Comprehensive Circulatory Metabolomics in ME/CFS Reveals Disrupted Metabolism of Acyl Lipids and Steroids (Germain, Levine, Hanson, 2020)

[SlamDancin]

A little quick research on Cholate;

https://www.jci.org/articles/view/16309

Cholesterol is converted into dozens of primary and secondary bile acids through pathways subject to negative feedback regulation mediated by the nuclear receptor farnesoid X receptor (FXR) and other effectors. Disruption of the sterol 12α-hydroxylase gene (Cyp8b1) in mice prevents the synthesis of cholate, a primary bile acid, and its metabolites. Feedback regulation of the rate-limiting biosynthetic enzyme cholesterol 7α-hydroxylase (CYP7A1) is lost in Cyp8b1–/–mice, causing expansion of the bile acid pool and alterations in cholesterol metabolism. Expression of other FXR target genes is unaltered in these mice. Cholate restores CYP7A1 regulation in vivo and in vitro. The results implicate cholate as an important negative regulator of bile acid synthesis and provide preliminary evidence for ligand-specific gene activation by a nuclear receptor.

Seems like this indicates a downregulation of CYP8B1 in at least women with ME, and there are expected downstream effects due to a negative feedback loop of Cholate (salt of Cholic Acid) on CYP7A1 and the synthesis of other primary bile acids.

@andyguitar
@mariovitali

 

[SlamDancin]

At this point how could you argue that the liver is not involved heavily in this disease? Hanson has replicated alterations in bile acid composition now twice as did Naviaux IIRC. Any thoughts @andyguitar ?

 

[SlamDancin]

Also I don’t know that I’m allowed to provide the source but a very trusted boutique supplement shop I use sells and I have bought a Palmito and Stearoyl (sp?) Phosphatidylcholine supplement. What was missed in the analysis is these cholines help to keep the Cardiolipin composition of the cell mitochondrial membranes more towards saturated as opposed to unsaturated, and this *may* affect PDH function. I’ll have to find the source on that but having a more saturated membrane is supposed to improve Mito function.

 

[Wishful]

At this point how could you argue that the liver is not involved heavily in this disease?

Ummm, because I haven't observed any liver-related effects on my ME? Granted that I hadn't had a comprehensive liver function test done, but none of the liver-related tests showed abnormalities. I just don't feel that there's a strong link between ME and liver function.

 

[SlamDancin]

@Wishful The liver is where bile acids are produced and we have several studies now showing abnormalities in composition of bile acids. Did you really have to start your post with “ummm?” It was just a postulation I was making not some sort of direct challenge of your knowledge or something. Maybe I shouldn’t have used the word “heavily.” All these cholines are also produced in the liver as well. So I would say it’s ‘likely involved’ but whether that translates to easily testable liver damage is still yet undetermined because no tissue studies have been done yet. This is just harmless brainstorming and I’m bed bound today so could you try to be a little more nice. I’d appreciate it thanks.

 

[SlamDancin]

I mean literally all the enzymes that metabolize these lipids and steroids can be found in the liver and some are mainly in the liver like CYP7A1 and CYP8B1. How else would changes in the metabolism of these bile acids occur without changes in function of these enzymes in the liver?

 

[mariovitali]

@Wishful

Unfortunately, normal liver tests cannot rule out liver disease. Personally, i have seen an ME patient with normal LFTs to have significant Liver fibrosis (found using a test called Fibroscan).

More here :

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6112813/

On FB Groups of ME search for posts suggesting liver and gallbladder problems. you will find numerous posts.

 

[SlamDancin]

@mariovitali Liver enzyme tests are also transient and one pwME on twitter told me that they were tested four times. Twice abnormally high during PEM and twice were normal during baseline.

 

[Wishful]

I feel that it's more likely that any liver function abnormalities are downstream effects of ME. If liver function and digestion were strongly linked to my ME, I would expect to see more diet-related effects on my ME; that changing the fat content of my diet would have stronger effects. I just haven't seen anything to convince me that my liver is 'heavily involved'.

I still feel that it's primarily a neurological disorder, and that effects measured elsewhere in the body are downstream effects.

 

[Wishful]

One more thought on analyses like this one: some of the effects noticed might be the result of different lifestyles between PWME and controls. The majority of PWME probably are less active, mentally and emotionally as well as physically. I would expect to see measurable differences in metabolic products, hormone levels, etc. For that matter, some of the similarities between measurements for PWME and people with other chronic life-limiting disorders might be due to this as well.

 

[mariovitali]

@Wishful

Yes, these are all possibilities but at the point that we are in , i feel that we cannot dismiss liver involvement as a possibility that easily.

 

[andyguitar]

At this point how could you argue that the liver is not involved heavily in this disease? Hanson has replicated alterations in bile acid composition now twice as did Naviaux IIRC. Any thoughts @andyguitar ?

I mean literally all the enzymes that metabolize these lipids and steroids can be found in the liver and some are mainly in the liver like CYP7A1 and CYP8B1.

Unfortunately, normal liver tests cannot rule out liver disease.

In my view all these posts support the probability that dysfunction of the liver is something that needs to be taken seriously. Next task for me is to look at the relationship between lipids that were low and the steroids that were low. One other point I would like to make is that it has often been reported that the onset of the illness began at a time when the patient was taking a drug. Antibiotics, pain meds ect have all been mentioned over the years. All can cause liver problems.

 

[mariovitali]

Some few examples (i leave the best for last) :


Fibroscans of ME/CFS Patients suggesting significant Liver fibrosis

To the best of my knowledge, no such testing has ever been performed in ME patients.

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Possible Inflammation of the Liver ? : ME/CFS Study
Title : Changes in the transcriptome of circulating immune cells of a NZ cohort with ME/CFS (2019) Sweetman et al :



From supplemental material :

https://journals.sagepub.com/doi/su...8820402/suppl_file/Supplementary_Material.pdf


PPAR Signaling is also mentioned :


The TNFR2 signalling pathway (Supplementary Table S4) regulates TNFα activity by antagonizing TNFα-induced apoptosis, especially in highly activated T cells. LPS-stimulated mitogen activated protein kinase (MAPK) (Supplementary Table S4) drives the inflammatory response in macrophage immune cells. Peroxisome Proliferator-Activated Receptors (PPAR) signalling was also identified as affected (Supplementary Table S4). PPAR signalling molecules regulate metabolic processes in heart muscle tissue, inflammation and oxidative stress and facilitate interactions between circadian, metabolic (lipid metabolism) and cardiovascular pathways




Link of study :


https://doi.org/10.1177/2058738418820402

__________________________________________________________________________

TH17 and Tregs : controlled by Bile acids?

In January 2020, Derya Unutmaz presented his latest paper where it is suggested that ME patients have dysregulated TH17 and Tregs.


Title of paper : Bile acid metabolites control TH17 and Treg cell differentiation(in mice)


The paper contains many concepts we are seeing in ME/CFS : SS31 , Tryptophan metabolism (Dr Robert Phair), DRP1 (Dr Bhupesh Prusty). A suggested target for further research is the NLRP3/Inflammasome activation.


https://www.nature.com/articles/s41586-019-1785-z




__________________________________________________________________



NIH Presentation - Dr. Mark Davis

Dr Mark Davis, presentation at NIH, mentions FGF21 which is associated with Liver / Gall bladder function:

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Gilbert’s Syndrome (a liver condition) and ME :

https://www.meassociation.org.uk/2007/01/symptoms-and-diagnosis/



And


https://healthunlocked.com/britishlivertrust/posts/902639/the-real-gilberts-syndrome


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Fibromyalgia Symptoms and Liver Disease

“Consistent with prior investigations of patients with HCV [4], we identified a high prevalence of fibromyalgia in patients with cirrhosis, affecting nearly one-third of our large patient cohort. However, our data also provide new and important insights. First, widespread chronic pain meeting criteria for fibromyalgia was not limited to HCV, but also affected patients with other underlying causes of liver disease. Second, in HCV-infected individuals, viremia was not associated with widespread pain. Third, NASH and HCV had a comparable prevalence of fibromyalgia. Taking together with the fact that mood disorders and sleep disturbances were the best independent predictors of fibromyalgia in our cohort, this suggests that central sensitization rather than inflammatory or viral processes plays a key role in this common comorbidity.”

Link of study :



https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4688457/

__________________________________________________________________________


Fibromyalgia and Liver fibrosis, Johns Hopkins Study :
Title : A predictive algorithm to identify genes that discriminate individuals with fibromyalgia syndrome diagnosis from healthy controls


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255277/


Note hepatic fibrosis below :

___________________________________________________________________


Increased risk of chronic fatigue syndrome following psoriasis: a nationwide population-based cohort study
Background

The onset of chronic fatigue syndrome (CFS) has been shown to be associated with several immunological conditions such as infections or atopy. The aim of this study was to clarify the risk of chronic fatigue syndrome following the diagnosis of psoriasis, an immune-related dermatological disease, by analyzing the National Health Insurance Research Database of Taiwan.

https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-019-1888-1


Recall that Dr. Naviaux and Dr. Maureen Hanson identifies Bile acid metabolism disruption :



Interestingly, psoriasis may be treated with the use of Bile acids :



https://www.ncbi.nlm.nih.gov/pubmed/29908580


https://www.ncbi.nlm.nih.gov/pubmed/14643904


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ME/CFS-like symptoms after Airplane accident in Holland

“Mental health care was available after the crash to all affected residents and service personnel. After about a year many residents and service personnel began approaching doctors with physical health complaints, which the affected patients blamed on the El Al crash. Insomnia, chronic respiratory infections, general pain and discomfort, impotence, flatulence, and bowel complaints were all reported. 67% of the affected patients were found to be infected with mycoplasma, and suffered from symptoms similar to the Gulf War syndrome or chronic fatigue syndrome-like symptoms.”

https://en.wikipedia.org/wiki/El_Al_Flight_1862


Possible cause : Organophosphates ?


https://www.nytimes.com/1998/10/02/...nt-was-in-el-al-plane-lost-in-1992-crash.html


https://en.wikipedia.org/wiki/El_Al_Flight_1862#Cargo


___________________________________________________________________

Traumatic Brain Injury (TBI) + ME/CFS

TBI affects the liver through Vagus nerve and cholinergic signalling :

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

 

[andyguitar]

In January 2020, Derya Unutmaz presented his latest paper where it is suggested that ME patients have dysregulated TH17 and Tregs.

I found that paper very interesting @mariovitali and if you put those finding together with what this paper found (and did'nt find) to my mind there is compelling evidence that ME/CFS is an autoimmune disorder/metabolic disorder. I expect that puts me in a minority. Thanks for posting all the info. Facinating stuff. Particularly helpful was the effect of brain injury on liver function. I've been wondering about that as head injury has been reported now and again as the starting point of the illness by some.

 

[mariovitali]

@andyguitar

The following is a slide listing hepatotropic viruses, meaning viruses that affect liver function. A lot of entries we have heard before in there. I don't believe this is yet another coincidence :

 

[SlamDancin]

@andyguitar It’s too early for me to source this at all let alone as impressively as mariovitali but chronic brain injuries could create the autoantibodies that then can damage the liver. I have some certain autoantibodies against a brain structure called asialogangliosides, that seem to mainly then affect the liver through downregulating NK cell function *specifically* in the liver. This is why I think @mariovitali is exactly right. At the LEAST, liver tissue should be studied in ME/CFS because there could easily be tissue specific effects going on there that won’t show up in systemic testing, NK cell functioning for example.

 

[Rufous McKinney]

Ummm, because I haven't observed any liver-related effects on my ME? Granted that I hadn't had a comprehensive liver function test done, but none of the liver-related tests showed abnormalities. I just don't feel that there's a strong link between ME and liver function.

In my case (Eppstein barr lifetime)....inbalance in Liver Qi is the primary over-riding issue which is then influencing my Spleen Qi....and this is the focus of at least a decades worth of herbs I take to better balance things.

If western medicine would like to help me, feel free.

Meanwhile- I go where I can get some relief. And there- I can find things to make some of this feel better.

 

[junkcrap50]

Great info and research on liver fibrosis and bile acids in CFS.

So, how can we evaluate our liver health thoroughly if we have no liver or bile symptoms? Or if functional liver tests aren't reliable /specific? Is the fibroscan the only way? Liver biopsy?

What indications would be needed to order a fibroscan?

 

[Rufous McKinney]

So, how can we evaluate our liver health thoroughly if we have no liver or bile symptoms?

Numerous pharmaceuticals suggest- careful monitoring of liver while taking X.

Anybody doing that liver monitoring? Not around here.....

 

[andyguitar]

At the LEAST, liver tissue should be studied in ME/CFS because there could easily be tissue specific effects going on there that won’t show up in systemic testing, NK cell functioning for example.

Is the fibroscan the only way? Liver biopsy?

Yes @SlamDancin careful examination of liver tissue should be done. I think liver biopsy would be the most useful way to go @junkcrap50 In the meantime I expect that simply improving the digestion of fats would be helpful. There are supplements that are used for this. How effective they are I dont know. Our resident 'Gutoligist' @ljimbo423 might have some ideas about improving fat digestion. When it comes to testing for liver dysfunction I wonder if young @Learner1 has any ideas. She is well up on testing and stuff like that. Thanks for the info on viruses that effect the liver @mariovitali The fact that Hepaititis causes symptoms that are in some ways similar to me/cfs was something that occured to me many years ago. But the match is not that close enough to be certain about it. The other visuses? Who knows but certainly a possibiility. More interested in Cholate at the moment. I need to get out more!!