Intermittent fasting - restricting daily hours of eating - and ME/CFS

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The IDO2 tryptophan trap hypothesis

Spoiler: parts of this post about the IDO2 metabolic trap hypothesis

There are some issues and concerns around the IDO2 tryptophan trap hypothesis about ME. These are my current thought directions, and should not be considered scientific fact. Please comment, add links, agree or disagree, or move this post to somewhere better if you are a moderator.


Concerns over biases and the Unknown

There are two big ones here. However let me start with a caveat. If the data is confirmed that over 98% of people with ME have an IDO2 mutation then this is a major leap forward. Its not small. Its the most significant advance in ME research ever. If confirmed, and it leads to tests or treatments, this might win a Nobel prize. Its that big. Of course if its wrong or misleading its a very different thing, which depends on why its wrong or misleading.


Possible Sample Bias

The biggest risk is bias, isn't it always? According to a video presentation by Ron Davis perhaps 69/70 patients tested have a mutation in IDO2 that may render this enzyme ineffective. How many of the patients in this sample are severe patients, given the ongoing severe patient study? Its possible that IDO2 may not be causal for ME at all, but rather causal for severity of ME? That is still an advance however.


Probable Co-Causality

The more likely concern is that an IDO2 mutation or variant is not causal but co-causal. Indeed this seems overwhelmingly likely. With a prevalence of ME of maybe 0.2% and CFS at maybe 0.4%, and gene variants at maybe 40%, active affect of these variants in this population is very low. Other factors play a huge role, and we are only really discussing the immune activation issue right now. There are possibly other necessary causal factors, and maybe many others.

It is still possible that its just about immune cells that reach a particular molecular state without needing other factors, but I doubt it. There is however still a chance that this is all that is needed, and perhaps numbers of cells affected are critical in determining outcomes.


Other Possible Issues of this Hypothesis

The discussion, at least on forums and maybe not places like OMF, seems to have a focus on blood resident and migrating immune cells, and possibly places like lymph nodes. Probably not all of us, but I would like to expand the focus and explain why this might be very important. Some of this has been touched on in discussions on this forum if I recall correctly.


Cell Types

First we don't know its limited to immune cells. Other cells in which the IDO genes are expressed might be impacted. This has many ramifications, but I will discuss some of them in the next concern, even though they also apply here.


Resident Immune Cells

Second, the majority of immune cells are not in the blood. They are tissue resident immune cells, especially in the gut. Maybe all tissues have resident immune cells except possibly immune priveliged tissue, though the brain has its own specialized immune system.
Most pathogens, and some toxins, have tissue specific affinities or impact. With viruses this is in part due to the availability of cell receptors they can bind to.

So if we have something like Coxsackie virus in a person, it affects tissues including gut, muscle and heart (a specialized muscle). The immune cells in all these places, if they have IDO pathways, may also be affected if the person has an ineffective IDO2 variant. So while the blood immune cells might cause problems all over the body, the affected resident immune cells might cause issues in any tissue that was infected, or by activation from blood or migrating immune cells.

This means that specific symptoms might arise following the specific pattern of infection of a specific pathogen. No wonder there is so much variation, even ignoring diet, genetics, co-mordities and so on. This raises the question as to whether or not many infections give rise to the core disease, though specific location and severity variations with specific pathogen effects alter symptomology.

The pattern of tryptophan overloaded cells is also likely to show variation. Their number and distribution are likely to be critical.


Two IDO2 historical research issues

It seems to me that the reasons already discussed elsewhere as to why this was missed pretty well cover it. Early genetic studies in ME looked at rare and uncommon mutations. Assumptions meant that researchers were not thinking about common genetic problems.

Another issue is that IDO2 is a backup gene. With a highly effective primary gene in IDO1, this IDO2 gene was ignored. It did not matter. It took looking into the kinetics (rates of tryptophan conversion over time) to show there was a problem.


My thoughts on Researchers

All of our biomedical researchers, and a few dealing with the social and political side, deserve support. I have great regard for Ron Davis and many of his colleagues, but we should not put them on a pedestal. We should listen, critically review, and provide financial and other support when we can. We are participants, even if in a very minor way as engaged patients, or a bigger way as volunteers in studies or regular financial donors.

__________________

Personal Comment

Am I well enough to blog again? We will see. I have more clarity tonight, right after yet another nap.

I have had major cognitive issues these last few years, verging on dementia at times, but seem to have been continuously improving over one and a half years of intermittent fasting. My sleep is better, I have fewer symptoms, fewer food intolerances, and better bloodwork. Fasting might not be the reason I seem to be improving though, but I can be hopeful it will continue.

More blogs to come? This blog only took a couple of hours from first thoughts to the finish, though I will pause for some hours before reviewing it prior to posting. A few hours of moderate clarity matter.

Let me be clear that there is no sign that fasting is reversing my ME, just improving specific symptoms.

 

your intermittent fasting—is it several days a week/month eating no food? Or several days eating very low calorie?

 

More restricted feeding time, usually 16/8 fasting, but occasionally 20/4 and rarely 36/12. I was forced into this as there are ZERO treatments that can safely treat my type 2 diabetes. Even insulin, though I also think insulin is a poor choice for other than acute treatment in type 2s. Metformin almost killed me, and I nearly lost a leg in the process.

Not eating on weekends, or every other day, are popular choices.

I do fasting in part because it can be done with any diet restrictions. You can do fasting vegan, carnivore, keto, low carb, or common food. Low carb is currently best for my circumstances. Low calorie fasting mimicing diets I have not tried.

Calorie restriction studies often include fasting, even in rodents. Feed them a tiny amount and its usually eaten in minutes followed by fasting the rest of the day.

There are some people who should not fast however. Many with very restricted eating capacity should probably not do so, but this is unresearched. After all, they are already not eating enough.

Longer discussions on fasting or repeated discussions should probably go to a new thread.

 

Someone please start a thread on fasting, or reduced food intake, and whether or not this helps in any way. Thanks.

Done

 

can you please say what you mean by:

> More restricted feeding time, usually 16/8 fasting, but occasionally 20/4 and rarely 36/12.

i assume you mean soemthing like 16h no eating and 8h where you eat at whatever times during those 8h?

[personal note: i often do something like [iiuc] 20/4 without wanting to.

this occurs even when i am very hungry or am experiencing blood sugar symptoms which are hard on my m.e.

for example, often i do not remember to eat, or remember but stm goes out hte window, or remember that food is there. these are memory issues, not at all specific to eating. they seem sort of possibly related to the next issue.

often i cannot initiate movements like moving my arm to the right by one foot so that i can start eating. this seems to be something like severe executive dysfunction. it is also not at all specific to eating. a problem all over the place.

i also often do not eat because rinsing fluoride is too hard on me, or lifting arm is too hard on me, or there is no food brought for me to eat. i have been told i have prediabetes. so i wonder if this not-eating thing is actually partly good.

idk anything about prediabetes etc. so i had not heard of these 20/4 type numbers before or what the theory is.]

please note that alex suggested a possible new thread. brain cannot do atm.

 

Yes. This is standard terminology in fasting. There are all sorts of abbreviations. Basically you go without food for at least 16 hours in this form. Currently I am on 20/4 which means twenty hours a day with no food. I am saving money too as I am not buying so much and my larder is overfull.

I too have issues making food. My biggest problem is finding the energy to cook when I need to eat, or even at any other time when I might put food away for reheating, which sometimes leads to longer fasts. This not only a physical issue, including exhaustion, its what happens then. Kitchen accidents are much more likely if I am exhausted, my arms go places they shouldn't, and I can forget how to cook, what ingredients to use when and so on. So many times I have left out a key ingredient, its annoying. I also have to constantly sit down and get up again to avoid standing too long, which is exhausting in itself. So my ME might mean I eat less healthy food, packaged food etc., which is not ideal at any time. My chaotic sleep schedule also makes timing of everything an issue, even taking meds.

What usually happens and happened to me is that over time, starting in days but getting better over years, the body adapts and stops burning so much carbohydrate and moves to fat sources. Hunger can be a problem early on but is less and less a problem over time. Cravings are different though ... I still want that pizza, pie, chip (or French fry). I have few foods that I seriously crave though, and thankfully I do not live above a bakery or that would be a real problem for me. I have never really craved sugar, but savoury baked goods are my Kryptonite.

Dieting can lower metabolic rate and cause muscle mass loss much more rapidly than fasting.

Let me re-emphasize a caveat - fasting is not for everyone. Many ME patients cannot do this.

If someone would like to start a new thread then moderators please feel free to move this post. There is lots to say about prediabetes and diabetes. I am distracted right now as my microwave shorted out and almost caught fire, and I am figuring out how to get another one.