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

[Bdeep86]

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.

Yes it's to me something I stand firmly behind after many years of heavy research. It just requires a certain paradigm shift to really get it. I am giving a very stripped down version from my site. Many emailed me and requested it. I may start a new thread with the concept of FXR dysregulation taking place rather than just overactivation, see many factors go into this, its not as straightforward as simply conjugated bile stimulating the receptors. There are more factors, but this concept is a good starting place.

 

[nandixon]

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?

Most if not all of the studies that might tie Akt/mTORC1 and FXR together are mice or rat studies, so I don't know if we can say anything for certain but here are two possibilities:

First possibility:

SIRT1 controls FXR in a negative way, meaning the more SIRT1 is activated the less active FXR is.

SIRT1 also negatively controls mTOR (mTORC1), but mTOR also negatively controls SIRT1, i.e., they apparently control each other reciprocally. If SIRT1 activity increases then mTOR activity decreases. Likewise, if mTOR activity increases then SIRT1 activity decreases.

Thus, an under-activated Akt/mTORC1 can lead to increased SIRT1 which can then lead to decreased FXR.

So the hierarchy in this first possibility would be:

Akt/mTORC1--> SIRT1--> FXR

(Reference for the above.)

Second possibility:

It hasn't been definitively shown in humans (I actually didn't realize this in a post I made earlier), but FXR may have some control over ceramide production.

In this case, increasing FXR could increase ceramides (Naviaux found these to be low in ME/CFS) which could then increase sphingosine-1-phosphate (S1P) which could then activate Akt/mTORC1 via the S1P receptor, S1PR1.

So the hierarchy in this second possibility would be:

FXR--> ceramides--> S1P--> S1PR1--> Akt/mTORC1

(Reference for the above. Please note that the tauro-β-muricholic acid mentioned in that article is not found in humans.)

I can't remember if I might have seen a third possibility or if I was able to rule it out.

Lastly, note that with either of the two known possibilities for connecting Akt/mTORC1 with FXR, an FXR agonist would theoretically be what is needed to improve things - assuming it might possibly be helpful.

Edit: I'm not sure if we need more bile or not. Maybe some do and some don't. But you're right that agonism of FXR would decrease the amount of bile.

 

[Bdeep86]

Most if not all of the studies that might tie Akt/mTORC1 and FXR together are mice or rat studies, so I don't know if we can say anything for certain but here are two possibilities:

First possibility:

SIRT1 controls FXR in a negative way, meaning the more SIRT1 is activated the less active FXR is.

SIRT1 also negatively controls mTOR (mTORC1), but mTOR also negatively controls SIRT1, i.e., they apparently control each other reciprocally. If SIRT1 activity increases then mTOR activity decreases. Likewise, if mTOR activity increases then SIRT1 activity decreases.

Thus, an under-activated Akt/mTORC1 can lead to increased SIRT1 which can then lead to decreased FXR.

So the hierarchy in this first possibility would be:

Akt/mTORC1--> SIRT1--> FXR

(Reference for the above.)

Second possibility:

It hasn't been definitively shown in humans (I actually didn't realize this in a post I made earlier), but FXR may have some control over ceramide production.

In this case, increasing FXR could increase ceramides (Naviaux found these to be low in ME/CFS) which could then increase sphingosine-1-phosphate (S1P) which could then activate Akt/mTORC1 via the S1P receptor, S1PR1.

So the hierarchy in this second possibility would be:

FXR--> ceramides--> S1P--> S1PR1--> Akt/mTORC1

(Reference for the above. Please note that the tauro-β-muricholic acid mentioned in that article is not found in humans.)

I can't remember if I might have seen a third possibility or if I was able to rule it out.

Lastly, note that with either of the two known possibilities for connecting Akt/mTORC1 with FXR, an FXR agonist would theoretically be what is needed to improve things - assuming it might possibly be helpful.

Edit: I'm not sure if we need more bile or not. Maybe some do and some don't. But you're right that agonism of FXR would decrease the amount of bile.

Sirt1 is also playing a role. I have in my notes that I suspect its inhibition by acute alcohol may also be helping helping provide symptom relief. It does regulate both FXR and Mtor (ampk does as well).

Sirt1 deactylates the FXR receptor, i'm guessing acute alcohol beneficial effects prevents this rather than its influence on antagonizing the FXR. it may be in some cases boosting FXR signaling.

 

[Bdeep86]

Edit: I'm not sure if we need more bile or not. Maybe some do and some don't. But you're right that agonism of FXR would decrease the amount of bile.

It isn't a matter of needing more bile or not. You have to restore the system. FXR does more than influence our bile production it also influences its transporters. Bile transport is as critical if not more critical than the bile production its self.

 

[Bdeep86]

Hey guys I posted the simplified theory on my page. Thanks for any feedback! Part 3 will be more technical.

Simplified FXR Gut-Liver Disharmony Theory:

Okay, so I have been asked by several people to propose a more stripped down version of my theory. I recognize that I will have some very unwell people visiting my site and perhaps, in this series, it will be best to start with a basic theory and slowly become more technical as the concepts build and the picture becomes clearer.

So let’s start from the top.

In the most straightforward non-technical manner, what I believe is happening is the communication between the gut and liver has become dysfunctional. The liver and gut essentially work together to maintain proper digestion and energy homeostasis. Bile acids and bile acid sensors have a critical role in maintaining the communication between the liver and the gut. This bile homeostasis and sensor signaling is where I feel the breakdown in communication is being sustained.

So, is it a liver issue or is it a gut issue?

In a way it is both; it is a cycle that sustains itself. Better to look at it as a dysfunctional system within the body, or, as I referred to it, as a gut-liver disharmony.

Bile is needed to sustain a healthy environment in the gut: it stimulates intestinal contractions for bowel movements, it maintains the proper PH levels, and it is anti-microbial. When there is a hiccup in the continual flow of bile into the intestines, it opens up a huge window for the wrong bacteria to take hold. This is where the real dysfunction starts to set in. As the new bacteria begins take hold, a process of deconjugating the bile acids that are coming in starts to occur. This means that the bile that is getting through to the gut is being broken down and altered at a higher rate, which leads to the disrupted signaling of the bile receptors in the gut. Too rapid of deconjugation can actually suppress the bile sensors in the gut. Basically, you have restricted bile flow, and the bile that is getting through is being metabolized at a very rapid rate.

How does this start?

Realistically, it can start in either the gut or the liver. The liver controls gut status and vice versa. I would say it starts through the liver. Acute stress, viral infection, over-exertion, and inflammation will all put the brakes on the bile and lock up the liver function. It decreases bile synthesis and transport. Our bodies do this as a means to slow down digestion in an act of self-preservation. When you have this disruption in bile flow, opportunistic bacteria and parasites quickly move in. So, even after the event has passed, whether it was viral or the stressor has gone, the bacteria and parasites have already taken hold.

Which sensor is dysfunctional?

I believe, at the most refined point of this entire theory, the dysfunction is with the Farnesoid X Receptor (FXR). Particularly, I feel the dysfunction lies in the FXR receptors that are located in the gut (they are also in the liver), specifically those in the Illeum. The signaling from this receptor in the gut has a profound influence on the liver and bile homeostasis. It is heavily implicated in the progression of various liver conditions. This is not the only bile sensor that is important to note; TGR5 and S1P sensors are also contributing, but I feel that FXR is the most critical. It not only controls metabolic gene expression in the liver but also greatly effects micro biome bacteria composition. Various other factors from AMPK, SIRT1 regulation and even body temperature can all influence this receptors signaling ability.

I will elaborate further down the road on the FXR receptor as this is where things can get quite technical. I discovered the FXR receptor after investigating Peroxisome Proliferator Receptor Alpha signaling, which I still feel is impaired in people suffering from CFS. I don’t believe that this receptor is down-regulated but I feel that its DNA-binding capacity has been greatly diminished by inflammatory cytokines in the liver (NF-Kappa-B), which is controlled by FXR signaling. Again, this is for a later post.

What are the downstream consequences of this gut-liver disharmony?

This is a major question I have been asked recently. The downstream consequences are so substantial that it is hard to really even begin to grasp: from leptin resistance to liver toxicity to mitochondria dysfunction and many, many, many more. It is really massive and will require some time to fully write out. I plan on doing so but want the theory out now for people to chew on. Please keep in mind that there are many factors that go into the ability for this receptor to perform.

Is it possible to correct this?

Yes, I believe it is. The program I have been assembling for some time now has many different factors. Some lifestyle adjustments, dietary adjustment, and a few key agents. I am still refining this and it may take a little more time until it is completed.

 

[adreno]

When you have this disruption in bile flow, opportunistic bacteria and parasites quickly move in. So, even after the event has passed, whether it was viral or the stressor has gone, the bacteria and parasites have already taken hold.

So knocking out bad bacteria is part of it?

 

[Bdeep86]

So knocking out bad bacteria is part of it?

With the program (not sure if I can call it a protocol) bacteria being knocked out will be a natural consequence, because we are reversing what allowed it in. But yes, this bacteria and the microbiome needs to be adjusted to restore the harmony.

 

[M Paine]

If bile synthesis was impaired, I might have expected some signs like heartburn, heightened cholesterol/blood bilirubin levels... or some other liver test metrics to be out. Has anybody had a fecal bile acid test done? Is there any objective evidence for this theory?

 

[jump44]

If bile synthesis was impaired, I might have expected some signs like heartburn, heightened cholesterol/blood bilirubin levels... or some other liver test metrics to be out. Has anybody had a fecal bile acid test done? Is there any objective evidence for this theory?

Ive had elevated bilirubin on every blood test for the last ten years.
Also elevated porphyrins in a blood, urine, and stool test.

cholesterol was elevated as well at one point but seems thyroid meds and some other things brought it down.

 

[Bdeep86]

If bile synthesis was impaired, I might have expected some signs like heartburn, heightened cholesterol/blood bilirubin levels... or some other liver test metrics to be out. Has anybody had a fecal bile acid test done? Is there any objective evidence for this theory?

Again its not just the synthesis of bile, it involves the transport, proper stimulation of the receptors. Even then this doesn't fully account for all disruptions of the FXR receptor which is at the focal point for me. This could even be influenced by Sirt1, AMPK, Low Body temps, p300. This has systems within the systems. A couple quick things you can do is see if stools are lighter in color. Constipation and diarrhea switching another common sign. Low levels of fat soluble vitamins. I would expect to see low levels of acute phase reactant proteins from the liver such as ceruloplasmin. Dyslipidemia, subclinical hyperglycemia.

There is a urine test that is available to look at bile. I don't know all the details or its reliability.

 

[Bdeep86]

Ive had elevated bilirubin on every blood test for the last ten years.
Also elevated porphyrins in a blood, urine, and stool test.

cholesterol was elevated as well at one point but seems thyroid meds and some other things brought it down.

Yeah cholesterol abnormalities would make sense and I expect many would have that. As for porphyrins, FXR regulates this as well.

 

[jump44]

Yeah cholesterol abnormalities would make sense and I expect many would have that. As for porphyrins, FXR regulates this as well.

very interesting, I am pretty sure that porphyrins are something that arent supposed to be elevated at all from all my reading on it, and even though like I said they came back elevated on 3 different tests I had, I had doctors just looking at my results cross eyed and having pretty much no clue, so I never pursued it further. It would be nice to at least have an understanding as to why this might be occuring.

 

[eljefe19]

I've always had high cholesterol

 

[Bdeep86]

I've always had high cholesterol

Yeah has a lot to do with FXR's relationship to the PPAR family in my opinion. This PPAR family is mostly what lead me to the FXR receptor.

 

[Bdeep86]

very interesting, I am pretty sure that porphyrins are something that arent supposed to be elevated at all from all my reading on it, and even though like I said they came back elevated on 3 different tests I had, I had doctors just looking at my results cross eyed and having pretty much no clue, so I never pursued it further. It would be nice to at least have an understanding as to why this might be occuring.

See this is another major discussion, but it is also significant and needs to happen. If you want more explanation on the porphyrin relationship we can talk. That gets pretty technical. I want to get out another article in the next couple days, was considering this or the Sirt1 & AMPK influence. This opens up a whole other can of worms. There are systems within systems involved in this. The main foundation for what I want people to understand simply in the beginning is that the gut-liver disharmony is where this all starts. All of these other issues are downstream.

 

[kangaSue]

Another good summary of this (FXR) is at http://themedicalbiochemistrypage.org/fxr.php

 

[Bdeep86]

So i'm wondering where peoples interest level is in this still. I am thinking about writing my next article over the next couple days. I am wondering if I go deeper and write about what is happening on a cellular level or if I continue to ease into things more technical. Or if I just write everything out and release it all at once.

 

[eljefe19]

I'd be curious to see it all at once.

 

[Hilary]

Hi @Bdeep86 - I'm still interested although only able to follow intermittently. The more I delve, the more I'm convinced about a malfunctioning gut/liver/gall bladder being at the root of things - for me anyway. Even though I struggle with the science, I think I agree with @eljefe19.

 

[collie]

This is really interesting I was diagnosed with Gilbert's at 17 after a bad case of mono. I have always had liver discomfort and yellows eyes but never elevated bilirubin in the blood also had my gallbladder out 7 years ago. After being put on artemisinin by my naturopath I felt great for 3 weeks had normal bowels. He kept me on it too long without puksing and liver became inflamed I have had the worst relapse ever in the last 5 weeks starting with terrible diarrhea and food intolerances then progressing to unreal fatigue and all the usual awful symptoms returning only starting to come back to some kind of baseline now. Was only discussing with the wife I think the liver is were I need to focus and get that working well with the gut would be interested to know more when you are ready.