ATD 5: New Findings on Post-Race Oxidative Stress, What are ‘Lipopolysaccharides’ and Why You Should Care, Iron-Deficiency Anemia, and More

August 25, 2016
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We are back with Dr. Tommy Wood for another edition of Ask the Doc. Three major areas covered in this episode:

Monitoring of the oxidation reduction potential or redox status of ultra runners post-race

  • Discussion on oxidative stress focusing on this new study: “Variations In Oxidative Stress Levels In Three Days Follow-Up In Ultra-Marathon Mountain Race Athletes
  • ROS generation during strenuous exercise:
    • Activated neutrophils
    • Xanthine oxidase
      • Hypoxanthine (high ATP turnover and degradation) produced by exercising muscle. Converted to xanthine and urine acid by XO using oxygen w/superoxide as a byproduct
      • Allopurinol before TdF time trial resulted in lower levels of AST, CK, and lipid oxidation (malondialdehyde) compared to placebo
    • NADPH oxidase
    • Mitochondria – some
  • After (ultra)marathons, increases in:
    • CK, IL-6, CRP, 8-OH-2dG, cardiac troponin, ferritin, GSH
  • In this study: 12 males sampled at the Olympic Mythical Trail 103km ultra, in effort to find a better understanding of the adaptive mechanisms against oxidative stress induced by athletic events, overall to help improve recovery, health and performance.
    • 24, 48, 72h post-race (8/12 males finished)
    • Lower glutathione (GSH) in red blood cells for 72hr afterwards
    • RedoxSYS Diagnostic System
      • Increased static oxidation reduction potential (sORP)
      • Decreased capacity oxidation reduction potential (cORP)
      • More oxidants (oxidized thiols, superoxide radical, hydroxyl radical, hydrogen peroxide, nitric oxide, peroxynitrite and transition metal ions
      • Fewer antioxidants (vitamin C, vitamin E, β-carotene and uric acid)
  • In the average person, antioxidant supplementation (vitamins C, E, ALA etc) decrease training response (less hormetic stress)
  • During repetitive or exhaustive exercise (sprints ie bleep test), NAC supplementation -> increased GSH and slower fatigue
  • Overall the data on anti-oxidants and performance is VERY conflicting
    • Depends on dose of drug, dose of exercise, and how trained the person is
    • Supplement or take NAC (or allopurinol?) during long or multi-day races
    • Minimize during training or high stress periods (travel etc)
      • If doing so much you need antioxidants over a long period of time, are you doing too much?
      • Fix other issues?
  • Increased intensity of exercise -> gut permeability and LPS translocation
    • Inflammation long-term -> cardiac damage and AF and arrhythmias?
  • Study of non-trainers vs moderate vs heavy trainers
    • Moderate groups had highest glutathione

What the heck are lipopolysaccharides (LPS) and why should we care?

  • Bulletproof Radio mention
  • LPS produced by Gram -ve bacteria
    • Absorbed either through a leaky gut
    • OR bound onto proteins in blood lipid fractions
    • Gets into chylomicrons after a fat-heavy meal
  • Causes increased cortisol levels, inflammation, increased cholesterol
    • Inflammation and mood or brain fog
    • Depression
  • U-shaped curve of LDL and mortality
    • LDL (chylomicrons, HDL as well) bind to LPS
    • Chronic increases and inflammation -> increased LDL (protective)
      • Indicates low-level endotoxinaemia
    • Acute or more severe inflammation:
      • Decreased liver synthetic capacity
      • Lipoprotein production drops
      • LDL drops
      • Lipids can’t leave liver -> fatty liver
      • Those with sepsis who get a drop in HDL and LDL are more likely to die (survivors increase cholesterol production)
    • Decreased LDL -> increased death rate from infections
    • Giving human blood lipids to mice exposed to toxic levels of endotoxin reduces mortality
  • Some people think that it ALL comes back to endotoxins
    • Increased LDL
      • Not causative necessarily
      • Chronic inflammation
    • Some bacteria (Strep mutans also inactivated by chylomicrons) incl. Klebsiella are associated with atherosclerotic plaques
    • Circulating endotoxins are higher in those with T2DM and CVD regardless of other factors (BMI, blood lipids, blood glucose etc)
    • T2DM people get increased endotoxin release after a “high fat meal”
      • Higher baseline values in obese and impaired glucose tolerant
      • Suggests increased gut permeability already (more LPS can get in)
    • Short-term insulin peaks can be anti-inflammatory to combat the effect of endotoxinaemia
      • So hyperinsulinaemia might be a protective response to endotoxins
      • Then causes issues with growth and intimal thickening/hypoxia -> greater lipid deposition
    • White adipose tissue inflammation means fat IR therefore fat is no longer a useful defence mechanism against extra calories?
    • Corn oil/PUFA lowers LDL by dramatically increasing endotoxinaemia?
  • Introducing fat bombs on top of a bad gut
    • More LPS -> more IR -> greater need to restrict carbs in a feed-forward manner
  • What about a high-fat diet causing an increase in cholesterol? Is this ok, and what you need to know about cholesterol and fat in the diet.
  • Western diet
    • Acellular carbohydrates promote a more inflammatory gut microbiota
    • Gut inflammation not just LPS-associated
      • Mice infected with E. coli with less inflammatory LPS still get IR and leptin resistance
    • Gluten etc increase gut permeability
    • Large amounts of fat increase translocation of LPS across gut
  • Ricardo Carvalho aka O Primitivo
    • WHO death from various causes vs total cholesterol
    • Lowest all-cause mortality at 200-240
    • Lower cholesterol -> increased mortality from infectious diseases

Iron-Deficiency Anemia

  • Female athlete hoping for some insight regarding iron deficiency anemia
  • Mechanisms involved in the etiology of iron deficiency anemia beyond insufficient iron intake, such as iron absorption and transport.
  • Other solutions instead of “eat more red meat”? Something else going on downstream?
  • Adverse GI outcomes associated with iron supplementation.
  • Studies show reduced iron bioavailability in vegetarian diet despite similar iron intakes.
  • Get iron from haem-iron i.e. animal based foods for better absorption and consume with fruits and veggies to enhance absorption further (vitamin C).
    • Proferrin is a haem iron
  • What to avoid having when you’re eating iron rich foods (i.e. caffeine, etc)?
    • Grains, nuts, seeds (phytates)
      • If celiac, best to just remove all grains
    • Coffee/tea/red wine – polyphenols and tannins
      • BUT moderate alcohol can increase uptake (beer the most?)
    • Dairy products (calcium)
    • Other metals (from supplements)
  • Do non-weight-bearing cross-training?
  • Most iron “intake” comes from recycling of old RBCs and iron stored in macrophages in the liver and spleen
    • 1-2mg/day vs 22mg/day
    • Need 20-25mg/day
      • Women need ~1mg/day more
    • 70% of body iron is in Hb
  • High prevalence of iron deficiency +/- anaemia in athletes (>50% in some studies)
    • Higher sTfR (not an acute phase protein) – TIBC
    • Lower ferritin (<20)
  • An athlete’s iron stores are compromised via several well-established exercise-related mechanisms:
    • Haemolysis, haematuria, sweating, and GI bleeding
      • Check for FOB 
      • Menstruation in females
      • “Regular weight-bearing exercise of moderate to high intensity can increase iron losses by 30% to 70%”
      • Iron lost in sweat decreases with heat acclimation
      • Under intensive training, 5-7ml (doubled) blood loss in the gut per day
        • Lose ~0.5mg/ml of iron
  • Exercise duration and intensity are negatively associated with Hb, Hct, and serum ferritin concentrations in highly-trained athletes
    • Replacing iron in iron deficient women leads to improved speed, reduced HR, and reduced lactate in a treadmill test
  • Exercise-induced hepcidin regulation
    • Serum iron and inflammation (esp. IL-6) increase after exercise (>70% VO2Max)
      • Direct impact (runners), inflammation (IL-6) and ROS can induce haemolysis to increase serum iron during/after exercise
      • Seen in swimming, cycling, rowing, weight training
      • More IL-6 when glycogen is depleted and in hot environments
    • Results in increased hepcidin production in the liver
      • Variable response – responders vs non-responders?
        • Marathon runners 24-72h after race.
        • Non-responders had higher baseline levels
        • May have sampled too late
      • Can rapidly reduce serum iron and Hb production
        • Decreased ferroportin on brush border of duodenal gut cells (enterocytes) -> decreased iron absorption
        • Sequestration of iron into macrophages
        • Reduced iron recycling
      • Smaller hepcidin response in the iron deficient
    • In matched intensity/volume cycling vs running, running seems to cause a greater increase in hepcidin
  • Most studies include single periods of exercise or races, rather than an accumulated effect over time.
    • 9 weeks of military combat training in females leads to decreases in iron status, with decreases associated with worse performance
      • Ferritin decreased
      • RDW increased
      • sTfR increased
      • Of 94 women, 7->17 became iron deficient
      • 1-1.5h of high-intensity exercise 4-6d/week (16,000 steps)
      • Combated with a high-iron supplement bar?
    • 8 Weeks of interval and fartlek training in women
      • Increased sTfR
      • Decrease in Hb and RBCs
      • Decrease in hepcidin (smaller responses due to deficiencies?)
    • More long-term studies done in females
  • Experimentally, injecting LPS -> IL-6 (and CRP) -> hepcidin peak 3h later
    • Almost identical to that seen after high-intensity exercise
  • People at risk of lower iron stores:
    • Infections esp. H. pylori – blood loss
    • Other gut infections
      • Part of the job of hepcidin is to drive the sequestration of iron to prevent iron being available to pathogens
      • Also used to generate ROS to kill pathogens
      • When iron is scarce, certain bugs upregulate iron sequesters (siderophores)
      • E. coli, Klebsiella, proteus, citrobacter, enterobacter (Gram -ves)
      • Enterochelin – highest affinity of any siderophore
      • Candida – transferrin
    • NSAIDs
    • Vegetarian or vegan diets? Especially females
    • Heavy menstrual bleeding or IUD
    • Genetics
      • 80% of French Olympic champions have some kind of HFE mutation
        • 12 tested
        • More likely in aerobic or fight sports
        • Not necessarily associated with increased Hb
        • May reduce exercise-induced hepcidin increases
        • Maintain a higher serum iron
        • Improved recovery and cardiac function
    • Hypothyroid (thyroid meds?)
      • In one person, changes in thyroid status result in changes in ferritin
  • Iron and bugs
    • All bacteria (except, most commonly, Lactobacilli) need iron
    • Old blood in transfusions increases risk of bacteraemia
      • Free iron from haemolysed blood supports bacterial growth
    • Iron deficiency protects against malaria
    • In theory iron supplementation will promote bacterial growth BUT
      • If iron deficient, need to figure out the cause
      • Restricting iron isn’t going to fix an infection or improve iron status

One Comment

  • Tony Johnson says:

    Wowser, some heavy stuff in that one.. So for the insulin resistant among us what do we eat? Can’t eat carbs, sugar spikes and can’t eat fat due lps, leaky gut and endotoxins, this isn’t looking good for me.. IR due to my family history and job (longhaul pilot with multiple monthly nights out of bed). Help!


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