Chronic Fatigue Syndrome Support Group
Chronic Fatigue Syndrome (ME/CFS) describes a sense of exhaustion and post-exertion malaise, even when you have gotten enough rest and sleep. The disease is characterized by six months of incapacitating fatigue experienced as profound exhaustion and extremely poor stamina, and problems with concentration and short-term memory. The cause is unknown, but it is a...
I wanted to get another thread going to maybe try and round up a few more pieces of the puzzle.
"...a blood-based test that successfully identified participants in a study with chronic fatigue syndrome. The test, which is still in a pilot phase, is based on how a person’s immune cells respond to stress. With blood samples from 40 people — 20 with chronic fatigue syndrome and 20 without — the test yielded precise results, accurately flagging all chronic fatigue syndrome patients and none of the healthy individuals"
Also, I am on the DS Hidradenitis Suppurativa forum, and I think over there we are dealing with chronic infection and it sounds like it's biofilm, and I keep trying to figure out how to explain biofilm to people without sounding as depressing and hopeless as most literatures makes it sound. Most things I read make it sound like biofilm is invincible in the face of antibiotics, and sometimes its hard to tell whether that's true or whether that's just the occasion for a absurd number of research projects and papers into "invincible" biofilm. I think even Robin Patel at the Mayo Clinic has probably been lead up the wrong path before on that.
I often refer people to things that Dr. Randall Wolcott writes about biofilm. As I understand it, he was an understudy of the fellow that is called "the father of biofilm" for pioneering the field in the 1970s. I wanted to check in again recently and see how far he's gotten with putting knowledge into practice. He is a wound care specialist and deals with a lot of wound infections where chronic ones often seem to involve biofilm, and deals with things like diabetic foot ulcers a lot. I squinted at the fine print to see how he is getting even such nasty infections "75% cleaned up" but the only thing new I cound find in the description was that they were choosing antibiotics according to what people were infected with, which may constitute the "targeted antibiotic therapy" that the cutting edge HS research from the Pasteur Institute has been calling for - and we may be able to read into that any number of cases of chronic wound healing failures because of the wrong choice of antibiotics, rather than the "invincibility" of biofilm, which might be cause for optimism.
I don't think this is going to be the be-all, end-all then, but while I was Googling for that, I stumbled over a number of references to a therapeutic strategy for dealing with biofilm of PYRUVATE DEPRIVATION.
Basically I found this
APRIL 23, 2019
New dispersion method to effectively kill biofilm bacteria could improve wound care
by Binghamton University
https://phys.org/news/2019-04-dispersion-method-effectively-biofilm-bacteria.html
"Researchers at Binghamton University, State University of New York have developed a method to treat bacterial infections which could result in better wound care.
Biofilms are a structured community of bacterial cells that are adherent to inert or living surfaces. What makes these structures special is that living within these biofilm communities makes its resident bacteria resistant to antibiotics. A research team led by Karin Sauer, professor of biological sciences at Binghamton University, demonstrated that two important human pathogens, P. aeruginosa and S. aureus, need pyruvate to form these structured biofilm communities that are inherently resistant to antibiotics. In turn, the research team demonstrated that removal of pyruvate induces a physiological change in biofilm bacteria that has two consequences: 1) it causes them to disassemble the biofilm structure in a process referred to as biofilm dispersion; and 2) it renders biofilm bacteria more susceptible to antibiotics.
"Our in vitro laboratory findings translated to animals and chronic wound infections, as exposing infected burn wounds to pyruvate depleting conditions not only reduced the bacterial burden present in these wounds, but also enabled the effective killing of biofilm cells by the antibiotic tobramycin," Sauer said.
Biofilm infections are almost impossible to treat by conventional antibiotic therapy."
There we go with the gloom, doom and hopeless again...
Next I Googled for "elevated pyruvate"
What does elevated pyruvate mean?
An elevated lactate-to-pyruvate (L:P) ratio may indicate inherited disorders of the respiratory chain complex, tricarboxylic acid cycle disorders and pyruvate carboxylase deficiency. Respiratory chain defects usually result in L:P. ratios above 20.
https://medlineplus.gov/genetics/condition/pyruvate-carboxylase-deficiency/
What causes high pyruvate levels?
Pyruvate carboxylase deficiency is an inherited disorder that causes lactic acid and other potentially toxic compounds to accumulate in the blood. High levels of these substances can damage the body's organs and tissues, particularly in the nervous system.Aug 18, 2020
I think most of us have heard of lactate or lactate in relation to ME/CFS?
When I Googled for "pyruvate depletion" I found more articles like the first one.
Pyruvate-depleting conditions induce biofilm dispersion and enhance the efficacy of antibiotics in killing biofilms in vitro and in vivo
by J Goodwine · 2019 · Cited by 17 · Related articles
https://www.nature.com/articles/s41598-019-40378-z
https://cysticfibrosisnewstoday.com/2019/03/22/new-strategy-may-help-boost-antibiotic-efficacy-cf-patients/
Removing a key metabolite called pyruvate from Pseudomonas aeruginosa and Staphylococcus aureus bacteria biofilms — two of the most common bacteria found in cystic fibrosis (CF) patients — could help boost the effectiveness of antibiotics, a study reports...
To test their hypothesis, researchers used an enzyme called pyruvate dehydrogenase (PDH) that degrades pyruvate into other molecules.
They observed that P. aeruginosa bacteria in biofilms treated with PDH were reduced by up to 2.9 log (by about 794 times) with increasing concentrations of the enzyme. A similar observation was made with S. aureus biofilms.
Researchers then tested whether molecules that fuel PDH activity, such as NAD+ and CoA cofactors, could play a role in biofilm maintenance, and saw that providing these molecules alone had no effect."
And etc.
So about New Year's Eve I got cocky and tried taking quercetin again. It's supposed to be a mast cell stabilizer, probably among other functions. Just like last year I seemed to get great benefits, but woke up worse than ever and with such respiratory distress that I don't want to touch the stuff again (this is the very same thing as last year, works wonders but I paid for it the next day), and I don't know how to explain that but I clearly got the impression that even though it really helped with muscle fatigue and so forth, that it might also have been giving aid and comfort to an infection that is playing a role in the symptoms and that mast cells may be responding to infection, perhaps in absentia of other immune cells like phagocytes, the "first responders".
I certainly got the sense that mast cells could be responsible for most of my symptoms, though, seeing again what quercetin seemed capable of doing about them at least in the short term
I think Paolo Maccallini and Ron Davis have both gotten a little bit into mast cells and a possible role in ME/CFS, but I'm not sure how far they've gotten overall https://paolomaccallini.com/2016/06/02/fatica-post-sforzo-e-mastociti/
I also tried to catch up with Amy Proal a bit. I don't quite worship the ground she walks on (I was not impressed with the whole Marshall Protocol business, to name one) but I do have tremendous respect for her and if she has any shortcomings, it may be because she's on the cutting edge of things where there is so much to deal with that it's enough to confuse anyone.
http://microbeminded.com/
Interview with Resia Pretorius: how bacteria, viruses and their inflammatory products can impact blood clotting in chronic disease
August 6th, 2020 by Amy Proal
"...At the beginning of the interview, Resia explains why her lab started studying bacteria in the blood of patients with Parkinson’s and Alzheimer’s disease. When she started the research, most of the scientific community did not think bacteria were capable of persisting in human blood. In fact, that’s what Resia and her students also believed. However, two of her students were trying to perform studies on Alzheimer’s and Parkinson’s blood and, to their surprise, kept finding bacteria in the blood samples. At first, they assumed that the bacteria must be contaminants (they assumed the bacteria in the samples were derived from the lab or the external environment as opposed to the human body). But, as they performed an increasing number of sterilizing approaches in an effort to prevent this bacterial “contamination,” nothing worked. Finally, they were forced to consider the possibility the bacteria in their samples might not be contaminants, but actual organisms present in Alzheimer’s and Parkinson’s blood..."
That seems to be a problem I often face with doctors and why I've gotten almost no help overall, is that they can't bring themselves to believe there is infection present as if they are aren't aware of any of the relevant research and aren't going to take a patient's word for anything even if you give them references.
Searching also took me to Amy's Twitter account where things appear to have been quiet most of the year (back in April there were posts that she might have caught Covid and then things were very quiet until a New Year's greeting and a link to a paper she'd worked on
Amy Proal, PhD
@microbeminded2 - 17h Happy 2021!
@MBVanElzakker and I are excited to share our new article published in #Immunometabolism: “Pathogens Hijack Host Cell Metabolism: Intracellular Infection as a Driver of the Warburg Effect in Cancer and Other Chronic Inflammatory Conditions”:
https://ij.hapres.com/htmls/IJ_1341_Detail.html
I don't want to get into splitting hairs too much at the moment, but there are probably some distinctions to be made so that it may not be correct to make any sweeping connections between CFS and cancer, but it really is an interesting paper even if one can't believe everything they read.
Anyway, the P-word (PYRUVATE) also appears here right out of the gate
"INTRODUCTION
A central focus of immunometabolism research relates the metabolic signaling changes of cells to their function. Nearly all mammalian cells adapt their metabolism to transition from quiescent states to activated states that allow for more rapid energy production and changes in cellular capacity [1–3]. A primary example of this phenomenon is known as the Warburg effect. The Warburg effect refers to a metabolic shift in which cells move towards preferentially using aerobic glycolysis rather than oxidative phosphorylation (OXPHOS) to generate ATP and macromolecules [1,4]. More specifically, under normal resting conditions, most cells begin the process of generating energy by metabolizing glucose to pyruvate. Pyruvate is then shuttled into the mitochondria where it is oxidized by the tricarboxylic acid (TCA) cycle to generate ATP via the electron transport chain. This process is called oxidative phosphorylation and can generate up to 36 ATP per molecule of glucose [2]. Cells that enter a classic Warburg effect metabolism shift from using OXPHOS for ATP production to an alternate form of energy production called aerobic glycolysis [5]. During aerobic glycolysis, cells still convert glucose directly to pyruvate but pyruvate is subsequently fermented to lactate in the cell cytoplasm, even in the presence of adequate oxygen. Under such conditions, only 2 molecules of ATP are generated per molecule of glucose."
Maybe all this is just saying the same things as usual but in a different way, but basically what I'm wondering is
1) If having your mitochondria decoupled leads to elevated cellular pyruvate which in turn may promote intracellular biofilm.
2) Just in case research never makes up its mind about how tough biofilm really is, whether we may be looking at something that could help to purge cells of infections that may be causing problems in ME/CFS and perhaps numerous other conditions.
Another theory that popped into my head about why quercetin seemed to be counterproductive popped into my head is that it's probably a powerful antioxidant, and another curious thing I found was that apparently Dr. Patel had signed onto an idea promoted by some of a handful of researchers I particularly admire (I refer to them as the "Musketeers"; at first there were three of them), who claimed that at least in the lab dish, antioxidants could protect microbes from antibiotics.
About all I can really say is that the day after quercetin was very much like the day after getting into one of my "no-no foods", can barely move, don't think I can breathe (even if I can), massive distress in the chest, huge outbreak of Tourette's (and indulging the Tourette's seems to help me get my breath back whether or not I've really lost it). As far as my breathing goes, what actually seems to be happening is a lot of hyperventilating, which is one of as many as 7 different ME/CFS symptoms I think I have, although I can't get a diagnosis because the tests come back "normal" except for low Vitamin D, and recently when I tried supplementing even about 1/20th of the daily recommended dose as a cautious start, within in the week I'd had two breathing attacks so dramatic that neighbors responded, and an uncharacteristically acute panic attack as well that also got the neighbors worried, so I've bagged the Vitamin D too.
Basically still tired of getting worse instead of better when I follow doctor's orders and really wanting to get to the bottom of what's going on here.
Anyway, Happy New Year. I hope this year we find some real answers even if we have to ferret them out ourselves.
Many thanks for the reply. Agreed, it's a lot to take in and I wish the focus of the article were a little more on bacteria particularly, but I think a lot of it touches on things that have been discussed here before, mitochondrial decoupling and so forth.
I think this might be a particularly telling passage
"More specifically, under normal resting conditions, most cells begin the process of generating energy by metabolizing glucose to pyruvate. Pyruvate is then shuttled into the mitochondria where it is oxidized by the tricarboxylic acid (TCA) cycle to generate ATP via the electron transport chain. This process is called oxidative phosphorylation and can generate up to 36 ATP per molecule of glucose [2]. Cells that enter a classic Warburg effect metabolism shift from using OXPHOS for ATP production to an alternate form of energy production called aerobic glycolysis [5]. During aerobic glycolysis, cells still convert glucose directly to pyruvate but pyruvate is subsequently fermented to lactate in the cell cytoplasm, even in the presence of adequate oxygen. Under such conditions, only 2 molecules of ATP are generated per molecule of glucose."
I know I've posted a lot about adenosine, which microbes may produce, and which I believe can decouple mitochondria.
So here we seem to get lactate production independent of mitochondria and a very poor return on fuel efficiency at only 2 molecules of ATP produced from a molecule of glucose vs 36 molecules of ATP from a molecule of glucose with things running in a more healthy and efficient mode. Sounds to me a bit like Post-Exertional Malaise with low energy production and lots of lactic acid/lactate.
Also, the article by Goodwine et al https://www.nature.com/articles/s41598-019-40378-z extends the same caution that Dr. Davis or I might - there seems to be a bit of consensus that biofilm is in some ways better behaved that ordinary bacteria, and that while "waking it up" (dispersal) may help make it more vulnerable, it may also make some microbes more dangerous by allowing them further spread and exhibit greater virulence and aggression.
"As planktonic cells have been reported to be more susceptible than their sessile counterparts to killing by the immune system, it is likely that PDH treatment may improve the ability of the host to eradicate recalcitrant bioflm infections. Our findings, however, are in contrast to reports by Fleming et al. Using the enzyme glycoside hydrolases to disaggregate biofilms in a mouse wound model, the authors noted large-scale dispersal events, apparent by dissemination of infection and possibly lethal septicemia in the absence of antibiotic therapy".
(Sessile = biofilm, planktonic = ordinary free circulating microbes)
It sounds as if the wisest course might be to combine biofilm dispersal methods with antibiotic agents so that they wake up and become more vulnerable to antibiotics.
Also, the abstract for that article has a really good recap of some basics about biofilm and why it is such an important subject
""Biofilms are defined as a structured community of bacterial cells enclosed in a self-produced polymeric matrix and adherent to inert or living surfaces. The ability to form a biofilm is a common trait of a diverse array of microbes, including lower order eukaryotes, with biofilms having been recognized as the dominant mode of bacterial growth. Biofilms are the root cause of a variety of chronic infections such as lung infections in patients suffering from cystic fibrosis and infections related to indwelling medical devices such as ventilator-associated pneumonia in intubated patients, and urinary tract infection due to catheters. The National Institutes of Health estimated that 65% of all nosocomial infections are due to bacteria growing as biofilms and that biofilms are responsible for over 80% of microbial infections. Furthermore, the United States Center for Disease Control (CDC) estimated that biofilms are the etiologic agent in 60% of all chronic infections, including biofilms associated with cystic fibrosis (CF), burn wounds, and chronic wounds..."
Again though, with numbers like that I wonder if biofilm is really so "invincible" to antibiotics even in a biofilm state. They'd make you think antibiotics went on the market when they didn't work 2/3 or 4/5 of the time, whereas a higher clinical success rate may indicate cases where they've worked on biofilm.
So hopefully there is cause for cautious optimism not only that the pieces are falling into place and fitting together, but also that better treatment options could be in sight.