The American Journal of Clinical Nutrition

The modern Western diet (MWD) provides high linoleic acid (LA) exposure, typically contributing 6-9% of total caloric intake. These high LA levels have fueled a longstanding debate regarding whether this dietary pattern confers benefit or risk. Importantly, LA intake is disproportionately elevated among lower socioeconomic populations due to greater reliance on industrial seed oils and ultra-processed foods. Despite decades of research, controlled dietary intervention studies directly evaluating the biological consequences of varying LA exposure remain limited. The current randomized, double-blind intervention compared the effects of a 12-week Low LA diet (2.5% energy) versus a High LA diet (10.0% energy) in healthy adults. Primary outcomes included plasma highly unsaturated fatty acid (HUFA) concentrations and ex vivo zymosan-stimulated whole-blood oxylipin generation. Fifty- two participants completed the intervention. High LA exposure resulted in a marked reduction in plasma n-3 eicosapentaenoic acid (EPA) concentrations compared with the LowLA arm. In contrast, levels of arachidonic acid (ARA), dihomo-gamma-linolenic acid (DGLA) and docosahexaenoic acid (DHA) did not differ by dietary LA exposure. Analysis of oxylipin species revealed that levels of EPA-derived relative to ARA-derived mediators were significantly reduced in the High LA arm. These findings reveal that higher dietary LA selectively suppresses EPA pools and EPA-derived oxylipins without altering ARA, shifting the lipid mediator balance toward a more n-6-dominant profile.

Background: Diet is a modifiable risk factor for cardiometabolic disease, yet establishing causality remains challenging. Mendelian randomisation (MR) leverages genetic variants as instrumental variables (IVs) to enable causal inference. Method: Using two-sample MR, we assessed the causal effects of four principal component-derived dietary patterns (DPs) - Unhealthy, Healthy, Meat-based, Pescatarian - on twelve cardiometabolic outcomes: body mass index, coronary artery disease, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, triglycerides, systolic blood pressure, diastolic blood pressure, type 2 diabetes, fasting glucose and insulin, and glycated haemoglobin. Two sets of IVs were employed: conventional genome-wide significant variants associated with each DP, rigorously filtered for pleiotropy and directionality; and biologically informed variants in chemosensory receptor genes, given the role of taste and smell perception in shaping food choices. Results: Using conventional IVs, the Pescatarian DP reduced fasting insulin ({beta}IVW = -0.10 pmolL-1 per SD increase in Pescatarian DP score, 95% Confidence interval [CI] [-0.15, -0.04]; P = 1.19x10-3), which survived multiple sensitivity analyses. Associations between the Unhealthy DP and elevated blood pressure and glycated haemoglobin were likely undermined by heterogeneity and pleiotropy, with insufficient IVs for robust sensitivity testing. Chemosensory receptors yielded null findings, reflecting insufficient power. Conclusion: Rigorously filtered conventional IVs supported the causal nature of well-established diet-disease relationships, demonstrating MR's utility in strengthening causal inference in nutritional epidemiology. Chemosensory IVs demonstrated limited utility for DPs, likely reflecting the heterogeneous and complex sensory profiles of overall diets. Future efforts should consider using guideline-based dietary scores to facilitate translation of findings.

BackgroundDiet is central to cardiovascular disease (CVD) prevention, yet free-living studies rarely capture what people eat at home or how closely they follow an assigned diet due to limitations in self-reporting. Short-term inpatient feeding studies, with all meals provided and supervised intake, allow direct assessment of the physiological effects of dietary patterns. Objectivesi) To compare the short-term effects of a UK-National Institute for Health and Care Excellence (NICE) aligned diet versus a Western-style diet on CVD risk factors, metabolic phenotypes and microbiome; ii) To evaluate whether urinary metabolic phenotyping can objectively classify dietary adherence in adults with increased CVD risk. MethodsIn a controlled inpatient randomized crossover trial, 18 adults at elevated CVD risk completed two 72 h isocaloric diets: NICE-compliant and Western-style. Repeated-measures MCCV-PLS-DA assessed NMR fasting serum and 24 h urine metabolomic phenotypes. Univariate analyses examined CVD markers, urinary metabolites, serum SCFAs, and gut microbial richness and -diversity. ResultsDiet modulated CVD risk markers, with the NICE compliant diet lowering systolic blood pressure and atherogenic lipid parameters, whereas the Western-style diet increased these measures (all q < 0.05). The Western-style diet reduced microbial richness and tended towards lower -diversity. Urinary metabolic phenotyping identified 27 discriminatory metabolites between the diets reflecting food intake. Most diet-linked metabolites diverged from baseline within 24 h; microbiome derived metabolites demonstrated early and sustained divergence across 72 h. The urinary MCCV-PLS-DA model extended from a previously published framework in healthy adults, robustly classified dietary adherence (Q2Y=0.96), and correctly predicted allocated dietary intervention at earlier timepoints (24-48 h). ConclusionsUrinary metabolic phenotyping offers a sensitive and non-invasive tool for objectively assessing dietary intake. Short-term adherence to contrasting dietary patterns produced rapid, diet-specific metabolic and microbial effect in individuals at elevated CVD risk and differentially impacted cardiovascular risk profiles. This trial was registered at the ISRCTN registry (https://www.isrctn.com/ISRCTN44705179).

Introduction Acute malnutrition in children aged 6-23 months remains critical in Tigray, Ethiopia, where global acute malnutrition (GAM) rates have reached emergency levels. Small-quantity lipid-based nutrient supplements (SQ-LNS) show promise for prevention, but evidence from post-conflict settings is limited. Objective This study evaluated SQ-LNS effectiveness in preventing acute malnutrition and rightward shifting in the distribution of weight-for-height among young children in post-conflict Tigray, Ethiopia. Methods A non-randomized cluster trial enrolled 8,442 children aged 6-23 months across four districts. The intervention group (n=6,838) received daily 20g SQ-LNS sachets for six months plus behavior change communication; the control group (n=1,604) received standard nutrition programming. Primary outcomes were acute malnutrition prevalence (WHZ < -2 or MUAC < 12.5cm) and distribution of weight-for-height z-scores. Data were collected biweekly and analyzed using longitudinal comparisons and difference-in-differences (DiD) estimation. Results Acute malnutrition declined from 22.1% to 4.2% in the intervention group (17.9 percentage point reduction) versus 19.6% to 11.4% in controls (8.2-point reduction). Mean WHZ scores increased from -0.35 to +0.33 in the intervention group (gain of +0.68 z-scores), while controls improved from -0.79 to -0.63 (gain of +0.16). The net intervention effect (DiD) showed a 4.9 percentage point reduction in WHZ-defined GAM and a 9.7-point reduction in MUAC-defined GAM. Mean WHZ and MUAC increased significantly more in the intervention group (DiD: +0.52 z-scores and +3.88 mm, respectively). Critically, the entire WHZ distribution shifted rightward, indicating population-level nutritional improvement, not merely reduced caseloads. Conclusions Six months of daily SQ-LNS effectively prevented acute malnutrition and shifted the entire weight-for-height distribution rightward among young children in post-conflict Tigray. Benefits extended beyond treatment, lifting whole-population nutritional status and building resilience. Findings support SQ-LNS inclusion in post-conflict nutrition packages and highlight the importance of assessing distributional outcomes, not just prevalence, when evaluating nutritional interventions. Trial registration number This trial was registered as NCT06103084.

Long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) are candidate preventive agents for breast cancer. With emerging evidence of epigenetic regulation of the tumor microenvironment, tissue-level epigenetic effects may represent an important target for cancer prevention. In a randomized Phase II sub-study (high-dose 5 g/day vs low-dose 1 g/day for 12 months; n = 17; Clinicaltrials.gov: NCT02295059), DNA methylation (DNAm) of the breast environment was profiled by reduced-representation bisulfite sequencing (RRBS). DNAm was assessed genome-wide, at individual gene promoters, and for locus-level heterogeneity which has been linked to epigenetic dysregulation that can precede breast cancer. Both doses induced promoter DNAm changes, but their responses diverged: low-dose samples showed increased CpG variance and more differentially methylated promoters without pathway enrichment, whereas high-dose samples had reduced DNAm heterogeneity and promoter enrichment in inflammation signaling pathways. Many overlapping differentially methylated promoters changed in opposite directions between doses. The finding that high-dose n-3 PUFA affects DNAm fidelity in the breast adipose suggests a new potential mechanism for n-3 PUFA-mediated prevention of breast cancer development. Together with the dose-specific, directionally discordant DNAm responses in breast adipose, this study has important implications for both advancing n-3 PUFA for breast cancer prevention and dose selection in future n-3 PUFA supplementation trials.

BackgroundHigher-quality diets have been associated with lower levels of ectopic fat deposited in the viscera and liver, which is hypothesized to be mediated in part by the gut microbiota. ObjectivesWe tested this hypothesis in a multi-ethnic imaging study using global (microbiome-wide) testing as well as a high-dimensional multiple-mediators regression framework to identify bacterial genera in the human gut that mediate the association between diet quality and ectopic adiposity. MethodsWe analyzed the cross-sectional data of 1,400 older adults (age 60-77) from five racial/ethnic groups in the Multiethnic Cohort Adiposity Phenotype Study (2013-2016). Overall diet quality was defined by adherence to the MIND diet. The relative abundance of 151 bacterial genera was quantified from 16S rRNA gene sequencing of the stool samples. Visceral fat, liver fat, and the presence of MASLD (metabolic dysfunction-associated steatotic liver disease) were determined based on magnetic resonance imaging (MRI). We used high-dimensional mediation analysis (HDMA) to estimate gut microbial mediation in the linear regression of visceral fat or liver fat, or in logistic regression of MASLD, on the MIND adherence score, adjusted for potential confounders. ResultsHigher diet quality was associated with lower ectopic adiposity: 12% less visceral fat area, 23% less liver fat, and a 49% less likelihood of having MASLD, comparing the highest to the lowest quartile of the MIND score. Using a distance-based global test, we confirmed overall significant microbial mediation of the inverse diet-ectopic fat association. From HDMA, four bacterial genera were identified as mediating the protective association with visceral fat, with the largest mediation conferred by Lachnospiraceae UCG.001 (12.2%). Two genera (Lachnoclostridium, Weissella) were shown to mediate the MIND association with both liver fat and MASLD. In particular, Lachnoclostridium mediated 13.6% of the liver fat association and 10.8% of the MASLD association, and Lachnospiraceae UCG.001 additionally mediated 12.1% of the liver fat association. ConclusionsOur results support the hypothesis that the gut microbiota contributes to conveying the effect of diet quality on preferred body fat distribution, e.g., involving bacteria that are known to produce short-chain fatty acids (Lachnospiraceae) or secondary bile acids (Lachnoclostridium).

Introduction High consumption of ultra-processed foods (UPF) is associated with adverse health outcomes and weight gain. Despite increasing calls for behavioural strategies to reduce UPF intake, no theory-informed intervention targeting UPF reduction has been evaluated in UK adults in alignment with national dietary guidance. We assessed the feasibility, acceptability, and preliminary behavioural and clinical outcomes of a multi-component intervention designed to reduce UPF consumption (and increase physical activity (PA)/minimally processed food (MPF) intake). Methods In this exploratory single-arm pre-post study, adults (N=45) living with overweight or obesity and habitual UPF intake [&ge;]50% of total energy were offered a 6-month behavioural intervention following a controlled feeding phase (UPDATE trial, stage 1). The intervention was developed using the Behaviour Change Wheel and Capability, Opportunity, Motivation-Behaviour (COM-B) model and included one-to-one sessions with a behavioural scientist, tailored print and digital materials, peer-support meetings, and a moderated group chat. Feasibility outcomes included uptake, retention, and intervention fidelity. Secondary outcomes included COM-B constructs, dietary intake, PA, clinical and self-reported outcomes, and qualitative feedback. Results Uptake was 91% (41/45). Retention at 6 months was 68% (28/41), with 83% (34/41) providing follow-up data (intention-to-treat). Median attendance at one-to-one sessions was 86% (interquartile range (IQR): 57-100) with 56% (23/41) attending all sessions (per-protocol). Fidelity to core behaviour change techniques was high. At 6 months, COM-B scores improved for healthy eating (+7%, standard deviation (SD): 8; p<0.001) and physical activity (+5%, SD: 9; p=0.013). UPF intake decreased by 25% of total energy (95% confidence interval (95%CI): -32, -17), with a corresponding increase in minimally processed foods (+23%; 95%CI: 17, 29). Vigorous physical activity increased (+60 min/week, IQR: 0-180), weekday sitting time decreased (-61 min/day, SD: 110), and weight reduced by 3.8 kg (IQR: -8.5-1.0; p=0.001). Findings were similar in per-protocol analyses. Qualitative data indicated perceived improvements in wellbeing and habit formation. Conclusion This theory-informed intervention demonstrated good feasibility and acceptability and was associated with improvements in targeted behavioural mechanisms and health-related outcomes. A randomised controlled pilot trial is warranted to evaluate effectiveness and refine implementation.

BackgroundTime-restricted eating (TRE) has gained popularity for weight loss and metabolic health. While some evidence suggests greater benefits when TRE aligns with circadian rhythms--characterized by early daytime eating and avoidance of nighttime intake, often referred to as early TRE (eTRE), other studies report no meaningful differences between eTRE, other TRE approaches with or without exercise, or calorie restriction (CR), and robust comparative evidence remains limited. AimTherefore, the aim of this network meta-analysis (NMA) is to evaluate the physiological effects of eTRE, midday time-restricted eating (mTRE), late time-restricted eating (lTRE), with and without exercise, CR, and control (without prescribed energy or fasting windows) on anthropometric measures and cardiometabolic markers in adults with cardiometabolic risk factors. MethodsA comprehensive literature search was conducted in four major databases (PubMed, Web of Science, Scopus, and Embase) up to April 24, 2025. A Bayesian NMA was performed, using a control group as the reference comparator across interventions. Treatment effects were expressed as mean differences with 95% confidence intervals. The relative ranking of the included arms on the outcomes was assessed using surface under the cumulative ranking curve, values derived from the NMA, where higher values reflect a higher probability of superior effectiveness. Resultsa total of 40 trials comprising 3259 subjects were included in the analysis. There were significant reductions in most anthropometric measures in all intervention groups compared to control group. Whereas eTRE and eTRE + exercise (EX) significantly improved glucoregulatory outcomes compared to control, eTRE + EX showed superior results over other interventions. ConclusionWhile our results did not detect statistically significant differences between TRE patterns and CR, the consistent SUCRA rankings in favor of eTRE (particularly with exercise) suggest that meal timing may play an important role in metabolic regulation.

BackgroundSevere acute malnutrition (SAM) among children under 5 years of age is generally treated in outpatient settings providing caregivers with weekly ready-to-use therapeutic food (RUTF) rations to be administered at home. Recent updates to global treatment guidelines suggest that RUTF dose can be reduced once children progress to moderate stage (MAM). No evidence exists on the optimal timing of the dosage reduction or on ideal visit frequency. ObjectivesWe aimed to test the impact of 1) immediate RUTF dose reduction (1a) versus including a 2-week transition (1b) among children admitted with SAM and 2) fortnightly (2a) versus weekly (2b) visit frequency during MAM phase among children admitted with SAM and MAM. Methods and findingsThis prospective cluster-randomized controlled non-inferiority trial followed a 2 x 2 factorial design and divided 39 health areas (clusters) of Nara, Mali, into 4 groups implementing: A) 1a+2a B) 1a+2b, C) 1b+2a, and D) 1b+2b. Simplified, combined treatment was used providing 2 daily RUTF sachets to children admitted as SAM (mid-upper arm-circumference=MUAC<115mm or edema) and 1 daily RUTF sachet to children admitted with MAM (MUAC 115-124mm). Recovery was declared when a child reached MUAC [&ge;]125mm and absence of edema for 2 consecutive visits. Depending on the randomization arm, children admitted with SAM transitioned into receiving 1 daily RUTF sachet immediately upon reaching MUAC[&ge;]115mm (A+B) or after 3 consecutive visits (2 weeks) with MUAC[&ge;]115mm (C+D). Weekly visits were applied for all children with MUAC<115mm and then depending on randomization arm, visits continued weekly (A+C) or fortnightly (B+D) in the MAM phase. The main outcome was recovery and a non-inferiority margin of 10% was applied. Between April and December 2023, a total of 6249 children with MUAC<125mm or edema were admitted to treatment including 1451 children with SAM. On average 98% of children recovered with a mean duration of treatment of 6 weeks. Immediate transition resulted in non-inferior recovery compared to 2-week transition from SAM to MAM and no differences were observed in program outcomes (proportion of recovered, defaulted, non-recovered, transferred to inpatient care and deceased). However, we observed a non-significant trend of slight increase in the proportion of children regressing back to SAM after being MAM among children following immediate transition compared to those benefitting from 2-week transition. Fortnightly visit frequency in MAM phase resulted in non-inferior recovery compared to weekly visits throughout and no differences were observed in program outcomes. Duration of treatment was 2.5 weeks longer with fortnightly visits during MAM phase resulting in 23 sachets higher RUTF consumption compared to weekly visits throughout. ConclusionsWe recommend applying weekly visits throughout treatment where feasible for both children with MAM and SAM at admission and including a 2-week transition period before reducing the RUTF dose for children admitted with SAM once they reach MAM criteria. Trial registrationThe study was registered to clinicaltrials.gov (NCT06594341).

Gene-environment interactions (GEI) contribute to circulating polyunsaturated fatty acid (PUFA) and monounsaturated fatty acid (MUFA) profiles. GEI may partly explain differences in trait variance across genotype groups. To identify GEI for circulating unsaturated fatty acids, we adopted a two-stage strategy. First, we detected quantitative trait loci associated with trait variance (vQTLs). Second, we tested these vQTLs for interaction with fish oil supplements (FOS). We performed genome-wide vQTL screens for 14 plasma PUFA and MUFA phenotypes in a UK Biobank subset of 200,478 participants. At the genome-wide significance threshold (p < 5.0 x 10-8), we identified 172 vQTL-trait pairs across all 14 traits, and 16 of these vQTLs had no marginal genetic effect on the corresponding trait. We found 46 non-overlapping loci across all phenotypes, with an average of 12 vQTLs per trait. Omega-6% and PUFA% had the most independent vQTLs (N = 24) while DHA% and Omega-3% had the least (N = 1 and 2, respectively). For each of the 172 vQTL-trait pairs, we tested the interaction effect of the vQTL with FOS on the corresponding trait. We found six significant interaction signals in DHA, DHA%, Omega-3, Omega-3%, LA, and Omega-6/Omega-3 ratio around the FADS1/2, ZPR1, and SUGP1/TM6SF2 genes. Our results provide a comprehensive resource of vQTLs and gene-FOS interactions shaping the circulating levels of unsaturated fatty acids.

Although the co-occurrence of diarrhea and malnutrition is well documented, research has largely focused on the acute management of diarrheal illness. Despite its importance, longitudinal evidence characterizing post-diarrheal recovery trajectories is sparse. We sought to characterize post-diarrheal nutritional recovery trajectories among children aged 6-35 months who were malnourished at enrollment using data from the Enterics for Global Health (EFGH) Shigella Surveillance study (2022-2024). EFGH enrolled children aged 6-35 months presenting with medically-attended diarrhea and followed them at 4 weeks and 3 months post-enrollment. This analysis included children with baseline wasting, stunting, or underweight (z-score < -2) and complete anthropometric follow-up. Latent class mixed-effects models were used to identify distinct post-diarrheal growth trajectories based on changes in anthropometric z-scores over time. Multinomial modified Poisson regression models examined associations between baseline factors and trajectory membership. Among 9,480 enrolled children, 16.5% (n=1,561) were wasted, 22.7% (n=2,155) stunted, and 21.0% (n=1,994) underweight at baseline. Wasting showed greater recovery potential (80.8%) compared with stunting (38.5%) and underweight (40.3%). Recovery was shaped by factors across multiple levels. Clinical severity markers ( prolonged diarrhea, dehydration, and hypoxemia) increased the risk of nutritional failure. Age also influenced outcomes: infants were more likely to worsen, whereas older toddlers more often experienced stagnation. Interventions including exclusive breastfeeding, oral rehydration therapy, appropriate antibiotics, and zinc supplementation, improved outcomes, while unimproved sanitation undermined recovery. These findings highlight the need for integrated strategies combining infection control, nutritional rehabilitation, and water, sanitation, and hygiene interventions tailored to the childrens developmental stage. Key MessagesO_LIPost-diarrheal nutritional recovery is highly heterogeneous, with wasting showing the greatest potential for improvement, while stunting and underweight often result in persistent growth stagnation. C_LIO_LIBaseline anthropometric deficits alone are insufficient to predict recovery, highlighting the need for dynamic monitoring and individualized management. C_LIO_LIInfants are particularly vulnerable to acute nutritional deterioration, while older toddlers frequently experience growth stagnation. C_LIO_LIModifiable protective factors including exclusive breastfeeding, ORS, zinc, and appropriate antibiotics, improved outcomes, whereas poor sanitation undermined recovery. C_LIO_LIIntegrated strategies, tailored to a childs developmental stage, combining clinical care, nutrition, and environmental interventions are critical to support sustained child growth and development. C_LI

As plant-based (PB) diets become more common among UK children, understanding their nutritional adequacy and environmental impact is vital. This study assessed nutrient intake and dietary greenhouse gas emissions among children following omnivorous, vegetarian, and vegan diets. A cross-sectional analysis was conducted using three-day weighed food diaries from 39 UK children aged 2-12 years (omnivore n=15; and PB: vegetarian n=11; vegan n=13). Nutrients were analysed with and without supplementation using Nutritics software. GHGEs were calculated at the ingredient level (kgCO2e/day) and grouped by Eatwell Guide food categories. No dietary group met all nutrient reference values. Omnivores exceeded recommended intakes for saturated fat and free sugars while failing to meet the recommended intake for fibre, whereas PB children had intakes of these nutrients in the healthy range. PB diets were adequate in protein and vitamin B12 even in the absence of supplementation. Vegan children also met iron requirements from diet alone, whereas omnivore and vegetarian children did not meet iron targets without supplementation. Vitamin D intake was insufficient across all groups when supplements were excluded, with only vegan children achieving recommended levels through supplementation. Zinc requirements were met only by vegetarian children with the aid of supplements and were not met by vegan or omnivore children with or without supplementation. Iodine intake remained inadequate in vegan children even with supplementation. Mean daily GHGEs differed significantly between diet groups (p < 0.001): omnivores having the highest emissions, while vegans had the lowest emissions: 46% lower than omnivores, and 20% lower than vegetarians. Well-planned PB diets can meet most nutrient needs in UK children when supported by fortified foods and supplements, while substantially reducing dietary GHGEs compared with omnivorous diets. Shifting away from animal protein and dairy provides the greatest opportunity for improving both nutritional quality and environmental sustainability.

Background: The timing of energy intake could be important in the development of obesity. However, most observational evidence stems from adults, anthropometric defined obesity outcomes, single meal timing phenotyping, and traditional regression modeling. Objective: We aimed to describe meal timing patterns in adolescents and determine if they associated with fat mass by modeling the median and all other percentiles of the frequency distribution. Methods: We analyzed data from the Sleep and Growth Study 2 (S-Grow2, N=286, 12-13y). Participants completed 3-day 24-hour dietary recalls and time stamped eating occasions were used to define 8 meal timing traits, with aide from self-reported wake and bed timing. Principal component analysis (PCA) identified multi-dimensional meal timing patterns. Fat mass index (FMI) was estimated using dual energy X-ray absorptiometry. Quantile regression assessed if there were associations between meal timing traits and FMI across the entire FMI frequency distribution. Results: The typical first and last eating occasions were 8:00am (40 minutes after waking) and 8:00pm (2.7 hours before sleep), respectively, thus the eating period typically lasted 11.5 hours per day. The typical eating period midpoint was 2:15pm, and the timing when 50% of energy intake was consumed typically occurred at 3:15pm. PCA revealed three meal timing patterns: 1) Delayed Start, Condensed Eating Period (43% of variance; shorter eating period and delayed timing of first eating); 2) Late, Sleep Proximal Eating (30% of variance; later timing of last eating and extended eating period), and 3) Later Energy Intake (10% of variance; delayed energy intake midpoint). Higher scores for the Delayed Start, Condensed Eating Period pattern associated with higher body mass index and FMI at the upper tails of their distributions. Conclusions: Distinct multidimensional meal timing patterns emerged in early adolescence, with the delayed start, condensed eating period pattern potentially associated with higher adiposity.

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.

Obesity and related cardiometabolic diseases pose significant global health challenges. Konjac glucomannan, a soluble dietary fiber, has shown promise in managing these conditions. However, rigorous studies are necessary to establish its benefits on human health. We designed a parallel-arm, triple-blind, placebo-controlled RCT to test the effects of glucomannan (3 g/day, 12 weeks) on body weight and composition, lipid profile, glucose metabolism, inflammation, adipokines, intestinal permeability, gut microbiota, and fecal metabolites in 40 adults. Participants were randomly assigned to either the glucomannan or placebo group, with both groups adhering to personalized hypocaloric diets and moderate physical activity. Outcomes were analyzed as intention-to-treat using linear mixed-effect models. Irrespective of the treatment, our intervention reduced body weight (mean: -2.39 kg; 95% CI: -3.38, -1.40), BMI (-0.83 kg/m2; -1.15, -0.52), and waist (-2.70 cm; -3.87, -1.53). Glucomannan promoted additional benefits not obtained with the placebo, reducing body fat measured by DEXA (body fat%: -2.16%; -3.04, -1.28; VAT: -20.0 cm2; - 29.2, -10.8; FMI: -0.98 kg/m2; -1.34, -0.62), LDL (-14.1 mg/dL; -23.4, -4.9), and the atherogenic index (-0.50; -0.80, -0.21). It also diminished the Framingham score of 10-year risk of coronary heart disease (-0.370; -0.625, -0.115), C reactive protein (-1.01 mg/L; -2.18, 0.15), leptin (-2.06 ng/mL; -4.48, 0.365), and leptin/adiponectin (-0.282; -0.603, 0.040). The two treatments had similar intakes, physical activity, and adherence to the intervention. There were no adverse effects. This intervention fostered health benefits in a population at high risk of cardiometabolic diseases. Konjac glucomannan was an effective co-adjuvant for further reducing risk factors.

Vitamin B2 (riboflavin) is a key redox cofactor that may modulate gut microbial ecology, yet conventional supplements are absorbed proximally and have limited colonic exposure. We evaluated whether colon-targeted riboflavin alters microbiome composition, function and network structure as well as host biomarkers in healthy older adults. In a randomized, double-blind, placebo-controlled, parallel-group clinical trial (N=348; 50-70 years), participants received colon-targeted riboflavin (1.4, 10, or 75 mg/day) or placebo for 12 weeks. The primary endpoint was the change in fecal microbial composition, while secondary endpoints encompassed microbiome function, host health biomarkers, and clinical outcomes. Shotgun metagenomics and fecal/blood biomarkers were assessed at baseline, week 4, and week 12. Although no significant changes were observed between groups in overall community-wide diversity metrics (alpha and beta diversity), colon-delivered riboflavin significantly altered the relative abundance of several microbial taxa compared with placebo. The most pronounced effects on microbiome composition, function, and network structure were observed with the 10 mg dose at week 12, reflected by within-group increases in alpha diversity, the largest rise in total species counts, higher HACK index values indicating greater community resilience, and distinct shifts in KEGG module abundance, including enhanced potential for riboflavin biosynthesis. Supplementation with 75 mg riboflavin led to higher fecal butyrate concentrations at week 4 versus placebo, while the lowest dose (1.4 mg) significantly reduced the dysbiosis index within groups and modestly improved network structure across groups. All three doses (1.4, 10, and 75 mg) influenced keystone species abundance. No between-group differences were observed for gastrointestinal symptoms, quality-of-life measures, fecal pH, high-sensitivity C-reactive protein (hs-CRP), calprotectin, or soluble CD14, except for an increase in plasma riboflavin concentrations at 75 mg after 12 weeks, indicating colonic absorption. The product was safe and well-tolerated across all doses. These findings indicate that colon-targeted riboflavin can act as a functional modulator of the human gut microbiome, with the most consistent effects observed at 10 mg and additional dose-specific effects at 1.4 mg and 75 mg. Future studies are warranted to establish related health benefits, either as a standalone intervention or in combination with classical pre-, pro-, or postbiotics, particularly in target populations such as individuals with IBS, stress, mild cognitive decline, or early metabolic or inflammatory alterations.

Background: Creatine monohydrate (typically 5 to 20 g/day) has a well-established safety profile across diverse populations. Creatine hydrochloride (CR-HCl) is a highly soluble creatine formulation that may allow effective supplementation at substantially lower doses (750 mg to 3 g/day); however, controlled human safety data specific to CRHCl remain limited. Objective: To evaluate the short-term laboratory safety and tolerability of low dose CRHCl supplementation administered for 28 days in healthy adults. Methods: This single center, single arm, singl blind pilot safety study enrolled 11 healthy adults (10 females, 1 male; mean age 44.6 plus/minus 7.2 years). Participants consumed 750 mg/day CRHCl for 28 consecutive days while maintaining their usual diet and physical activity patterns. Fasting blood and urine samples were collected at baseline and Day 28. Laboratory assessments included hematological, lipid, and clinical chemistry biomarkers. Pre and post changes were evaluated using paired parametric and nonparametric tests, baseline-adjusted regression models, bootstrap confidence intervals, and false discovery rate (FDR) correction. Results: All participants completed the intervention. No clinically meaningful changes were observed in lipid parameters, hematologic indices, renal markers, or most chemistry analytes after adjustment for multiple comparisons. Fasting glucose increased modestly (8.1 mg/dL) prior to multiplicity adjustment but was not statistically significant after FDR correction and remained within reference ranges. Serum bicarbonate decreased slightly (2.4 mmol/L); although statistically detectable in parametric analysis, values remained within physiological limits and were not consistently supported by nonparametric testing.

Dietary patterns worldwide have shifted toward increased consumption of ultraprocessed foods (UPFs), which has been linked to higher disease burden. One mechanism proposed to impact both their consumption and contribution to metabolic disease is altered post-ingestive metabolic response in comparison to nutritionally similar foods. Here, we recruited 57 healthy-weight 18-45-year-old adults to examine the effects of food processing on postprandial metabolism and brain response. Despite nutritional matching, UPF meals evoked a greater insulinemic and energetic response with attenuated carbohydrate oxidation relative to non-UPF meals. Next, between-condition differences in peak carbohydrate oxidation were associated with mesolimbic and superior temporal gyrus activation in response to food cues. Finally, although food value did not differ between conditions, brain responses correlated with food valuation were positive for non-UPF but negative for UPF in visual cortex and striatum. These findings demonstrate that food processing influences post-ingestive metabolism in a way that could help explain long term health effects and differences in food reward through mechanisms beyond calories and macronutrient composition alone.

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)

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