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.