Nutrients

BackgroundIntolerance to oral iron is thought to result in poor adherence and persistence of nutritional deficit amongst women of childbearing age, however few studies have evaluated oral iron intolerance, iron deficiency and anaemia in this setting. Iron-whey protein microspheres (IWP) could help. MethodsWe documented self-reported oral iron gastrointestinal intolerance, ferritin and haemoglobin levels in a screening study of women of childbearing age. Following a washout period of 16 days, we randomised 59 of these women with iron deficiency, stratified according to the presence of anaemia, to three doses of IWP: (14mg daily, 25mg daily and 50mg daily). We excluded those with established gastrointestinal disease, potential allergy to whey protein and severe anaemia. The primary endpoint was persistence and adherence (>80% based on pill-counts). Secondary endpoints included changes in self-reported oral iron gastrointestinal intolerance, gastro-intestinal symptom rating scale (GSRS), serum iron, serum ferritin, transferrin saturation and haemoglobin levels. ResultsA total of 128 (62.7%) of the participants had low iron stores (ferritin < 30 {micro}g/L), 65 (31.9%) had moderate to severe iron deficiency (ferritin <12 {micro}g/L) and 33 (16.2%) had iron deficiency anaemia. Amongst 59 women who participated in the prospective study, 48 (81.4%) were classified as adherent/persistent with therapy using IWP compared to 12 (20.3%) taking the prior oral iron p<0.0001. These patients also showed significantly fewer reports of gastrointestinal intolerance with IWP (0.59 {+/-} 0.91) and lower GSRS scores (6.2 {+/-} 7.5) compared to the previous oral iron product (3.98 {+/-} 2.22, and 15.6 {+/-} 9.7 respectively, both P<0.0001). There were no differences in adherence, self-reported adverse GI effects and GSRS between the dose groups during the study. Serum iron levels increased across the whole cohort from 11.3 {+/-} 7.4 mol/L to 20.5{+/-} 11.0 mol/L (P<0.0001), transferrin saturation levels increased from 18.4 {+/-} 13.3 % to 33.6 {+/-} 17.6 % (P<0.0001) and median ferritin levels overall increased from 8.00 [IQR 6.00;13.0] to 15.5 [IQR 9.00;24.2] {micro}g/L at 12 weeks (P=0.0002). Haemoglobin levels increased from 11.36 g/dL (95%CI 10.95 to 11.77) to 12.40 g/dL (95%CI 12.03 to 12.76, P=0.0007) in patients with anaemia and were normalised in most patients taking 50mg IWP daily. ConclusionsLow iron, iron deficiency and anaemia are common in women of childbearing age with a history of intolerance to oral iron. Patients with low iron (ferritin < 30 {micro}g/L) and moderate to severe iron deficiency (ferritin <12 {micro}g/L) have similar impairment of energy. IWP can improve self-reported oral iron adherence and tolerability as well as iron stores, haemoglobin and tiredness in these women.

The consumption of probiotics may influence childrens gut microbiome and metabolome, which may reflect shifts in gut microbial diversity composition and metabolism. These potential changes might have a beneficial impact on health. However, there is a lack of evidence investigating the effect of probiotics on the gut microbiome and metabolome of children. We aimed to examine the potential impact of a two (Streptococcus thermophilus and Lactobacillus delbrueckii; S2) vs. three (S2 + Bifidobacterium animalis subsp. lactis strain BB-12) strain-supplemented yogurt. Included in this study were 59 participants, aged one to five years old, recruited to phase I of a double-blinded, randomized controlled trial. Fecal samples were collected at baseline, after the intervention, and at twenty days post-intervention discontinuation, and untargeted metabolomics and shotgun metagenomics were performed. Shotgun metagenomics and metabolomic analyses showed no global changes in either intervention groups gut microbiome alpha or beta diversity indices. The relative abundance of the two and three intervention bacteria increased in the S2 and S2 + BB12 groups, respectively, from Day 0 to Day 10. In the S2+BB12 group, the abundance of several fecal metabolites was reduced at Day 10, including alanine, glycine, lysine, phenylalanine, serine, and valine. These fecal metabolite changes did not occur in the S2 group. Future research using longer probiotic intervention durations and in children at risk for gastrointestinal disorders may elucidate if functional metabolite changes confer a protective gastrointestinal effect.

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

Anaemia remains a significant public health issue in India, despite five of control programs. Anaemia affects 52-67% of target populations in India despite five decades of control programmes. We conducted a review of reviews and meta-analyses (SRMAs) of regional studies to evaluate daily versus intermittent oral iron and iron-folic acid (IFA) supplementation across age groups. We identified 21 SRMAs (17 high-quality, 4 moderate-quality) and 44 regional studies from India and South Asia. IFA prophylaxis consistently improved haemoglobin levels (4.1-8.8 g/L increase) and ferritin concentrations, reducing anaemia risk by 23-70% across all age groups. IFA prophylaxis consistently improved haemoglobin levels (4.1-8.8 g/L increase) and ferritin concentrations, reducing anaemia risk by 23-70% across all age groups. Daily and intermittent regimens showed similar haematological outcomes in children, adolescents, and women of reproductive age. Among pregnant women, daily supplementation was superior for haemoglobin and ferritin levels, though intermittent dosing had fewer gastrointestinal side effects. These findings support weekly IFA supplementation for non-pregnant beneficiaries as an evidence-based strategy, even in settings where anaemia prevalence exceeds 40%. Further research on long-term safety in non-iron-deficient populations is needed.

Nutrition plays a pivotal role in depression, but dietary interventions are usually not personalized and do not consider patients microbial and human molecular functions. This preliminary study evaluated the effectiveness of precision supplements (PS) on depression symptoms as part of a personalized nutrition subscription plan that accounts for the gene expression activity of the microbiome and the human host. People with depression, 86 taking PS and 45 controls responded to the patient health questionnaire-9 (PHQ-9) at two time points an average of [~]6 months apart. Categorical changes were evaluated using the PHQ-9 score system, and clinically significant categorical differences were observed between the two groups (effect size = 0.48; p <0.001). The difference in differences was calculated using multiple group propensity score weighting adjusting for age, sex, BMI, and physical activity, and the PHQ-9 score decreased by [~]4 points ([~]29%) for the intervention group (t0: 13.75+-3.80, t1: 9.78+-6.42) vs Controls (t0: 14.07+-3.64, t1: 13.59 +-6.65). Thus, precision supplement use over [~]6 months significantly reduced depression symptoms, with 69.8% of the individuals in the intervention group improving their category to no/low depression vs. 15.6% in the control group.

Diet is known to affect the gut microbiome and metabolome composition in adults, but this has not been fully explored in infants. Dietary patterns from 1 year-old infants (n=182) from the South Asian Birth Cohort (START) study were compared to gut microbiome alpha and beta diversity and to taxa abundance differences. Diet - serum metabolite associations were identified using multivariate analysis (partial least squares-discriminant analysis, PLS-DA) and univariate analysis (T-Test). Dietary biomarkers identified from START were also examined in a separate cohort of white Caucasian infants (CHILD Cohort Study, n=82). Lastly, the association of diet with gut microbiome and serum biomarkers, considering maternal, perinatal and infant characteristics was investigated using multivariate forward stepwise regression. A dietary pattern characterized by breastfeeding, supplemented by formula and dairy was the strongest predictor of the gut microbiome that also differentiated the serum metabolome of infants. The formula and dairy dietary pattern was associated with a panel of circulating metabolites in both cohorts, including: S-methylcysteine, branched-chain/aromatic amino acids, lysine, dimethylglycine, and methionine. Breastfeeding status, the prominent feature of the dietary pattern, was also associated with a sub-set of serum metabolites in both cohorts. In START, this diet pattern was associated with the metabolites tryptophan betaine, 2-hydroxybutyric acid, tyrosine, phenylalanine, and trimethyl-N-oxide. In the CHILD Cohort Study(CHILD), breastfeeding status was associated with the metabolites aminooctanoic acid, 3-hydroxybutyric acid, and methyl-proline. The results of our study suggest that breastfeeding has the largest effect on the composition of the gut microbiome and the serum metabolome at 1 year, even when solid food diet and other covariates are considered.

BackgroundInsufficient dietary intake and/or reduced gastrointestinal absorption lead to low vitamin B12 (B-12) status. In a secondary data analysis of the results of the B-12 absorption (CobaSorb) test and B-12 supplementation trial in a B-12 insufficient Indian rural community, we explored characteristics of B-12 absorption and its association with post-supplementation plasma B-12 concentration. ObjectiveTo study i) the distribution of plasma holo-transcobalamin (holoTC) response during the CobaSorb test, and ii) determinants of plasma B-12 response to long-term, oral supplementation with physiological dose B-12. MethodsThe participants (parents and children in the Pune Maternal Nutrition Study) first underwent a B-12 absorption study Subsequently, they participated in a 12-month-long, double-blind RCT of daily oral B-12 (0, 2, or 10 {micro}g) and folic acid (0 or 200 {micro}g). Circulating B-12 was measured at baseline and after 4 and 12 months of supplementation. A linear mixed-effect model was used to study the predictors of B-12 absorption and response to supplementation. ResultsThree hundred and thirteen participants included children (n=109, 57 boys, mean age 9y, weight 21.9 kg, BMI 13.6 kg/m2), mothers (n=108, 30y, 47.7 kg, 19.3 kg/m2), and fathers (n=96, 37y, 59.3 kg, 21.4 kg/m2). The plasma holoTC response during the absorption test was continuously distributed and was negatively associated with weight and positively with the dose of B-12. Response to long-term B-12 supplementation was positively predicted by absorption test response, dose of B-12, length of supplementation, and compliance. ConclusionsThe continuous distribution of plasma holoTC response during the absorption test supports a graded absorption of B-12. CobaSorb protocol could be used to unravel the intricacies of B-12 absorption. Clinical Trial Registry number and website where it was obtainedISRCTN59289820. DOI: https://doi.org/10.1186/ISRCTN59289820 https://www.isrctn.com/

Shifts in the maternal gut microbiome and vitamin D deficiency during pregnancy have been associated, separately, with health problems for both the mother and the child. Yet, they have rarely been studied simultaneously. Here, we analyzed gut microbiome (from stool samples obtained in late pregnancy) and vitamin D level (from blood samples obtained both in early and late pregnancy) data of pregnant women in the Vitamin D Antenatal Asthma Reduction Trial (VDAART), a randomized controlled trial of vitamin D supplementation during pregnancy, to investigate the association of vitamin D status on the pregnant womens microbiome. To find associations we ran linear regressions on alpha diversity measures, PERMANOVA tests on beta diversity distances, and used the ANCOM-BS and Maaslin2 algorithms to find differentially abundant taxa. Analyses were deemed significant using a cut-off p-value of 0.05. We found that gut microbiome composition is associated with the vitamin D level in early pregnancy (baseline), the maternal gut microbiome does not show a shift in response to vitamin D supplementation during pregnancy, and that the genus Desulfovibrio is enriched in women without a substantial increase in vitamin D level between the first and the third trimesters of pregnancy. We conclude that increasing the vitamin D level during pregnancy could be protective against the growth of sulfate-reducing bacteria such as Desulfovibrio, which has been associated with chronic intestinal inflammatory disorders. More in-depth investigations are needed to confirm this hypothesis.

Purpose: Iron deficiency impairs sports performance, and female athletes are particularly vulnerable. High-dose iron supplements, commonly used to prevent iron depletion and performance impairments, may cause gastrointestinal side effects and disrupt the gut microbiota. Whether lower doses can improve iron status without adverse effects remains unclear. The aim of this study was to characterize iron intake and iron status in female soccer players during the competitive season and investigate effects of low-dose iron supplementation on iron status, safety-related outcomes and gut microbiota. Methods: In a two-arm parallel randomized controlled trial, female soccer players (median age 21) were randomized to an intervention group (n=12) receiving 3-month low-dose iron supplementation (27 mg elemental iron/day) or a control group (n=11) without supplementation. Blood/fecal samples were collected at baseline and 3-month follow-up. Dietary intake was estimated using 7-day food diaries. Between-group differences were analyzed per protocol (n=18) using ANCOVA with baseline adjustment. Results: The players had inadequate baseline iron intake (median 11.2 mg/day) and 43% had serum ferritin indicating iron depletion (<35 g/L). At follow-up, no significant between-group difference was found for serum ferritin, but fewer athletes in the intervention group experienced decreases from baseline to follow-up (P<0.05). Moreover, serum iron was higher in the intervention group (Pgroup=0.05). No between-group differences were observed for gastrointestinal symptoms or liver damage biomarkers. On the contrary, the intervention led to lower IL-6 (Pgroup=0.04) and higher gut microbial -diversity (Pgroup=0.01) compared to controls. Conclusions: The low-dose iron supplementation was well tolerated, attenuated decreases in iron stores, increased gut microbial diversity and attenuated systemic inflammation in female soccer players with suboptimal dietary iron intake. However, potential adverse effects of long-term exposure cannot be excluded.

Vitamin D is essential for bone and metabolic health. Deficiency remains a global health issue, particularly among older adults and ethnic minorities with darker skin pigmentation. Data on circannual variation these groups remain sparse. This study reports vitamin D status in older adults ([&ge;]65 years) and ethnic adults ([&ge;]18 years, Fitzpatrick classes IV-VI) in northern Britain during the screening phase of a supplementation trial. Participants were screened for inclusion between December 2024 and August 2025. Serum 25-hydroxyvitamin D (25(OH)D) was assessed in dried blood spots followed by LC-MS/MS analysis. 299 participants were screened. Vitamin D insufficiency or deficiency (<50 nmol/L) was noted in 54.8% of older adults and 72.1% of ethnic individuals. These rates did not decline during summer months. These findings highlight persistently high rates of vitamin D insufficiency across high-risk groups in northern Britain and underscore the inadequacy of sunlight exposure as a corrective measure.

BackgroundBreastmilk confers numerous benefits to infants relative to formula milk, such as promoting metabolic health and supporting immune homeostasis. However, in-depth mechanistic insights comparing the influence of breastmilk versus formula milk across different compartments are lacking. MethodsSeveral datasets interrogating the effects of breastmilk versus formula milk were curated, including transcriptomes of infant intestinal organoids, intestinal gene expression microarray, and single cell RNA-seq data for infant peripheral blood mononuclear cells (PBMCs). Comparative analyses were performed, with a specific focus on differences at a signal pathway level. ResultsComparative analyses revealed that intestinal exposure to breastmilk was linked to elevated gluconeogenesis, as well as reprogramming of other metabolic, nutrient-sensing and immunerelated pathways. Contrarily, in PBMCs, formula milk feeding was linked to upregulation of apoptosis-related pathways across all PBMC subsets. ConclusionsBreastmilk reprograms the transcriptomic landscapes of infant intestine, particularly promoting intestinal gluconeogenesis. This might explain its metabolic advantages via modulating metabolic homeostasis. Different effects were found in PBMCs, where formula milk is linked to enhanced apoptotic signalling in the infants developing immune cell subsets.

BackgroundFor very preterm infants, human milk is often fortified with formula products based on processed bovine milk. Intact bovine colostrum (BC) is rich in anti-inflammatory milk factors and considered an alternative. Our objective was to investigate if BC affects anti-inflammatory/TH2 immunity and infection risk in very preterm infants. MethodsIn a secondary analysis of a multicenter, randomized controlled trial (NCT03537365), very preterm infants (26-31 weeks gestation, 23% small for gestational age, SGA) were randomized to receive BC (ColoDan, Biofiber, Denmark, n=113) or a conventional fortifier (PreNAN, Nestle, Switzerland, n=116). Infection was defined as antibiotic treatment for five or more consecutive days. Levels of 29 cytokines and chemokines were measured in plasma before and after start of fortification. ResultsInfants fortified with BC showed more infection episodes (20 vs. 12%, P<0.05) and tendency to higher cumulative infection risk (hazard ratio, HR 1.9, P=0.06), particularly for SGA infants (HR 3.6, P<0.05). Additionally, BC-fortified infants had higher levels of TH2 related cytokines and chemokines (IL-10, MDC, MCP4) and reduced levels of cytokines related to TH1/TH17 responses (IL-15, IL-17, GM-CSF). The differences were most pronounced in SGA infants, displaying higher levels of TH2-related IL-4, IL-6, and IL-13, and lower interferon-{gamma} and IL-1 levels in the BC group ConclusionInfants fortified with BC show delayed transition from TH2-to TH1-biased systemic immunity, especially for SGA infants. This was associated with more frequent antibiotic use, indicating elevated sensitivity to infection. Thus, an anti-inflammatory milk supplement like BC may delay systemic immune development in preterm infants with effects depending on weight at birth.

BackgroundPregnant women are advised to take folic acid supplements before conception and during the first three months of pregnancy. Many women continue folic acid supplementation throughout pregnancy, and concerns have been raised about associations between excess folic acid intake and adverse child health outcomes. Unmetabolized folic acid (UMFA) is found in serum at higher folic acid intakes and has been proposed as a biomarker for excess folic acid intake. ObjectiveTo determine if removing folic acid from prenatal multivitamin and mineral supplements after 12 weeks of pregnancy reduces concentrations of serum UMFA at 36 weeks gestation. DesignA double-blind, parallel-group, randomized controlled trial. Women with a singleton pregnancy 12-16-weeks gestation were randomly assigned to a multi-micronutrient supplement containing no folic acid (intervention) or 800 {micro}g folic acid/day (control) from enrolment until 36 weeks gestation. Maternal serum was analyzed for UMFA and secondary outcomes of red blood cell and serum folate at 36 weeks gestation. ResultsUMFA was detected in most of the 103 randomized women (86% >limit of detection). However, only 12% (n=11/90) of serum samples were above the limit of quantification (0.55 nmol/L), preventing analysis of UMFA concentrations. Fewer women had detectable UMFA in the no folic acid group compared to the 800 {micro}g folic acid group (72% [n=33/46] vs. 98% [n=43/44]; p = 0.001). Maternal serum and red blood cell folate concentrations were lower in the no folic acid intervention group compared to the control group (median 23.2 vs. 49.3 nmol/L, 1335 vs. 1914 nmol/L, respectively; p< 0.,001) and no woman was classified as folate deficient. ConclusionsRemoving folic acid from prenatal multivitamin and mineral supplements reduced the number of women with detectable UMFA at 36 weeks gestation, however, differences in UMFA concentration between treatment groups were not quantifiable.

BackgroundNicotinamide adenine dinucleotide (NAD) is a crucial coenzyme involved in cellular energy homeostasis whose levels decline notably with aging, which has prompted interest in NAD+ boosting to help combat age-related diseases and dysfunction. Numerous clinical trials have demonstrated safety and efficacy for B3 vitamins, such as nicotinamide riboside (NR), to increase NAD+ levels and augment the NAD+ metabolome. Limited impact on clinically relevant outcomes or quality of life have been demonstrated, however. ObjectiveThis randomized, double-blind, placebo-controlled, remote pilot study examined the effects of supplementation with Qualia NAD+(R) on whole blood NAD+ levels and quality of life measures. MethodsStudy participants consumed Qualia NAD+ daily for 28 consecutive days. NAD+ levels were the primary outcome and measured using a self-administered, non-invasive blood spot assay test conducted at baseline and at study end. Quality of life questionnaires were the secondary outcomes and reported bi-weekly. NAD+ levels and questionnaire data were analyzed using a linear mixed-effects model to compare within-group and between-group differences over time as compared to baseline. Independent t-tests were utilized to compare safety and tolerability between study groups. ResultsTwenty-five healthy adults aged 40 - 65 (56% female) consumed Qualia NAD+ (n = 9) or placebo (n = 16) Overall, Qualia NAD+ significantly increased NAD+ levels an average of 74% compared to a 4% increase observed in the placebo group (p < 0.001). Within-groups comparisons for Qualia NAD+, and changes in NAD+ levels comparing Qualia NAD+ and placebo were also significant (p < 0.001). Improvements in the overall and somatic categories (p = 0.02 and p = 0.04) were observed for males only comparing baseline to the end of the study. No adverse events were reported. ConclusionsQualia NAD+, a novel nutraceutical formulated with multiple vitamins, nutrients, and botanical compounds, effectively increased whole blood NAD+ levels and may improve some symptoms of aging in males. Clinicaltrials.gov identifier: NCT06812416.

Short-chain fatty acids (SCFAs) are circulating metabolites generated by gut microbiota. Recently, a link between age-related muscle loss and gut microbiota has been described, and SCFAs could play a mediating role in this relationship. Acetic, propionic, and butyric acid are the abundant forms and are considered to have health benefits, less is known about valeric and caproic acid. In a cross-sectional study including 155 healthy volunteers, we investigated the relationship between muscle area, as well as intramuscular adipose tissue measured by magnet resonance imaging and circulating SCFAs. SCFAs and additional parameters were measured from serum and sport activities recorded by means of a questionnaire. We found a significant positive association between valeric acid (VA) levels and the thigh cross-sectional muscle area in males. This relationship was independent of age, BMI and weekly training times and was not observed in females. No associations between other SCFAs and the thigh muscle cross-sectional area were observed. To our knowledge, this is the first human study demonstrating a significant relationship between thigh muscle mass and VA, supporting the thesis of the "gut-muscle axis" with VA as a possible interacting player, on the one hand, affected by sex differences, on the other.

BackgroundMitochondria-driven oxidative/redox stress and inflammation play a major role in chronic kidney disease (CKD) pathophysiology. Compounds targeting mitochondrial metabolism may improve mitochondrial function, inflammation, and redox stress; however, there is limited evidence of their efficacy in CKD. MethodsWe conducted a randomized, double-blind, placebo-controlled crossover trial comparing the effects of 1200 mg/day of coenzyme Q10 (CoQ10) or 1000 mg/day of nicotinamide riboside (NR) supplementation to placebo in 25 people with moderate-to-severe CKD (eGFR <60mL/min/1.73 m2). We assessed changes in the blood transcriptome using 3-Tag-Seq gene expression profiling and changes in pre-specified secondary outcomes of inflammatory and oxidative stress biomarkers. For a subsample of participants (n=14), we assessed lymphocyte and monocyte bioenergetics using an extracellular flux analyzer. ResultsThe (mean{+/-}SD) age, eGFR, and BMI of the participants were 61{+/-}11 years, 37{+/-}9 mL/min/1.73m2, and 28{+/-}5 kg/m2 respectively. Of the participants, 16% had diabetes and 40% were female. Compared to placebo, NR-mediated transcriptomic changes were enriched in gene ontology (GO) terms associated with carbohydrate/lipid metabolism and immune signaling while, CoQ10 changes were enriched in immune/stress response and lipid metabolism GO terms. NR increased plasma IL-2 (estimated difference, 0.32, 95% CI of 0.14 to 0.49 pg/mL), and CoQ10 decreased both IL-13 (estimated difference, -0.12, 95% CI of -0.24 to -0.01 pg/mL) and CRP (estimated difference, -0.11, 95% CI of -0.22 to 0.00 mg/dL) compared to placebo. Both NR and CoQ10 reduced 5 series F2-Isoprostanes (estimated difference, -0.16 and -0.11 pg/mL, respectively; P<0.05 for both). NR, but not CoQ10, increased the bioenergetic health index (BHI) (estimated difference, 0.29, 95% CI of 0.06 to 0.53) and spare respiratory capacity (estimated difference, 3.52, 95% CI of 0.04 to 7 pmol/min/10,000 cells) in monocytes. ConclusionSix weeks of NR and CoQ10 improved in oxidative stress, inflammation, and cell bioenergetics in persons with moderate to severe CKD.

SummaryO_ST_ABSBackgroundC_ST_ABSProtein-energy malnutrition is still problematic worldwide. It directly impacts growth and development, especially in children. We investigated the long-term effects of egg supplementation on the growth, biochemical indices, and microbiota of primary school children. MethodsA randomized controlled cluster study was carried out in six rural schools in Thailand. Participants were randomly assigned into three groups: 1) whole egg (WE) - consuming 10 additional eggs/week [n = 238], 2) protein substitute (PS) - consuming yolk-free egg substitute equivalent to 10 eggs/week [n = 200], and 3) control group (n= 197]). Demographic and biochemical indices, and microbiota composition were measured at weeks 0, 14, and 35. Findings635 students (8 to 14 years old) were recruited (51{middle dot}5% female). At baseline, 17% of the participants were underweight, 18% were stunted, and 13% were wasted. At week 35, compared to the control group, body weight and height increased significantly in WE (3{middle dot}6 {+/-} 23{middle dot}5 kg, P<0{middle dot}001 and 5{middle dot}1 {+/-} 23{middle dot}2 cm, P<0{middle dot}001). No significant differences in weight or height were observed between PS and Control. Prealbumin levels were higher (1{middle dot}5 {+/-} 8{middle dot}158{middle dot}6314 mg/dL, P<0{middle dot}001) in WE, but not in PS, compared to control. Significant decreases in total cholesterol, triglycerides, and LDL cholesterol were observed in the WE, but not in the PS groups. HDL cholesterol tended to increase in WE (0{middle dot}7 {+/-} 25{middle dot}2 mg/dL, ns). Neither the alpha nor beta diversity of the bacterial diversity was significantly different among all groups. After WE supplementation, the overall relative abundance of Bifidobacterium increased by 1{middle dot}28-fold as compared to baseline and the differential abundance analysis also indicated that Lachnospira increased significantly and Varibaculum decreased. InterpretationLong-term whole egg supplementation is an effective, feasible and low-cost intervention to reduce protein-energy malnutrition, particularly in low-middle-income countries. Whole egg supplementation improves growth and nutritional biomarkers, and positively impacts gut microbiota without adverse effects on blood cholesterol levels. FundingAgricultural Research Development Agency (ARDA) of Thailand (PRP6105022310, PRP6505030460).

D-Glucosamine (GlcN), a monomer produced by the hydrolysis of chitosan, is a dietary supplement used worldwide to mitigate cartilage degeneration. Previous reports have shown that some dietary glucosamine migrates to the colon. However, the effect of glucosamine alone on colonic microbiota and bowel movements remains poorly understood. In this study, we evaluated the effect of glucosamine on the growth of 46 dominant human colonic bacterial species and 24 other important bacteria in vitro. Among the 70 gut bacterial species tested, the growth of 57 (81%) was significantly enhanced by 0.5% (w/v) GlcN, with the most prominent growth activity (>5-fold) observed in Anaerotruncus colihominis, Pseudoflavonifractor capillosus, and Roseburia hominis. These results indicate that a wide range of the tested gut bacteria can utilize GlcN, similar to the effect of conventional dietary fiber in improving bowel function. Next, we conducted an open-label, single-arm trial involving 29 healthy individuals to determine the effects of 1500 mg GlcN/day, a commonly used dose. Stool color significantly changed during the 2 weeks of GlcN intake from brown to ocher (p < 0.01), suggesting enhanced colonic fermentation. The stool odor and the sensation of incomplete evacuation improved significantly (p < 0.05). Numerical measurements of bowel movements revealed significant increases in stool volume, defecation frequency, and the number of days of defecation during GlcN intake (p < 0.001). Thus, dietary glucosamine may stimulate gut microbiota growth in the colon and promote bowel movements. This study was registered with the University Hospital Medical Information Network (regd. no. UMIN000056757).

BackgroundTo be universally applicable in treatment of severe COVID-19, novel therapies, especially those with little toxicity and low cost, are urgently needed. We report here the use of one such therapeutic combination involving two commonly used nutraceuticals, namely resveratrol and copper in patients with this disease. This study was prompted by pre-clinical reports that sepsis-related cytokine storm and fatality in mice can be prevented by oral administration of small quantities of resveratrol and copper. Since cytokine storm and sepsis are major causes of death in severe COVID-19, we retrospectively analyzed outcomes of patients with this condition who had received resveratrol and copper. Methods & FindingsOur analysis comprised of 230 patients with severe COVID-19 requiring inhaled oxygen who were admitted in a single tertiary care hospital in Mumbai between April 1 and May 13 2020. Thirty of these patients received, in addition to standard care, resveratrol and copper at doses of 5.6 mg and 560 ng, respectively, orally, once every 6 hours, until discharge or death. These doses were based on our pre-clinical studies, and were nearly 50 times and 2000 times less, respectively, than those recommended as health supplements. A multivariable-adjusted analysis was used to model the outcome of death in these patients and evaluate factors associated with this event. A binary logistic regression analysis was used, with age, sex, presence of comorbidities and receipt of resveratrol-copper as covariates. Data were updated as of May 30 2020. The number of deaths in resveratrol-copper and standard care only groups were 7/30 (23.3%, 95% CI 8.1%-38.4%) and 89/200 (44.5%, 95% CI 37.6%-51.3%), respectively. In multivariable analysis, age >50 years [odds ratio (OR) 2.558, 95% CI 1.454-4.302, P=0.0011] and female sex (OR 1.939, 95% CI 1.079-3.482, P=0.0267) were significantly associated, while presence of co-morbidities was not significantly associated (OR 0.713, 95% CI 0.405-1.256, P=0.2421) with death. There was a trend towards reduction in death in patients receiving resveratrol-copper (OR 0.413, 95% CI 0.164-1.039, P= 0.0604). ConclusionsWe provide preliminary results of a novel approach to the treatment of severe COVID-19 using a combination of small amounts of commonly used nutraceuticals, which is non-toxic and inexpensive, and therefore could be widely accessible globally. The nearly two-fold reduction in mortality with resveratrol-copper observed in our study needs to be confirmed in a randomized controlled trial.

Key PointsThis section will be completed further ImportanceToddlerhood is a key window of opportunity for development of musculoskeletal system and microbiome. In this study we tested the efficacy of a synbiotic-based young child formula on bone and muscle strength and microbiome maturation in young children during motor-skill development. InterventionIn this randomized, double-blind controlled trial, children aged 2-3 years received either an experimental young child formula (EYCF) containing a combination of Limosilactobacillus reuteri DSM 17938 and galacto-oligosaccharides (GOS) or a minimally fortified milk (CM) for 6 months. A third arm remained on their habitual diet. Main outcomes and measuresBone quality (tibia speed of sound), muscle strength (handgrip), microbiota composition (shotgun metagenomics) and functionality (fecal metabolome) were evaluated at baseline, and after 3 months and 6 months of intervention. Microbiota and metabolomic features were associated to each other and to clinical bone and muscle readouts at the same timepoints. ResultsTibial speed of sound was significantly increased after 6 months (primary end point, p<0.01) and 3 months (p<0.05) of EYCF vs CM feeding. These effects on bone strength were paralleled by significantly higher muscle strength after 6 months in EYCF vs CM. The intervention significantly remodeled microbiome composition, with enrichment of L. reuteri, and higher bifidobacteria presence in the stools of EYCF vs CM children at both 3 and 6 months. Increased L. reuteri abundance after 6 months of EYCF consumption was associated with higher bone quality and muscle strength. Stool metabolomics were significantly modulated by EYCF consumption with 45 metabolites significantly modified and associated to microbiome compositional changes such as Bifidobacterium spp. and L. reuteri expansion. Pairing of metagenomic and metabolomic signatures induced by EYCF revealed an enrichment of tryptophane and indole metabolism which significantly associated to bone and muscle strength clinical outcomes. Conclusions and relevanceConsumption of an experimental young child formula containing a L. reuteri + GOS synbiotic improves musculoskeletal development in toddlers that was associated with a modulation of microbiota composition and functionality. These results provide novel mechanistic insights on gut-musculoskeletal crosstalk during early life and demonstrate that nutritional interventions targeting the microbiome can support healthy bone and muscle development and may contribute to functional motorskills acquisition during childhood. Trial registrationThe trial was registered at clinicaltrial.gov as NCT04799028