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Major Research Group Highlights Inflammation Energy Production Connection in ME/CFS

We propose that chronic low-grade inflammation induces and/or maintains persistent fatigue by inducing an imbalance between cellular-energy availability and cellular- and behavioral energy expenditure.  Lacourt et al. 2018

Neurosci. 2018 Apr 26;12:78. doi: 10.3389/fnbeh.2018.00078. eCollection 2018. The High Costs of Low-Grade Inflammation: Persistent Fatigue as a Consequence of Reduced Cellular-Energy Availability and Non-adaptive Energy Expenditure. Lacourt TE1, Vichaya EG1, Chiu GS1, Dantzer R1, Heijnen CJ1.

Inflammation, the brain and energy metabolism – it’s like the trifecta in chronic fatigue syndrome (ME/CFS) research. It seems like virtually everyone in the ME/CFS field believes that all three are involved but that belief only carries so much weight in a small field. What this field really needs is buy-in from outside researchers who can help move it forward.

That appears to have happened recently when a major research group lead by Robert Dantzer penned a review paper proposing that low-grade inflammation is causing energy production problems in chronic fatigue syndrome (ME/CFS) and probably many other diseases. The authors didn’t shy away from the chronic fatigue syndrome (ME/CFS) connection. In fact, they lead their review paper off with it, placing the fatigue in ME/CFS in the same context as the fatigue in cancer, MS, rheumatoid arthritis and others.

Major Stanford Study Indicates Chronic Fatigue Syndrome (ME/CFS) is Inflammatory Disorder

The study was published in the Frontiers in Neuroscience journal series which is touted as the 1st most cited series in the Neurosciences journal field.

The Dantzer group’s involvement in the intersection between inflammation and energy production is welcome but not entirely surprising; it’s a logical outcome of their past work. Dantzer spearheaded the now accepted idea that the immune system produces the symptoms of “sickness behavior” (fatigue, headache, muscle aches, sore throat, etc.) that occur during an infection which serve to reduce our energy usage and to keep us isolated from others (they posit to prevent pathogen spread).

What’s new is his group’s focus on the energy production process itself – a focus, interestingly, made possible largely by the work of ME/CFS researchers. The piece, with lead author Tamara LaCourt, shows how low-grade inflammation can cause the same energy problems we’re seeing in ME/CFS: a metabolic switch from energy-efficient, oxygen-based energy production process to a fast-acting, inefficient glycolysis-based approach.

Immune cells aren’t like other cells; jumping into action causes them to rev their motors up tremendously, placing enormous stress on their energy production systems. As they do this, they switch from a focus on aerobic energy metabolism to what the authors call “aerobic glycolysis” in order to churn out energy more quickly. That process results in less mitochondrial energy production and the increased production of toxic by-products like lactate.  Plus, over time this process results in reduced nutrient availability and less energy for the rest of the body.

low energy chronic fatigue

The authors believe that inflammation and metabolic and energy problems come together to produce a final common endpoint: fatigue.

Several studies from the Solve ME/CFS Initiative are examining whether the energy production of immune cells in ME/CFS is up to the task.

Prolonged inflammation also tends to result in two other energy production problems: increased insulin resistance and reduced glucose tolerance. Reduced glucose tolerance smacks glucose uptake by immune cells at the very time that they’re clamoring for it, causing the body to break down fats and proteins, thus removing resources it would ordinarily use elsewhere.  In yet another whack at the energy production, inflammation increases reactive oxygen species production which can hammer mitochondrial energy production.

The authors believe that neurons – which rely on glycolytic processes in astrocytes to get their energy – may be hit hardest by chronic inflammation.  This is because insulin resistance – a common outcome of chronic inflammation – destroys the glycolytic process in astrocytes, causing neurons to get their energy from fats – a slower and less efficient process.

Miller’s work on ME/CFS suggests that problems with the basal ganglia – the dopamine-producing center of the brain – may be causing problems with movement, reward and fatigue in ME/CFS. That’s a particularly interesting finding given that dopaminergic neurons in the brain are particularly vulnerable to inflammation. Shungu’s studies, which have consistently found high lactate and low gluthathione levels in the ventricles of ME/CFS patients brains, suggest that high levels of oxidative stress could be causing inflammation in the brain itself.

Plus, even low-level inflammation can disrupt a key element in ME/CFS and FM – sleep – which, in turn, increases fatigue. Simply altering one’s circadian rhythm (i.e. one’s sleep times) can have significant metabolic effects, leading to increased glucose levels and decreased insulin sensitivity.  The effects don’t end with sleep; sleep deprivation results in the need for increased energy expenditures the next day.

Is Poor Sleep Pummeling the Immune System in ME/CFS and Fibromyalgia? A Vicious Circle Examined

Then add in the extra ten percent in extra energy needs that chronic low-level inflammation imposes on the body – and the potential for a dramatic drop in energy production rises.   (We’ll find out more about total energy production in ME/CFS during the metabolic chamber tests in the NIH’s intramural study).

The authors believe that impaired energy production represents a “final common pathway” in persistent fatigue.

Leader in the Field

“In sum, most evidence for an association between fatigue and mitochondrial functioning comes from CFS, indicating lower levels of antioxidants and possible reductions in mitochondrial ATP production.” The authors.

We understandably don’t think of researchers in the small ME/CFS research field as being pioneers in the medical research field at large, but some have ploughed brand new ground. Suzanne Vernon’s computational biology work at the CDC was so novel that an entire issue of the Pharmacogenomics journal was devoted to it. Gordon Broderick and Travis Craddock’s expansion of that work at Dr. Klimas’s Institute of NeuroImmune Medicine has taken computational biology further – much further – in ME/CFS than in any other field. Ron Davis and Mark Davis at Stanford are using new HLA gene typing and T-cell technologies to try and nail down what is activating ME/CFS patients’ immune systems.

ME/CFS researchers’ attempts to understand the intersection between mitochondrial problems and fatigue are clearly breaking new ground as well.  According to the authors of this review article, 21 of the 25 studies examining the intersection between mitochondrial problems and fatigue have been produced by ME/CFS researchers. Researchers we all know ( e.g. Naviaux, Montoya, Hornig and Lipkin, Fluge and Mella) were cited again and again in the overview.

The authors even cited Workwell’s groundbreaking 2013 study which indicated that a shift to glycolytic energy production occurred during the second day of a two day exercise test in ME/CFS. They also singled out the 2017 Tomas study which found that under conditions of cellular stress, the mitochondria in ME/CFS patients’ cells were unable to rise to the occasion.

Turning to the metabolomics studies, the authors cited three ME/CFS studies which have pointed to “reduced metabolic activity”.  They believe the metabolic changes seen in ME/CFS reflect a chronic over-reliance and eventual depletion and abandonment of lipid metabolism, which results in a greater use of carbohydrate stores; hence the greater reliance on glycolysis and impaired aerobic energy production. In short, the authors believe the metabolomic studies in ME/CFS are demonstrating the same metabolic shift that the authors propose occur in states of chronic low-grade inflammation.

Interestingly, the authors proposed that many ME/CFS patients are probably exceeding their daily energy stores.  That, of course, makes perfect sense given Staci Stevens’s and Workwell’s findings that, for some patients, simply sitting upright puts them into an aerobic energy deficit.

For all its possible connections, the idea that fatigue in ME/CFS is simply the result of “low-grade inflammation” seems untenable given the disability present – unless that inflammation is found in the brain. The Simmaron Research Foundation is bringing the brain, the immune system and metabolism together in a way that’s never been seen before in ME/CFS.

The Simmaron Research Foundation’s first ME/CFS cerebral spinal fluid study suggested that an immune dysregulation, the likes of which approached that found in multiple sclerosis, may be present in the ME/CFS patients’ central nervous systems. Their second outlined an atypical ME/CFS subset. Their current CSF (cerebrospinal fluid) study – an expanded version of the first study which includes a metabolomic component – will be the first to potentially merge immune and metabolic findings in the most energetically active part of the body – the brain.

Peterson’s Atypical Subset Opens New View of ME/CFS in Columbia/Simmaron Publication

Plus, stay tuned for a report suggesting that inflammation is not just present, but pervasive, in ME/CFS patients’ brains.

 

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39 Comments

  • Issie

    June 30, 2018 at 5:34 pm - Reply

    I stick to my belief and what I’ve been saying for years – inflammation and autoimmune – is the “core”. Glad to see that those who can do testing are getting to the “core” problem and not just looking at symptoms (which could be compensation – and the lesser evil).

    As for brain inflammation – that was scientifically proven with me. Last year on my Neuro Quant MRI – my brain was swollen and compressing two major places within it. Creating issues with memory, brain fog and all sorts of problems. This year, happy to say, all is back to normal. I’m also doing a whole lot better all around. Treatment for CIRS and Lyme has been a step forward. Has helped with my POTS too.

    Issie

    • Cort Johnson

      July 1, 2018 at 2:23 am - Reply

      Glad to hear that can be turned around 🙂

  • Tom

    June 30, 2018 at 6:02 pm - Reply

    Can the “metabolic switch from energy-efficient, oxygen-based energy production process to a fast-acting, inefficient glycolysis-based approach” be seen in all cells in the body? How is this seen and measured? Has anyone done a muscle biopsy and or mitochondrial DNA sequencing to look for actual damage in the mitochondria of CFS/ME patients? Is the mitochondria just downshifting or becoming damaged by oxidative stress due to this stressed state? Are the mitochondria of CFS/ME sufferers being permanently damaged or can they be upshifted to normal when the cause is mitigated.

    It would seem easier to look for mitochondrial misbehavior in other high energy use cells such as muscle as opposed to immune cells and astrocytes within the brain. The consequences of its affect on immune cells and astrocytes would seem far worse but it would seem muscle cells are easier to study. I participated in Dr. Naviaux’s metabolomics study and fell into the CFS/ME group solidly but also had a muscle biopsy which showed problems in my thigh muscle mitochondria. I wonder if that damage reported by UCSF pathology is related to CFS/ME or some other unrelated problem?

    Is there any thinking around Miller’s work about whether basal ganglia dopaminergic neurons are being irreversibly damaged as in neurons in the substantia nigra in Parkinson’s disease? Do Parkinson’s treatments like dopamine agonists have any affect on CFS/ME sufferers.

    Is the immune system being triggered by a pathogen and activated which in turn is causing inflammation which in turn is causing the mitochondrial dysregulation which in turn is affecting brain cells – or some other sequence. Or is it a viscous multipath feedback system where something like a pathogen’s immune response sets things in motion and all these problems are reinforcing one another and the whole control system gets stuck in a “survival mode” like state? Have any confirmed CFS/ME sufferers suddenly had resolution suggesting a stuck state versus widespread irreversible damage? Dr. Naviaux had described CFS/ME as resembling a hypometabolic state similar to dauer that seems hopeful if this model is close.

    Has any of the recent work suggested this immune system, inflammation, metabolic and mitochondrial dysfunction might be reversible or has anyone found damage or changes that could be permanent in any of the cells or DNA of the systems.

    • Cort Johnson

      July 1, 2018 at 2:22 am - Reply

      Great questions. Ron Tompkins will be doing some of the muscle work in the new OMF sponsored Harvard ME/CFS Collaborative Center. Avindra Nath is also having muscle biopsies done in the Intramural NIH Study.

      Andrew Miller’s basal ganglia studies were amongst the most fascinating ME/CFS studies I’ve ever seen. My guess is that those dopamninergic neurons are not being irreversibly damaged as in Parkinson’s. https://www.healthrising.org/blog/2014/09/15/unrewarding-reward-basal-ganglia-inflammation-fatigue-chronic-fatigue-syndrome/

      No evidence that I know of has been found of mutations in mitochondrial DNA. I would bet on an autoimmune or autoimmune like process set in place by a pathogen for a substantial number of people with ME/CFS. I would also bet given the lack of physical damage in ME/CFS that the process is potentially entirely reversible.

      • David

        July 2, 2018 at 8:12 am - Reply

        Hi Cort
        You say that no mt mutations have been observed does this include the Japanese studies which showed integration of EBV virus sequences in Mt DNA. If I recall correctly the virus integrated in regions influencing both immune and metabolic functions. Would you say there’s a link here?

  • Dave

    June 30, 2018 at 8:06 pm - Reply

    No mention of pem though….the most disabling aspect of ME

    • Cort Johnson

      July 1, 2018 at 2:15 am - Reply

      Yes but I would not expect PEM to show up in a review of fatigue by an outside group. PEM is a term that was basically invented to explain ME/CFS. This review paper was trying to explicate fatigue to a broad research community which has no understanding of PEM.

      Given that it made sense that it would no mention PEM. Ultimately fatigue is the term that gets other researchers interested enough in ME/CFS to help them eventually understand PEM.

    • TK

      July 1, 2018 at 5:11 am - Reply

      PEM is quite similar to over-training syndrome which is through to be caused by prolonged inflammation.

      • jpvernieri

        July 4, 2018 at 7:21 pm - Reply

        I think that not only PEM but the whole clinical mpresentation of ME/CFS resembles Overtraining

  • Howard

    July 1, 2018 at 12:39 am - Reply

    Yes, I agree, inflammation and autoimmune issues are the keys.

    In my experience reducing inflammation through, diet, acupuncture, supplements & activity, were most helpful. Also Improving my sleep pattern was essential.

    I am convinced that brain inflammation has been a major contributor to my ME/CFS symptoms. Therefore it’s good to see the effort going into this research.

    Also, I could not agree more to focus on the bodies energy production. I have often thought that my body was not getting enough or the right nutrients from my food to cause me feeling exhausted all the time, with no reserve.
    Since I have been on a high-fat low carb diet my energy levels have improved.

    Let’s hope all this research leads to a breakthrough for so many suffers from autoimmune conditions?

    • Cort Johnson

      July 1, 2018 at 2:08 am - Reply

      I found the effects of poor sleep on the immune system and inflammation fascinating. Poor sleep actually results in increased levels of inflammation the next day….

      Stay tuned for some big news on the neuroinflammation found in ME/CFS.

      Congrats on the progress.

      • Howard

        July 5, 2018 at 11:09 am - Reply

        Thanks, Cort,
        Yes, I have been slowly improving for the past 4-5 years. A change in my diet has also helped. I am now on a low carb high-fat diet with the help of a good dietician. She has also suggested an occasionally fast. She works with people with Immune problems.
        In my experience is there is no one quick solution to ME/CFS, just self-monitoring, listening to your body and building a supportive environment, whatever that takes, is so important.

  • Aidan

    July 1, 2018 at 12:48 am - Reply

    If this condition was autoimmune it would have shown up in the small fiber neuropathy work already done by Dr. Anne Oaklander it has not but Glucose does play a major role in small fiber neuropathy & her work is showing we are not getting enough Glucose to our muscles

    • Cort Johnson

      July 1, 2018 at 2:06 am - Reply

      Interesting. Dr. Kaufman said at the Dysautonomia Conference that he’s finding SFN in about 80% of his ME/cFS patients (!).

      • Helen S.

        July 1, 2018 at 8:42 pm - Reply

        That is interesting Cort, as from what I’ve read from various sources is that about 20% of people with M.E. don’t have pain as a symptom. I and my 2 family members with M.E. are in this fortunate situation, although even without the pain it’s no picnic. I wonder if it’s the same 80% who have SFN and pain?

  • Raquel

    July 1, 2018 at 1:58 am - Reply

    All this Makes sense!!!

  • TK

    July 1, 2018 at 4:49 am - Reply

    The thing is, there is no evidence of prolonged/low grade inflammation in CFS patients in particular. Conversely, such inflammation is also present in healthy people and they don’t keel over like CFS patients. My guess is that prolonged inflammation have sensitized CFS patients and their body is over-reacting to normal inflammation as if we over-exerted past our homeostatic limit. But I have my own prejudice, of course, since I succumbed to CFS after years of over-training past my limit.

    Here is an article by Danzer et al, which was written in 2008 and I read like a bible, about how inflammation translates to fatigue and sickness through hypothalamic system: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2919277/

    • Cort Johnson

      July 1, 2018 at 2:36 pm - Reply

      Nice point TK. Yes, traditional measures of inflammation have not found it in either ME/CFS or FM. I like the sensitization hypothesis. I believe that Jarred Younger believes the same.

    • Michiel Tack

      July 5, 2018 at 10:10 am - Reply

      Interesting remark. But maybe it’s just a matter of location? Maybe the location (in the brain) of chronic low grade inflammation accounts for the differences between ME/CFS and other inflammatory diseases like depression?

      I don’t buy the sensitization theory though. It probably plays its part in the symptomatology of ME/CFS but I doubt that it can explain its crippling disability. Central sensitization has been reported in chronic low back pain, chronic neck pain, whiplash injuries, chronic tension headaches, migraine headaches, osteoarthritis of the knee, endometriosis and so on (http://www.instituteforchronicpain.org/understanding-chronic-pain/what-is-chronic-pain/central-sensitization). So I do not think it can be recognized as the main pathology that causes ME/CFS.

  • dejurgen

    July 1, 2018 at 9:22 am - Reply

    “This is because insulin resistance – a common outcome of chronic inflammation – destroys the glycolytic process in astrocytes, causing neurons to get their energy from fats – a slower and less efficient process.”

    That links to another interesting point: transport of fat trough the blood-brain barrier is very poor. That in turn leads to two other consequences:
    A) Fat content in the brain comes very (critical?) low.
    B) Fat stores must be restored by converting glucose/acetylCOA to fat.

    That in turn has more conseuences:
    A) As the brain is a very “fatty” organ, having fat “depletion” likely impairs optimal functioning.
    A) Some fatty acids are intracellular signaling molecules. If fat is short in the brain signaling may be hit as well. Signaling is key in the brain.
    B) Depleted fat stores have to be restored by using glucose, an already constrained resource due to the high glucose consumption caused by the glycolytic process.
    B) Fat construction from glucose (trough acetylCOA derived from glucose) requires NADPH https://en.wikipedia.org/wiki/Fatty_acid_metabolism. That may sound OK, but NADPH is a vital resource to recycle “spent” glutathione to its active form. If large scale fat construction is needed in the brain then glutathione will take a big hit. Low glutathione will increase oxidative stress and damage. Probably worse: glutathione is also a vital component in proper protein construction and folding. Complex protein production is *the* key mechanism by which information in DNA is converted to thousand of hormones, enzymes, cofactors… regulating how our bodies work. If glutathione is too low both protein production will be lower as well as protein misfolding rates will be much higher. This will lead to severe ER (endoplasmic reticulum) stress which can provoke further oxidative stress by itself. Probably worse here too: high misfolding rates are easiest handled by strongly reducing protein construction rates and increasing refolding attempts. As near all of cell functioning and signaling critically depends on steering by these proteins I believe this results in a direct translation to strongly reduced metabolism speed. It sounds like a good candidate to be the core component of ME CDR or “Dauer” IMO.

    • dejurgen

      July 1, 2018 at 10:05 am - Reply

      Split for readability.

      This has links to “common patient’s treatments”. One is providing alternative fuel/building block components:
      * Keto diet delivers ketones. Ketones can both serve as fuel and as source for acetylCOA for fatty acid construction supplementing glucose. Downside: in order to get significant amount of ketones glucose has to be very low so it is not an “increase all” option. IMO a keto diet with much medium chain triglycerides starts producing ketones at a somewhat higher glucose level. This might help improve keto diet performance in ME.
      * Other energy sources can cross the brain-blood barrier as well: short chain fatty acids, medium chain fatty acids and essential fatty acids (wouldn’t be that essential if they couldn’t get past this barrier as they can’t be produced in our bodies would they, looked it up and there is research about it).
      * Short chain fatty acids are rare in food: butter is one of them. A major source of short chain fatty acids is our gut microbiome transforming soluble fiber to SCFA. That links to both the vegan diet (high fiber content) and gut problems (lack of good microbiome).
      * Medium chain FA can pass the barrier too; research does not tell speed is high but it can be done; once again it may lead to supplementing MCFA and may account in part for the anti-inflammatory action of cocos fat. I prefer grinded cocos itself: contains other nutrients besides MCFA and… plenty of fiber.
      * All Omega’s can pass the barrier too; research does not tell speed is high but it can be done; It does link to anti-inflammatory properties of Omega-3 but also can explain why (if Omega-3 supply is sufficient) that large amounts of Omega-6 are not necessarily pro-inflammatory in ME patients: all Omega’s transported trough the brain-blood barrier can be used. Competition of essential enzymes between Omega-3 and 6 may be mitigated by using the later ASAP as fuel.

      I’ll add another look at this and its link to vegan/keto diet and too high blood glucose levels:
      * Too high blood glucose levels are dangerous (diabetic necrosis) and thus too high glucose peaks must be curbed ASAP.
      * When glycogen levels are low in the liver, converting glucose to glycogen is a primary path. Does not seem to cost NADPH as far as I could find.
      *A* When glycogen stocks are maxed out no more glycogen production can be done to lower blood glucose levels. Transforming glucose to triglycerides (FA) must start at full speed. This cost plenty of NADPH.
      *B* When meals with high glycemic index are eaten blood glucose levels spike high. Production of glycogen may be too slow to safely reduce the spike and triglyceride production may start as well.
      *B* makes high (refined) sugar diets very inflammatory.
      *A* makes high carb low fat diets very inflammatory.
      *A* makes high carb whatever fat high caloric diets very inflammatory.
      * Keto diet is clearly low carb.
      * Vegan diet is often low GI with plenty of fiber. Most vegan diets also contain plenty protein and fat.
      * Frutarian diets seem problematic due to higher GI and carb content. IMO eating smaller portions to reduce blood glucose spiking and limiting total caloric intake to prevent too often a liver with full glycogen stores is key here. Having good gut microbiome to produce SCFA or run away with callories if caloric input is too high seems key too.
      * (Intemittend) fasting clearly flushes glycogen stores.
      * In all these scenarios blood triglyceride levels may be a good indicator of success in preventing too much NADPH-costing-FA-production.
      * One can argue that in average persons 60% of NADPH comes from the phosphate pentose pathway so a high carb consumption is OK because it also creates NADPH. I don’t argue against that (see frutarian) diet. I argue that it is very hard to have a high carb diet without a large scale FA synthesis costing this advantage.
      * Keto diets have other means to produce (maybe somewhat smaller) amounts of NADPH but they need to construct far less FA to control blood glucose levels.

    • Cort Johnson

      July 1, 2018 at 2:47 pm - Reply

      Wow. I had never heard of fat transport through the blood brain barrier – and you can conceivably link poor fat transport to glutathione issues. Totally agree that high protein/fat diets are best. I was just told by an exercise physiologist if you start your day off with a high fat/protein meal that will set your system to utilize fats for the rest of the day – and vice versa with high carb breakfasts.

      • dejurgen

        July 1, 2018 at 5:32 pm - Reply

        “I had never heard of fat transport through the blood brain barrier”
        I can search links some day if you like, but not now. Too busy these days.
        Plant Omega-3 may as well not compete as much as believed with other Omega-3.

        ” – and you can conceivably link poor fat transport to glutathione issues.”
        Easier finding links here: https://www.cell.com/trends/biochemical-sciences/pdf/S0968-0004(17)30200-1.pdf “It has been known for several years that glucose depletion can lead to protein unfolding and induction of the unfolded protein response (UPR)…” and
        “One other potential NADPH-dependent ER-localized reductase is ERFAD (FOXRED2). This homolog of glutathione reductase has been implicated in… …ERFAD is a flavoprotein that contains a consensus motif for NADPH binding, but does not contain cysteine residues at the positions of the active-site cysteines in glutathione reductase.”
        Seems a very interesting paper, read other sources, I must reads this long one later.

        “Totally agree that high protein/fat diets are best.”
        Good for maybe many, maybe best for many but some people may do poor on it, like people with protein intolerance for example.

      • dejurgne

        July 1, 2018 at 5:47 pm - Reply

        There is a chance that cutting of pieces from long chain FA to form ketones is not done till the entire LSFA is consumed. If the body would be able to it could provide significant advantages to stop cutting when the LSFA is shortened to MSFA or SCFA and put it in the bloodstream as it would produce “almost free” additional fats that can cross the blood-brain barrier. It could also help understanding why intermittent fasting could be more effective then theoretical expected.
        Would anyone have heard of research indicating such or showing blood values of MSFA or SCFA to be higher in keto patients then expected? If so, I’d love to have a link!

      • dejurgen

        July 1, 2018 at 5:49 pm - Reply

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        There is a chance that cutting of pieces from long chain FA to form ketones is not done till the entire LSFA is consumed. If the body would be able to it could provide significant advantages to stop cutting when the LSFA is shortened to MSFA or SCFA and put it in the bloodstream as it would produce “almost free” additional fats that can cross the blood-brain barrier. It could also help understanding why intermittent fasting could be more effective then theoretical expected.
        Would anyone have heard of research indicating such or showing blood values of MSFA or SCFA to be higher in keto patients then expected? If so, I’d love to have a link!

      • dejurgen

        July 11, 2018 at 9:33 am - Reply

        hi, here are some links:

        https://onlinelibrary.wiley.com/doi/abs/10.1111/joim.12166: “Conclusions … Oral supplementation with n‐3 FAs conferred changes in the n‐3 FA profile in CSF, suggesting transfer of these FAs across the BBB in adults.”

        https://www.intechopen.com/books/neurochemistry/the-blood-brain-barrier-regulation-of-fatty-acid-and-drug-transport:
        “FA transport from blood into paren‐chymal neurons is much more difficult than other cells since the tight junctions of the BBB severely restrict passage into the brain” -> severly restrict does mean few, but more then none
        “The mechanism of FA transport into the brain remains controversial… …Alternatively, others
        studies indicate that FA may enter into cells via specific protein-mediated transport” -> other mechanism then just passing the tight BBB junctions are amongst the hypothesized transfer mechanisms. I found for example studies describing such potential alternative (and slower) mechanism for omega-3
        Note: several mechanisms are described that can increase BBB permeability and thus increase FA transport speed, but also pathogen transport speed. One of them is high amounts of arachidonic acid but it’s role still remains controversial.
        “In addition, transport appeared to be dependent upon fatty acyl chain length and degree of
        unsaturation.” -> omega’s are unsaturated, omega 3 and 6 poly unsaturated, 7 and 9 mono unsaturated affecting speed crossing the BBB; vegan diets contain plenty of unsaturated fats of the supposedly (science inconclusive) inflammatory type; if however the brain would use them as fuel or transforms them to other fats…
        Note: BBB transport of SCFA is even easier as they are shorter, more links to be found

      • dejurgen

        July 11, 2018 at 9:50 am - Reply

        While searching links to FA crossing the BBB I did found a few interesting things about medium chain FA:

        https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(17)30408-8.pdf

        “However, some studies have challenged the central role of ketones because medium-chain fatty acids, which are part of a commonly used variation of the diet (the medium-chain triglyceride ketogenic diet), have been shown to directly inhibit AMPA receptors (glutamate receptors), and to change cell energetics through mitochondrial biogenesis.” -> mitochondrial biogenesis might be very fine in ME/FM IMO. As I describe earlier cutting parts from LCFA to form ketones will result in MCFA as a by-product IF the cutting stops (for at least part of the FA) when MCFA length is reached.

        https://gut.bmj.com/content/gutjnl/15/3/180.full.pdf:
        “Medium chain triglycerides which contain predominantly C8 and Clo saturated fatty acids have been found to be of value in the treatment of fat malabsorption due to a variety of causes including, for example, pancreatic insufficiency and intestinal disease” -> intestinal disease (IBS, overgrowth…) is common in ME/FM
        “Short and medium chain fatty acids have been reported to exhibit a narcotic effect on various species of experimental animals when given in large intravenous doses” -> less pain with more SCFA and MCFA; keto diet may produce SCFA and MCFA as byproduct from cutting larger FA; vegan diet produces SCFA by gut flora converting indigestible fiber (and resistant starch?) to SCFA

        Note: keto diets with MCFA supplementation are an effective alternative to classic keto diets; ketones start beiing produced earlier and results start at higher carb intake
        My ideas: in both keto and vegan or pseudo-vegan diet increasing MCFA intake may be benificial; I prefer grinded cocos as it’s the whole product with the fiber my gut flora may convert to SCFA

      • dejurgen

        July 14, 2018 at 4:37 pm - Reply

        I found another interesting link between difficult fat transport to the brain (BBB), gluthathione, NADPH and energy metabolism:

        https://link.springer.com/chapter/10.1007/978-4-431-55651-0_1
        “ROS inhibits multiple glycolytic enzymes… …Consistently, glycolytic inhibition promotes flux into the oxidative arm of the pentose phosphate pathway to generate NADPH. NADPH is critically important, as it provides the reducing power that fuels the protein-based antioxidant systems and recycles oxidized glutathione.”
        -> A) So lack of NADPH reduces speed of glycolisys.

        http://jb.asm.org/content/189/18/6665.full
        “In this study we demonstrate a metabolic network promoting NADPH production and limiting NADH synthesis as a consequence of an oxidative insult.”
        “The activity and expression of glucose-6-phosphate dehydrogenase, malic enzyme, and NADP+-isocitrate dehydrogenase, the main generators of NADPH, were markedly increased during oxidative challenge.”
        “On the other hand, numerous tricarboxylic acid cycle enzymes that supply the bulk of intracellular NADH were significantly downregulated. These metabolic pathways were further modulated by NAD+ kinase (NADK) and NADP+ phosphatase (NADPase), enzymes known to regulate the levels of NAD+ and NADP+.”
        “Thus, NADK and NADPase play a pivotal role in controlling the cross talk between metabolic networks that produce NADH and NADPH and are integral components of the mechanism involved in fending off oxidative stress. ”
        “If an aerobic organism is to survive, it is essential that an adequate supply of NADPH is available. This nicotinamide nucleotide provides a reductive environment that enables the oxidative cell to nullify the reactive oxygen species (ROS) generated as a consequence of oxidative phosphorylation, a process key to the generation of ATP… …Catalase, superoxide dismutase (SOD), and glutathione peroxidase are some of the enzymes that help decrease oxidative tension during aerobic respiration (4). However, the effectiveness of these proteins as the scavengers of ROS depends on the availability of NADPH.”
        “Hence, the production of this reducing agent is an integral part of the oxidative energy-generating machinery of all aerobic organisms. Production of ATP via oxidative phosphorylation cannot proceed effectively in the absence of a continual supply of NADPH (14, 31).”
        “Hence, a fine balance has to be maintained between these two nicotinamide nucleotides if a cell is to function in an efficient manner. Thus, a normal functioning cell has to have adequate levels of NADPH and ATP and a small amount of NADH.”
        -> B) A good ratio between NADPH, ATP and NADH has to be maintained.
        -> C) If NADPH is dropping too low, NADH and ATP metabolism are inhibited (basically the Krebbs cycle stops producing sufficient ATP) and NADPH is produced instead.

        D) We also know that large amounts of oxidative stress do cause a CDR, shifting mitochondria from producing ATP to ROS/H202.

        -> So combining A) B) C) and D): if strong oxidative stress is present, even more ROS/oxidative stress is produced. In order to counteract this both glycolisys and the (NADH/ATP producing part of the) Krebbs cycle itself are strongly downregulated in favor of the phosphate pentose pathway and the parts of the Krebbs cycle that can shift production from NADH to NADPH. That’s starving cells from energy by strongly blocking both aerobic as anaerobic paths.
        -> As NADPH is consumed by both oxidative stress as by fat synthesis, constructing fat in a brain under oxidative stress has a lot of potential to be problematic.

        Note: Ketogenic diets seem to follow another path: upregulation of genes encoding anti-oxidants and their enzymes https://iubmb.onlinelibrary.wiley.com/doi/full/10.1002/iub.1627 “increase the transcription of genes encoding antioxidant enzymes, including superoxide dismutase 2, catalase, glutathione peroxidase, and hundreds of other genes.”

        • Issie

          July 14, 2018 at 10:04 pm - Reply

          The latest thing my naturopath doc is into is NAD. She gives it IV. I just took the Life extension version. Did two bottles. I don’t know if it made that much of a difference – since I’m already doing better as a whole. But it may be worth a try for some.

          I don’t do full out keto. But I do 16 hour intermediate fast every day. I use coconut milk and a few sprays of MCT oil in coffee and put a shake of cinnamon and ginger in it. All helps!

          Isdie

  • Erik Johnson

    July 1, 2018 at 1:56 pm - Reply

    I contacted Robert Dantzer after Mold Warriors was published in 2005 and told him about “Mold at Ground Zero for CFS” and Dr Shoemaker’s work. After a short correspondence where he almost seemed interested, he ceased communication with no followup or contacting Dr Shoemaker.

    https://www.bmj.com/rapid-response/2011/10/30/depression-sixth-sense

    —————————————————————————————————————-

    Mold Warriors by Dr Ritchie Shoemaker
    Gateway Press 2005

    Chapt. 23
    Mold at Ground Zero for CFS

    History Doesn’t Remember the Names of the Critics

    The history of Chronic Fatigue Syndrome (CFS) begins in Incline Village, Nevada in 1985. In the medical history of CFS, each of the concepts applies–failed theories and failed criticism.
    One victim, Erik Johnson, told everyone who would listen that mold was a cause of CFS. He came up with his theory at the wrong time in the politics of medical opinion, as a unknown viral cause was blamed instead. Johnson tried repeatedly to get the attention of leading CFS researchers then and now to look at what he knew about mold sensitivity. None of the heralded CFS researchers would listen.
    Twenty years passed before Erik’s mold opinions were vindicated. I wasn’t in Incline Village; I have no idea what really happened there.

  • konijn

    July 1, 2018 at 9:22 pm - Reply

    I am disapointed that when you look at pub med, it is just about chronic fatigue. Not ME/cfs and all the other symptoms that come allong with it. Just chronic fatigue. As if that is ME/cfs.
    I suffer for 30 years and am since decades 95 to 99% bedridden still getting worse and worse.
    All the “studys/hypothesis/and broken promisses and other bla, bla words,…”I have read over the many, many years, if for every word that was written, was given worldwide 1 dollar, we would be cured.
    We need tons off money, big studys, brilliant researchers, and so on. That is what I want. I want to be helped.
    Luckily there are a few brilliant scientists and is for excample the omf, together with all the other scientists pushing things forward. But they have all one thing in common, in fact allmost no money to do regourous research.
    And I meean for excample 100,000,000.00million.
    So must we really be thankfull for such an article? I can not cope anymore… I could cry! I am desperate! And this article will help me in no way.

    • Cort Johnson

      July 2, 2018 at 4:47 am - Reply

      I don’t understand. Every reference to ‘chronic fatigue syndrome is to an ME/CFS researcher. Because this review is published in a good journal it should reach quite a few other researchers – who now know that the inflammation in ME/CFS may be causing metabolic breakdowns that are resulting in fatigue. If you want more researchers to study ME/CFS articles like this are an excellent way to get them interested.

      • konijn

        July 2, 2018 at 1:51 pm - Reply

        It is from pub med. It is the beginning off the text. “Chronic or persistent fatigue is a common, debilitating symptom of several diseases. Persistent fatigue has been associated with low-grade inflammation in several models of fatigue, including cancer-related fatigue and chronic fatigue syndrome.”

        What got to me was the simply “chronic fatigue” and in many deseases. I thought I am much more then just simply chronic fatigued. They even not began with ME/cfs. Just chronic fatigued… It is like saying, oh, I am fatigued to.I am bedridden. So a little bit different then chronic fatigued an with much more symptoms.

        That is why I reacted so.

        It is also not a study. Just a hypothesis off what other real reseachers have found.

  • Kathryn

    July 2, 2018 at 1:10 pm - Reply

    LOL, I haven’t read the article and comments yet because I got stopped dead at this:

    “research group lead by Robert Dantzer”

    The proper word is:

    led
    led/

    I understand perfectly how ”lead” was used, because of it’s dual pronouncement, and I
    have done the same thing, but being led astray by the lead of the introduction of the researcher on this subject, caused my brain to say, ”What!? is that correct!? I must go check that know-it-all google” Now I can read the article, for which I thank you, Cort. Ahhh…

    past and past participle of lead1.

  • Andrew David Shiller

    July 5, 2018 at 5:31 am - Reply

    You said “the basal ganglia – the dopamine-producing center of the brain”.
    That doesn’t sound quite right.
    The substantia nigra is the main source of dopamine–those are the cells that degenerate in Parkinson’s disease.
    The basal ganglia are motor-system areas that work on movement and integration of movement.

    • Cort Johnson

      July 6, 2018 at 5:12 pm - Reply

      These brain structures can be confusing particularly since the basal ganglia are composed are several of them. This is what Wikipedia says about the substantial nigra.

      Substantia nigra

      The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. Substantia nigra is Latin for “black substance”, reflecting the fact that parts of the substantia nigra appear darker than neighboring areas due to high levels of neuromelanin in dopaminergic neurons.[1] It was discovered in 1784 by Félix Vicq-d’Azyr,[2] and Samuel Thomas von Sömmerring alluded to this structure in 1791.[3] Parkinson’s disease is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta.[4]

  • jpvernieri

    July 5, 2018 at 9:32 pm - Reply

    Cort, correct if I’m wrong, but I think that the autopsy report from that young, british patient who died from ME showed vascular damage//low garde inflamation in the spinal cord and basal ganglia.
    maybe that’s why some patients report symptom relief from dopaminergic antidepressives?

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