Monday, 5 March 2018

Sulfur in CFS - signals in the noise?

Some findings presented at a recent CFS conference got me interested in sulfur again. What is the current picture? How does it fit with everything else? Here’s a mini-review of my reading.

Sulfur

Sulfur is the 7th most abundant element in the body 1. Most has been presumed to come from dietary proteins, specifically the two sulfur-containing amino acids – methionine and cysteine. However, a substantial amount also comes from other organosulfur compounds in plants (e.g. allium and cruciferous veg) and inorganic sulphates (i.e. water and food) 2.

Methionine is the most essential sulfur-containing nutrient and can be converted to other sulfur metabolites. Initially, methionine is adenosylated (by MAT) to s-adenosyl-methionine (SAM, aka AdoMet), a methyl-donor, which is then demethylated to s-adenosyl-homocysteine (SAH) and hydrolysed (by SAHH) to homocysteine. Homocysteine can be remethylated back to methionine (MS and BHMT pathways) or catabolised by via the transsulfuration pathway (CBS and CGL) to other sulfur metabolites (e.g. cysteine/GSH, taurine and H2S). Enzymes in these pathways use energetic and B vitamin-derived cofactors/substrates – e.g. MTHFR (B2, B3, B9), MS (B9, B12), MSR (B2, B3), MAT (ATP), SAHH (B3), CBS (B6) and CGL (B6).

Homocysteine is the infamous marker of sulfur metabolism, since elevated levels (hyperhomocysteinemia, e.g. >15uM 3) are associated with many diseases. As above, homocysteine metabolism is dependent on 1-carbon metabolism (i.e. folate and methionine/SAM cycles) and transsulfuration pathways, which are regulated by cell activity and metabolic homeostasis (e.g. SAM and redox) 4–8. In healthy people, blood homocysteine fluctuates throughout the day in relation to circadian rhythms (~7-10uM) 9 and can be transiently increased by protein/methionine intake 10–12. Elevated homocysteine may result from many factors including genetics, age, diet and disease processes.

...in ME/CFS

There are not many studies which have looked at sulfur metabolism in ME/CFS. Here I have pulled together the most relevant findings I am aware of in the published literature and presented at conferences.

Peripheral findings

Since the late 90s, there have been several amino/organic acid studies on blood and urine. Some early studies found changes to sulfur metabolites (i.e. methionine, cysteine, taurine or sulfate) in vaguely defined 13,14 and standard criteria ME/CFS 15. More recently, the largest study so far (n=153) found lower levels of many serum amino acids (incl. methionine, but not cysteine) in females only 16; for comments see 17. Other recent metabolomic studies found some changes implicating sulfur-related pathways, including methylation (MetS, B12 and betaine) 18,19 and taurine 20.

Surprisingly, homocysteine has rarely been measured. Over 20 years ago, in 1997, a small study on 12 women with CFS/FM found a couple (17%) had elevated blood homocysteine 21. Most recently, at a 2017 OMF conference, Dr Moreau reported finding very elevated plasma homocysteine levels (~30uM) in 20% of >100 CFS patients, which correlated illness severity. There were no changes to B vitamins (B6, B9 and B12), but low vitamin C in males (YouTube). He will further investigate the cause of the high homocysteine. Note, plasma homocysteine largely results from liver and kidney metabolism, so may implicate these organs.

Several early studies measured RBC glutathione (GSH) and found either no, low or varied changes in CFS subgroups (reviewed in 22). Moreover, in a very small muscle biopsy study, total GSH was elevated, alongside markers of oxidative stress, suggesting a compensatory mechanism 23.

At the 2009 IACFS/ME conference, interesting results of an uncontrolled pilot study on 21 women with CFS/FM were presented 22. This study found lower plasma GSH/GSSG, RBC SAM and plasma/cell folates. Biomarkers and symptoms improved with 6 months of multi-vitamin supplementation. This result supported a link between methylation and GSH status, similar to that previously found in autism 22.

Central findings

In the early 1997 study above on women with CFS/FM, while blood homocysteine was only elevated in a minority, they all had increased cerebrospinal fluid (CSF) homocysteine (avg. 3x) and most ‘suspiciously low’ CSF B12, both of which correlated symptoms 21. Note, there were no changes to CSF methionine, cystathionine and MMA. These results suggested impaired B12-dependant remethylation of homocysteine in the CNS 21.

In 2009, an initial neuroimaging study failed to find significant changes to brain GSH in ME/CFS 24. However, subsequent studies found brain GSH was low and related to ventricular lactate and symptoms in CFS (as well as controls and MDD) 25,26. Note, GSH had a much stronger association with CFS symptoms than lactate 25. Further, a validation study reported that N-acetyl-cysteine (NAC) could boost brain GSH and markedly improve symptoms (conference abstract 27). Note, NAC not only supplies cysteine for GSH synthesis, but may also promote homocysteine catabolism to cystathionine and H2S 28.

Causes?

Why might sulfur metabolism be affected in some with CFS? Here are some possibilities:
  • Genetics? Common gene variations can influence sulfur metabolism (e.g. MTHFR and MSR snps) 29. Some interaction between MTHFR snps and the response to B12/folate supplementation was reported in CFS 30.
  • Cofactor deficiencies? As mentioned above, enzymes of sulfur metabolism require B vitamin-derived cofactors. In CFS, some studies have found lower B12 18,21, folate 31, B6 32, FAD 18, NAD+ 33 and NAD(P)H 34. ATP is also required for the synthesis of SAM and GSH (which are required to form methyl-B12 35,36), and the conversion of vitamins B2, B3 and B6 to their active cofactor forms. Note, MAT may depend on de novo ATP synthesis from serine 37. Some studies find evidence of bioenergetic dysfunction and low ATP in ME/CFS 20,33,38. Note however, neuroimaging studies have found no changes to brain ATP (at rest) 25, while NAC boosts brain GSH 27.
  • Gut microbiome? The gut microbiome appears to regulate systemic bioavailability and metabolism of H2S 39. Gut bacteria may also produce and supply significant folate to the body 40, but compete for B12 41. In particular, SIBO has been reported in CFS 42, which has been associated with low B12 status in other conditions 41.
  • Oxidative stress? Oxidative stress upregulates transsulfuration flux 4. Further, since both folate and B12 are sensitive to oxidation 35,43, oxidative stress has been suggested to impair MS-dependant remethylation activity in various conditions 44–47, including CFS 21,22.
  •  Inflammation? Conditions of chronic inflammation and tissue breakdown are associated with increased homocysteine levels and sulfur excretion in humans 1,6. Stimulation of immune cells can increase sulfur metabolism 48 and homocysteine release 49. In animal models, sepsis increases methionine transsulfuration to cysteine 50 and inflammation can deplete vitamin B6 51. In ME/CFS, immune activity may be related to illness duration 52, severity 53 and bacterial translocation 54,55.
  • Autoimmunity? Autoantibodies may block proteins mediating nutrient uptake, such as the folate receptor 56 and megalin 30,45. The latter was mentioned in relation to brain B12 in CFS 30.

Effects?

What are the effects of altered sulfur metabolism in CFS? Various theories have considered GSH 25,57–59, methylation 21,59 and H2S in CFS 60. Here I will briefly review some possibilities.

GSH

Brain GSH correlated symptoms in CFS, suggesting clinical significance 25. Moreover, a small validation study on 16 people with CFS reported that 4 weeks of NAC treatment normalised brain GSH and markedly improved symptoms; whereas brain GSH did not change in a healthy control group on the same treatment (conference abstract 27). This might support causality between GSH and symptoms in CFS - but by what mechanism? GSH is the substrate of major intracellular antioxidant systems regulating redox signaling and buffering oxidative stress 61. Consequently, low GSH could have many detrimental effects on cell functions and viability 59, and is associated with neurological diseases 45,57. Interestingly, brain GSH inversely correlated lactate in CFS (and combined study group), suggesting a relationship with bioenergetics 25. The authors suggested oxidative stress may impair brain blood flow and energy metabolism in CFS 25.

Low GSH could affect many redox-sensitive metabolic and signaling pathways. Of particular interest here, low GSH may promote a functional B12 deficiency, since glutathionylcobalamin serves as a precursor to methylcobalamin, the cofactor for MS 35. Further, neuronal mitochondrial oxidative stress can deplete methyl-folate 43. Therefore low GSH and oxidative stress might impair B12/folate-dependant remethylation of homocysteine, aggravating the dysfunctions discussed below.

Homocysteine

Both plasma homocysteine (Moreau) and CSF homocysteine/B12 21 also correlated symptoms in CFS. Further, some preliminary therapeutic reports suggest B12 and folate supplementation can improve biomarkers and symptoms in ME/CFS 22,30,62. For instance, a small uncontrolled pilot study on 21 women with CFS/FM reported that 6 months treatment with B vitamins normalised several biomarkers (i.e. SAM, GSH and folates), while lowering and improving symptoms (i.e. energy, sleep, mental clarity, pain and wellbeing) (conference report 22).

Plasma homocysteine levels may be as high as ~30uM in severe CFS. These levels and far higher (>100uM) are seen in some other disorders (e.g. advanced kidney disease 63, severe nutrient deficiency and genetic diseases 64,65). The clinical significance probably depends on aetiology - what is blood homocysteine a marker of and which tissues are affected 66–69? Levels of around 30uM won’t necessarily be associated with CFS-like symptoms (e.g. nitrous oxide abuse 70). But perhaps this anecdote is noteworthy. The recent BBC series 'doctor in the house' included someone struggling with long-standing health issues, including a history of stroke and ongoing fatigue, exhaustion and sleep issues. Nothing had shown up in tests, until his homocysteine came back at 35uM. This seemed related to a gene variation, while multi-vitamin supplementation rapidly improved his condition and dropped his homocysteine to 7uM (YouTube).

Homocysteine has many effects in cell and animal models (e.g. hypomethylation, homocysteinylation, NMDA receptor and oxidative stress), which may occur at different levels. Interestingly, the acute effects of homocysteine have been studied in humans via methionine or homocysteine-loading with assessment of vascular function 12,71–74 and metabolic, lipid or inflammatory markers 75,76. For instance, in young healthy adults, oral methionine or homocysteine acutely increases homocysteine (e.g. from 10 to 25, or 50uM respectively) and impairs blood flow (i.e. brachial artery flow-mediated dilation) 12,71,72. This occurs even at low increments of homocysteine (i.e. 2-3uM) 12 and is most tightly related to the reduced form of homocysteine 72. Of additional relevance to severe CFS, this vascular dysfunction is prevented by vitamin C 71, and may be related to homocysteine-induced oxidative stress and depletion of nitric oxide 77,78. Note, not all methionine-loading studies find these changes to peripheral or cerebral blood flow 73, while in others there may be age-dependence 74, suggesting underlying physiology/health (antioxidant status?) is important. Consistent with vascular changes, the methionine-loading test also frequently induces clinical symptoms, such as dizziness, resulting in impaired perception and vigilance 79.

Methylation

In the methionine/SAM cycle, accumulation of homocysteine can promote feedback-inhibition or reversal of the SAHH reaction and increase SAH 80,81, a potent inhibitor of most SAM-dependent methylation reactions, thus lowering the methylation potential (SAM/SAH) 82,83. SAM is involved in over 50 methyl-transfer reactions to DNA, proteins, phospholipids and other small metabolites 82. Quantitatively, the major methyl consumers are biosynthesis of phosphatidylcholine (membranes, lipoproteins, bile, mucus, etc.) and creatine (energy recycling, etc.) 84–86. Sensitivity to SAH is methyltransferase and tissue-specific 83. Some pathways in particular have been implicated. For instance, in human studies, plasma homocysteine directly correlates SAH, which negatively correlates phosphatidylcholine (level and PUFA/DHA content) in blood/RBC 87,88 and DNA methylation in lymphocytes (Fig 2) 83. Note, SAM also plays a non-methyl role in polyamine biosynthesis (i.e. spermidine and spermine); although in cell studies SAM depletion had a greater effect on methylation 89,90.

Dysregulation of the methionine cycle has further repercussions for other connected metabolites/pathways. For instance, elevated homocysteine and inhibition/reversal of SAHH activity may deplete adenosine by trapping it in SAH 91. Conditions of low SAM or high homocysteine may promote compensatory BHMT activity at the expense of betaine 64,92. Low B12/MS activity and SAM may favour higher MTHFR activity and trapping of folate as methyl-THF. Low SAM may slow transsulfuration flux (i.e. CBS 5) and GSH metabolism (i.e. Nrf2/GCL 93,94 and GST activity 95), which could link methylation and redox status in some conditions 5,96. Note, depletion of transsulfuration products (e.g. GSH/GSSG 4 and taurine 97) will increase CBS activity, but this may be limited by SAM, which stabilises CBS 5.

Long-term…?

In some studies, CFS has been associated with risk factors for cardiovascular disease (CVD) 98–100, the primary cause of death globally. CVD-related changes in CFS include increased arterial stiffness 100 and endothelial dysfunction (i.e. brachial artery flow-mediated dilation and forearm skin vasodilation) 98, which in turn, may be related to several factors including age, inflammation and oxidative stress 98–100.

Sulfur metabolism is of major relevance to ageing and related diseases. Methionine restriction and transsulfuration pathways promote stress resistance, healthspan and longevity in animal models 101,102. Conversely, in humans elevated homocysteine (even more so SAH) is an independent risk factor for CVD 69, as well as other conditions including osteoporosis 103 and cognitive decline 104,105. Similarly, loss of thiol redox (incl. Cys/CySS and GSH/GSSG) is associated with CVD 61 and other age-related diseases 106. Note, low RBC GSH was associated with CVD risk factors in CFS 107.

So could sulfur be important in some with ME/CFS?

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