Iron Status In Humans Research Articles

Prebiotics, Probiotics, and Postbiotics in the Prevention and Treatment of Anemia.

Iron deficiency anemia (IDA) is very common and affects approximately 1/3 of the world’s human population. There are strong research data that some probiotics, such as Lactobacillus acidophilus and Bifidobacterium longum improve iron absorption and influence the course of anemia. Furthermore, prebiotics, including galactooligosaccharides (GOS) and fructooligosaccharides (FOS), increase iron bioavailability and decrease its destructive effect on the intestinal microbiota. In addition, multiple postbiotics, which are probiotic metabolites, including vitamins, short-chain fatty acids (SCFA), and tryptophan, are involved in the regulation of intestinal absorption and may influence iron status in humans. This review presents the actual data from research studies on the influence of probiotics, prebiotics, and postbiotics on the prevention and therapy of IDA and the latest findings regarding their mechanisms of action. A comparison of the latest research data and theories regarding the role of pre-, post-, and probiotics and the mechanism of their action in anemias is also presented and discussed.

Early-life adversity is associated with poor iron status in infancy.

Exposure to early-life adversity (ELA) and iron deficiency early in life are known risk factors for suboptimal brain and socioemotional development. Iron deficiency may arise from and co-occur with ELA, which could negatively affect development. In the present study, we investigated whether ELA is associated with iron deficiency in infants receiving no iron supplementation. This study is a secondary analysis of extant data collected in the 1990s; participants were healthy infants from working-class communities in Santiago, Chile (N = 534, 45.5% female). We measured stressful life events, maternal depression, and low home support for child development during infancy and assessed iron status when the infant was 12 months old. Slightly more than half of the infants were iron-deficient (51%), and 25.8% were iron-deficient anemic at 12 months. Results indicated that ELA was associated with lower iron levels and iron deficiency at 12 months. The findings are consistent with animal and human prenatal models of stress and iron status and provide evidence of the association between postnatal ELA and iron status in humans. The findings also highlight a nutritional pathway by which ELA may impact development and present a nutritionally-focused avenue for future research on ELA and psychopathology.

Genotype Score for Iron Status Is Associated with Muscle Fiber Composition in Women.

Human muscle fiber composition is heterogeneous and mainly determined by genetic factors. A previous study reported that experimentally induced iron deficiency in rats increases the proportion of fast-twitch muscle fibers. Iron status has been reported to be affected by genetic factors. As the TMPRSS6 rs855791 T/C and HFE rs1799945 C/G polymorphisms are strongly associated with iron status in humans, we hypothesized that the genotype score (GS) based on these polymorphisms could be associated with the muscle fiber composition in humans. Herein, we examined 214 Japanese individuals, comprising of 107 men and 107 women, for possible associations of the GS for iron status with the proportion of myosin heavy chain (MHC) isoforms (I, IIa, and IIx) as markers of muscle fiber composition. No statistically significant correlations were found between the GS for iron status and the proportion of MHC isoforms in all participants. When the participants were stratified based on sex, women showed positive and negative correlations of the GS with MHC-IIa (age-adjusted p = 0.020) and MHC-IIx (age-adjusted p = 0.011), respectively. In contrast, no correlation was found in men. In women, a 1-point increase in the GS was associated with 2.42% higher MHC-IIa level and 2.72% lower MHC-IIx level. Our results suggest that the GS based on the TMPRSS6 rs855791 T/C and HFE rs1799945 C/G polymorphisms for iron status is associated with muscle fiber composition in women.

Branched-chain amino acids are linked with iron metabolism.

BackgroundThe branched-chain amino acids (BCAAs) valine, leucine and isoleucine are reported to influence erythropoiesis and the human iron status. Large study cohorts encompassing biomarkers of iron metabolism and BCAAs are still lacking.MethodsWe investigated potential interactions between blood concentrations of all three BCAAs valine, leucine and isoleucine and biomarkers of iron metabolism [i.e., hemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), iron, transferrin, ferritin, transferrin saturation, soluble transferrin receptor (sTfR)] in 430 outpatients referred for a medical health check-up. Linear regression models were performed to assess possible associations between variables.ResultsAll three BCAAs were positively correlated with Hb, ferritin and the sTfR (r-values: 0.145–0.382; P values: <0.001–0.003). The strongest correlation was observed between valine and Hb (r=0.382; P value <0.001). Linear regression models showed a statistically significant influence of all three BCAAs on Hb and ferritin (β-coefficients: 0.173–0.351; all P values: <0.001). Seventeen patients with anemia (4%) were found with significantly lower serum BCAA concentrations compared to 413 non-anemic individuals (P<0.05).ConclusionsThese data indicate a pathophysiological link between the three BCAAs valine, leucine and isoleucine and the human iron indicators Hb and ferritin. Further studies are needed to clarify the exact causal mechanisms of these findings.

3068 – LINK BETWEEN BRANCHED-CHAIN AMINO ACIDS, IRON METABOLISM AND ANEMIA – A NEW PATHOPHYSIOLOGICAL CONCEPT

<h3>Background</h3> Branched-chain amino acids (BCAAs) are reported to influence erythropoiesis and the human iron status. This study is aimed at investigating potential interactions between blood concentrations of all three BCAAs valine, leucine and isoleucine and indicators of human iron status. <h3>Methods</h3> Overall, 430 outpatients referred for a medical health check-up were included in this study. They underwent investigation of valine, leucine and isoleucine and biomarkers of iron metabolism (i.e., hemoglobin [Hb], mean corpuscular volume [MCV], mean corpuscular hemoglobin [MCH], iron, transferrin, ferritin, transferrin saturation, soluble transferrin receptor [sTfR]). Linear regression models were performed to assess possible associations between variables. <h3>Results</h3> All three BCAAs were positively correlated with Hb, ferritin and the sTfR (r-values: 0.145 – 0.382; P-values: <0.001 – 0.003). The strongest correlation was observed between valine and Hb (r = 0.382; P-value < 0.001). Linear regression models showed a statistically significant influence of all three BCAAs on Hb and ferritin (ß-coefficients: 0.173 – 0.351; all P-values: < 0.001). Seventeen patients with anemia (4%) were found with significantly lower serum BCAA concentrations compared to 413 non-anemic individuals (P < 0.05). <h3>Conclusions</h3> These data indicate a pathophysiological link between the three BCAAs valine, leucine and isoleucine and the human iron indicators hemoglobin and ferritin. Anemic individuals had significantly lowered serum BCAA concentrations compared to non-anemic subjects and lowered BCAA concentrations were observed with lowered ferritin levels.

The Combined Application of the Caco-2 Cell Bioassay Coupled with In Vivo (Gallus gallus) Feeding Trial Represents an Effective Approach to Predicting Fe Bioavailability in Humans.

Research methods that predict Fe bioavailability for humans can be extremely useful in evaluating food fortification strategies, developing Fe-biofortified enhanced staple food crops and assessing the Fe bioavailability of meal plans that include such crops. In this review, research from four recent poultry (Gallus gallus) feeding trials coupled with in vitro analyses of Fe-biofortified crops will be compared to the parallel human efficacy studies which used the same varieties and harvests of the Fe-biofortified crops. Similar to the human studies, these trials were aimed to assess the potential effects of regular consumption of these enhanced staple crops on maintenance or improvement of iron status. The results demonstrate a strong agreement between the in vitro/in vivo screening approach and the parallel human studies. These observations therefore indicate that the in vitro/Caco-2 cell and Gallus gallus models can be integral tools to develop varieties of staple food crops and predict their effect on iron status in humans. The cost-effectiveness of this approach also means that it can be used to monitor the nutritional stability of the Fe-biofortified crop once a variety has released and integrated into the food system. These screening tools therefore represent a significant advancement to the field for crop development and can be applied to ensure the sustainability of the biofortification approach.

Assessment of human iron status: A cross-sectional study comparing the clinical utility of different laboratory biomarkers and definitions of iron deficiency in daily practice

ObjectivesNo full international consensus exists on disease markers to be used for assessing the human iron status. Therefore this study was conducted to compare performances of serum ferritin and transferrin saturation (TSAT) versus soluble transferrin receptor (sTfR)/log ferritin and reticulocyte hemoglobin content (CHr), also known as Thomas-plot, in the diagnosis of iron deficiency (ID). Design and methodsA total of 445 consecutive hospitalized patients, referred for routine testing of the actual iron status, were included. Logistic regression models for the probability of functional ID (CHr<28pg) were constructed for all 445 patients, for 225 patients without (C-reactive protein [CRP]≤0.5mg/dL) and 220 patients with acute-phase reaction (CRP>0.5mg/dL). ResultsBased on the Thomas-plot analyses, 153/445 (34.38%) patients were identified with ID. When ID was diagnosed by means of serum ferritin levels<30ng/mL and TSAT levels<20%, 105/445 (23.60%) and 215/445 (48.31%) patients were identified with ID, respectively. The sTfR/log ferritin ratio showed the best positive predictive values (PPV) (62.50 and 64.41%) to indicate functional ID in patients without as well as with acute-phase reaction compared to sTfR (58.14 and 61.67%), ferritin (32.50 and 32.86%) and TSAT (26.74 and 42.86%). ConclusionsIn clinical practice, the prevalence of ID and the accuracy to detect functional ID are dependent on marker selection and its definition. Regarding the results of this work, for laboratory investigation of ID, however, we suggest using Thomas-plot analyses in combination with ferritin single-marker measurements to efficiently identify patients with ID.

Advanced Glycation End-Products Promote Lipogenesis in Liver of Fructose-Drinking Mice

Rooibos: Effect on Iron Status of South African Adults at Risk for Coronary Heart Disease Jeanine L Marnewick, Irma Venter, Fanie Rautenbach, Henry Neethling, and Maritha Kotze Cape Peninsula University of Technology, South Africa University of Stellenbosch, South Africa Gknowmix (Pty) Ltd, South Africa The effect of rooibos (Aspalathus linearis) herbal tea (also referred to as “red tea”) consumption on the iron status of asymptomatic adults at an intermediate to high risk for developing coronary heart disease was a secondary objective of a recent clinical study. Rooibos is an infusion/tisane made from the dried, fermented leaves and stems of Aspalathus linearis (Brum.f) Dahlg. (Family Fabaceae; tribe Crotalarieae), a legume indigenous to the Cedarberg region of the Western Cape, South Africa. Traditional/fermented rooibos (“red tea”) is different from black, green and oolong teas made from Camellia sinensis, in that it contains different and unique polyphenolic constituents. Rooibos does not contain caffeine and is considered to have a low tannin content when compared to C. sinensis teas. To date very few studies have reported on the effect of rooibos on markers of iron status in humans. After consuming 6 cups of rooibos daily for 6 weeks, serum iron, ferritin, transferrin, TIBC and percentage Fe saturation were determined to assess the iron status of the participants (n=40) aged 30-60 yrs. Dietary intake was calculated with the use of estimated dietary records completed during the study periods. No significant (P>0.05) changes in these biochemical parameters were recorded after completion of the rooibos and control study periods. It was concluded that, for this study, when taking into account the iron status, habitual dietary composition and genetic variation in the HFE gene affecting iron absorption, the intake of rooibos did not have an adverse effect on the participants’ resultant iron status at the end of the intervention study period. The results from this study population agree with previous findings where the study populations differed, i.e. South African students (6-15 yrs) and apparently healthy young men (21-34 yrs) and does therefore not make it unreasonable to suggest that rooibos, in the South African context, does not have an adverse effect on markers of iron status. Long-term studies are needed to further investigate the relationship between rooibos consumption and iron status in various South African populations.

Human Glutaredoxin 3 Forms [2Fe-2S]-Bridged Complexes with Human BolA2

Human glutaredoxin 3 (Glrx3) is an essential [2Fe-2S]-binding protein with ill-defined roles in immune cell response, embryogenesis, cancer cell growth, and regulation of cardiac hypertrophy. Similar to other members of the CGFS monothiol glutaredoxin (Grx) family, human Glrx3 forms homodimers bridged by two [2Fe-2S] clusters that are ligated by the conserved CGFS motifs and glutathione (GSH). We recently demonstrated that the yeast homologues of human Glrx3 and the yeast BolA-like protein Fra2 form [2Fe-2S]-bridged heterodimers that play a key role in signaling intracellular iron availability. Herein, we provide biophysical and biochemical evidence that the two tandem Grx-like domains in human Glrx3 form similar [2Fe-2S]-bridged complexes with human BolA2. UV-visible absorption and circular dichroism, resonance Raman, and electron paramagnetic resonance spectroscopic analyses of recombinant [2Fe-2S] Glrx3 homodimers and [2Fe-2S] Glrx3-BolA2 complexes indicate that the Fe-S coordination environments in these complexes are virtually identical to those of the analogous complexes in yeast. Furthermore, we demonstrate that apo BolA2 binds to each Grx domain in the [2Fe-2S] Glrx3 homodimer forming a [2Fe-2S] BolA2-Glrx3 heterotrimer. Taken together, these results suggest that the unusual [2Fe-2S]-bridging Grx-BolA interaction is conserved in higher eukaryotes and may play a role in signaling cellular iron status in humans.

Algorithms for Iron and Zinc Bioavailability: Are they Accurate?

Several bioavailability algorithms have been proposed for iron and zinc, confirming the need for these tools while emphasizing the challenge of deriving algorithms with accepted accuracy. This manuscript briefly reviews current evidence on the accuracy of proposed algorithms. Iron absorption is strongly influenced by both body iron status and dietary availability, and most evidence suggests that these do not interact. There is considerable evidence of a logarithmic relationship between percent iron absorption and serum ferritin that allows a simple and accurate computation of how human iron status affects absorption (in the absence of inflammation). Computing the effect of dietary variation on nonheme iron absorption has been challenging because of multiple influential dietary factors and incomplete knowledge of their chemical characteristics, food composition, interactions, and dose-response relationships. At present there is no fully validated algorithm for dietary iron bioavailability. Predicting zinc absorption is less complex. Fractional zinc absorption is substantially influenced by the amount of zinc consumed, and this factor, together with ingested phytic acid, account for a considerable degree of the variance. A multivariate saturation model based on these two variables has been derived using data from multiple studies and independently validated with a single large data set.

Of mice and men, periodic limb movements and iron: how the human genome informs the mouse genome

The gene, BTBD9, was recently linked to restless legs syndrome, periodic limb movements and iron status in humans. In a homologous region in mouse, an area containing btbd9 was also identified as being related to iron homeostasis. This finding is important as iron status in brain has been implicated in restless legs syndrome.

The Haptoglobin 2-2 Phenotype Affects Serum Markers of Iron Status in Healthy Males

Human iron status is influenced by environmental and genetic factors. We hypothesized that the genetic polymorphism of haptoglobin (Hp), a hemoglobin-binding plasma protein, could affect iron status. Reference values of serum iron status markers were compared according to Hp phenotypes (Hp 1-1, Hp 2-1, Hp 2-2; determined by starch gel electrophoresis) in 717 healthy adults. Iron storage was investigated in peripheral blood monocyte-macrophages by measuring cytosolic L- and H-ferritins and by in vitro uptake of radiolabeled ((125)I) hemoglobin-haptoglobin complexes. In males but not in females, the Hp 2-2 phenotype was associated with higher serum iron (P <0.05), transferrin saturation (P <0.05), and ferritin (P <0.01) concentrations than Hp 1-1 and 2-1, whereas soluble transferrin receptor concentrations were lower (P <0.05). Moreover, serum ferritin correlated with monocyte L-ferritin content (r = 0.699), which was also highest in the male Hp 2-2 subgroup (P <0.01). In vitro, monocyte-macrophages took up a small fraction of (125)I-labeled hemoglobin complexed to Hp 2-2 but not to Hp 1-1 or 2-1. The Hp 2-2 phenotype affects serum iron status markers in healthy males and is associated with higher L-ferritin concentrations in monocyte-macrophages because of a yet undescribed iron delocalization pathway, selectively occurring in Hp 2-2 subjects.

Effects of Long-Term Calcium Supplementation on Iron Status in Adolescent Females

LEARNING OUTCOME: The 4-year calcium supplementation did not affect serum ferritin and iron deficiency anemia indices in adolescent females. The recent recommendations of National Institutes of Health for increasing calcium (Ca) intake in adolescent females to 1200-1500 mg/day raised a concern about its effects on other minerals, namely iron. The previous studies examining the effects of Ca supplementation on iron status in humans resulted in mixed conclusions. The objective of our study was to investigate the effects of Ca supplementation on iron status during a 4-year period. A sample of 354 healthy, Caucasian females were enrolled in the study at the average age of 10.8 y; one half was randomly assigned to receive 1000 mg/d Ca as Ca citrate malate and another half placebo. Blood was drawn once a year and serum ferritin was analyzed by the automated procedure (Hitachi Analyzer), while red blood cell indices and hemoglobin were determined at the end of the 4-year follow-up. The subjects completed 3-day dietary records annualy, which were analyzed on Nutritionist III. The average annual compliance with pill intake was 70%. Table presents yearly data (mean±SD): There was no statistical difference between placebo and Ca supplemented group in corresponding hemoglobin (13.4±0.8 vs. 13.2±0.9, p= 0.1), hematocrit (38.5±2.4 vs. 37.9±2.5, p=0.2), red blood cell count (4.4±0.3 vs. 4.4±0.3, p=0.3), mean corpuscular volume (86.6±3.5 vs. 86.5±4.0, p=0.8), and mean corpuscular hemoglobin concentration (34.8±0.6 vs. 34.7±0.7, p=0.1). Our results indicate that long-term (4 years) calcium supplementation in adolescent females has no effect on iron stores, as measured by serum ferritin, or indices of iron deficiency anemia.

High intakes of tin lower iron status in rats.

The effects of relatively low (1, 10, and 50 mg/kg) and high (100 and 200 mg/kg) dietary concentrations of tin (added as stannous chloride) on iron status of rats were determined. After feeding the diets for 28 d, feed intake and body weights were not significantly affected. Iron concentrations in plasma, spleen, and tibia as well as percentage transferrin saturation were decreased in rats fed the diets supplemented with 100 or 200 mg tin/kg. In rats fed the diet containing 200 mg tin/kg, group mean hemoglobin, hematocrit, and red blood cell count were slightly lowered but total iron binding capacity was not affected. Iron status was not influenced by dietary tin concentrations lower than 100 mg/kg. If these results can be extrapolated to humans, then it may be concluded that tin concentrations in the human diet, which range from 2 to 76 mg/kg dry diet, do not influence iron status in humans.

Inflammation in the lungs of patients diagnosed with Cystic Fibrosis: Association with iron deficiency

Cystic Fibrosis (CF) is characterized by a wide spectrum of phenotypic characteristics such as; deep coughing, increased mucous production, and weight loss. However, only recently was the role of inflammation on the etiology of the disease recognized. CF is characterized as a cyclic progression of infective exacerbations and stable periods initiated by the presence of Pseudomonas Aeruginosa (PA). An increase in inflammatory cytokines/mediators and a decrease in anti-inflammatory cytokines contribute to the net inflammation and overall tissue destruction of the lungs. PA is associated with the low iron status that is seen in 60-75% of the CF population, through the presence of iron sequestering siderophores which distract iron from the tissues. Iron deficiency (ID) initiates further symptoms such as; fatigue, tachycardia, weakness, brittle nails etc, in addition to those caused by CF. The colonization of PA may be the cause or a result of increased iron (ferritin) concentrations in the lungs, but independent of the original relationship, results in a decreased iron status. Iron is used by PA under hypoxic conditions such as in the fibrosis lung, as a source of energy. Studies on the relationship between CF and ID contribute a variety of possible causes although currently no direct connection has been discovered. At this stage, further studies in this area are needed. This review will primarily focus on the affects of CF on iron status in humans, and secondarily examine the effect of mediators of inflammation in respects to ID.