I was interested in the key metabolites that Naviaux mentioned in the paper, but couldn't help wondering about the hundreds of others that were tested. When the data was released on the metabolomics workbench site I made a few graphs, but didn't have an account to post it here.
It is a very simple analysis of the raw metabolomic data in the Naviaux paper. Each blue column represents a different metabolite. Data is presented using ratio of average of sick patients to average of healthy patients; and without measuring variance or statistical significance. (nb the authors do more sophisticated analyses than this to obtain their fold change scores published in the paper.) Nevertheless some patterns can be seen.
The fact people have more metabolites low than high is a decent sign of hypometabolism, although most are not very very low. I find it interesting that men have more metabolites lower, but also more *just* below normal levels.
[Note axis truncation in the male results. The very high result is nicotinamide n oxide, which is all driven by one absurdly large outlier among male patients. Who knows what's going on there. What's especially odd is nicotinamide n oxide drives the lowest result (0.37) in females. It just seems like a non-normally distributed variable.)
I'm a little new here and haven't yet gotten the hang of all the nuances of this site, so please excuse my butting in here like this.
I'd created another thread this week about my experiences with B6 deficiency an the relationship to heme and sphingolipid production and immune function. I was asked to copy what I posted there into this discussion, so here goes... I'll look forward to hearing if you all think this might be important in light of Naviaux's findings...
This describes PLP (P5P or B6) and it's importance in sphingolipids and immune function.
Reduced availability of PLP is associated with reduction
in several components ofthe immune response, includ-
ing significant decreases in lymphocyte numbers, espe-
cially T-helper cells and IL-2 production in humans.6
Lymphocytes isolated from vitamin B6-deficient subjects
also show reduction of lymphoproliferative responses to
mitogens that activate both T and B cells when grown in
a culture medium containing adequate concentration of
PLP.6 This has been attributed to the lower numbers of
T-helper cells in the lymphocyte population from vitamin
B6-deficient subjects. Maturation and egress of lympho-
cytes, especially T-cells, from thymus and lymph nodes
relies on the gradient of sphingosine-1-phosphate (S1P).
PLP-dependent enzymes play a major role in the synthe-
sis and breakdown of S1P, which is a potent metabolite
that regulates inflammation and immune response pro-
cesses such as cell growth, survival, differentiation, lym-
phocyte trafficking, vascular integrity, and cytokine
and chemokine production.58,59 PLP is required for the
activity of serine palmitoyl transferase that catalyzes the
condensation of serine and palmitoyl CoA into 3-keto-
dihydrosphingosine, which is then converted to S1P
in a series of reactions.58–60 PLP is also a cofactor for
sphingosine-1-phosphate lyase, which irreversibly cleaves
S1P to regulate its concentration.58,59,61 A gradient of S1P
is required for lymphocyte egress from thymus and
peripheral lymphoid organs, which is maintained by S1P
lyase.62 Administration of vitamin B6 antagonist 4’ deoxy-
pyridoxine interferes with the S1P gradient, results in
accumulation of mature lymphocytes in the thymus, and
depletes B- and T-lymphocytes from lymph causing lym-
phopenia.62 These conditions can be reversed by provid-
ing excess vitamin B6 in the diet.62 During inflammation,
S1P concentration increases in the inflamed peripheral
tissues,63 which functions as a chemoattractant for the
One of the intermediate products during the synthe-
sis of S1P from 3-keto-dihydrosphingosine is ceramide,
which plays an important role in inflammatory processes.
Ceramide functions as a second messenger mediating the
effects of tumor necrosis factor-a and interferon-g on
programmed cell death and regulating senescence.64,65 An
increase in cellular ceramide concentration is observed in
cystic fibrosis, experimental autoimmune encephalomy-
elitis, and diet-induced insulin resistance, all of which are
marked by chronic inflammation.66–68 The importance of
ceramide in these diseases is demonstrated by the fact
that manipulation of ceramide concentration via inhibi-
tion of serine palmitoyl transferase or mutation of sph-
ingomyelinase, reverses the pathology of the disease.66–68
Ceramide-1-phosphate, which is derived from ceramide,
activates mast cells that mediate inflammation.69
Thus, it is possible that is a higher demand exists for
PLP during inflammation due to the role of PLP in the
synthesis of S1P and ceramide, and maintenance of S1P
Microglial activity in people at ultra high risk of psychosis and in schizophrenia; an [11C]PBR28 PET brain imaging study
Authors: Peter S Bloomfield, Sudhakar Selvaraj, Mattia Veronese, Gaia Rizzo, Alassandra Bertoldo, David R Owen, Michael AP Bloomfield, Ilaria Bonoldi, Nicola Kalk, Federico Turkheimer, Philip McGuire, Vincenzo de Paola, and Oliver D Howes.
It was published in Am J Psychiatry. 2016 January ; 173(1): 44–52. doi:10.1176/appi.ajp.2015.14101358.
They used the following method to test for elevated microglia activity in the brain:
"Elevations in microglial activity can be measured in vivo with positron emission tomography (PET) using radioligands specific for the 18kD translocator-protein (TSPO), which is expressed on microglia (14). Investigations using the first generation radiotracer (R)- [ 11C]PK11195 have revealed an increase in TSPO binding in medicated patients with schizophrenia when compared to healthy controls (6, 7). The first investigation of microglia using PET in schizophrenia, in a cohort of 10 patients, revealed a total grey matter elevation of microglial activity in the five years following diagnosis (6). The most recent investigation in seven chronically medicated patients with schizophrenia using (R)-[11C]PK11195 demonstrated an elevation in hippocampal binding potential and a non-significant 30% increase in total grey matter binding potential (7)."
Just wondering if any of the ME CFS researchers have used this method?
There has been a 'correction' posted on the PNAS website which reads as following:
MEDICAL SCIENCES Correction for “Metabolic features of chronic fatigue syndrome,” by Robert K. Naviaux, Jane C. Naviaux, Kefeng Li, A. Taylor Bright, William A. Alaynick, Lin Wang, Asha Baxter, Neil Nathan, Wayne Anderson, and Eric Gordon, which appeared in issue 37, September 13, 2016, of Proc Natl Acad Sci USA(113:E5472–E5480; first published August 29, 2016; 10.1073/pnas.1607571113).
The editor, R.W.D., wishes to note that he has consulted with R.K.N. with respect to R.W.D.’s son’s metabolism and with E.G. with respect to R.W.D.’s son’s care. These consultations played no role in the work or the editing of this paper. R.W.D.’s son was not a subject in this study. After this research study was completed, written, and edited, R.W.D., as chair of the Open Medicine Foundation (OMF) Scientific Advisory Board, asked R.K.N. to join the board and began collaborating with him and E.G. on follow-up studies related to this work. Thus, R.W.D. now has a professional relationship with R.K.N. and E.G. The OMF provided a grant to R.K.N. to support the follow-up studies. The OMF and R.W.D. played no role in the work described in this paper.
My uneducated guess is that this chronically reduced metabolic rate at the cellular level is not simply a case of being stuck in the "low" position. Rather, it's driven by another chronic process that won't resolve, like an infection or autoimmunity, or an alteration in the microbiome (perhaps initiated by an infection), and one or more of those things is leading to chaos at the cellular level. Fix the problem upstream and, hopefully, the cellular metabolism will return to normal.
At the moment, at least, I think the real importance of this finding is in its diagnostic value as a biomarker. That in itself is HUGE.
I am just now reading this string, and I LOVE what you are proposing, Forbin. Because with me, this ALL started with an acute mold inhalation. And I'm part of 24% of the population that needs extra help getting the mold out of me. So all I can do is HOPE that as I get it out, I "might" return to normal...or at least be better than I am now.
For anyone waiting to hear news about the replication study it looks like it's been delayed again.
It was tentatively scheduled to be published 'this fall' and then 'late this fall' but it's now early next year.
I was hoping for an early Christmas present.
I found this about gene UGT8 catalyzes transfer of galactose to ceramide during biosynthesis of galactocerebrosides which are abundant sphingolipids of the myelin membrane of the CNS and peripheral nervous system