Comprehensive Circulatory Metabolomics in ME/CFS Reveals Disrupted Metabolism of Acyl Lipids and Steroids: Levine,Hanson et al 2020

Bile acid metabolism disruption has been identified through the methods i use since 2015 so i had time to look at the specific topic for quite some time. There is a variability involved when it comes to bile acids testing however this is applicable for increase of bile acids. The problem arises when a patient eats too close to the point in time where his/her blood is drawn (e.g less than 12 hours). The only case where i would imagine -this is a speculation, i am not a medical professional- to have low levels of bile acids (as in the case of the study) would be if patients eat a very small quantity of food or have no food at all. I don't believe that this is applicable for most of the patients in the cohort that was tested. Standardisation of food intake is a very good idea nevertheless.

 

Chris Armstrong discussed lower levels of hydrochloric acid in a (October 2016) webinar Interesting that lower hydrochloric acid levels in the gut, and the consequent disruption of gut mictobiome) is also discussed in this paper*

[

https://www.youtube.com/watch?v=mlhz7GRAqsg

- 50.59 minutes ish.].



*Extract from this paper (Hanson & others):
"The compounds measured in our datasets, considered long‐chained acyl cholines, were found to block the effect of acetylcholine on the rabbit and guinea‐pig tissues tested, and depressed spontaneous hydrochloric acid secretion by the rat stomach. Blood pressure problems are one of the many symptoms encountered by ME/CFS patients [36], especially when considering the common dysfunction in orthostatic intolerance (Table 1). A decrease in long‐chained acyl cholines could explain a disruption in blood pressure regulation, manifested by dizziness, lightheadedness, blurred vision, and near syncope when assuming and maintaining the upright position. We also know that patients are affected by irritable bowel syndrome [36], among many other intestinal disruptions (Table 1). A decrease in long‐chained acyl cholines could disrupt hydrochloric acid secretions with consequences that could be as far reaching as leaky gut symptoms and altered gut microbiome populations."

 

The med I use is an a7nachr modulator.

 

Does it work and specifically what is it intended to do?

 

It docks at the allosteric site of the a7 nicotine receptor.
These receptors are on many cells. It has many effects.

 

I am relying mainly on the comments above (thank you) and the authors’ conclusion, but the paper seems to be saying that looking at the blood metabolomics in the way that has been done to date, by a variety of researchers, has basically drawn a blank. That also means, if I've understood this right, that the early promise of the Bob Naviaux study has not been fulfilled.

5. Conclusions​

We are reporting on the largest number of metabolites in the ME/CFS field to date, about 1750

plasma compounds, encompassing 20 super‐pathways and 113 sub‐pathways. However, we have not unequivocally identified a plasma biomarker or set of biomarkers with abundances drastically
different between controls and ME/CFS patients, despite the fact that our clinical data indicates our patient cohort had a substantial level of disability (Table 1). The same conclusion can be drawn from examining various groups’ prior reports, including ours, where distinct populations were recruited, alternate instrumentation was used, or even serum was analyzed instead of plasma [9 refs]...​

As for the significant findings:

Conclusion:...Nevertheless, the metabolites emphasized as a result of our analysis, most specifically acyl cholines and steroids, should be considered in light of the metabolic impact even modest changes can have along with the complexity of sources that drain metabolites into the circulatory system. Indeed, the changes observed might result from a disturbance occurring in another part of the body (e.g., brain, muscles), one whose impact may be diluted in plasma...​

That looks to me to be more speculative, particularly given the point above about the significant age difference between patients and controls and how that could affect results. Subject also were not matched on exercise, inevitably, and perhaps that's could affect the results as well. And several people inc @Trish highlighted potential dietary difference. These ‘confounding’ factors make it harder to be certain the positive findings are important. Or if they are cause or effect (the authors seem to be arguing for cause).

This looks more significant, where the authors plot a way forward for the field:

... Acquisition of samples in conditions that increase patient symptoms (e.g., PEM) could further widen the observed gap between the plasma metabolome of patients and controls. Because liquid biopsies such as plasma and serum remain the most accessible resource from human subjects, our results combined with more explorative metabolomics will help stimulate our efforts before we move toward different, yet more invasive sample collection techniques.

Furthermore, set‐enrichment statistics with a control for false discovery rates can be used to identify chemical groups instead of individual metabolites that can be associated with a disease or phenotype. Follow‐up studies can develop new targeted analytical methods to measure those chemical groups in studies with power calculations from this discovery stage data.​

Overall, this appears to be an excellent study that helps move the field forward substantially. It says, we tried this, and were not really getting anywhere. Perhaps we can make progress if we try a different tack. This is so much better than the situation we’ve often seen in the past, where one promising study gets a lot of attention and quoted for years afterwards - without any follow-up research to see if the initial finding is reliable/meaningful.

Hats off to Maureen Hanson, Susan Levine and all the authors for a thorough study.

And please point out if my analysis is flawed. Migraines prevent me taking a thorough look at this.

 

On the face of it these may be downstream effects as @spinoza577 suggests.
@Jonathan Edwards suggested immune dyaregulation)(here - https://www.s4me.info/threads/me-cf...maintains-status-quo.12949/page-2#post-228595)
Chris Armstrong suggested a Sepsis type reaction maintaining ME [2016 Webinar]

 

I agree, it's a good study, but sadly we have not yet identified anything of particular interest, given the studies so far.

 

@Snow Leopard @Simon M

What are your comments regarding Cholate which was found 3-fold lower than controls ?

 

It is an interesting finding, but it is from this particular study. I don't think it's a consistent finding across the many studies we've seen to date. Judging by the language used by Maureen Hanson and colleagues in the conclusion, they are not betting their houses on this being a critical result. (Notes their emphasis on taking different approaches for future metabolomics studies.)

The two other NIH collaboratives, run by Ian Lipkin at Columbia and Derya Unutmaz at Jackson laboratories, both include metabolomics studies. If those two replicates the choline findings then they will start to look very significant.

It is replicated findings that have been so hard to come by in ME/CFS research.

 

Like Simon, I don't know what to make of it at this stage. Plasma bile acid concentration varies over a large range in healthy participants. Bile acids tend to be end products of cholesterol metabolism diet and related variables may be different between patients and controls too. Age and sex can also effect results (though the latter obviously doesn't apply to the current study since there were no men). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836658/

 

Dr Hanson posted this on twitter tonight:

https://twitter.com/user/status/1224526594636754945

 

A commonly used prevalence is 0.42 or 0.4% of the adult population --- might have used that approach.

 

https://twitter.com/user/status/1265335568382275584


eta:
https://www.mdpi.com/2218-1989/10/5/216

 

Thanks for posting. I wanted to read the letter, but was unable to see it. Any way of unlocking it??Merci.