The study analyzed over 600 endogenous metabolites in each ME/CFS patient using HILIC-ESI-MS/MS on a ABSCIEX 5500 QTRAP tandem mass spectrometer. It measured the ME/CFS cohort metabolite levels in selected pathways and compared them against age matched controls. The metabolites comparisons were analyzed using a statistical package showing both overlapping metabolite abnormalities and unique metabolite abnormalities.
It clearly showed the ME/CFS cohort had metabolic pathway distrubances as hypothesized in Dr. Naviaux paper:
http://www.sciencedirect.com/science/article/pii/S1567724913002390
"Abstract
The cell danger response (CDR) is the evolutionarily conserved metabolic response that protects cells and hosts from harm. It is triggered by encounters with chemical, physical, or biological threats that exceed the cellular capacity for homeostasis. The resulting metabolic mismatch between available resources and functional capacity produces a cascade of changes in cellular electron flow, oxygen consumption, redox, membrane fluidity, lipid dynamics, bioenergetics, carbon and sulfur resource allocation, protein folding and aggregation, vitamin availability, metal homeostasis, indole, pterin, 1-carbon and polyamine metabolism, and polymer formation. The first wave of danger signals consists of the release of metabolic intermediates like ATP and ADP, Krebs cycle intermediates, oxygen, and reactive oxygen species (ROS), and is sustained by purinergic signaling. After the danger has been eliminated or neutralized, a choreographed sequence of anti-inflammatory and regenerative pathways is activated to reverse the CDR and to heal. When the CDR persists abnormally, whole body metabolism and the gut microbiome are disturbed, the collective performance of multiple organ systems is impaired, behavior is changed, and chronic disease results. Metabolic memory of past stress encounters is stored in the form of altered mitochondrial and cellular macromolecule content, resulting in an increase in functional reserve capacity through a process known as mitocellular hormesis. The systemic form of the CDR, and its magnified form, the purinergic life-threat response (PLTR), are under direct control by ancient pathways in the brain that are ultimately coordinated by centers in the brainstem. Chemosensory integration of whole body metabolism occurs in the brainstem and is a prerequisite for normal brain, motor, vestibular, sensory, social, and speech development. An understanding of the CDR permits us to reframe old concepts of pathogenesis for a broad array of chronic, developmental, autoimmune, and degenerative disorders. These disorders include autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), asthma, atopy, gluten and many other food and chemical sensitivity syndromes, emphysema, Tourette's syndrome, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), chronic traumatic encephalopathy (CTE), traumatic brain injury (TBI), epilepsy, suicidal ideation, organ transplant biology, diabetes, kidney, liver, and heart disease, cancer, Alzheimer and Parkinson disease, and autoimmune disorders like lupus, rheumatoid arthritis, multiple sclerosis, and primary sclerosing cholangitis."
Once the study is published, I'm hopeful it will show to the broader scientific community that many of these syndromes without known causes are tied to subtle metabolic system disturbances. Our metabolic systems are highy redundant usually reliable chemical systems able to tolerate and adapt to most envirnomnetal assults - but now all. Mainstream medicine recognizes many DNA based metabolic problems since DNA errors at birth lead to DNA's inability to fabricate the appropriate metabolite intermediates required for our chemical engine to function properly. Its analgous to an automobile being built without a piston. The engine won't run. Its biologically like a bear hybernating in the winter but spring doesn't reverse the metabolic slowdown. Or like the persister bacteria being researched in Lyme. Our metaboloic systems have evolutionary mechanisms that allow shutdown that can get stuck.
But mainstream medicine also acknowledges acquired metabolic disturbances such as Diabetes. But the majority of acknowleded metabolic disturabances that causes disease are fairly catastrophic and easily observable such as a loss of insulin/glucose regulation in Diabetes. That's analgous to a 5 year old car blowing a piston and losing a cylinder. It still runs but now well and is noisy and without help will destroy the car - kill the patient. What Dr. Naviaux shows is there are more subtle losses of metabolic homeostasis that can cascade and the pathways can get "stuck" since they have memory that can overcome the redundancies that normally allow it to maintain metabolic homeostasis or balance. I see it like say Microsoft Windows aquiring too many virus's until it begins running slow due to problems aquired in its registry.
This is particularly troublesome when basic functions such as the Krebs cycle, mitochondrial process ets.. are altered and won't recover. I believe once the study is puplished, a key focus in CFS/ME and syndrome research will begin to take these permanent metabolic disturbances into account and metabolomics will be become the key to personal medicine for those suffering with syndromes. Instead of your doctor ordering a CMP-14 and CBC, a metabolomics test will look at a 1000 blood metabolites simultaneously. Then the results will be compared with a known age matched control normal and when metaboilites are 3.5 standard deviations low, they will be flagged and investigated.
Think about the research $$ put into DNA. DNA is important but defines you at the moment of conception. It defines proteins critical to metabolism but that must be added to a lifetime of environmemtal exposures do understand how the "body system" is functioning "now". So your DNA is a player but a key flaw that effects metabolism will show up at birth. But a weakness or predisposition must be added to a lifetime of environmental infections, toxins etc... to determine "todays" health. The metabolomics technology allows taking asnapshot of how ones metabolism is "working" NOW. And just like DNA is compared against a reference to spot SNPs or nuceotide errors, when metabolomics sees a key metabolite in a critical pathway 5 standard deviations low, that's meaningful since it has an upstream cause and downstream cascade implications that redundancy may not be able to overcome.
It will give both doctors and researchers one or more metabolic pathway targets to try and address not unlike Dr. Naviaux work on Autism where the metabolic disturbance found could be simulated in mice and reversed and then led to a fundamental partial Autism treatment possibility.
https://health.ucsd.edu/news/releases/Pages/2015-06-10-clinical-trial-for-autism-treatment.aspx
This study might lead to similar approaches based on trying to alter the "stuck" pathways using the same fundamental strategy. The study is based on our understanding of the metabolic system chemistry system.
http://www.sigmaaldrich.com/content...ral_Information/metabolic_pathways_poster.pdf
I suspect we have a long way to go from study results to effective treatment but I believe its far beyond cytokine profiles and other starting strategies. I suspect the cytokine profiles found are a result of metabolic pathway alterations where the immune system is responding to the problems caused by the "stuck" pathway(s) and impact of downstream cascades.
I strongly urge helping with Dr. Naviaux's funding since NIH and private money is tight. His work on Autism is successful could divert his funding and attention to that worthy cause and away from CFS/ME. So if all 2 million CFS/ME sufferers see his upcoming paper and give only $10, I suspect that $20 million will lead to a cure or treatment.
If you want to see all the other areas competing for Dr.Naviaux's research $$ - just search PubMed for him:
http://www.ncbi.nlm.nih.gov/pubmed/?term=naviaux+RK
Just Autsim work:
http://www.ncbi.nlm.nih.gov/pubmed/?term=naviaux+RK+autism
"Reversal of autism-like behaviors and metabolism in adult mice with single-dose antipurinergic therapy."
The basis of the Autism trials today at UCSD
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4080315/
It clearly showed the ME/CFS cohort had metabolic pathway distrubances as hypothesized in Dr. Naviaux paper:
http://www.sciencedirect.com/science/article/pii/S1567724913002390
"Abstract
The cell danger response (CDR) is the evolutionarily conserved metabolic response that protects cells and hosts from harm. It is triggered by encounters with chemical, physical, or biological threats that exceed the cellular capacity for homeostasis. The resulting metabolic mismatch between available resources and functional capacity produces a cascade of changes in cellular electron flow, oxygen consumption, redox, membrane fluidity, lipid dynamics, bioenergetics, carbon and sulfur resource allocation, protein folding and aggregation, vitamin availability, metal homeostasis, indole, pterin, 1-carbon and polyamine metabolism, and polymer formation. The first wave of danger signals consists of the release of metabolic intermediates like ATP and ADP, Krebs cycle intermediates, oxygen, and reactive oxygen species (ROS), and is sustained by purinergic signaling. After the danger has been eliminated or neutralized, a choreographed sequence of anti-inflammatory and regenerative pathways is activated to reverse the CDR and to heal. When the CDR persists abnormally, whole body metabolism and the gut microbiome are disturbed, the collective performance of multiple organ systems is impaired, behavior is changed, and chronic disease results. Metabolic memory of past stress encounters is stored in the form of altered mitochondrial and cellular macromolecule content, resulting in an increase in functional reserve capacity through a process known as mitocellular hormesis. The systemic form of the CDR, and its magnified form, the purinergic life-threat response (PLTR), are under direct control by ancient pathways in the brain that are ultimately coordinated by centers in the brainstem. Chemosensory integration of whole body metabolism occurs in the brainstem and is a prerequisite for normal brain, motor, vestibular, sensory, social, and speech development. An understanding of the CDR permits us to reframe old concepts of pathogenesis for a broad array of chronic, developmental, autoimmune, and degenerative disorders. These disorders include autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), asthma, atopy, gluten and many other food and chemical sensitivity syndromes, emphysema, Tourette's syndrome, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), chronic traumatic encephalopathy (CTE), traumatic brain injury (TBI), epilepsy, suicidal ideation, organ transplant biology, diabetes, kidney, liver, and heart disease, cancer, Alzheimer and Parkinson disease, and autoimmune disorders like lupus, rheumatoid arthritis, multiple sclerosis, and primary sclerosing cholangitis."
Once the study is published, I'm hopeful it will show to the broader scientific community that many of these syndromes without known causes are tied to subtle metabolic system disturbances. Our metabolic systems are highy redundant usually reliable chemical systems able to tolerate and adapt to most envirnomnetal assults - but now all. Mainstream medicine recognizes many DNA based metabolic problems since DNA errors at birth lead to DNA's inability to fabricate the appropriate metabolite intermediates required for our chemical engine to function properly. Its analgous to an automobile being built without a piston. The engine won't run. Its biologically like a bear hybernating in the winter but spring doesn't reverse the metabolic slowdown. Or like the persister bacteria being researched in Lyme. Our metaboloic systems have evolutionary mechanisms that allow shutdown that can get stuck.
But mainstream medicine also acknowledges acquired metabolic disturbances such as Diabetes. But the majority of acknowleded metabolic disturabances that causes disease are fairly catastrophic and easily observable such as a loss of insulin/glucose regulation in Diabetes. That's analgous to a 5 year old car blowing a piston and losing a cylinder. It still runs but now well and is noisy and without help will destroy the car - kill the patient. What Dr. Naviaux shows is there are more subtle losses of metabolic homeostasis that can cascade and the pathways can get "stuck" since they have memory that can overcome the redundancies that normally allow it to maintain metabolic homeostasis or balance. I see it like say Microsoft Windows aquiring too many virus's until it begins running slow due to problems aquired in its registry.
This is particularly troublesome when basic functions such as the Krebs cycle, mitochondrial process ets.. are altered and won't recover. I believe once the study is puplished, a key focus in CFS/ME and syndrome research will begin to take these permanent metabolic disturbances into account and metabolomics will be become the key to personal medicine for those suffering with syndromes. Instead of your doctor ordering a CMP-14 and CBC, a metabolomics test will look at a 1000 blood metabolites simultaneously. Then the results will be compared with a known age matched control normal and when metaboilites are 3.5 standard deviations low, they will be flagged and investigated.
Think about the research $$ put into DNA. DNA is important but defines you at the moment of conception. It defines proteins critical to metabolism but that must be added to a lifetime of environmemtal exposures do understand how the "body system" is functioning "now". So your DNA is a player but a key flaw that effects metabolism will show up at birth. But a weakness or predisposition must be added to a lifetime of environmental infections, toxins etc... to determine "todays" health. The metabolomics technology allows taking asnapshot of how ones metabolism is "working" NOW. And just like DNA is compared against a reference to spot SNPs or nuceotide errors, when metabolomics sees a key metabolite in a critical pathway 5 standard deviations low, that's meaningful since it has an upstream cause and downstream cascade implications that redundancy may not be able to overcome.
It will give both doctors and researchers one or more metabolic pathway targets to try and address not unlike Dr. Naviaux work on Autism where the metabolic disturbance found could be simulated in mice and reversed and then led to a fundamental partial Autism treatment possibility.
https://health.ucsd.edu/news/releases/Pages/2015-06-10-clinical-trial-for-autism-treatment.aspx
This study might lead to similar approaches based on trying to alter the "stuck" pathways using the same fundamental strategy. The study is based on our understanding of the metabolic system chemistry system.
http://www.sigmaaldrich.com/content...ral_Information/metabolic_pathways_poster.pdf
I suspect we have a long way to go from study results to effective treatment but I believe its far beyond cytokine profiles and other starting strategies. I suspect the cytokine profiles found are a result of metabolic pathway alterations where the immune system is responding to the problems caused by the "stuck" pathway(s) and impact of downstream cascades.
I strongly urge helping with Dr. Naviaux's funding since NIH and private money is tight. His work on Autism is successful could divert his funding and attention to that worthy cause and away from CFS/ME. So if all 2 million CFS/ME sufferers see his upcoming paper and give only $10, I suspect that $20 million will lead to a cure or treatment.
If you want to see all the other areas competing for Dr.Naviaux's research $$ - just search PubMed for him:
http://www.ncbi.nlm.nih.gov/pubmed/?term=naviaux+RK
Just Autsim work:
http://www.ncbi.nlm.nih.gov/pubmed/?term=naviaux+RK+autism
"Reversal of autism-like behaviors and metabolism in adult mice with single-dose antipurinergic therapy."
The basis of the Autism trials today at UCSD
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4080315/
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![ME/CFS lecture | Dr Nancy Klimas | 2011 [Chronic Fatigue Syndrome / SEID / New Zealand] - YouTube](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)
