Changes in Gut and Plasma Microbiome following Exercise Challenge in ME/CFS

[msf]

Thanks anyway for the statistical analysis. I would say that they are very likely to have clinical significance, but I guess they didn´t show that in the study.

 

[Jonathan Edwards]

I have not read this through too carefully but as far as I can see all the data are on relative abundance of bacterial groups as indicated by DNA.

So the study appears to show nothing about increases in amount of bacteria in the blood following exercise, and so nothing relevant to leaky gut hypotheses, cytokines or whatever.

And I cannot really make head or tail of figures 2 and 3 in terms of a scientific story. Maybe I am tired. Some of the younger members may be able to point out that I have missed important aspects, but I am not holding my breath.

 

[Kati]

It depends on what you mean as exercise. If walking to the bathroom causes PEM then that's exercise for you.
I would guess the patients volunteering for this trial were on the mild side.

Let's not go there again please. Be thankful for those willing and able to participate to this kind of science, knowing that these subjects sacrificed months of their health in order to have science measure the effects of exercise.

 

[msf]

This was what the study said:

All DNA samples were quantified using the Qubit DSDNA HS assay kit (Life
Technologies, Grand Island, NY) and stored at -80°C until use

I believe the tests offered by Redlabs and another lab in America work on the same principle.

I do not understand the full implications of Figure 2 either.

Ah, I see what you mean, Prof. Edwards - they were measuring changes in relative abundance too.

 

[John Mac]

Let's not go there again ease. Be thankful for those willing and able to participate to this kind of science, knowing that these subjects sacrificed months of their health in order to have science measure the effects of exercise.

I'm very grateful to those who volunteered for this study. My point was I would hope and expect the researchers not to ask the more severely ill patients to undertake this maximal exercise test.

 

[inuk2600]

This seems to match up well with the activation of quorum-sensing virulence.

The quorum-sensing signal autoinducer-3 (AI-3) is the native signaling ligand for the QseC sensor and is used by many species of gram negative bacteria to activate virulence. The QseC plays a role in invasion of epithelial cells and intramacrophage survival.

The stress hormones epinephrine and norepinephrine are both used by the bacterial QseC sensors in the place of AI-3.

It could be this particular mechanism that accounts for the traversal of bacteria through the intestinal epithelium during stress i.e. leaky gut (I always hated that term).

I suggested this connection for CFS and PEM on the Marshall Protocol forum a few years ago (when I was into that kind of thing), and looks like it might be getting some promising support with this new study.

As a personal aside, I'd like to add that I've suffered with episodes of IBS and a distressing type of intestinl gas that would make me sick with fatigue and cognitive impairment in my late teens before I was slammed with full on CFS that coincided with the stress and effort of pushing myself to succeed after graduation.

The small molecule drug LED209 was found in a special search to specifically disrupt the QseC sensor. I would love to try this drug right now as my CFS is currently raging strong.

Also, it is most likely that an additional factor, like a genetic weakness (an SNP?) is present in the CFS sufferer which makes them prone to invasion via this particular virulence, since you can torture the holy hell out of most people and they bounce back fairly quickly after the stressor is removed.

Finally, and this one is a bit of a stretch but very intereseting... Look at figure 3 on Light's CFS exercise test http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2757484/

Note that the adrenergic function genes are the furthest off baseline compared to controls. Also note that the mRNA samples were taken from leukocytes. Could it be the disruption of the adrenergic negative feedback system by the bacteria that have invaded the macrophages(leukocytes) resulting in a bias towards runaway stress?


References:

http://iai.asm.org/content/78/3/914.full

http://www.nanomedjournal.com/article/S1549-9634(14)00548-6/abstract

http://www.sciencemag.org/content/321/5892/1078.abstract

http://www.marshallprotocol.com/view_topic.php?id=13710&forum_id=39&highlight=QseC

 

[msf]

I think I´m starting to see the logic of the study - if the relative abundances of different genera of bacteria changed more after exercise in ME patients than in controls, then it suggests that the change in intestinal permeability after exercise in ME patients is greater than that in controls.

 

[msf]

Ok, I was trying to make more sense of this study but I´m going to give up because it´s starting to annoy me. Why couldn´t they publish the relative abundances of all the genera in the blood at the different time points? Did they run out of graphs? Without this, we don´t know if the relative abundances of the genera in the blood changed more after exercise in ME patients than in controls, even if they did in the three genera they published the results for. What´s the point in a table that shows the mean relative abundances of the different genera from all the time points? Did they run out of tables? I don´t understand studies like this - is journal space that hard to come by?

 

[kangaSue]

Do we know specifically what it is about "exercise" that increases permeability? An increase of lactate or some other product of cell metabolism?

Seeing as many CFS patients also complain of gastrointestinal disturbances, I would suggest intestinal mucosal ischemia could be a reason for increased gut permeability. The oxygen demand from the intestinal mucosa layer is tripled during the digestion process, exercising after food intake can divert this blood flow from the mucosa to skeletal muscle. Possibly, a low blood volume and the resultant decreased oxygen potential could also exacerbate the situation.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1378153/pdf/gut00547-0078.pdf

http://download.springer.com/static...00187d5c1b20af0586d479c0fde4239ddb1f09b13e923

 

[msf]

I believe KDM thinks that some kind of ischemia is contributing to this.

 

[John Mac]

The oxygen demand from the intestinal mucosa layer is tripled during the digestion process, exercising after food intake can divert this blood flow from the mucosa to skeletal muscle.

Do you know how long this oxygen demand lasts after eating?
I'm wondering if it's advisable to just sit and relax after eating

 

[MeSci]

Do you know how long this oxygen demand lasts after eating?
I'm wondering if it's advisable to just sit and relax after eating

IMO, yes. As we have difficulty producing energy, we need to let our guts have as much energy as they need for the initial digestion. I don't know if people still talk about 'letting your food go down' as they did when I was young, but it's something I do now as, if I don't, I sometimes get a degree of dyspepsia and/or even slight regurgitation. I try to leave it at least 30-60 minutes after a medium-sized meal (I can't eat large meals) before doing anything that involves bending.

 

[kangaSue]

Do you know how long this oxygen demand lasts after eating?
I'm wondering if it's advisable to just sit and relax after eating

http://www.ncbi.nlm.nih.gov/books/NBK53094/
It's a highly variable and complicated process, different parts of the system, superior mesenteric artery for instance, needs extra oxygenated blood flow for 2 hours or more after eating.The oxygen demand is driven, in part, by both acid secretion and nutrient absorption so it depends also on how fast your stomach empties as well. Slowed motility is not uncommon in ME/CFS. Exercise also slows stomach emptying so there is good reason to relax for a while after eating.

Actually, the mesentery arteries alone can be the cause of mucosal ischemia. Low flow state or restricted blood flow through the mesentery microvascular network can induce ischemia due to spasm in these small vessels.

Gastric ischemia can also be induced in healthy individuals through intense exercise.
http://jap.physiology.org/content/91/2/866

There is a test for chronic gastrointestinal ischemia called Gastric Exercise Tonometry involving exercise at a submaximal level but I'm not sure if that only detects ischemia when there is an occluded mesentery artery present. I think the test is relatively unknown other than in Holland where it was devised.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1914298/

I had a duplex doppler ultrasound that picked up an increased flow velocity in my superior mesentery artery which turned out to be due to non-occlusive spasm of the artery causing gut ischemia so that is an option to try.

 

[anciendaze]

Those statements above about gastric ischemia induced by exercise, even in healthy individuals, are true. Part of the "flight or fight" response shuts down digestion in favor of more urgent concerns. This is a non-trivial process controlled by the autonomic nervous system, and we have widespread indications many ME/CFS patients have some degree of dysautonomia, though we don't know the cause.

The idea of bacterial translocation in the gut causing symptoms of PEM seems promising. That malaise is regularly described as "flu like", and influenza definitely does cause similar disturbances in the gut. I would also point out that the time scale on which symptoms of a brief flu disappear is not too different.

Instead of trying to pick out useful information from the data published here I'm going to suggest a measurement which should be much simpler. If bacterial translocation is taking place more seriously when ME/CFS patients exercise, some common bacteria should be well represented. In particular e. coli., a proteobacterial sp., is likely to leave components in the blood, even if living bacteria do not reach the bloodstream and cause sepsis. There is a real connection here with possible mitochondrial dysfunction because the membrane of e. coli., like that of mitochondria, contains substantial cardiolipin.

I'm suggesting this because there have been inconsistent reports of anti-cardiolipin antibodies (ACA) in ME/CFS patients for years. If these are generated in response to bacterial translocation, and wash out over a number of days without exercise, the time scale might fit. Since we have no idea of the relation between previous patient exercise and past ACA measurements this could explain earlier inconsistent results.

Looking for a dynamic response to common pathogens strikes me as more likely to yield results than searching for rare pathogens when we don't even know precisely what we are looking for and what tissues to search.

 

[Snow Leopard]

Ok, I was trying to make more sense of this study but I´m going to give up because it´s starting to annoy me. Why couldn´t they publish the relative abundances of all the genera in the blood at the different time points? Did they run out of graphs? Without this, we don´t know if the relative abundances of the genera in the blood changed more after exercise in ME patients than in controls, even if they did in the three genera they published the results for. What´s the point in a table that shows the mean relative abundances of the different genera from all the time points? Did they run out of tables? I don´t understand studies like this - is journal space that hard to come by?

Good questions. And no, there is no space limit in PLOS One!

 

[John Mac]

Cort has posted on this study

http://www.cortjohnson.org/blog/2015/12/21/exercise-gut-chronic-fatigue-syndrome-me-cfs/

 

[MeSci]

Cort has posted on this study

http://www.cortjohnson.org/blog/2015/12/21/exercise-gut-chronic-fatigue-syndrome-me-cfs/

The finding of an 'inability to ramp up heart rate to normal levels during exercise' seems to conflict with a finding in many of us that heart rate actually rises excessively in response to very little exertion, doesn't it? Could that indicate sub-groups, perhaps?

 

[anciendaze]

The finding of an 'inability to ramp up heart rate to normal levels during exercise' seems to conflict with a finding in many of us that heart rate actually rises excessively in response to very little exertion, doesn't it? Could that indicate sub-groups, perhaps?

There are subgroups, but the problem with many heart rate measurements is that the "ramp up" has already taken place because of the exertion necessary to reach a clinic. If you don't know the patient's basal heart rate you really don't know how much it has risen. If stroke volume is small due to diastolic dysfunction you may quickly reach the point where increases in heart rate do not cause increased cardiac output. In that case, it is actually a good thing if heart rate stops rising at the point where the individual reaches maximum cardiac output. You may be seeing a compensating mechanism for the problem rather than the problem itself.

For healthy individuals there is a relatively small difference between basal heart rate and that taken while sitting or standing quietly. For patients with serious orthostatic intolerance this is likely not true.

Normal human variation in heart rates between different individuals is fairly large. If you don't know basal heart rate, and don't know how heart rate responds to modest challenges, an isolated number during exercise testing doesn't mean much.

 

[MeSci]

There are subgroups, but the problem with many heart rate measurements is that the "ramp up" has already taken place because of the exertion necessary to reach a clinic. If you don't know the patient's basal heart rate you really don't know how much it has risen. If stroke volume is small due to diastolic dysfunction you may quickly reach the point where increases in heart rate do not cause increased cardiac output. In that case, it is actually a good thing if heart rate stops rising at the point where the individual reaches maximum cardiac output. You may be seeing a compensating mechanism for the problem rather than the problem itself.

For healthy individuals there is a relatively small difference between basal heart rate and that taken while sitting or standing quietly. For patients with serious orthostatic intolerance this is likely not true.

Normal human variation in heart rates between different individuals is fairly large. If you don't know basal heart rate, and don't know how heart rate responds to modest challenges, an isolated number during exercise testing doesn't mean much.

I was thinking of home-based measurements used to aid pacing and try to prevent PEM.

Could you summarise how diastolic dysfunction might reduce stroke volume? My diastolic blood pressure varies much less than my systolic pressure, which fluctuates wildly even if I am inactive. Is this relevant? My heart rate doesn't vary a great deal, but it seems to increase quite normally in response to exertion.

 

[anciendaze]

I was thinking of home-based measurements used to aid pacing and try to prevent PEM.

Could you summarise how diastolic dysfunction might reduce stroke volume? My diastolic blood pressure varies much less than my systolic pressure, which fluctuates wildly even if I am inactive. Is this relevant? My heart rate doesn't vary a great deal, but it seems to increase quite normally in response to exertion.

Diastolic dysfunction is not a problem seen in variation of diastolic blood pressure. It is part of the dynamic behavior of heart muscle during the part of the cycle when it should be relaxing. The muscle does not recover from contraction rapidly enough to allow full filling of the ventricle. You need careful measurement of the size of the ventricle and motion of walls during heart beat to calculate the stroke volume. Once you have this it is easy to find cardiac output via the heart rate times the stroke volume. Most people with ME/CFS show substantially reduced cardiac output.