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.

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.

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.

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.

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: