Lipid Replacement Therapy®, Fatigue and Dysbiosis – the Mitochondrial and Immune Connection
On the front line of primary care the two most common complaints are fatigue and gastrointestinal problems. Fatigue is the most common; up to 45% of consultations mention fatigue as the major complaint., If unresolved, it can progress to the point that it causes disability comparable to that found in chronic medical patients., Most people suffering from fatigue do not initially seek primary care intervention but self-treat with stimulants such as caffeine, herbs, tonics and sugars. Although these can provide short-term increases in energy and perception of reduced fatigue, they have potential long-term adverse health effects. ,
Common disorders of the gastrointestinal (GI) tract account for about 50 million visits per year to physicians trained in traditional allopathic or osteopathic medicine. This amounts to 30% to 50% of all people with persistent abdominal symptoms who seek help once their own experimentation with food selection and over the counter medications has been exhausted. Just as with patients complaining of fatigue, it is a loss of quality of life that most frustrates them. , Their symptoms might be an expression of a physical illness (e.g., Crohn’s disease), a mental illness (e.g., panic disorder), and/or a functional disorder. About half of all adults who consult a primary care physician or gastroenterologist because of chronic abdominal discomfort for more than three months are ultimately diagnosed as having a functional bowel disorder. Loss of health-supporting GI bacterial symbiosis, a state known as dysbiosis, represents a primary trigger in both functional and pathological disorders of the digestive tract. Studies have demonstrated that intestinal dysbiosis, characterized mainly by altered bacterial composition and loss of diversity, is strongly associated with the development of gut dysfunction. We will explain the molecular connection between fatigue and dysbiosis that pivots around mitochondrial health and discuss current evidence for membrane related treatments using lipid replacement therapy (LRT®).
The integrity of mitochondrial membranes is critical to cell function and energy metabolism. This membrane is the frontier between cell survival and death.
Overview of Fatigue
Just as many roads lead to Rome, many conditions lead to fatigue. But at the core is mitochondrial dysfunction. The mitochondria are the energy powerhouses of our cells. And the mitochondria cannot function, or cannot generate energy through electron transport, without healthy and intact membranes. The integrity of mitochondrial membranes is critical to cell function and energy metabolism.
Fatigue begins and ends with the mitochondrial membrane. Guido Kroemer, M.D., Ph.D., a French scientist known for his groundbreaking work on the mitochondrial membrane, has called this membrane the “battleground on which opposing signals combat to seal the cell’s fate…the frontier between survival and death.” His discovery that mitochondria control cell death was considered revolutionary, and it has shaped much subsequent research.
In healthy cells, the inner mitochondrial membrane where the electron transport system is located is nearly impermeable, and this is important in establishing inner membrane trans-membrane chemical/electrical potential essential for oxidative phosphorylation. When a cell begins to die, it is in large part due to disrupted, damaged, increasingly permeable mitochondrial membranes. Permeability of the mitochondrial membranes constitutes a point-of-no-return in programmed cell death. Importantly, mitochondria are responsible for production of most of our cell’s reactive oxygen species (ROS) and some reactive nitrogen species (RNS). Significant oxidative damage to mitochondrial membranes represents the point-of-no-return of programmed cell death pathways that culminate in apoptosis or regulated cell death leading to necrosis.
Mitochondrial membrane permeability is affected in ischemia, viral and bacterial infections, metabolic diseases, neurobehavioral and neurodegenerative diseases, among other disorders, according to Kroemer and colleagues. For example, viral proteins can induce mitochondrial membrane permeability, followed by swelling and fragmentation.11 It appears that chronic neurodegenerative diseases, such as Alzheimer’s, amyotrophic lateral sclerosis, Huntington’s and Parkinson’s disease, may also involve mitochondrial dysfunction and increases in mitochondrial permeability. Many other conditions, such as heart disease, metabolic syndrome, dysbiosis related illnesses and even psychiatric conditions have been linked to loss of mitochondrial membrane function and increases in membrane permeability.
How Damaged Mitochondria Wreak Havoc
Damage to mitochondrial components, especially the delicate inner mitochondrial membrane, leads to the release of toxic proteins, including caspases and other enzymes. These proteins are normally confined in the mitochondria, but once released these proteins go through several steps that trigger the formation of a potent inflammatory molecular complex called an inflammasome. New evidence has placed inflammasomes at the center stage of complex diseases like metabolic syndrome and cancer, as well as the regulation of the microbial ecology in the intestine and the production of ATP.,,,,,, Inflammasomes are regarded by some scientists as ‘guardians of the body’ because of the way they orchestrate host defenses and their role in the pathogenesis of inflammatory diseases.
Lipid replacement therapy (LRT)® that emulates the amount and composition of the mitochondrial lipids assures that mitochondrial membrane permeability is maintained in the optimal range
Once the inner membrane of the mitochondria is damaged, its core ability to produce energy in the form of ATP and to maintain optimal mitochondrial nutrient uptake and utilization necessary for ATP production are impaired. The result is perceived as persistent fatigue.
Mitochondria are also responsible for many metabolic circuits and signaling pathways. Just a few examples of these include: oxidative phosphorylation; biosynthesis of key molecules, including heme and certain steroids as well as in many catabolic energy relevant pathways, such as the β-oxidation of fatty acids; and regulation of calcium homeostasis.
In addition, the immune system is stimulated by molecular byproducts of mitochondrial damage to produce inflammatory cytokines. If inappropriately regulated, these cytokines then sustain and even promote local and systemic inflammation in a ‘feed-forward’ cycle of inflammatory messengers. Once the mucosal innate immune system is switched on to high-alert by the inflammasome, GI bacteria become involved in this process, and the local specialized sensors become hyper-responsive to bacterial triggers from the gastrointestinal tract – even from previously tolerated bacteria. This leads to loss of mucosal barrier integrity in the gut, dysbiosis, inflammation and fatigue. , More inflammasomes are then produced, leading to a vicious cycle and chronic tissue damage.
How to Restore the Mitochondrial Membrane
The mitochondrial membrane contains the major classes of phospholipids found in all cell membranes, including phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), phosphatidylserine
(PS), and phosphatidic acid (PA), as well as phosphatidylglycerol
(PG), the precursor for cardiolipin (CL); which is predominantly located in the mitochondria.
Using lipid replacement therapy (LRT®) in the form of a stable oral supplement that emulates the amount and composition of the mitochondrial lipids assures that inappropriate oxidative membrane damage is prevented, damaged membrane phospholipids are replaced and mitochondrial membrane permeability is maintained in the optimal range. It also reduces the number of mitochondrial DNA deletions. Thus LRT® can be used to restore mitochondrial and other cellular membrane functions via delivery of undamaged replacement lipids to cells and that, in turn, can reduce inflammasome promotion.
Recent clinical trials using patients with chronic fatigue or chronic fatigue syndrome have shown the benefit of LRT®. Using naturally occurring membrane phosphatidyl lipids listed above, mitochondrial electron transport function can be restored and moderate to severe chronic fatigue can be significantly reduced in the process. 
In one impressive study LRT® reduced fatigue 35.5% in aging adults and significantly improved mitochondrial function to a level that was similar to that found in young, healthy adults
In recent studies, LRT and B Vitamins given for 6 months or more has also reduced the blood levels of the amino acid homocysteine, which are related to increased risk for cardiovascular disease, stroke, cognitive loss, depression and immune dysfunction. 
The use of LRT® is attractive as a safe and effective intervention in the treatment of persistent and transient fatigue. Studies have been conducted on various populations, from those with normal health and function to those undergoing complex treatments for cancer and those with persistent fatigue. These groups have shown between 30-45% improvement in fatigue perception and function 25,26,27 utilizing the internationally recognized Piper Fatigue Scale.  In addition, in concert with significant fatigue reduction, a cross-over clinical trial has shown that mitochondrial function was also significantly improved.  Even in severely fatigued patients with chronic fatigue syndrome or fibromyalgia syndrome, LRT® reduced fatigue by 43.1%.25
In one impressive study LRT® reduced fatigue 35.5% in aging adults and significantly improved mitochondrial function to a level that was similar to that found in young, healthy adults. 30
Mitochondria, the Gut and Immune Regulation: An Evolving Comprehension
As indicated, recent studies suggest that mitochondria are significant players in the orchestration of innate immune responses via the inflammasome, which results in the production and release of the pro-inflammatory cytokines IL-1β and IL-18., These, in turn, contribute to the symbiosis/dysbiosis of the bacterial organisms that reside in our digestive tract. The digestive tract is home to trillions of bacteria, and is also the site of greatest density of innate immune receptors in the body. These receptors are key mediators in the management and maintenance of immune responses and tolerance, and play a role in determining bacterial composition. Their inappropriate activation and their expression mediated by IL-1β and IL-18 leads to altered innate immune receptor hyper-responsiveness and may contribute to immune-mediated inflammatory diseases as well as fatigue via inflammasomes that induce dysbiosis.
Thus it’s likely that mitochondrial damage creates fatigue not only directly by impairing mitochondrial function, but also indirectly through pro-inflammatory promotion of cytokines and inflammasomes, the consequences of which include local inflammation, loss of mucosal barrier integrity, dysbiosis and fatigue. , A cautiously optimistic idea is now taking hold that invokes using mitochondrial-induced symbiosis of the gut microbiota to track, target and treat a plethora of diseases, even ones beyond the confines of the gastrointestinal tract.
This sequence of events places mitochondria at the cross roads of bioenergetics, cell death signaling, microbial ecology and the innate and adaptive immune system, and associated inflammation.
Inflammation is, of course, an essential immune response that enables survival during infection or injury and maintains tissue homeostasis under a variety of noxious conditions. Inflammation comes at the cost of a transient decline in local tissue function, which in turn contributes to the pathogenesis of diseases and loss of function related to altered homeostasis. Inflammation, at least at the molecular level, has been described as the ‘common soil’ of altered health and function.
Lipid Replacement: An Ideal Approach?
Pro-inflammatory cytokines are capable of inducing many if not all the cardinal symptoms of CFS in humans. , The use of LRT® is attractive, since it can restore mitochondrial membranes and the gut milieu, including its delicate lining at the same time. The resolution of inflammasome-induced dysbiosis makes a considerable contribution towards improving mitochondrial fitness; just as mitochondrial fitness contributes to the management of healthy, gut-mediated immune reactivity and associated symbiosis.
The results of using LRT® and the subsequent recovery from fatigue provided by LRT® are consistent and profound.25,26,27,28,30
This health altering intersection of immunity, inflammasome activation, oxidative stress and dysbiosis, can be found in the membranes of the mitochondria residing in our cells – not only of the gastrointestinal tract but all other tissues as well.
The clinical use of LRT® has the potential to decrease the adverse effects of aging on mitochondria and improve mitochondrial function in various chronic diseases, diminish fatigue and improve altered states of mucosal immunity and associated microbial ecology through the participatory resolution of inflammasome-mediated dysbiosis. The improvement in terms of restitution of mucosal and immunological tolerance has potential health benefits that extend systemically..,
In summary, LRT® is not just the dietary substitution of lipids with proposed health benefits; it is the actual replacement of damaged cellular lipids with undamaged lipids to ensure proper structure and function of cellular structures, mainly cellular and organelle membranes that contribute to important functional support of good health.25,30
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 Maes M, Twisk FN, Kubera M, Ringel K. Evidence for inflammation and activation of cell-mediated immunity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): increased interleukin-1, tumor necrosis factor-α, PMN-elastase, lysozyme and neopterin. J Affect Disord. 2012;136(3):933-939. Epub 2011 Oct 4. View Abstract
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 Nicolson, G.L. and Ellithrope, R. Lipid replacement and antioxidant nutritional therapy for restoring mitochondrial function and reducing fatigue in chronic fatigue syndrome and other fatiguing illnesses. J. Chronic Fatigue Syndr. 2006;13(1): 57-68. View Full Paper
 Ellithorpe RA, Settineri R, Mitchell CA, Jacques B, Ellithorpe E, Nicolson GL. Lipid replacement therapy drink containing a glycophospholipid formulation rapidly and significantly reduces fatigue while improving energy and mental clarity. Funct Food Health Dis. 2011;1(8): 245-254. View Full Paper
 Nicolson GL, Ellithorpe RR, Ayson-Mitchell C, Jacques B, Settineri R. Lipid Replacement Therapy with a Glycophospholipid-Antioxidant-Vitamin Formulation Significantly Reduces Fatigue Within One Week. J Am Nutraceut Assoc. 2010;13(1):10-14 View Full Paper
 Nicolson GL, Ellithorpe R and Settineri R. Blood homocysteine levels are significantly reduced with a glycophospholipid formulation (NTFactor® plus vitamin B-complex): a retrospective study in older subjects. Paper in Preparation.
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 Agadjanyan M, Vasilevko V, Ghochikyan A, Berns P, Kesslak P, Settineri R, Nicolson GL. Nutritional supplement (NTFactor) restores mitochondrial function and reduces moderately severe fatigue in aged subjects. J Chronic Fatigue Syndr 2003;11(3):23-26. View Full Paper
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- Fatigue, Immunity and Inflammation:– Their Resolution Using Natural Medicine.
- Mitochondria and the Anti-Aging Role Of Lipid Replacement Therapies
- A Special Note from Garth Nicolson PhD Why Lipid Replacement Therapy(LRT®) is Key to our Health
- Mechanisms of Membrane Repair and the Novel Role of Oral Phospholipids (Lipid Replacement Therapy®) and Antioxidants to Improve Membrane Function.
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