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Augmentation and gut microbiome

Posted: Wed Sep 04, 2019 11:24 am
by Frunobulax
Over the last months I was amazed in how many context the microbiome plays a fundamental role. I wonder if anybody has considered the microbiome in the context of augmentation?

I found little research connecting RLS to gut microbiota research, but one thing caught my eye: https://neurosciencenews.com/restless-leg-syndrome-microbiome-14191/. The authors speculate that the reason behind RLS may not be BID, but dietary iron deficiency and/or gut inflammation. A lot of other stuff suggests a connection. The gut microbiome is known to produce a lot of neurotransmitters, apparently 90% of the serotonin are produced in the gut. It was known for a long time that disbalances in the gut microbiome are strongly linked to depression (https://www.nature.com/articles/d41586-019-00483-5), and it shouldn't surprise us that similar connections are observed for dopamine https://www.ncbi.nlm.nih.gov/pubmed/31098656. There is a good overview on the gut-brain connection here https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4259177/.

Gut bacteria are highly affected by drugs, but also change the way in which drugs are metabolized https://link.springer.com/content/pdf/10.1007%2Fs00213-019-5185-8.pdf. Natural enemies of the gut microbiome are of course antibiotics, but antidepressants are also considered to be detrimental to gut health. Therefore we may see a vicious circle in some cases, as the microbiome deteriorates as a consequence of the treatment and consequently (a) the initial condition may worsen (if it was a consequence of a microbiome dysfunction) and (b) drugs may become less efficient as the microbiom plays a role in the metabolization of the drugs. PD has been linked to certain changes in the microbiome (see e.g. https://www.sciencedirect.com/science/article/pii/S235239641930372X). I considered Parkinson as relevant, as there is the dopamine connection and of course the use of the same drugs.

So this is the theory. Changes to the gut microbiome cause a dietary iron deficiency. (We know that Ferritin levels are unreliable anyway, and high ferritin levels may simply indicate silent inflammation.)
Once RLS is treated with dopamine agonists (DAs), we may see a number of effects:
  • Dopamine agonists may damage the microbiome further, further reducing the iron uptake. Again, I have found nothing specific linking DAs to the gut microbiome, but PD patients are known to have specific anomalies https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0142164 and I consider it quite possible that they are caused by DAs.
  • It's possible that the metabolization is also affected (=drug tolerance). However, as augmentation is defined as a change in symptom severity and earlier onset this can't be the only thing going on here.
  • This theory explains why augmentation is partially reversible. With time, some gut bacteria restore themselves. However, severe damages may never be repaired as we live in a mostly bacteria-free environment and don't digest as many different types of bacteria as our ancestors did. Also there may be secondary effects (leaky gut, which is a consequence of damaged microbiome) that may not revert itself after stopping the DAs.
  • It also makes sense that opioids do not cause augmentation, as opioids are known to be fairly gut-friendly.
  • Cycling drugs may prevent augmentation, as the microbiome has time to regenerate in the breaks from DA treatment.

I think that a lot of facts fit this theory, and I don't see anything that would contradict it. It would also explain partially why iron IVs are only efficient for a subset of RLS patients. (I'm still struggling with the BID theory as the main RLS reason. If this is true, why are iron IVs only efficient for a percentage of the RLS patients?) Assume that there are several causes to RLS, the most common one iron deficiency, but perhaps some patients (say 30%) have a different cause. Assume also that dopamine agonists can cause a long-term iron deficiency. If the RLS is treated with dopamine agonists, we would see only a slow progression for the patients that had iron deficiency in the first place (slow augmentation), as there is no new quality to the pathomechanics. The patients that had a different RLS cause could however see a fast augmentation, as the DAs introduce a second pathomechanic (iron deficiency on top of whatever was causing RLS in the first place).

So if the theory is correct,
  • Patients in augmentation should respond extremely well to iron IVs, better than RLS patients in general.
  • DA treated RLS patients should show characteristic changes in the gut microbiome that get more pronounced with higher doses and longer exposure.
  • Some patients should respond well to microbiome restoration (fecal transplants), especially the ones who augmented.

Anyone care to pitch this to the medical authorities at the foundation? :)

I know that my RLS got better by changing my diet and treating leaky gut. 8 months ago (with normal diet) I was at 30mg Oxycodone with frequent RLS symptoms. I switched to low carb, and switched again to mostly ketogenic lectin-free diet and leaky gut treatment (glutamine, bone broth, prebiotics etc.) 2 months ago. Now I am down to 25mg and no RLS symptoms at all, experimenting with a further reduction to 20mg. However, my Ferritin was always high and a recent iron IV (2 months ago) didn't improve things. But I consider this a long term treatment, we'll see how my RLS is after a year of lectin free diet.

As a practical matter, RLS patients should (a) do a microbiome analysis (stool sample) to check if there are problems there, (b) do a leaky gut test (zonulin blood test) and (c) experiment with a ketogenic lectin free diet rich in prebiotics and polyphenols (known to restore microbiom balance and repair leaky gut).

Re: Augmentation and gut microbiome

Posted: Wed Sep 04, 2019 1:00 pm
by stjohnh
Interesting theory, and I too have been amazed at the wide ranging effects of varying gut bacteria environment.

Problem is, BID (Brain Iron Deficiency) has been shown to be the cause of RLS by numerous methods. The basics are:
1) Autopsy studies of brains of patients with RLS show low brain iron.
2) Functional MRI, tagged CT scans, etc. show low brain iron in RLS patients.
3) Animal models with low brain iron (from fruit flys to rats) show RLS like symptoms.
4) Many patients with RLS and no evidence of blood iron deficiency get better when given IV iron.

The absence of low iron in the blood, liver, spleen, bone marrow, etc. in most patients with RLS argues against a general problem with iron (like dietary malabsorption, inadequate oral iron in the diet, etc.)

Re: Augmentation and gut microbiome

Posted: Wed Sep 04, 2019 2:11 pm
by Frunobulax
stjohnh wrote:Interesting theory, and I too have been amazed at the wide ranging effects of varying gut bacteria environment.

Problem is, BID (Brain Iron Deficiency) has been shown to be the cause of RLS by numerous methods. The basics are:
1) Autopsy studies of brains of patients with RLS show low brain iron.
2) Functional MRI, tagged CT scans, etc. show low brain iron in RLS patients.
3) Animal models with low brain iron (from fruit flys to rats) show RLS like symptoms.
4) Many patients with RLS and no evidence of blood iron deficiency get better when given IV iron.


That's not necessarily a contradiction to my theory. I just pointed out that this theory is robust even if BID is not the only cause of RLS. BID may be the cause or just another symptom, so far we have only correlation. For all we know, RLS may be caused by something that uses up the iron stores in the brain. Or for some patients BID is the primary reasons and for other patients BID is the consequence of something else, so RLS is a symptom of some other condition.

I'm not trying to explain RLS here, only augmentation. My assumptions are only that (a) damage to the microbiom causes dietary iron deficiency, which in turn causes BID and (b) BID causes RLS. Both strictly in the sense of "cause and effect", I don't require the reverse (iron deficiency comes ALWAYS from damage to the microbiom, and RLS comes ALWAYS from BID).

Say RLS may be caused by (a) dietary iron deficiency, (b) some process that uses up iron (possibly silent inflammation) such that the brain has less iron than usual, or (c) something completely different (possibly a problem with iron transport into the brain). If we treat this with DAs we'll damage the microbiom, will worsen RLS over time. If the initial reason for RLS was dietary iron deficiency, then we may see a very slow augmentation. If the reason was something else, then the additional dietary deficiency may cause quick augmentation.

But the timeframe fits. If we're not talking antibiotics (which are the equivalent of an atom bomb in the gut), changes are slow and become more pronounced with time. Months, years, all this is consistent with damage to the microbiom.

I fit that theory in any case: I augmented very quickly, I have high ferritin and iron IVs didn't help me. But I absolutely had damage to my microbiom, which was the result of later microbacterial tests. I also had leaky gut.

Re: Augmentation and gut microbiome

Posted: Wed Sep 04, 2019 2:16 pm
by Frunobulax
Frunobulax wrote:
  • This theory explains why augmentation is partially reversible. With time, some gut bacteria restore themselves. However, severe damages may never be repaired as we live in a mostly bacteria-free environment and don't digest as many different types of bacteria as our ancestors did. Also there may be secondary effects (leaky gut, which is a consequence of damaged microbiome) that may not revert itself after stopping the DAs.


I should add that we may see two effects here. One is the downregulation of receptors, whose reveral could be responsible for the lessening of augmentation symptoms in the first 2 weeks after augmenting (assuming a cold turkey stop). But there is certainly another, long term effect where RLS symptoms subside slowly after switching to opioids, which may be due to the regeneration of the microbiom. At least for me, I had 8 months with really bad RLS symptoms and it took a full year until my medication (30mg Oxycodone even back then) was reliable enough to give me 3-4 nights of decent sleep per week.

And of course regeneration of the microbiom will be extremely slow with a typical western diet (if it happens at all), but faster with a low carb, high prebiotics diet.

Re: Augmentation and gut microbiome

Posted: Wed Sep 04, 2019 5:36 pm
by leo_sch
Frunobulax wrote:
I know that my RLS got better by changing my diet and treating leaky gut.


Bee propolis is very good for many things, also for leaky gut.

A good article about propolis in general: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4964312/

Best wishes,
Leo

Re: Augmentation and gut microbiome

Posted: Sun Sep 15, 2019 4:33 am
by Bridgercan
Fascinating discussion and research.

Pardon the pun, but my gut says we’re getting closer to uncovering what the links between the gut microbiome, BID, and RLS symptoms are. My gut also agrees with the hypothesis? theory? DAs somehow are damaging to the gut biome and are what lead in some way to augmentation. I can’t explain why this intuitively seems “correct” to me, but it does. In dealing with this disease, I’ve become very attuned to my body over the years. It ‘knows” often within a day or two, if not hours, if a medication for a given issue or symptoms will work. I’ll be the first to grant this is pretty “woo-woo” and lacking in any measurable evidence, but my little voice has a pretty good batting average. When my sleep specialist recently wanted to take me above the maximum recommended dosage for rotigotine patch my body and mind quite literally rebelled. I completely disagreed with the doctor’s logic that I needed to go to 6mg patch to verify that I was in augmentation, when the augmentation algorithm indicated I was already there. Having been through it before with pramixepole, my body was clear in saying no to a higher dose. Yet another doctor fired; I’ve an appointment with another specialist next week.

For me a diet consistently free of sugar, dairy, and processed foods, low in carbs, and high in protein, vegetables and fruit will reduce my symptoms from severe to moderate. I had to quit alcohol and coffee completely but my body is quite fine with black or green tea or Yerba mate for my morning beverage.

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

But in the meantime, I want to be done with DAs, the risks are just too high. Will see what opioids my future holds...

Re: Augmentation and gut microbiome

Posted: Sun Sep 15, 2019 6:53 am
by badnights
A year ago, I had two ferric carboxymaltose IV treatments; sadly no change in symptoms noted in the weeks and months following. Another mystery...
But in the meantime, I want to be done with DAs, the risks are just too high.


Bridgercan, I wonder if the IV iron simply couldn't overcome the augmentation. If you had not been augmenting, maybe you would have noticed a benefit. Did the infusions affect your ferritin concentration at all?

Re: Augmentation and gut microbiome

Posted: Sun Sep 15, 2019 2:22 pm
by Frunobulax
Bridgercan wrote:Pardon the pun, but my gut says we’re getting closer to uncovering what the links between the gut microbiome, BID, and RLS symptoms are. My gut also agrees with the hypothesis? theory? DAs somehow are damaging to the gut biome and are what lead in some way to augmentation. I can’t explain why this intuitively seems “correct” to me, but it does.


Once you start really reading about it, a lot of pieces fall into place. Gut microbiome damage explains a LOT of things, a possible pathogenesis of autoimmune and neurodegenerative diseases, the link between Diabetes/Prediabetes and all those degenerative diseases, why some traditional treatment approaches work (that focuses on the gut, like traditional chinese medicine)... I've been able to explain such a lot of things, and the beautiful thing is: It's all backed by research, and so far I can't find any contradictory research. I don't believe that there is one thing that triggers all and explains all those diseases, but let's say gut microbiome issues could be a major contributer to the health problems of many patients.

I've seen and read fascinating talks and articles about all this. Did you know that most of these "civilisation" diseases like arteriosklerosis, diabetes and gout suddenly cropped up in ancient egypt, when wheat farming became common? Those guys would typically suffer from severe diabetes and arteriosklerosis at age 30-40, and the killer: They basically ate exactly what nutritionists recommend today, lots of carbs, whole grain, little or no meat and animal fat. (Apparently there are some techniques to determine this now, similar to carbon dating. And we have enough reasonably well preserved mummies for this research.) And at the same period, about 5.000-10.000 years ago, humans in other countries like (todays) UK, which were hunters and gatherers and ate no grains at all and little carbs overall, were completely free of these diseases. I can't believe that we ignore all this research in our way of life (and most of all in our health system).

Re: Augmentation and gut microbiome

Posted: Sun Sep 15, 2019 5:23 pm
by badnights
Frunobulax wrote:But there is certainly another, long term effect where RLS symptoms subside slowly after switching to opioids, which may be due to the regeneration of the microbiom. At least for me, I had 8 months with really bad RLS symptoms and it took a full year until my medication (30mg Oxycodone even back then) was reliable enough to give me 3-4 nights of decent sleep per week.

And of course regeneration of the microbiom will be extremely slow with a typical western diet (if it happens at all), but faster with a low carb, high prebiotics diet.

I've written elsewhere that in the 2 years following a change in my diet (2014-2016), I was able to reduce my hydromorph contin dosage to half of what it was. I had been "diagnosed" with leaky gut and SIBO. I went through a months'-long protocol designed to fix the SIBO, plus the whole diet change to deal with the leaky gut and to re-populate with good bugs. I figured that I was able to subsequently reduce my meds so much because (1) I had fixed the leaky gut and eliminated the SIBO, and (2) I was eating better and absorbing better so my cells now had an array of necessary nutrients available that they hadn't had before.

It has occurred to me since then that maybe a third factor was involved, namely, recovery of the dopamine receptor system after augmentation. I first changed my diet three years or so after augmentation. Maybe some improvement was going to happen anyway as the dopamine receptor system receoved, regardless of diet, or (more likley, I think) assisted by diet. This thought didn't actually occur to me until I had also gone through a one-year plateau and then a sudden improvement in well-being (though no medication reduction), related to my body's return to a normal circadian rhythm.

Your posts always get me thinking about things.

Re: Augmentation and gut microbiome

Posted: Mon Sep 16, 2019 5:14 am
by Bridgercan
badnights wrote:
Bridgercan, I wonder if the IV iron simply couldn't overcome the augmentation. If you had not been augmenting, maybe you would have noticed a benefit. Did the infusions affect your ferritin concentration at all?


Hmm-perhaps. I began augmenting May 2018, went cold turkey off pramixepole early June and by the third week of June I was out of augmentation. So about two months past without DAs before beginning the IVs. At the time I was on 30mg OxyContin and 3-3.5g of kratom. My ferritin level late July was 99. Later that fall it was 380.

My primary care doctor, who is the best doctor I’ve ever had, had my ferritin tested recently, came in at 402. She also ordered my vitamin D level checked, that came in low as usual at 23, even after midday summer sun exposure 3x/week for fifteen minutes. I live at altitude and have fair skin that burns easily. I mention this because we’re wondering what’s going: is it inflammation, is there an absorbtion issue, as I don’t respond to less than 20,000iu Vitamin D supplements. Another rabbit hole to ponder jumping into...

Re: Augmentation and gut microbiome

Posted: Mon Sep 16, 2019 5:16 am
by Bridgercan
Frunobulax wrote:I can't believe that we ignore all this research in our way of life (and most of all in our health system).


Right?!?

Re: Augmentation and gut microbiome

Posted: Mon Sep 16, 2019 6:07 am
by badnights
ferritin tested recently, came in at 402. She also ordered my vitamin D level checked, that came in low as usual at 23, even after midday summer sun exposure 3x/week for fifteen minutes. I live at altitude and have fair skin that burns easily. I mention this because we’re wondering what’s going: is it inflammation, is there an absorbtion issue, as I don’t respond to less than 20,000iu Vitamin D supplements. Another rabbit hole to ponder jumping into...
It's so baffling! Rabbit-hole indeed. When you think you have something figured out, along happens something else that refutes your new theory. It's easy to get tired of it all.

Maybe you should try a leaky-gut protocol (pick one, any one; I don't think the details matter); if absorption is an issue, then it will probably have led to inflammation.

Re: Augmentation and gut microbiome

Posted: Mon Sep 16, 2019 7:19 am
by Frunobulax
Bridgercan wrote:My primary care doctor, who is the best doctor I’ve ever had, had my ferritin tested recently, came in at 402. She also ordered my vitamin D level checked, that came in low as usual at 23, even after midday summer sun exposure 3x/week for fifteen minutes. I live at altitude and have fair skin that burns easily. I mention this because we’re wondering what’s going: is it inflammation, is there an absorbtion issue, as I don’t respond to less than 20,000iu Vitamin D supplements. Another rabbit hole to ponder jumping into...


Vitamin D is another curious thing that seems strongly connected to LG/SIBO. There is a study in Hawaii with people with an average of 28h a week sun exposure, and most of them were still vitamin D deficient (https://www.ncbi.nlm.nih.gov/pubmed/17426097). Only a few selected foods contain vitamin D (some fish, eggs, some mushrooms, some milk products). I also know that vitamin D is soluble in fat (and not water), so a low-fat diet will cause deficiencies in any case. And of course sunscreen will block vitamin D production, so sun exposure alone is not enough.

Gundry writes that 100% of his patients with autoimmune diseases are vitamin D deficient, and that vitamin D activates stem cells in the gut, protecting against LG/SIBO. And apparently malnourished children reacted well to ultra-high doses of vitamin D (200.000IE twice), gaining weight rapidly https://www.medscape.com/viewarticle/896391. But I still feel that there is something that we don't understand here. The diet of our ancestors couldn't have been that rich in vitamin D (compared to those of us eating low carb), so maybe those autoimmune reactions or environmental factors (glyphosate and the like) burn our vitamin D stores. I read somewhere that sun exposure just activates vitamin D, so if there are not enough substrates in the food we'll be deficient regardless, but I'm not sure if this is backed up by enough research. As always, more research is needed...

I take 5000IE a day. It took half a year to raise my level from 20 to 30, so 20.000IE is not that much in my book.