Part 2: A more simplified version of the theory.

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.

Part 1: Dysfunction of Farnesoid X Receptor In the Ileum Driving Liver and Gut Disharmony, A Sustained Cycle In Chronic Fatigue Syndrome.

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.

After many years of relentless research into 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, dysfunction 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 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 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/pmc/articles/PMC4215539/

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/288862/2013/09/24/research/adjusting-bacteria-intestines-may-lead-obesity-treatments

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

https://www.researchgate.net/publication/51773581_Selective_Activation_of_Nuclear_Bile_Acid_Receptor_FXR_in_the_Intestine_Protects_Mice_Against_Cholestasis

https://www.researchgate.net/publication/8012731_Regulation_of_pyruvate_dehydrogenase_kinase_expression_by_the_farnesoid_X_receptor