Reversal of CVD with diet and lifestyle

Among the ocean of research, I’m very interested in natural interventions which have reversed common diseases, since they help reveal basic ecology. Here’s a mini-review based around my initial reading of such CVD trials.

Cardiovascular disease (CVD) is the leading cause of mortality worldwide, accounting for 31% of all deaths (WHO). The most common forms are coronary artery and cerebrovascular diseases (affecting heart and brain, respectively) driven by atherosclerosis (i.e. plaque build-up) ^1,2. Further, CVD and intracranial atherosclerosis are also linked to dementia ^3,4, another leading cause of death (e.g. Dementia Hub).

Chocolate vs. CFS: flavanols and beyond

There have now been several preliminary studies testing the effects of phytochemical-rich plants in ME/CFS, some of which show benefit (discussed later). Of these, I find the 2010 trial with chocolate particularly intriguing ¹.

This was a very small pilot trial (UK, n=10 CFS, Fukuda criteria + severe fatigue; no mood disorders, no drugs) to test the effect of polyphenol-rich chocolate for 8 weeks on symptoms. It had a double-blind, placebo-controlled, crossover design (8–2–8), with several subjective outcomes; and high methodological quality in a recent systematic review ². The active treatment arm had an improvement in fatigue, anxiety, depression and disability (pre–post effect: –35%, –37%, –45% and +31%, respectively); anecdotally, 2 people with short illness duration even returned to work ¹. For reference, this is a greater reduction in fatigue, depression and anxiety than over a year of CBT or GET in the large PACE trial (UK, n=641 CFS, multiple criteria), which used some of the same outcome measures ³.

Is NAD low in CFS?

Nicotinamide adenine dinucleotide (NAD) performs central roles in metabolism as a redox cofactor and enzyme substrate. NAD is synthesised via several pathways; in essence from tryptophan (i.e. de novo pathway) or vitamin B₃ precursors (i.e. Preiss-Handler and salvage pathways), with addition of ribose-phosphate (from PRPP) and AMP (from ATP), and amidation to form NAD ¹. Several enzymes (e.g. sirtuins, PARPs and CD38) catabolise NAD by removing the whole ADP-ribose portion releasing nicotinamide (NAM), which can be recycled to NAD in the salvage pathway, or methylated (via NNMT) and excreted.

NAD metabolism is regulated by circadian rhythms ² and daily activities ³, while levels may decline with ageing ^4,5 and disease ⁶. Several authors have also suggested NAD may be low in ME/CFS, based on suspected pathophysiology ^7–10. Currently, there are scarce studies in this area, but below are some preliminary findings I’ve scraped together.

Redox in CFS: to what do we owe this electron flow?

Oxidative stress has long been implicated in CFS. Here are some data summary tables from a draft paper on redox in CFS written around this time. They generally show how an oxidative redox status may affect many molecules and tissues, and associate with many symptoms.

Homocysteine on the brain: many paths to many problems

2019 – end edit and update.

Homocysteine might be important in many neurological disorders, especially cognitive decline. I’ve been reading about potential mechanisms—there are a lot! Here’s an attempt to arrange some things of interest as a mini-review.

Homocysteine is a sulfur-containing amino acid, derived from the metabolism of dietary methionine. Homocysteine exists in various forms ¹ and is metabolised via two main pathways: remethylation and transsulfuration. Homocysteine remethylation to methionine maintains levels of SAM, the major methyl-donor, required in over 50 methylation reactions to DNA/RNA, proteins, phospholipids and other metabolites ². Whereas homocysteine catabolism via the transsulfuration pathway yields many other important sulfur metabolites (e.g. cysteine/glutathione, H₂S and taurine). Both of these pathways depend upon B vitamin-derived substrates/cofactors and are regulated by various physiological processes.

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 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.

Dysbiosis and D-lactate

Lactate (C₃H₆O₃) is an intermediate of carbohydrate metabolism, produced from pyruvate during lactic acid fermentation. Lactate can exist as two enantiomers/stereoisomers, L- and D-lactate, with L-lactate being the main form present in the body. Human cells produce L-lactate from glucose and alanine, while a small amount of D-lactate can be produced via the methylglyoxal pathway ¹. However gut microbes can produce both L- and/or D-lactate as major metabolic by-products ².

Elevated gut and/or blood levels of D-lactate are seen in several conditions and may be harmful ^1–3. An overgrowth of D-lactate-producing gut bacteria has also been implicated in ME/CFS ^4–6; although blood levels and biological interactions/associations have not yet been investigated, making the relevance unclear. Still, I think we can learn something from general research on D-lactate production by the gut microbiota.

Gut fermentation: modulation by diet and disease

The gut microbiome seems capable of influencing almost every system in the body. This occurs through direct microbe-immune interactions and microbial metabolites. The collection of all metabolites in the gut is known as the gut metabolome, which acts as a bridge between the gut microbiome and health/disease.

In ME/CFS there is some initial evidence for gut dysfunction - several studies indicate gut dysbiosis, infections and inflammation. These are all things which will affect gut metabolism, although there is no direct research here yet. Anecdotally however, altered ‘gut fermentation’ is often considered important. Here is a mini review of some recent research in this area - relating to evolution, diet and disease factors; some of which may be relevant in ME/CFS.

Salicylic acid: are we already taking aspirin?

Salicylic acid has a long history of use in medicine. Nowadays it’s a common ingredient in many skincare products and central component of the anti-inflammatory drugs aspirin (acetylsalicylic acid, ASA) and mesalazine (5-aminosalicylic acid, 5-ASA). Major pharmacological targets of salicylic acid include inhibition of COX (inflammation) and activation of AMPK (energy homeostasis).

Perhaps less well known, is that salicylic acid is a natural phenolic molecule widely distributed throughout nature. Salicylic acid is present in many plants; the name derives from the willow tree (Latin Salix) where it was originally obtained. Low levels of salicylic acid are also already present in the blood of animals, both carnivores and herbivores, some of which may come from internal biosynthesis and the rest from diet ¹.

Why is there autoimmunity in ME/CFS?

Several lines of evidence suggest autoimmunity is involved in ME/CFS.

Firstly, there are similarities in both the demography (e.g. female dominance) and general immunological milieu of ME/CFS with established autoimmune conditions ^1–4. Secondly, a large array of autoantibody responses to various signaling molecules, cell-surface receptors and intracellular molecules have long been reported in ME/CFS ^1,5,6. Note however, the number of people with these autoantibody responses varies widely, and their functional significance is not yet clear ⁷. Thirdly, several preliminary trials have shown that Rituximab (CD20 antibody which depletes peripheral B cells) can induce a moderate-major remission in around 60% of people (followed by relapse). The delayed response (2-7 months) seems consistent with the gradual removal of existing antibodies ^8,9, and autoantibodies to autonomic receptors do decline with clinical response ⁶.

However, why is there even autoimmunity at all? Why would the body start attacking itself? Bad luck, or system failure? Here is a little exploration of just that.

Is ME/CFS an immunodeficiency disorder?

ME/CFS has long been associated with infections. A large variety of viral ,bacterial and even protozoan infections have been implicated as triggers ^1–4 . There is also some evidence for persisting chronic infections - elevated antibody responses to several viruses are found in at least some CFS subsets ^1,2,5,6, and increased viral presence has been found in blood cells, muscle tissue and the GI tract ^7–10. CFS patients also appear to have an increased rate of upper respiratory tract infections (URTIs), as recently confirmed by objective virology and antibody levels ¹¹.

Autonomic dysfunction in ME/CFS: a role for the immune system?

Autonomic dysfunction (dysautonomia) is a major feature of ME/CFS ^1–4. The autonomic nervous system regulates many organs and things of relevance (e.g. blood flow, heart rate, immune function and energy metabolism) ⁵, so could contribute to multi-system dysfunction.

Are carbs really that bad?

Low carbohydrate (carb) diets are advocated for all kinds of health conditions (incl. ME/CFS), by Atkins/weight-loss/Paleo movements and some alternative MDs. These movements demonise carbs and oversimplify their role in health and disease. So here is a reappraisal of the humble carb.

Many things influence hydrogen sulfide metabolism

Some time ago hydrogen sulphide (H₂S) was suggested to play a role in ME/CFS ^1,2. Since then the general research literature has continued to forge ever more intricate and compelling links between H₂S, health and disease. Gone are the days of H₂S being exclusively viewed as an environmental toxicant; H₂S is now widely recognised as a major biological mediator (even in mitochondria! ³). Recently H₂S was even found to mediate the beneficial effects of dietary restriction on stress resistance and lifespan ⁴.

Why does gut dysbiosis always involve Enterobacteriaceae?

Several studies by Maes et al. have implicated Enterobacteriaceae in CFS. Specifically there are elevated antibody responses to the LPS of commensal Enterobacteriaceae which correlates immune markers and abdominal symptoms ^1,2. This suggests Enterobacteriaceae or their components (LPS) have translocated from the gut into the body (i.e. leaky gut) and stimulated an immune response. This post compiles some factors found to influence Enterobacteriaceae growth and translocation in other diseases, which may also be of some relevance in ME/CFS.

Contrabiotics block intestinal pathogens

Foods can beneficially shape the gut microbiota through their prebiotic or antibiotic/antimicrobial effects. On the other hand some food components are able to block the adhesion and invasion of undesirable bacteria, thereby promoting their passage out the gut, and these have recently been termed contrabiotics ¹. Contrabiotics have their most obvious application with infectious diarrhea and inflammatory bowel disease, but might also have some relevance in general dysbiosis and small intestinal bacterial overgrowth (SIBO).

Immune stability requires microbial diversity?

The gut microbiota regulates many aspects of host physiology, including immunity. This has long been emphasised by germ-free (i.e. microbiota-free) mice, which have a grossly underdeveloped immune system and enhanced susceptibility to infection, among other physiological deficits. More recent research is gradually showing how gut microbes influence every major immune cell type, from their birth in bone marrow (i.e. haematopoiesis), to the differentiation and functional activity/priming of immune cells throughout the body (e.g. gut, blood, spleen, nervous system, etc.).

Carotenoids and skin colour: a redox-dependent display of health?

There has been some interesting research recently on carotenoids and skin colour ^1–3, which has also made it into the mainstream media. The potential links between carotenoids, skin colour and health intrigue me, as explained below.

Diarrhea resets the gut microbiome

I read this recent paper with interest: ‘Gut microbial succession follows acute secretory diarrhea in humans’ (mBio, 19 May 2015) ¹. This study used current techniques (i.e. 16s rRNA and metagenomic sequencing) to measure the recovery of the gut microbiota following acute diarrhea caused by Vibrio cholerae (Cholera) and enterotoxigenic E. coli (ETEC). Recovery of the gut microbiota took 30 days, 4 major stages/steps were identified, and these were explained by ecological theory and metagenomics ¹, as described below: