Are there people that managed to deal with candida overgrowth by using RS? Did anyone fully recovered? Also are there any people on this thread that were not able to tolerate methylfolate and they managed to take it after they started RS?
The reason I am asking is that methylfolate could actually feed candida so maybe this is the reason that some people can not tolerate that.
Sorry, very long.
I think you need to look at methylfolate as an immunomodulating agent that becomes particularly relevant to all humans with high oxidative stress burdens. In ME/CFS the processes whereby bioavailable folate is synthesized, made accessible to various tissues, and interconverted is inhibited by a number of different mechanisms, but I believe there is a very central role for conditions that exist in the colon in mediating an immune response. We speak of supplementation of this micronutrient without regard for the particular mechanisms in which folate is selectively transported to the lining of the cells in the colon, which is is distinct from any other tissues.
The collapse of the population that provides folate synthesis and interconversion has enormous consequences on immunity, but the interrelationships between different organisms implies that all the key bacterial organisms need to be supported to restore an appropriate immune response. There is much more involved than getting reduced folate to our cells; the colon requires a continuous supply of reduced folate delivered to the epithelium, and there are multiple transport systems, which presumably control the accessibility to this nutrient when things go wrong. One of the most basic common denominators of this population of commensals that I think will soon be proven to have been compromised in ME/CFS is their high sensitivity to oxygen. This is true not just in speaking of microbial density and the species ability to withstand oxidation, but also includes the individual capacity of our microbes to reduce folate. The strength of association between "aerointolerance" and reduced folate synthesis may suggest that this evolved to inhibit the immune response when oxidative conditions predominated.
I believe the high "response" rate in this patient population to more bioavailable forms of this vitamin not only suggests that there is poor bio-availability, but that there is a high priority to limit the availability of tetrahydrofolate and its more reduced forms simply because of the importance of folate to the immune response. When we orally supplement reduced folate, this may allow for enhanced availability of microbial synthesized reduced folate to the intestinal epithelium. We are, however, also, likely over-riding a natural process of moderating the immune response, so there may be a downside to this supplementation.
We know that these reduced forms of folate are central in the metabolism of proteinogenic amino acids; which is certainly critical to the immune response, via countless mechanisms. The one most are familiar with is limiting methionine recycling, cysteine availability and the sulfur metabolism. This is one powerful means of suppressing the immune system, because it curtails the immune response stimulated by our intake and metabolism of amino acids. For example, while we think of glutathione as an antioxidant, which it it is, it also binds to nitric oxide, and plays a part in stimulating an immune cascade.
While Methionine is just one amino acid, it is particularly significant because if you suppress methionine you suppress the synthesis of threonine and all proteins. Various immunocompromised conditions/diseases demonstrate not only glutathione depletion, but inhibition of protein synthesis, which has been specifically tied to the inhibition of synthesis of these amino acids. Methionine synthase is therefore a very powerful control point because it limits the regeneration of methionine, and hence threonine. Inhibition of methionine, threonione, and glutathione is seemingly a programmed consequence of oxidative stress. This inhibition of protein synthesis is also exactly the same way that most popular category of antibiotics used to treat gram-negative bacteria works, so the process may serve to hinder the growth and replication of these organisms.
I suspect that with the multitude of human pathogens, such a central focus on gram-negative pathogens seems exaggerated, but I think their virulence is simply unparalleled, and their relationship with humans has evolved since our creation leading to countless regulatory measures to limit the harm they can cause. Our modern diets have clearly enhanced the threat that they present, as have antibiotics. The findings, such as 4-5x's the level of bacteria in the blood of those with type II diabetes is simply not getting enough attention. As far as I know, this can only be explained by bacterial translocation from the GIT. This also may underscore the power of polysaccharides that not only resist digestion, but as Ripley has discussed, are small enough to enter the circulatory system. This might represent another important means of sustaining the microbes that make their way into the extra-intestinal tissues and blood.
The quantity of endotoxin in a single GIT could kill thousands of humans, but we are largely protected while the intestinal epithelium and mucosal barrier are preserved. The TLR-4 receptors, which initiate the inflammatory response are typically not accessible in the GIT, they are protected by the mucosal barrier. It is only with the changes in the microbially-maintained mucosal layer that these are exposed, and when permeability is enhanced, the extraintestinal tissues, which do have exposed TLR-4 receptors, precipitate such a potent immune response.
Inhibition of protein synthesis via limiting threonine biosynthesis limits cellular proliferation, and this is is essentially what happens when tetrahydrofolate is limited at a molecular level. Inhibiting the synthesis of tetrahydrofolate suppresses the immune response because it is the principal co-factor required as part of the one carbon metabolism, which participates in the synthesis of RNA and DNA. Folic acid has to be reduced to 5,6,7,8-Tetrahydrofolic Acid. Limiting tetrahydrofolate has the power to dampen the immune response and protect us because it has the ability to affect DNA synthesis. This is the same method used to suppress cell growth in cancer cells, but in ME/CFS, I think it principally serves to dampen the synthesis of immune cells and limit the immune response.
A robust responses to MTHF may simply imply that patients have energy deficits as ATP/NADPH is required for DHFR and MTHFR, In this respect, tetrahydrofolate and methyltetrahydrofolate synthesis can be inhibited simply by mitochondrial dysfunction. Mitochondrial function has to be coordinated with all the systems that have the potential to cause great harm. NADPH availability affects a lot of processes, including the detoxification system our uses to neutralize nearly every sort of toxin we encounter. In this regard, it's scarcity serves to limit the burden that we are subjected to, including the mobilization of toxins from all our tissues that is mediated by glutathione.
As alluded to above though, very special circumstances exist in the colon, where there is a complex ecosystem involving the microbial synthesis and interconversion of folates. Some speak of the dietary intake obviating the need for this bacterial biosynthesis and interconversion, but I think this is unlikely when you look not just at the microbial folate synthesizing and conversion capabilities, but the complicated transport systems, which allow for these various forms of folates to saturate the tissues in the colonic intestinal epithelium. Folate availability to cells and uptake in the colon is distinctly different than in the small intestine where most folate is taken up for systemic distribution and supports the microbial organisms in the small intestine that are net consumers of folate.
With uncontrolled oxidative stress, I think there is an obvious means to control the reduction of folate when energy metabolism falters. This impacts the processes of generating DNA via de novo synthesis (which requires tetrahydrofolate) and limits the extent of amino acid metabolism. These mechanisms that seem to downregulate the immune response seems to be paired to mechanisms that protect our cells. For example the primary cysteine synthesizing enzymes are directly linked to the creation of short chain fatty acids, butyrate and propionate. In other words, biochemically, there is a diversion of methionine metabolites to products that almost exclusively protect us from oxidative stress. Enhancement of the sulfur amino acid metabolism does not do this.
In terms of the immune response, the effects of providing methylfolate to those with ME/CFS may relate to the creation of immune cells and the effects these create in the inflammatory cascade. I think this could be a deliberate regulatory mechanism that happens to inhibit the mobilization of endotoxins, because a robust immune response is what allows for cell wall destruction and the massive inflammatory response that would ensue if there was existing intestinal epithelial dysfunction. I also suspect that limiting cell turnover by suppressing tetrahydrofolate biosynthesis may also inhibit the exchange of the mucosal lining in other ways; I speculate that it basically preserves status quo so that the endotoxin is less accessible (physically) to stimulate an immune response.
