Augmentation and gut microbiome

Use this forum to discuss any issues associated with Augmentation
Frunobulax
Posts: 196
Joined: Mon Jun 02, 2014 7:41 pm

Re: Augmentation and gut microbiome

Postby Frunobulax » Thu Oct 03, 2019 2:19 pm

stjohnh wrote:
Bridgercan wrote:...A year ago, I had two ferric carboxymaltose IV treatments; sadly no change in symptoms noted in the weeks and months following. Another mystery...


Unfortunately, IV Iron helps only around 50% of those that get it. Not clear why, but RLS is definitely a heterogeneous disease affected by a bunch of different genes. Its possible that some people have BID on the basis of abnormal endogenous opioid production or receptors, or as others have pointed out, that the blood-brain barrier iron-transport functions are so abnormal in some people that the high blood iron from an IV infusion is still not high enough to get the needed amount of iron into the brain.


RLS onset in childhood and teenage years happens, but it's less common than onset in a later age (AFAIK). If it's a genetic issue with iron transport, why is RLS in children rare? And how does augmentation come into this?

Once more I would caution against putting all eggs in one basket (BID theory). Don't stop exploring the other theories. If iron IVs help only 50% of patients, there are at least two possible conclusions: (a) the iron doesn't reach the brain or (b) iron is not the problem for these patients. Do we have any hard evidence that (a) is more likely than (b), or even that it's always (a)? Some patients have no problems at all with low iron levels. It is wide open if high iron levels are good or bad (and how high or low iron translates to the parameters that we can measure today, as we don't have a reliable indicator yet). Some doctors claim that iron levels should be as low as possible as long as you don't have anemia. (I disagree with them, but I can't prove them wrong as we lack the hard data.)

There is one practice that I strongly recommend: The more I start to believe in some theory, the more time I spend thinking about alternatives and criticism. We do go blind on one eye if we are set on a theory, and tend to adapt facts to the theory and not the other way around. I don't think all the facts fit the BID theory, and we can't afford to ignore them, even if the BID theory may be correct for 90% of the patients. If it's wrong even for 10% then we're not yet close to understanding the RLS pathogenesis.

Something may appear obvious, but it can still be incorrect. 40 years ago everybody "knew" that eating saturated fat leads to high saturated fat in the blood (triglyzerides), high cholesterol and CVD. So we replaced saturated fat with carbohydrates and vegetable oils, sugar with artifical sweeteners, and boom! diabetes increased by a factor of 4, obesity by a factor of 3.(We have very well designed studies today that fat in the blood is mainly driven by carbs in the diet, so high-fat low-carb diet lowers triglyzerides. Which is totally counterintuitive, but perfectly logical if you go into the bichemical details.)

Rustsmith
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Re: Augmentation and gut microbiome

Postby Rustsmith » Thu Oct 03, 2019 8:48 pm

RLS onset in childhood and teenage years happens, but it's less common than onset in a later age (AFAIK). If it's a genetic issue with iron transport, why is RLS in children rare?


RLS in childhood may not be all that rare. We need to remember that even my adult doctors are not adequately diagnosing RLS so why should pediatricians be any different. How many of those kids that have been tagged as ADHD really have RLS? You also need to remember that low serum iron levels are more common in women in their child bearing years and that secondary causes of RLS such as kidney disease, MS and Parkinsons are not conditions common in childhood. Those cases drive up the number of adult cases.

And how does augmentation come into this?


I am not sure that I understand this comment. Augmentation has to do with improper function of the dopamine system following treatment with a medication that influences the dopamine receptors. BID complicates this due to the fact that iron is critical to the manufacture of natural dopamine, so BID simply aggravates and/or accelerates a situation where the medication is already heading toward augmentation.

Once more I would caution against putting all eggs in one basket (BID theory). Don't stop exploring the other theories.
Research is definitely not putting all the eggs in one basket, but the evidence for BID is very strong. Research grade instruments are already starting to be able to detect BID in RLS and the role of iron in the reactions that generate the various neurotransmitters involved in RLS. One of the key animal models for RLS also uses mice with BID. However, there are many other lines of research currently underway that seek to determine things such as why opioids are so effective when they don't address iron or dopamine, what are the roles of the various genes that have strong correlations with RLS and what is the interrelationship between adenosine, dopamine, glutamate, opioids and eventually maybe even cannabinoids?

I should also add that I am part of the minority with chronically high serum ferritin levels and I also have very severe RLS. One of the studies that I am hoping may shed some light on my situation is looking at the process of how ferritin moves from the blood, through the cells that make up the blood-brain barrier and eventually into the brain. It turns out that it is not as simple as a ferritin molecule passing through the blood-brain barrier cell. Apparently there are chemical reactions within that cell that convert ferritin into (if I remember correctly) a simple ferrous ion that can then pass into the brain. And this is not as simple as breaking down the ferritin protein shell to release the iron, the iron itself also undergoes chemical changes. So as we begin to understand that process, it may very well be that there are a number of steps in that "simple" process that can become less efficient and thereby reduce the rate of iron transport.

Finally, there are also studies that are beginning to question whether BID is due to the problems with iron transport into the brain or if it is a matter of losing too much iron from the brain through some process that has not yet been identified. Could it be that one or more of the "RLS genes" is somehow causing our brains to "dump" too much iron? At this point, only time and continued research funding will tell.
Steve

Augmentation Evaluation http://bb.rls.org/viewtopic.php?f=4&t=9005

Opinions presented by Discussion Board Moderators are personal in nature and do not, in any way, represent the opinion of the RLS Foundation, and are not medical advice.

Frunobulax
Posts: 196
Joined: Mon Jun 02, 2014 7:41 pm

Re: Augmentation and gut microbiome

Postby Frunobulax » Tue Oct 08, 2019 5:07 pm

Rustsmith wrote:
And how does augmentation come into this?


I am not sure that I understand this comment. Augmentation has to do with improper function of the dopamine system following treatment with a medication that influences the dopamine receptors. BID complicates this due to the fact that iron is critical to the manufacture of natural dopamine, so BID simply aggravates and/or accelerates a situation where the medication is already heading toward augmentation.


I meant, what is the mechanism of augmentation if we assume that we have a problem with transporting iron to the brain? Is augmentation just (or mainly) a downregulation of receptors that has nothing to do with BID? It's not a rhetorical question, I'm trying to see how things fit together.

Rustsmith wrote:
Once more I would caution against putting all eggs in one basket (BID theory). Don't stop exploring the other theories.
Research is definitely not putting all the eggs in one basket, but the evidence for BID is very strong. Research grade instruments are already starting to be able to detect BID in RLS and the role of iron in the reactions that generate the various neurotransmitters involved in RLS. One of the key animal models for RLS also uses mice with BID. However, there are many other lines of research currently underway that seek to determine things such as why opioids are so effective when they don't address iron or dopamine, what are the roles of the various genes that have strong correlations with RLS and what is the interrelationship between adenosine, dopamine, glutamate, opioids and eventually maybe even cannabinoids?


Correlation is not causation. If we have a 100% correlation between RLS and BID (and that's what the research shows), there are still 4 possibilities: (1) BID causes RLS. (2) RLS causes BID. (3) Both have a common cause. (4) Other (possibly different pathologies). I'd really like to know which of the 4 it true, but I get the feeling that many people just assume (1) and move ahead, and this could be completely wrong. (We assumed that the amyloid plaques are responsible for Parkinson, and created drugs to stop the plaques. Not it turns out that these plaques are a form of defense, and fighting the plaques will speed up the disease. So we spent many billions for research on PD that not only went nowhere.)

Just for the sake of the argument, here is are 2 theories that I just drew out of my hat, so they are probably both wrong. (Well, not completely drawn out of my hat. I'm still learning about these things, but I'm on thin ice here.) But it will illustrate what I mean.
Known facts:
  • Iron forms ROS (reactive oxygen species), and many people think iron values should actually be low. However, ROS may cause inflammation if our oxidative stress gets too high, but act as part of regularoty processes in low doses. So if they are too low then we're in trouble too.
  • ROS are neutralized via antioxidants like alpha lipoic acid, vitamin D, vitamin C, coenzyme Q10.
  • Many diseases like PD and MS are very likely caused by inflammation in the brain. I've been thinking a lot about whether RLS may be in this category too. (Did anybody do SPECT scans of RLS brains?)

Theories:
  1. What if RLS is inflammation in the brain, where some catalyst makes it more likely that iron reacts to ROS? As a result the iron is depleted (BID) and possibly not available for the other biological functions, but the cause of the problem would be the inflammation and the BID is just the cause. So the iron is responsible for the inflammation via the catalyst.
  2. Or, maybe we have an inflammation, and the body reacts by producing something that is designed to counter the inflammation but essentially acts as a chelator and binds iron. (Like glutathion, which is supposed to be an antioxidant.) In this case, iron is not responsible for the inflammation but gets depleted nevertheless because the body reacts.

In both theories the BID is not be the cause of the problem, but a symptom. Drugs like opioids or alpha-2-delta ligands may reduce symptoms because they "relax" the inflamed brain regions, inhibiting whatever causes the urge to move.

A third theory of course is that BID does cause RLS, but that BID can be a consequence of an inflammation (OR a problem with iron uptake or transport). Basically, for patients with high iron (ferritin and transferrin%) like you and me an infection would be the cause, and consequently iron IVs would have no or little effect. For other patients with an uptake/transport issue, iron IVs would help.

You see, I prefer to work by throwing out a lot of theories. Eventually I'll settle on one if I have a clear cut favorite that seems to fit all the facts, but until then I'll go through them all (no matter how unlikely they sound) and try to eliminate them by finding some facts that do not fit.

Curious. We know that iron IVs and alpha-2-delta ligands help only a part of the patients (I figure about 50% each). Do we have any correlation here? Do iron IVs maybe help patients that got relief from Lyrica/Gabapentin?

But I guess we should switch to a separate thread in the appropriate subforum, as we went a bit off topic.

Frunobulax
Posts: 196
Joined: Mon Jun 02, 2014 7:41 pm

Re: Augmentation and gut microbiome

Postby Frunobulax » Tue Oct 08, 2019 6:19 pm

Rustsmith wrote:
RLS onset in childhood and teenage years happens, but it's less common than onset in a later age (AFAIK). If it's a genetic issue with iron transport, why is RLS in children rare?


RLS in childhood may not be all that rare.


Ah, another question. Is it becoming more common, or are just our diagnosis criteria better? If it is becoming more common, there might be a connection to conditions that are also becoming more common, like diabetes (400% compared to 40 years ago), PD, Alzheimer.

We know that even the ancient greeks described RLS, but I heard only about rare cases so maybe it was less common. But obviously it's impossible to tell unless we invent a time machine as recreational measure while solving RLS :)

Oh, I got Alzheimer and PD mixed up in my post above. Too late to edit now.


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