From saturated fat to arterial plaque: cholesterol and beyond

This article is a work in progress and regularly updated as I study this topic.

Cardiovascular diseases (CVDs) are still the leading cause of death globally (OWID), but vary markedly by demographics and in relation to various lifestyle factors. In particular, in the second half of the 20^th century, the seminal Seven Countries Study illuminated associations with diet, especially saturated fatty acids (SFAs), which at 50-year follow-up remain strongly associated with coronary heart disease mortality (n=16 cohorts, r=0.92) ¹. Many other studies have further probed this relationship, and while some inconsistency emerged, so has context. For instance, some prospective cohort studies and meta-analyses thereof fail to find independent associations with SFA intake ²; however, studies performing substitution analyses generally report that replacing SFAs (mainly from animals) with unsaturated fatty acids (UFAs; from plants and fish) or complex carbohydrates (from whole grains) lowers CVD risk and mortality (e.g. US ^3–8, Europe ^9–11 and pooled ^12,13). Importantly, in the US it was also revealed that SFAs are typically replaced by refined grains and added sugars, which are also associated with CVD, potentially explaining prior null findings ⁴. In addition, dietary SFAs are also highly correlated with animal-sourced MUFAs (r=>0.8), which may have obscured favourable associations seen only with plant sources ^7,8.

Redox and the gut microbiome

Host redox biology shapes the gut microbiome and vice versa; relationships which may be important in oxidative stress-associated disease and ageing. Here’s an overview…

Gut oxygen

Reduction-oxidation (redox) processes play fundamental roles in biology, while shifting redox environments have shaped the evolution of life on this planet. The primordial earth was virtually anoxic when life appeared ~3.8 billion years ago, with the advent of photosystem II (i.e. early photosynthesis) and geochemical changes eventually increasing atmospheric oxygen (O₂) (i.e. Great Oxidation Event). This exposed life to a double-edged sword: a toxic oxidant and an energetically favourable respiratory acceptor. Consequently, while some committed anaerobes became confined to anoxic zones, others went aerobic, creating the present dichotomy ^1,2. Moreover, aerobic metabolism facilitated the evolution of complex multicellular metazoa ^3,4, and novel biogeographical redox environments therein. In particular, the human gut is populated by trillions of microbes, predominantly anaerobes, which have co-diversified with us acquiring traits such as O₂ intolerance ⁵.

Differential effects of fats on gut–host health

Dietary fats are ubiquitous and essential, while their quantity and quality modulate health. Recently, effects on the gut microbiome are being revealed. This post explores their differential effects on the gut–host dialog and underlying mechanisms relevant to many diseases.

Dietary fats appear to differentially affect human physiology; and perhaps most notoriously in the case of cardiovascular disease (CVD), the leading cause of death globally. For instance, in large observational studies, substitution analyses suggest opposing effects of saturated vs. monounsaturated and polyunsaturated fatty acids (i.e. SFAs vs. MUFAs and PUFAs, respectively) on CVD ^1–3; a relationship tested and supported by meta-analyses of randomised controlled trials (RCTs) ⁴, and referenced in many dietary guidelines. Further, in 3–4 week RCTs on healthy adults, adjusting the habitual palmitate/oleate ratio (i.e. the most abundant SFA/MUFA) affects blood/tissue lipids, alongside energy metabolism, immune activity and brain function ^5–11. And even single meals with different fats can have markedly different effects on postprandial cardiometabolic biomarkers ¹².

Oxidative ageing: from proximate to ultimate causes

Oxidative stress seems really important in age-related decline and disease—but what causes it? Here I’ve tried to express a broadening perspective, by exploring its core, context and ultimate causes; and largely anchored in human studies where possible.

We all die—what matters is how. While human life expectancy has increased, non-communicable diseases are now the major cause of disability and death globally (WHO and OWID). These are mostly age-related diseases (e.g. CVD, cancer, COPD, dementia, etc.), which develop slowly over time, and coexist as multimorbidity (e.g. most people >65 in US/UK ^1,2); resulting in functional decline/frailty and socioeconomic burden (i.e. ↓ productivity, ↑ sick care). This situation is growing globally, as populations are ageing, and diseases occur earlier—so we may live longer but sicker ¹. Moreover, this invisible epidemic underlies susceptibility to (communicable) infectious diseases, such as COVID-19 ³, elevating chronic disease to acute threat.

Synthetic vs. organic B12 metabolism—is cyanocobalamin inferior?

Cyanocobalamin is a common synthetic form of vitamin B₁₂ used in supplements and fortified foods—how does it compare to natural forms?

Vitamin B₁₂ (cobalamin, Cbl) has the most complex structure of all vitamins, which consists of a central cobalt atom bound to a corrin ring, a displaceable lower (a) ligand (5,6-dimethylbenzimidazole, DMBI) and a variable upper (b) ligand (e.g. cyano-, methyl-, 5’-deoxyadenosyl-, etc.) ¹ (see).

Cbl was originally isolated as cyanocobalamin (CNCbl), which was later recognised as an artefact arising from extraction methods ². Further advances led to identification of natural forms in microbes, animals and humans ^2–5, where methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl) serve as vital coenzymes for methionine synthase (MS) and methylmalonyl-CoA mutase (MCM), respectively.

Supplement concerns—an appeal to nature

I’ve become increasingly concerned about the efficacy and safety of some typical nutritional supplements—here’s why.

Initially, my concern is a logical appeal to nature. Food contains a complex matrix of chemicals in the balance and structure of life, to which our physiology (e.g. digestion, metabolism and microbiome) is adapted. By comparison, supplements supply concentrated food ingredients, to an extreme of isolated chemicals in unnatural forms and mega doses. My concern is fed by some studies reporting on potentially negative effects and long-term health outcomes (see table); common themes are the use of synthetic/isolated nutrients and high doses (note their use also in ME/CFS studies ^1–5). Could these deviations from nature impair bioactivity or induce imbalances which limit efficacy and introduce risk? Some specific examples are discussed below.

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.

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.

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.).

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: