Endotoxin: Poisoning from the Inside Out
Ray Peat, PhD on Endotoxin
Exercise Induced Stress
Stress — A Shifting of Resources
Exercise and Endotoxemia
Carbohydrate Lowers Exercise Induced Stress
Low carb + intensive training = fall in testosterone levels
Exercise and Effect on Thyroid Hormone
Exercise Induced Menstrual Disorders
Ray Peat, PhD: Quotes Relating to Exercise
Ray Peat, PhD and Concentric Exercise
Potential Adverse Cardiovascular Effects from Excessive Endurance Exercise
Running on Empty
How does estrogen enhance endotoxin toxicity? Let me count the ways.
Bowel Toxins Accelerate Aging
Ray Peat, PhD on the Benefits of the Raw Carrot
Protection from Endotoxin
Protective Bamboo Shoots
The effect of raw carrot on serum lipids and colon function
Are Happy Gut Bacteria Key to Weight Loss?
(I personally don’t agree with the treatment options listed, but the actions of LPS during stress and exercise are valid and worthy of your time especially considering the exercise world’s complete ignorance of the topic. -FPS)
by Gary Huber, DO, AOBEM
The endurance athlete is viewed as a model of aerobic efficiency, possessing tremendous cardiovascular health. Certainly we can agree that exercise induces a great number of benefits to our physiology and greatly improves the quality of life, but evidence exists that excessive exercise can cause cardiovascular damage. The heavy endurance athletes such as triathletes, marathon runners, and cyclists spend hours upon hours in a state of physiologic stress. Was the human body truly built to withstand this repetitive high oxidative stress exposure? There is literature to suggest that for some, the damage caused by ischemia to the bowel and the resultant endotoxemia leads to vascular and myocardial damage that in fact increases the risk for arrhythmic and atherosclerotic change. This article is written by an endurance sport enthusiast, so it is not intended to derail such activities but rather to explore this issue of lipopolysaccharides (LPS) and the cardiac damage that occurs so that we can ascertain the true risk involved and explore options for avoidance.
In a US population of more than 300 million people, 350,000 sudden cardiac deaths, or 111 events per 100,000 people, occur annually. Within this population, we understand that risk is secondary to lifestyle, age, and a host of other factors such as the building inflammation that often accompanies poor lifestyle and dietary decisions. But in a youthful age group who is exercising, we don’t expect sudden cardiac deaths. We have all heard tragic stories of the young athlete who dies on the field only to discover that he had an undiagnosed valvular or vascular defect. But there are a significant number of cases in which no identifiable anatomical defect can be found, yet the cause of death is listed as cardiac in nature. In a well-known study by Harmon published in 2011 in the journal Circulation, they reported a sudden cardiac death rate of NCAA athletes of 1 per 44,000 annually, or roughly 2.3/100,000.1 This might seem high, given that we are speaking of young athletes; but a look at CDC population-based data shows that cardiac-related death in the general population aged 15 to 24 is 2.5 per 100,000 people.2-5
One of the problems with the Harmon study is that the researchers did not document autopsy findings, and we are left to guess at the actual cause of cardiac death. This problem appears to be related to increased intensity of training, as the death rate is increased 2-fold from high school athletes to those on college teams.6,7
A 25-year review of autopsies in military recruits by Eckart showed a higher than expected rate of nontraumatic death at 13 per 100,000 recruits per year.8 86% of these deaths were related to exercise. Of those determined to be cardiac in origin, 61% were secondary to coronary artery pathology. The surprising finding is that despite autopsy, 35% of deaths determined to be nontraumatic sudden death were idiopathic. Another 20% of the cardiac deaths were diagnosed as myocarditis. Is it possible that the physical demand of these recruits played a role in the idiopathic and myocarditis deaths? That is an issue worth exploring through the lens of endotoxemia.
It has been demonstrated that LPS from gram-negative bacteria adversely affects cardiomyocytes, leading to apoptotic cell death.9-12 It is this apoptotic cell death that directly contributes to other forms of heart failures such as myocarditis, congestive heart disease, diabetic cardiomyopathy, chronic pressure overload, and ischemia-reperfusion injury.13-21 So as we view the myocarditis, arrhythmic, and other cardiovascular deaths in athletes, we have to ask, is it possible that the very activities which we love – our endurance sports – are acting as the nidus for LPS toxicity that is poisoning our hearts?
Defining the Problem
Engaging in prolonged endurance training or endurance events creates multiple physiologic stressors to alter our physiology. Blood flow must be redirected from central gut and liver to the peripheral muscle mass as well as the skin to facilitate heat release. This leads to a relative bowel ischemia as the splanchnic blood flow is reduced by 80%.22-24 Further exacerbating this ischemia is the simple volume loss due to sweat, the mechanical damage from the microtrauma of running, as well as thermal insult from rising body temperatures that all combine to worsen the mucosal damage occurring in the gut lining.25,26 This shock-induced damage results in loss of intestinal wall integrity and death to gram-negative organisms. The cell walls of gram-negative bacteria are composed of LPS, also known as endotoxins. LPS comprise 75% of the cell walls of gram-negative bacteria, and a single gram-negative bacterial cell wall can release 1 million LPS molecules into circulation.27,28
Excessive release of LPS secondary to bowel ischemia and loss of barrier effect can overwhelm the portal circulation and the Kupffer cells’ ability to neutralize them, resulting in entry to the general circulation where they cause significant adverse symptoms. The intestinal permeability induced by these sporting activities is thought to explain the high rate of occurrence of GI complaints such as diarrhea, cramps, and vomiting.29-31 The occurrence of GI issues has been reported to range from 30% to 93% of all endurance athletes and represents a common problem that is often unrecognized as a serious sign of endotoxemia. Recall that LPS endotoxemia is the process of sepsis, so other sepsislike symptoms may emerge, including fever, shivering, headache, and muscle ache.32-38
Endurance training clearly taxes liver function, as demonstrated by the Moncada-Jimènez study wherein endurance athletes completing a duathlon demonstrated endotoxemia in 50% of participants.39 Beyond that, all participants showed an increase in both AST and ALT level after their event. This reflects that during periods of endurance training, the reduction in splanchnic blood flow leading to bacterial death and translocation across the intestinal wall enter the portal circulation to reach the liver and induce the acute phase response. This same finding has been demonstrated in all types of endurance sport athletes, including cyclists, marathoners, and others.40-42
Sepsis represents our best understanding of endotoxins. Patients with sepsis experience fever, dizziness, GI complaints, shivering, and cardiovascular collapse secondary to the LPS presence in the bloodstream. I would contend that if you have ever watched someone finish a marathon, the temperature regulation issues, the gut effects, the shivering, and other symptoms that occur are just a milder version of sepsis. The mechanism is the same, and unfortunately the cardiovascular risk is a part of this picture. Yes, endurance athletes are jeopardizing their heart health and potentially causing heart damage every time they train and compete. Their cardiovascular efficiency may be enhanced, but the LPS release is causing myocyte damage.
LPS can cause direct stimulation of cytokines, including TNF-alpha, which leads to severe problems; but low levels of LPS can cause damaging effects without the stimulation of cytokines. There is a multilevel response potential such that low levels of circulating LPS can cause cardiac apoptosis without stimulating excess cytokine response. It has a direct toxicity beyond its cytokine effect by directly engaging the myocyte via the toll-like receptor-4 (TLR-4).43 Low levels in the nanogram-per-milliliter range can alter myocyte function.44,45
LPS can stimulate cardiac myocytes to release TNF-alpha and nitric oxide to induce apoptosis via an autocrine manner, but this level of damage occurs in the microgram/ml range. LPS at low levels does not rely on NO or TNF-alpha to cause apoptosis.46-49
So LPS exposure, whether high dose in micrograms or low dose in nanograms, has multiple mechanisms of action to induce cardiac damage. LPS in low doses (10 ng/ml) decreased the ratio of the antiapoptotic protein Bcl-2 relative to the proapoptotic protein Bax, thus influencing apoptosis. The Li study showed that in vivo use of LPS in low dose caused a 2-fold increase in apoptosis that was blocked by the use of losartan.50 The ability of LPS to independently induce apoptosis outside cytokine contribution is via stimulation of cardiac AT1 receptors. Angiotensin II induces caspase-3 enzymes which trigger apoptosis.51,52 A single low dose of LPS that caused no appreciable distress and no adverse impact on blood pressure was sufficient to increase cardiac apoptosis. Low levels of LPS have been shown to be clinically relevant in multiple disease processes without causing overt distress or blood pressure changes.53-55
In the Jeukendrup study, 29 triathletes were followed with blood test before and after an Ironman distance triathlon, and a full 93% reported GI issues; 68% had endotoxemia defined as LPS levels >5 pg/ml.56 Other measures of note were IL-6 levels elevated 27-fold and CRP increased 20-fold. Interestingly, this study followed these athletes with blood measures 16 hours after the race and found that the rate of endotoxemia had increased from 68% to 79% at the 16-hour mark, demonstrating the extended effect of such physical efforts. The prealbumin level was reduced by 12%, consistent with acute phase reactions wherein the body directs efforts in making CRP and fibrinogen at the expense of making albumin and prealbumin. This is expected in the face of high CRP which was documented. In another extreme endurance event, Brocke-Utne demonstrated an endotoxemia occurrence rate of 81%.57
A Look at the Cellular Mechanism of Endotoxemia
LPS in the circulation binds LBP (lipopolysaccharide binding protein) to form a complex LPS-LBP which binds to the cell membrane of Kupffer cells, reacting with the TLR-4 receptor and triggering the activation and translocation of NF-kB.58,59 So both the endotoxin and the oxidative stress of intense sporting activity induce production of NF-kB, thus upregulating pro-inflammatory cytokines.
LPS release causes activation of the coagulation and the complement cascade.
The pathway for this activity is through the toll-like receptor 4 (TLR-4). Cardiac myocytes express TLR-4 receptors and are susceptible to direct damage by LPS exposure.44,45,60,61
LPS stimulation of TLR-4 receptors causes depression of the myocyte contractility; they impair beta-adrenergic reactivity, and induce apoptosis through the cardiac renin-angiotensin system and the angiotensin type 1 receptors. This stimulation can lead to cardiac fibrosis.9-12, 62-66
In studies by Lew et al. in 2013, researchers exposed mice to low levels of LPS that caused no discernible clinical adverse events and yet with chronic exposure demonstrated development of fibrosis and increased mortality.66 Lew et al. found that the use of losartan, which had previously been shown effective in Li’s study, had no effect in their mouse model.
Mechanisms for LPS exposure include67-70:
1. sports, endurance activity, strenuous exercise
2. high-fat meals
3. periodontal disease
4. chronic type 2 diabetes
6. chronic infections, URIs, etc.
7. metabolic syndrome
9. heart failure
These can cause levels of LPS in the picogram to nanogram/ml range.71
Chronic recurrent exposure of LPS by athletes can be compared to the low chronic levels of exposure seen with people with periodontal disease, smokers, chronic infections, or chronic heart failure.72 These low levels of LPS are seen in humans with chronic heart failure, suggesting a slow destructive apoptotic occurrence.
This is eerie with relation to the NCAA athletes or the military recruit studies. In Lew’s study, the mice received low doses of LPS on a weekly basis, showing mild transient effects that resolved within hours. Sounds like symptoms associated with doing a hard interval workout or a long training ride. The LPS-treated mice appeared normal, with good activity and normal hemodynamic measures, including normal LV size and function, but then over time demonstrated an increased mortality with unexpected deaths. This sounds like endurance training with weekly doses of hard efforts that release LPS, causing transient symptoms and low-IgG anti-LPS levels, while causing cardiac fibrosis and apoptosis, resulting in an increased risk for sudden cardiac death which has been documented.
Short-term benefits may be seen with our innate immune response to transient inflammation. Mann’s experiments, which employed a short-term preload with LPS, demonstrated a protective effect, similar to the concept of hormesis.73 But he went on to report that the chronic nature of the inflammatory process of repeated LPS exposure is damaging, leading to atherosclerosis. The recurrent activation of TLR-4 is damaging to cardiovascular health and produces fibrosis of the myocyte.
LPS is involved in plaque rupture and vascular signaling. TLR-4 is upregulated and concentrated in the shoulder region of plaque, which is where rupture most commonly occurs. There is a clear association between bacterial infection and, in the case of our endurance athletes, chronic bacterial LPS exposure and the development of atherosclerosis. TLR-4-induced inflammation has been linked to plaque instability, and potential for acute coronary syndrome.73
The review by Venardos discusses the importance of myocardial antioxidant enzyme systems such as the glutathione peroxidase (GPX) and the thioredoxin reductase (TxnRed) system and their important role against oxidative stress and recovery in cardiac tissue.20 The GPX and TxnRed are both selenocysteine-dependent enzymes. The sweat losses of all minerals, not the least of which are selenium, iodine, and magnesium, play a role in elevating risk; and their absence reduces myocytes’ ability to withstand oxidative challenges.
Defining Endotoxemia in Various Reports
Endotoxemia is defined as an LPS level greater than 5 pg/ml. In reviewing this literature, various definitions have been employed as well as various tests and reagents to identify it; and as such, several factors need to be taken into consideration. Depending on the reagent used and whether methods to remove LPS inhibitory substances are used, the level can vary widely. For example some reagents used to measure LPS are also sensitive to B-glucan from fungi, so use of this type of test will yield higher levels of LPS being reported. These are the factors that create confusion when comparing studies but the evidence is still greatly significant in well-controlled studies using proper reagents that LPS is real and problematic.
Chronic effect of LPS exposure
Anti-LPS antibodies are produced by the body to bind LPS when present. These levels are lower in endurance athletes both before and after endurance events and thought to represent the chronic low levels of LPS occurring in these athletes from regular training resulting in “drainage” of adequate levels of IgG anti-LPS.74,75
There is chronic leakage of LPS secondary to long-term mucosal damage and recurrent efforts leading to low IgG anti-LPS and thus the suspicion of chronic cardiac exposure to LPS and myocyte damage. The fact that TNF-alpha may not be detected in the blood is not a surprise, as TNF-alpha has a very short half-life, and even in patients with documented sepsis, the presence of TNF is typically only found in 4% to 54% of patients.76
We know that endurance athletes struggle with frequent upper respiratory tract infections (URI) secondary to the immune suppressive effect of their sport.77 Immune suppression after extreme efforts has been documented to last for 3 to 72 hours post exertion.78 The stress incurred by the HPA axis and all of the resultant immune and cytokine reactions result in a decline in the IgA levels, leaving the gut unprotected and vulnerable to barrier defects.78 The simple application of vitamin C has been shown to reduce URI frequency post endurance events.79
As stated in the opening of this article, the goal is not to condemn endurance sports but rather understand the potential risk of damage of such activity and proceed in a manner that not only ensures greater health but likely improves athletic performance as well. There are several well-studied approaches that offer promise as well as safety in their application.
Resveratrol suppresses endotoxin-induced production of pro-inflammatory cytokines and activates the Nrf2 antioxidant defense pathway in vivo. Classic elevation in creatine kinase (CK) and lactate dehydrogenase (LDH) is seen with cardiac damage secondary to exposure to LPS. Hao, employing an in vivo mouse study, demonstrated that pretreatment with resveratrol significantly reduced LPS-induced elevation in CK and LDH.80 Echocardiogram demonstrated a preservation of ejection fraction that had previously been reduced in the face of LPS administration. These investigators further pursued this topic by culturing human cells in LPS with resveratrol and demonstrated a significant reduction in apoptosis and necrosis in the resveratrol cultured cells.
Vitamin C reduces bacterial overgrowth, and endotoxemia, and reduces the intestinal barrier defect. Vitamin C in doses of just 1000 mg prior to a significant training effort has been shown to be effective in producing a protective antioxidant effect, maintains the gut barrier effect, and reduces LPS leakage into the circulation.81
Patients with IBD, a common condition found in endurance athletes, show significantly reduced levels of vitamin C in mucosal tissue compared with non-IBD controls.82 The study by Abhilash showed that vitamin C improved the integrity of mucosal tissue, reduced damage from LPS, protecting the liver and reducing fibrosis secondary to oxidative insult.83
Lactobacillus plantarum produces lipoteichoic acid (LTA), which has been shown to reduce LPS-induced TNF-alpha expression and downregulate the TLR-4 activity.84,85 The goal with this type of treatment is to produce tolerance against the effects of LPS. Reducing the acute LPS effect may translate into reduction of the cumulative cardiovascular damage long term.
Curcumin has been employed for a multitude of benefits related to reduction in inflammation. Its use in the treatment of inflammatory bowel disease and inhibition of ulcer formation has been well studied and documented. Constituents of curcumin have a protective effect and inhibit intestinal spasm while increasing gastrin, secretin, bicarbonate, pancreatic enzyme, and mucous secretion.86
Turmeric’s anti-inflammatory activity may lead to improvement in obesity and obesity-related diseases such as heart disease and diabetes. Curcumin interacts with hepatic stellate cells and macrophages, wherein it suppresses several cellular proteins such as transcription factor NF-kB and STAT-3, and activates Nrf2 cell signaling pathway.87
In a 2009 study, curcumin was used to block the muscle-wasting effects of LPS.88 There was a dose dependent reduction in muscle loss in mice injected with LPS. Curcumin inhibited p38 kinase activity (involved in stress-induced apoptosis) in LPS-affected muscle.89 Knowing the muscle-wasting effects of endurance sports in conjunction with the known release of LPS, curcumin would seem a safe and natural approach for reduction of oxidative stress and preservation of bowel function and integrity.
One last variable needs consideration in this topic. Chagnon cited evidence in 2005 of a cardiac-derived myocardial depressant factor known as macrophage migration inhibitory factor (MIF).12 It appears that MIF is a critical piece to the mechanism of cardiac damage from LPS, yet its exact mechanism remains unclear. MIF is released from myocardium in response to LPS and acts as an inflammatory mediator, disrupting immune homeostasis. In a mouse study wherein investigators employed an anti-MIF antibody they were able to demonstrate a complete blockade of the LPS effect on myocytes. The blockade of MIF resulted in an increase in Bcl2/Bax ratio (an antiapoptotic result), inhibiting the release of mitochondrial cytochrome c, which in turn prevents caspase 3 activation (another antiapoptotic effect) and reduces DNA fragmentation.
Given that MIF is in fact an inflammatory mediator in immune homeostasis, it is quite possible that the multidimensional impact of resveratrol, vitamin C, and curcumin is having a direct effect on MIF. Given that these botanicals and nutrients have multiple mechanisms of action, including effects on mitochondrial function, PGC-1a, cyclooxygenase enzymes, NF-kB, and cytokine production, including TNF-alpha, their combined impact may indeed block cardiovascular damage.
A controlled study to assess the combined impact of these protective elements on endurance athletes will likely never be done; but given the information discussed here, I think that it is more than prudent to share this approach with all endurance athletes, as it represents the potential for reducing sudden cardiac events and promoting greater health overall.
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Dr. Gary Huber is president of the LaValle metabolic institute. He spent 20 years as an emergency medicine physician before joining Jim LaValle in the practice of integrative medicine at LMI. Dr. Huber is an adjunct professor teaching integrative medicine practice at the University of Cincinnati College of Pharmacy as well as a clinical preceptor for pharmacy students. Dr. Huber also lectures on hormone replacement therapies and integrative care for the American Academy of Anti-Aging Medicine for the University of South Florida. He has developed the Metabolic Code Professional Weight Loss Program that has proved very beneficial in reversing metabolic syndrome issues. Dr. Huber has a long-held interest in nutrition and human physiology as it relates to wellness and longevity. He has served as medical director for the Flying Pig Marathon and is presently on the board of directors for Loveland’s Amazing Race, a local charity event.