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 disturbances 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 highly redundant unusually reliable chemical systems able to tolerate and adapt to most environmental pressures - but not 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 analogous to an automobile being manufactured without a piston. The engine won't run from the beginning. An acquired metabolic problem is biologically like a bear hibernating in the winter but spring doesn't reverse the metabolic slowdown while in the cold cave. Or like the persister bacteria being researched in Lyme. Our metabolic systems have evolutionary mechanisms that allow shutdown to protect the organism that can get stuck.
But mainstream medicine also acknowledges acquired metabolic disturbances such as Diabetes. But the majority of acknowledged metabolic disturbances that causes disease are fairly catastrophic and easily observable such as a loss of insulin/glucose regulation in Diabetes. That's analogous to a 5 year old car blowing a piston and losing a cylinder long after its manufactured. It still runs for a while but 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 acquiring too many errors or virus's until it begins running slow due to problems memorized in its registry or elsewhere on disk.
This is particularly troublesome when basic functions such as the Krebs cycle, mitochondrial process etc.. are altered and won't recover. I believe once the study is published, a key focus in CFS/ME and syndrome research will begin to look using metabolomics at these potentially permanent metabolic disturbances into account and metabolomics could 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 metabolites are some number of standard deviations low or high, 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 peptides/proteins critical to metabolism but that must be added to a lifetime of environmental exposures to 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 pressures from infections, toxins etc... to determine "today's" health. The metabolomics technology allows taking a snapshot of how ones metabolism is "working" NOW. Like analyzing Window's registry properly after its runn with dozens of applications for years. And just like DNA, it is compared against a reference to see an SNP nucleotide errors, while metabolomics sees a key metabolite level in a critical pathway based on standard deviations low or high. It'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 as being tested in Autism. The study is based on our understanding of the metabolic system chemistry system. An example is here:
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. They are almost certainly related.
I strongly urge helping with Dr. Naviaux's funding since NIH and private money is tight. His work on Autism if 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 his Autism 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/
