral supplementation, in women with deficient intakes, during pregnancy to reduce pre-eclampsia remain an important area for experimental and clinical research.

Nutrition, Immunosenescence, and Infectious Disease: An Overview of the Scientific Evidence on Micronutrients and on Modulation of the Gut Microbiota.

The immune system is key to host defense against pathogenic organisms. Aging is associated with changes in the immune system, with a decline in protective components (immunosenescence), increasing susceptibility to infectious disease, and a chronic elevation in low-grade inflammation (inflammaging), increasing the risk of multiple noncommunicable diseases. Nutrition is a determinant of immune cell function and of the gut microbiota. In turn, the gut microbiota shapes and controls the immune and inflammatory responses. Many older people show changes in the gut microbiota. Age-related changes in immune competence, low-grade inflammation, and gut dysbiosis may be interlinked and may relate, at least in part, to age-related changes in nutrition. A number of micronutrients (vitamins C, D, and E and zinc and selenium) play roles in supporting the function of many immune cell types. Some trials report that providing these micronutrients as individual supplements can reverse immune deficits in older people and/or in those with insufficient intakes. There is inconsistent evidence that this will reduce the risk or severity of infections including respiratory infections. Probiotic, prebiotic, or synbiotic strategies that modulate the gut microbiota, especially by promoting the colonization of lactobacilli and bifidobacteria, have been demonstrated to modulate some immune and inflammatory biomarkers in older people and, in some cases, to reduce the risk and severity of gastrointestinal and respiratory infections, although, again, the evidence is inconsistent. Further research with well-designed and well-powered trials in at-risk older populations is required to be more certain about the role of micronutrients and of strategies that modify the gut microbiota-host relationship in protecting against infection, especially respiratory infection.

Importance of micronutrients and organic nitrogen in fermentations with Torulaspora delbrueckii and Saccharomyces cerevisiae.

The current use of non-Saccharomyces yeasts in mixed fermentations increases the relevance of the interactions between yeast species. In this work, the interactions between Saccharomyces cerevisiae and Torulaspora delbrueckii were analyzed. For this purpose, fermentations with and without contact between strains of those yeast species were performed in synthetic must. Fermentation kinetics, yeast growth and dynamics were measured over time. Additionally, the effects of nitrogen and other nutrient supplementations on the mixed fermentations were determined. Our results showed that S. cerevisiae did not always dominate the sequential fermentations, and experiments without yeast contact (in which T. delbrueckii cells were removed from the medium before inoculating S. cerevisiae at 48 h) resulted in stuck fermentations except when the inoculum size was increased (from 2 × 106 to 108 cells/mL) or there was a supplementation of thiamine, zinc and amino acids at the same concentration as initially found in the synthetic must. Our findings highlight the importance of inoculum size and ensuring the availability of enough micronutrients for all yeast species, especially in sequential fermentations.

Interaction between selenium and essential micronutrient elements in plants: A systematic review.

Nutrient imbalance (i.e., deficiency and toxicity) of microelements is an outstanding environmental issue that influences each aspect of ecosystems. Although the crucial roles of microelements in entire lifecycle of plants have been widely acknowledged, the effective control of microelements is still neglected due to the narrow safe margins. Selenium (Se) is an essential element for humans and animals. Although it is not believed to be indispensable for plants, many literatures have reported the significance of Se in terms of the uptake, accumulation, and detoxification of essential microelements in plants. However, most papers only concerned on the antagonistic effect of Se on metal elements in plants and ignored the underlying mechanisms. There is still a lack of systematic review articles to summarize the comprehensive knowledge on the connections between Se and microelements in plants. In this review, we conclude the bidirectional effects of Se on micronutrients in plants, including iron, zinc, copper, manganese, nickel, molybdenum, sodium, chlorine, and boron. The regulatory mechanisms of Se on these micronutrients are also analyzed. Moreover, we further emphasize the role of Se in alleviating element toxicity and adjusting the concentration of micronutrients in plants by altering the soil conditions (e.g., adsorption, pH, and organic matter), promoting microbial activity, participating in vital physiological and metabolic processes, generating element competition, stimulating metal chelation, organelle compartmentalization, and sequestration, improving the antioxidant defense system, and controlling related genes involved in transportation and tolerance. Based on the current understanding of the interaction between Se and these essential elements, future directions for research are suggested.

The Roles and Pathogenesis Mechanisms of a Number of Micronutrients in the Prevention and/or Treatment of Chronic Hepatitis, COVID-19 and Type-2 Diabetes Mellitus.

A trace element is a chemical element with a concentration (or other measures of an amount) that is very low. The essential TEs, such as copper (Cu), selenium (Se), zinc (Zn), iron (Fe) and the electrolyte magnesium (Mg) are among the most commonly studied micronutrients. Each element has been shown to play a distinctive role in human health, and TEs, such as iron (Fe), zinc (Zn) and copper (Cu), are among the essential elements required for the organisms' well-being as they play crucial roles in several metabolic pathways where they act as enzyme co-factors, anti-inflammatory and antioxidant agents. Epidemics of infectious diseases are becoming more frequent and spread at a faster pace around the world, which has resulted in major impacts on the economy and health systems. Different trace elements have been reported to have substantial roles in the pathogenesis of viral infections. Micronutrients have been proposed in various studies as determinants of liver disorders, COVID-19 and T2DM risks. This review article sheds light on the roles and mechanisms of micronutrients in the pathogenesis and prevention of chronic hepatitis B, C and E, as well as Coronavirus-19 infection and type-2 diabetes mellitus. An update on the status of the aforementioned micronutrients in pre-clinical and clinical settings is also briefly summarized.

The neuroprotective roles of Dietary Micronutrients on Parkinson's disease: a review.

Parkinson's disease (PD) is a prevalent elderly neurodegenerative disease. The nature of PD is strongly bounded with certain cellular processes, including oxidative stress, neuro-inflammation, apoptosis, and mitochondrial dysfunction. Therefore, many clinical and pre-clinical studies have reported protective effects of certain dietary micronutrients for PD. Hence, this review tried to introduce a series of important dietary micronutrients, which to our best of knowledge, were among those compounds known as beneficial for PD with a high consensus. The compounds possess neuroprotective properties (e.g. anti-oxidation, anti-inflammation, anti-apoptosis, boosting mitochondrial performance, regulating autophagy process). Thus, the compounds probably may act on several cellular targets to prevent the development of PD or to attenuate the progress of the disease. Investigating these compounds probably can lead to the development of novel supplementary therapeutic approaches, as well as refinement of dietary regimen of PD patients.

Leafy vegetables fortification enhanced the nutritional profile and reduced the glycemic index of yellow cassava pasta.

Food-to-food fortification of yellow cassava flour with leafy vegetable powders (Amaranthus and Telfairia occidentalis) was employed in this study to develop cassava-vegetable spaghetti-like pasta products (YP, YPA5, YPA10, YPU5, YPU10, YPA5O). The nutritional profile, micronutrient retention, bioaccessibility, starch digestibility and in vitro glycemic index were assessed. The incorporation of leafy vegetable powder enhanced the nutritional quality of the yellow cassava pasta (YCP) products. The fortification increased (up to 3-fold) the protein in fortified YCP, increased the fibre (11%), doubled the ash and increased the beta-carotene (about 7-fold), iron (72%) and zinc contents by 10%. The phenolic content of fluted pumpkin leaf-fortified pasta with 10% leaf powder inclusion (YPU10) was 1100 µg GAE g-1, almost four times higher than that of the unfortified YCP. Leaf powders in the cassava pasta also favoured the retention of micronutrients during cooking and slowed down the starch digestibility. The retention during cooking was up to 91% in YPU10 for beta-carotene with no loss in iron, while the bioaccessibility of beta-carotene was impeded, the zinc retention was high and became significantly more bioaccessible with leaf addition and cooking. The estimated glycemic index of YCP was reduced by 19% and 15% in YPU10 and YPA10, respectively. The inclusion of the vegetables also reduced the glycemic index of the fortified YCP. Thus, adding leafy vegetable powder up to 10% into YCP is a promising approach to both valorise yellow provitamin A biofortified cassava and enhance the nutritional value.

Micronutrient Improvement of Epithelial Barrier Function in Various Disease States: A Case for Adjuvant Therapy.

The published literature makes a very strong case that a wide range of disease morbidity associates with and may in part be due to epithelial barrier leak. An equally large body of published literature substantiates that a diverse group of micronutrients can reduce barrier leak across a wide array of epithelial tissue types, stemming from both cell culture as well as animal and human tissue models. Conversely, micronutrient deficiencies can exacerbate both barrier leak and morbidity. Focusing on zinc, Vitamin A and Vitamin D, this review shows that at concentrations above RDA levels but well below toxicity limits, these micronutrients can induce cell- and tissue-specific molecular-level changes in tight junctional complexes (and by other mechanisms) that reduce barrier leak. An opportunity now exists in critical care-but also medical prophylactic and therapeutic care in general-to consider implementation of select micronutrients at elevated dosages as adjuvant therapeutics in a variety of disease management. This consideration is particularly pointed amidst the COVID-19 pandemic.

Micronutrient deficiencies in heart failure: Mitochondrial dysfunction as a common pathophysiological mechanism?

Heart failure is a devastating clinical syndrome, but current therapies are unable to abolish the disease burden. New strategies to treat or prevent heart failure are urgently needed. Over the past decades, a clear relationship has been established between poor cardiac performance and metabolic perturbations, including deficits in substrate uptake and utilization, reduction in mitochondrial oxidative phosphorylation and excessive reactive oxygen species production. Together, these perturbations result in progressive depletion of cardiac adenosine triphosphate (ATP) and cardiac energy deprivation. Increasing the delivery of energy substrates (e.g., fatty acids, glucose, ketones) to the mitochondria will be worthless if the mitochondria are unable to turn these energy substrates into fuel. Micronutrients (including coenzyme Q10, zinc, copper, selenium and iron) are required to efficiently convert macronutrients to ATP. However, up to 50% of patients with heart failure are deficient in one or more micronutrients in cross-sectional studies. Micronutrient deficiency has a high impact on mitochondrial energy production and should be considered an additional factor in the heart failure equation, moving our view of the failing myocardium away from an "an engine out of fuel" to "a defective engine on a path to self-destruction." This summary of evidence suggests that supplementation with micronutrients-preferably as a package rather than singly-might be a potential therapeutic strategy in the treatment of heart failure patients.

Micronutrient homeostasis in plants for more sustainable agriculture and healthier human nutrition.

The provision of sustainable, sufficient, and nutritious food to the growing population is a major challenge for agriculture and the plant research community. In this respect, the mineral micronutrient content of food crops deserves particular attention. Micronutrient deficiencies in cultivated soils and plants are a global problem that adversely affects crop production and plant nutritional value, as well as human health and well-being. In this review, we call for awareness of the importance and relevance of micronutrients in crop production and quality. We stress the need for better micronutrient nutrition in human populations, not only in developing but also in developed nations, and describe strategies to identify and characterize new varieties with high micronutrient content. Furthermore, we explain how adequate nutrition of plants with micronutrients impacts metabolic functions and the capacity of plants to express tolerance mechanisms against abiotic and biotic constraints. Finally, we provide a brief overview and a critical discussion on current knowledge, future challenges, and specific technological needs for research on plant micronutrient homeostasis. Research in this area is expected to foster the sustainable development of nutritious and healthy food crops for human consumption.

Phospholipid and menthol based nanovesicle impregnated transdermal patch for nutraceutical delivery to diminish folate and iron deficiency.

Adequate micronutrient availability is particularly important in women, children and infants. Micronutrient deficiencies are the major cause of maternal and neonatal morbidity. To overcome this, WHO recommends the use of folic acid and iron supplements for reducing anaemia and improving the health of the mother and infants. Oral intake of supplements for nutritional deficiencies are associated with gastric irritation, nausea, constipation and non-patient compliance due to associated taste. In case of absorption deficiency nutrients administered orally pass-through digestive tract unabsorbed. In the present study, we propose transdermal delivery of nutraceuticals to avoid the limitations associated with oral intake. Transdermal delivery has limited use because of the closely packed barrier of the stratum corneum that limits the permeability of molecules across skin. Here, we have used biomimetic nanovesicles impregnated in transdermal patches for delivery of folic acid and iron. Nanovesicles are prepared using an abundant component of cell membrane, phosphatidyl choline and a permeation enhancer. Further these nanovesicles are impregnated onto polyacrylate based transdermal patch.In vitrostudies have shown the ability of nanovesicles to fluidise skin lipids and penetrate into deeper skin.In vivoapplication of transdermal patches gradually increased the systemic concentration of nutraceuticals. Post application of the patch, five-fold increase in plasma folic acid concentration and 1.5-fold increase in plasma iron concertation was achieved in 6 h. Developed nanovesicles were compatible with keratinocytes and fibroblasts as testedin vitroand have the potential to enhance the cellular uptake of molecules. Skin irritation studies on human volunteers have confirmed the safety of nutraceutical loaded nanovesicles. Thus, the developed nutraceutical loaded transdermal patches provide a potential, easy to use platform for micronutrient delivery in infants and mothers.

Ameliorative effect of enhanced Fischer ratio flaxseed protein hydrolysate in combination with antioxidant micronutrients on ethanol-induced hepatic damage in a rat model.

Alcohol abuse causes severe metabolic abnormalities inducing hepatic damage and malnutrition. Since higher Fischer ratio proteins have therapeutic value in liver diseases, an investigation was undertaken to study the ameliorative effect of the enhanced Fischer ratio flaxseed protein hydrolysate (EFR-FPH) alone and in combination with antioxidant micronutrients on ethanol-induced hepatotoxicity in a rat model. The EFR-FPH was prepared by dual enzymatic hydrolysis and charcoal treatment of flaxseed protein. The ratio of the branched-chain:aromatic amino acids (Fischer ratio) was found to be 7·08. The EFR-FPH, characterised using LC-MS/MS, showed the abundance of free leucine and isoleucine compared with phenylalanine and tyrosine. The matrix-assisted laser desorption/ionisation-time of flight MS analysis revealed the larger peptides present in EFR-FPH with mass 2·3 kDa. The EFR-FPH improved the nutritional status, liver function and antioxidant defense in the ethanol hepatotoxicity-induced rat model. The hepatoprotective effect of EFR-FPH was significantly enhanced when combined with selenium or vitamin E. Ethanol-induced changes in the liver tissue were effectively suppressed in the groups receiving EFR-FPH. Flaxseed-based hepatoprotective dietary supplement was formulated incorporating an optimum level of EFR-FPH (10 %) based on sensory acceptability and was fortified with selenium and vitamin E. The hepatoprotective formulation significantly lowered aspartate transaminase, alanine transaminase, alkaline phosphatase and bilirubin by 47, 61, 55 and 78 %, respectively, and improved the antioxidant defense in the ethanol hepatotoxicity-induced rat model. The current investigation suggests that EFR-FPH in synergy with antioxidant micronutrients is potent in ameliorating ethanol-induced hepatotoxicity and has a potential to form a hepatoprotective dietary supplement.

Selenium-associated differentially expressed microRNAs and their targeted mRNAs across the placental genome in two U.S. birth cohorts.

Selenium is an important micronutrient for foetal development. MicroRNAs play an important role in the function of the placenta, in communication between the placenta and maternal systems, and their expression can be altered through environmental and nutritional cues. To investigate the associations between placental selenium concentration and microRNA expression in the placenta, our observational study included 393 mother-child pairs from the New Hampshire Birth Cohort Study (NHBCS) and the Rhode Island Child Health Study (RICHS). Placental selenium concentrations were quantified using inductively coupled plasma mass spectrometry, and microRNA transcripts were measured using RNA-seq. We fit negative binomial additive models for assessing the association between selenium and microRNAs. We used the microRNA Data Integration Portal (mirDIP) to predict the target mRNAs of the differentially expressed microRNAs and verified the relationships between miRNA and mRNA targets in a subset of samples using existing whole transcriptome data (N = 199). We identified a non-monotonic association between selenium concentration and the expression of miR-216a-5p/miR-217-5p cluster (effective degrees of freedom, EDF = 2.44 and 2.08; FDR = 3.08 × 10-5) in placenta. Thirty putative target mRNAs of miR-216a-5p and/or miR-217-5p were identified computationally and empirically and were enriched in selenium metabolic pathways (driven by selenoprotein coding genes, TXNRD2 and SELENON). Our findings suggest that selenium influences placental microRNA expression. Further, miR-216a-5p and its putative target mRNAs could be the potential mechanistic targets of the health effect of selenium.

Acceptability of home fortification with multiple micro-nutrients among Sri Lankan children.

Micronutrient deficiencies are mostly hidden; clinically less visible compared to macronutrient deficiencies. Food fortification with multiple micronutrients (MMN) is provided for children between 6-23 months, daily for two months at three-time points. We assessed the acceptance and adherence of this nutritional intervention in an urban community setting in Sri Lanka. This cross-sectional study enrolled caregivers of children aged 7 to 23 months with a cluster sampling method. Caregivers ' acceptance of taste and smell, health gains, ease of use, and need perception (Cronbach's reliability: 0.801) were assessed. Also, anemia knowledge (Cronbach's reliability: 0.642), MMN knowledge, and reported adherence (number of sachets consumed per month) were evaluated through a self-administered questionnaire. Adequate adherence was defined as the use of ≥80% sachets. The univariate and multivariate statistical analysis examined the association of acceptability, adherence, and anemia knowledge with independent variables (socio-demographic, household characteristics, and knowledge). The survey included 153 respondents. The Median (range) age of children was 12 months (7-23). The mean (SD) acceptability score was 66.82% (9.78%). Acceptance of sensory qualities (smell/taste) had a lower score than perceived health benefit. Most consumed MMN adequately (72.5%). The mean (SD) anemia knowledge score was 62.20% (25.79%). In multivariate analysis, child's age (OR: -0.360, 95% CI:-0.510,-0.211) and father's education (OR: 2.148, 95% CI: 0.439, 3.857) were independently associated with acceptability. Child's age (OR: -0.108, 95% CI:0.818, 0.985), anemia knowledge (OR:0.016, 95% CI: 1.003, 1.031) and acceptability (OR:0.236, 95% CI:1.140, 1.406) were significant determinants of adherence. Anemia knowledge was significantly associated with the mother's education and household income when adjusted. In conclusion, unpleasant smell/taste and daily schedule were reported as barriers to MMN use. Yet, perception and trust regarding health benefits were encouraging. Reported adherence was somewhat high. Improving acceptability and anemia knowledge could enhance adherence further in this population.

BMI, Alcohol Consumption and Gut Microbiome Species Richness Are Related to Structural and Functional Neurological Abnormalities.

Background: The incidence of neurological diseases is increasing throughout the world. The aim of the present study was to identify nutrition and microbiome factors related to structural and functional neurological abnormalities to optimize future preventive strategies. Methods: Two hundred thirty-eight patients suffering from (1) structural (neurodegeneration) or (2) functional (epilepsy) neurological abnormalities or (3) chronic pain (migraine) and 612 healthy control subjects were analyzed by validated 12-month food frequency questionnaire (FFQ) and 16S rRNA microbiome sequencing (from stool samples). A binomial logistic regression model was applied for risk calculation and functional pathway analysis to show which functional pathway could discriminate cases and healthy controls. Results: Detailed analysis of more than 60 macro- and micronutrients revealed no distinct significant difference between cases and controls, whereas BMI, insulin resistance and metabolic inflammation in addition to alcohol consumption were major drivers of an overall neurological disease risk. The gut microbiome analysis showed decreased alpha diversity (Shannon index: p = 9.1× 10-7) and species richness (p = 1.2 × 10-8) in the case group as well as significant differences in beta diversity between cases and controls (Bray-Curtis: p = 9.99 × 10-4; Jaccard: p = 9.99 × 10-4). The Shannon index showed a beneficial effect (OR = 0.59 (95%-CI (0.40, 0.87); p = 8 × 10-3). Cases were clearly discriminated from healthy controls by environmental information processing, signal transduction, two component system and membrane transport as significantly different functional pathways. Conclusions: In conclusion, our data indicate that an overall healthy lifestyle, in contrast to supplementation of single micro- or macronutrients, is most likely to reduce overall neurological abnormality risk and that the gut microbiome is an interesting target to develop novel preventive strategies.

Metabolic Effects of Vitamin B1 Therapy under Overnutrition and Undernutrition Conditions in Sheep.

As a precursor for a universal metabolic coenzyme, vitamin B1, also known as thiamine, is a vital nutrient in all living organisms. We previously found that high-dose thiamine therapy prevents overnutrition-induced hepatic steatosis in sheep by enhancing oxidative catabolism. Based on this capacity, we hypothesized that thiamine might also reduce whole-body fat and weight. To test it, we investigated the effects of high-dose thiamine treatment in sheep under overnutrition and calorie-restricted undernutrition to respectively induce positive energy balance (PEB) and negative energy balance (NEB). Eighteen mature ewes were randomly assigned to three treatment groups (n = 6 each). The control group (CG) was administered daily with subcutaneous saline, whereas the T5 and T10 groups were administered daily with equivoque of saline containing 5 mg/kg and 10 mg/kg of thiamine, respectively. Bodyweight and blood biochemistry were measured twice a week for a period of 22 days under PEB and for a consecutive 30 days under NEB. Surprisingly, despite the strong effect of thiamine on liver fat, no effect on body weight or blood glucose was detectable. Thiamine did, however, increase plasma concentration of non-esterified fatty acids (NEFA) during NEB (575.5 ± 26.7, 657.6 ± 29.9 and 704.9 ± 26.1 µEqL-1 for CG, T5, and T10, respectively: p < 0.05), thereby favoring utilization of fatty acids versus carbohydrates as a source of energy. Thiamine increased serum creatinine concentrations (p < 0.05), which paralleled a trending increase in urea (p = 0.09). This may indicate an increase in muscle metabolism by thiamine. Reduction of fat content by thiamine appears more specific to the liver than to adipose tissue. Additional studies are needed to evaluate the potential implications of high-dose vitamin B1 therapy in muscle metabolism.

Micronutrient imbalance and common phenotypes in neural tube defects.

Neural tube defects (NTDs) are among the most common birth defects, with a prevalence of close to 19 per 10,000 births worldwide. The etiology of NTDs is complex involving the interplay of genetic and environmental factors. Since nutrient deficiency is a risk factor and dietary changes are the major preventative measure to reduce the risk of NTDs, a more detailed understanding of how common micronutrient imbalances contribute to NTDs is crucial. While folic acid has been the most discussed environmental factor due to the success that population-wide fortification has had on prevention of NTDs, folic acid supplementation does not prevent all NTDs. The imbalance of several other micronutrients has been implicated as risks for NTDs by epidemiological studies and in vivo studies in animal models. In this review, we highlight recent literature deciphering the multifactorial mechanisms underlying NTDs with an emphasis on mouse and human data. Specifically, we focus on advances in our understanding of how too much or too little retinoic acid, zinc, and iron alter gene expression and cellular processes contributing to the pathobiology of NTDs. Synthesis of the discussed literature reveals common cellular phenotypes found in embryos with NTDs resulting from several micronutrient imbalances. The goal is to combine knowledge of these common cellular phenotypes with mechanisms underlying micronutrient imbalances to provide insights into possible new targets for preventative measures against NTDs.