Bayesian Statistics Improves Biological Interpretability of Metabolomics Data from Human Cohorts (Brydges, Che, Lipkin, Fiehn 2023)

Murph

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Metabolites
2023 Aug 31;13(9):984.
doi: 10.3390/metabo13090984.

Bayesian Statistics Improves Biological Interpretability of Metabolomics Data from Human Cohorts​


Christopher Brydges 1 , Xiaoyu Che 2 3 , Walter Ian Lipkin 2 4 , Oliver Fiehn 1



Abstract​


Univariate analyses of metabolomics data currently follow a frequentist approach, using p-values to reject a null hypothesis. We here propose the use of Bayesian statistics to quantify evidence supporting different hypotheses and discriminate between the null hypothesis versus the lack of statistical power.

We used metabolomics data from three independent human cohorts that studied the plasma signatures of subjects with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The data are publicly available, covering 84-197 subjects in each study with 562-888 identified metabolites of which 777 were common between the two studies and 93 were compounds reported in all three studies.

We show how Bayesian statistics incorporates results from one study as "prior information" into the next study, thereby improving the overall assessment of the likelihood of finding specific differences between plasma metabolite levels. Using classic statistics and Benjamini-Hochberg FDR-corrections, Study 1 detected 18 metabolic differences and Study 2 detected no differences.

Using Bayesian statistics on the same data, we found a high likelihood that 97 compounds were altered in concentration in Study 2, after using the results of Study 1 as the prior distributions. These findings included lower levels of peroxisome-produced ether-lipids, higher levels of long-chain unsaturated triacylglycerides, and the presence of exposome compounds that are explained by the difference in diet and medication between healthy subjects and ME/CFS patients.

Although Study 3 reported only 92 compounds in common with the other two studies, these major differences were confirmed. We also found that prostaglandin F2alpha, a lipid mediator of physiological relevance, was reduced in ME/CFS patients across all three studies. The use of Bayesian statistics led to biological conclusions from metabolomic data that were not found through frequentist approaches. We propose that Bayesian statistics is highly useful for studies with similar research designs if similar metabolomic assays are used.
 
Murph

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This study has a bland title but it's a actually a useful reanalysis of some big datasets using a new technique. Instead of just using p-values on one dataset, they use "Bayesian" techniques and combine the datasets to get new insights.

What pops out most is the peroxisome, a little organelle in our cells, that is involved in a bunch of the compounds that are anomalous. It is also related to the endoplasmic reticulum that recent NIH data suggested might be going awry.

Full text article here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10535181/

In the full text they note, "a profound downregulation of unsaturated phospholipid ethers and plasmalogens (Figure 6 and Figure 7), which are exclusively produced by peroxisomes"

and

"the results of the Bayesian analysis further strengthened the biological interpretation of peroxisome damage as an important factor underlying ME/CFS: very long chain polyunsaturated triacylglycerides were found at increased levels in ME/CFS subjects (Figure 6), pointing to a lack of oxidation in peroxisomes that exclusively perform this reaction (not mitochondria). Peroxisome damage is further supported by the specific increase in phosphatidylcholines with polyunsaturated very-long-chain fatty acids."

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

We don't talk about peroxisomes much except in the context of ppar, the energy homeostasis receptor. But the p in ppar stands for peroxisome.

tl;dr new statistical method suggests overlooked cellular organelle could be worthy of study.
 
Forummember9922

Forummember9922

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Anything with big datasets is so awesome and makes me feel hopeful.

I hate to bring up herpesviruses again as their increased presence could be downstream of more important culprits but they’re not peaceful tenants: https://www.nature.com/articles/s42003-022-03867-y

(Peroxisomal very long-chain fatty acid transport is targeted by herpesviruses and the antiviral host response)​

I am personally drawn towards research with fatty acids because, only since CFS, large amounts of Omega 3's have given me suicidal thoughts. Whereas before they made me calm as a cucumber.
 
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Wishful

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Looks like a promising line of research. Peroxyisomes do seem like a good candidate for explaining many aspects of ME, such as messing around with neural function. A quick check shows plenty of papers linking peroxysome deficiency with neural problems. My guess is there's a lot of functions involving peroxysomes that are still undiscovered.
 
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Wishful

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Forummember9922 said:
I am personally drawn towards research with fatty acids because, only since CFS, large amounts of Omega 3's have given me suicidal thoughts.
Click to expand...
Tryptophan (I assume through the KYN pathway to QUIN) had the same effect on me, and B12 did once as well. There's some malfunction in ME that can lead to suidical thoughts.

My ME is affected by specific fatty acids, so I agree that they are involved too. I'm not sure that it's a promising line of research, since fatty acids would have so many direct and indirect effects on the body, so, what to look for? Some trials supplementing specific fatty acids and looking for effects on ME might find something.
 
Murph

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Just on peroxisome function, there's this new and totally out of left field paper by some Canadians that suggests a certain kind of lipid called a plasmalogen is at fault. Plasmalogens are made in the peroxisome

https://www.sciencedirect.com/science/article/pii/S0361923023001272?via=ihub#sec0115

2023 Sep:201:110702.

Chronic inflammation, neuroglial dysfunction, and plasmalogen deficiency as a new pathobiological hypothesis addressing the overlap between post-COVID-19 symptoms and myalgic encephalomyelitis/chronic fatigue syndrome

Adriano Maia Chaves-Filho 1 , Olivia Braniff 1 , Angelina Angelova 2 , Yuru Deng 3 , Marie-Ève Tremblay 4
Abstract

After five waves of coronavirus disease 2019 (COVID-19) outbreaks, it has been recognized that a significant portion of the affected individuals developed long-term debilitating symptoms marked by chronic fatigue, cognitive difficulties ("brain fog"), post-exertional malaise, and autonomic dysfunction. The onset, progression, and clinical presentation of this condition, generically named post-COVID-19 syndrome, overlap significantly with another enigmatic condition, referred to as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Several pathobiological mechanisms have been proposed for ME/CFS, including redox imbalance, systemic and central nervous system inflammation, and mitochondrial dysfunction.

Chronic inflammation and glial pathological reactivity are common hallmarks of several neurodegenerative and neuropsychiatric disorders and have been consistently associated with reduced central and peripheral levels of plasmalogens, one of the major phospholipid components of cell membranes with several homeostatic functions.

Of great interest, recent evidence revealed a significant reduction of plasmalogen contents, biosynthesis, and metabolism in ME/CFS and acute COVID-19, with a strong association to symptom severity and other relevant clinical outcomes. These bioactive lipids have increasingly attracted attention due to their reduced levels representing a common pathophysiological manifestation between several disorders associated with aging and chronic inflammation.

However, alterations in plasmalogen levels or their lipidic metabolism have not yet been examined in individuals suffering from post-COVID-19 symptoms. Here, we proposed a pathobiological model for post-COVID-19 and ME/CFS based on their common inflammation and dysfunctional glial reactivity, and highlighted the emerging implications of plasmalogen deficiency in the underlying mechanisms. Along with the promising outcomes of plasmalogen replacement therapy (PRT) for various neurodegenerative/neuropsychiatric disorders, we sought to propose PRT as a simple, effective, and safe strategy for the potential relief of the debilitating symptoms associated with ME/CFS and post-COVID-19 syndrome.

Plasmalogens have been measured in mecfs and found to be low.

There's a thing called plasmalogen replacement therapy that shows promise in several diseases! i'm going to see what is out there.
 
Murph

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So when it comes to plasmalogen replacement therapy the main answer seems to be shark liver oil*. Available on the supplements market, well-studied, well-tolerate and found to be useful by serious scientists from my own hometown in reducing inflammatory markers:

https://pubmed.ncbi.nlm.nih.gov/34146594/

J Lipid Res. 2021; 62: 100092.
Published online 2021 Jun 17. doi: 10.1016/j.jlr.2021.100092
PMCID: PMC8281607
PMID: 34146594

Shark liver oil supplementation enriches endogenous plasmalogens and reduces markers of dyslipidemia and inflammation​

Sudip Paul,1,2 Adam Alexander T. Smith,1 Kevin Culham,1 Kevin A. Gunawan,1 Jacqueline M. Weir,1 Michelle A. Cinel,1 Kaushala S. Jayawardana,1 Natalie A. Mellett,1 Man K.S. Lee,3 Andrew J. Murphy,2,3 Graeme I. Lancaster,2,3 Paul J. Nestel,1 Bronwyn A. Kingwell,4 and Peter J. Meikle1,2,∗

*Anyone else hate when you do a serious scientific search and you end up considering a product that sounds like it would be administered by a wizened old crone from a medieval village?!
 
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Wishful

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I did some searching about plasmalogens, and found several papers that support my observations about fatty acids, especially SCFAs, affecting brain function. Carnitine is potent too, which is something that worked for me during one period. It looks way too complicated for me to point to some molecular pathway and say "This explains why fibre made my symptoms worse", but those papers certainly make my responses seem reasonable. Reading those papers also makes me surprised that we don't notice more dramatic effects from eating a bran muffin vs eating a no-fibre meal.

Poor sharks if someone pushes this product as the next "super health" product.

The wizened crone wouldn't be pushing shark bits unless that village was far from the sea. The point of exotic animal parts is that there's no local experience to prove that it doesn't have amazing effects.
 
Murph

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The results of peroxisome dysfunction are defintiely consistent with some observations made in mecfs.

It is possible what we have is lingering viruses fucking with our peroxisomes and creating problems with membrane lipids and mitochondria downstream of that. I'm not saying this is super likely, but it's deinfitely in the category of: possible and literally nobody has looked at this.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8868334/

Peroxisomal Stress Response and Inter-Organelle Communication in Cellular Homeostasis and Aging​

Jinoh Kim* and Hua Bai*
Ana L. Santos, Academic Editor
Author information Article notes Copyright and License information PMC Disclaimer

Go to:

Abstract​

Peroxisomes are key regulators of cellular and metabolic homeostasis. These organelles play important roles in redox metabolism, the oxidation of very-long-chain fatty acids (VLCFAs), and the biosynthesis of ether phospholipids. Given the essential role of peroxisomes in cellular homeostasis, peroxisomal dysfunction has been linked to various pathological conditions, tissue functional decline, and aging. In the past few decades, a variety of cellular signaling and metabolic changes have been reported to be associated with defective peroxisomes, suggesting that many cellular processes and functions depend on peroxisomes. Peroxisomes communicate with other subcellular organelles, such as the nucleus, mitochondria, endoplasmic reticulum (ER), and lysosomes.

These inter-organelle communications are highly linked to the key mechanisms by which cells surveil defective peroxisomes and mount adaptive responses to protect them from damages. In this review, we highlight the major cellular changes that accompany peroxisomal dysfunction and peroxisomal inter-organelle communication through membrane contact sites, metabolic signaling, and retrograde signaling. We also discuss the age-related decline of peroxisomal protein import and its role in animal aging and age-related diseases. Unlike other organelle stress response pathways, such as the unfolded protein response (UPR) in the ER and mitochondria, the cellular signaling pathways that mediate stress responses to malfunctioning peroxisomes have not been systematically studied and investigated. Here, we coin these signaling pathways as “peroxisomal stress response pathways”. Understanding peroxisomal stress response pathways and how peroxisomes communicate with other organelles are important and emerging areas of peroxisome research.
 
Forummember9922

Forummember9922

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I got the 99$ bottle from Dr Goodenows brand, Ill let you know if it does anything. Certainly the whole ideology of plasmogens looks attractive - based on published findings in CFS and a short amount of community testimonials. It also fits nicely as an upstream issue in the big picture.
 
Forummember9922

Forummember9922

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Experiencing some type of worsening/herx(?) especially mental symptoms. I also just started regularly taking Salicinium.
 
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Rufous McKinney

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If I have to participate in the death of sharks in order to be alive, OH WELL.

I am absolutely not doing that.

The sharks are all being killed and mostly wasted, currently. Any form of participating in this, I am not doing.
 
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Peroxisomal dysfunction decreases plasmalogen, resulting in the inhibition of mitochondrial fission.. Peroxisomal dysfunction activates nuclear gene transcription through the transcription factors PPARα, AP-1, or Hnf4. The accumulation of long-chain fatty acids (LCFAs) activates PPARα to upregulate LONP2 and CAT expression to restore peroxisomal function. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8868334/

Ether lipids serve as ligands for nuclear receptors like PPARα or PPARγ. Upon ligand binding in the nucleus, or in the cytoplasm triggering nuclear translocation, the PPARs bind to response elements in the DNA. As heterodimers with the retinoid X receptor (RXR) which are Vitamin A receptors, PPARs associate with coactivators, thus inducing the expression of target genes.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951609/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116601/

PPARα activation plays a protective role in regulating ER stress during disease development. Our data further demonstrated the subtle regulation of PPARα activation in mild-ER stress conditions promotes cell survival, and PPARα inhibition in serious ER stress conditions promotes apoptosis. https://www.nature.com/articles/s41419-020-02811-4

Peroxisome Proliferator Activated Receptors α and γ Require Zinc for Their Anti-inflammatory Properties. All PPAR agonists tested lost their potency to downregulate the TNF-α–induced inflammatory response in zinc-deficient cells. However, if zinc was added back, all PPAR agonists significantly downregulated the TNF-α–mediated induction of inflammatory transcription factors NF-κB and AP-1 and significantly reduced the expression of their target genes, VCAM-1 and IL-6 https://www.sciencedirect.com/science/article/pii/S0022316623029346?via=ihub

Er stress is regulated by zinc also
https://forums.phoenixrising.me/thr...-treatment-for-cfs.37244/page-98#post-2451850
https://forums.phoenixrising.me/thr...s-chronic-fatigue-syndrome.90582/post-2443553

There is mechanistic evidence suggesting that the deacetylation process catalyzed by SIRT4 may enhance GNPAT degradation which lowers plasmologens.
https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-023-02613-0 https://www.nature.com/articles/s41388-020-1156-0

We show that SIRT4 decreases PPARα activity and consequently expression of PPARα target genes in a cell-autonomous manner. We further demonstrate that SIRT4 deletion activates PPARα activity through activation of SIRT1 by NAD+. Thus, our findings highlight a novel connection between SIRT4 and signaling to PPARα. NAD+ increases PPARα target gene expression. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3838178/

homocysteine lowers PPARa. Homocysteine has recently been found to be a competitive inhibitor of the nuclear transcription factors: Peroxisome proliferator activated receptors (PPARs) alpha and gamma. https://link.springer.com/article/10.1186/1475-2891-3-4
https://www.ncbi.nlm.nih.gov/pubmed/16439690

Peroxisomes are key regulators of cellular and metabolic homeostasis. These organelles play important roles in redox metabolism, the oxidation of very-long-chain fatty acids (VLCFAs), and the biosynthesis of ether phospholipids. The synthesis of plasmalogens, a class of ether phospholipids that represent ∼20% of the total phospholipid mass in humans, is initiated in the peroxisomes and completed in the ER. tethering to the ER was shown to be required for maintenance of plasmalogen levels and is influenced by cellular oxidative stress and other factors. Tethering of peroxisomes to the ER is necessary for peroxisome growth, the synthesis of plasmalogen phospholipids, and the maintenance of cellular cholesterol levels. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5294787/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8868334/
https://www.embopress.org/doi/full/10.15252/embr.201947928

PPARa activation (such as by using Palmitoylethanolamide (PEA)) or the synthetic drug fenofibrate
and combined with chelated zinc/zinc amino acids may be one method suggested by the research.
 
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Violeta

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Fucoidan is a PPAR activator? Can one conclude that PPAR activators increase plasmalogens?

Fucoidan is a polysaccharide derived from brown algae and seaweed that activates peroxisome proliferator-activated receptor (PPAR) α and β, which are key proteins in regulating cholesterol:

https://pubmed.ncbi.nlm.nih.gov/310...,treatment of hyperlipidemia-related diseases.

These results demonstrated that fucoidan can improve lipid transfer from plasma to the liver by activating SR-B1 and LDLR and inactivating PCSK9 and upregulate lipid metabolism by activating PPARα, LXRβ, ABC transporters, and CYP7A1. In the small intestine, this fucoidan can decrease cholesterol absorption and increase cholesterol excretion by activating NPC1L1 and ABCG5 and ABCG8, respectively. In conclusion, fucoidan from A. nodosum may lower lipids by modulating RCT-related protein expression and can be explored as a potential compound for prevention or treatment of hyperlipidemia-related diseases.
 
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