Traumatic Brain Injury, Bile Acids and Blood Brain Barrier

cc @Perrier

I had a discussion with Jen Brea on Twitter regarding Traumatic Brain Injury (TBI) and ME.

TBI was something i never looked at but i do recall that there are cases of patients that got ME after car accidents.

I performed an analysis for TBI to summarise all available information around TBI and the software identified the following:

1. Inflammation
2. Excitotoxicity
3. Hypoperfusion (less likely)
4. CYP7A1 disruption (related to Bile acids metabolism)
5. Glutamate metabolism disruption


CYP7A1 was of high interest, since Machine Learning first identified the disruption of Bile acids as a potential research area as early as 2015 ( which was also mentioned at my presentation at the LSHTM for EUROMENE)


Please see the following study : Vagus nerve, cholinergic signalling , Liver , Bile acids metabolism disruption. Figure 1 gives a very good representation of the mechanism involved but i cannot copy it here.

Title of study :

Hepatic alterations are accompanied by changes to bile acid transporter-expressing neurons in the hypothalamus after traumatic brain injury

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5247752/

Another study showing glutamate metabolism disruption after TBI :

 

Very interesting and relatively sure a major finding and not a coincidence. ME\CFS is a brainsteminjury. But whst caused it?

 

A possible consequence of whiplash and/or traumatic brain injury is pituitary and/or hypothalamus damage. Both types of damage have potentially devastating impacts on all sorts of hormones in the body.

 

I read references regarding this possibility and yes, it seems that when such an event takes place, there are major disturbances to the hormonal system. From what i understand, TBI can have different consequences iwhich is related to the extension of damage being done. What i wanted to discuss here, is that for one more time we have a a new route through which bile acids metabolism disruption takes place and as it seems from latest research, bile acids have many more roles than fat absorption.

Other routes of Bile acid metabolism disruption are : Viral Infections, Toxic substances and Hepatotoxic Medications.


Some references :


Emerging roles of bile acids in mucosal immunity and inflammation

https://www.nature.com/articles/s41385-019-0162-4


Bile acids acting as inflammation regulators may protect against IBD
https://www.drugtargetreview.com/news/54158/bile-acids-acting-as-inflammation-regulators-may-protect-against-ibd/


and (posted recently by @Andy in the forum)

Bile acid metabolites control TH17 and Treg cell differentiation.
https://www.ncbi.nlm.nih.gov/pubmed/31776512

 

Sorry will need more time to process this, but it should be born in mind that various causes of brain trauma, from head injury to CVA, can also be associated with the symptom of ongoing chronic fatigue. We do not yet reliably know if this is similar to or distinct from ME.

There is the evidence, that for a small number, stabilisation of the spine and/or the cranio-spinal joint (struggling to remember the correct words) seems to result in dramatic improvement, it we do not yet definitely know what the reason for this improvement is, to what percentage of people currently diagnosed with ME this is relevant and whether they represent a distinct category misdiagnosed as having ME or a subgroup of people with ME. It seems rather random at present when ‘subgroups’ with a causal aetiology are identified whether they become a new distinct diagnosis or not. I guess this will remain a pulling up ourselves with our own boots straps process until we have a commonly agreed clinical diagnostic test for ME.

Similarly, for some the onset of their ME is associated with physical and/or psychological trauma, such as a car crash. This might be interpreted as raising the possibility that a subgroup of ME is caused by brain injury. However association is not proof of causation, and although an interesting area of speculation, a lot of questions remain unanswered. Was it coincidence, did the ME in some way predate the trauma, which was just a trigger for the first occurrence of PEM, was it the physical or psychological aspect of the trauma or both that precipitated the ME, etc? Just as we are not in a position to say with any certainty for the much larger subgroup that the infection associated with their onset was the primary cause of their ME, we need to understand more before saying brain injury can be a primary cause of ME.

 

Bile Acid Metabolism and Signaling
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4422175/

Glucuronidation
https://www.sciencedirect.com/topics/neuroscience/glucuronidation

 

We do not know what is going on , that's for sure. I have not stated that brain injury is the primary cause of ME but i am suggesting hypotheses and research targets. The software i use identifies associations which do not imply causations. I was just referring to references that some individuals can get ME through different routes and accidents are one such route :


From Harvard Medicine :

https://www.health.harvard.edu/a_to_z/chronic-fatigue-syndrome-a-to-z