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Fecal metagenomic profiles in subgroups of patients with ME/CFS

Messages
516
I spent years trying to get up to a therapeutic dose of antibiotic herbs and I couldn't because the bacteria that was being killed off (die-off), in my gut, caused flares in my symptoms that I could not tolerate. I believe the die-off is from the lipopolysaccharides (LPS) in the cell walls of gram negative bacteria in my gut, being killed off and the LPS pass through an over-permeable gut (leaky gut).

It took me 4 months to get up to a very small dose of antibiotic herbs, with a lot of die off along the way. I then took a 10 day course of Rifaximin at 1200mg a day and was able to go up to 15-20 times the dose of antibiotic herbs, in just a month or so, with very little die off or symptom flares. So the connection of symptoms and high dysbiotic gut bacteria, for me, is clear.

Rifaximin only works in the small intestine and is not absorbed into the blood stream. So the improvements I made were from lowing the bacterial overgrowth in my small intestine.

These interventions have greatly improved my level of physical functioning and my well being, profoundly, along with a starch free diet and high dose probiotics. I haven't felt this good in many years. I am certain my symptoms are directly connected to the level of dysbiotic bacteria in my gut.

If I want to worsen my symptoms, all I have to do is take too high a dose of berberine, oil of oregano etc. A high enough dose would put me in bed I'd be suffering so much and I rarely even take naps now. I firmly believe that Lipkin, Hornig, Chris Armstrong and others will, in time, show that the gut is the core issue.
I'm curious, does Lipkin write about SIBO in this or another study? I agree you can't get anywhere without addressing that if you have it, it just makes disease management impossible, but to what degree is the small intestine in CFS/ME deranged as opposed to standalone SIBO? I guess I would like to see study like this comparing CFS/ME+SIBO to CFS/ME and SIBO instead of IBS.

(I do the same nowadays, avoiding starch and fiber and I mostly sip orange juice all day +select fibers... I would rather not get too many flavonoids but I'll forcefully get tons of hesperidin this way and it happens to curtail LPS in bunch of studies http://www.tandfonline.com/doi/pdf/10.1080/08923973.2016.1214142 )
 

Manganus

Senior Member
Messages
166
Location
Canary islands
Thanks to @Murph for the abstract of the paper. Very good, convenient and understandable. :)

There is a wording that I find intriguing:

EDIT: got to the discussion section and here it is in their own words: "An altered microbiome is postulated to lead to increased gut permeability (“leaky gut”) and intestinal inflammation with gastrointestinal symptoms. Increased translocation of lipopolysaccharides (LPS) from gram-negative bacteria leads to autoantibody production, disruption of tight junctions, and both local gastrointestinal and systemic inflammation [12, 32, 33]."

I wonder if I understand the hypotized process correctly:
  1. Gram-negative intestinal bacteria increase in number and emit so much more of lipopolysaccharides, that
  2. the tight junctions (that like a zipper connect endothelial cells) burst more often than the cells are able to re-establish them.
  3. When a couple of neighboring tight junctions are destroyed, then the process of junctions bursting becomes irreversible,
  4. and the endothelial cells emit a set of cytokines to alert white blood cells about the irreversibly bursted tight junctions.
  5. The result of this irreversible bursting is that gaps are produced between the cells of the intestinal wall.
  6. Through the fine gaps intestine content is filtered out, or leaked, ending up in the lymphatic system,
  7. where some kind of immune system cell gets excited over the traces of lipopolysacchariedes from gram-negative bacterias, at the same time as
  8. white blood cells arriving at the gaps emit their own set of cytokines to modulate the ongoing inflammation, and attract more white blood cells untill the enothelial wall is repaired.
  9. Due to the resulting profile of cytokines, antibody-production is geared up and the control station turned off, where autoantibodies ought to be discovered and destroyed.
I guess someone has allready established a connection from LPS to bursting tight junctions?
 

Murph

:)
Messages
1,799
Thanks to @Murph for the abstract of the paper. Very good, convenient and understandable. :)

There is a wording that I find intriguing:



I wonder if I understand the hypotized process correctly:
  1. Gram-negative intestinal bacteria increase in number and emit so much more of lipopolysaccharides, that
  2. the tight junctions (that like a zipper connect endothelial cells) burst more often than the cells are able to re-establish them.
  3. When a couple of neighboring tight junctions are destroyed, then the process of junctions bursting becomes irreversible,
  4. and the endothelial cells emit a set of cytokines to alert white blood cells about the irreversibly bursted tight junctions.
  5. The result of this irreversible bursting is that gaps are produced between the cells of the intestinal wall.
  6. Through the fine gaps intestine content is filtered out, or leaked, ending up in the lymphatic system,
  7. where some kind of immune system cell gets excited over the traces of lipopolysacchariedes from gram-negative bacterias, at the same time as
  8. white blood cells arriving at the gaps emit their own set of cytokines to modulate the ongoing inflammation, and attract more white blood cells untill the enothelial wall is repaired.
  9. Due to the resulting profile of cytokines, antibody-production is geared up and the control station turned off, where autoantibodies ought to be discovered and destroyed.
I guess someone has allready established a connection from LPS to bursting tight junctions?

probably you understand it better than me but in my mind, the LPS are being produced, and it is an unrelated failure of the microbial ecology that provides the increased intenstinal permeability, rather than the LPS being so many that they force their way through.
 

aaron_c

Senior Member
Messages
691
I don't think anyone has posted this already... @Kati I believe this is the full paper, do you want to edit your first post so people can see it? Also, it might be nice to change the name of the thread to "Fecal metagenomic profiles in subgroups of patients with ME/CFS" to make it easier to find.

Also RE @AdamS 's comment about how this may be showing that our metabolics influences our microbiome moreso than the other way around:

The study also found a difference between people with CFS with IBS sympoms and people with CFS without IBS. Perhaps this will help those of us with IBS to figure out how to move to just having CFS?

40168_2017_261_Fig1_HTML.gif


Edit: The following chart is of ME/CFS vs control, it doesn't really illustrate the point I was making. But I'm leaving it up because it's interesting.

upload_2017-4-26_17-51-55.png
 
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aaron_c

Senior Member
Messages
691
Also this:

upload_2017-4-26_18-3-42.png


The arrows indicate "changes in the ME/CFS without IBS group (compared to ME/CFS with IBS)." So...MAYBE those of us with IBS would want to kill off Bacteroides vulgatus Anaerotruncus colihominis, and possibly Klebsiella pneumoniae and Parabacteroides distasonis? And/or increase Prevotella buccalis, Ruminococcus lactaris, Eubacterium hallii, Faecalibacterium cf, Clostridium methylpentosum, and maybe Faecalibacterium prausnitzii and Prevotella copri too?
 
Another news article about the paper http://www.sciencealert.com/another-study-just-linked-chronic-fatigue-syndrome-to-gut-bacteria
Includes a nice dig at PACE :)
But there are still no effective treatments for the disease, and no cure - some commonly prescribed treatments for the condition have been cognitive behavioural therapy and exercise, neither of which have any evidence to support they work, and could actually be doing more harm than good.

ETA: And another, http://www.medicalnewstoday.com/articles/317116.php
 
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aimossy

Senior Member
Messages
1,106
If some find useful - here are some background things regarding Ian Lipkin and Mady Hornig.

'Hunting down the cause of ME/CFS & other challenging disorders – Lipkin in London' by Simon McGrath

'Gut bugs misbehaving? The microbiome and ME/CFS' by Simon McGrath

'Dr Mady Hornig’s storming science in ME/CFS at conference in Sweden!' by The Microbe Discovery Project

Lipkin and Hornig's thoughts may have changed since these above times based on what the are seeing in the lab.


From the Microbe Discovery Project home page there is some information on their work and cohorts:

"Current program of ME/CFS research
Analysis and Testing
The researchers are working on figuring out one of the central problems in ME/CFS: “heterogeneity”. This basically means there are probably many different subgroups of patients, some of who are likely to have different diseases, all caught under the current ME/CFS umbrella. The team are working with 5 different ME/CFS specialist clinicians at different sites across the US, along with other US researchers. They hope that the foundation they develop for a Center of Excellence in ME will ultimately have a global component.

They are implementing cutting edge technology and science looking into pathogen discovery; immune signatures; gene expression and variants; antibodies to viruses, bacteria and fungi that lead to autoimmune type of responses as well as phage approaches for anti-pathogen antibodies. Other high-tech approaches, some of which were developed by Dr. Lipkin and his lab include, MassTag PCR – High throughput sequencing, the new VircapSeq – VERT test, a 51 cytokine and chemokine immunoassay panel, metabolomics and proteomics.

They are investigating the oral pharyngeal (mouth and throat) and gut microbiome, spinal fluid and analysing gene expression. This is a phenomenal amount of work involving many people with carefully characterized cohorts from the ME/CFS expert clinicians that they collaborate with. The programme entails a huge amount of investigation and discovery. The research will help reveal the molecular detail of what might be going wrong for people with ME/CFS.

Cohorts
Pure Pathogen Discovery Projects

National Institutes of Health/NIAID 150 cases, 150 controls: blinded multisite viral analysis (XMRV/pLMV)Samples still banked, able to be used.

With Dr Montoya, Stanford University 284 cases, 196 controls: pathogen discovery

Chronic Fatigue Initiative 200 cases, 200 controls: pathogen discovery, immune signatures, metabolomics, proteomics. Subset of 50/50 controls: microbiome, longitudinal immune analysis (12 – 18 months after 1st sampling )

Other Projects

Cerebro spinal fluid study, with Dr Petersen 60 cases, 60 multiple sclerosis/no disease controls: pathogen discovery, immune signatures, proteomics and metabolomics. Cerebrospinal fluid bathes the brain, and these samples give a unique window on what’s happening in the brain.

Dr Peterson “unusual” cases 10 cases, 10 matched controls.

TruCulture exercise study 23 cases, 23 controls ( in development )

Large Microbial Discovery and Immunity study in ME/CFS

National Institutes of Health/NINDS/Microbe Discovery Project (in progress) 125 cases, 125 matched controls: sample collection in blood at 2 time points, stool and saliva at 4 time points over a year. Microbiome (bacteriome, mycobiome, virome), proteomics, metabolomics, immunology, genetics and epigenetics. Foundation for the establishment of a Center of Excellence."


The work they want to do that needs donations is here

The Microbe Discovery Project blog on the latest paper is here
 

Marco

Grrrrrrr!
Messages
2,386
Location
Near Cognac, France
My interpretation is that they did not find a common cytokine profile that distinguished patients from controls. "Elevated cytokines" is a bit of a misleading term, cytokines can be either more or less abundant, and pro or anti-inflammatory. What Mady Hornig and their team recognised, is that patients who have had this disease a short time, display a different cytokine profile than patients who have had the disease a long time. If you read the paper Distinct plasma immune signatures in ME/CFS are present early in the course of illness, you can see for yourself that when patient groups are split by duration of illness, the cytokine profiles are identifiable.

The authors of the paper we are discussing in this thread have made mention of this, and seem aware of the issue:

  • No changes were observed in immune markers--a finding that may reflect the dearth of participants who had been ill for a short time; earlier research suggests immune changes may only be evident when comparing short and long duration cases

It might be that given a different cohort, the picture might be somewhat different. It's unclear. We know in other cases of long term immune activation, that the immune system has ways of dampening itself.

Yes I'm aware of that. The point I was making was that the long duration cases do rather contradict a hypothesis based on bacterial translocation causing systemic inflammation as an ongoing driver of ME/CFS symptoms.

Rather than just 'different' systemic inflammation should be easily recognisable. That's not to say that an inflammatory process at the early stages might not be able to establish a stable self-perpetuating (neuro)immune disease state in the absence of ongoing peripheral stimulation - but that's a different hypothesis.
 

Solstice

Senior Member
Messages
641
Also this:

View attachment 20881

The arrows indicate "changes in the ME/CFS without IBS group (compared to ME/CFS with IBS)." So...MAYBE those of us with IBS would want to kill off Bacteroides vulgatus Anaerotruncus colihominis, and possibly Klebsiella pneumoniae and Parabacteroides distasonis? And/or increase Prevotella buccalis, Ruminococcus lactaris, Eubacterium hallii, Faecalibacterium cf, Clostridium methylpentosum, and maybe Faecalibacterium prausnitzii and Prevotella copri too?

I'd be very careful about just trying to strike off different bacteria without any testing or help from a specialized doctor. I had a bacteroides overgrowth(40%) and now I am left with a streptococcus overgrowth. Both take different meds to cure apparently.
 

Forbin

Senior Member
Messages
966

Nice write up, but I think it errs when it says:
They found that seven distinct intestinal bacterial species were strongly associated with ME/CFS, so much so that an elevated presence of all of them could predict a diagnosis.

The paper actually says:
Based on findings from TDA, LEfSe, and prediction models, Faecalibacterium,Roseburia,Dorea,Coprococcus, Clostridium, Ruminococcus, and Coprobacillus were strongly associated with ME/CFS; their combined relative abundance appeared to be predictive of diagnosis.

Relative abundance
can be either up or down, and, so far as I can tell, relative to controls, the levels of the seven predictive bacteria in ME/CFS patients were:
  • Faecalibacterium down
  • Roseburia down
  • Dorea down
  • Coprococcus down
  • Clostridium up
  • Ruminococcus down
  • Coprobacillus up
 
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Messages
1,478
thats really strange..it has always been said that CFS patients could not tolerate alcohol!
I think this seems to be mixed with a smaller group finding some benefit from alcohol. I can't find where this discussion was but from memory there was a difference in experience. It would be interesting to link this to severity of other symptoms (e.g. PEM severity, scale of disability, severity of gut issues etc.)
 

aimossy

Senior Member
Messages
1,106
From the paper and broken up for easier reading.

"Distinct bacterial metabolic pathways in ME/CFS


Bacterial metagenomic data were used to predict differences in functional metabolic pathways in the ME/CFS subgroups. Altogether, 455 individual bacterial metabolic pathways were identified and analyzed.

In superpathway analyses (total 131 superpathways), LEfSe revealed that bacterial vitamin B6 biosynthesis and salvage, pyrimidine ribonucleoside degradation, and atrazine degradation were significantly enriched while bacterial pathways for the biosynthesis of arginine, polyamine, unsaturated fatty acid (FA), and mycolate were significantly reduced in the ME/CFS compared to the controls (Fig. 5a).

The ME/CFS + IBS group had predicted enrichment in bacterial pathways for fucose, rhamnose, atrazine degradation and L-threonine biosynthesis, reduced heme, AA and polyamine biosynthesis, and reduced purine, pyrimidine, and unsaturated FA metabolism compared to the controls (Fig. 5b).

In the ME/CFS without the IBS group, predicted bacterial pathways of vitamin B6 biosynthesis and salvage, pyrimidine ribonucleosides, atrazine, glycerol and sulfolactate degradation were increased, whereas unsaturated FA and mycolate biosynthesis were decreased compared to the controls (Fig. 5c).

Nonparametric Mann-Whitney U test with Benjamini-Hochberg correction (adjusted p < 0.2) further supported findings from LEfSe showing enrichment in the pathway of atrazine degradation in both the ME/CFS and ME/CFS + IBS groups compared to the controls; predicted bacterial pathways of arginine, polyamine biosynthesis, and pyrimidine ribonucleoside degradation were reduced in the ME/CFS + IBS (Additional file 1: Table S3).

Based on nonparametric Mann-Whitney U test with Benjamini- Hochberg correction (adjusted p < 0.2), ME/CFS showed 440 altered representation of individual bacterial metabolic pathways linked to the tricarboxylic acid [21] cycle, alcohol and aromatic compound degradation, and FA/lipid metabolism (Additional file 1: Table S3).

The ME/CFS +IBS group was associated with altered bacterial pathways for FA/lipid metabolism, aromatic compounds biosynthesis, and carbohydrate (CHO)/carboxylate degradation (Additional file 1: Table S3)."
 

msf

Senior Member
Messages
3,650
All very interesting but apart from obvious examples (dysentery) is there any evidence that the gut microbiota directly and unamiguously cause any disease?

When you say the gut microbiota, you mean commensal bacteria, don´t you? Salmonella cause Salmonellosis, Yersinia cause Yersiniosis, Shigella cause Shigellosis, and so on. It seems to me to be rather naive (given what we know about evolution) to assume that there are ´good´ bacteria and ´bad´ bacteria and that never the twain shall meet. In fact, numerous species of commensal bacteria have been shown to be pathogens under certain circumstances - the most obvious of these is sepsis, where your commensal bacteria stand a good chance of killing you outright. Therefore, I believe a more useful question is whether the gut microbiota are having a effect in a particular illness, which is what they are trying to determine in this study.
 

Marco

Grrrrrrr!
Messages
2,386
Location
Near Cognac, France
Given that we seem to be starting to find subsets of patients I'm not surprised that some might be able to tolerate alcohol even if the majority don't. Obviously why there might be this difference will only come out through more research along similar lines as this paper.

Sorry (I seem to be disagreeing with you a lot on this thread - not intentional) but this is one of those often repeated fallacies. Jason finds alcohol intolerance reported by generally less than 50% with the percentage varying between 22 and 52% for those diagnosed with CFS or ME/CFS sourced from three patient populations.

See table 3 :

Contrasting Chronic Fatigue Syndrome versus Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3728084/
 

Marco

Grrrrrrr!
Messages
2,386
Location
Near Cognac, France
When you say the gut microbiota, you mean commensal bacteria, don´t you? Salmonella cause Salmonellosis, Yersinia cause Yersiniosis, Shigella cause Shigellosis, and so on. It seems to me to be rather naive (given what we know about evolution) to assume that there are ´good´ bacteria and ´bad´ bacteria and that never the twain shall meet. In fact, numerous species of commensal bacteria have been shown to be pathogens under certain circumstances - the most obvious of these is sepsis, where your commensal bacteria stand a good chance of killing you outright. Therefore, I believe a more useful question is whether the gut microbiota are having a effect in a particular illness, which is what they are trying to determine in this study.

Yes I was contrasting an imbalance in commensal bacteria with a pathogenic infection and I agree that it may seem 'naive' to assume that there are good and bad bacteria. In addtion to sepsis, your commensal bacteria can also kill you in severe heat stroke but in both cases it isn't the balance or inbalance of commensal bacteria that triggers the process.

So I'm afraid I'm back to wanting to see an example of gut microbiota imbalance causing disease.
 

msf

Senior Member
Messages
3,650
Well, it seems to me that, given that the microbiota can drive symptoms (i.e. sepsis), the composition of that microbiota is quite likely to have an effect on it, unless you believe that all bacteria are created equal. As others noted above though, you seem to have chosen a straw man - no one has mentioned the gut microbiota causing ME, they have only mentioned it having an effect on the symptomology of the disease.