“This work opens a fresh path to both understanding the biology of CFS and, more importantly to patients, a robust, rational way to develop new therapeutics for a disease sorely in need of them.” Robert Naviaux

The Dafoe’s looked at each other in astonishment. They’d tested Whitney, their sick son, in every which way and had found problems but nothing that had reflected how ill he was – until now. His metabolomic results revealed row after row of abnormalities – some of which were levels of magnitudes off the charts. Instantly a new world opened up for them.

Two days ago the first metabolomics study in chronic fatigue syndrome (ME/CFS) using a similar approach was published. It may end up opening a new world for everyone with chronic fatigue syndrome (ME/CFS) as well. Ron Davis certainly thinks so. He believes “It is the most important and groundbreaking study of ME/CFS to date” and that Naviaux’s metabolomics research put us “finally on the right path to understanding ME/CFS”.

Unbeknownst to the Davis’s, Robert Naviaux – a pioneer in the metabolomics field- had begun his own study of ME/CFS patients. Naviaux’s metabolomics studies on diseases like autism, depression, PTSD and traumatic brain injury had caught Dr. Eric Gordon’s and Dr. Neil Nathan’s eyes. During a Lyme conference in San Diego, they’d approached him: was he interested in doing an ME/CFS study? Naviaux’s PhD in virology and human genetics had left him interested in the post-infectious ME/CFS patients since the 1980’s, and he grabbed at the chance.

At some point Gordon, who was one of Whitney Dafoe’s doctors, suggested that Naviaux meet Ron Davis. Metabolomics had always been part of Davis’s “omics” core, but he hadn’t expected the results he’d gotten and it had become a major area of interest for him. When Naviaux met Davis a partnership with the Open Medicine Foundation (OMF) was borne. (Naviaux now sits on the OMF”s scientific advisory board, talks with Davis regularly, and the OMF is helping to fund Naviaux’s expanded ME/CFS study.)

Very few metabolomics studies have been done in ME/CFS and none on the level of the Naviaux study. What a piece of serendipity it was that these two figures – a short plane ride away from each other – ended up being connected through Ron Davis’s son.

The Study

Metabolic features of chronic fatigue syndrome. Robert K. Naviauxa,b,c,d,1, Jane C. Naviauxa,e, Kefeng Lia,b, A. Taylor Brighta,b, William A. Alaynicka,b, Lin Wanga,b, Asha Baxterf, Neil Nathanf,2, Wayne Andersonf, and Eric Gordon. www.pnas.org/cgi/doi/10.1073/pnas.1607571113

Naviaux began the paper touting the advantages he believes metabolomics brings for the analysis and treatment of complex diseases. At the most basic level there’s our genes and the environment and not much else. Throw these two together and you get metabolism and metabolites – the byproducts of cellular function. Measuring these metabolites gives you a snapshot of the cells physiology. Naviaux believes studying the metabolic by-products of our cells provides more biologically relevant information than any other approach and is more cost-effective as well.

In this study Naviaux, Eric Gordon, Neil Nathan and others examined 612 metabolites from 63 biochemical pathways in the serum of 45 ME/CFS patients (Fukuda / CCC criteria) and 37 age and sex-matched controls.

Twenty of the 63 biochemical pathways were highlighted in ME/CFS. Eighty percent of the metabolites that were abnormal were down-regulated. Nine of the biochemical pathways were altered in both men and women.

The Mitochondria and the Cell Danger Response

Mitochondrial metabolism is so fast that, like the canary in the coal mine, it’s the first organelle to detect danger or toxicity.

Naviaux believes the mitochondria are able to sense every kind of danger – from pathogens to pH changes to toxic elements from pesticides, heavy metals, etc. to inflammation. They sense trouble in the form of an infection when they detect a drop in voltage caused by the diversion of electrons (NADH / NADPH) to make viral components or respond to a broad variety of toxins.

In the cell danger response (CDR) the mitochondria respond instantaneously to that loss by decreasing their oxygen consumption – thus thwarting pathogens from using the building blocks of the cell to replicate. Because the oxygen is no longer being used, it builds up in the cells causing a oxidatively charged environment which interrupts viral synthesis. The CDR also stiffens the membrane of the cell to stop pathogens from exiting it, warns other cells of the danger, and emits ATP in order to warn other cells to get their defenses up.

Naviaux tends to think ecologically; where others see hardened cell membranes as a sign of damage, he sees them as a wall that the cell builds to keep the pathogens inside the cell. When others see the leakage of ATP, ADP, H202 and factors as a sign of cellular damage, Naviaux sees these substances as early warning signals to other cells.

Inside the cell ATP is an energy molecule, outside the cell it’s a “danger molecule”. Cells, Naviaux noted, work so hard to make ATP, that the fact that they would actually export it outside the cell was highly significant. Finding ATP outside a cell is a sign that something major has gone wrong.

Hunkering Down

“These facts suggest that CFS is an evolutionarily conserved, genetically regulated, hypometabolic state similar to dauer that permits survival and persistence under conditions of environmental stress but at the cost of severely curtailed function and quality of life.” Naviaux

Naviaux believes that sometimes survival means hunkering down; essentially shutting down the cell as much as possible. In the cell danger response you don’t engage the danger, you try to outlast it. Naviaux noted that many low energy states from diapause, hibernation, estivation, torpor, ischemic preconditioning, autophagy, caloric restriction have been described in the literature.

The fatigue in ME/CFS, Naviaux believes, is due to an active and purposeful inhibition of the mitochondria. The mitochondrial are not broken – they’re throttled back to a low idle. In the face of danger they’re shutting down and exporting ATP outside the cell to warn other cells that danger is present.

A Hypometabolic Disease?

There’s a lot of talk about subsets but these results suggest that a core hypo or low metabolic state may underlie all of them. No matter what kind of trigger started the disease or whether one was male or female, a core hypometabolic state stood out. The metabolites were a bit different in males and females but the core finding – a low energy state – showed up in both.

Naviaux’s isn’t the only study to find evidence of hypometabolism or to suggest that a hypometabolic state exists in ME/CFS. Marian Lemle first proposed a hypometabolic state was present in ME/CFS in a 2007 paper. (Read the paper here.) She published a paper, “Hypothesis: chronic fatigue syndrome is caused by dysregulation of hydrogen sulfide metabolism” suggesting that ME/CFS patients existed in hibernation-like/hypometabolic state in 2009. She proposed that the fatigued state ME/CFS patients were locked into protected them from the damages of overexertion. You can find more about her hypothesis in a 2009 interview Hydrogen Sulfide and Chronic fatigue Syndrome: The Originator Speaks.

The Zinn’s found ‘a global expression of CNS hypoactivation” Barnden found reduced brainstem activity. The Lipkin/Hornig immune and spinal fluid studies showed evidence of reduced immune activity in ME/CFS. Other studies have found reduced cortisol, reduced aerobic output, low blood volume, decreased parasympathetic nervous system activity and reduced natural killer cell functioning. Hypometabolism or hypoactivation seems to be the coin of the realm for ME/CFS.

Dr. Unger recently revealed, though, that ME/CFS patients display a wide variety of symptoms. Most people believe the disease is full of subsets – perhaps even different diseases. If the disease is at its most basic level homogeneous, where might the vaunted heterogeneity in ME/CFS come from? Ron Davis suggests that genetic polymorphisms might be one source and is working on a study that marries genes and metabolomics in ME/CFS. Davis has asserted that a mitochondrial shutdown operating at different levels in different systems could explain every symptom seen in ME/CFS.

An Evolutionary Hijack?

CFS is an evolutionarily conserved, genetically regulated, hypometabolic state similar to dauer that permits survival and persistence under conditions of environmental stress but at the cost of severely curtailed function and quality of life. Naviaux

Naviaux believes that the systems of people with ME/CFS have been hijacked by an evolutionary state that is adaptive during periods of great stress. The stressor in many ME/CFS patients is often an infection, but as Naviaux’s study showed can include chemical exposures, physical and psychological trauma, and no discernible trauma at all.

It appears that when Naviaux says evolution he means an ancient, genetically embedded response that first showed up in organisms far older than humans. In this evolutionary state the organism reconfigures its metabolism to use the least energy possible.

The closest animal state to what Naviaux’s results suggest is happening in ME/CFS occurs in worms which enter into a “dauer” state to survive harsh conditions. (Dauer is a German word for endurance). The ability of these worms to endure – they can live four-eight times longer in the dauer state than their usual lifespan – is so unusual that they’ve been studied extensively by biologists.

The metabolites altered in ME/CFS patients are similar to those seen in the cell danger response with one major difference: the metabolites that are upregulated in the CDR are down-regulated in ME/CFS and vice versa. (ME/CFS just had to be different.) The metabolic response in ME/CFS doesn’t look like the responses seen in inflammation, infection or metabolic syndrome – three processes that have been conjectured to be present in ME/CFS at one time or another.

The difference shows up most in metabolites called sphingolipids which accounted for almost 50% of the metabolic issues found. (Reductions in phospholipid metabolites were also prevalent. Many other alterations were found but these were the major ones.)

Sphingolipids play important roles in signal transmission particularly in nervous system tissues, and are believed to protect cell membranes against harmful environmental factors. Sphingolipid metabolites, such as ceramide – the most common disrupted metabolite involved in ME/CFS – are involved in signaling cascades involving stress responses, inflammation, cell death and much more.

Naviaux said he wasn’t surprised to find the sphingolipids reduced in ME/CFS – he’d found sphingolipid reductions in other hypometabolic diseases like autism and Gulf War Syndrome but he was surprised at how depleted they were in ME/CFS. No other disease he’s examined has had nearly the amount of sphingolipid reduction found in this one.

Naviaux believes this upside-down pattern “may represent a fundamental response to oppose the spread of persistent viral and intracellular bacterial infections.” In an MEAction blog that Naviaux was impressed with, Jaime described what may be happening. She suggested that ceramides might be down-regulated in order to disrupt the ‘lipid rafts’ that some pathogen use to enter the cells. It’s another method of locking down the cell. Jaime also proposed that Naviaux’s work suggests that Rituximab may be disrupting the same lipid rafts in ME/CFS.

A Living Death

A long-lived dauer-like state is clearly pathological and evolutionarily suboptimal in humans (how does one reproduce when one is in such bad shape?), but it could help explain a strange conundrum: how some people with ME/CFS get really, really sick without dying.

During a call Ron Davis mused on how ill people with ME/CFS can get without dying. In other diseases the kind of disability seen in the most severely ill ME/CFS patients is a prelude to death. Once people get THAT sick they’re usually going to die; a process has been started that’s going to result in death.

But that generally doesn’t happen in ME/CFS. People can remain functionally in what appears to be a near death state for a long time. That could suggest a way has been found to keep the body alive in a very low energy state. Naviaux believes the state may be protective against conditions like hypertension, dyslipidemia, central obesity, and insulin resistance.

There’s obviously many downsides to being a in low energy state. Naviaux stated that because it takes more energy to relax than to react, anxiety, tension and hypersensitivity are likely outcomes of being caught in a low energy state.

Diagnostic Test

Using just eight and thirteen metabolites in males and females, respectively, Naviaux was able to diagnose 95 and 96% percent of the male and female ME/CFS patients correctly. The metabolite signature in the ME/CFS patient relative to the healthy controls, was so different, in fact, that even using a single metabolite worked pretty well in identifying who was who.

If future studies can validate Naviaux’s findings, a biological diagnostic signature signaling that ME/CFS patient are in a hypometabolic state may have been found. Creating a true diagnostic signature will require comparing ME/CFS to other diseases, and those studies are underway.

Turning the Worm – Treatment

You can bring a mitochondria to oxygen but you can’t make them use it. Naviaux

Metabolomics reveals a new window into the underlying biology of CFS that makes us very hopeful that effective treatments will be developed soon and tested in well-controlled clinical trials. Naviaux

Naviaux doesn’t believe the answers are going to come from the usual treatments for damaged mitochondria. He spent the first part of his career studying people with genetically caused mitochondrial damage. People with ME/CFS, autism, and other diseases have mitochondrial problems, but they are completely different from people with genetically determined mitochondrial diseases. Their mitochondria are turned off, not broken. It’s a matter of getting them to turn back on.

Naviaux’s idea of ME/CFS patients being captured by some sort of aberrant evolutionary process seems reminiscent of Broderick’s idea of patients being caught in suboptimal state or a new normal. Given the embeddedness of this state, Broderick believes it will take considerable “force” (or better yet skill) to move ME/CFS patient back to health. Dr. Cheney – who floated the idea that people with ME/CFS were locked into a kind of protective state years ago – has talked of a similar push-pull phenomenon; he could push an ME/CFS patient towards health but it was as if their systems pulled them back again.

If Naviaux is right ME/CFS probably didn’t happen because of one breakdown; many changes needed to occur for this hypometabolic state to take over and it’s probably going to take careful, calibrated changes to entice the system back to normal.

Although all the metabolic abnormalities Naviaux found in ME/CFS could be a consequence of low NADPH availability, Naviaux cautioned

that simply adding NADPH wouldn’t work. Incremental improvements in NADPH production could theoretically be achieved by using treatments focused on folate, B12, glycine, and serine pools, and B6 metabolism but the clinical studies to show this have not been done.

He compared an ME/CFS patient to a car that’s sat for a long winter. You can’t just turn the car over and expect it to run well. You have to replenish the fluids and ready the car before starting the engine, otherwise you can damage it further. Treatment is not simply about replenishing the metabolites that are low. The low metabolites reflect a distortion of a network – they themselves are not the cause.

Antivirals, he and Ron Davis have cautioned, could do more than good when given to a person without a clear sign of infection. Antivirals and antibiotics, it turns out, can pound the mitochondria. (Statins, valproate, and metformin can do the same.)

Many antibiotics like tetracyclines, erythromycin, and the fluoroquinolones (eg, Cipro), and antivirals like acyclovir, fialuridine, AZT, and ddC also inhibit mitochondrial functions when used chronically (usually for more than about 3 weeks). Because mitochondria are descendants of free-living bacteria, their machinery for protein synthesis, RNA synthesis, and DNA replication are susceptible to many antibiotics, and for reasons unique to mitochondrial DNA synthesis, they are also sensitive to antivirals. Chronic use of these drugs can do more harm than good if there is no longer good evidence for an active infection. Naviaux

Check out more about antivirals, treatment and other aspects of the paper in Naviaux’s ME/CFS Q & A here.

Ultimately, effective treatments will require approaching the system in an integrated fashion using nutrition, metabolism, uncovering triggers and stressors and understanding the role exercise plays. Understanding what happened to trigger the entry into a dauer-like state of low energy and how to get the system to exit that state will be critical.

Ron Davis envisions a core treatment regimen accompanied by more personalized treatments and suggests that Naviaux’s findings could explain why some treatments could work for some people but not for others. The different secondary pathways found in men and women suggests gender will effect treatment. Plus most of the metabolites (75%) altered in the ME/CFS patients were “personalized”; that is they were mostly unique to the individual, and these will help guide treatment regimens. Age matters as well. In fact, studies in which the participants are not age and gender matched will cause metabolomics results to wash out.

The proper treatment regimens for ME/CFS will clearly take some time – but perhaps not a lot of time – to be created. On the bright side Naviuax believes the evidence is there for all to see in the chemistry. It’s just a matter of figuring it out.

Rapidly Expanding Field

The good news is that the metabolomics field is rapidly developing. This study, Naviaux said, couldn’t have been done five years ago. In the next two years the capacity to efficiently study and uncover more metabolic compounds may double. The bad news is that the rapid growth in the field inherently brings some costs. Laboratories are developing new techniques that need to be standardized and cross-validated. Researchers need to know that study results done with X instrument will mean the same thing as studies done with Y instrument.

Naviaux’s next ME/CFS study will be fifty percent larger and include people from across the U.S. It will also include a metabolomics center at UC Davis in order to hurry the process of validation and standardization along.

Has the light bulb come on for ME/CFS? Has the underlying problem been identified? Naviaux believes he’s found a basis for methodically plumbing a disease in which treatments even by the experts are too often hit and miss. I heard a well-known ME/CFS doctor once blurt out in a burst of honesty “We’re just guessing most of the time”.

Naviaux’s path is not an easy one and it won’t be completed in a day. It requires understanding scads of complex biochemical reactions, for one thing, but Naviaux believes that our growing ability to eavesdrop on our cells physiology will open the door to understanding and treating hypometabolic states like ME/CFS.

Time will tell.

Conclusions

A biochemical signature has been found, which if replicated, could provide the first diagnostic biomarker for the disease

A core hypometabolic state appears to underly the heterogeneity we see in ME/CFS.

The hypometabolic state ME/CFS patients find themselves in has become pathological. it may derive, though, from evolutionary process designed to allow an organism to hunker down and conserve resources during a pathogen attack or other situation.

From a hypometabolic state in the brain, to the reduced immune activity in longer duration patients, to the reduced aerobic functioning, the low cortisol and parasympathetic nervous system functioning, and now to the metabolism, a state of low functioning appears to be characteristic of ME/CFS.

The hypometabolic state in ME/CFS differs from the kind of cell danger response seen in inflammatory diseases and infection but is similar to that seen in autism and related diseases. The degree of reduction in the sphingolipid metabolites seen in ME/CFS, however, was extraordinary and may reflect a different way of preventing the spread of infection.

Treatment is a complex process which involves first adjusting metabolic pathways to allow the cell to slip out of the danger response and resume normal functioning, and then using the signaling processes to tell the cell that “the danger has passed”. Doing so will require more than refilling the tank of depleted metabolites. While the process is complex, Naviaux believes the chemical signals he is finding will ultimately lead to clear treatment pathways.

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