I´m reading the whole long thread a second time, to understand as much as possible of the (a great thank you all for posting) interesting informations.
According to vegas post concerning LPS/MTHF and histamine: how do you handle this? Should we lower the often recommended dosage of 800 mcg daily with the double MTHFR-mutation? Or will the histamine disappear with lowering LPS (through potential gut healing with RS+fibres+probiotics or fermented foods?)
Regards, jepps
I would worry less about a protocol that establishes precise, but arbitrary recommendations and use your symptoms as a guide. While we know that this active form of folate can participate in reactions that degrade histamine, methyltetrahydrofolate supplementation can result in a robust immune response, one that many have variously described, including myself, as a "detox" reaction.
I would argue that in ME/CFS (and perhaps most inflammatory disease processes) this immune response and the associated histamine response will often far exceed the effects of this micronutrient in affecting those processes that would inhibit the histamine response and its metabolism. Its roles in your immune response are numerous, but the high response rate to MTHF (and GcMAF), I think strongly suggests that a bacterial pathophysiology is implicated.
There are macrophage folate receptors that can respond quite dramatically to exogenous supplementation of MTHF. When someone who has an impaired ability to synthesize (and interconvert) methyltetrahydrofolate increases cellular concentrations via oral supplementation, these receptors will sense this artificial MTHF saturation and prompt a phagocytic response. You can largely throw out the SNP's from this equation I think, although some may have relevance, because the biosynthesis of MTHF is inhibited by design. It is most certainly an evolutionary adaptation that protects humans from excessive oxidative/nitrosative stress.
The macrophage response, which is one vital component of our defenses against bacterial pathogens, is exquisitely complicated, but many are familiar with the contributions of vitamin D and the vitamin D receptor. One thing bacterial toxins and lipopolysaccharide do specifically is inhibit the VDR protein; they downregulate VDR mRNA and this similarly serves to protect us against an excessive, and life-threatening, immune response. Histamine is just one part of this inflammatory cascade.
The interplay between the receptors stimulated by vitamin D and active folate is quite fascinating, I won't bore you with the details, but, UV exposure stimulates the synthesis of water-soluble vitamin D, but at the same time it oxidizes many forms of folate in blood plasma. You can control the biosynthesis of Vitamin D by limiting your UVB exposure. For example, I find that when I travel to the subtropics in the summer, I have to limit exposure to the sun secondary to the massive increase in vitamin D synthesis, which precipitates an excessive immune response. One of the ways this is immune response is limited is by the synthesis of melanin, which of course adds pigmentation and reduces the synthesis of vitamin D. There are actually many other countermeasures that serve to inhibit an excessive immune response. One of these is actually the release of histamine as this has been found to induce the biosynthesis of melanin. We also accumulate phenolic compounds, in part because the organisms that degrade these are involved in maintaining the intestinal epithelium. A primarily product of bacterial metabolism of phenols is melanin; in effect our microbes also seemingly try to protect us from excessive immune stimulation as well as they cannot live without us.
Of course there has to be a balance, melanin decreases the synthesis of vitamin D effectively inhibiting the immune response, but at the same time it protects folate from oxidation in plasma. Your blood of course regularly and rapidly circulates so that it routinely comes in contact with the superficial capillaries that perfuse the skin and are susceptible to UVA & UVB radiation. This is where people with inflammatory diseases can be highly susceptible to sun exposure because MTHF is the primary form of folate that circulates in blood plasma. MTHF is highly resistant to UVA and UVB photodegradation, other forms of folate including folic acid, are readily oxidized in the sun. In this regard, those with impaired ability to biosynthesize MTHF and interconvert folates are likely to be influenced by excessive UV exposure. The protective response appears to involve limiting our biosynthesis of vitamin D and preserving our supply of non-methylated folates since MTHF is generally not oxidized by our exposure to the sun.
As I have discussed before, the colon is a net producer of folate and those bacterial organisms that are highly sensitive to oxygen are the best producers of MTHF. Some have asserted that this relatively small quantity of folate is a minor consequence to health, but I think the preserved folate transport system in the colon and the distinct response of different forms of folates at different receptor sites suggests otherwise. Without going into detail, it has been discovered that macrophage response varies depending upon the tissues and different forms of folate have variable effects in the lymphatic system versus the small intestine, for example.
In addition to the fact that highly-oxidizing environmental conditions limit the growth of these folate synthesizers, the conditions also serve to limit the efficiency of the microbial synthesis and the interconversion--again, as I see it, the conditions serve to limit the immune response, I think this is inescapable. Similarly, it is clear that the microbial and human relationship is far more complex and critical that previously believed.
I think MTHF is beneficial for a number of reasons including protecting other folates from oxidation and I have derived benefits from it, but obviously, in making an argument that its synthesis is purposely downregulated, there is a downside to supplementing with this. I have to be particularly careful with this in the summer when my vitamin D levels are up because it is clear that the sun exposure reduces my already diminished access to this vitamin. I don't notice a big effect at 36 degrees latitude, but 25 degrees kills me. Personally, I do much better on small, but regular doses of MTHF and not letting levels go to high or low.
I do believe you will see a response that diminishes over time as the epithelial dysfunction is restored secondary to restoration of a more optimal intestinal microbiome, but I can only speculate as I don't have an appreciable histamine response. A combination of resistant polysaccharides that stimulate those organisms that maintain the intestinal epithelium in the colon combined with properly fermented LAB has given me the best results.
