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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
Treatment
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.
Correspondence:
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ghuber@huberpm.com
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Notes
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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.
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