ME/CFS researcher Derya Unutmaz's hypothesis on cause of ME/CFS....

ljimbo423

Senior Member
Messages
1,489
Likes
3,095
Location
United States, New Hampshire
Putting the patient back together

Unutmaz hypothesizes that ME/CFS is caused by a change in a patient’s microbiome after an infection. Our microbiome consists of our microbes—trillions of bacteria, viruses, and fungi that are living in and on our bodies.

A misbalance in our microbes can change the makeup of our entire microbiome, which triggers an inflammatory response and causes the immune system to perceive that there is still a danger in our bodies – even when an infection is long gone.
LINK

Here is a study that has the same basic hypothesis-

One current model of disease suggests that a trigger event (e.g. infection) results in a chronic inflammatory state characterized by increased proinflammatory cytokine production, increased reactive oxygen and nitrogen species, altered intracellular signaling,

increased intestinal permeability and systemic activation of innate immune receptors, altered glutaminergic and dopaminergic neurotransmission, mitochondrial dysfunction, and aberrant autoimmune responses
We hypothesized that the ecology of the gut microbiota of ME/CFS patients would differ from that of matched healthy controls and that these differences would be associated with increased bacterial translocation from the gut to the circulatory system following exercise challenge with corresponding worsening of symptoms (i.e, pain, fatigue, and mood).

The results presented here add further to the previous findings suggesting that ME/CFS patients have an altered gut microbiome and further suggest that increased bacterial translocation following exercise provides a potential explanation for the profound post-exertional malaise experienced by some ME/CFS patients.
LINK

This is what another leading ME/CFS researcher, Chris Armstrong says about an altered microbiome and increased intestinal permeability (Leaky gut) causing PEM-

Well we all experience a bacteremia when we exercise. The type of bacteria that enter your bloodstream are usually quite controllable by your immune system but if your gut is further compromised they may release more

bacteria into your blood or more pathogenic species or your immune system may already be depleted. This is the concept for the chronic sepsis or SIRS and this is what I think may be behind PEM.
LINK


That's 2 leading ME/CFS researchers that have the same hypothesis, so far! It's no surprise to me, that all of the 5 ME/CFS collaborative research teams are focused on the gut, immune system, metabolomics and the brain.

There are also 5 more teams working for the Solve ME/CFS initiative (SMCI). They are also mainly focused on the gut, immune system and metabolomics-

We will update our community on these projects as they kick off in January 2018. Importantly, these studies will advance the knowledge for diagnosis and characterization of ME/CFS in at least five key areas where we still have considerable knowledge gaps:

  1. Biomarkers for initiation (infection) and metabolic derangement in ME/CFS (Team 1, Sweden)
  2. Epigenetic regulation in specific immune cell types (Team 2, USA and Spain)
  3. Intestinal virome alterations and abnormalities in ME/CFS (Team 3, United Kingdom)
  4. Immunometabolism of T cells and monocytes in ME/CFS (Team 4, Germany)
  5. Antibody reactivities against autoantigens & the microbiome in ME/CFS (Team 5, Israel)
  1. LINK
I think many of these researchers have a pretty good idea of what the root cause of ME/CFS is.

That's why they are researching these specific areas. Their challenge is finding the biological bio-markers to connect the gut, immune system, metobolomics and the brain.

I have no doubt they will do it!:thumbsup::)

Jim
 
Last edited:

Wishful

Senior Member
Messages
1,231
Likes
1,715
None of that shows a strong causal link. It could just as well be that ME/CFS causes the observed changes in the microbiome. I still believe that immune activation, such as from viral infection or vaccination, is the start of ME/CFS for most of us. I'm not expecting a cause or cure involving the microbiome.

The exercise->leaky gut->PEM hypothesis seems a bit weak too. It doesn't seem to fit the precision and consistency of the 24 hr delay I experience, or the fact that some quite strenuous exercise doesn't cause PEM, but muscle-damaging activity does. Muscle damage ->IFN-g -> PEM seems a much better match to observational data.
 

Wishful

Senior Member
Messages
1,231
Likes
1,715
There's no reason not to state hypotheses publicly. Such possibilities are worth checking out, and publicity might get more funding. I don't think that testing a hypothesis that proves false is detrimental enough to a career that you'd want to hide your research. None of that convinces me that their hypothesis is correct.
 

mariovitali

Senior Member
Messages
1,076
Likes
1,096
Professor Unutmaz is a great person first of all.

In trying to contact with Researchers regarding the Liver Hypothesis, i understood something that is very important. You get their attention when whatever you are saying proves or is highly relevant to their Research.

If a Researcher has received 5 Million to look at the gut and is an Immunologist, he will not care if your theory points to the Liver.

I have nothing against Researchers and i am not trying to blame anyone here. I am just saying that there are limitations that we need to be aware of.

Coming now to the Gut, i do believe it is important. I do believe that a leaky gut may cause several ME/CFS Symptoms given what i see algorithmically and from what some patients have told me.

I disagree however that for all ME/CFS patients the origin is from microbiome changes after infection. This makes an assumption that a person can get ME/CFS only after an infection, which is not the case for all patients.
 

Learner1

Administrator
Messages
3,490
Likes
6,045
Location
Pacific Northwest
This is a complex disease and several researchers have noted that there are subgroups of us.

For example, Jarred Younger found an infection subgroup and an autoimmune subgroup.

Many of us have abnormalities in many systems - digestive, nervous, endocrine, immune, musculoskeletal, etc. as well as mitochondrial dysfunction. It's not clear what the root cause is, which is why the researchers are pursuing many theories.
 
Messages
1,188
Likes
5,623
personal anecdote: I have clear dysbiosis . I can't eat fodmaps or dairy or egg. My guts are sensitive.

But I wasn't always like this. First decade of my illness my guts were basically normal.

This leaves me confused about the role of the gut in my own case.
 

LINE

Senior Member
Messages
109
Likes
175
Location
USA
The gut holds 70% of the immune system which you can read two ways, the first is the majority of the immune system lies there for a reason, that is, the gut is suspectible to infection and will respond to pathogens (localized infection). The second is the gut could become dysregulated due to a systemic infection in that the immune system is responding to the larger infection and the gut is being damaged as a fallout reaction.

Gut infections create a very bad environment for the body by creating a leaky gut which causes systemic inflammation. With any serious form of inflammation, there will be much oxidative damage which injures the cells and systems of the body. Glutathione and other endogenous antioxidants (catalase, superoxide dismutase*) are used up quickly to neutralize the oxidative stress and with the reduced antioxidants, it lowers the detoxification and immune systems.



*Note that the ROS (reactive oxygen species) discussed below are largely created by the immune system, the author notes that exogenous antioxidants help the endogenous antioxidants. Also note that ROS and RNS (Reactive Nitrogen Species) are very strong chemicals that are potent oxidizers and cause mitochondrial distress = low cell energy or fatigue.

source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2952083/
Under physiological conditions, the human antioxidative defense system including e.g., superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione (GSH) and others, allows the elimination of excess reactive oxygen species (ROS) including, among others superoxide anions (O2.-), hydroxyl radicals (OH.), alkoxyl radicals (RO.) and peroxyradicals (ROO.). However, our endogenous antioxidant defense systems are incomplete without exogenous originating reducing compounds such as vitamin C, vitamin E, carotenoids and polyphenols, playing an essential role in many antioxidant mechanisms in living organisms.
 
Last edited:

Wishful

Senior Member
Messages
1,231
Likes
1,715
I was thinking more about the original post's implication that 'more people studying this hypothesis means that this hypothesis is correct'. How many people (leading experts?) jumped on the PACE/GET bandwagon?

I do accept that gut function is important, and could be part of ME/CFS for some people. I just haven't been convinced that it is the answer to ME/CFS. The evidence against seems stronger than the evidence in favour.
 

ljimbo423

Senior Member
Messages
1,489
Likes
3,095
Location
United States, New Hampshire
personal anecdote: I have clear dysbiosis . I can't eat fodmaps or dairy or egg. My guts are sensitive.

But I wasn't always like this. First decade of my illness my guts were basically normal.

This leaves me confused about the role of the gut in my own case.
Hi Murph- I think it's a common misconception that one has to have Irritable bowel syndrome (IBS) or gut symptoms to have dysbiosis and increased intestinal permeability (leaky gut).

This study, shows much higher levels of bacterial sequences in the blood, from the gut, after an exercise challenge, in ME/CFS patients over controls. Showing increased intestinal permeability or leaky gut.

It shows that only 3 out of 10 ME/CFS patients had mild gut symptoms. So, 7 out of 10 ME/CFS patients reported no gastrointestinal symptoms at all. However they had a significant increase in intestinal permeability.

Particularly germane to this study, only 3 of the 10 patients and 2 of the 10 controls reported gastrointestinal symptoms and all participants reported mild severity and symptoms present “a little of the time.”
What is also really interesting to me, is that the higher levels of bacterial sequences in the blood of the ME/CFS patients over controls, was maintained for 72 hours or 3 days.

This is the same time frame for the worst PEM symptoms for many people with ME/CFS.

There was also a significant difference in clearance of specific bacterial phyla from blood following exercise with high levels of bacterial sequences maintained at 72 hours post-exercise in ME/CFS patients versus clearance in the controls.
LINK


Jim
 

ljimbo423

Senior Member
Messages
1,489
Likes
3,095
Location
United States, New Hampshire
Coming now to the Gut, i do believe it is important. I do believe that a leaky gut may cause several ME/CFS Symptoms given what i see algorithmically and from what some patients have told me.

I disagree however that for all ME/CFS patients the origin is from microbiome changes after infection. This makes an assumption that a person can get ME/CFS only after an infection, which is not the case for all patients.
I think he used the phrase "after an infection" as an example because so many people do get ME/CFS after an infection.

I think Derya Unutmaz's larger point is this quote from him-

A misbalance in our microbes can change the makeup of our entire microbiome, which triggers an inflammatory response and causes the immune system to perceive that there is still a danger in our bodies – even when an infection is long gone.
As I understand that, he is talking about dysbiosis and increased intestinal permeability (leaky gut).

A viral or bacterial infection or repeated viral or bacterial infections, seems to be a major factor in triggering ME/CFS.

However, there are many things that cause or contribute to dysbiosis and increased intestinal permeability.

Stress (physical or mental stress), poor diet, antibiotics, excessive drinking, food poisoning, parasitic infections and non-steroidal anti-inflammatory drugs are some of the most common causes.

My own personal experience with developing ME/CFS is that I got it after a viral infection at 18 years old. However, I recovered to about 80% for many years, after about 2 years.

Then slowly started to decline again until I was unable to work any more.

Jim
 

ljimbo423

Senior Member
Messages
1,489
Likes
3,095
Location
United States, New Hampshire
This is a complex disease and several researchers have noted that there are subgroups of us.

For example, Jarred Younger found an infection subgroup and an autoimmune subgroup.

Many of us have abnormalities in many systems - digestive, nervous, endocrine, immune, musculoskeletal, etc. as well as mitochondrial dysfunction. It's not clear what the root cause is, which is why the researchers are pursuing many theories.
I think it's very possible that researchers will find many subgroups in ME/CFS.

If lipopolysaccharides (LPS) from the gut are causing immune system activation, mitochondrial dysfunction and low grade brain inflammation, I think that could explain many of the dysfunctional systems in the body you mention, if not all of them.

LPS are also routinely used all around the world, in lab experiments to cause neuro-inflammation (brain inflammation). LPS have also been shown to cause the mitochondrial switch to glycolosis seen in ME/CFS.

Glucose Utilization in M(LPS) Macrophages
Early studies indicated that avid glucose consumption in LPS-activated dendritic cells and macrophages sustains high rates of aerobic glycolysis, or “Warburg metabolism” (Figure (Figure1C).1C).
LINK

I think individual epigenetics and genetics play a big role in how this disease presents itself in each of us.

Also, it effects almost every system in the body, if not every one. Which makes it much more likely to present differently in each person.

Given it's widespread effects in the body and each persons individual epigentics and genetics, I think subgroups are very likely.

Jim
 

Moof

Senior Member
Messages
506
Likes
1,258
Location
UK
personal anecdote: I have clear dysbiosis . I can't eat fodmaps or dairy or egg. My guts are sensitive.

But I wasn't always like this. First decade of my illness my guts were basically normal. This leaves me confused about the role of the gut in my own case.
Me too! Severe food intolerances, SIBO, continuing IBS even after sorting the food intolerances I know about, h. pylori infection that has caused B12 malabsorption. But for the first 30 years of my ME, I was fine – I could eat absolutely anything.

I realise this doesn't necessarily mean there were no problems going on underneath the radar, but other family members have also developed these problems in middle age, even though they've never had ME. So the issues may actually be related more to age or h. pylori (we seem to be particularly susceptible to it), than they are to my ME.
 

ljimbo423

Senior Member
Messages
1,489
Likes
3,095
Location
United States, New Hampshire
The gut holds 70% of the immune system which you can read two ways, the first is the majority of the immune system lies there for a reason, that is, the gut is suspectible to infection and will respond to pathogens (localized infection). The second is the gut could become dysregulated due to a systemic infection in that the immune system is responding to the larger infection and the gut is being damaged as a fallout reaction.

Gut infections create a very bad environment for the body by creating a leaky gut which causes systemic inflammation. With any serious form of inflammation, there will be much oxidative damage which injures the cells and systems of the body. Glutathione and other endogenous antioxidants (catalase, superoxide dismutase*) are used up quickly to neutralize the oxidative stress and with the reduced antioxidants, it lowers the detoxification and immune systems.
Very well said and I agree.:thumbsup:

Jim
 
Last edited:

Neunistiva

Senior Member
Messages
390
Likes
1,997
If exercise causes bacterial translocation from the gut and that could explain post-exercise PEM then how is PEM caused by weird things like conversation, loud sounds, washing hair, etc. explained?

Do things like talking really also cause bacterial translocation?

I personally don't like when so much weight is put on exercise when it's any exertion that crashes us.
 
Messages
34
Likes
21
"causes the immune system to perceive that there is still a danger in our bodies – even when an infection is long gone"

There we go again with saying something (such as bacteria or virus) isn't there just because the researchers can't find it.
Reminds me of how Dr.s of old were so resistant to hand washing because they couldn't see the bacteria and viruses they were spreading when going patient to patient.

I think that when the gut is imbalanced it's because of ongoing infection of some type and at some level, and the infection is not easily detected in the blood. Certain viruses and bacteria are notorious for leaving the blood stream and settling in various organs and even the brain. Hard to test for microbes in the brain.
 

junkcrap50

Senior Member
Messages
407
Likes
607
"causes the immune system to perceive that there is still a danger in our bodies – even when an infection is long gone"

There we go again with saying something (such as bacteria or virus) isn't there just because the researchers can't find it.
Reminds me of how Dr.s of old were so resistant to hand washing because they couldn't see the bacteria and viruses they were spreading when going patient to patient.

I think that when the gut is imbalanced it's because of ongoing infection of some type and at some level, and the infection is not easily detected in the blood. Certain viruses and bacteria are notorious for leaving the blood stream and settling in various organs and even the brain. Hard to test for microbes in the brain.
I agree. Maybe I"m missing something, but how come these smart researches can't understand there [can be] a cellular infection and virus/microbe IN THE CELL but is not replicating and not in the blood stream?
 
Last edited:

JES

Senior Member
Messages
781
Likes
1,553
There we go again with saying something (such as bacteria or virus) isn't there just because the researchers can't find it.
Ron Davis in fact found fewer viruses in patients than in healthy controls, at least according to what he reported last December (thread). You are correct that it might still be that they are not looking with the right methods and I believe research is still continuing in this aspect. But if it were a virus/bacteria, they would first have to actually find it and only then can they start to look at developing a treatment for it, so it would be a long road. Meanwhile they might as well explore other hypotheses, which if they are correct might bring a very quick cure in a matter of a year or two.