Co-Administration of Iron and Bioavailable Curcumin Reduces Levels of Systemic Markers of Inflammation and Oxidative Stress in a Placebo-Controlled Randomised Study

Ferrous sulphate (FS) is widely used as an iron supplement to treat iron deficiency (ID), but is known to induce inflammation causing gastric side-effects resulting in poor adherence to supplement regimens. Curcumin, a potent antioxidant, has been reported to suppress inflammation via down regulation of NF-κB. The aim of the present double blind, placebo-controlled randomised trial was to assess whether co-administration of FS with a formulated, bioavailable form of curcumin (HydroCurc™) could reduce systemic inflammation and/or gastrointestinal side-effects. This study recruited 155 healthy participants (79 males; 26.42 years ± 0.55 and 76 females; 25.82 years ± 0.54), randomly allocated to one of five different treatment groups: iron and curcumin placebo (FS0_Plac), low dose (18 mg) iron and curcumin placebo (FS18_Plac), low dose iron and curcumin (FS18_Curc), high dose (65 mg) iron and curcumin placebo (FS65_Plac), and high dose iron and curcumin (FS65_Curc). Completed questionnaires and blood samples were collected from all participants at baseline (day 1), mid-point (day 21), and at end-point (day 42). Results showed a significant reduction in IL-6 in the FS65_Curc group (0.06 pg/mL ± 0.02, p = 0.0073) between the mid-point and end-point. There was also a significant reduction in mean plasma TNF levels in the FS65_Curc (0.65 pg/mL ± 0.17, p = 0.0018), FS65_Plac (0.39 pg/mL ± 0.15, p = 0.0363), and FS18_Curc (0.35 pg/mL ± 0.13, p = 0.0288) groups from mid-point to end-point. A significant increase was observed in mean plasma TBARS levels (0.10 µM ± 0.04, p = 0.0283) in the F18_Plac group from baseline to end-point. There was a significant association with darker stools between FS0_Plac vs. FS65_Plac (p = 0.002, Fisher’s exact test) suggesting that high iron dose in the absence of curcumin leads to darker stools. A reduction in inflammation-related markers in response to co-administering supplemental iron alongside formulated curcumin suggests a reduction in systemic inflammation. This supplementation approach may therefore be a more cost effective and convenient alternative to current oral iron-related treatments, with further research to be conducted.     

Postnatal Iron Supplementation with Ferrous Sulfate vs. Ferrous Bis-Glycinate Chelate: Effects on Iron Metabolism,Growth, and Central Nervous System Development in Sprague Dawley Rat Pups

Iron-fortified formulas and iron drops (both usually ferrous sulfate, FS) prevent early life iron deficiency, but may delay growth and adversely affect neurodevelopment by providing excess iron. We used a rat pup model to investigate iron status, growth, and development outcomes following daily iron supplementation (10 mg iron/kg body weight, representative of iron-fortified formula levels) with FS or an alternative, bioavailable form of iron, ferrous bis-glycinate chelate (FC). On postnatal day (PD) 2, sex-matched rat litters (n = 3 litters, 10 pups each) were randomly assigned to receive FS, FC, or vehicle control until PD 14. On PD 15, we evaluated systemic iron regulation and CNS mineral interactions and we interrogated iron loading outcomes in the hippocampus, in search of mechanisms by which iron may influence neurodevelopment. Body iron stores were elevated substantially in iron-supplemented pups. All pups gained weight normally, but brain size on PD 15 was dependent on iron source. This may have been associated with reduced hippocampal oxidative stress but was not associated with CNS mineral interactions, iron regulation, or myelination, as these were unchanged with iron supplementation. Additional studies are warranted to investigate iron form effects on neurodevelopment so that iron recommendations can be optimized for all infants.     

Iron Protein Succinylate in the Management of Iron Deficiency Anemia: A Comparative Study with Ferrous Sulphate at Low and High Therapeutic Doses

Oral iron supplementation constitutes the first line treatment for iron deficiency anemia (IDA), with daily doses between 80 mg and 200 mg of elemental iron. Ferrous salts, such as ferrous sulphate (FeSO₄), while efficacious, frequently give rise to gastrointestinal side effects. In the present paper we attempted to directly compare the efficacy of an alternative to the FeSO₄ formulation, which presents a better tolerability profile, iron protein succinylate (Ferplex^®). In a diet-induced anemia model, rats were treated by oral gavage with vehicle, FeSO₄, or Ferplex^® at a human-dose equivalent of 80 mg and 200 mg of elemental iron. We evaluated the change in anemia-related hematological and biochemical parameters, conducting a histological examination of the intestine at sacrifice. Results indicate that both types of iron supplementation are equally effective in the treatment of IDA, restoring hemoglobin, hematocrit, erythrocytes, free iron and transferrin levels in 15 days, with no statistical differences between treated groups and control. The impact of anemia on body weight was also attenuated following treatment with both iron supplements. Thrombocyte and reticulocyte levels, altered by the anemic condition, returned to homeostasis after 15 days of either FeSO₄ or Ferplex^® treatment. Importantly, the lower and higher doses of iron were equally effective, thus supporting the current school of thought which states that lower therapeutic doses are sufficient for management of IDA. In addition, the study shows for the first time that oral treatment with Ferplex^® does not increase serum hepcidin. Finally, Ferplex^® induced minimal iron depositions in the intestinal tissue compared to FeSO₄.     

A Study of the Effects of Latent Iron Deficiency on Measures of Cognition: A Pilot Randomised Controlled Trial of Iron Supplementation in Young Women

Rates of iron deficiency are high amongst healthy young women. Cognitive impairment occurs secondary to iron deficiency in infants and children, but evaluation of the impact on cognition among young women is inconsistent. The aim was to determine the suitability of the IntegNeuro test battery for assessing cognitive function in iron-deficient and iron-sufficient young women. A pilot double-blinded, placebo-controlled intervention trial was conducted in iron-deficient (serum ferritin ≤ 20 μg/L and haemoglobin > 120 g/L) and iron-sufficient young women (18–35 years). Cognitive function and haematological markers of iron status were measured at baseline and follow-up. Iron-deficient participants (n = 24) were randomised to receive placebo, 60 mg or 80 mg elemental iron daily supplements for 16 weeks. A control group of iron-sufficient participants (n = 8) was allocated to placebo. Change scores for Impulsivity and Attention were significantly greater in plasma ferritin improvers than in non-improvers (p = 0.004, p = 0.026). IntegNeuro was easy to administer and acceptable to young women. Based on the differences in Memory and Attention scores between iron-deficient participants on iron treatment and those on placebo, it was decided that between 26 and 84 participants would be required in each iron treatment group for an adequately powered extension of this pilot RCT.     

Reducing Iron Content in Infant Formula from 8 to 2 mg/L Does Not Increase the Risk of Iron Deficiency at 4 or 6 Months of Age: A Randomized Controlled Trial

Many infant formulas are fortified with iron at 8–14 mg/L whereas breast milk contains about 0.3 mg/L. Another major difference between breast milk and infant formula is its high concentration of lactoferrin, a bioactive iron-binding protein. The aim of the present study was to investigate how reducing the iron content and adding bovine lactoferrin to infant formula affects iron status, health and development. Swedish healthy full-term formula-fed infants (n = 180) were randomized in a double-blind controlled trial. From 6 weeks to 6 months of age, 72 infants received low-iron formula (2 mg/L) fortified with bovine lactoferrin (1.0 g/L) (Lf+), 72 received low-iron formula un-fortified with lactoferrin (Lf−) and 36 received standard formula with 8 mg of iron/L and no lactoferrin fortification as controls (CF). Iron status and prevalence of iron deficiency (ID) were assessed at 4 and 6 months. All iron status indicators were unaffected by lactoferrin. At 4 and 6 months, the geometric means of ferritin for the combined low-iron groups compared to the CF-group were 67.7 vs. 88.7 and 39.5 vs. 50.9 µg/L, respectively (p = 0.054 and p = 0.056). No significant differences were found for other iron status indicators. In the low-iron group only one infant (0.7%) at 4 months and none at 6 months developed ID. Conclusion: Iron fortification of 2 mg/L is an adequate level during the first half of infancy for healthy term infants in a well-nourished population. Adding lactoferrin does not affect iron status.     

Efficacy and Safety of Ferrous Bisglycinate and Folinic Acid in the Control of Iron Deficiency in Pregnant Women: A Randomized,Controlled Trial

Iron deficiency in pregnancy is a major public health problem that causes maternal complications. The objective of this randomized, controlled trial was to examine the bioavailability, efficacy, and safety of oral ferrous bisglycinate plus folinic acid supplementation in pregnant women with iron deficiency. Subjects (12–16 weeks of gestation, n = 120) were randomly allocated to receive oral iron as ferrous bisglycinate (equiv. iron 24 mg) in supplement form with folinic acid and multivitamins (test group, n = 60) or as ferrous fumarate (equiv. iron 66 mg iron, control group, n = 60) after breakfast daily. Iron absorption was assessed by measuring fasted serum iron levels at 1 and 2 h immediately after supplementation. Hematological biomarkers and iron status were assessed before intervention, and at 3 and 6 months. Side effects were monitored throughout the intervention. A significant increase in serum iron was seen in both groups (p < 0.001) during the bioavailability assessment; however, the test group increases were comparatively higher than the control values at each timepoint (p < 0.001). Similarly, both test and control groups demonstrated a statistically significant increases in hemoglobin (Hb) (p < 0.001), erythrocytes (p < 0.001), reticulocytes (p < 0.001), mean corpuscular volume (MCV) (p < 0.001), mean corpuscular hemoglobin (MCH) (p < 0.001), mean corpuscular hemoglobin concentration (MCHC) (p < 0.001), % transferrin saturation (p < 0.001), and ferritin (p < 0.001) at 3 and 6 months after supplementation. However, in all cases, the test group increases were numerically larger than the control group increases at each timepoint. The test intervention was also associated with significantly fewer reports of nausea, abdominal pain, bloating, constipation, or metallic taste (p < 0.001). In conclusion, ferrous bisglycinate with folinic acid as a multivitamin nutraceutical format is comparable to standard ferrous fumarate for the clinical management of iron deficiency during pregnancy, with comparatively better absorption, tolerability, and efficacy and with a lower elemental iron dosage.     

The Effects of a Multivitamin/Mineral Supplement on Micronutrient Status,Antioxidant Capacity and Cytokine Production in Healthy Older Adults Consuming a Fortified Diet

Background: Inadequate micronutrient intake among older adults is common despite the increased prevalence of fortified/enriched foods in the American diet. Although many older adults take multivitamin supplements in an effort to compensate, studies examining the benefits of this behavior are absent.

Objective: To determine whether a daily multivitamin/mineral supplement can improve micronutrient status, plasma antioxidant capacity and cytokine production in healthy, free-living older adults already consuming a fortified diet.

Methods: An eight-week double-blind, placebo-controlled clinical trial among 80 adults aged 50 to 87 years (mean=66.5±8.6 years).

Results: Multivitamin treatment significantly increased (p<0.01, compared to placebo) plasma concentrations of vitamins D (77 to 100 nmol/L), E (27 to 32 μmol/L), pyridoxal phosphate (55.1 to 75.2 nmol/L), folate (23 to 33 nmol/L), B12 (286 to 326 pmol/L)), C (55 to 71 μmol/L), and improved the riboflavin activity coefficient (1.23 to 1.15), but not vitamins A and thiamin. The multivitamin reduced the prevalence of suboptimal plasma levels of vitamins E (p=0.003), B12 (p=0.004), and C (p=0.08). Neither glutathione peroxidase activity nor antioxidant capacity (ORAC) were affected. No changes were observed in interleukin?2, ?6 or ?10 and prostaglandin E₂, proxy measures of immune responses.

Conclusions: Supplementation with a multivitamin formulated at about 100% Daily Value can decrease the prevalence of suboptimal vitamin status in older adults and improve their micronutrient status to levels associated with reduced risk for several chronic diseases.     

Brain Training and Sulforaphane Intake Interventions Separately Improve Cognitive Performance in Healthy Older Adults,Whereas a Combination of These Interventions Does Not Have More Beneficial Effects: Evidence from a Randomized Controlled Trial

Background: Earlier studies have demonstrated that a single-domain intervention, such as a brain-training (BT) game alone and a sulforaphane (SFN) intake, positively affects cognition. This study examined whether a combined BT and SFN intake intervention has beneficial effects on cognitive function in older adults. Methods: In a 12-week double-blinded randomized control trial, 144 older adults were randomly assigned to one of four groups: BT with SFN (BT-S), BT with placebo (BT-P), active control game (AT) with SFN (AT-S), and active control game with placebo (AT-P). We used Brain Age in BT and Tetris in AT. Participants were asked to play BT or AT for 15 min a day for 12 weeks while taking a supplement (SFN or placebo). We measured several cognitive functions before and after the intervention period. Results: The BT (BT-S and BT-P) groups showed more improvement in processing speed than the active control groups (AT-S and AT-P). The SFN intake (BT-S and AT-S) groups recorded significant improvements in processing speed and working memory performance unlike the placebo intake groups (BT-P and AT-P). However, we did not find any evidence of the combined intervention’s beneficial effects on cognition. Discussion: We discussed a mechanism to improve cognitive functions in the BT and SFN alone interventions.     

Efficacy of a Multi-Component m-Health Diet,Physical Activity,and Sleep Intervention on Dietary Intake in Adults with Overweight and Obesity: A Randomised Controlled Trial

This three-arm randomised controlled trial evaluated whether (1) a multi-component weight loss intervention targeting diet, physical activity (PA), and sleep was effective at improving dietary intake over six months and 12 months, compared with a control, and (2) the enhanced diet, PA, and sleep intervention was more effective at improving dietary intake than the traditional diet and PA intervention. A total of 116 adults (70% female, 44.5 years, BMI 31.7 kg/m²) were randomised to either traditional diet and PA intervention; enhanced diet, PA, and sleep intervention; or wait-list control. To examine between-group differences, intervention groups were pooled and compared with the control. Then, the two intervention groups were compared. At six months, the pooled intervention group consumed 1011 fewer kilojoules/day (95% CI −1922, −101), less sodium (−313.2 mg/day; 95% CI −591.3, −35.0), and higher %EI from fruit (+2.1%EI; 95% CI 0.1, 4.1) than the controls. There were no differences in intake between the enhanced and traditional groups at six months. At 12 months, the pooled intervention and control groups reported no significant differences. However, compared to the traditional group, the enhanced reported higher %EI from nutrient-dense foods (+7.4%EI; 95% CI 1.3, 13.5) and protein (+2.4%EI; 95% CI 0.1, 4.6), and reduced %EI from fried/takeaway foods (−3.6%EI; 95% CI −6.5, −0.7), baked sweet products (−2.0%EI; 95% CI −3.6, −0.4), and packaged snacks (−1.1%EI; 95% CI −2.2, −0.3). This weight loss intervention reduced total energy and sodium intakes as well as increased fruit intake in adults at six months. The enhanced intervention group reported improved dietary intake relative to the traditional group at 12 months.     

Daily Inclusion of Resistant Starch-Containing Potatoes in a Dietary Guidelines for Americans Dietary Pattern Does Not Adversely Affect Cardiometabolic Risk or Intestinal Permeability in Adults with Metabolic Syndrome: A Randomized Controlled Trial

Poor diet quality influences cardiometabolic risk. Although potatoes are suggested to adversely affect cardiometabolic health, controlled trials that can establish causality are limited. Consistent with potatoes being rich in micronutrients and resistant starch, we hypothesized that their inclusion in a Dietary Guidelines for Americans (DGA)-based dietary pattern would improve cardiometabolic and gut health in metabolic syndrome (MetS) persons. In a randomized cross-over trial, MetS persons (n = 27; 32.5 ± 1.3 year) consumed a DGA-based diet for 2 weeks containing potatoes (DGA + POTATO; 17.5 g/day resistant starch) or bagels (DGA + BAGEL; 0 g/day resistant starch) prior to completing oral glucose and gut permeability tests. Blood pressure, fasting glucose and insulin, and insulin resistance decreased (p < 0.05) from baseline regardless of treatment without any change in body mass. Oral glucose-induced changes in brachial artery flow-mediated dilation, nitric oxide homeostasis, and lipid peroxidation did not differ between treatment arms. Serum endotoxin AUC_{0–120 min} and urinary lactulose/mannitol, but not urinary sucralose/erythritol, were lower in DGA + POTATO. Fecal microbiome showed limited between-treatment differences, but the proportion of acetate was higher in DGA + POTATO. Thus, short-term consumption of a DGA-based diet decreases cardiometabolic risk, and the incorporation of resistant starch-containing potatoes into a healthy diet reduces small intestinal permeability and postprandial endotoxemia.