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.

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.

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.

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.

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: