Salt Matters

Introduction

 The health outcomes associated with a high salt diet are generally negative, and include increased risk of cardiovascular disease risk, stroke, and kidney disease (1).  Because salt intake influences the total osmolarity of your blood, increased consumption of salt, aka sodium-chloride (NaCl), rich foods results in the body shunting more fluid to the blood, which requires various compensatory mechanisms, including increased workload on the cardiovascular system (2).  There is substantial evidence that those at risk for cardiovascular disease due to high blood pressure should reduce NaCl intake.  However, recent high impact studies have been published that demonstrate salt intake may also influence the progression of other diseases.

Salt sources in American diet (source NIH)

There has been a significant increase in the incidence and frequency of autoimmune disease in the American population over the last half-century (3).  Examples of these diseases include inflammatory bowel disease, rheumatoid arthritis, type I diabetes, multiple sclerosis, and lupus erythematosis.  In order to understand whether certain environmental factors may be responsible for the increased incidence of autoimmune disorders in the United States, researches have examined the relationship between changes in the Western diet and immune function.  Increased consumption of processed foods or “fast” foods containing copious amounts of NaCl has represented a significant dietary change over the past half-century (4), although the relationship between high NaCl intake and autoimmune disease has not been well characterized.

Cutting Edge

Recent studies published in Nature Letters have provided a solid foundation for future research focused on the relationship between NaCl intake and autoimmune immune disease.  A recently discovered immune cell, known as a T_h17 T cell, has been suggested to play a role in the etiology of numerous autoimmune and proinflammatory diseases.  T_h17 cells are known to heavily participate in chronic inflammatory diseases as well as hyperactivation of the immune system during immune responses to various pathogens such as influenza (5).  Because these cells are mediators of inflammation, they play a critical role in protecting the host from infectious agents, however, excessive activation of the immune system resulting in chronic inflammatory or hyperinflammatory responses has potentially lethal consequences to the host.

Thus under normal circumstances, T_h17 cells are tightly regulated immune cells that are present at relatively low frequencies in the body.  In has been demonstrated that T_h17 cells can be found at increased numbers during autoimmune disease, and deletion of T_h17 cells using genetic ablation reduces the severity of autoimmunity (5, 6).  These observations reinforce the notion that T_h17 cells are critical mediators of autoimmune disease.  Because our understanding of these cells is in its infancy, it is not quite understood what factors determine the production of T_h17 cells.  However, among various cytokines, the inflammatory cytokine, interleukin 23 (IL-23), has been shown to stabilize and reinforce T_h17 development (7).  

In two very timely publications, scientists show that high sodium (Na) plays a role in the development and pathogenic nature of T_h17 cells.  Studying the molecular aspects of T_h17 cell differentiation, Wu et al. show high Na concentrations induce the activation of signaling within T cells that supports development into T_h17 cells (8).  This was shown to be related to the activation of an intracellular protein known as serum glucocorticoid kinase 1 (SGK1), a salt-sensitive protein, meaning its activation is highly dependent on salt concentrations.  Activation of SGK1 in T cells results in increased sensitivity to IL-23, which as mentioned earlier supports T_h17 development.  

In the vary same issue of Nature Letters Kleinewietfeld et al. discovered culture of human T cells in media containing increasing NaCl concentrations promoted the development of T_h17 cells in a dose dependent fashion (9).  Using an “experimental” model of autoimmunity, the authors of this study fed mice that were destined to develop autoimmune encephalitis (an autoimmune disease similar to multiple sclerosis) a high salt diet and found that mice fed a high NaCl diet presented with more severe autoimmunity than mice fed a normal NaCl diet (9).  Further studies by Wu et al. found that mice fed a high salt diet alone had marked increase in the frequency of T_h17 cells in gut associated lymphoid tissues, and that mice harboring a genetic deletion of SGK1 had reduced T_h17 cell development in response to a high salt diet.  Perhaps even more important, Wu et al. present data in agreement with Kleinewietfeld et al. in that mice fed a high salt diet exhibited more severe autoimmunity than mice fed a normal salt diet and that this severe autoimmunity was SGK1 dependent.  

Conclusions

Ok, great, but what does this all mean? 

I’m sure the media will blow most of this out of proportion... (Foxnews).   Do these studies say that having a high salt intake will result in autoimmune disease?  NO. 

These are experimental models of autoimmunity, in which mice are immunized with proteins that forcefully induce autoimmunity.  However, these two studies form an attractive hypothesis supporting the role of the Western diet in immune dysfunction.  Furthermore, these data provide framework for future studies examining the direct role of NaCl intake on the incidence of autoimmunity, especially in individuals who might be genetically predisposed to developing autoimmune disease.

What can be taken away from these studies is that there is some evidence that excess salt in the diet can alter immune cell development, which has dangerous implications if one is predisposed to developing autoimmunity (such as in these mice).  The authors conclude that determining whether a “true low-salt diet, representing the conditions in which Homo sapiens were environmentally selected in Africa” has the potential to reduce risk of autoimmunity will be very difficult because of Western culture, which to me is a truly disappointing conclusion (obviously they’ve never heard of Paleo!).  Instead the authors suggest looking for pharmacological agents that block the molecular pathways described above (yay, just give people more drugs and lets continue to eat like crap!).  I think based on these studies there is real evidence that high salt diets have the potential to further exacerbate inflammatory responses which are clearly detrimental to human health.   

Works Cited

1.         Brown IJ, Tzoulaki I, Candeias V, Elliott P. Salt intakes around the world: implications for public health. Int J Epidemiol. 2009 Jun;38:791-813.

2.         Appel LJ, Frohlich ED, Hall JE, Pearson TA, Sacco RL, Seals DR, Sacks FM, Smith SC, Jr., Vafiadis DK, Van Horn LV. The importance of population-wide sodium reduction as a means to prevent cardiovascular disease and stroke: a call to action from the American Heart Association. Circulation.  Mar 15;123:1138-43.

3.        Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part II: Noninfectious factors. Ann Neurol. 2007 Jun;61:504-13.

4.         McGuire S. Institute of Medicine. 2010. Strategies to Reduce Sodium Intake in the United States. Washington, DC: The National Academies Press. Adv Nutr.  Nov;1:49-50.

5.         Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 Cells. Annu Rev Immunol. 2009;27:485-517.

6.         Lee Y, Awasthi A, Yosef N, Quintana FJ, Xiao S, Peters A, Wu C, Kleinewietfeld M, Kunder S, et al. Induction and molecular signature of pathogenic TH17 cells. Nat Immunol.  Oct;13:991-9.

7.         Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem. 2003 Jan 17;278:1910-4.

8.         Wu C, Yosef N, Thalhamer T, Zhu C, Xiao S, Kishi Y, Regev A, Kuchroo VK. Induction of pathogenic T17 cells by inducible salt-sensing kinase SGK1. Nature.  Mar 6.

9.         Kleinewietfeld M, Manzel A, Titze J, Kvakan H, Yosef N, Linker RA, Muller DN, Hafler DA. Sodium chloride drives autoimmune disease by the induction of pathogenic T17 cells. Nature.  Mar 6.

Dietary nitrate and nitrite may provide a performance boost

It is widely accepted that increased intake of the preservative sodium nitrite found in processed meats such as deli meats, bacon, and hot dogs is associated with negative health outcomes for certain subgroups of the population (1).  These associations have resulted in dietary nitrates and nitrites receiving a “bad name.”  However, scientists have been quick to point out that diets proven to be beneficial for cardiovascular health contain high amounts of fruits and vegetables, are low in sodium and contain polyphenols, potassium, fiber, and, you guessed it, nitrate! (2)  If dietary nitrates and its reduced form, nitrite, are so harmful, then why do we encourage consumption of fruits and vegetables containing these compounds?

Interestingly, dietary nitrate can reduce blood pressure through conversion to nitric oxide resulting in increased vasodilatation (3).  Thus, it stands to reason that enhanced nitrate intake contributes to the cardioprotective effect of dark green leafy vegetables, which are a particularly rich source of nitrate (2).  Evidence is emerging that consumption of dietary nitrate not only has positive effects on blood pressure, but that it also has the ability to enhance some parameters of exercise performance (3)!  I want to point out, this is independent of nitric oxide induced vasodilation.


In a recent study, subjects consuming 0.5L of beetroot juice prior to exercise exhibited a reduction in systolic blood pressure, as well as decreased oxygen consumption during walking and running (4). Indeed, beetroot juice is a rich source of dietary nitrate as well as other metabolically active compounds including antioxidants and polyphenols. In order to control for these variables, the authors of this study removed nitrate from the beetroot juice to use as a control. It became apparent that the positive effects on exercise observed in this study were due to the nitrate content of beetroot juice. Importantly, results from this study as well as others indicate dietary nitrate increased time to exhaustion in constant speed severe intensity running and cycling as well as decreasing the oxygen cost of exercise, indicating improved exercise economy (3, 5).  While the mechanisms by which dietary nitrate improves these parameters remains to be fully understood, by use of a nitrate free beetroot juice, the authors definitively show that dietary nitrate has a positive physiological response to exercise.

These studies provide a valuable dietary modification of exercise performance. By reducing the oxygen cost at moderate and severe intensity running, one is reducing the energy cost of running.  According to the authors, 4 days of dietary nitrate supplementation induced improvements equivalent to those observed following 6-9 weeks of physical training (4).  Ideally enhanced running economy translates to enhanced endurance; however this parameter was not assessed during this study.


So how do we actually apply this knowledge to our sport, you ask?  I am certainly not going to run around with beetroot juice in my bottles.  What it boils down to is that there are not a lot of nitrate/nitrite supplements available - mostly because they are associated with the generation of N-Nitrosocompounds, a carcinogen thought to increase the risk of developing colon cancer.  I think for this reason, you will not see a lot of companys (Clif, Gu, Powerbar, Hammer, etc.) pursue utilizing this interesting nutrient.  However, as Hord et al. point out, the generation of these carcinogens is highly dependent upon the presence of vitamin C and lipids (fat).  This is likely to occur during the consumption of salami for example (due to the fact it is preserved with nitrates and vitamin C and also has a high fat content) but is less likely to take place when eating lean deli meats, or during the consumption of a meal rich in dietary nitrates like can be found in spinach or beets.  Dietary nitrates are thought to have a half life of 5-8 hours in circulation, thus we can try to incorperate these into our meal the night before a race, or if we have a supplement, immediately before, and during.  This would also suggest we need a fresh bolus half way through a 24 hour endurance event.  Using reference 2 I have provided a table classifying nitrate concentrations in commonly consumed vegetables.  To me, it is interesting to think that there are some elite athletes who are known for their diets, think Scott Jurek, Dave Scott, Devon Crosby-Helms, and others who are open with their vegetable rich diets, may actually be benefiting from dietary nitrate.  After having a conversation with Dr. Norm Hord, the author of an excellent review on this subject, he pointed out that V8 (the vegetable kind, not the sugary juice) is actually based in beetroot juice and is an excellent source of nitrate.  My stomach rolls at the thought of drinking a V8 during a long run, but heck with all that salt, it might not be so bad.

TABLE 3

Classification of vegetables according to nitrate content

Nitrate content (mg/100 g)
Very low, <20	Artichoke, asparagus, broad bean, eggplant, garlic, onion, green bean, mushroom, pea, pepper, potato, summer squash, sweet potato, tomato, watermelon
Low, 20 to <50	Broccoli, carrot, cauliflower, cucumber, pumpkin, chicory
Middle, 50 to <100	Cabbage, dill, turnip, savoy cabbage
High, 100 to <250	Celeriac, Chinese cabbage, endive, fennel, kohlrabi, leek, parsley
Very high, >250	Celery, cress, chervil, lettuce, red beetroot, spinach, rocket (rucola)

Works Cited

1.    Gilchrist M, Winyard PG, Benjamin N. Dietary nitrate--good or bad? Nitric Oxide.  Feb 15;22:104-9.
2.    Hord NG, Tang Y, Bryan NS. Food sources of nitrates and nitrites: the physiologic context for potential health benefits. Am J Clin Nutr. 2009 Jul;90:1-10.
3.    Ferreira LF, Behnke BJ. A toast to health and performance! Beetroot juice lowers blood pressure and the O2 cost of exercise. J Appl Physiol.  Mar;110:585-6.
4.    Lansley KE, Winyard PG, Fulford J, Vanhatalo A, Bailey SJ, Blackwell JR, DiMenna FJ, Gilchrist M, Benjamin N, Jones AM. Dietary nitrate supplementation reduces the O2 cost of walking and running: a placebo-controlled study. J Appl Physiol.  Mar;110:591-600.
5.    Bailey SJ, Winyard P, Vanhatalo A, Blackwell JR, Dimenna FJ, Wilkerson DP, Tarr J, Benjamin N, Jones AM. Dietary nitrate supplementation reduces the O2 cost of low-intensity exercise and enhances tolerance to high-intensity exercise in humans. J Appl Physiol. 2009 Oct;107:1144-55.