Hi, all.

Hydrogen sulfide (H2S) has been getting more attention lately in connection with
CFS.

As I think many of you know, the methylation cycle and glutathione are both parts of the overall sulfur metabolism in the body, as is the production of H2S.

The various reactions that can produce H2S in the body include parts of the
human metabolism, and also the metabolism of certain bacteria in the gut.

The first place I heard about H2S in connection with CFS was from Dr. Amy Yasko, who
emphasizes that people who have genetic polymorphisms in their cystathionine beta synthase (CBS) enzyme, along with a methylation cycle block, will tend to generate more H2S.

I also heard about sulfur-related topics from Susan Owens, who runs the Yahoo
sulfurstories group and the group about trouble with Epsom salts. On the latter
topic, I have speculated that people who don't tolerate Epsom salts well may
have sulfate-reducing bacteria (SRBs) in their gut, which convert sulfate to
hydrogen sulfide. SRBs have been found in the gut in some people. As far as I
know, the human metabolism does not have a pathway for chemically reducing
sulfate, so I think the bacteria must be responsible for converting the sulfate to more chemically reduced species, such as H2S and eventually sulfite, and thus producing the sulfate intolerance in these people. Sulfate is the main form of sulfur normally excreted in the urine.

In the human metabolism, the two enzymes of the transsulfuration pathway, i.e.
cystathionine beta synthase (CBS) and cystathionine gamma lyase (CGL), aka
cystathionase, are capable of producing H2S from cysteine or homocysteine.

In my 2008 revision of the Glutathione Depletion--Methylation Cycle Block
hypothesis, described in the set of PowerPoint slides in the files section of
the cfs-yasko group's website, I proposed that cysteine becomes oxidized to cystine in
the oxidative stress condition present in CFS, and that CGL then catalyzes a pathway
starting with cystine that produces hydrogen sulfide and thiosulfate. I based
this on research summarized by Martha Stipanuk, who has worked a lot in this
area with rats.

I just heard a few days ago from Prof. Ruma Banerjee, who is probably the
leading researcher in the area involving the human sulfur metabolism and vitamin
B12, that the human version of CGL does not use cystine as a substrate under
normal conditions, which the rat version does. I'm not sure yet whether it
would do so under oxidizing conditions, so this aspect of my hypothesis is still
a little "up in the air" at this point. It is clear from our clinical study (also
in the files section of the cfs-yasko website) that the methylation cycle block in CFS is linked to
glutathione depletion, so there has to be a way to explain where the sulfur
metabolites that are dumped down the transsulfuration pathway when there is a
methylation cycle block actually go, since they don't go into making more
glutathione. This aspect needs more research.

Marian Lemle has proposed that hydrogen sulfide is involved in CFS. I had the privilege of meeting her at the
Reno conference in March, where we both presented poster papers. She is also a
friend of Prof. Dick Deth, who works primarily on autism, and who is very knowledgeable about the sulfur metabolism. Marian got
her paper published in the journal Medical Hypotheses, and she also presented
her hypothesis to the federal CFS Advisory Committee last October. Marian didn't
get into the biochemistry of how H2S is produced (she is a science writer, not a
scientist per se), but she noted that the symptoms of H2S poisoning are similar
to those of CFS, and that was the basis for her hypothesis that H2S is involved
in CFS. I thought this was interesting work, and I have interacted with her
concerning how her work and mine might be connected.

This past week, Dr. Kenny de Meirleir held a press conference and gave a talk at
the M.E. conference in London about what he reported to be a major breakthrough
in M.E. research. (By the way, Marian "hopped a plane to London" when she heard
that the press conference was to be held, and she was there for it, and for the
one-day M.E. conference that followed.)

Dr. de Meirleir and his group have found that hydrogen sulfide is elevated in
the urine in the most severely ill M.E. patients, and his company is now
offering a qualitative urine test for H2S. His view seems to be that the H2S is
being produced by bacteria in the gut in the severely ill patients, and I think
he is probably right about that.

I think that we will eventually be able to tie all of this together, but it will
take some careful lab work to nail it down.

Here are some speculations about what goes on: First, the sulfur in the human
body originates in the diet (and supplements, if they are used). It comes in as
sulfur-containing amino acids (methionine, cysteine, cystine, and taurine), and
also in the form of sulfate and a few other sulfur-containing species. The
sulfur in whatever amount of H2S is produced, by either the human metabolism or
the bacteria in the gut, must originate in the diet (and supplements) People who bathe in Epsom salts will absorb some sulfate through their skin.

In a normal, healthy person, a lot of the sulfur-containing substances are
digested in the gut and are absorbed into the blood, while some remain in the
gut. Also, some are transported into the gut via the bile, from the liver.
Bacteria in the gut therefore have access to some of it, and I think we are all
familiar with the rotten egg smell that can be associated with flatus, which
comes from hydrogen sulfide. So it is not unusual for bacteria in the gut to be
producing hydrogen sulfide.

It is quite common in CFS that there is dysfunction in the digestive system.
This can include low stomach acid, slow gastric motility, insufficient secretion
of pancreatic enzymes, insufficient secretion of bile, gluten or casein
sensitivity, fructose or lactose intolerance, candidiasis, dysbiotic bacteria,
intestinal permeability (leaky gut), a variety of other food sensitivities,
secretory IgA deficiency, protozoal or helminthic parasites, and others.

Under these circumstances, I think it is quite likely that less of the
sulfur-containing substances will be absorbed into the blood, and more will be
metabolized by bacteria in the gut. The results would likely be less methionine
available for the body's use (including for the methylation cycle), and more
hydrogen sulfide produced by bacteria in the gut, which can be absorbed into the blood, have
toxic effects on the cells of the body, and be excreted in the urine.

As I noted in a recent post, some of the people who have not responded to the
simplfied treatment approach for lifting the methylation cycle block appear to
be low in methionine. If there is not enough methionine available, the
methylation cycle will operate slowly, even if the partial block has been
lifted, because there is not enough "cargo" to be carried around this cycle or
to feed the transsulfuration pathway.

I think this fits in well with what Dr. de Meirleir has reported. If
sulfur-containing substances aren't being absorbed into the body, they would be
available to feed the bacteria in the gut.

I've also noted that in some of the most severely ill PWCs, the condition of the
gut is so dysfunctional that they are not able to derive much nutrition from
their food. Again, I think this is consistent.

So what does this mean for treatment? I think it means that if a person is
treated early enough in their illness, when their gut is still functioning
relatively well, the simplified treatment approach is likely to work. If their
methionine is low, they may also need to supplement it, or to increase their
protein intake in general, perhaps together with betaine HCl to augment stomach
acid and digestive enzymes to help break down the protein in the gut, so that
the amino acids can be absorbed.

If a person is severely ill, so that the digestive system is no longer able to
deliver much nutrition to their body, then I think it is likely that the
hydrogen sulfide level in their urine will be elevated, as Dr. de Meirleir has
reported, because the absorption of the sulfur-containing substances will be
lowered. In these cases, it seems reasonable to suspect that many of the
serious symptoms that are experienced are effects of hydrogen sulfide. Also in
these cases, there may need to be intravenous feeding until the gut is in better
condition, and the simplified treatment approach may not help until the gut is
in condition to absorb nutrients, and the methionine level is high enough that
the methylation cycle is being fed with it.

So how do we know where to draw the line between cases in which the simplified
treatment will work, and cases that will require additional efforts? I think
that measuring the methionine level in a urine amino acids test is one thing
that can be done, and perhaps the H2S test being offered by Dr. de Meirleir's
company would be another way to gauge this. This is all very new, so we don't
have experience to go on yet, but I do think all of this will fit together.

Best regards,

Rich <br><br>[<i>This Message was Edited on 05/31/2009</i>]

[This Message was Edited on 05/31/2009]

Hi Rich!

Thanks so much for your excellent and informative overview of H2S in CFS. I really enjoyed it - you have such a great writing style!

I hope this will offer all of us help.

I am struggling. I have the CBS upregulation and have had a fever for almost 2 yrs that has left me severely debilitated that I barely function. Then in March 09 I developed swallowing problems after a dental appt - that has affected my eating - which really has set me back. No answers from medicine for either issue.

I want nothing more in the world than some help so the suffering isn't so severe.

So I am holding on to this as a glimpse of hope and help.

God Bless,

Elisabeth

thank you for the info.

!!!!!!!!!!!!!!!!!!!!!!

bigmama2

Thanks for the information. I have been following the Dr. DeMeirlier reports and found your info interesting.

Thanks for taking the time to give this info to all of us!!!!

Hi Rich!

Thank you so much for explaining this in layman's terms.

Forebearance

just want to echo the thanks others have expressed

Hi Rich:

You mentioned above "there may need to be intravenous feeding until the gut is in better
condition, and the simplified treatment approach may not help until the gut is
in condition to absorb nutrients".

How can the gut function be improved? Just by what you suggested to improve absorption of methionine (betaine HCl to augment stomach
acid and digestive enzymes to help break down the protein in the gut, so that
the amino acids can be absorbed)?

Thanks,
Zip

Thanks a lot for the post, Rich.

You said "The results would likely be less methionine
available for the body's use (including for the methylation cycle), and more
hydrogen sulfide produced by bacteria in the gut, which can be absorbed into the blood, have
toxic effects on the cells of the body, and be excreted in the urine."

Wouldn't this mean that if you take some antibiotics against the H2S producing bacteria that the problem should be gone? I mean intravenous feeding would be another solution. Most of us have problems with digestion si intravenous feeding in my eyes would be worth a try anyways but isn't the H2S approach a little bit too simplified?

Hi, zipk and spirospero.

I think treatment would have to depend on the severity of the case. If the gut's absorption can be helped by knocking out the bacteria, and helping to boost the stomach acid and the digestive enzymes (as well as controlling to diet to avoid foods that may be contributing to the problems in the gut), and building up the friendly bacteria by using probiotics, then I would think that would be preferable. My understanding is that this approach does work in many cases, and I believe it is the type of approach that Dr. de Meirleir uses, when possible.

However, my understanding is that in the abstract released last week, Dr. de Meirleir was discussing the most seriously ill patients. In some of those cases, I think the body would need to be built up using intravenous feeding, which will build up the gut as well as other organs, and then it will be in better condition to be able to digest and absorb nutrients.

Best regards,

Rich

[This Message was Edited on 06/01/2009]

"Wouldn't this mean that if you take some antibiotics against the H2S producing bacteria that the problem should be gone? "

Even if we knock back the bad bacteria, there is still re-populating with good bacteria that has to happen over time, plus all the knock-on damage from years of malfunctioning metabolism to be repaired. Damage to the gut lining, plus to cell membranes and probably nerve sheaths from altered fatty acid metabolism, rewiring the brain to respond to 'normal' inputs instead of fighting fires all the time... it all takes a lot of time and energy for the body systems to fix.

And I often think we shoot ourselves in the foot by using up all the energy a new treatment or healing regime provides, before it can be used by the body to repair the years of miscellaneous tissue damage. It's hard not to do that, because we're all so excited at the prospect of getting ANY of our old life back. But the protocol of using only half the energy you have on any given day, and saving the rest for your body to heal itself with, is probably a crucial piece of whatever treatment plan works for each of us.

Every once in a while, during the past 3 decades, understanding of ME has lurched forward in a way that was synchronous with the patient's experience. This really seems like another very good lurch to me!

Seemingly crazy things are fitting together like Epsom salts. I'm always warning people about the dangers of Epsom salt baths (I've posted about it here, actually) and they are always looking at me like I've taken leave of my senses. Sooner or later, everything I have experienced and reported to my doctor makes sense.

Now I'm wondering if my rapidly worsening symptoms when given sulfa drugs is connected. I have refused to take them for many years but early in my illness, when I had repeated urinary tract infections, I was put on Bactrim for long periods of time during and following which I was much, much worse. However, tetracyclines have consistently made me feel better. Do sulfa drugs impact this situation, does anyone know?

Lurching towards a cure,
Rafiki

ETA I realize that "sulfa" drugs may not be the same as sulfur but now that I'm reading: sulfide, sulfur, sulfate... I'm wondering.



[This Message was Edited on 06/01/2009]

Thank you for the post and your continuing support of all of us!

Best wishes,

Mary

Dear Sir,

I have some questions regarding your insightful comment.
Is your theory still valid? If yes, what about whey protein supplementation? Does it make any sense? Wouldn't it be utilized by the above mentioned bacteria?? Whould you favor liposomal glutathione to WPC?

What about immunomodulating agents like Nexavir and Proboost? I suppose that they might cause a shift back to TH1 immunity and thus cut off or decrease oxidative stress and indirectly reverse hormonal imbalance.

I also have bad experience regarding probiotics (VSL3). In my experience they cause a significant deterioration in fogy brain but also significant improvement in fatigue. I just do not see how is it achieved.

Awaiting your kind answer,

I just read about the announcement this morning on Cort Johnson's site, and posted something I turned up in a google search, about the possible connection between heavy metals and hydrogen sulfide -- and was wondering if you could comment on it:

"When gut bacteria or fungi are attacked by something like a heavy metal molecule (e.g. mercury), they have a special defense mechanism (called a “resistance gene”) that produces Hydrogen Sulfide (H2S) gas, which binds to the attacker and neutralizes it. Subsequently this highly toxic and poisonous H2S gas is created in the gut. H2S can impair the immunity system, especially in the area of neutrophil function, which is used to fight the original yeast in the gut, and hence one can hit a vicious cycle. H2S is very similar to mercury, in that it can bind to many of the things that mercury binds to and inactivate them. In other words, all the bad things that mercury can do, as described here, H2S can do. H2S can also convert the safer Inorganic mercury to the more dangerous Organic mercury, as described here. H2S has a very special circular relationship with the heavy metals; and therefore, it is a very special gas.”

Andy Cutler PhD talks repeatedly about people who are mercury toxic having trouble with sulfur foods, and how they should avoid them while chelating because apparently they can partially chelate heavy metals, but not fully, so they stir up problems if one has mercury or other heavy metal toxicities.

So...just wondering if you think this may be part of the picture in regards to higher levels of hydrogen sulfide???

Thanks in advance Rich,

Dan

:)

Hi, Dan.

I think you've raised an interesting issue concerning the interaction between heavy metals and hydrogen sulfide in CFS. I also see that there is quite a bit of published literature in the journals about sulfate-reducing bacteria (which produce H2S) and the methylation of mercury. I'm going to have to get hold of some of the papers and study them before I will be able to respond half-way intelligently to the issues you raised. It does look to me as though this interaction could be important in CFS, given the new recognition of the elevated hydrogen sulfide production in quite a few people with CFS. I'll try to get a little more up to speed on this.

Thanks for raising this issue.

Rich

Dear Rick,

Do you have any idea about the possible reason for deterioration of "foggy brain" after taking VSL3 probiotics? It can wonderfully reduce anxiety and improve energy but I lose my ability to read and think. Same experience with ProBoost(thymic Protein A). ANxiety disappears together with my ability to read and think. Both products cause excessive drowsiness.

Many thanks.

Hi, Sceptical.

I think that's really interesting, but I don't have a good explanation for it.

Perhaps these treatments are stimulating your immune system, which is causing die-off of some bacteria, perhaps releasing endotoxin, to which your immune system responds, and that affects blood flow to your brain via producing type 3 hypersensitivity vasculitis, and hence affects your cognition. I'm only guessing about this, since I don't have any test data on you.

Have you done any testing of your G.I. system or your immune system?

The Diagnos-techs Expanded G.I. Panel is a very comprehensive panel for testing the digestive system.

The VIPDx Immunobilan test looks at antibodies to gram negative anaerobic intestinal bacteria in the blood.

Best regards,

Rich

Hi,

Many thanks for your answer first.

I do not wish to take your time, thus I give you a concise explanation first. I live in Central-Europe where lab tests are scarcely available. I was tested in Brussels and sent some tests also to the USA. My basic problem is that the number of competing and often conflicting CFS theories are limitless (HHV6, Enterovirus:Chia, enterobacter:Maes, hydrogen sulife:DeMeirleir, Cytokine inflammation, etc) but I do not fit in any theory. (I fear this is the majority of us.)

Anyway, CFS developed in my case after a nasty tonsillitis in 2001. I screwed it up. I ate row eggs and stuff in the gym... and I developed a resistant enterobacter infection. First came extreme somnolence then - when I was studying in the USA - after a cold I developed extreme anxiety, profound fatigue and inability to read. I came home after graduation in an extremely bad medical condition but I could not find any treatment center in Europe until early 2008. (details omitted because my prof will be able to indetify me).

REDLAB
Ribonuclease activity was high 125, fragmented RNAA normal, normal elastase, low T-killer (11), poor cellular immunity, low IgA, endotoxin:9 (low positive), Immunobilan:dysbiosis, c4A normal (rather low), autoimmun: normal, food intolerance regarding yiest (high), and sugar (high-medium), mild fructose intolerance, no lactose intolerance, low pancreatic output, oxidative stress panel:high (1), digetive panel: overabundance of enterobacter, later enterococcus and strepto, 0 bifidus but this was performed after a 9-months antibiotics treatment... so it might be just the result of that. Negative chlamydia, mycoplasma, negative routine blood test, negative TSH, T3, T4, normal growth hormone level (median value), normal T cell mitogen stimulation but positive for HHV6 nested PCR and IgG and positive PCR for EBV but negative IgG, VCA-IgG...

After one year on NEXAVIR, VSL3, B12 IM (2 per week), liposomal glutathione and antibiotics
Ribonuclease activity down to 59 (mild elevation), still positive HHV6 PCR, questionable EBV and elevated oxidative stress (2:REDLAB). Leaky gut is sometimes positive, sometimes negative (REDLABS) No further improvement during the last one year.

RESULT: I never catch any disease but I still suffer from fatigue, I am not exhausted, I can work out 50 min 3/week very slowly and look like a drug addict after that (but I cannot run), I have GAD (generalized anxiety) and I can read again. Moreover foggy brain still an issue. Working in my profession tires me out, cannot focus or retain any data, sleep 10-11 hours, cannot continue my doctoral studies in the USA b/c studying is off limit to my brain. I also react to various stressors (cold, heat, studying, anxiety, etc) very poorly and I am very slow. I also continue to have blueish finger nails. I am practically in a survival mode at a very high cost.

My prof put me on antibiotics again (after one year) to treat my new type of dysbiosis (strepto, enterococc now) but my medical condition was hugely deteriorating from that. Both fatigue and axiety has deteriorated and oxidative stress is also worse (2 up from 1) than ever before. Therefore I stopped taking antibiotics after 2 months. This is also why I am sceptical about the idea that GI tract is the basis of CFS. After more than 1 year on various antibiotics I always test positive for something else. First enterobacter was treated and then I developed enterococcus and strepto. I am not sure this is the right way and I have a hunch that I am as a cfs patient simply predisposed to dysbiosis until favorable conditions (say low IgA, HPA axis dysregulation) persist.

My problem is that I do not continue to improve and my medical condition is still not good. I have some viral reactivation which does not seem to be the root of the problem (mildly elevated Ribonuclease L act., PCR is not very reliable, IgG not increasing) My antioxidant status is very poor and I still have dysbiosis. Otherwise my blood tests are normal. If I stop taking NEXAVIR and VSL3 (but take B12, gluththione...) fatigue and anxiety is coming back. When I stopped taking VSL3 for a months I could hardly sit I was so exhausted. If I raise the dosage of NEXAVIR, it results in extreme drowsiness. If I raise the dosage of VSL3 first extreme drowsiness then inability to read and think reappears but no anxiety. This is why I included Thymic Protein A in a vain hope to inactivated the underlying infection if any. Anxiety has disappeared (but is gonna come back as soon as I stop taking it) but I am now losing my ability to think and read again. I am so sick of this disease.

I would like to try out your approach on my own because I would love to move somehow forward. I do not suffer from any other disease. Something causes my symptoms to persist despite improving blood tests. It is a big problem that I am very overstimulated. Any attempt to overcome fogy brain and fatigue by using either ALC (250mg) or ALA (100mg), choline (50mg), low dose Q10, chlorella, increased amount of glutathione, etc. was thwarted by increased anxiety despite meaninles dosages. I was thinking of trying out taurine as an antioxidant and tranquillizer but it might also backfire because some cfs patients have high taurine. I am also sceptical about my ability to take p. serine because of my bad experience with choline. I am also unable to take TMD (toxic metal detox, S&P) to detox proposed by my prof due to its mild stimulating effect.

I am stuck here. What should I do now?? Do patients recover by the treatment proposed by you? If you have any idea just let me know.

Many thanks in advance.

Hello,

I do not believe in H2S metabolism theory of CFS. If it is still true H2S is not produced by gut bacteria. I was put on various antibiotics for 13 months and symptoms are still the same. I think that this disease just make us predisposed to gut dysbiosis. Researcher confuse correlation with causation. It is not their fault because it is just research.

a