Nutrients

BackgroundFolate deficiency is a global nutritional problem associated with multiple adverse health outcomes, including impaired one-carbon metabolism and elevated homocysteine levels (hyperhomocysteinemia). Gut microbiota-mediated folate biosynthesis has emerged as a promising strategy for improving host folate status. This study aimed to isolate folate-producing probiotic strains, clarify their folate synthesis mechanisms, and evaluate their regulatory effects on folate metabolism and gut microbiota in folate-deficient mice. MethodsHigh-throughput cultivation and screening were performed to isolate folate-producing probiotics. Whole-genome sequencing, pathway reconstruction, and metabolite profiling in fermented milk were used to explore folate biosynthesis pathways and potential microbial cross-feeding interactions. A folate-deficient mouse model was established to evaluate the effects of a probiotic cocktail on serum folate, homocysteine (Hcy) levels, and gut microbiota composition using microbiological assays, biochemical analyses, qPCR, 16S rRNA gene sequencing, alpha diversity analysis, principal coordinates analysis (PCoA), and Linear discriminant analysis Effect Size (LEfSe) analysis. ResultsOver 1,000 bacterial isolates were obtained, and over 10 strains, mainly belonging to Lactobacillus, Bifidobacterium, and Bacillus, showed folate production levels above 100 ng/mL. Genomic analysis revealed that most selected probiotic strains lacked genes involved in para-aminobenzoic acid (pABA) biosynthesis but retained downstream folate synthesis modules, suggesting a potential dependence on pABA-producing gut commensals for precursor supply through microbial cross-feeding. In fermented milk, probiotic strains mainly produced bioactive folates (5-MeTHF and THF), with strain-specific production capacities; L. plantarum, W. coagulans, and B. animalis subsp. lactis significantly increased 5-MeTHF levels in fermented milk. In vivo, high-dose probiotic intervention significantly elevated serum folate (p<0.01) and reduced Hcy (p<0.05) in folate-deficient mice, while medium-dose intervention showed no significant effects. The probiotic strains colonized the mouse gut in a dose-dependent manner: high-dose group exhibited >4,000-fold increase in relative abundance (Bifidobacteriaceae and Bacillaceae enriched), medium-dose group only enriched Bacillaceae, and low-dose group showed no effective colonization. High dose probiotic treatment enhanced gut microbial species diversity (increased Shannon index) and restored folate deficiency-induced gut microbiota dysbiosis (PCoA clustering closer to normal group). ConclusionThis study screened high folate-producing probiotic strains and demonstrated their ability to synthesize active 5-MeTHF, which may rely on microbial cross-feeding in gut microbiota. Furthermore, we demonstrated that folate-producing probiotic intervention significantly improves folate status and Hcy metabolism and restores gut microbiota homeostasis in folate-deficient mice. These findings suggensted that such probiotics could serve as a safer, more physiological intervention for folate deficiency and hyperhomocysteinemia, especially in populations with MTHFR polymorphisms.

ContextVitamin B12 deficiency is common among vegans and vegetarians due to limited intake of animal-derived foods. Identifying safe, plant-based sources of vitamin B12 is essential to address this nutritional gap. AimsThis study evaluated the efficacy and safety of Chlorella vulgaris tablets in improving vitamin B12 deficiency. Settings and DesignA double-blind, randomized, placebo-controlled trial was conducted among 46 healthy adults with vitamin B12 deficiency (serum levels 107-210 pmol/L). Methods and MaterialParticipants were randomized (1:1) to receive C. vulgaris (1 g twice daily) or identical placebo for 12 weeks. Primary outcome was change in serum vitamin B12; secondary outcomes included folic acid, homocysteine, methylmalonic acid (MMA), and quality of life (WHO-QoL). Assessments were conducted at baseline and week 12, with safety monitored through liver and kidney function tests and adverse event reporting. Statistical Analysis UsedSample size (n=46) was calculated with 90% power and 10% dropout allowance. Data were analyzed using SPSS v22. Non-parametric tests were applied after normality assessment, with p<0.05 considered significant. ResultsOf 46 participants (mean age 35.5 {+/-} 11.2 years; 69.6% female), mean serum vitamin B12 levels were significantly higher in the C. vulgaris group than in the placebo group at 12 weeks (214.4 {+/-} 160.8 vs 55.9 {+/-} 15.0 ng/mL; P < .001). No significant differences were observed in folic acid, homocysteine, MMA, or QoL scores between groups. No adverse events were reported. ConclusionsSupplementation with Chlorella vulgaris significantly improved serum vitamin B12 levels, suggesting its potential as a safe, plant-based alternative for managing vitamin B12 deficiency. Key MessagesO_LIPlant-based Chlorella vulgaris improved vitamin B12 levels significantly C_LIO_LIRandomized trial in B12-deficient healthy adults over 12 weeks C_LIO_LINo adverse effects observed on liver or kidney function tests C_LIO_LIQuality of life improved across all domains in the intervention group C_LI

Background: Maternal micronutrient deficiencies (MNDs) and inflammation contribute to adverse birth outcomes While the individual effects of MNDs have been studied, the consequence of co-occurring MNDs remains unclear. Objectives: To examine the associations between maternal micronutrient deficiencies and inflammation with adverse birth outcomes (ABOs). Methods: Data from 5,408 pregnant women across 11 datasets from 10 countries were analyzed. Descriptive analyses explored the distribution of MNDs (iron, vitamin A, zinc, serum folate, vitamin D, and vitamin B12) and inflammation (c-reactive protein >5 mg/L or -(1)-acid glycoprotein > 1g/L) by maternal characteristics (age, height, education, socioeconomic status [SES]) using chi-square tests. Associations of 1) single MNDs and inflammation and 2) co-occurring MNDs (2 deficiencies at a time) with low birth weight (LBW, < 2500 g), preterm birth (PTB, < 37 wks), and small-for-gestational age (SGA, < 10th percentile for gestational age), were examined using modified Poisson regression to estimate relative risk (RR), adjusting for age, SES, and dataset. Results: Young maternal age and short height were associated with up to 9.7% and 25% higher prevalence of MNDs and inflammation, respectively. Lower education and SES level were associated with higher prevalence of Vitamin B12 deficiency. Women with folate deficiency had an increased risk of LBW (RR [95% CI]: 1.22 [1.06, 1.39]). Co-occurring MNDs for folate and vitamin B12 were also associated with increased LBW risk (1.38 [1,1.9]) as was folate deficiency without iron (1.28 [1.09, 1.51]) or vitamin B12 deficiency (1.67 [1.09, 2.56]) compared with mothers without either deficiency. Iron deficiency without vitamin B12 deficiency was associated with a reduced LBW risk (0.4 [0.2, 0.79]). Conclusion: Maternal MNDs, especially folate and vitamin B12, are linked to adverse birth outcomes. Complex nutrient interactions highlight the need to explore these relationships to improve maternal and neonatal health interventions.

Fermented foods are increasingly recognized for their health-boosting potential, yet the mechanisms involved are not fully resolved. Here, we tested whether kombucha reshapes the gastrointestinal microbiome and whether these changes are associated with stress-related behaviors under contrasting dietary backgrounds. Male C57BL/6 mice were fed either a total Western diet (TWD) or a control diet (CTRL) supplemented with kombucha or water three times weekly for seven weeks. Depressive-like and anxiety-related behaviors were evaluated using the forced swimming (FST) and marble burying tests (MBT). Ileum, cecum, and colon microbiomes were profiled via 16S rRNA, ITS2, and shotgun metagenomics, while feces and whole brains were profiled by LC-MS metabolomics. Serum cytokines were measured by ELISA. Results highlight diet-dependent effects of Kombucha on behavioral, microbial and metabolic outcomes. Kombucha reduced immobility in the FST under both diets, whereas fewer marbles buried were observed only under TWD. Kombucha intake enriched Bifidobacterium pseudolongum in the ileum under CTRL and TWD diets, while cecal microbial functions related to amino acid metabolism were stimulated mainly under CTRL. Only CTRL mice receiving kombucha showed higher fecal acetate and butyrate together with lower fecal levels of neurochemically relevant amino acids, including glutamine, phenylalanine, tryptophan, and tyrosine. Under TWD, kombucha was associated with lower spleen weight and altered brain tryptophan/kynurenine profiles. These findings identify kombucha as a food intervention that can remodel gastrointestinal microbial and neuroactive metabolism in a diet depending manner. Associations with reduced depressive and anxiety-related behaviors are promising but warrant further exploration. Key HighlightsO_LIKombucha supplementation reshaped the mice gastrointestinal microbiome and its neuroactive potential C_LIO_LIKombucha intake was associated reduced depressive and anxious like behaviors C_LIO_LIThe potential of kombucha to modulate microbial, metabolic and behavioral outcomes may be dependent on subject dietary background C_LI

BackgroundCreatine monohydrate (typically 5-20 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 - 3 g/day); however, controlled human safety data specific to CR-HCl remain limited. ObjectiveTo evaluate the short-term laboratory safety and tolerability of low-dose CR-HCl supplementation administered for 28 days in healthy adults. MethodsThis single-center, single-arm, single-blind pilot safety study enrolled 11 healthy adults (10 females, 1 male; mean age 44.6 {+/-} 7.2 years). Participants consumed 750 mg/day CR-HCl 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-post changes were evaluated using paired parametric and nonparametric tests, baseline-adjusted regression models, bootstrap confidence intervals, and false discovery rate (FDR) correction. ResultsAll 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. ConclusionsSupplementation with 750 mg/day CR-HCl for 28 days was well tolerated and was not associated with clinically meaningful alterations in routine laboratory biomarkers. These preliminary findings support the short-term tolerability of low-dose CR-HCl and provide a basis for larger randomized, placebo-controlled studies to further evaluate its safety profile.

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 & AimsHigh-fat diets (HFDs) are a major modifiable risk factor for intestinal health. Current research focuses primarily on palmitate (C16:0); however, myristate (C14:0, rich in dairy products) has been minimally investigated. HFDs increase ceramide generation which drives endoplasmic reticulum (ER) stress; with both sphingolipids and ER stress being key contributors to intestinal biology. Whether different fatty acids uniquely impact sphingolipid metabolism and ER stress in intestinal biology has not been well defined. MethodsHuman colon epithelial cells were utilized to determine the role of ceramide synthases (CerS) 5 and 6 on myristate-induced ER stress using pharmacologic inhibitors and siRNA. Intestinal epithelial cell specific CerS5 and/or CerS6 knockout mice of both sexes were fed a control, high milk-fat, or high lard-fat diet for 16 weeks. Cells and colon tissues were analyzed for lipids, mRNA, and protein. ResultsMyristate treatment increased C14:0-ceramide and induced IRE1-dependent ER stress. Inhibition of CerS suppressed these effects, yet knockdown of CerS5/6, the primary enzymes generating C14:0-ceramide, unexpectedly exacerbated IRE1 activation both in vitro and in vivo, potentially due to depletion of dihydro(dh)sphingosine. ConclusionsCerS are required for myristate-induced IRE1 activation and restoration of the sphingoid base pool provides partial protection from intestinal ER stress. SYNOPSISThis study identifies a new mechanism linking dietary fats to intestinal cell stress. Ceramide synthases drive ER stress triggered by myristate, a dairy-derived fat, while restoring sphingoid bases partially protects cells, revealing a new role for sphingolipids in shaping intestinal responses to diet. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=193 SRC="FIGDIR/small/728542v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@a6e246org.highwire.dtl.DTLVardef@518c0eorg.highwire.dtl.DTLVardef@1c21140org.highwire.dtl.DTLVardef@1fa993e_HPS_FORMAT_FIGEXP M_FIG C_FIG

ObjectiveThe average American consumes 55% of their daily energy from ultraprocessed foods (UPF) created through industrial processes and additives not used at home. We investigated if a high-UPF diet alters brain response to milkshake compared with a diet free-from UPF (NonUPF) in emerging adults, who are in a critical period for brain development and typically consume high amounts of UPF. MethodsIn a randomized controlled crossover trial participants aged 18-25 completed two, 2-week controlled feeding periods including a UPF (81% UPF) and nonUPF (0% UPF) diet. Before and after each diet intervention participants consumed milkshake concomitant with functional magnetic resonance imaging. ResultsIn the entire cohort, there were no differences between diet conditions in brain response. An exploratory analysis revealed orbitofrontal cortex (OFC) response to milkshake decreased after the UPF diet and increased following the NonUPF diet in adolescents (18-21 years) but not young adults (22-25 years). Habitual UPF intake (gs) was positively associated with OFC response to milkshake independent of diet intervention in all participants. ConclusionsAn acute UPF dietary intervention may only alter brain response in adolescents. Further work is needed to determine potential vulnerability of adolescents to changes in dietary UPF on brain response to rewards.

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.

BackgroundChronic malnutrition in early childhood is a multifactorial condition associated with long-term impairments, yet the physiological and gut microbial pathways underlying differential growth trajectories remain poorly understood. ObjectiveWe aimed to characterize phenotypic growth trajectories and identify the associated gut microbial and body composition signatures in infants during the first year of life. MethodsWe analyzed longitudinal data from birth to 12 months in a South African cohort (Soweto, n=45). Individual linear growth trajectories were modeled using the Jenss-Bayley equation, and children were clustered based on model parameters to identify phenotypic subgroups. Body composition (fat-free mass and fat mass) was measured via deuterium dilution at 6 and 12 months, and gut microbiome development was assessed using 16S rRNA gene amplicons at 4, 6, and 12 months. ResultsWe identified distinct phenotypic subgroups including healthy growth, catch-up growth, and growth faltering, that were obscured at the cohort level. These trajectories diverged most dynamically within the first 6 months of life. Integrated analysis revealed that in the growth faltering cluster, height-for-age and fat-free mass z-scores stabilized between 6 and 12 months, whereas fat mass z-scores (FMZ) declined. This trade-off is consistent with a catabolic state where energy reserves are prioritized for lean tissue and bone growth. Furthermore, at 6 months, the growth faltering cluster was enriched with opportunistic pathobionts (e.g., Paraclostridium). In contrast, the catch-up cluster exhibited a transient enrichment of facultative anaerobes (e.g., Enterobacter), supporting a hypothesis that these oxygen-tolerant taxa may help bridge a transitional microbial state in partially oxygenated or inflamed environments to enable physiological recovery. ConclusionsEarly childhood chronic malnutrition phenotypes in South African infants can be defined by distinct microbial and body composition signatures that diverge within six months of life. Integrated interventions should target both host anabolic state and microbiome transitions to support recovery.

Background The study aimed to estimate healthcare costs associated with malnutrition in Swedish older adults. Methods We conducted a cohort study using data from the population-based Swedish National Study on Aging and Care in Kungsholmen (SNAC-K, N = 2982), a geriatric inpatient cohort of complex patients (N = 7680), and a cohort of individuals with cognitive impairment from the Swedish Register of Cognitive/Dementia Disorders (SveDem, N = 64192). At risk of malnutrition and malnutrition were ascertained by the Mini-Nutritional Assessment in SNAC-K and the geriatric inpatient cohort. In SveDem, body mass index was used for identifying malnutrition. Healthcare resource use was derived from regional and national registers. Associations between malnutrition and healthcare costs in 2024 Swedish kronor (SEK) were analyzed using two-part models and generalized linear regression models, adjusting for demographic and clinical factors. Findings In the community, at risk of malnutrition and malnutrition were associated with an increase in annual healthcare costs of 2267 SEK (95% CI: 64,4469) and 1846 SEK (95% CI: -6802,10493), respectively. In geriatric patients, healthcare costs over 6 months in individuals at risk of malnutrition and individuals with malnutrition were 60205 SEK (45613,74798) and 86619 SEK (68362,104875) higher than those without malnutrition. In people with cognitive impairment, malnutrition was associated with higher annual healthcare costs (22170 SEK, 95% CI: 15152,29188). Interpretation Both at risk of malnutrition and malnutrition are associated with higher healthcare costs in Swedish older adults. The study findings are important for informing future economic evaluations of malnutrition interventions in Swedish older adults.

Background: The European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines on nutrition for cancer patients provides evidence based dietary recommendations that is routinely deployed by dieticians in oncology settings. Although these can be culturally adapted, they do not adequately address inter individual variability in treatment related gastrointestinal symptoms and appetite, issues that increase malnutrition risk in cancer patients. Ayurveda, on the other hand, lacks nutrient based guidelines but offers a well grounded dietary framework to assess digestive function and personalise diets. This study investigated the feasibility of combining the two approaches in a clinical setting. Methods: Consenting adult cancer patients diagnosed with any type and stage of cancer were recruited. At baseline, digestive strength, dietary intake, quality and frequency and Patient Generated Subjective Global Assessment (PGSGA) score were recorded. Based on this, personalised meal plans (MPs) that combine nutrient guidelines from ESPEN and traditional food concepts to support digestive strength were provided to participants. Follow ups ranged from 4 weeks to 6 months, at which digestive strength and PGSGA was noted. To evaluate against a benchmark, meal plans were theoretically constructed using Ayurveda concepts (traditional MP) or ESPEN guidelines (Standard MP) alone. Results: Data is presented for 33 participants, of which 52% had weak digestive strength. Baseline intake averaged 879 kcal/day, well below the recommended 1400 to 1600 kcal/ day level. Traditional MPs improved energy intake but were protein insufficient, aspects that were addressed in the standard MPs. Diet quantity (1417 kcal/day), quality and frequency improved on the integrated MP, with 3 patients achieving optimal digestive strength. Personalised counselling reduced malnutrition risk, as reported by PGSGA score. Conclusion: Customising dietary advice by overlaying nutrient guidelines with Ayurveda dietary concepts is feasible. The evaluation of digestive strength holds promise for personalising nutrition therapy. Trial Registration: CTRI/2023/07/055657

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

BackgroundCarnitine plays an obligatory role in energetics owing to its role in the translocation of long-chain fatty acids into the mitochondrion for oxidation. Here, we determined the metabolic and behavioral consequences of systemic carnitine deficiency (SCD) in mice. MethodsFemale C57BL/6J mice were randomized to receive normal drinking water (control, n = 8) or drinking water supplemented with mildronate 4g.L-1 (mildronate, n = 8) for 21 days. Body composition was assessed at baseline and post treatment. Metabolic and behavioral phenotyping was performed continuously over 72 hours following 14 days of control or mildronate treatment. Stable isotope were used to assess whole-body substrate oxidation. Carnitine subfractions were quantified in skeletal muscle and liver, as was mitochondrial respiratory function. Liver and muscle samples also underwent proteomic analysis. ResultsMildronate treatment depleted total carnitine in muscle and liver by [~]97% (P < 0.001) and [~]90% (P < 0.001), respectively. Carnitine depletion was accompanied by lower total energy expenditure (P = 0.01), attributable to lower voluntary wheel running (P = 0.01). Oxidation rates of palmitate (P < 0.01) but not octanoate were lower whereas rates of glucose oxidation were greater in carnitine depleted mice (P < 0.01). Mitochondrial respiratory capacity was unaltered by carnitine deficiency. Carnitine deficiency remodeled muscle and liver proteomes to support lipid oxidation and energy production. SummaryIn mice, carnitine deficiency is characterized by decreased long-chain fatty acid oxidation despite preserved mitochondrial respiratory capacity. Carnitine deficiency resulted in lower voluntary exercise and a concomitant reduction in energy expenditure.

Hericium erinaceus (Lions Mane) is a functional mushroom with a long history of culinary and traditional use, as well as potential neurotrophic and mood{square}modulating properties. Evidence for its effects on cognitive performance under real{square}world conditions, however, remains limited. In this randomized, double{square}blind, placebo{square}controlled trial, adults aged 40-75 years with self{square}reported cognitive difficulty completed a one{square}week baseline followed by eight weeks of daily supplementation with 2 g of H. erinaceus fruiting body and mycelial biomass or placebo. Cognitive performance using a computerized battery, as well as daily subjective assessments of sleep and wellbeing, were collected remotely. 109 Participants were included in the primary analysis (H. erinaceus, n = 57; placebo, n = 52). H. erinaceus was associated with significantly greater improvement in visual attention and working memory (Juggle Factor task), subjective sleep quality, morning restedness, and mood compared with placebo (p < 0.05). No adverse events were reported in participants receiving H. erinaceus. Together, H. erinaceus supplementation modestly improved visual attention and was associated with faster improvements in sleep quality, restedness, and mood in adults with subjective cognitive concerns.

Abstract Objective: Frailty is an important concern in old age. Inflammation can cause frailty. Anti-inflammatory food supplements can play a role in slowing down frailty processes and consequences. This study explored the views of people (aged 50-89 years) on the need to develop a frailty supplement, preferences for its form and how older people could be encouraged to use such a supplement. Design: We conducted semi-structured qualitative interviews and used a framework method to analyse the data. Participants: 30 participants from a city in the UK. Setting: These participants were recruited from social housing, care homes, foodbanks and the wider population. Participants were from diverse ethnic, gender and age backgrounds. Results: Participants identified a strong need for the development of a food-based supplement for frailty. They expressed excitement for the supplement and viewed it as something which they would be happy to integrate in their daily food routine. In terms of preferences, our participants wanted to have multiple options, however, a biscuit-based supplement was preferred by most. The participants preferences were mainly based on taste of the supplement, its effectiveness, convenience in use and affordability. Muslim participants in the sample said they would be happy to use this supplement if it was developed using Halal ingredients. In terms of creating awareness and encouraging people to use the proposed supplement, participants suggested a variety of marketing methods. These included: word of mouth, face to face sessions with older adults, social media, especially YouTube and advertising on TV. Conclusion: The participants were generally open to the idea of a food-based supplement and felt that it could easily fit with their existing food practices and lifestyles. Keywords: older adults, frailty, food supplement, co-creation, healthy ageing

IntroductionLow dietary diversity has been identified as a predictor of depression outcomes in high-income countries, while evidence is scarce from low-income settings where poor nutrition and depression often co-occur. In this study, we estimate the relationship between dietary diversity and depression among adults in rural western Kenya. MethodWe conducted a cross-sectional analysis of 311 participants enrolled in the Bridging Income Generation through Group Integrated Care program. We assessed depressive symptoms using the 20-item Centre for Epidemiologic Studies for Depression Scale (CES-D), and measured dietary diversity as the number of five food groups consumed in previous 24-hours using a validated dietary diversity scale. We used linear regression to estimate the association between high dietary diversity (consumption of all the five food groups) and continuous depression scores, adjusting for key covariates. We tested for effect measure modification by wealth status. We conducted a secondary analysis using quantile regression to explore variation across depression scores distributions. ResultsHigher dietary diversity was associated with fewer depressive symptoms [adjusted {beta} (95% CI): -3.49 (-6.62, -0.38)]. The association was stronger among individuals with low wealth backgrounds [adjusted {beta} (95% CI): -6.00 (-10.46, -1.42)] relative to those with high wealth backgrounds [adjusted {beta} (95% CI): -0.53 (-4.76, 3.68); Wald p-value for interaction term =0.0003]. The effect sizes for the association were larger at higher quantiles, notably at 75th [adjusted {beta} (95% CI): -4.00 (-10.13, 2.13)] and 90th [adjusted {beta} (95% CI): -1.59 (-7.43, 4.25)] compared to those at lower quantiles for 10th [adjusted {beta} (95% CI): -0.59 (-2.46, 1.28) and 25th [adjusted {beta} (95% CI): -0.82 (-4.14, 2.50), though wide confidence intervals limited the precision of effect estimates. ConclusionIn rural western Kenya, higher dietary diversity was associated with lower depression symptoms, particularly among participants from lower wealth backgrounds, and particularly among those with scores consistent with more severe depression symptoms. These findings suggest that improving dietary diversity may offer mental health benefit to the most socioeconomically disadvantaged individuals and could be a promising strategy to reduce depression in resource poor settings. Future work could leverage longitudinal and experimental studies for improved inference and should investigate mechanisms through which dietary diversity may influence depression.

BackgroundSeveral genetic variants have been identified to modify the effects of fish oil supplementation (FOS) on increasing circulating omega-3 fatty acids, but it remains unexplored whether polygenic predisposition to low circulating omega-3 fatty acids modifies these effects. ObjectiveTo test if polygenic scores (PGS) for circulating omega-3 fatty acids modify the associations of FOS with corresponding circulating concentrations. MethodsWe developed PGS models for absolute circulating concentrations of total omega-3 fatty acids (Omega-3), docosahexaenoic acid (DHA), and their relative percentages in total fatty acids (Omega-3% and DHA%), using a multi-ethnic genome-wide association study (N=136,016). PGS models were validated in 437,803 UK Biobank participants of European (EUR), Central/South Asian (CSA), African, and East Asian genetic ancestries. Linear models tested PGS-by-FOS interactions on corresponding observed circulating concentrations. Discovery analysis was performed separately in 237,380 EUR participants and each non-EUR group. Replication analyses were performed using oily fish intake and in another 178,935 EUR participants. ResultsIn EUR participants, PGS explained 5.3-11.1% of the phenotypic variance, and significant PGS-by-FOS interactions were detected across all four circulating omega-3 traits. Among participants in the bottom 5% of the PGS distribution, FOS was significantly associated with a 0.40 SD (95% CI: 0.39-0.44) increase in Omega-3. This association effect was 11.1% larger than the population average ({beta} = 0.36; 95% CI: 0.35-0.37; PInt = 0.016) and 42.8% larger than that in participants in the top 5% of the PGS distribution ({beta} = 0.28 SD; 95% CI: 0.25-0.32; PInt = 4.03X10-10). These interaction patterns were consistently observed in CSA ancestry and confirmed in replication and sensitivity analyses. ConclusionsPGS modify the associations of FOS with circulating omega-3 fatty acids in EUR and CSA populations, with larger FOS effects in participants with lower PGS. These findings support the development of genome-informed precision nutrition.

Frailty is an age-related syndrome characterized by biological dysfunction and reduced physiological reserve in response to stressors. Its prevalence is increasing with population aging, resulting in a substantial health burden due to adverse outcomes on health, such as cardiovascular disease and mortality. Ultra-processed foods (UPFs), defined as industrial formulations made primarily from processed ingredients, have received increasing attention due to their potential role in the development and progression of frailty. This systematic review and meta-analysis examined the association between ultra-processed food intake and the risk of frailty in older adults. This study systematically searched for all relevant studies published up to January 2026. Ten observational studies involving 105327 participants, comprising 6 prospective and 4 cross-sectional studies, were included in the systematic review, of which 6 were eligible for meta-analysis. Random-effects models were employed to estimate pooled effect sizes and 95% confidence intervals (95% CIs). Meta-analysis showed that higher consumption of UPFs was significantly associated with an increased risk of frailty (pooled OR = 1.43, 95% CI = [1.02-2.005], p = 0.041). Narrative synthesis further supported a positive association between UPF intake and frailty or related outcomes. Our findings suggest that a higher consumption of ultra-processed foods may contribute to frailty risk, potentially through inflammatory pathways. However, given the high heterogeneity, results should be interpreted with caution. Overall, our findings suggest that reducing UPF consumption may be a promising target for public health strategies to prevent frailty in ageing populations.

Objective To assess serum 25-hydroxyvitamin D [25(OH)D] levels in a health examination population in Guiyang, a low-latitude, high-altitude, and cloudy city in southwestern China, and to identify key determinants using machine learning. Methods This retrospective study included 10,931 adults (>20 years) who underwent health checkups at Guiyang First People's Hospital between February 2019 and April 2025. Beyond conventional statistical comparisons, a two-stage machine learning approach was applied: LASSO regression for feature selection, followed by an optimized Random Forest regression model (mtry = 2). SHapley Additive exPlanations (SHAP) were used to quantify variable importance. Results The median serum 25(OH)D level was 36.63 (IQR 24.77,53.17) nmol/L. Vitamin D deficiency (<50 nmol/L) was present in 70.98% of participants, while sufficiency (>75 nmol/L) was only 7.35%. Significantly lower levels were observed in females, in adults aged <30 years (deficiency rate 85.6%), and during spring. The optimized Random Forest model achieved a cross-validated RMSE of 21.427. SHAP analysis revealed a clear hierarchy of importance: age (mean SHAP = 5.604) > season (4.104) > sex (1.533) {approx} BMI (1.501). Conclusion Vitamin D deficiency is highly prevalent in the Guiyang health examination population. Age and season are the dominant determinants, far outweighing sex and BMI. Targeted interventions should focus on young adults, females, and the spring season, especially in regions with similar cloudy highland climates.