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.

Ascorbate supports folate?

Folate (vitamin B₉) is an essential carrier of 1-carbon (1C) units for DNA synthesis and methylation. More specifically, this involves reduced tetrahydrofolate (THF; H₄PteGlu) derivatives which are highly sensitive to oxidation; initially to dihydrofolate (DHF; H₂PteGlu), before eventually being destroyed by irreversible scission of the C₉–N₁₀ bond. It has long been known that the antioxidant ascorbic acid (vitamin C) can reduce DHF (to THF) and protect folate from degradation ¹. Further, in humans, dietary ascorbate and THF synergistically correlated RBC folate ², and ascorbate supplementation boosted the blood response to both natural 5-methyl-THF (over 8 hours) ³ and synthetic folic acid (after 45 days) ⁴, supporting physiological relevance.

Solid vs. liquid fat—a biophysical perspective

As reviewed previously, dietary fats have differential effects on the body in relation to various mechanisms. This post explores why from a more fundamental perspective.

The body is largely an aqueous environment, compartmentalised by amphipathic lipid barriers/membranes containing specific hydrophobic fatty acids; and similarly, lipids are transported in amphipathic lipoproteins and metabolised by water-soluble enzymes (e.g. lipases). However, dietary fats have diverse structures and physiochemical properties. Foremost, unsaturated fatty acids (UFAs) are liquid at body temperature (37°C), while saturated fatty acids (SFAs) have higher melting points, which increase with chain length, resulting in short–medium chain fatty acids (e.g. C3–11:0) being liquid and longer chains solid; with a parallel relationship to water insolubility (Wiki). Could these basic characteristics underlie some of their differential effects?

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.

Redox regulation of immunity

This data summary table collects studies showing how redox and Nrf2 regulate immunity and infections. I may finish a full post on this at some point.

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.

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.

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.

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.

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.