Natural Killer Cells and Microbiome

A reader with ME/CFS wrote:

One of the many tests over the years has been Natural Killer cell function. Many CFS patients from what I understand have low NK cell function.
 Any clue how this is related to microbiome and ways to possibly reverse this or restore NK function? Could this just be due to gut dysregulation?

This has been my assumption for over 6 years. The following is what I could find that has been documented:

  • “Some effects of modulation by probiotics include cytokine production by epithelial cells, increased mucin secretion, increased activity of phagocytosis, and activation of T and natural killer T cells, stimulation of immunoglobulin A production and decreased T cell proliferation. Intestinal microbiota has a major impact on the systemic immune system. ” [2019]
  • ”  Some probiotics have been found to regulate immune responses via immune regulatory mechanisms. T regulatory (Treg) cells, T helper cell balances, dendritic cells, macrophages, B cells, and natural killer (NK) cells can be considered as the most determinant dysregulated mediators in immunomodulatory status.  ” [2019]

The gut microbiota is a key element to support host homeostasis and the development of the immune system. The relationship between the microbiota and immunity is a 2-way road, in which the microbiota contributes to the development/function of immune cells and immunity can affect the composition of microbes…. Our results indicate that intestinal NKT cells are important modulators of intestinal homeostasis and that gut microbiota composition may be a potential target in the management of inflammatory bowel diseases.  

Fecal IgA Levels and Gut Microbiota Composition Are Regulated by Invariant Natural Killer T Cells. [2019]

The review compiles data from multiple studies on the role of microbiota in the innate immune response and the development and differentiation of CD4+ T cells, a major component of the adaptive arm of the immune response. As a result of dysbiosis, invariant natural killer T cells may induce T helper 2 cell differentiation and immunoglobulin E isotype switching through the release of Interleukin-4 and Interleukin-13. Furthermore, degradation of immunoglobulin A antibodies, increased circulating mast cells and basophils, and inflammation are among other mechanisms by which dysbiosis can induce or exacerbate asthma. 

The Role of Gut Microbiota in Atopic Asthma and Allergy, Implications in the Understanding of Disease Pathogenesis. [2019]

Some bacterial species (e.g. Prevotella, Citrobacter rodentium, Collinsella aerofaciens, Segmented filamentous bacteria) participate in the creation of the pro-inflammatory immune status, presumably via epitope mimicry, modification of self-antigens, enhanced cell apoptosis mechanisms, and destruction of tight junction proteins and intestinal barrier integrity, all leading to the development and maintainance of inflammatory arthropathies… The underlying mechanisms include dysbiosis-mediated changes in the functional activity of the intestinal immune cell subsets, such as innate lymphoid cells, mucosa-associated invariant T cells, invariant natural killer T cells, T-follicular helper and T-regulatory cells. In turn, disturbed functionality of the gut-associated immune system is shown to promote the overgrowth of many bacteria, thus establishing a detrimental vicious circle of actively maintaining arthritis.

A cross talk between dysbiosis and gut-associated immune system governs the development of inflammatory arthropathies. [2019]

Recent evidence indicates that memory is also present in the innate immune cells such as monocytes/macrophages and natural killer cells. These cells exhibit pattern recognition receptors (PRRs) that recognize microbe- or pathogen-associated molecular patterns (MAMPs or PAMPs) expressed by the microbes. Interaction between PRRs and MAMPs is quite crucial since it triggers the sequence of signaling events and epigenetic rewiring that not only play a cardinal role in modulating the activation and function of the innate cells but also impart a sense of memory response. 

Potential Role of Gut Microbiota in Induction and Regulation of Innate Immune Memory. [2019]

Bottom Line

I stopped following studies on natural killer cells a few years ago because the evidence pointed to them being a secondary effect of issues with the microbiome. In other words, a symptom and not a cause. Symptom relief is good but it does not deal with the root cause. Altering natural killer function by drugs do have a chance of causing a cascade into the microbiome ( it is a 2-way road ), unfortunately drugs also have unknown side effects. I have focused on the microbiome because it is easier to do in one sense (no need to talk a MD into prescribing, no fight with insurance company to pay for it), it is also more complex to do — which is why I ended up writing a fuzzy logic artificial intelligence system to do it.