I believe the observed partial methylation block is the consequence of increased oxidative stress that leads to low glutathione. But what's depleting glutathione is the question. I really don't believe methylation defects generally result in low glutathione. They certainly don't help, but not usually the cause. I find that as long as I keep on top of killing fungus in the gut and eliminating SIBO with a drug like Rifaximin symptoms improve tremendously. And I no longer need the B12/Folate to feel better. Many try to load themselves up with probiotics when they have SIBO. This just adds fuel to the fire, and in reality, one should avoid probiotics when treating SIBO as the small intestine should be sterile. Swallowing Amphotericin B lavage may be a better idea than Nystatin/Difflucan as it is apparent that many actually don't have Candida species, but possibly another fungus (usually seen as large quantity of unidentifed fungus on Metametrix tests). I wonder if this is generally Aspergillus of the gut as it is the second most common fungal infection and given the study that CFS patients have a significant quantity of Aspergillus-related toxins in the urine. Spirostat used to look for Aspergillus spp. and other fungi in their fungi panel, but last I checked, they are not accepting samples. I'm not aware of any other labs that have a comparable fungi test. In the case of a non-Candida fungal infection, 35% hydrogen peroxide (starting with 1 or 2 drops in water) may work well too. However, it won't kill Candida spp. The die off was intense for a few days, but I felt like a new person and have a lot more energy since. I understand this treatment is controversial for a number of reasons. Is the low stomach acid and low bile acid/bile salts environment good breeding grounds for an Aspergillus infection of the gut? I would have to research this as I don't know the answer. It seems after you get this all under better control, digestion gets better (stomach acid increases), gallbladder function may improve (as observed by color and consitency of stool or functional lab tests). Subsequently, you would expect better absorption of vitamins/minerals/amino acids. After all this, you feel much less toxic, so I would guess glutathione would go up. It would be interesting monitoring glutathione before and after such a protocol. Interestingly, it doesn't seem that most experience die off with the non-systemic antibiotic Rifaxmin. Just improvement (even if temporary). However, treating fungus is another story, and die off can be very severe. Reactions to systemic antibiotics are often unpleasant as well for whatever reasons, but like I said it's not usually the case with Rifaxmin. Many have high ammonia levels, so it makes sense that Rifaxmin will help with neurocognitive symptoms in these cases. Rifaxmin is used to bring down ammonia levels for those with hepatic encephalopathy (which has many overlapping symptoms). So I guess the question we are left with is what triggered the gut problems. Virus, bacteria, fungi, parasite (e.g. Giardia)? Maybe a synergistic combination of all these factors? But I guess my point is addressing gut infections may be a good way to possibly lift the block and increase glutathione status.