Comments on H2S & Methylation Cycle in CFS

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ProHealth

Rich Van Konynenburg

5/31/09

comments on hydrogen sulfide

and the methylation cycle in CFS

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

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.

n 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.

n got her paper published in the journal Medical

Hypotheses, and she also presented her hypothesis

to the federal CFS Advisory Committee last October.

n 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, n " 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