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
[ 06-02-2009, 01:46 PM: Message edited by: m0joey ]
Posted by nomoremuscles (Member # 9560) on :
Thanks for posting this m0joey. I'm a member of the Yahoo Yasko group but have not been opening the messages of late (just burned with all of it for now) and would definitely have missed this.
It will take some digesting, assuming, of course that I have right gut bugs to get the job done.
Posted by Cass A (Member # 11134) on :
Dear M0Joey,
What is "M.E."?? (Here referenced as the M.E. conference and M.E. research)
Best,
Cass A
Posted by Jill E. (Member # 9121) on :
M.E. is Myalgic Encephalomyelitis (if I remember correctly from the CFS conferences I used to attend) - the name for CFS in the U.K., etc.
Thanks MOJoey for posting this. I'm supposed to start the simplified methylation cycle protocol (my test was abnormal) but have been putting it off because I feel so lousy, and tend to get really sick when even teeny amounts of toxins are released.
Do you know which lab can test the methionine level in the urine?
Thanks, Jill
Posted by ukcarry (Member # 18147) on :
Yes, you're right about ME,Jill, though lots of people here in UK use CFS/ME [or ME/CFS] nowadays so that it is more widely recognised.
Thanks for posting this here, Joey. I have some hopes that this may eventually lead to a more structured treatment, especially as press interest so far has been high,