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

[MeSci]

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.

Would an ECG/EKG give a clue to this?

 

[jimells]

Would an ECG/EKG give a clue to this?

Impedance cardiography measures cardiac output:

Impedance cardiography (ICG) is a noninvasive technology measuring total electrical conductivity of the thorax and its changes in time to process continuously a number of cardiodynamic parameters, such as Stroke Volume, SV, Heart Rate, HR, Cardiac Output, CO, Ventricular Ejection Time, VET, Pre-ejection Period and others.

In contrast to other technologies, which use man-made transducers to measure physiologic parameters, the unique feature of ICG is that it uses the body segment (I.e., the thorax) as a transducer. Two pairs of electrodes, placed at the beginning of the transducer (the root of the neck) and at its end (the diaphragm level), are used to detect the impedance changes caused by a high-frequency, low magnitude current flowing through the thorax between additional two pairs of electrodes located outside of the measured segment. The sensing electrodes also detect the ECG signal, which is used as a timing clock of the system.[1]

I think I'm missing something important about this study. Is it correct to say the study claims bacteria is moving from the gut to the blood? If so, why aren't these bacteria detected as part of the numerous studies that have looked for viruses and bacteria?

Even if the bacteria are cleared in a few days, I should think at least a few people in these studies would have PEM on the day their blood was drawn.

 

[anciendaze]

In very general terms an EKG will only show certain kinds of damage after it becomes fairly serious. It will not tell you much about cardiac output, and reduced cardiac output often precedes classic heart attacks.

There is more inference required for impedance cardiography than I like, though it can sometimes indicate reduction in cardiac output. The problem is that relationships between some variables are based on studies in healthy individuals. I'm convinced we are dealing with dysfunctions which call some of these relations into question. For that reason I would prefer measurements made by echocardiography which actually produces images of the beating heart. There are problems with these if the operator doesn't handle such things as synchronization properly, but these are known difficulties. The result will be a direct measurement of the changing volume of the left ventricle which gives stroke volume.

In talking about bacteria in the gut it is probably a mistake to think these are completely excluded from healthy tissues. Absorption of food requires close contact with material in the gut, and immune cells patrolling the surface must be close enough to the blood stream to pick up the oxygen they need to survive. Translocation simply means the bacteria are able to penetrate a few layers deeper into tissues. It need not mean living bacteria persist in the blood. There are very active defenses against this, and I'm thinking those defenses are responsible for many symptoms.

What I was getting at above is less about the absolute level of ACA antibodies in the bloodstream, than about changes as a result of exercise, which nobody has looked for. If exercise produces dramatic increases it seems safe to say that some aspect of gut physiology is defective.

In standard clinical practice an unusually high result on one visit will be confirmed by a second reading. If these readings are not consistently high the isolated reading will be dismissed as an error. The chances of an ME/CFS patient exercising to exhaustion prior to both visits is negligible.

A different point I'd like to address here has to do with the definition of ME/CFS patients. Rather than continue the long-running battles over a particular definition, I would like to propose to find abnormal responses wherever they occur and find out what is going on in those people. How you decide which people to test would then be less important, as long as you have a test which can distinguish patients with some condition from controls by a particular criterion. We might well find this condition is related to diseases nobody has considered.

Increased bacterial translocation in response to exercise seems like one such objective criterion. A drop in anaerobic threshold in response to an exercise challenge over 24 hours earlier would be another. A third possible objective measure could be evidence of abnormal response to orthostatic challenge, either POTS or NMH. There are even more sophisticated measurements of autonomic function that could clarify what we mean by dysautonomia.

My point is that investigating and treating conditions on which we can develop objective measures might resolve many or most patient problems. Even if this is not possible it could well lead to progress on the subject of etiology, where we have stagnated for a generation.

 

[kangaSue]

Irregular or insufficient cardiac output is another one of the causes of intestinal ischemia because of non-occlusive mesenteric microvascular dysfunction. Breaks in the intestinal mucosal barrier can be in localized pockets or extensive areas in either small or large bowel. Repeated ischemic events can result in an accumulation of dead cell debris in the microvascular network preventing the return to full function, similar to the plugging up of larger vessels from plaque build-up.

 

[anciendaze]

Notice that we are talking about episodic changes in physiology. Standard medical practice tends to ignore these as random variations or instrumental errors. We and our doctors don't have much idea of how well mechanisms lumped together under the term "homeostasis" are performing unless there is an actual breakdown requiring dramatic medical interventions like a coronary artery bypass. Measures to indicate such conditions as atherosclerosis are indirect, and about half of all heart attacks take place without warning. We are not measuring the effectiveness of unassisted physiological response to challenges expected in ordinary life. This is not simply true of the heart, it could be said about nearly every kind of natural physiological control mechanism.

I can't be all that unusual in knowing two people who were screened for heart problems and given a good prognosis a few weeks before they were hospitalized with classic heart attacks.

Complaints of orthostatic intolerance are generally ignored unless they result in actual syncope. Emergency personnel will tell you that they see people all the time who pass out and are discharged with advice that they need to avoid dehydration. (The problem disappeared when IV saline was administered.) Nobody seems to be wondering about episodic hypovolemia and defects in regulation of fluids and electrolytes which are not immediately life-threatening. The result is that the same patients show up repeatedly with the same problems. These patients are then blamed for the problem. If they worry about syncope pitching them into an accident, they can be accused of "catastrophizing". Either way doctors are off the hook.

The effect of repeated cerebral ischemia on mental function is fairly well known. So why is there little effort to avoid this beyond exhortation to drink fluids and exercise? It should be no surprise that the population of people suffering mental decline and/or being confined to bed long before they die keeps steadily increasing. Neither patients nor society see this as desirable.

Just today I have seen a news item about treating even patients with normal blood pressure with drugs that lower blood pressure. What they are talking about is mean blood pressure, and the supposition is that keeping mean values low will also lower peak blood pressures which cause strokes, etc. There is very little concern for defects in regulation of blood pressure which cause large episodic changes. Those changes go down as well as up, and you can easily find people in nursing homes who are medicated to the point it is dangerous for them to stand up.

Those of us who experienced problems with orthostatic tolerance in our teens or twenties got a preview of what awaits most of the general population in old age.

What's wrong with this picture?

 

[Jonathan Edwards]

I think I'm missing something important about this study. Is it correct to say the study claims bacteria is moving from the gut to the blood? If so, why aren't these bacteria detected as part of the numerous studies that have looked for viruses and bacteria?

Even if the bacteria are cleared in a few days, I should think at least a few people in these studies would have PEM on the day their blood was drawn.

I am certainly missing something about this study. It does not appear to claim that bacteria move from gut to blood. The results are all given as relative abundances so I don't think we know that there was any change in the amount of bacteria getting in to blood. Maybe before exercise the levels in blood were 100 for A and 60 for B and after exercise they were 50 for A and 60 for B. That would give an increase in relative abundance of B. Discussion of gut permeability seems to be jumping the gun if we do not know if there was evidence for an increase.

 

[Marky90]

I am certainly missing something about this study. It does not appear to claim that bacteria move from gut to blood. The results are all given as relative abundances so I don't think we know that there was any change in the amount of bacteria getting in to blood. Maybe before exercise the levels in blood were 100 for A and 60 for B and after exercise they were 50 for A and 60 for B. That would give an increase in relative abundance of B. Discussion of gut permeability seems to be jumping the gun if we do not know if there was evidence for an increase.

Thanks for clarifying this with the above example! I originally jumped the gun and thought this supported the leaky gut theory (and that was after reading the study...), I suspect a few others might have as well.

Now I will be careful the next time i read a study containing "relative abundances"

 

[justy]

I get PEM long before my activity levels reach that of "exercise", and so do many others.

and here lies he problem for those of us with severe M.E - everything we do apart from laying still in bed causes PEM so we are constantly battling and never recovering

I see this as corroborating evidence that supports the findings of Maes (IgM to gut bacteria in the blood)

I was recently found to have IGM and IGA to a whole host of gut bacteria in my blood. No idea if this relates to this study or not, but its not a nice thing to see.

 

[anciendaze]

That comment by Jonathan Edwards about relative abundances is quite valid. However, I'm not at all sure what any particular individual means by "leaky gut", which makes it difficult to decide anything on that subject.

What I think we can say is that exercise seems to be causing changes in evidence of bacterial sp. in the bloodstream. This is not the same as finding intact bacteria in the blood. Most evidence found in lymphatic organs is wreckage of defunct bacteria.

Because exercise is generally associated with temporary reductions in blood flow to the gut, I don't believe the hypothesis of increased bacterial translocation is particularly far-fetched. There are better-known examples of bacterial translocation as a result of ischemia. There is also research showing a relation between bacterial translocation and impaired immunity. The kind of impairment in ME/CFS has to be less severe than most examples leading to progressive disease. This does not rule out more limited episodic impairment.

What is most significant here is that researchers were looking for transient changes with the right timescale for PEM. This is long overdue. Nothing in nature requires that medical problems should produce objective evidence that is convenient for medical researchers to measure independent of a context like exercise. To approach a disease characterized by exercise intolerance that way is perverse.

 

[adreno]

Assuming this study has merit, what would be the treatment? Abx to knock out bacterial overgrowth? Strengthening of the intestinal barrier?

 

[Jonathan Edwards]

Assuming this study has merit, what would be the treatment? Abx to knock out bacterial overgrowth? Strengthening of the intestinal barrier?

You still seem to be assuming that there were more bits of bacteria after exercise but as far as I can see the study, and whatever merit it may have, is not about that.

 

[adreno]

You still seem to be assuming that there were more bits of bacteria after exercise but as far as I can see the study, and whatever merit it may have, is not about that.

Well, in that case we are reading the study differently. From the discussion I strongly get the impression that increased intestinal permeability and bacterial translocation of the gut microbiome into the bloodstream is what the authors are describing/observing:

Blood is generally considered sterile, although evidence of transient, asymptomatic bacteremia has been reported following dental extraction [52] and intestinal insult [53]. In the context of ME/CFS, systemic responses to gut microorganisms suggest that bacterial translocation across the intestinal barrier may also occur as part of this disease [9,23–26]. The notion that exercise may also result in translocation of bacteria across the intestinal barrier is particularly interesting, especially in the case of ME/CFS where post-exertional malaise can be a key characteristic of the disease. Following maximal exercise testing, we detected bacterial signal in blood samples from both ME/CFS patients and healthy controls. Consistent with differences in the intestinal microbiomes between the two groups, we noted an increased relative abundance of Firmicutes, particularly those from Clostridium clusters XIVa and IV, in blood samples from ME/CFS patients at 15 minutes post-exercise challenge. In vitro functional studies will be able to address this observation better. However, we speculate that some members of Firmicutes and Bacilli because of their stronger cell walls and inherent ability to survive in harsher environmental conditions may have contributed to it surviving longer in bloodstream. Further investigation of the potential for transient translocation of intestinal microorganisms into the bloodstream following exercise and how the dysbiosis characteristic of certain disease states, such as ME/CFS, might influence this translocation may provide considerable insight into how the microbiome influences disease symptoms.

 

[Jonathan Edwards]

Well, in that case we are reading the study differently. From the discussion I strongly get the impression that increased intestinal permeability and bacterial translocation of the gut microbiome into the bloodstream is what the authors are describing/observing:

That is what they are discussing but I didn't find anywhere where they say they observed it. (If you did, let me know as I may have missed it.) It looks as if this is what they were hoping to find. This is very common in scientific papers. A junior member of the team is giving the job of looking at something that is trendy and they get some data which does not actually confirm the trendy idea but since that is what they were supposed to be working on they still talk as if it was confirmed. As one member of PRs signature says rather neatly most of science is an exercise in trying to find evidence to support your idea rather than trying to find an idea that fits with the evidence.

 

[John Mac]

That is what they are discussing but I didn't find anywhere where they say they observed it.

Isn't this their observation?

Following maximal exercise testing, we detected bacterial signal in blood samples from both ME/CFS patients and healthy controls. Consistent with differences in the intestinal microbiomes between the two groups, we noted an increased relative abundance of Firmicutes, particularly those from Clostridium clusters XIVa and IV, in blood samples from ME/CFS patients at 15 minutes post-exercise challenge.

 

[MeSci]

Isn't this their observation?

Following maximal exercise testing, we detected bacterial signal in blood samples from both ME/CFS patients and healthy controls. Consistent with differences in the intestinal microbiomes between the two groups, we noted an increased relative abundance of Firmicutes, particularly those from Clostridium clusters XIVa and IV, in blood samples from ME/CFS patients at 15 minutes post-exercise challenge.

See this post which explains why a change in relative abundance does not mean the same as a change in abundance.

 

[Jonathan Edwards]

I was recently found to have IGM and IGA to a whole host of gut bacteria in my blood. No idea if this relates to this study or not, but its not a nice thing to see.

But I would have thought that was a good thing, Justy. In fact that is pretty much what IgA is for - it is an antibody present in the blood and secreted at mucosal surfaces to protect you against micro-organisms at such surfaces. If you did not have IgA to bacteria they would be more likely to stay alive if they got into blood.

 

[adreno]

I am certainly missing something about this study. It does not appear to claim that bacteria move from gut to blood. The results are all given as relative abundances so I don't think we know that there was any change in the amount of bacteria getting in to blood. Maybe before exercise the levels in blood were 100 for A and 60 for B and after exercise they were 50 for A and 60 for B. That would give an increase in relative abundance of B. Discussion of gut permeability seems to be jumping the gun if we do not know if there was evidence for an increase.

Okay, so we are seeing changes in the microbiome, i.e. relative levels of different species compared to each other. However the absolute levels (bacterial reads) of the species should also be known to the researchers.

If the increase in relative abundance of e.g. firmicutes were actually due to a decrease in absolute levels of other species, and not due to an increase in the levels of firmicutes, it would invalidate their hypothesis of bacterial translocation from the gut. This would actually make this paper incredibly amateurish or outright fraud (if they neglected to mention a finding that invalidates their hypothesis). Somehow it's hard for me to believe this would be the case.

 

[M Paine]

For those wondering why this paper didn't include absolute population counts, this is due to a functional limitation when performing metagenomic studies using the 454 pyrosequencing technique used in this paper.

"Strictly quantitative measures, in which absolute abundances are inferred, can be discounted outright for current pyrosequencing technologies, as upper (and effectively lower) constraints on the number of total reads produced are imposed."

Quantifying microbial communities with 454 pyrosequencing: does read abundance count?

 

[Jonathan Edwards]

Okay, so we are seeing changes in the microbiome, i.e. relative levels of different species compared to each other. However the absolute levels (bacterial reads) of the species should also be known to the researchers.

If the increase in relative abundance of e.g. firmicutes were actually due to a decrease in absolute levels of other species, and not due to an increase in the levels of firmicutes, it would invalidate their hypothesis of bacterial translocation from the gut. This would actually make this paper incredibly amateurish or outright fraud (if they neglected to mention a finding that invalidates their hypothesis). Somehow it's hard for me to believe this would be the case.

Unfortunately that applies to the majority of published scientific papers these days. I appreciate that many people are not aware of this, but it is the sad truth.

Thanks to @M Paine for a useful explanation for the absence of evidence of total increase. The authors should have made this clear and also made it clear how much it limits the interpretation of their data.

 

[PhoenixDown]

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0145453

Inclusion and Exclusion Criteria
Standard medical history was reviewed and a physical exam was conducted for each subject to rule out any major illnesses other than ME/CFS. Routine blood and urine chemistry tests were also used to screen for exclusionary medical conditions or other conditions that may explain the patients’ symptoms. Exclusionary conditions included untreated hypothyroidism, sleep disorders, side effects of medication, relapsing of past medical issues (e.g. Lyme disease, hepatitis B or C), major psychiatric issues, including major depressive disorder with psychotic or melancholic features, alcohol or other substance abuse within two years of the onset of ME/CFS, and severe obesity as defined by a body mass index (BMI) of greater than 40 kg/m2. Potential participants were also excluded if they had: 1) current use of immunomodulatory medications, stool softeners, laxatives, anti-diarrheal agents, antibiotics, or probiotics, 2) current use of opioids, 3) a history of cardiovascular disease or uncontrolled hypertension, or 4) current fatigue sufficient to interfere with or preclude exercise testing. Patients were asked to confirm the absence of exclusionary medications on the day of testing and to list other current medication use. Although we did not explicitly exclude for low-dose antidepressant use, gastrointestinal disease, or smoking, which could influence gut flora, none of the participants were currently taking this class of medication, reported any gastrointestinal disorder, or were smokers. Further, none of the participants were diagnosed with depression.

It doesn't mention an established criteria such as the ICC 2011 criteria, which is a shame, having said that they excluded quite a lot of alternative causes of symptoms, also they referenced Fukuda 1994 not sure if that's what they used.

As already stated by @Simon the number of ME/CFS patients was only 10 which is disappointing. About a year ago I gave my doctor a list studies showing objective abnormalities in ME/CFS and Fibromyalgia, he dismissed them all due to sample size and claimed the best evidence shows that GET is the best treatment for CFS.