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Clostridium Butyricum - A Game Changer?

Sidereal

Senior Member
Messages
4,856
This will surprise no one here.

Biochem Int. 1992 Jul;27(3):431-8.
Oxalate production from glyoxylate by lactate dehydrogenase in vitro: inhibition by reduced glutathione, cysteine, cysteamine.
Sharma V1, Schwille PO.
Author information

Abstract
Lactate dehydrogenase is known to act as a dismutase converting glyoxylate to oxalate and glycolate. LDH (sources: human erythrocytes, human plasma; rabbit muscle; rat liver) activity was assayed at 340 nm using glyoxylate (5.0 mmol/l) and NADH. The LDH activity (approx. % of control) in all the cases decreased respectively in the presence of 5.0 and 10.0 mmol/l of cysteine (45 and 20), cysteamine (45 and 20), and GSH (55 and 30). This decrease in LDH activity resulted in decreased oxalate production from glyoxylate (0.5 mmol/l). A 50% inhibition in oxalate production was observed in presence of 0.3 mmol/l cysteine, 0.35 mmol/l cysteamine, and 2.0 mmol/l GSH. The results suggest that the net LDH activity towards oxalate production may be regulated by the free SH-groups in the cell. This possibility needs evaluation as a tool to lower endogenous oxalate production and the associated risk of stone formation.
 

Sidereal

Senior Member
Messages
4,856
Sidereal, you completely overestimate me. ;)

:rofl:

Look, I don't know anything about oxalates. The pathway in Gondwanaland's diagram says that glyoxylate can be turned into glycine with the help of alanine glyoxalate aminotransferase or shunted towards oxalate production thanks to lactate dehydrogenase (LDH).

The paper I linked to would seem to suggest that the presence of free thiols (sulfhydryl groups -SH) is what determines which way it will go. They have shown that less oxalate is produced when more cysteine/glutathione is around due to a reduction in lactate dehydrogenase (LDH) activity. The paper therefore suggests that endogenous oxalate production is regulated by your redox state. Then again, what isn't?

As you know, people like Rich van K identified sulfur metabolism as a key area of metabolic dysfunction in ME/CFS and there is a whole subforum of people here trying to jack up their glutathione by using methylation supplements. (A mistaken approach.)

There is also a whole subculture on the internet who attribute symptoms of autism, ME/CFS, FM and metabolically related conditions to mercury poisoning and oxalates. Anecdotally, many such people have exquisite sensitivity to dietary intake of free thiols.

As for oxalates, while reducing dietary oxalate intake may help, it would seem to be quite futile in the grand scheme of things given the fire in the kitchen oxidative stress situation in severe ME/CFS. It probably helps people with milder conditions. Personally, I have suffered a massive increase in calcium oxalate production with any attempt to raise energy production via prebiotics and this was clearly an endogenous production issue. This is telling me there's a breakdown going on in this pathway. In my case, I eat almost no nuts, seeds or vegetables and I only took beet briefly so it can't be due to excessive dietary intake.
 

adreno

PR activist
Messages
4,841
The paper I linked to would seem to suggest that the presence of free thiols (sulfhydryl groups -SH) is what determines which way it will go. They have shown that less oxalate is produced when more cysteine/glutathione is around due to a reduction in lactate dehydrogenase (LDH) activity. The paper therefore suggests that endogenous oxalate production is regulated by your redox state. Then again, what isn't?
Just take some NAC?
 

Gondwanaland

Senior Member
Messages
5,092
Clin Sci (Lond). 1989 Mar;76(3):303-9.
Inhibition of endogenous oxalate production: biochemical considerations of the roles of glycollate oxidase and lactate dehydrogenase.
Bais R1, Rofe AM, Conyers RA.
Author information

Abstract
1. Both the peroxisomal, flavin-linked glycollate oxidase [(S)-2-hydroxy-acid oxidase; EC 1.1.3.15] and the cytosolic, nicotinamide-adenine dinucleotide (NAD)-linked lactate dehydrogenase (L-lactate dehydrogenase; EC 1.1.1.27) are thought to contribute to the formation of oxalate from its immediate precursors, glycollate and glyoxylate, but the relative contributions of each enzyme to endogenous oxalate production is not known. 2. In rat liver homogenates, [14C]oxalate production from labelled glycollate is halved and that from labelled glyoxylate is increased fourfold by the addition of either NAD or NADH. 3. In isolated rat hepatocytes, the 3-hydroxy-1H-pyrrole-2,5-dione derivatives of glycollate, which are specific inhibitors of glycollate oxidase, have a greater effect on glycollate metabolism than on glyoxylate metabolism. 4. These findings are consistent with an important role for lactate dehydrogenase in oxalate formation from glyoxylate. 5. With human and rat liver homogenates and with purified human liver glycollate oxidase and rabbit muscle lactate dehydrogenase, DL-phenyl-lactate (2 mmol/l) completely inhibits glycollate oxidase but has not effect on lactate dehydrogenase. On the other hand, the reduced form of a chemically synthesized, NAD-pyruvate adduct (1 mmol/l) almost completely inhibited lactate dehydrogenase but had no effect on glycollate oxidase. 6. Either alone or in combination, DL-phenyl-lactate and reduced NAD-pyruvate adduct reduce oxalate production from glycollate and glyoxylate in isolated rat hepatocytes, but do not abolish it completely. 7. These findings support a role for another enzyme, probably glycollate dehydrogenase (EC 1.1.99.14), in oxalate production in integrated cell metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)
http://www.ncbi.nlm.nih.gov/pubmed/2647367
 

Gondwanaland

Senior Member
Messages
5,092
I am thinking ALA is the way to go. Tiny doses throughout the day like on the frequent dose chelation forums.
And the whole ordeal of supplementing minerals that go away with it :ill:
I think I prefer methylation, at least people with amalgams like me are also invited to the party
 

alicec

Senior Member
Messages
1,572
Location
Australia
@alicec, super informative, thanks. What sorts of things apart from VSL3 have you found useful for the oxalate issue? It's interesting that acidophilus is recommended. Out of all probiotics, it's the one I can least tolerate. It has always given me what @adreno and I tend to refer to as lactate hell. It's the same reaction I get from glycine/DMG supplements so perhaps this indicates that oxalates were being mobilised from tissue. It sure felt like being stabbed with shards of glass lol. :vomit:

In the post above http://forums.phoenixrising.me/inde...icum-a-game-changer.37324/page-22#post-601132 I attached info on probiotics from the trying low oxalate group. Unfortunately the testing for oxalate digestion has been very limited, so the only known strains which are good at it are two L. acidophilus and one B.lactis (BL-07). There have been no recent updates on the Ox-thera product (Oxalobacter formigenes) which has been given orphan drug status by the FDA. One day soon it will hopefully be available.

The importance of the probiotics is that signalling from the gut that appropriate flora are present seems to be necessary before oxalate dumping will happen. Daily probiotic use is recommended by the trying low oxalate group for this reason. VSL 3, which has been tested and found to be one of the good ones, is the usual recommendation (even though we don't know what actual strains are in it). I have never looked for a preparation containing B. lactis BL-07 without any acidophilus but one probably exists. Adding this could be very important in persuading your body to start dumping its oxalate stores. It will probably be necessary to start low and increase slowly.

As I also noted in that post I stopped taking the VSL 3 at the end of March before the uBiome test and decided not to start again and see what happened. I have been thinking about this for a while and making the post prompted me to add it back. I have definitely deteriorated over the past month or so. Of course many things could be responsible for this (including just the after effects of getting rid of so much Proteobacteria) but oxalate accumulation could be part of it - certainly I have some of the symptoms. I added it back two days ago and will see what happens.

I first became aware of my oxalate problems in late 2013 and had an OAT test from GPL which Susan Owen's analysed (she is not longer doing this due to ill-health). This showed that I was becoming an endogenous oxalate producer. Glyceric and glycolic were elevated (showing that AGT was no longer taking them down that benign path) as well as oxalate, plus there were many indicators of deranged metabolism in pathways know to be adversely affected by oxalate. The most important of these are B6, B1 and biotin dependant, as well as sulphur and glutathione related.

Susan recommended boosting all of those pathways with the appropriate B vitamins, topical magnesium sulphate, plus various antioxidants - as well as the probiotics. Plus there are various other strategies that help, such as calcium or magnesium salts with meals to bind dietary oxalate, arginine for pain, etc. Antioxidants are very important since it is oxidative stress which causes the original problem with AGT (by causing conformational change in the enzyme so it no longer binds its B6 cofactor) but they and the B vitamins often precipitate uncomfortable oxalate dumping. Start low and go slow, one at a time, is the recommendation.

I have attached a document from the trying low oxalate group where a moderator replied to a question about supplements for endogenous oxalate production in a succinct way with recommendations almost all in one place (the problem with the site is that most of the info is scattered and hard to find) . She didn't canvas biotin, which is also very important. Susan recommends 20 - 40 mg daily (but start with maybe 1 mg or less if very sensitive).

I am not as sensitive to supplements as you seem to be though there are certainly plenty that cause me problems. I have been able to get my B6 up to 50 mg P5P plus 75 mg pyridoxine. This is not nearly as high as the upper recommended target but more causes too many problems for me. I do revisit from time to time but have so many others things that I am trying that it is some time since I have tried to up the dose.

Magnesium is also necessary to support B6 dependant enzymes and the recommendation is twice as much as B6, plus topical magnesium sulfate (or epsom salts baths) but I have always taken a lot of that.

I also take 20 mg biotin and 50 mg allithiamine daily.

Regarding antioxidants, I won't have a bar of the recommendations for NAC and glutathione (apart from causing me problems I don't think it is a good recommendation) and I take moderate-high doses of vit A, gamma E, tocotrienols, ubiquinol, silymarin extract, r-lipoic acid. I used to take high doses of vit C but stopped this on Susan's advice. Ascorbate is converted to oxalate. I went to 500 mg/day and have just upped it to 1 g/day (more than recommended) because on a recent OAT I am showing quite low vit C markers.

I don't think the particular antioxidants taken are so important as taking a tolerated mix to help counter the on-going oxidative stress.

I have had two OATs since and all of the B6, B1 and biotin markers have normalised and on the most recent one, glyceric and glycolic were low normal. Oxalate is high normal but that is a good thing I think since it means I am getting rid of it. Glutathione-related markers were also fine. On a recent Genova test I did have an elevated marker for lipid peroxidation, but not too dramatically bad. Antioxidants are among the group of supplements I do have problems with and so far I have not been able to find anything else to deal with this.

In general I am hoping that ultimately the gut strategy will deal with a lot of these issues in a more permanent way but in the meantime I keep taking the relatively high doses of the various supplements.

Have to go now (more acupuncture) but if I think of anything else will post later.
 

Attachments

  • Supplements for Endogenous Oxalate Production.pdf
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Gondwanaland

Senior Member
Messages
5,092
So far I saw no mention to silica supplementation. For several years Volvic was the only water that would satiate my thirst. Unfortunately I only had access to it in 1992-1993 and again for 2 months in 2012. In 2012 I had what I now know was a tremendous dumping through the skin. Not sure if it was the water or the rye bread though. Probably the combo.

Last year I started silica supplementation and it was the only thing to make my brain fog go away. This year I stopped it since I started taking it homeopathically in a continuous way, and then back in Feb I restarted to dump. For other reasons I tried Benfothiamine and experimented "no benefits", only the comeback of an old gluten rash in my right thigh (I'm GF for 2 yrs now) o_O

Then a few weeks ago I started an increased concentration of the homeopathy and had to quit it due to unbearable dumping. My homeopath warned me that there would be a "short" dumping, but I just can't handle it right now :ill:

It has been relieving to be able to make some sense of and find a common thread for everything I have been through my whole life. For the 1st time I found something that explains everything, and I am assuming even my DVTs in 2011. :wide-eyed:

Thank you so much, Alice, for such helpful and informative posts. :bouquet:
 

alicec

Senior Member
Messages
1,572
Location
Australia
As for oxalates, while reducing dietary oxalate intake may help, it would seem to be quite futile in the grand scheme of things given the fire in the kitchen oxidative stress situation in severe ME/CFS. It probably helps people with milder conditions. Personally, I have suffered a massive increase in calcium oxalate production with any attempt to raise energy production via prebiotics and this was clearly an endogenous production issue. This is telling me there's a breakdown going on in this pathway. In my case, I eat almost no nuts, seeds or vegetables and I only took beet briefly so it can't be due to excessive dietary intake.

Back from acupuncture and have now read the studies posted by @Sidereal and @Gondwanaland which I hadn't seen when I made my previous post.

You are spot on @Sidereal. I have gently suggested on a number of threads on PR that it would behove people to pay more attention to the potential for endogenous oxalate production in ME/CFS but I guess everyone is so overwhelmed by so many pressing issues that it is hard to give it priority. A low-moderate oxalate diet is just a way to take some of the pressure off but it solves nothing if we are on the slippery slope to endogenous production.

The two studies add a new wrinkle to the story since they show that redox status is important at the LDH step as well as at AGT and also that another enzyme may be involved in oxalate formation.

This doesn't change the strategy however. It is at AGT that everything starts to go wrong, allowing accumulation of intermediates which LDH just happens to be able to act on (its real and useful substrate is of course pyruvate). Toxic oxalate results and this in turn damages many enzyme systems, including AGT; a vicious cycle is set in train.

Certainly addressing redox status might help to disable the LDH conversion but it is even more critical to helping AGT to work properly and thus stop the problem at its source. Since AGT is B6 dependant and oxidative stress adversely affects the enzyme's capacity to bind its cofactor, supply of B6, in relatively large amounts, is the second way to help the enzyme function better. This is the core of the intervention.

Note also that oxalates derange several aspects of the glutathione system, again contributing to a self-perpetuating cycle.

Addressing redox/antioxidant status is absolutely critical to breaking the vicious cycle and as I said before I don't think it matters what actual antioxidants are taken. A mixture of whatever is tolerated spread out over the day seems like a good plan. Increase as tolerated, remembering that they are likely to cause oxalate dumping. Add B6 as early as possible but proceed very cautiously.

The remaining strategies aim to counter the secondary derangements caused by oxalates - eg to biotin and B1 dependant enzymes, to sulphur metabolism etc. Add these in when possible. Remember that most of this stuff was worked out for autistic children, many of whom were desperately ill and supersensitive (often non-verbal - how did their poor mother's cope) but it was done and huge improvements were made. I think the ME/CFS community could learn a lot from this achievement.

Finally I am reminded of @Vegas's thoughtful posts on the resistant starch thread about the influence of the gut flora on redox status. This is part of why I hope that modification of the microbiota might be the ultimate way to fix the problem.
 

alicec

Senior Member
Messages
1,572
Location
Australia
I don't want to derail this thread but since I have mentioned my struggles with lymphatic congestion (especially in the head/neck) and have received a lot of advice on this thread, I wanted to pass on information about a treatment that I had yesterday.

I went to a physiotherapist who I knew was experienced with lymphoedema hoping she might be able to show me some techniques that could help. From my description of symptoms she said that she thought there was something else going on as well as lymphatic congestion and offered a treatment which she thought would make a big difference very quickly. We could return to the lymphatics later.

This is called the Watson Headache Technique and involves alignement of C1, C2 and C3 along with release of attendant tight muscles. She said she has found that problems in the cervical spine and lymphatic congestion in the head often go together and exacerbate each other. Certainly the pressure from above and below play havoc on the nerves and can cause a myriad of problems (headache and migraine are very common but not the only ones), including she thought my blurred vision and feeling of pressure in the head.

I did have tightness and soreness in that area of the neck so readily agreed. The result was quite amazing. There was an immediate loosening and lightening of the whole head and neck area and as the afternoon went on, I was thinking more clearly with very little blurred vision.

This morning I felt better than I have for weeks, much clearer in the head. I have been sitting at the computer for a while making these posts and am just starting to notice tightening and soreness in the back of the neck and blurred vision starting. So off to do the exercises she showed me.

I'm having another treatment next week, then she'll talk about the lymphatics.
 

Asklipia

Senior Member
Messages
999
I am just starting to notice tightening and soreness in the back of the neck and blurred vision starting. So off to do the exercises she showed me.
Please share these exercices @alicec if and when you have the energy. I am extremely interested.
Lots of good wishes!
:hug::hug:
Asklipia
 

alicec

Senior Member
Messages
1,572
Location
Australia
Please share these exercices

Just chin tucks but with very particular instructions.

Stand against a wall with a pillow behind the back, the top of which is at shoulder height. Lean back comfortably into the pillow. Tuck the chin well, but not jammed into the chest. Keeping the chin tucked, push the head back. Do not raise the chin. You know you are doing it correctly if you feel it across the shoulders and/or between the shoulder blades. If you feel it in the neck you have either tucked the chin too much or you have lifted your chin.

Hold for 20 sec, completely relax and repeat once or twice.

Repeat the cycle as often as you like but at least twice daily.
 

Sidereal

Senior Member
Messages
4,856
There have been no recent updates on the Ox-thera product (Oxalobacter formigenes) which has been given orphan drug status by the FDA. One day soon it will hopefully be available.

I did see that a few months ago when I was looking into this stuff. I also read a review paper about their studies. I can no longer recall the specifics (need to dig it up again) but the impression I got was that it was hard to deliver this stuff and colonise the gut. The general impression I got was that the human randomised studies didn't really meet their endpoints. I wonder if this is the reason for the delays and silence.

It seems there is a product by an Indian pharmaceutical company already on the market? This study used it:

http://www.ncbi.nlm.nih.gov/pubmed/25645091

Curiously, they only compared oxalate excretion over time in the two groups (the comparator arm was potassum + magnesium citrate) and didn't report time x group interaction or group differences post-treatment. I presume because they weren't statistically significant? :lol: How does this stuff get published?

Anyway, the product seems to contain Oxalobacter, L. acidophilus, L. rhamnosus and B. lactis. And FOS. :depressed:
 

Asklipia

Senior Member
Messages
999
Oxalobacter formigenes = to find some I used to make salads with the outside wilted cabbage leaves. Supposed to be plentiful in there.
Thanks a lot to @alicec for sharing her exercise.
 
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