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.

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.

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.

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).

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: