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

[Bdeep86]

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...

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

Cool I will look at these, thanks guys.

 

[Bdeep86]

Not to get too off, but are there people here on PR that have tried this?

 

[M Paine]

Very few it seems.

 

[Bdeep86]

NOTE: I have decided to revise my theory and attribute the gut-liver axis disharmony to FXR dysfunction rather than over activation. Because of limited resources and data it is difficult to call whether it is over activated or under. Either results in liver-gut disharmony which I still maintain is what drives and sustains CFS. The therapies I have in mind to correct this disharmony are the same regardless of if it is over or under activated.

 

[adreno]

Because of limited resources and data it is difficult to call whether it is over activated or under

It isn't clear in all cases. And it might not matter in practice. What matters is that the signal-to-noise ratio is likely low.

 

[Bdeep86]

It isn't clear in all cases. And it might not matter in practice. What matters is that the signal-to-noise ratio is likely low.

Right, the environment around it is what needs changing.

 

[M Paine]

Exercise is known to reduce bile production, is that correct?

 

[Bdeep86]

Exercise is known to reduce bile production, is that correct?

Yes

 

[M Paine]

So in your model, what accounts for the inflammatory response seen in patients? What is triggering inflammation in other words?

 

[gregh286]

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

Interesting.
I met 2 fully recovered cfs people in the last 4 years who where both adamant they needed to do liver flushes every 6 weeks or cfs returns.
Took it with a pinch of salt tbh.
Detox therapies help me tremendously so compromised liver function in cfs certainly alive and well.

 

[Bdeep86]

Interesting.
I met 2 fully recovered cfs people in the last 4 years who where both adamant they needed to do liver flushes every 6 weeks or cfs returns.
Took it with a pinch of salt tbh.
Detox therapies help me tremendously so compromised liver function in cfs certainly alive and well.

Did they use the flushes to recover? The liver in my opinion is central and it is being controlled by the gut. Both become stagnant.

 

[Bdeep86]

So in your model, what accounts for the inflammatory response seen in patients? What is triggering inflammation in other words?

I really wouldn't even know where to begin. So many avenues on so many levels its really incredible how many things are going on at once. I suppose we could start with the nuclear receptor family issues that arise because of this gut-liver axis dysfunction. I originally started looking at this stuff after a conversation with a practitioner when I was on vacation in colorado who utilizes high CBD marijuana in cases of metabolic dysfunction. I was intrigued cause I have limited use with marijuana and saw that it stimulates PPAR-a & -y. These control so much, including energy homeostasis.

Tracing PPAR-a I saw that it was controlled in a major way by the FXR receptor. I still believe that PPAR-a isn't downregulated but its DNA binding capacity is greatly diminished by NF-kappa-b p65. Any alteration in PPAR alone has considerable downstream consequences. From leptin to microglial activation. This is just one event that takes place that can contribute to an inflamed state. I could list off several. I plan on doing more entries in my blog it, I just haven't been getting the interest to take the time to do them. I will either way I just have a lot going on right now.

 

[gregh286]

Did they use the flushes to recover? The liver in my opinion is central and it is being controlled by the gut. Both become stagnant.

Yeah the soda bicarb job with olive oil. I did one a few.years back and felt great that day energy wise.
My ass wasn't as good. Nearly needed a new one off ebay. It's brutal.
Vowed never again.

 

[Vitalic]

Great effort. Things are beginning to get interesting.

 

[Bdeep86]

Great effort. Things are beginning to get interesting.

Thank you. There will be some debate about specific receptors at play. But one thing I truly feel will be demonstrated is that the concept of the liver gut disharmony. I stand strongly behind this. I also feel it will be shown that this disharmony is largely based around bile flow and alterations in the microbiome influencing bile receptor sites and it is in fact the gut shutting down liver function. The liver is key to all of this. Nice profile picture that is my favorite album.

 

[Hilary]

Hi @Bdeep86 - I am really interested in all this although I can't get my head round the science very well. (I'm no scientist and my brain is currently turned to porridge). My illness started with nearly a year of different infections, culminating in pneumonia - I had 6 rounds of antibiotics in a period of 9 months. From early on, gall bladder issues (difficulty with digestion and terrible gall bladder pain) were part of the picture and although I was threatened with GB removal, tests established it is structurally fine but extremely sluggish in function. I haven't done a liver flush for a long time but am now reminded that they were very helpful when I did do them (olive oil, apple juice, lemon juice, ginger, milk thistle and garlic from memory). Constipation was also an ongoing issue.
I've been doing quite a bit of work on my gut and also trying to clear heavy metals (which I assume tend to accumulate - along with other toxins - because of the liver's inefficiency/malfunctioning?) and digestion is slowly improving but it's always been my gut feeling (ouch) that the digestion and state of the gut are at the root of things.

 

[Bdeep86]

Hi @Bdeep86 - I am really interested in all this although I can't get my head round the science very well. (I'm no scientist and my brain is currently turned to porridge). My illness started with nearly a year of different infections, culminating in pneumonia - I had 6 rounds of antibiotics in a period of 9 months. From early on, gall bladder issues (difficulty with digestion and terrible gall bladder pain) were part of the picture and although I was threatened with GB removal, tests established it is structurally fine but extremely sluggish in function. I haven't done a liver flush for a long time but am now reminded that they were very helpful when I did do them (olive oil, apple juice, lemon juice, ginger, milk thistle and garlic from memory). Constipation was also an ongoing issue.
I've been doing quite a bit of work on my gut and also trying to clear heavy metals (which I assume tend to accumulate - along with other toxins - because of the liver's inefficiency/malfunctioning?) and digestion is slowly improving but it's always been my gut feeling (ouch) that the digestion and state of the gut are at the root of things.

It can depend how you get in your situation. For most I think it is the liver that starts this whole process. Stress, virus, inflammation...ect puts a lock on liver function. When the bile goes, the environment in the gut changes and becomes dysfunctional, as bile is a natural antimicrobial. From there the gut now controls the liver. In some cases with antiobiotics that can definitely cause a shift in the microbiota to alter liver function.

 

[Hilary]

Chronic stress - from multiple causes - was also part of the picture.. Bit of a toxic mess all round.

 

[Bdeep86]

Chronic stress - from multiple causes - was also part of the picture.. Bit of a toxic mess all round.

Have you had any luck in your case? What sort of therapies are you having now?

 

[eljefe19]

Cimetidine, phytoceramides, bile acids, and TUDCA seem to be making a real difference for me @Bdeep86 and btw I ordered a gram of Obeticholic Acid. Pm me for details.