Corrigendum: Safe and effective delivery of supplemental iron to healthy adults: a two-phase, randomized, double-blind trial - the safe iron study.

[This corrects the article DOI: 10.3389/fnut.2023.1230061.].

Revisiting the Definition of 'Healthy' Participants in Substantiation of Structure/Function Claims for Dietary Supplements.

Concepts and definitions of 'healthy' have been evolving within clinical treatment algorithms as well as reference standards such as Body Mass Index and Dietary Reference Intakes. Consumers' perception of the word 'healthy' is also changing to reflect longer life span, need to stay active and in a good state of mental well-being while managing multiple diseases. Guidelines from the US Food and Drug Administration indicate that substantiating evidence for support of Structure/Function (S/F) claims for dietary supplements is best derived from clinical research conducted in a 'healthy' population. S/F claims cannot be represented to diagnose, treat, cure or prevent any disease. However, in this context, the term 'healthy' is non-descriptive and largely interpreted as an absence of disease. Guidelines for treatment of disease have been broadened to include biomarkers of disease risk such that the pool of 'healthy' volunteers eligible to be enrolled in clinical trials for S/F claim substantiation is greatly diminished. This perspective presents the challenges faced by the food and dietary supplement industry and by researcher efforts designed to substantiate S/F claims and suggest the phrase 'physiologically stable' or 'apparently healthy' as descriptions better suited to replace the term 'healthy.'

Safe and effective delivery of supplemental iron to healthy adults: a two-phase, randomized, double-blind trial - the safe iron study.

Introduction: The safety of novel forms of iron in healthy, iron-replete adults as might occur if used in population-based iron supplementation programs was examined. We tested the hypotheses that supplementation with nanoparticulate iron hydroxide adipate tartrate (IHAT), an iron-enriched Aspergillus oryzae product (ASP), or ferrous sulphate heptahydrate (FS) are safe as indicated by erythrocyte susceptibility to malarial infection, bacterial proliferation, and gut inflammation. Responses to FS administered daily or weekly, and with or without other micronutrients were compared. Methods: Two phases of randomized, double-blinded trials were conducted in Boston, MA. Phase I randomized 160 volunteers to six treatments: placebo, IHAT, ASP, FS, and FS plus a micronutrient powder (MNP) administrated daily at 60 mg Fe/day; and FS administered as a single weekly dose of 420 mg Fe. Phase II randomized 86 volunteers to IHAT, ASP, or FS administered at 120 mg Fe/day. Completing these phases were 151 and 77 participants, respectively. The study was powered to detect effects on primary endpoints: susceptibility of participant erythrocytes to infection by Plasmodium falciparum, the proliferation potential of selected pathogenic bacteria in sera, and markers of gut inflammation. Secondary endpoints for which the study was not powered included indicators of iron status and gastrointestinal symptoms. Results: Supplementation with any form of iron did not affect any primary endpoint. In Phase I, the frequency of gastrointestinal symptoms associated with FS was unaffected by dosing with MNP or weekly administration; but participants taking IHAT more frequently reported abdominal pain (27%, p < 0.008) and nausea (4%, p = 0.009) than those taking FS, while those taking ASP more frequently reported nausea (8%, p = 0.009). Surprisingly, only 9% of participants taking IHAT at 120 mg Fe/day (Phase II) reported abdominal pain and no other group reported that symptom. Discussion: With respect to the primary endpoints, few differences were found when comparing these forms of iron, indicating that 28 days of 60 or 120 mg/day of IHAT, ASP, or FS may be safe for healthy, iron-replete adults. With respect to other endpoints, subjects receiving IHAT more frequently reported abdominal pain and nausea, suggesting the need for further study. Clinical Trial Registration: ClinicalTrials.gov, NCT03212677; registered: 11 July 2017.

Healthy adults supplemented with a nutraceutical formulation containing Aloe vera gel, rosemary and Poria cocos enhances the effect of influenza vaccination in a randomized, triple-blind, placebo-controlled trial.

The study objective was to examine the role of a formulation, UP360, containing rosemary and Poria cocos extracts and Aloe vera gel powder, in healthy adults on supporting immune function with influenza vaccination. A 56-day randomized, triple-blind, placebo-controlled, parallel study consisted of a 28-day pre-vaccination period, an influenza vaccination on Day 28 and a 28-day post-vaccination period. Men and women ages 40-80 who had not yet been vaccinated for the flu were randomized to UP360 or Placebo (n = 25/group). At baseline, Days 28 and 56, blood lymphocyte populations, immunoglobulins (Ig), and cytokines were measured, and quality of life (QoL) questionnaires administered. The Wisconsin Upper Respiratory Symptom Survey (WURSS)-24 was completed daily by participants to measure incidence of upper respiratory tract infection (URTIs). In the post-vaccination period, TCR gamma-delta (γδ+) cells, known as γδ T cells, increased with UP360 supplementation compared to Placebo (p < 0.001). The UP360 group had a 15.6% increase in influenza B-specific IgG levels in the post-vaccination period (p = 0.0006). UP360 significantly increased the amount of circulating glutathione peroxidase (GSH-Px) from baseline at Day 28 (p = 0.0214), an enzyme that is important for neutralizing free radicals. While UP360 supplementation initially decreased levels of anti-inflammatory cytokine IL-1RA in the pre-vaccination period, IL-1RA levels were increased in the post-vaccination period (p ≤ 0.0482). Levels of IL-7 increased from baseline at Day 56 with UP360 supplementation (p = 0.0458). Despite these changes in immune markers, there were no differences in URTI symptoms or QoL between UP360 and Placebo. These results suggest UP360 supplementation was beneficial in eliciting a healthy, robust immune response in the context of vaccination. No changes in subjective measures of URTI illness or QoL demonstrated that participants' QoL was not negatively impacted by UP360 supplementation. There were no differences in clinical chemistry, vitals or adverse events confirming the good safety profile of UP360. The trial was registered on the International Clinical Trials Registry Platform (ISRCTN15838713).

A Randomized, Double-Blind, Placebo-Controlled, Parallel Study Investigating the Efficacy of a Whole Coffee Cherry Extract and Phosphatidylserine Formulation on Cognitive Performance of Healthy Adults with Self-Perceived Memory Problems.

INTRODUCTION: Cognition refers to brain functions including memory, learning, and thought processing and is increasingly important to individuals. However, impairment of cognitive function is a concern among North American adults. Therefore, effective and reliable treatments are needed. METHODS: This randomized, double-blind, placebo-controlled study examined the effects of 42 days of Neuriva® supplementation, a whole coffee cherry extract and phosphatidylserine supplement, on memory, accuracy, focus and concentration and learning among 138 healthy adults (40-65 years) with self-reported memory problems. Plasma brain-derived neurotrophic factor (BDNF) levels, Computerized Mental Performance Assessment System (COMPASS) tasks, the Everyday Memory Questionnaire (EMQ), and Go/No-Go tests were assessed at baseline and day 42. RESULTS: As compared to placebo, Neuriva® supplementation elicited greater improvements at day 42 in numeric working memory COMPASS task accuracy outcomes (p ≤ 0.024) which assessed memory, accuracy, and focus and concentration, and reaction time outcomes (p ≤ 0.031) which assessed memory as well as focus and concentration. Neuriva® supplementation improved overall accuracy (p = 0.035) in the picture recognition task that assessed memory, accuracy, and learning compared to placebo. No significant differences between groups were observed for BDNF, the EMQ, or Go/No-Go tests. CONCLUSION: Results suggest 42 days of Neuriva® supplementation was safe, well tolerated, and beneficial in improving memory, accuracy, focus and concentration, and learning in a healthy adult population with self-reported memory problems.

Examining the Systemic Bioavailability of Cannabidiol and Tetrahydrocannabinol from a Novel Transdermal Delivery System in Healthy Adults: A Single-Arm, Open-Label, Exploratory Study.

INTRODUCTION: Transdermal cannabinoids may provide better safety and bioavailability profiles compared with other routes of administration. This single-arm, open-label study investigated a novel topical transdermal delivery system on the pharmacokinetics of cannabidiol (CBD) and tetrahydrocannabinol (THC). METHODS: Participants were 39.5 ± 7.37 years old and healthy, based on a review by the Medical Director. Blood was collected pre-dose and 10, 20, 30, and 45 min, and 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 h after topical application of 100 mg CBD:100 mg THC. Psychoactive effects were assessed prior to each timepoint. Area-under-the-curve (AUC0-12 h), maximum concentration (Cmax), time to maximum concentration (Tmax), area-under-the-curve to infinity (AUCI), terminal elimination rate constant (λ), terminal half-life (t½), and absorption rate constant (ka) were measured individually for CBD and THC. Safety was assessed by clinical chemistry, hematology, and adverse events. RESULTS: AUC0-12 h for CBD and THC was 3329.8 ± 3252.1 and 2093.4 ± 2090.6 pg/mL/h, with Cmax of 576.52 ± 1016.18 and 346.57 ± 776.85 pg/mL, respectively. Tmax for CBD and THC was 8 h, ranging from 2.5 h to 12 h and 10 min to 12 h, respectively. AUCI for CBD and THC was 6609.2 ± 7056.4 and 3721.0 ± 3251.7 pg/mL/h, with t1/2 of 5.68 ± 1.5 and 5.38 ± 1.25 h, respectively. CBD was absorbed at a faster rate compared with THC (123.36 ± 530.97 versus 71.5 ± 1142.19 h-1) but with similar λ (0.12 ± 0.029 versus 0.13 ± 0.03 h-1). No psychoactive effects were reported. Transdermal cannabinoid delivery was safe and well tolerated in the population studied. CONCLUSION: To our knowledge, this is the first pharmacokinetic study in humans that demonstrated CBD and THC entering systemic circulation via transdermal administration . This study represents an important contribution to understanding the pharmacokinetics of transdermal cannabinoids. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier-NCT05121506 (November 16, 2021).

Role of Acacia catechu and Scutellaria baicalensis in Enhancing Immune Function Following Influenza Vaccination of Healthy Adults: A Randomized, Triple-Blind, Placebo-Controlled Clinical Trial.

OBJECTIVE: The study aimed to examine the role of an Acacia catechu and Scutellaria baicalensis formulation, UP446, on supporting immune function in response to influenza vaccination. METHODS: A randomized, triple-blind, placebo-controlled, parallel study consisted of a 56-day intervention period with a 28-day pre-vaccination period, an influenza vaccination on Day 28 and 28-day post-vaccination period. Fifty healthy adults 40-80 years of age who had not received their flu vaccine were randomized to either UP446 or Placebo. At baseline, Days 28 and 56, immune and oxidative stress markers were measured in blood and a quality of life questionnaire was administered. Participants completed the Wisconsin Upper Respiratory Symptom Survey (WURSS)-24 daily. RESULTS: In the post-vaccination period, total IgA and IgG levels increased in participants supplemented with UP446 vs. those on Placebo (p ≤ 0.026). As well, influenza B-specific IgG increased 19.4% from Day 28 to 56 and 11.6% from baseline at Day 56 (p ≤ 0.0075). Serum glutathione peroxidase (GSH-Px) was increased in the pre-vaccination period and from baseline at Day 56 with UP446 supplementation (p ≤ 0.0270). CONCLUSION: These results suggest a 56-day supplementation with UP446 was beneficial in mounting a robust humoral response following vaccination. Increasing GSH-Px in the pre-vaccination period may help improve antioxidant functions and potentially mitigate the oxidative stress induced following vaccination.

A randomized, double-blind, placebo-controlled, cross-over pilot study to investigate the efficacy of Rest-ZZZ formula in healthy participants with occasional sleeplessness.

The purpose of this study was to investigate the safety and efficacy of Rest-ZZZ, a natural sleep supplement, in healthy adults without a diagnosed sleep disorder. This randomized, double-blind, placebo-controlled, cross-over study consisted of three 7-day supplementation periods with either Rest-ZZZ, Diphenhydramine (DPH), or Placebo, with a 7-day washout. Twenty-seven participants were randomized to one of three intervention sequences and the Healthy People Sleep Quality Index (HPSQI), Quality of Life (QoL), and Profile of Mood States (POMS) questionnaires were assessed at the beginning and end of each supplementation period. Rest-ZZZ and Placebo showed improvements in sleep-related QoL (p ≤ 0.044) and total mood disturbance (TMD) (p = ≤ 0.028). Fatigue-Inertia was reduced by all study products (p ≤ 0.031). DPH did not result in any significant improvements on sleep quality parameters. A subgroup analysis of participants ≤ 45 years found enhanced efficacy of Rest-ZZZ and improvement in sleep-related QoL vs. Placebo (p = 0.007), as well as improvements in sleep duration (p = 0.007), sleep debt (p = 0.011), and sleep-related QoL (p = 0.033). DPH supplementation resulted in significant improvement in only sleep debt (p = 0.038). Rest-ZZZ had a safe hematology and chemistry profile. Rest-ZZZ resulted in restful sleep that generated corresponding improvements in sleep-related QoL and overall mood. Rest-ZZZ is an efficacious sleep supplement with a favorable safety profile, particularly in those aged 25-45 years.

Breaking new frontiers: Assessment and re-evaluation of clinical trial design for nutraceuticals.

Despite sophisticated study designs and measurement tools, we have yet to create an innovative space for diet and dietary supplements in the health care system. The path is challenging due to current hierarchies of scientific evidence and regulatory affairs. The role of the randomized, double-blind, placebo-controlled clinical trial (RCT) as a research approach functions well to characterize the benefits and risks of drugs but lacks the sensitivity to capture the efficacy and safety of nutraceuticals. While some facets of RCTs can be relevant and useful when applied to nutraceuticals, other aspects are limiting and potentially misleading when taken in their entirety. A differentiation between guidelines for evidence-based medicine and the evidence required for nutrition spotlight the need to reconceptualize constituents of the RCT and their applicability with relevance to health promotion. This perspective identifies the limitations of the traditional RCT to capture the complexities of nutraceuticals and proposes the N-of-1 as Level 1 evidence better suited for the proof of efficacy of nutraceuticals.

Examining the Efficacy of a Very-Low-Carbohydrate Ketogenic Diet on Cardiovascular Health in Adults with Mildly Elevated Low-Density Lipoprotein Cholesterol in an Open-Label Pilot Study.

Background: The objective of this open-label pilot study was to investigate the efficacy of a very-low-carbohydrate ketogenic diet (VLCKD), known as Nic's Ketogenic Diet, for 140 days on cardiometabolic markers in healthy adults with mildly elevated low-density lipoprotein cholesterol (LDL-C). Methods: Study assessments were conducted at Day 0, 28, 56, 70, 84, 112, and 140, and weight and blood pressure (BP) were measured and fasting blood was collected for analysis of plasma lipids. A DEXA scan was performed and body mass index recorded on Day 0, 70, and 140. Blood glucose, inflammatory, and thyroid markers were measured on Day 0 and 140. Compliance was assessed using weekly 3-day food records and daily blood glucose and ketone monitoring. Results: The results showed that body fat percentage decreased by 2.25% and 4.41% at Day 70 and 140, respectively (P ≤ 0.012). Significant reductions in android, gynoid, and android/gynoid fat ratio and increases in muscle mass occurred by Day 70 and 140. Total cholesterol, LDL-C, and high-density lipoprotein cholesterol were increased and systolic BP and glycated hemoglobin (HbA1c) were decreased at Day 140 (P < 0.05). Following this VLCKD for 140 days was found to be safe and was well tolerated. Conclusion: The VLCKD showed beneficial changes in body composition and cardiometabolic markers in eutrophic and overweight participants in a 140-day study suggesting a future role for this diet in populations at cardiovascular disease risk. Future research with larger sample size in a randomized double blind clinical trial is warranted to confirm these results. Clinical Trial Registration number: NCT04195594.

The Lipid-Soluble Forms of Choline Enhance Ex Vivo Responses from the Gut-Associated Immune System in Young Female Rat Offspring.

BACKGROUND: In humans, the development of gut-associated lymphoid tissue (GALT) occurs in the first years of life and can be influenced by diet. OBJECTIVES: The objective of this study was to determine the effect of dietary choline on the development of gut-associated lymphoid tissue (GALT). METHODS: Three feeding trials were conducted in female Sprague-Dawley rats. Beginning 3 d before parturition (studies 1 and 3) or at day 10 of gestation (study 2), control dams consumed a 100% free choline (FC) diet until the end of the lactation period. In studies 1 and 3, test dams consumed a high-glycerophosphocholine (HGPC) diet [75% glycerophosphocholine (GPC), 12.5% phosphatidylcholine (PC), 12.5% FC] and a 100% PC diet, respectively (both 1 g of choline/kg diet). In study 2, test dams consumed a high-sphingomyelin (SM) and PC (SMPC) diet (34% SM, 37% PC, 17% GPC, 7% FC, 5% phosphocholine) or a 50% PC diet (50% PC, 25% FC, 25% GPC), both 1.7 g of choline/kg diet. Immune cell phenotypes and ex vivo cytokine production by mitogen-stimulated immune cells were measured. RESULTS: Feeding of the HGPC diet lowered T-cell IL-2 (44%), IFN-γ (34%), and TNF-α (55%) production in mesenteric lymph nodes (MLNs) compared with control. Feeding both SMPC and 50% PC diets during the lactation and weaning periods increased IL-2 (54%) and TNF-α (46%) production after T-cell stimulation compared with control. There was a lower production of IL-2 (46%), IL-6 (66%), and TNF-α (45%), and a higher production of IL-10 (44%) in both SMPC and 50% PC groups following ovalbumin stimulation compared with control in MLNs. Feeding a diet containing 100% PC increased the production of IFN-γ by 52% after T-cell stimulation compared with control. CONCLUSION: Feeding a diet containing a mixture of choline forms with a high content of lipid-soluble forms during both the lactation and weaning periods enhances ex vivo immune responses from the GALT in female Sprague-Dawley offspring.

The role of maternal nutrition during pregnancy in the intergenerational transmission of childhood adversity.

Adverse childhood experiences (ACEs) of a woman can lead to dysregulated hypothalamus-pituitary-adrenal (HPA) axis during pregnancy, which can in turn adversely affect her offspring HPA axis function. Choline and docosahexaenoic acid (DHA) are dietary factors with the potential to favorably modify the stress response system. The current study aimed to investigate whether maternal choline intake and DHA status moderate the effects of maternal ACEs exposure on maternal and infant HPA axes function. Participants were a sub-sample of the prospective longitudinal Alberta Pregnancy Outcomes and Nutrition (APrON) study consisting of 340 mothers and 238 infants. We collected data on maternal ACEs, maternal choline intake (24-hour dietary recall) and serum phospholipid DHA concentrations (at each trimester). Women self-collected saliva samples on two consecutive days (at waking, +30 min, 1100 h, and 2100 h) in each trimester to calculate the cortisol awakening response (CAR) and total daytime cortisol. Infants' salivary cortisol was measured before and after (20, and 40 min) exposure to a blood draw stressor 3 months postpartum. During pregnancy, choline intake moderated (reduced) the association between maternal ACEs and CAR (ß = -0.003; 95% CI -0.006, -0.003), but not total daytime cortisol. DHA status did not moderate the association between ACEs and CAR or total daytime cortisol. Choline intake also moderated (reduced) the association between maternal CAR and infant cortisol during a stress task (ß = -0.0001; 95% CI -0.0002, -0.00003). Maternal DHA status revealed no modifying effects on these associations. Our findings suggest that maternal choline intake, but not DHA status, can buffer the associations between ACEs and maternal HPA axis, as well as maternal and infant HPA axes function.

A randomized, triple-blind, placebo-controlled, parallel study to evaluate the efficacy of a freshwater marine collagen on skin wrinkles and elasticity.

BACKGROUND: Collagen is the primary component in human skin. With age, there is loss of skin elasticity and collagen, resulting in wrinkle formation and reduction in skin appearance. AIMS: The objective of this randomized, triple-blind, placebo-controlled study was to evaluate the safety and efficacy of a hydrolyzed marine collagen (Vinh Wellness Collagen, VWC) on aspects of skin health and quality in women between 45 and 60 years of age. PATIENTS/METHODS: Assessments of skin wrinkles, elasticity, and self-reported appearance were conducted using the VISIA skin analysis system, Cutometer® , and Skin Quality Visual Analogue Scale. Outcomes were assessed at weeks 0 (baseline), 6, and 12. RESULTS: After 12 weeks, participants supplemented with VWC had a significant 35% reduction in wrinkle score (P = .035) from baseline. Participants in the VWC group showed a 24% greater reduction in wrinkles on the right side of the face than those on placebo. A planned subgroup analysis based on age showed women 45-54 years had a significant 20% and 10% improvement in cheek skin elasticity from baseline to week 6 (P = .016) and 12 (P = .022), respectively. At week 12, participants in the VWC group reported greater percentage improvements in overall skin score (9%) and wrinkle (15%), elasticity (23%), hydration (14%), radiance (22%), and firmness (25%) scores vs placebo. CONCLUSION: Supplementation with VWC was found to be safe and well-tolerated. The results of this study support the use of fish-derived hydrolyzed collagen for the improvement of skin health in an aging population.

A Novel Combination of Fruits and Vegetables Prevents Diet-Induced Hepatic Steatosis and Metabolic Dysfunction in Mice.

BACKGROUND: Epidemiological studies suggest that higher fruits and vegetables (F&V) consumption correlates with reduced risk of hepatic steatosis, yet evidence for causality and the underlying mechanisms is lacking. OBJECTIVES: We aimed to determine the causal relation between F&V consumption and improved metabolic disorders in mice fed high-fat (HF) (Experiment-1) or normal-fat (Experiment-2) diets and its underlying mechanisms. METHODS: Six-week-old male C57BL/6J mice were randomly grouped and fed diets supplemented at 0%-15% (wt:wt) with a freeze-dried powder composed of 24 commonly consumed F&V (human equivalent of 0-9 servings/d) for 20 wk. In Experiment-1, mice were fed an HF (45% kcal fat) diet with 0% (HF0), 5%, 10%, or 15% (HF15) F&V or a matched low-fat control diet (10% kcal fat). In Experiment-2, mice were fed an AIN-93 diet (basal) (B, 16% kcal fat) with 0% (B0), 5%, 10%, or 15% (B15) F&V supplementation. Body weight and composition, food intake, hepatic steatosis, inflammation, ceramide levels, sphingomyelinase activity, and gut microbiota were assessed. RESULTS: In Experiment-1, mice fed the HF15 diet had lower weight gain (17.9%), hepatic steatosis (48.4%), adipose tissue inflammation, blood (24.6%) and liver (33.9%) ceramide concentrations, and sphingomyelinase activity (38.8%) than HF0 mice (P < 0.05 for all). In Experiment-2, mice fed the B15 diet had no significant changes in weight gain but showed less hepatic steatosis (28.5%), blood and adipose tissue inflammation, and lower blood (30.0%) ceramide concentrations than B0 mice (P < 0.05 for all). These F&V effects were associated with favorable microbiota changes. CONCLUSIONS: These findings represent the first evidence for a causal role of high F&V intake in mitigating hepatic steatosis in mice. These beneficial effects may be mediated through changes in ceramide and/or gut microbiota, and suggest that higher than currently recommended servings of F&V may be needed to achieve maximum health benefits.

Feeding Buttermilk-Derived Choline Forms During Gestation and Lactation Modulates Ex Vivo T-Cell Response in Rat Dams.

BACKGROUND: Buttermilk contains a mixture of choline forms; it is high in phosphatidylcholine (PC) and sphingomyelin (SM), which could have an impact on immune system development and function. OBJECTIVES: We aimed to determine the effect of feeding buttermilk-derived choline forms during pregnancy and lactation on maternal immune function. METHODS: Sprague Dawley dams (n = 8 per diet) were randomly assigned midway through pregnancy (10 d of gestation) to 1 of 3 experimental diets, containing 1.7 g/kg choline: control [100% free choline (FC)]; buttermilk [37% PC, 34% SM, 17% glycerophosphocholine (GPC), 7% FC, 5% phosphocholine]; or placebo (50% PC, 25% FC, 25% GPC). Dams consumed the same diet until the end of the lactation period (21 d after parturition). Cell phenotypes and cytokine production by mitogen-stimulated splenocytes were measured and compared using 1-factor ANOVA test in order to asses the effect of diet on immune fuction of lactating dams (main outcome). RESULTS: After ConA stimulation, splenocytes from dams in the buttermilk group produced more IL-2 (30%), TNF-α (30%), and IFN-γ (42%) compared with both the placebo and control diets. Placebo-fed dams had a higher proportion of CD8+ cells expressing CD152+ (22%) in spleen, and splenocytes from dams that were fed the buttermilk and the placebo diets produced about 50% and 53% more IL-10 after LPS and OVA stimulation, respectively, compared with the control group. CONCLUSIONS: Feeding buttermilk-derived choline forms during pregnancy and lactation had a beneficial impact on the immune system of Sprague Dawley rat dams, especially on T-cell function.

Efficacy of Lactobacillus paracasei HA-196 and Bifidobacterium longum R0175 in Alleviating Symptoms of Irritable Bowel Syndrome (IBS): A Randomized, Placebo-Controlled Study.

Specific probiotic strains can alleviate the gastrointestinal (GI) symptoms and psychiatric comorbidities of irritable bowel syndrome (IBS). In this randomized, double-blind, placebo-controlled study, the efficacy of Lactobacillus paracasei HA-196 (L. paracasei) and Bifidobacterium longum R0175 (B. longum) in reducing the GI and psychological symptoms of IBS was evaluated in 251 adults with either constipation (IBS-C), diarrhea (IBS-D), or mixed-pattern (IBS-M). Following a 2-week run-in period, participants were randomized to one of three interventions: L. paracasei (n = 84), B. longum (n = 83) or placebo (n = 81). IBS symptoms, stool frequency and consistency and quality of life were assessed by questionnaires. The differences from baseline in the severity of IBS symptoms at 4 and 8 weeks were similar between groups. Participants in this study were classified, after randomization, into subtypes according to Rome III. Within the L. paracasei group, complete spontaneous and spontaneous bowel movement frequency increased in participants with IBS-C (n = 10) after 8 weeks of supplementation (both p < 0.05) and decreased in participants with IBS-D (n = 10, p = 0.013). Both L. paracasei and B. longum supplementation improved the quality of life in emotional well-being and social functioning compared with baseline (all p < 0.05). In conclusion, L. paracasei and B. longum may reduce GI symptom severity and improve the psychological well-being of individuals with certain IBS subtypes.

Safe and effective delivery of supplemental iron to healthy older adults: The double-blind, randomized, placebo-controlled trial protocol of the Safe Iron Study.

The forms of iron currently available to correct iron deficiency have adverse effects, including infectious diarrhea, increased susceptibility to malaria, inflammation and detrimental changes to the gut microbiome. These adverse effects limit their use such that the growing burden of iron deficiency has not abated in recent decades. Here, we summarize the protocol of the "Safe Iron Study", the first clinical study examining the safety and efficacy of novel forms of iron in healthy, iron-replete adults. The Safe Iron Study is a double-blind, randomized, placebo-controlled trial conducted in Boston, MA, USA. This study compares ferrous sulfate heptahydrate (FeSO 4·H 2O) with two novel forms of iron supplements (iron hydroxide adipate tartrate (IHAT) and organic fungal iron metabolite (Aspiron™ Natural Koji Iron)). In Phase I, we will compare each source of iron administrated at a low dose (60 mg Fe/day). We will also determine the effect of FeSO 4 co-administrated with a multiple micronutrient powder and weekly administration of FeSO 4. The forms of iron found to produce no adverse effects, or adverse effects no greater than FeSO 4 in Phase I, Phase II will evaluate a higher, i.e., a therapeutic dose (120 mg Fe/day). The primary outcomes of this study include ex vivo malaria ( Plasmodium falciparum) infectivity of host erythrocytes, ex vivo bacterial proliferation (of selected species) in presence of host plasma and intestinal inflammation assessed by fecal calprotectin. This study will test the hypotheses that the novel forms of iron, administered at equivalent doses to FeSO 4, will produce similar increases in iron status in iron-replete subjects, yet lower increases in ex vivo malaria infectivity, ex vivo bacterial proliferation, gut inflammation. Ultimately, this study seeks to contribute to development of safe and effective forms of supplemental iron to address the global burden of iron deficiency and anemia. Registration: ClinicalTrials.gov identifier: NCT03212677; registered: 11 July 2017.

Dietary supplementation with blueberry partially restores T-cell-mediated function in high-fat-diet-induced obese mice.

Blueberry, rich in antioxidant and anti-inflammatory phytochemicals, has been demonstrated to lower inflammatory status in adipose induced by high-fat diet (HFD) and obesity. The effect of blueberry on systemic immune functions has not been examined. C57BL/6 mice were randomised to one of three diets - low-fat diet (LFD), HFD and HFD plus 4 % (w/w) blueberry (HFD+B) - for 8 or 12 weeks. Ex vivo T-cell mitogens (concanavalin A (Con A); phytohaemagglutinin), T-cell antibody (anti-CD3; anti-CD3/CD28)-stimulated T-cell proliferation and cytokine production were assessed. After 8 weeks, both HFD groups weighed more (>4 g) than the LFD group; after 12 weeks, HFD+B-fed mice weighed more (>6 g) and had 41 % more adipose tissue than HFD-fed mice (P<0·05). After 12 weeks, T-cell proliferation was less in both HFD groups, compared with the LFD group. HFD-associated decrements in T-cell proliferation were partially (10-50 %) prevented by blueberry supplementation. At 12 weeks, splenocytes from HFD mice, but not from HFD+B mice, produced 51 % less IL-4 (CD3/CD28) and 57 % less interferon-γ (Con A) compared with splenocytes from LFD mice (P<0·05). In response to lipopolysaccharide challenge, splenocytes from both HFD groups produced 24-30 % less IL-6 and 27-33 % less TNF-α compared with splenocytes from LFD mice (P<0·05), indicating impaired acute innate immune response. By demonstrating deleterious impacts of HFD feeding on T-cell proliferation and splenocyte immune responses, our results provide insights into how HFD/obesity can disrupt systemic immune function. The protective effects of blueberry suggest that dietary blueberry can buttress T-cell and systemic immune function against HFD-obesity-associated insults.

Nutritional Modulation of Immune Function: Analysis of Evidence, Mechanisms, and Clinical Relevance.

It is well-established that the nutritional deficiency or inadequacy can impair immune functions. Growing evidence suggests that for certain nutrients increased intake above currently recommended levels may help optimize immune functions including improving defense function and thus resistance to infection, while maintaining tolerance. This review will examine the data representing the research on prominent intervention agents n-3 polyunsaturated fatty acids (PUFA), micronutrients (zinc, vitamins D and E), and functional foods including probiotics and tea components for their immunological effects, working mechanisms, and clinical relevance. Many of these nutritive and non-nutritive food components are related in their functions to maintain or improve immune function including inhibition of pro-inflammatory mediators, promotion of anti-inflammatory functions, modulation of cell-mediated immunity, alteration of antigen-presenting cell functions, and communication between the innate and adaptive immune systems. Both animal and human studies present promising findings suggesting a clinical benefit of vitamin D, n-3 PUFA, and green tea catechin EGCG in autoimmune and inflammatory disorders, and vitamin D, vitamin E, zinc, and probiotics in reduction of infection. However, many studies report divergent and discrepant results/conclusions due to various factors. Chief among them, and thus call for attention, includes more standardized trial designs, better characterized populations, greater consideration for the intervention doses used, and more meaningful outcome measurements chosen.

Feeding a Mixture of Choline Forms during Lactation Improves Offspring Growth and Maternal Lymphocyte Response to Ex Vivo Immune Challenges.

Study objectives were to examine the impact of feeding a mixture of choline forms, or a diet high in glycerophosphocholine (GPC) on maternal immune function and offspring growth during lactation. Lactating Sprague-Dawley rat dams (n = 6/diet) were randomized to one of three diets, providing 1 g/kg total choline: Control (100% free choline (FC)), Mixed Choline (MC; 50% phosphatidylcholine (PC), 25% FC, 25% GPC), or High GPC (HGPC; 75% GPC, 12.5% PC, 12.5% FC). At 3 weeks, cell phenotypes and cytokine production with Concanavalin A (ConA)-or lipopolysaccharide (LPS)-stimulated splenocytes and mesenteric lymphocytes were measured. Feeding MC or HGPC diets improved pups' growth compared to Control (+22% body weight, p < 0.05). In spleen, MC-and HGPC-fed dams had higher proportions of cytotoxic (CD8+) T cells expressing CD27, CD71 and CD127, total B cells (CD45RA+) and dendritic cells (OX6+OX62+), and produced less IL-6 and IFN-γ after ConA than Control-fed dams (p < 0.05). MC and HGPC LPS-stimulated splenocytes produced less IL-1ß and IL-6 than Control. ConA-stimulated mesenteric lymphocytes from MC and HGPC dams produced more IL-2 and IFN-γ than Control (p < 0.05). In summary, feeding a mixture of choline forms during lactation improved offspring growth and resulted in a more efficient maternal immune response following mitogenic immune challenge.