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).