The Journal of Nutrition

Adequate thymidylate (dTMP or the "T" base in DNA) levels are essential for stability of mitochondrial DNA (mtDNA) and nuclear DNA (nDNA). Folate and vitamin B12 (B12) are essential cofactors in folate-mediated one carbon metabolism (FOCM), a metabolic network which supports synthesis of nucleotides (including dTMP) and methionine. Perturbations in FOCM impair dTMP synthesis, causing misincorporation of uracil (or a "U" base) into DNA. During B12 deficiency, cellular folate accumulates as 5-methyltetrahdryfolate (5-methyl-THF), limiting nucleotide synthesis. The purpose of this study was to determine how B12 deficiency and dietary folate interact to affect mtDNA integrity and mitochondrial function in mouse liver. Mice expressing reduced methionine synthase (Mtr) levels were used to create a functional B12 deficiency. Folate accumulation, uracil levels, mtDNA content, and oxidative phosphorylation capacity were measured in male Mtr+/+ and Mtr+/- mice weaned onto either a folate-sufficient control diet (2 mg/kg folic acid, C) or a folate-deficient diet (FD, lacking folic acid) for 7 weeks. Mtr heterozygosity led to increased liver 5-methyl-THF levels. Mtr+/- mice consuming the C diet also exhibited a 40-fold increase in uracil in liver mtDNA. However, the combination of Mtr heterozygosity and exposure to the FD diet partially alleviated the level of uracil accumulation in mtDNA. Furthermore, Mtr+/- mice exhibited a 25% decrease in liver mtDNA content and a 20% decrease in maximal oxygen consumption rates. Impairments in mitochondrial FOCM are known to lead to increased uracil in mtDNA. This study demonstrates that impaired cytosolic dTMP synthesis also leads to increased uracil in mtDNA.

Early dietary exposure via human milk (HM) components offers a window of opportunity to support cognitive and temperamental development. While several studies have focused on associations of few pre-selected HM components with cognition and temperament, it is highly plausible that HM components synergistically and jointly support cognitive and behavioral development in early life. We aimed to discern the combined associations of a wide array of HM nutrients with cognition and temperament during the first six months of life and explore if there were persistent effects up to 18 months old, when HM is the primary source of an infants nutrition. The Mullen Scales of Early Learning and Infant Behavior Questionnaires-Revised were used to assess cognition and temperament, respectively, of fifty-four exclusively/predominantly breastfed infants in the first 6 months of life, whose follow-ups were conducted at 6-9, 9-12 and 12-18 months old. HM samples were obtained from the mothers of the participants at less than 6 months of life and analyzed for fatty acids (total monounsaturated fatty acids, polyunsaturated fatty acid, total saturated fatty acid (TSFA), arachidonic acid (ARA), docosahexaenoic acid (DHA), ARA/DHA, omega-6/omega-3 polyunsaturated fatty acids ratio (n-6/n-3)), phospholipids (phosphatidylcholine, phosphatidylethanolamine (PE), phosphatidylinositol (PI), sphingomyelin) and choline (free choline, phosphocholine (PCho), glycerophosphocholine). Feature selection was performed to select nutrients associated with cognition and temperament, respectively. The combined effects of selected nutrients were analyzed using multiple regression. A positive association between the arachidonic acid (ARA) and surgency was observed (p = 0.024). Significant effect of DHA, n-6/n-3, PE and TSFA concentrations on receptive language (R2 = 0.39, p = 0.025), and the elevated ARA, PCho, and PI with increased surgency (R2 = 0.43, p = 0.003) was identified, suggesting that DHA and ARA may have distinct roles for temperament and language functions. Furthermore, the exploratory association analyses suggest that the effects of HM nutrients on R.L. and surgency may persist beyond the first 6 months of life, particularly surgency at 12-18 months (p = 0.002). Our studies highlighted that various HM nutrients work together to support the development of cognition and temperament traits during early infancy.

BackgroundExposure to antigens is crucial for child immune system development, aiding disease prevention and promoting infant health. Some common food antigen proteins are found in human breast milk. However, it is unclear whether gluten antigens linked to celiac disease (CD) are transmitted through breast milk, potentially impacting the development of the infants immune system. ObjectiveThis study aimed to analyze the passage of gluten immunogenic peptides (GIP) into human breast milk. We evaluated the dynamics of GIP secretion after lactating mothers adopted a controlled gluten-rich diet. MethodsWe prospectively enrolled 96 non-CD and 23 CD lactating mothers, assessing total proteins and casein in breast milk, and GIP levels in breast milk and urine. Subsequently, a longitudinal study was conducted in a subgroup of 12 non-CD lactating mothers who adopted a controlled gluten-rich diet. GIP levels in breast milk and urine samples were assayed by multiple sample collections over 96 hours. ResultsAnalysis of a single sample revealed that 24% of non-CD lactating mothers on a regular unrestricted diet tested positive for GIP in breast milk, and 90% tested positive in urine, with significantly lower concentrations in breast milk. Nevertheless, on a controlled gluten-rich diet and the collection of multiple samples, GIP were detected in 75% and 100% of non-CD participants in breast milk and urine, respectively. The transfer dynamics in breast milk samples were long-enduring and GIP secretion persisted from 0 to 72 h. In contrast, GIP secretion in urine samples was limited to the first 24 h, with inter-individual variations. In the cohort of CD mothers, 82.6% and 87% tested negative for GIP in breast milk and urine, respectively. ConclusionsThis study definitively established the presence of GIP in breast milk, with substantial inter-individual variations in secretion dynamics. Our findings provide insights into distinct GIP kinetics observed in sequentially collected breast milk and urine samples, suggesting differential gluten metabolism patterns depending on the organ or system involved. Future research is essential to understand whether GIP functions as sensitizing or tolerogenic agents in the immune system of breastfed infants.

BackgroundMalnutrition still affects millions of children in Africa. Changes in the gut microbiome have been implicated in malnutrition, but there has been inconsistent nomenclature of microbes. This meta-analysis reviews the microbiome literature using natural language processing (NLP) methods. MethodologyWe searched PubMed for gut microbiome studies of undernourished children living in low-middle-income countries (LMICs). The primary analysis focused on continental coverage and study characteristics of microbiome research in sub-Saharan Africa. We also employed an NLP tool for normalising primary data from full-text publications in ss-Africa compared to other LMICs, and between diseased and healthy children. ResultsWe identified 16 studies. Most studies were conducted in Malawi and characterised the faecal microbiome using 16S rRNA sequencing. For comparison, 18 studies conducted in Bangladesh, India, Pakistan and Peru were included. With this, we identified frequently reported microbes that were distinctly identified in sub-Saharan Africa and highlighted possible signatures of an undernourished faecal microbiome across the globe. ConclusionThe consistent associations between elevated Pseudomonadota levels and severe acute malnutrition provides new insights into host-microbiome interactions in African contexts. However, the overlap between taxa associated with healthy and stunting underscores the need for further research to better inform potential targeted interventions in Africa.

Background Maternal iron requirements increase substantially during pregnancy, and ferritin concentrations typically decline as gestation progresses. However, the physiologic significance of this decline remains uncertain, and whether reductions in maternal iron stores relate to birth outcomes is unclear. Objectives To examine associations between maternal ferritin trajectories during pregnancy and postpartum and infant anthropometric outcomes. Methods We conducted a secondary longitudinal analysis of 1,496 mother - infant pairs from the Alberta Pregnancy Outcomes and Nutrition cohort. Serum ferritin was measured longitudinally in the second and third trimesters and at three months postpartum, with limited first-trimester data available. Values below 15 g/L indicated iron deficiency. Multivariable linear regression assessed associations between inflammation-adjusted third-trimester serum ferritin and infant birthweight and length. Change in serum ferritin between the second and third trimesters ({delta} ferritin) was examined as a marker of late-gestation iron mobilization. Postpartum serum ferritin was modelled using restricted cubic splines to account for nonlinear associations with birth weight and length. Results Ferritin concentrations declined progressively across pregnancy, with 61% of women classified as iron deficient in the third trimester. Lower inflammation-adjusted third-trimester ferritin was associated with higher birthweight, corresponding to approximately 84g higher birthweight per 2.7 - fold decrease in ferritin (p < 0.001). Women experiencing the largest decline in ferritin between the second and third trimester delivered infants approximately 155 g heavier than those with minimal change (p = 0.001). Higher birthweight was associated with greater odds of postpartum iron deficiency (OR per 1 kg = 1.83; 95% CI: 1.12 - 2.99). Conclusions In this healthy cohort, maternal iron depletion in late pregnancy was associated with higher birthweight, consistent with preferential fetal iron transfer. Women delivering larger infants exhibited higher odds of iron deficiency, suggesting sustained maternal iron depletion following greater fetal iron accretion.

Introduction: Infant neurodevelopment is associated with maternal nutritional status, yet few studies have evaluated the effects of balanced energy-protein (BEP) supplementation during pregnancy and/or lactation. Methods: The Maternal Infant Nutrition Trial (NCT03668977) was a 2x2 factorial, household randomized, unblinded, efficacy trial conducted in Sarlahi District, Nepal. Pregnant women were randomized to daily fortified BEP supplementation or no supplementation, and those with a live birth were re-randomized after delivery to supplementation or not until 6-months postpartum. The first 100 infants in each of the four intervention groups were enrolled in a neurodevelopment substudy. At 6-months, these infants underwent a cognitive, motor, language, and socioemotional assessment using the Bayley Scales of Infant and Toddler Development, fourth edition. Results: Baseline characteristics were similar across the four trial groups. A significant interaction (p< 0.05) between pregnancy and lactation supplementation groups was observed in the language domain only. Infants born to mothers who received BEP supplementation during pregnancy did not differ in standard scores for cognitive (mean difference (MD): 2.0, 95% confidence interval (CI): -0.29, 4.29), motor (MD: 0.98, 95% CI: -1.41, 3.36), or socioemotional (MD: -2.35, 95% CI: -5.27, 0.57) domains compared to the pregnancy control group. Similarly, for these three domains, there were no significant differences among infants whose mothers received BEP in lactation period vs. not. Infants born to mothers supplemented in both pregnancy and lactation had significantly higher mean language standard scores of 2.12 (95% CI: 0.16, 4.08; p-interaction = 0.015), driven by the expressive communication subtest, compared to those with no BEP supplementation in either period. Conclusion: BEP supplementation during pregnancy and/or lactation was not associated with improvements in cognitive, motor, or socioemotional domains at 6 months; however, infants of women supplemented in pregnancy and lactation had significant improvements in the language domain. Evaluation at later ages is warranted.

BackgroundEarly identification of malnutrition is critical for improving clinical outcomes in oncology patients. However, there are no established biomarkers for malnutrition screening. ObjectiveThis study aimed to identify circulating lipid species associated with malnutrition risk among oncology patients through lipidomic analysis. MethodsA cross-sectional study was conducted using plasma samples from oncology patients classified as at risk (n = 90) or not at risk (n = 90) for malnutrition using the Malnutrition Screening Tool (MST) (MST score = 0 versus [&ge;]2). All participants had head and neck, lung, or gastrointestinal cancer. Targeted lipidomics were conducted using LC-MS. Elastic net regression adjusted for confounding variables identified lipids associated with malnutrition risk. A weighted Lipid Malnutrition Risk Score was derived and evaluated using Receiver Operating Characteristic Area Under the Curve (ROC- AUC). Conditional multivariable logistic regression assessed the association of the lipid score with malnutrition risk. Lipid enrichment analysis was performed using Lipid Ontology (LION) enrichment framework. ResultsElastic net regression identified 12 lipids species that were inversely associated with malnutrition risk: cholesterol ester 20:0, ceramide 18:2;O2/26:0, lysophosphatidylcholine 26:0/0:0, lysophosphatidylinositol 18:2/0:0, phosphatidylcholine 34:5, phosphatidylcholine 40:8, phosphatidylethanolamine P-18:0/20:3, phosphatidylethanolamine P-18:1/18:2, phosphatidylethanolamine P-18:1/20:4, sulfated hexosylceramide 18:1;O2/16:0, sphingomyelin 18:2;O2/23:0, and triglyceride (O-50:1). One lipid, dihexosylceramide 18:1;O2/20:0, was positively associated with malnutrition risk. The weighted Lipid Malnutrition Risk Score was associated with increased risk for malnutrition risk (OR = 3.57, 95% CI 1.97-6.47, p < 0.001). Addition of the lipids score to established malnutrition risk factors improved model predictive performance, increasing the ROC-AUC from 0.78 (95% CI 0.71-0.84) to 0.90 (95% CI 0.86-0.94). LION enrichment analysis indicated downregulation of membrane structure and signaling lipids and upregulation of storage lipids. ConclusionThis study highlights the potential of lipidomics to identify biomarkers of malnutrition risk among oncology patients. Large, prospective studies are warranted to validate and expand upon these findings.

BackgroundMaternal nutritional interventions aim to address nutrient deficiencies in pregnancy, a leading cause of maternal and neonatal morbidity and mortality worldwide. How these interventions influence the placenta, which plays a vital role in fetal growth and nutrient supply, is not well understood. This is a major gap in understanding how such interventions could influence pregnancy outcomes and fetal health. We hypothesised that nutritional interventions influence placental phenotype, and that these placental changes relate to how successful, or not, the intervention is in improving pregnancy outcomes. MethodsWe conducted a systematic review and followed PRISMA-2020 reporting guidelines. Articles were retrieved from PubMed, Clinicaltrials.gov, and ICTRP-WHO using pre-defined search terms and screened by two reviewers using a 3-level process. Inclusion criteria considered articles published from January 2001-September 2021 that reported on clinical trials in humans, which administered a maternal nutritional intervention during the periconceptional or pregnancy period and reported on placental phenotype (shape and form, function or placental disorders). FindingsFifty-three eligible articles reported on (multiple) micronutrient- (n=33 studies), lipid- (n=11), protein- (n=2), and diet-/lifestyle-based (n=8) interventions. Of the micronutrient-based interventions, 16 (48%) associated with altered placental function, namely altered nutrient transport/metabolism (n=9). Nine (82%) of the lipid-based interventions associated with altered placental phenotype, including elevated placental fatty acid levels (n=5), altered nutrient transport/metabolism gene expression (n=4), and decreased inflammatory biomarkers (n=2). Of the protein-based interventions, two (66%) associated with altered placental phenotype, including increased placental efficiency (n=1) or decreased preeclampsia risk (n=1). Three (38%) of diet and lifestyle-based interventions associated with placental changes, namely placental gene expression (n=1) and disease (n=2). In studies with data on maternal (n=30) or offspring (n=20) outcomes, interventions that influenced placental phenotype were more likely to have also associated with improved maternal outcomes (11/15 [73%]) and offspring birth outcomes (6/11 [54%]), compared to interventions that did not associate with placental changes (2/15 [13%] and 1/9 [11%], respectively). ConclusionsPericonceptional and prenatal nutritional interventions to improve maternal/pregnancy health associate with altered placental development and function. These placental adaptations likely benefit the pregnancy and improve offspring outcomes. Understanding the placentas role in the success of interventions to combat nutrient deficiencies is critical for improving interventions and reducing maternal and neonatal morbidity and mortality globally.

BackgroundMaternal vitamin status preconception and during pregnancy have important consequences for pregnancy outcome and offspring development. Changes in status from preconception to early and late pregnancy and postpartum have been inferred from cross-sectional data, with lower pregnancy concentrations often ascribed to plasma volume expansion, but without truly longitudinal data from preconception through pregnancy and post-delivery, and sparse data on the influence of supplementation. This study characterized longitudinal patterns of maternal vitamin status from preconception, through early and late pregnancy, to 6-months post-delivery, and determined the influence of supplementation. Methods and FindingsBetween 2015-2017, 1729 UK, Singapore and New Zealand women aged 18-38 years planning conception were recruited from the community to a double-blind controlled trial and randomized to a standard (control) or an intervention supplement preconception and throughout pregnancy. Vitamins common to both supplements were folic acid and {beta}-carotene, with the intervention additionally including riboflavin, vitamins B6, B12 and D in amounts available in over-the-counter supplements, alongside iron, calcium and iodine (control and intervention) and myo-inositol, probiotics and zinc (intervention only). We measured maternal plasma concentrations of B-vitamins, vitamin D and insufficiency/deficiency markers (homocysteine, hydroxykynurenine-ratio, methylmalonic acid), at recruitment and 1-month after commencing intervention preconception, in early and late pregnancy, and post-delivery (6-months after supplement discontinuation). From all timepoint data, we derived standard deviation scores (SDS) to characterize longitudinal changes in controls and differences between control and intervention participants. At recruitment preconception, significant proportions had marginal or low plasma status for folate (29.2% <13.6 nmol/L), riboflavin (7.5% <5 nmol/L, 82.0% [&le;]26.5 nmol/L), vitamin B12 (9.1% <221 pmol/L) and vitamin D (48.7% <50 nmol/L). Among controls, plasma concentrations showed differing longitudinal patterns from preconception; riboflavin fell through early/late pregnancy, 25-hydroxyvitamin D was unchanged in early pregnancy, and vitamin B6 and B12 concentrations declined through pregnancy, becoming >1 SDS lower than baseline by 28 weeks gestation, with 54.2% developing a low late pregnancy vitamin B6 (pyridoxal 5-phosphate <20 nmol/L). Preconception, the control/intervention groups had similar baseline vitamin concentrations; 1-month after supplement commencement, plasma concentrations became substantially higher in intervention participants; riboflavin by 0.77 SDS (95%CI 0.68-0.87), vitamin B6 1.07 (0.99-1.14), vitamin B12 0.55 (0.46-0.64) and vitamin D 0.51 (0.43-0.60), with the higher levels maintained during pregnancy and marked reduction in insufficiency/deficiency markers (lower homocysteine, hydroxykynurenine-ratio, methylmalonic acid) and the late pregnancy prevalence of vitamin D <50 nmol/L reduced from 35.1% to 8.5%. Plasma vitamin B12 was still higher in the intervention group 6-months post-delivery. ConclusionSignificant proportions of preconception women have marginal or low status of folate, riboflavin, vitamin B12 and vitamin D, and many develop markers of vitamin B6 deficiency in late pregnancy. In the absence of supplementation, maternal plasma vitamin concentrations show differing longitudinal patterns from preconception to early and late pregnancy, suggesting plasma volume expansion does not wholly account for lower gestational concentrations. Preconception/pregnancy supplementation in amounts available in over-the-counter supplements substantially reduces the prevalence of deficiency/depletion markers before and during pregnancy, and a higher maternal plasma vitamin B12 was maintained during the recommended lactational period.

BackgroundPoor diet quality and high body mass index (BMI) contribute to inflammation, which may influence human milk composition and exclusive breastfeeding (EBF) duration. ObjectiveWe evaluated maternal diet and prepregnancy BMI as predictors of human milk C-reactive protein (CRP) and long chain fatty acid concentrations (%LCFA), and EBF duration. MethodsWe utilized the Global Exploration of Human Milk Study-Cincinnati subset (n=114), where healthy dyads continued follow-up if [&ge;]75% of feeds were breastmilk at 4 weeks postpartum. We computed a Dietary Inflammatory Index (DII) from diet recalls obtained between 4-13 weeks postpartum, where higher score indicates a more proinflammatory diet. Milk CRP and fatty acid analyses were performed on week 4 milk. We compared milk CRP across 4 combinations of DIIxBMI using the Kruskal Wallis test, with BMI categorized as normal versus elevated (<25 versus >25 kg/m2), and DII split at the median. Linear regression was used to examine DII and BMI as predictors of %LCFA. Logistic regression was used to examine DII tertiles and BMI as predictors of EBF duration. ResultsMilk CRP concentrations differed across DIIxBMI groups (p=0.009): the low DII/normal BMI group had the lowest milk CRP (n=30, median [Q1, Q3], 64.3 [38.2, 121.4] ng/mL) versus all other groups (n=70, 124.1 [71.2, 181] ng/mL, p=0.022). Lower milk %LCFA was predicted by higher DII score ({beta}{+/-}SE = -0.68 {+/-} 0.21, p=0.002, n=103) and higher BMI ({beta}{+/-}SE = -0.13 {+/-} 0.01, p=0.043, n=114). Having the highest DII tertile and elevated BMI lowered the odds of EBF at week 6 (OR [95% CI]: 0.26 [0.07, 0.85]) compared to the referent group (low or medium DII, normal BMI). ConclusionsMilk CRP concentrations were lowest in women with a more anti-inflammatory diet and normal BMI. Both higher BMI and proinflammatory diet predict lower milk %LCFA and lower EBF prevalence at week 6.

IntroductionTraditionally associated with undernutrition, increasing evidence suggests micronutrient deficiencies can co-exist with overnutrition. Therefore, this work aimed to systematically review the associations between iron, zinc and vitamin A status and weight status (both under- and overweight) in children and young people. MethodsOvid Medline, Ovid Embase, Scopus, and Cochrane databases were systematically searched for observational studies assessing micronutrient status (blood, serum, or plasma levels of iron, zinc, or vitamin A biomarkers) and weight status (body mass index or other anthropometric measurement) in humans under 25 years of any ethnicity and gender. Risk of bias assessment was conducted using the American Dietetic Association Quality Criteria Checklist. Where possible, random effects restricted maximum likelihood (REML) meta-analyses were performed. PROSPERO (CRD42020221523). ResultsAfter screening, 83 observational studies involving 190,443 participants from 44 countries were identified, with many studies having reported on more than one micronutrient and/or weight status indicator. Iron was the most investigated micronutrient, with 46, 28, and 27 studies reporting data for iron, zinc, and vitamin A status, respectively. Synthesizing 16 records of odds ratio (OR) from 7 eligible studies, overnutrition (overweight and obesity) increased odds of iron deficiency (OR [95%CI]: 1.51 [1.20, 1.82], p<0.0001, I2=40.7%). Odds appeared to be higher for children living with obesity (1.88 [1.33, 2.43], p<0.0001 I2=20.6%) in comparison to those with overweight (1.31 [0.98, 1.64], p<0.0001 I2=40.5%), although between group differences were not significant (p=0.08). ConclusionsOvernutrition is associated with increased risk of iron deficiency, but not zinc or vitamin A deficiencies, with an inverted U-shaped relationship observed between iron status and bodyweight. Our results highlight significant heterogeneity in the reporting of micronutrient biomarkers and how deficiencies were defined. Inflammation status was rarely adequately accounted for, and the burden of iron deficiency may well be under-recognised, particularly in children and young people living with overnutrition. Key questionsO_ST_ABSWhat is already known on this topicC_ST_ABS-summarise the state of scientific knowledge on this subject before you did your study and why this study needed to be done O_LILow-and middle-income countries are increasingly facing a double burden of malnutrition; that is, the coexistence of undernutrition (stunting, wasting, underweight) with overnutrition (overweight and obesity). C_LIO_LIWhile the relationship between undernutrition and critical micronutrients for childhood growth and development (e.g., iron, zinc, and vitamin A) is well established, less is known about the risk of micronutrient deficiencies in children and adolescents with overweight or obese, a hidden form of malnutrition. C_LIO_LIThere are limited data summarising associations between biomarkers of the most commonly limiting micronutrients and body weight status, particularly in children and young people. C_LI What this study adds-summarise what we now know as a result of this study that we did not know before O_LIOvernutrition increases the risk of iron deficiency, but not zinc or vitamin A deficiencies. C_LIO_LIThere is an inverted U-shaped relationship observed between iron status and bodyweight in children and young people, with iron deficiencies observed more frequent in both under- and overnutrition. C_LIO_LIStudies done to date have been heterogeneous in terms of populations studied, diagnostic criteria, and approaches to data analysis; few followed current guidelines for measuring inflammation and defining micronutrient deficiencies. C_LI How this study might affect research, practice or policy-summarise the implications of this study O_LIIncreased recognition by healthcare practitioners that children and young people living with overweight, or obesity are likely to be iron deficient; thereby improving clinical practice and care. C_LIO_LIThe gaps in evidence highlighted are addressed, with more research from currently underrepresented counties examining micronutrient deficiencies and the double burden of malnutrition. C_LIO_LIThe weaknesses in study design and reporting highlighted are addressed, with improved quality and reporting of micronutrient assessment in children and young people. C_LI

The importance of vitamin B12 (cobalamin) in numerous biological processes, including DNA synthesis and cellular energy production, underscores the need for therapeutic and public health strategies to address B12 insufficiency/deficiency in the population. Genetic variations in pathways influencing cobalamin absorption, transport, and metabolism can affect various direct and indirect measures of vitamin B12 status. To facilitate a structured approach to studying these genetic factors, we aimed to systematically curate and create a user-friendly web database that offers comprehensive data on genetic variants influencing B12 biomarkers. A Pubmed search was performed for 5 B12 traits (total serum/plasma B12, holotranscobalamin (active B12), total transcobalamin, holo haptocorrin, and methylmalonic acid) resulting in 493 research publications, of which 47 relevant publications were reviewed further. The database backend was built using MongoDB and the web interface was coded in PHP, JavaScript, HTML and CSS on an Apache HTTP server. We have manually curated and compiled the Cobalamin Associated Genetic Variant (CobVar) database, comprising a total of 324 genetic variant associations for 5 different vitamin B12 traits involving 222 unique genetic variants and 84 genes identified across several genome-wide association studies (GWAS) and candidate gene studies. About one-third of the total genetic variant associations have been reported in >1 independent studies and 15 variants in >1 ethnic group. FUT2 gene showed the maximum number of associations for total serum/plasma B12 (N=39), followed by MTHFR (N=24) and TCN2 (N=23). The database is accessible online at https://datatools.sjri.res.in/VBG/. CobVar is a vital resource for researchers and nutritionists, offering quick access to the latest developments in B12-related genetic variant research and serves as a valuable tool for advancing personalized treatment. Database URLhttps://datatools.sjri.res.in/VBG/.

BackgroundWheat flour, maize flour and rice (i.e. grains) fortification with folic acid is an important folate dietary source globally. There are no systematic reviews or meta-analyses evaluating the effect of mandatory grain fortification on folate insufficiency (using serum/plasma folate and red blood cell (RBC) folate), RBC folate levels or folate deficiency using RBC folate. This study assessed the effectiveness of mandatory grain fortification with folic acid on serum/plasma folate and red blood cell (RBC) folate levels and the risk of folate deficiency and insufficiency based on these biomarkers. MethodsWe searched PubMed and Embase with assistance from a professional library informationist. We selected studies from countries with mandatory grain fortification that include folic acid in standards if they reported primary pre- and post-fortification data on folate status outcomes. We ran meta-analyses in R using random effects models with results expressed as meta-differences of means (MDM) or meta-prevalence ratios (mPR) for continuous and binary outcomes respectively. All meta-estimates were accompanied by 95% confidence intervals (CI). ResultsWe screened 4,311 documents, identifying 31 articles which reported folate status outcomes (22 reported mean serum/plasma or RBC folate, 18 reported prevalence of folate deficiency or insufficiency). About 19% of studies were conducted in low- or middle-income countries. Mandatory fortification improved folate status, albeit with considerable heterogeneity across studies (I2[&ge;]73%). For serum/plasma folate levels, the MDM across all studies was 15.0 nmol/L (95% CI: 9.4-20.5). For serum/plasma folate insufficiency and deficiency, the mPR (95% CI) estimates were 0.17 (0.08-0.37) and 0.08 (0.03-0.23), respectively. For red blood cell folate levels, the MDM was 329.4 nmol/L (95% CI 243.9-414.9). For RBC folate insufficiency and deficiency, mPRs (95% CIs) were 0.16 (0.08-0.30) and 0.05 (0.01-0.46), respectively. ConclusionsMandatory grain fortification with folic acid increases blood folate levels and decreases the risk of folate insufficiency and folate deficiency.

Iron deficiency in pregnancy is related to many poor health outcomes, including anemia and low birth weight. A small number of previous studies have identified maternal body mass index (BMI) as potential risk factors for poor iron status. Our objective was to examine the association between pre-pregnancy BMI and iron status in a nationally representative sample of US adult women. We used data from the National Health and Nutrition Examination Survey (NHANES; 1999-2010) for pregnant women ages 18-49 years (n=1156). BMI (kg/m2) was calculated using pre-pregnancy weight (self-reported) and height (measured at examination). Iron deficiency (ID) was defined as total body iron (calculated from serum ferritin and transferrin receptor using Cooks equation) < 0 mg/kg and anemia as hemoglobin < 11 g/dL. Associations were examined using weighted Poisson regression models, adjusted for confounders (age, race/ethnicity, education, family income, and trimester). Approximately 14% of pregnant women had ID and 8% had anemia in this sample. There were no differences in the prevalence of ID or anemia in women with pre-pregnancy overweight and obesity (ID: overweight, adjusted prevalence ratio (PR)=1.28, 95%CI: 0.89-1.83; obesity, PR=0.75, 95%CI: 0.39-1.45; anemia: overweight, PR=1.08, 95%CI: 0.53-2.19; obesity, PR=0.99, 95%CI: 0.49-2.01) compared to women with a normal BMI. Findings from these US nationally representative data indicate that iron status in pregnancy does not differ by pre-pregnancy BMI. Since iron deficiency during pregnancy remains a significant public health concern, NHANES should consider measuring current iron status in upcoming cycles.

BackgroundDiets rich in monounsaturated fatty acids (MUFAs) and fiber support gastrointestinal health and the microbiome; however, the effect of whole foods relative to their isolated nutrients remains under-investigated. ObjectiveDetermine the impact of avocado consumption on gastrointestinal health and microbiome beyond the individual effects of MUFAs and fiber. MethodsAdults with overweight and obesity (n=43, mean age=41y, BMI=31.6kg/m2) completed a randomized, crossover, controlled feeding study with three 4-wk dietary interventions separated by 2-wk washouts: average American (AA), oleic acid + fiber (OF) nutrients, and avocado (AV). The base diet was supplemented with 209g avocado (AV), or isocaloric snacks high in MUFA/fiber (OF) or low in MUFA/fiber (AA). Outcomes included fecal microbiome (shotgun metagenomics), fecal microbial metabolites (short-chain [SCFA] and branched-chain [BCFA] fatty acids, phenols, indoles, and bile acids), intestinal permeability (24h urinary sweetener excretion), systemic (CRP, IL-6, LBP) and gut (fecal calprotectin and sIgA) inflammatory markers, and gastrointestinal tolerance symptoms. Statistical analysis included linear mixed models, Friedman tests, and multivariable association analysis. ResultsFecal acetate and total SCFAs were 28% and 18% higher in AV and OF conditions, compared to AA (p<0.001 & p=0.019, respectively). Total secondary bile acids in the AV condition were 34% and 24% lower compared to OF (p<0.001) and AA (p=0.011), respectively. Alistipes communis ({beta}=0.85, q=0.03) and Bacteroides uniformis ({beta}=0.50, q=0.14) were higher following AV, whereas Lachnospira eligens ({beta}=1.79, q <0.001) was higher following OF, compared to AA. Microbial genes involved in pectin, cellulose, and hemicellulose degradation were enriched in AV and OF. Fecal calprotectin was lower in AV (30%; p=0.03) and OF (26%; p=0.04) compared to AA, while sIgA was 34% lower following AV, compared to AA (p=0.01). ConclusionsAvocado and MUFA/fiber-matched control had similar fermentation, but distinct secondary bile acid and microbial profiles, emphasizing the food matrix and gut microbiome as key determinants of diet-health relations. Clinical Trial Registry number and website where it was obtainedhttps://clinicaltrials.gov/study/NCT05941728?intr=NCT05941728&rank=1

BackgroundHuman milk (HM) bioactive components can have immune modulatory functions, impact the gut microbiome, and may result in functional benefits when added to infant formula (IF). In this single-arm, prospective, intervention study, we tested the effectiveness of an IF with a whey protein concentrate co-enriched in -lactalbumin, milk fat globule membrane (MFGM), and Sn-2 palmitate resulting in protein and lipid profiles observed in HM. The outcomes tested were feeding tolerance, Bifidobacteria abundance, and intestinal and immune health of Chinese infants. MethodsPredominantly formula-fed (FF) and breastfed (BF) infants were enrolled between 3 and 28 days and assigned to the FF (N= 60) or BF (N=60) group, per their feeding practice, for 6 weeks. The primary endpoint was Infant Gastrointestinal Symptom Questionnaire (IGSQ) index score assessed using a validated IGSQ-13 questionnaire after 6 weeks of intervention; non-inferiority of FF vs BF was tested. Secondary endpoints included fecal Bifidobacteria abundance assessed using shotgun metagenomics sequencing; fecal short chain fatty acids (SCFAs) analyzed by ultra-performance liquid chromatography-tandem mass spectrometry; fecal markers of immune response, inflammation, intestinal barrier integrity (secretory immunoglobulin A sIgA), cytokines, calprotectin, 1 antitrypsin, lipocalin-2) assessed using enzyme-linked immunosorbent assay; stool consistency assessed using gastrointestinal (GI) diary; anthropometric assessments; quality of life; physician reported adverse events; and use of medications. ResultsGood GI tolerance was observed in both groups at V2 (mean{+/-}SD IGSQ score FF: 19.9{+/-}7.4; BF: 16.8{+/-}4.2); difference of means 1.35 [95% CI: -1.312, 4.012]). After 6 weeks, Bifidobacterium genus relative abundance was not significantly different between the groups. Total SCFAs were significantly higher (p<0.05) in the FF versus BF group, driven by increased levels of valeric and propanoic acids (p<0.05 for both). The IGSQ domain scores, stool consistency, fecal markers of immunity, inflammation, and intestinal barrier integrity (except lipocalin-2 which was significantly higher in BF vs FF), anthropometric Z-scores, common illnesses, antibiotic use, and adverse events were not significantly different between groups at week 6. ConclusionsOur results support the effectiveness of this tested infant formula in supporting good GI tolerance, growth, specific intestinal and immune health markers, and Bifidobacteria abundance similar to that of the BF group. Trial registrationNCT04880083 (2021-05-06)

Background: Yeast (Saccharomyces cerevisiae) is a model organism in agricultural and industrial fermentation with nutritional benefits, yet less is understood about its nutritional value for supporting whole-body protein synthesis in vivo, and its comparison to animal-based protein. Objective: This study aimed to determine the effect of microbial-based protein (yeast) compared to a high (whey) and low (collagen) quality animal-based protein on the ability to support whole-body protein synthesis using the indicator amino acid oxidation technique. Methods: Thirteen healthy participants (M: n=6, 24{+/-}4 yr; F: n=7, 27{+/-}7 yr) consumed eight hourly yeast (Y), whey (W), or collagen (CH) protein beverages at 0.9 g{middle dot}kg-1{middle dot}d-1 supplemented with L-[1-13C]phenylalanine in a randomized, cross-over, counterbalanced design. Breath and urine were collected to measure fraction of expired 13CO2 (F13CO2) and [1-13C]Phe oxidation (PheOx) as inverse correlates of whole-body protein synthesis. An a priori 20% noninferiority margin was used to determine equivalency between protein sources. A Visual Analog Scale (VAS) was provided to assess fullness and hunger by protein sources. Results: Protein source had no effect on F13CO2 (P=0.15) or PheRa (P=0.10). PheOx was greater in CH compared to both Y (14.94{+/-}2.16 vs. 12.93{+/-}2.80 mol{middle dot}kg BM-1{middle dot}h-1, P<0.05) and W (14.94{+/-}2.16 vs. 12.50{+/-}2.75 mol{middle dot}kg BM-1{middle dot}h-1, P<0.05) whereas there was no significant difference between Y and W (P=0.59). Change in PheOx (mean difference [90% CI]) between CH and W (2.44 mol{middle dot}kg BM-1{middle dot}h-1 [0.98, 3.90], P<0.05) and between Y and W (0.44 mol{middle dot}kg BM-1{middle dot}h-1 [-1.34, 2.21], P>0.99) confirmed respective inferiority and noninferiority to W compared to the 20% noninferiority margin (2.50 mol{middle dot}kg BM-1{middle dot}h-1), while Y was superior to CH (-2.00 mol{middle dot}kg BM-1{middle dot}h-1 [-3.01, -0.99], P<0.05). Protein source did not significantly influence satiety (P=0.32) or hunger scores (P=0.15). Conclusion: EAA-enriched whey and yeast protein similarly reduced PheOx as compared to EAA-deficient collagen hydrolysate, suggesting these proteins were similarly superior in supporting whole-body protein synthesis.

Deficiency of selenium, an essential trace element, has been implicated in adverse birth outcomes and the growth of infants and young children. We used data from a randomized controlled trial to examine associations between selenium biomarkers in whole blood (WBSe), serum and selenoprotein P (SEPP1) in maternal delivery and venous cord (VC) blood, and birth weight, and adverse birth outcomes. Furthermore, we examined associations between selenium biomarkers and infant growth outcomes (age adjusted length, weight, head circumference and weight-for-length z-scores) at birth, one, and two years of age using linear regression. WB and serum selenium in delivery and VC specimens were negatively associated with birth weight (adjusted {beta}, 95% CI: WBSe delivery: -26.6 (-44.3, -8.9); WBSe VC: -19.6 (-33.0, -6.1)); however, delivery SEPP1 levels (adjusted {beta}: -37.5 (-73.0, -2.0)) and VC blood (adjusted {beta}: 82.3 (30.0, 134.7)) showed inconsistent associations across biomarkers. We found small to moderate associations between infant growth and WBSe VC (LAZ {beta}, 95% CI, at birth: -0.05 (-0.1, -0.01)); 12-months ({beta}: -0.05 (-0.08, -0.007)). WAZ also showed weak negative associations with delivery WBSe (at birth: -0.07 (-0.1, -0.02); 12-months: -0.05 (-0.1, -0.005)) and in WBSe VC ({beta} at birth: -0.05 (-0.08, -0.02); 12-months: -0.05 (-0.09, -0.004)). Mechanisms connected to redox biology and its antioxidant effects have been causally associated with seleniums protective properties. Given the fine balance between nutritional and toxic properties of selenium, it is possible that WB and serum selenium may negatively impact growth outcomes, both in utero and postpartum.

Colorectal cancer (CRC) poses a major public health concern, with emerging evidence highlighting the critical role of the gut microbiota in CRC progression. Considering that diet is a major modifiable factor influencing CRC risk, partly through its interaction with the gut microbiome, this systematic review evaluated the effects of dietary intervention RCTs, including supplements, functional foods, whole foods, and dietary patterns, on the gut microbiome in at-risk individuals (PROSPERO: CRD42024530038). A search of PubMed, Scopus, and Web of Science identified 4,746 records, with 20 additional records sourced manually. Following screening, six studies met inclusion criteria, focusing on microbial diversity, taxonomic composition, and metabolites. Findings demonstrate that whole food interventions like navy beans and functional foods like rice bran increased microbial diversity over 4-8 wk; with no effects of rice bran over 24 wk. Navy beans (8 wk) enriched beneficial taxa (Faecalibacterium, Bifidobacterium), while a shorter 4-wk intervention using bean powder showed no taxonomic shifts. Both forms of navy bean increased amino acid derivatives and anti-inflammatory phenolic metabolites. Rice bran increased Lactobacillus over 24 wk but showed differing effects on Firmicutes over short (2 wk) versus longer (24 wk) durations. Rice bran also increased SCFAs (acetate, propionate) over 2 wk and phenolic metabolites (e.g., diosmin) while reducing pro-carcinogenic byproducts (p-cresol sulfate, glycodeoxycholate) over 4 wk. {beta}-glucan-enriched bread increased acetate over 12 wk but had minimal effects on microbial composition. Healthy Eating and Mediterranean dietary patterns did not alter taxonomic composition over 26 wk but reduced branched-chain bacterial fatty acids, indicating reduced proteolytic fermentation. This review underscores the potential of dietary strategies to modulate the gut microbiome in CRC-risk populations. However, limited RCTs and heterogeneity limit generalizability. Future research should conduct rigorous RCTs across the lifespan, using advanced microbiome and metabolite analyses and examining understudied dietary patterns to guide CRC prevention.

BackgroundProbiotics may enhance host iron bioavailability, offering a strategy to address iron deficiency. Fecal iron may be a useful non-invasive biomarker of such effects in infants. ObjectiveTo examine the use of fecal iron quantification in a randomized placebo-controlled trial (RCT) of neonatal administration of Lactiplantibacillus plantarum ATCC 202195 (LP202195), with or without fructooligosaccharide (FOS), in Dhaka, Bangladesh. MethodsFecal iron quantification using atomic absorption spectrometry (AAS) was optimized using standards and reference materials, and pilot-tested using pooled stool aliquots (n=32) from an observational cohort of young infants in Bangladesh (aged 0-64 days). The optimized AAS assay was then applied to individual stool samples collected at 14 days of age (n=307) in a RCT in which newborns aged 0-4 days were randomly allocated to one of five groups: placebo, 1-or 7-day regimens of LP202195, with or without FOS. Serum ferritin was measured at 2 months postnatal age (n=251). Effects of the 1-and 7-day LP202195 regimens were estimated using linear regression and expressed as mean percent differences relative to placebo, with 95% confidence intervals (95%CI). ResultsThe optimized AAS fecal iron assay had acceptable accuracy (91-99%), precision (within-and between-run coefficients of variation <10%), and recovery (93-112%), with a reportable range of 0.2 to 80 mg Fe per 100 g dry stool. In pooled samples from the observational cohort, fecal iron varied with age and feeding status. In the RCT, fecal iron concentrations did not significantly differ following1-day (% difference=9.8%, 95%CI:-19%, 49%; P=0.54) or 7-days (% difference=-6.1%, 95%CI:-31%, 28%; P=0.69) of LP202195 administration, versus placebo (geometric mean concentration=4.3mg Fe/100g dry stool (95%CI:3.3, 5.6); n=53). Inferences were unchanged when groups were disaggregated by FOS co-administration (P>0.05 for all). Similarly, there were no effects of LP202195 on serum ferritin at 2 months of age (P>0.05 for all). ConclusionsFecal iron quantification by AAS was valid and feasibly implemented in a trial of neonatal administration of Lactiplantibacillus plantarum ATCC 202195. However, the assay is resource-intensive and may not be more informative than conventional measures of iron status when studying the effects of probiotics/synbiotics on iron bioavailability. Clinical Trial RegistryClinicalTrials.gov identifier: NCT05180201