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Over Activation of Farnesoid X Receptor In the Ilium Driving Liver and Gut Disharmony

Discussion in 'Latest ME/CFS Research' started by Bdeep86, Jan 21, 2017.

  1. Bdeep86

    Bdeep86 Senior Member

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    I wanted to submit my theory as to what drives and sustains CFS after many years of research and many thousands of hours spent going over many journals. This is taken from my blog: https://naturalresetorg.wordpress.com/ I am hoping that something here resonates with people. There is so much involved in my view of what is all happening with CFS that I had to break this up and will release as I go. But this is the summary. Thanks for your time.

    Part 1: Over Activation of Farnesoid X Receptor In the Ilium Driving Liver and Gut Disharmony, A Sustained Cycle In Chronic Fatigue Syndrome.
    Posted on January 21, 2017 by Bob Myers
    After many years of relentless research in to the condition commonly referred to Chronic Fatigue Syndrome. I have decided to start to releasing my analysis and theory of what I feel has caused and is sustaining this awful condition. The analysis is derived from many areas of medicine, from Neurology to Traditional Chinese Medicine. My research into this condition I feel is reaching the end. I feel its time to submit my findings in order to shed insight into this horrific condition so that people can start to heal.

    Due to the overwhelming amount of information I have decided to divide it into a multipart series. I would like to begin with a summary of the theory.

    To first understand the viewpoint of this theory, it is important that some fundamental concepts are understood. In Traditional Chinese Medicine (TCM) fatigued based syndromes are often cited as being a disharmony of the Spleen and Liver. In TCM the concept of the Spleen and Liver are not the same as in Western medicine. While the physical Liver is in fact part of the Liver system in TCM, the Spleen many believe refers to pancreatic and gut health. There is a large focus in medicine on gut health, featuring therapies that typically involve high doses of probiotics and other agents to prevent intestinal inflammation. However, what is largely ignored is the need for a healthy functioning liver to maintain proper gut health. Bile synthesis is needed to maintain proper PH balance in the gut, which is critical for maintaining a healthy bacterial balance. It is also needed to stimulate intestinal contractions and breakdown fats.

    Much like TCM’s view point, in essence, I believe that at the core of CFS is a dysfunction in signaling between the gut and the liver. This occurs primarily through a receptor called Farnesoid X Receptor (FXR). This receptor, highly expressed in both the liver and the intestines, is a bile acid sensor. It is necessary to maintain many functions of liver and gut. However, over–activation of Farnesoid X Receptor leads to stagnant liver function, resulting in a fatty and dysfunctional liver condition. What takes place is an epigenetic change in the liver, or a metabolic reprogramming so to speak, that alters liver chemistry to cater to a low energy homeostasis. FXR changes liver energy utilization via an up regulation in something called pyruvate dehydrogenase kinase 4 (PDK4).

    The intestinal FXR activation also signals back to the liver to inhibit certain enzymes that are needed for conversion of cholesterol into bile. Clinical and sub–clinical dyslipidemia is often seen in cases of CFS. This stagnation in bile flow results in many profound consequences, it also greatly contributes to the perpetual FXR activation in the intestines. Once the bile flow has been compromised, an environment is created in the gut that allows for improper bacterial overgrowth. This is crucial as once this occurs more deconjugation of bile occurs in the gut.When this happens, levels of Tauro-Beta-Muricholic Acid are reduced due to increased deconjugation of bile acids by improper balance in gut microbiota. This is relevant because Tauro-Beta-Muricholic acid is a very potent FXR antagonist in the intestines. Studies have repeatedly show that supplementing this directly or increasing levels of Tauro-Beta-Muricholic acid along with Glycine-Beta-Muricholic acid has been shown to improve Non-Alcoholic Fatty Liver Disease.

    This could be a reason that some CFS patients report temporary relief while taking antibiotic and anti-parasitic medications. A possible explanation is a temporary reduction in deconjugating bacteria increases Tauro-Beta-Muricholic Acid. A study showed that Antibiotics accompanied by the antioxidant Tempol increased Tauro-Beta-Muricholic Acid levels in mice and helped reduce obesity.

    Some CFS sufferers also report a strange phenomena in which acute alcohol ingestion provides significant relief of symptoms immediately upon consumption and sometimes the following day. Acute alcohol ingestion has been shown to increase bile synthesis and flow rapidly . The mechanism that drives this occurrence is an inhibition of both liver and intestinal FXR receptors. It has been demonstrated that alcohol is a very potent FXR antagonist in the intestines which increases levels of Cytochrome P450 Family 7 Member 1 (CYP7A1), an enzyme that is chiefly responsible for the conversion of cholesterol into bile acid. There are also many who report feeling much more unwell after the consumption of alcohol. This would be expected as I believe liver dysfunction is largely implicated in what drives this disease. Cytochrome P450 enzymes are needed to break down toxins in the liver. Alterations in this from fatty liver may lead to more dramatic reactions to alcohol as less will be broken down in the liver and more will enter the blood stream. This may also explain the common feature of extreme sensitivity to medications, as more medications enter the blood.

    The compromised bile flow also results in constipation. Bile is necessary to stimulate intestinal contractions. PWCFS often cite having fluctuations between diarrhea and constipation. Clearly, this will create a perfect environment for leaky gut to set in. The issue that I believe compounds fatigue is that once leaky gut settles in, toxins enter the blood and further compound liver issues. Adding to an already overburdened liver. This I believe is what dictates the more severe cases of fatigue begin. Bile is what carries the toxins from the liver into the intestines to be excreted. Now that the bile is stagnant you start to see low levels of toxin clearance in the liver, further compounding liver dysfunction.

    Another interesting note is that a Kidney Dialysis medication called Sevelamer has been shown to antagonize FXR receptors in the intestine. Mice with Non-Alchoholic Liver Disease were administered this drug and after 12 weeks were shown to have significant reductions in liver steatosis a long with a reversal of innate immune dysregulation. A very common feature in people suffering from CFS.

    The scope of all the systems involved in sustaining this condition is massive. I will provide more more analysis over the next few weeks.

    Essentially what I am saying is that in CFS is a condition based around a miscommunication between the liver and gut that is mediated via FXR over activation due to alterations in the gut microbiome. It is not simply a liver condition or a gut condition but rather both feeding into each other.

    More to come. Below are some links to studies in which I made reference to. Please send me some feedback through the contact if you felt this helped you.

    https://www.ncbi.nlm.nih.gov/labs/articles/27605663/

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4700422/

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4629219/

    http://news.psu.edu/story/288862/20...cteria-intestines-may-lead-obesity-treatments

    http://www.nature.com/articles/ncomms3384

    https://www.researchgate.net/public...kinase_expression_by_the_farnesoid_X_receptor
     
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  2. WestOzGirl

    WestOzGirl

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    This resonates with me. Thank you for sharing your hypothesis.

    My introduction to ME was a slow and gradual decline over a period of about 2 years. The very first change I noticed, even before I felt the ME fatigue set-in, was a problem with my: bile, gallbladder and ability to digest fats properly. I will definitely be reading more into the farnesoid X receptor.
     
    merylg likes this.
  3. Bdeep86

    Bdeep86 Senior Member

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    Yes essentially FXR receptor puts the brakes on the livers bile flow, along with many other functions of the liver. I will have the second part to the post on my blog on Friday. There is quite a bit of information coming to the blog in regards to the theory and my paradigm on the condition. Keep in mind it is both the liver and gut that feed into each others dysfunction.
     
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  4. PDXhausted

    PDXhausted Senior Member

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    I'll be interested in hearing your ideas as this resonates with me as well-- I've developed pretty significant gut, dysbiosis, liver and gallbladder problems since my disease onset that all seem to tie into one another.

    I'm wondering- are there any natural or herbal FXR antagonizers?
     
  5. Bdeep86

    Bdeep86 Senior Member

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    For the intestines it gets tricky with FXR. There are a couple and I'm going to discuss them in my next post. You are correct all of those things you mentioned tie into each other. There is a lot of dysregulation going on with Nuclear Receptors, the disharmony between the liver and gut really is at the core of most CFS in my opinion. I'm glad this speaks to you. I am considering making a video demonstrating this whole process.
     
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  6. adreno

    adreno PR activist

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    So wouldn't supplementing bile acids help to break the vicious circle?
     
  7. Bdeep86

    Bdeep86 Senior Member

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    Yes this is part of it. It depends on the bile acid. If you supplement bile acids and you are rapidly deconjugating in your gut than you can wind up making things worse. As you will have more material being created that winds up being an FXR agonist. Both the liver and intestines must be supported. There are a few ways to skin this cat but certainly Bile Acid Therapy will be a major help. People who catch things early on this maybe enough, however more advanced cases this could actually wind up making things worse.
     
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  8. adreno

    adreno PR activist

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    Well I believe the supplemental bile acids you can buy are all conjugated already, so this sounds like a bad idea.
     
  9. Bdeep86

    Bdeep86 Senior Member

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    Not necessarily. It depends on the individual situation. Some people will be able to take something like TUDCA/UDCA without any support in the gut and this will help correct the issues. However, if the dysbiosis is too dramatic you will have the hyper deconjugation take place and then FXR agonism will go up. If you look in one of the studies I posted they utilized Tempol (liver and antioxidant support) along with antibiotics (gut / dysbiosis) in order to stimulate more of the FXR antagonist Tauro-Beta-Muricholic Acid.
     
  10. adreno

    adreno PR activist

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    Have you seen this thread? @mariovitali talks about bile acids and TUDCA.

    http://forums.phoenixrising.me/inde...ponse-and-a-possible-treatment-for-cfs.37244/
     
  11. Bdeep86

    Bdeep86 Senior Member

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    Yes I have seen that, for some people TUDCA by its self is going to be powerful.
     
  12. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    I think maybe it should be Ileum. The ilium is a bone.
     
  13. Bdeep86

    Bdeep86 Senior Member

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    Thank you, I knew I was typing this out and putting it up to quickly. I just want to get it out there. I'm hoping in some cases this is the cause and we can finally end this madness.
     
  14. M Paine

    M Paine Senior Member

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    @Bdeep86, how does your theory relate to the observation that B-cell depletion therapy is successful at reducing clinical signs of ME/CFS?
     
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  15. Bdeep86

    Bdeep86 Senior Member

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    Good question. If I were to take a guess, it would come back to the liver again. If I recall correctly B cells have a significant impact on liver injury. I am not sure of B cells relationship to FXR, however I do know that hepatic B cells can ramp up hepatic inflammation in a major way. Possibly the depletion of those is allowing for less inflammation in the liver which would allow for better DNA binding of many of the receptors that I feel are compromised. Also better liver function and bile flow in general. I found that the study showing that mice who took sevelamar (fxr intestinal and liver antagonist) had a reversal of innate immune dysregulation after taking the drug for 12 weeks to be very interesting. Although this has not been demonstrated in humans.

    Not sure if this answers your question, I would have to do some research to answer it in a more detailed way.
     
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  16. M Paine

    M Paine Senior Member

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    Fair enough.Thinking in terms of B-cells (hepatic or not) as the initiator or regulator of inflammation, it's hard to work out why there is a delay in achieving a response from B-cell depletion therapy in the absense of an anti-body related issue.
     
  17. nandixon

    nandixon Senior Member

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    It would work out better all around, I think, to have the problem be that FXR is under-activated rather than over-activated.

    That would fit with the low ceramides found in the Naviaux study (activation of FXR increases ceramide synthesis).

    It would allow for there to be inhibiting autoantibodies against the FXR receptor, which could explain rituximab's effect.

    And the positive antibiotic effect noted in the original post, presumptively from increased conjugated bile acids, would be due to agonism of sphingosine-1-phosphate receptors (e.g., S1PR2) rather than antagonism of FXR by tauro-beta-muricholic acid, which likely isn't found in humans in any significant amount. (S1P is made from ceramides and hence might be low if FXR is under-activated. And conjugated bile acids stimulate S1PR2 in addition to S1P.)

    I wonder if there are any known cases of autoantibodies targeting FXR?
     
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  18. Bdeep86

    Bdeep86 Senior Member

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    I had thought this originally, when I suspected some dysfunctional signaling of PPAR-a (which I still suspect is going on). It wasn't lining up with my other research however. It took me sometime to piece the whole thing together but I realized it was possibly being inhibited. There are many FXR intestinal agonist out there and I felt that some of these agents would have had better success if the FXR needed to be agonized in the gut. My theory written here was very rushed and basic form of what I think is happening. There is a whole network of things going on based around the nuclear receptor family, bile acids and dysbiosis.

    Is there another adaptive mechanism that could be influencing ceramide levels? I need to look into these more. Before I can weigh in on them.

    My other question which I am asking from a truly naive place, is what are the results like with Rutiximab? I know a couple people who tried it and it didn't help and I believe I read about Ron Davis son trying it and maybe getting worse. I figure you would have a good gauge of the results people are seeing.
     
  19. M Paine

    M Paine Senior Member

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    The results of some of the Rituximab work are quite well summed up by Dr Oystein Fluge in his recent talk here, it's a great watch...

     
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  20. eljefe19

    eljefe19

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    Here is the phase 2 trial of Ritux for CFS which is the best evidence we have so far.
     

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