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

[eljefe19]

Adreno I have revised my theory to say it is overall a general FXR dysfunction in the intestine, it is very hard to say without more resource if it needs agonism or antagonism. It realistically could be either. However, it doesn't change the protocol on how to correct this issue. It is the same for either.

I'll be trying Obeticholic Acid as soon as it arrives. This will give us some anecdotal evidence.

 

[Bdeep86]

I'll be trying Obeticholic Acid as soon as it arrives. This will give us some anecdotal evidence.

That is one thing I have not worked with, the brand name is extremely expensive to take. I think it was 70K a year.

 

[eljefe19]

That is one thing I have not worked with, the brand name is extremely expensive to take. I think it was 70K a year.

I was looking at some unrelated research chemicals at this one Canadian lab and found it. 110 dollars a gram. 100 doses at 10mg, which was used in the in vivo trials. Not a horrible price. I am not expecting a miracle, targeting the downstream targets hasn't exactly worked. I seem to be in one of my normal multiple day crashes, not helped by the bile supplements or mTOR supps.

 

[Bdeep86]

I was looking at some unrelated research chemicals at this one Canadian lab and found it. 110 dollars a gram. 100 doses at 10mg, which was used in the in vivo trials. Not a horrible price. I am not expecting a miracle, targeting the downstream targets hasn't exactly worked. I seem to be in one of my normal multiple day crashes, not helped by the bile supplements or mTOR supps.

Yeah you are sort of throwing a lot at it, I have a program in mind. I really do need to look into how much I can put out there and what I can legally say as I have no medical or health credentials.

 

[nandixon]

Not sure if this study has already been mentioned or if it applies:
...

Discovery of bile salt hydrolase inhibitors using an efficient high-throughput screening system.

...

Yes, it potentially applies. I also referenced it on another thread here.

 

[nandixon]

...
Bile Salt Hydrolase Activity in Probiotics
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However, the bacterial genera that would most likely be used as probiotics (bifidobacteria and lactobacilli) are not capable of dehydroxylating deconjugated bile salts...
...

The above study is effectively out of date in one sense. Since that study, new bile acid receptors have been discovered, namely the sphingosine-1-phosphate receptor, S1PR2. This receptor is activated by conjugated bile acids like TUDCA and taurocholic acid. Upon activation of S1PR2, the Akt/mTOR (mTORC1) pathway can also be activated. This may be helpful since the Akt/mTORC1 pathway appears to be under-activated in ME/CFS.

Therefore, the first question to ask is not whether dehydroxylating deconjugated bile acids by the probiotic species mentioned is a problem, but whether you want those probiotic species like L. acidophilus excessively deconjugating the conjugated bile acids in the first place in ME/CFS patients, because that reduces the overall activation of the S1PR2 receptors.

 

[JES]

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.

This is my experience, at some point during the next day after drinking about 6 portions of alcohol, I will feel better for maybe 6-12 hours. Needless to say, this isn't a good long-term solution for anyone.

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.

I will be ordering some TUDCA and report back in the upcoming weeks. Would something like Ox Bile have potential use in this theory as well? It seems to be a popular supplement among those who had their gallbladder removed.

 

[Bdeep86]

This is my experience, at some point during the next day after drinking about 6 portions of alcohol, I will feel better for maybe 6-12 hours. Needless to say, this isn't a good long-term solution for anyone.


I will be ordering some TUDCA and report back in the upcoming weeks. Would something like Ox Bile have potential use in this theory as well? It seems to be a popular supplement among those who had their gallbladder removed.

Alcohol is altering Bile homeostasis that much I can tell you for sure. It is obviously temporary but I believe it is influencing these bile sensors and temporarily correcting the FXR dysfunction, or perhaps another proposed bile sensor, but I am leaning towards the FXR.

TUDCA is a great agent and I see a lot of people here having interest in starting it, but I feel for some there are a couple other elements that need to be in place for people who are a little further along. TUDCA is awesome, so is UDCA which I have worked with in the past. UDCA typically comes in a solid pill form which is easier to manage when smaller doses need to be started. TUDCA mostly separates during the digestive process into UDCA. Something to consider. Jarrow Bile Factors is another great agent but may be needed further down the road. OX Bile I don't know that that would help much here. I don't think it would hurt, but I don't think it would help all that much.

 

[Hilary]

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

Hi @Bdeep86 - sorry for very slow reply to your question - been having work issues..
I have tried all sorts of things over the years with varying degrees of success (nothing startling but anything involving detox seems to help a little - liver flushes, Perrin technique, can't recall other stuff immediately). Recently I followed a 3 month protocol to remove nickel which has also helped somewhat - many fewer headaches. Now I'm on a gut healing programme and without doubt my digestion seems to be much more settled/approaching normal (though not there yet). I'm also reducing sleep meds. But energy and stamina are still feeble and I still tend to feel very 'wired'/nervy which I never used to be before I became ill.

Still interested in your research but I just cannot follow the science.. frustrating - used to have a fully functioning brain once..

 

[Bdeep86]

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

Hi @Bdeep86 - sorry for very slow reply to your question - been having work issues..
I have tried all sorts of things over the years with varying degrees of success (nothing startling but anything involving detox seems to help a little - liver flushes, Perrin technique, can't recall other stuff immediately). Recently I followed a 3 month protocol to remove nickel which has also helped somewhat - many fewer headaches. Now I'm on a gut healing programme and without doubt my digestion seems to be much more settled/approaching normal (though not there yet). I'm also reducing sleep meds. But energy and stamina are still feeble and I still tend to feel very 'wired'/nervy which I never used to be before I became ill.

Still interested in your research but I just cannot follow the science.. frustrating - used to have a fully functioning brain once..

I am going to revise and simply for my theory, i'll do my best to make sure people can follow as I know many people who are reading it have a hard time following.

 

[Bdeep86]

Guys i'm going to post it later today. I am going to do my best to simplify it down more. It can be tricky when it involves so many complex systems but i'll let you know when its up on the site. I also changed the URL to Naturalreset.org

 

[Bdeep86]

Having it proofread, should have it back tomorrow evening and will post when I get it back.

 

[Tunguska]

Look forward to seeing.

It looks as though Androsterone, popularized on some other forums, and that I've trying on and off over the last year, modulates FXR as an agonist: https://raypeatforum.com/community/...ivator-of-the-farnesoid-x-receptor-fxr.12628/

Furthermore, androsterone can function as an activator of FXR both in a transfection system using gal4-FXR fusion protein induction of reporter genes and in cultured cells using endogenous FXR/retinoid X receptor heterodimer activation of gene expression. Finally, androsterone treatment of castrated male mice induced expression of SHP, suggesting that androsterone may also regulate gene expression in vivo via the FXR

It's definitely a helpful substance and seems useful as an adjunct to targeting anabolism, so it might have some benefits on FXR and/or mTor, though it's hard to find the information on it.

(side note: anecdotally androsterone seems to reduce nocturia and frequent urination for me... I kept thinking back to nandixon's posts about reduced aldosterone through sphingolipids/mTor, but, it could have no relation...)

 

[jump44]

Look forward to seeing.

It looks as though Androsterone, popularized on some other forums, and that I've trying on and off over the last year, modulates FXR as an agonist: https://raypeatforum.com/community/...ivator-of-the-farnesoid-x-receptor-fxr.12628/


It's definitely a helpful substance and seems useful as an adjunct to targeting anabolism, so it might have some benefits on FXR and/or mTor, though it's hard to find the information on it.

(side note: anecdotally androsterone seems to reduce nocturia and frequent urination for me... I kept thinking back to nandixon's posts about reduced aldosterone through sphingolipids/mTor, but, it could have no relation...)

Funny ,Ive almost bought androsterone about 3 times now because ever since my cfs began my libido sexual function has decreased more and more year by year and now its to the point where I barely remember what a libido even is.
Its like even though I supposedly have normal male hormone levels they arent "working" in the way they should be. I used testosterone injections/gels for a time early in my illness and they had a normalizing effect even though I wasnt 100 percent by any means they certainly helped.

what have you noticed from this substance?

 

[adreno]

It looks as though Androsterone, popularized on some other forums, and that I've trying on and off over the last year, modulates FXR as an agonist: https://raypeatforum.com/community/...ivator-of-the-farnesoid-x-receptor-fxr.12628/

From reading that thread I learned that cafestol – from unfiltered coffee – is also an FXR agonist:

https://www.ncbi.nlm.nih.gov/pubmed/17456796

Might be worth a try to bring out that old french press.

 

[Gondwanaland]

Might be worth a try to bring out that old french press.

About its cholesterol-raising properties, I drink coffee brewed in a French press for at least 2 years now, and the only thing that raised my LDL cholesterol was adding cream to my coffee. One month of coffee+cream was enough to skyrocket it.

 

[Tunguska]

Funny ,Ive almost bought androsterone about 3 times now because ever since my cfs began my libido sexual function has decreased more and more year by year and now its to the point where I barely remember what a libido even is.
Its like even though I supposedly have normal male hormone levels they arent "working" in the way they should be. I used testosterone injections/gels for a time early in my illness and they had a normalizing effect even though I wasnt 100 percent by any means they certainly helped.

what have you noticed from this substance?

That's understandable, but I can't help much there sorry. Much like TUDCA I bought it primarily for the purported thyroimimetic action (labs aren't great and much symptom overlap with hypothyroidism, but no thyroid hormone seems to work).

Occasionally I take one or two 4-5mg doses early in the day during or after meal and it gives more energy and mental focus, definitely some GABA as advertised but not overpowering like progesterone can be. Taking too late keeps awake.

Like progesterone it has a noticeable and very useful bloodflow-promoting and relaxing effect on the body, albeit not as sedating, though I rely more on taking progesterone in the evening to get that (don't know if same mechanism). Worth saying is that androsterone is probably more appropriate in the context of these discussions (progesterone does seem like it can negatively affect anabolism and mTor circumstantially so it's more an evening substance).

Finally it has that positive effect on frequent urination for whatever reason.

(The real question of course is how much if any of those real benefits are directly or indirectly due to FXR activation, and then if it might have other more or less noticeable ones such as facilitating mTor on a more chronic basis...)

 

[adreno]

Still, I'm confused because FXR agonism reduces bile production – and we seem to need more bile, not less. How does this fit together with an underactivated Akt/mTOR pathway?

 

[Bdeep86]

Still, I'm confused because FXR agonism reduces bile production – and we seem to need more bile, not less. How does this fit together with an underactivated Akt/mTOR pathway?

What we need is restored homeostasis, this is not simply more synthesis, we need bile transporters to be working properly as well. If you synthesize more bile but it isn't transported then it does not good. In fact it can make things worse. Bile sensors including FXR and S1P which myself and @nandixon (has been theorizing about S1P)) have an axis with the AKT-Mtor pathway.

 

[jump44]

That's understandable, but I can't help much there sorry. Much like TUDCA I bought it primarily for the purported thyroimimetic action (labs aren't great and much symptom overlap with hypothyroidism, but no thyroid hormone seems to work).

Occasionally I take one or two 4-5mg doses early in the day during or after meal and it gives more energy and mental focus, definitely some GABA as advertised but not overpowering like progesterone can be. Taking too late keeps awake.

Like progesterone it has a noticeable and very useful bloodflow-promoting and relaxing effect on the body, albeit not as sedating, though I rely more on taking progesterone in the evening to get that (don't know if same mechanism). Worth saying is that androsterone is probably more appropriate in the context of these discussions (progesterone does seem like it can negatively affect anabolism and mTor circumstantially so it's more an evening substance).

Finally it has that positive effect on frequent urination for whatever reason.

(The real question of course is how much if any of those real benefits are directly or indirectly due to FXR activation, and then if it might have other more or less noticeable ones such as facilitating mTor on a more chronic basis...)

Thanks. Interesting it helps frequent urination. Thats been a symptom Ive had all throughout this which seems to get worse when Im in a bad state. might have to try this stuff eventually.

Has anyone here been diagnosed with "gilberts syndrome"? I find it ironic that I have and the whole time Ive been sick my liver/gallbladder has been a source of discomfort.. yet its considered a harmless condition. things like Sam-e, calcium d glucarate, tudca, tmg, all things that help gilberts have reliably always provided at least a little relief. I just wonder if it might be playing into this somehow. @Bdeep86 your proposed theory to me makes intuitive sense because as I said from the very beginning Ive had liver and gallbladder pain, twitching, heaviness, etc. will be keeping an eye on this thread.