Hypothesis ME CFS hydrogen sulfide metabolism

Discussion in 'Fibromyalgia Main Forum' started by tansy, Sep 20, 2008.

  1. tansy

    tansy New Member

    Hypothesis: Chronic fatigue syndrome is caused by dysregulation of hydrogen
    sulfide metabolism

    Journal: Med Hypotheses. 2008 Sep 15. [Epub ahead of print]

    Author: Marian Dix Lemle, Washington, DC 20008, United States, Fax: +1 202 775 0045

    NLM Citation: PMID: 18799269

    Chronic fatigue syndrome (CFS), which is also known as myalgic
    encephalomyelitis (ME), is a debilitating, multi-system disease
    whose etiology is unclear, and for which there are as yet no reliable

    Here the hypothesis is advanced that the multi-system
    disturbances in CFS/ME are caused by disturbances in the homeostasis
    of endogenous hydrogen sulfide (H2S) and result in mitochondrial

    Research on H2S -- the gas that causes the characteristic smell of
    rotten eggs -- dates to the 1700s and has shown a remarkable
    range of effects in both animals and humans. At high concentrations,
    H2S has a variety of biological toxicities including being
    instantaneously deadly; at low concentrations some evidence suggests
    that H2S has beneficial effects and can act as an endogenous
    biological mediator the third such gaseous mediator discovered
    (after nitric oxide and carbon monoxide).

    The brain, pancreas and
    the gastrointestinal tract produce H2S. Endogenous H2S plays a role
    in regulating blood pressure, body temperature, vascular smooth
    muscle, cardiac function, cerebral ischemia, and in modulating
    the hypothalamus/pituitary/adrenal axis. It even has been called
    a "master metabolic regulator."

    Recent research has demonstrated that at low, non-toxic doses,
    exogenous H2S produces a reversible state of hibernation-like deanimation
    in mice, causing a decrease in core body temperature,
    an apnea-like sleep state, reduced heart and respiration rates,
    and a severe metabolic drop [1]. These characteristics are not unlike
    the symptoms and extreme "de-animation" experienced by
    CFS/ME patients.

    Moreover, H2S affects biological networks that
    are disrupted by CFS including neurologic, endocrine and immunologic
    systems. Therefore, a plausible etiology of CFS is an increase
    in the activity of endogenous H2S, thereby inhibiting mitochondrial
    oxygen utilization.

    H2S and Mitochondria
    In this view, fatigue and the other CFS/ME symptoms could be
    due to diminished physiological and cellular energy due to reduction
    in the capacity of mitochondria to utilize oxygen and synthesize
    ATP. Specifically, H2S binds to the mitochondrial enzyme
    cytochrome c oxidase, which is part of Complex IV of the electron
    transport chain, and attenuates oxidative phosphorylation and ATP

    Consistent with this finding, recent research on low level H2S toxicity
    points to increased formation of free radicals and depolarization
    of the mitochondrial membrane, a condition that would
    decrease ATP synthesis [2].

    If poisoning renders mitochondria inefficient,
    one would expect cells to shift to anaerobic mechanisms, a
    shift that has been reported for CFS patients. Also consistent with
    this hypothesis is the fact that mitochondria are organelles descended
    from ancient eukaryotic sulfur-utilizing microbes. Thus, it
    is not surprising that they show a very high affinity for sulfide.

    Of course, H2S or sulfide may not directly affect mitochondria
    by binding to them. Genomic changes could mediate some of the
    effects of H2S. Some studies have found evidence for the involvement
    of the cytochrome c oxidase gene in CFS/ME.

    Also, investigators
    have found CFS abnormalities in genes related to fatty acid
    metabolism, apoptosis, mitochondrial membrane function, and
    protein production in mitochondria.

    Given a predisposing genetic
    background, H2S may lead to genomic instability or cumulative
    mutations in the mitochondrial DNA [3].

    Alternatively, the effects of H2S could be initially mediated by
    changes in the redox potential of cells or changes in their sulfur
    metabolism, especially in glutathione.

    Another possible mechanism
    is a direct effect of H2S on the immune system. Recent research
    indicates that exogenous hydrogen sulfide induces
    functional inhibition and cell death of cytotoxic lymphocyte subsets
    of CD8 (+) T cells and NK cells.

    Finally, H2S plays a pivotal role in both aerobic and non-anaerobic
    organisms as a signaling molecule.

    Bacteria in the gut both produce
    H2S and utilize it as a substrate alternative to oxygen. This is of
    particular relevance in the gastrointestinal tract, where unusually
    high levels of gram-negative bacteria, which increase intestinal permeability,
    have been found in patients with CFS/ME [4].

    In addition
    to bacteria, yeast, mold and other fungi also emit H2S.
    CFS/ME is a model disease for multisystem disturbance. It is my
    hypothesis that mitochondria, organelles required by every cell to
    sustain life, are unable to adequately utilize oxygen.

    This mitochondrial
    disturbance could be due to the combined effects of
    anaerobic conditions known to occur in CFS and associated low-level
    H2S toxicity. This increase in H2S alters fine signaling necessary
    for body homeostasis, and causes CFS.

    Understanding the role of
    H2S in the body, and, in particular, in mitochondrial function,
    may provide a unifying lens through which to view the diverse
    manifestations of this complex disease.

    [1] Blackstone Eric, Morrison Mike, Roth Mark B. H2S induces a suspended
    animation-like state in mice. Science Magazine 2005;308(5721):518.
    [2] Eghbal MA, Pennefather PS, OBrien PJ. H2S cytotoxicity mechanism involves
    reactive oxygen species formation and mitochondrial depolarisation.
    Toxicology 2004;203(13):6976. PMID: 15363583.
    [3] Attene-Ramos MS, Wagner ED, Gaskins HR, Plewa MJ. Hydrogen sulfide induces
    direct radical-associated DNA damage. Mol Cancer Res 2007 [PMID: 17475672].
    [4] Maes M, Mihaylova I, Leunis JC. Increased serum IgA and IgM against LPS of
    enterobacteria in chronic fatigue syndrome (CFS): indication for the
    involvement of gram-negative enterobacteria in the etiology of CFS and for
    the presence of an increased gut-intestinal permeability. J Affect Disord
    2007;99(13):23740. PMID: 17007934.
  2. ulala

    ulala New Member

    How to decrease h2s? I found an article that says that Pepto Bismol decreass it in the colon.

    GASTROENTEROLOGY 1998;114:923-929
    Bismuth Subsalicylate Markedly Decreases Hydrogen Sulfide Release in the Human Colon
    Research Department, Minneapolis Veterans Affairs Medical Center, Minneapolis, Minnesota

    Background & Aims: Hydrogen sulfide is one of the main malodorous compounds in human flatus. This toxic gas also has been implicated in the pathogenesis of ulcerative colitis.

    Therefore, a treatment that reduces colonic H2S levels could be clinically useful in the treatment of flatus odor and of ulcerative colitis. In this study the ability of bismuth subsalicylate, a compound that binds H2S, to reduce H2S release in the colon, was tested. Methods: Homogenates made from human and rat feces were incubated with and without bismuth subsalicylate, and gas production was measured.

    Fecal samples from 10 healthy subjects were analyzed before and after ingestion of bismuth subsalicylate (524 mg four times a day) for 3-7 days. Results: Fecal homogenates showed a dose-dependent relationship between the concentration of bismuth subsalicylate and H2S release.

    Treatment of subjects with bismuth subsalicylate produced a >95% reduction in fecal H2S release. Conclusions: The ability of bismuth subsalicylate to dramatically reduce H2S could provide a clinically useful means of controlling fecal and/or flatus odor and of decreasing the putative injurious effects of H2S on the colonic mucosa.

    GASTROENTEROLOGY 1998;114:923-929
  3. findmind

    findmind New Member

    How many tablespoons is this, to have to take 4 times a day?

    This is a very interesting article, and we have heard of this sulfide problem in CFS/ME before.

    Let's keep this bumped, ok? I intuit that it is valuable.

  4. jole

    jole Member

    This certainly makes more sense than the "cell phone, microwave" theory!!!

    I think whenever we find out what really causes our DD it will be a combination of things...because we all know none of us are entirely the same or react to treatments the same. ***Jole***
  5. mbofov

    mbofov Active Member

    I just wonder what originally causes the disregulation of hydrogen sulfide?

    And if this has anything to do with sensitivity to sulfur-containing foods like garlic?

    Thanks for posting --

  6. findmind

    findmind New Member

    more people need to read this.


  7. Rafiki

    Rafiki New Member

    Thanks so much Tansy for bring us, once again, some really interesting stuff! If the details of this hypothesis are correct it certainly seems credible.

    A caution about Pepto Bismol. The Bismuth in Pepto Bismol can cause neurotoxicity and other problems when consumed in amounts exceeding the recommended daily dose or when taken for a longer time than recommended. I'm not sure this is a safe substance to consume over a long period of time.

    Again, great article Tansy! Thank you mucho!

  8. Rafiki

    Rafiki New Member

    I could not remember what term was used in this piece to describe ME (aka CFS) but was struck by it's perfection and came back to find it.

    De-animation (along with the other things listed like low core temp.) describes perfectly what has happened to me.

    Even when I do not feel particularly ill, I experience a degree of de-animation that renders me almost unrecognizable as my old self.

    Before ME, and between onset and relapse, I could not speak with my tongue without also speaking with my mouth. (EDIT: LOL! Of course I couldn't! LOLOL! What I meant to say was that I could not speak without using my hands! LOL!) I was ridiculously animated. Now, I am still. Even on my best days I am still. I am de-animated. Fighting the stillness brings illness. (I did not mean to rhyme but too foggy to write a better sentence.)

    Anyone else find this description particularly apt?

    Peace out,

    [This Message was Edited on 12/09/2008]
  9. simonedb

    simonedb Member

    yep that stood out to me too when I read it
    I hadnt thought of it that way before but realised its true
    when I am around people I have noticed I try to act animated at times and it takes work, even putting on the big smile etc, that most of time my facial features just want to relax, its sort of frightening like a zombie......!
  10. tansy

    tansy New Member

    is such a good way of explaining what happens when we try to push ourselves out of those periods when everything seems to be functioning in bottom gear or the brakes are stuck on. This is often the time when the malaise is at it's worst. I still find myself trying to do too much because becoming absorbed in something is an attractive alternative to having to acknowledge how physicaly overwhelming ME and CFS can be.

    As for lack of hand gestures when talking; I have observed this in othrs as well as myself; friends and neighbours say it is one of various signs they use to judge what kind of day I am having. Weakness in the uper limbs means I cannot use my arms so much just as Facial Weakness affects my expressions.

    Do you find you lose intonation too?

    tc, Tansy

  11. simonedb

    simonedb Member

    do you guys know what ramifications are if you need antibiotics, are some safer than others in light of this?
  12. Jayna

    Jayna New Member

    Tansy wrote: As for lack of hand gestures when talking; I have observed this in othrs as well as myself; friends and neighbours say it is one of various signs they use to judge what kind of day I am having. Weakness in the uper limbs means I cannot use my arms so much.

    I absolutely have noticed this. Some days I find myself actually tucking my hands under my thighs in my chair, so they stay warm and out of the way. Moving them for any reason seems like a HUGE amount of effort.

    Not sure about the facial expressions but I can sure tell when it's too much effort to smile or put inflections into my voice.

  13. Rafiki

    Rafiki New Member

    Weak arms and a change in my facial expression have marked my illness from the very beginning.

    When first ill I could not wash my hair myself and it remains a big chore. When I relapsed after many years of being semi-functional it was heralded by an inability to do repetitive movements with my arms -- I was at a friends birthday party and everyone was to clap in time to the music (don't remember why) and I couldn't. I could clap 2 or 3 times and then my arms would hang limply at my sides.

    When first ill my then husband knew how I felt from certain indicators on my face -- a dark circle around my mouth, a laxity and a lack of expression. I don't know if I still get the dark circle around my mouth but the laxity and lack of expression have been indistinguishable from Parkinson's when I have been most ill.

    I have been managing my illness lately by truly living within my abilities and not pushing to the point of malaise. I have a fragile adult child living with me in a very small space and I was motivated to do this because of the negative effects my illness might have on her. Also, it seemed more than I could bear to have to deal with serious malaise under these conditions. I have been very still except for essential movements. I have not engaged in any recreational movement. No drawing or painting. Virtually no walks with the dog although there is an extremely pleasant area almost outside my door to have a pleasant stroll. No applying makeup. No lively conversations save with my kid. No social activities. No long phone conversations. Answering emails and posting here on my laptop while reclining is the most strenuous thing I do. I have pared everything back to just the bare necessities.

    Virtually all of my symptoms have been much more stable. I have felt much less malaise. My cognitive issues are about the same. I hasten to add I have also been treated, not for the first time, with several lengthy courses of abx. However, I believe the stillness has helped me as much if not more than the abx.

    One becomes a different person, for sure. I also practice meditation and when others notice the difference in me I explain it away as the results of my meditative practice and my new Zen self. I am more Zen, for sure, but I'd be running around being vividly Zen if not for ME.

    It is very odd to be aware of the energy expenditure necessary to do every single thing including smiling. Smiling now feels the way lifting weights might have felt before ME. There is effort involved. Most people are unaware of the effort necessary to smile. No matter what, though, we must continue to smile! A smile on one's face feeds back to one's brain and neurotransmitters supportive of happiness are generated.

    I sometimes wonder if the lax, mask like expression does not, in a similar fashion, feed back to the brain a message that we are depressed triggering neurotransmitter activity in keeping with depression.

    As the great Buddhist teacher Thich Nhat Hahn (sp?!) advises: Smile, breathe and go slowly.


    PS Tansy, it just occurred to me that perhaps we were altogether too vivid before and used up all our juice! I'm joking. I have to.

    And, yes, my intonation is pretty flat and I am aware of the energy necessary to simply talk... or listen... or look... or be. It's crazy.

    Thank you again, for all your effort! You are a treasure!

    [This Message was Edited on 12/12/2008]
  14. richvank

    richvank New Member

    Hi, Tansy and the group.

    For what it's worth, elevation in the production of hydrogen sulfide is part of the glutathione depletion--methylation cycle block hypothesis for the pathogenesis of CFS.

    It comes into the picture like this:

    When there is a state of oxidative stress in the body, as has been shown by many studies to be present in CFS, the equilibrium between cysteine and cystine can be expected to shift in the direction of the cystine or oxidized state. This has two important consequences: First, since cysteine is the rate limitiing amino acid for making glutathione, this shift decreases the rate of production of glutathione and unfortunately acts to preserve the state of oxidative stress. I believe that this is part of the interaction between glutathione depletion and a partial block in the methylation cycle, which makes CFS a chronic condition. Second, cystine is the substrate for an alternative reaction catalyzed by the enzyme cystathionine gamma lyase, which is at the beginning of a pathway that produces hydrogen sulfide, and eventually thiosulfate. I have heard anecdotal reports of elevated thiosulfate in the urine of some PWCs, so I think there is at least a little experimental evidence for this pathway being upregulated in CFS, but more measurements are needed to be sure.

  15. Rafiki

    Rafiki New Member

    I do wish you could use your brain and education to create your posts and then lend your gifts to me in order that I can fully understand them!

    Does there exist anywhere a totally dumbed down version of this theory for scientific dullards like me? I would so like to grasp it!


  16. richvank

    richvank New Member

    Hi, Rafiki.

    I posted my response in a separate thread, in case other people might be interested.

  17. Rafiki

    Rafiki New Member

    Haven't seen it yet but sure it will be illuminating.

    Thanks for your time,
  18. Rafiki

    Rafiki New Member

    Haven't seen it yet but sure it will be illuminating.

    Thanks for your time,
  19. winsomme

    winsomme New Member

    bumping this post in light of the Dr DeMeirleir test post.
    [This Message was Edited on 05/28/2009]
  20. cfsgeorge

    cfsgeorge New Member

    thanks for digging this up. i hope rich continues to help us here.