Improving the Iron Status of Athletes With Pre-, Pro- and Synbiotics
Condition: Iron-deficiency; Iron Deficiency Anemia; Iron Deficiency (Without Anemia)
MeSH terms: Anemia; Anemia, Iron-Deficiency; Iron Deficiencies
Study type: Interventional

Summary: 
      Iron deficiency (ID) is the most common micronutrient deficiency worldwide, and poor iron
      bioavailability is a major cause. While 30% of female athletes are affected by ID, and its
      consequences are highly relevant to athletic performance, ID affects women and children
      around the world with consequences just as relevant, if not more so (e.g. school performance,
      work capacity and thus wage earning). With poor iron absorption being a cause of ID in active
      women, it is especially important to discover simple ways to improve iron (Fe) uptake. While
      some studies have suggested that consumption of prebiotic fiber may improve Fe absorption in
      animal models, there have been few studies examining the effects of synbiotic supplementation
      (consumption of both a prebiotic and probiotic that work together) on Fe uptake in adult
      females (athletes and non-athletes).

      A recent pilot study demonstrated a substantial improvement in Fe uptake in female athletes
      after 4 and 8 weeks of synbiotic supplementation compared to placebo during Fe repletion with
      a low dose of ferrous sulfate (FeSO4). If synbiotic supplementation can improve the Fe
      bioavailability of FeSO4 (which is ~30%) in ID women during repletion of Fe status, it could
      possibly improve the Fe bioavailability of non-heme Fe sources, as well as mixed meals.

      Research Question: What is the effect of synbiotic supplementation (a supplement containing a
      prebiotic + a probiotic), compared to prebiotic supplementation or a placebo, on Fe uptake
      and the gut microbiome in ID athletes during low-dose Fe repletion?

      Hypothesis: In the proposed study, we hypothesize that synbiotic supplementation along with
      Fe repletion with a low dose of FeSO4 will have greatest impact on athletes' Fe uptake due to
      alterations in the microbiome, which will be assessed.
    

Detailed description: 
      The following Specific Aims will help us to answer this research question: To screen the iron
      status of athletes at the beginning of training season and determine the prevalence of anemia
      and iron depletion on our NCAA Division III campus. To determine the differences in Fe uptake
      with consumption of a synbiotic, prebiotic, and placebo supplements along with low-dose Fe
      supplementation in ID athletes. To determine the differences in the microbiome with
      consumption of a synbiotic, prebiotic, and placebo supplements along with low-dose Fe
      supplementation in ID female athletes. This aim will help us mechanism behind change in iron
      status with a functional fiber (e.g. synbiotic supplementation).

      This data is essential to advance our understanding of how Fe uptake in active persons can be
      enhanced by functional fiber supplementation, as well as by REAL foods containing functional
      fibers, which could help ameliorate ID not only for athletes here in the US but for people
      around the globe.

      The design is a randomized, placebo-controlled crossover trial, which will use each
      participant as her/his own control, in addition to a placebo treatment being administered in
      a counter-balanced order with the other treatments.

      Participants: King's is a Division III College and currently has >85 eligible female athletes
      on the rosters of a variety of competitive sports teams. During a recent RCT, about 30 active
      women were screened and >30% were ID (1). For the proposed study, given the effect size
      observed in previous work (6), we need n=10 to complete the 18-week randomized crossover
      trial (e.g. so recruiting n=13 would allow for a "normal" 20% attrition rate during the trial
      due to injuries, illnesses, etc).

      Iron Status Screening: Athletes from King's will be asked to volunteer via recruitment email.
      To address Aim 1, at baseline (and after NCAA health clearance), athletes will have their
      iron status screened via venous blood sample at the beginning of their season in the Human
      Performance Lab in the Alley Center (Complete Blood Count, which includes Hgb); Serum
      ferritin; C-Reactive Protein for inflammation adjustment of ferritin). Anthropometrics and
      body composition will be measured and health, dietary and training information will also be
      collected. Standard demographic information, and medical history will be self-reported by
      each participant using computer-based questionnaires. All athletes with normal iron status
      (Hgb >12.0 g/dL AND sFer>30.0 µg/L) will be given their iron status results and offered a
      Nutrition Consultation by a MS Nutrition Student under the supervision of the PI. Athletes
      will not be eligible to participate in the study if pregnant, wishing to become pregnant,
      breastfeeding, having a condition or taking medication impacting Fe status, or not healthy
      enough to train/participate in their sport.

      Crossover Trial: To address Aims 2 and 3, women athletes identified as ID (sFer<30.0 µg/L)
      will be invited to participate in a 18-week double-blind, randomized, crossover trial with
      concurrent daily Fe supplementation (100 mg FeSO4/d, Puritan's Pride). Participating ID
      athletes will receive the following treatments for 4 weeks each, in a randomized,
      counter-balanced order: a) synbiotic supplement (RegularGirl), b) prebiotic supplement
      (SunFiber), and c) placebo (maltodextrin). There will be a 3-week wash-out period between
      treatments (see Figure 1). In our pilot study, we observed a strong response within a 4-week
      time period.

      Volunteers will be asked to mix the supplemental functional fiber source (or placebo) packet,
      all identically packaged and only visible as white powder, with any food or beverage once
      daily. They will also asked to consume 100 mg FeSO4 per day as a single low-dose Fe tablet
      once per day, either in the morning or in the evening, avoiding consumption with coffee/tea
      or supplemental calcium source. Throughout the 18-week study, athletes will be asked to
      complete a daily training, medication, compliance, stool (using the Bristol Stool Scale, BSS)
      and GI symptom log. Compliance will also be measured by research staff via weekly pill and
      packet counts.

      Iron status (as described in Screening above) and dietary intake (via 24-h recall and FFQ)
      will be measured at the beginning and end of each treatment point of the trial (see "X" in
      Figure 1). Fecal samples will be collected at beginning and end of each timepoint for
      analysis of the microbiome (see "X" in Figure 1) using self-collection vials provided
      (OMNIgene-GUT, OMG-200, DNA GenoTek). Volunteers will not be asked to alter their usual food/
      dietary intake in any way during the trial. At the end of the study, athletes will be given
      their endpoint lab results and offered a Nutrition Consultation by a MS Nutrition Student
      under the supervision of the PI.

      Iron status (as described in Screening above) and dietary intake (via 24-h recall and FFQ)
      will be measured at the beginning and end of each treatment point of the trial (see "X" in
      Figure 1). Fecal samples will be collected at beginning and end of each timepoint for
      analysis of the microbiome (see "X" in Figure 1) using self-collection vials provided
      (OMNIgene-GUT, OMG-200, DNA GenoTek). Volunteers will not be asked to alter their usual food/
      dietary intake in any way during the trial. At the end of the study, athletes will be given
      their endpoint lab results and offered a Nutrition Consultation by a MS Nutrition Student
      under the supervision of the PI.

      Time and effort: 15.5 hours over the 18 week study Blood sampling and body measurements will
      take about 15 min, 6x during the trial (1.5 h total) Completion of forms will take about 15
      min 6 x during the trial (1.5 h total) Stool collection will take about 5 min, 6 times during
      trial (0.5 h total) Meeting at the Alley Center Human Performance Lab weekly will take ~ 5
      min, 18x over the course of the study (1.5 h total) Consumption of iron supplement and packet
      every day and daily record-keeping will take <5 min/day * 126 days during 18 week study
      (<10.5 h total)

      Data analysis plan: All analyses of sFer will be adjusted for inflammation. Briefly, GLM
      Repeated measures ANOVA will be used to assess the effect of the treatments on iron status,
      GI symptoms, etc. (Time-by-Tx effects will be examined). All statistical analyses will be
      performed using SPSS (most recent version), and results will be considered statistically
      significant at p<0.05 for main effects.
    

Intervention name(s): Partially hydrolyzed guar gum + bifidobacterium lactis; Partially hydrolyzed guar gum; Maltodextrin
Intervention type(s): Dietary Supplement; Dietary Supplement; Dietary Supplement
Intervention description(s): Synbiotic Supplement: Contains 5 grams of prebiotic fiber (Sunfiber®) and 8 billion active probiotics (Bifidobacterium lactis).; 5 g Partially hydrolyzed guar gum; 5 g Maltodextrin
Other intervention name(s): RegularGirl; SunFiber
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: This is a double-blind, randomized, placebo-controlled crossover trial.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment