Thursday, 4 July 2013

Gut microbiota regulation of host immune function - implications for ME/CFS?

Interactions between the gut micrbiota and host immune function have been the subject of several recent reviews 1–5. This emerging field of research offers a new angle on conditions associated with aberrant inflammation and immune activity. I have been following this research with much interest and have written a little below with implications for ME/CFS.

The gut microbiota
The gut contains of trillions of microbes from hundreds of species, collectively known as the ‘gut microbiota’, while all their genes are referred to as the ‘gut microbiome’. The gut microbiota is dominated by bacteria from four main phyla (i.e. Firmicutes, Bacteroidetes, Actinobacteria and Proteobacteria), and also contains lower levels of yeasts and archaea 6–8. Resident gut microbes benefit the body in various ways, such as by extending digestive capabilities, producing metabolites which nourish the colon, providing competitive resistance to pathogenic microbes, and providing complex stimuli for immune system development.

Immune surveillance of bacteria
As well as containing the major microbiota of the body, the gut also harbours the largest reservoir of immune tissue in the body - the gut-associated lymphoid tissue (GALT). This immune tissue aggregates in Peyer’s patches, a major site for immunological surveillance of the gut lumen. Microbes have a different composition to human cells and express various pathogen-associated molecular patterns (PAMPs) which can be detected by the immune system. Some more familiar examples include lipopolysaccharide (LPS), lipoteichoic acid, flagellin, peptidoglycan and DNA. PAMPs are detected by pattern recognition receptors (PRRs) such as the membrane-associated toll-like receptors (TLR) and cytoplasmic NOD-like receptors (NLR). These receptors are expressed on cells present in the gut barrier such as enterocytes, intraepithelial lymphocytes and dendritic cells. Bacteria/antigen can also be internalised by M cells and presented to dendritic cells residing below the gut barrier in the lamina propria.

Gut microbiota stimulation of host immune development
The gut microbiota crucially regulates the maturation, balance and activity of the GALT and systemic immunity. Germ-free mice have smaller Peyer’s patches, fewer immune cells (e.g. plasma cells and intraepithelial lymphocytes), a T helper response skewed toward Th2, impaired IgA secretion and other immunological deficiencies 2,9. Similarly suppression of different bacterial communities with various antibiotics can alter local and systemic immune activity 2,10,11. Accordingly germ-free or antibiotic-administered mice have increased susceptibility to enteric infection, common viruses and aberrant inflammation 12.

Gut microbiota stimulation of host immune tissue occurs both via interactions with PRRs and microbial metabolites, with different microbes promoting different immune responses. In simple terms, the presence of a healthful gut microbiota can be thought of as essentially priming the immune system to improve its performance against infectious threats (e.g. Th1 and Th17). Although some recent findings do suggest some particular viral infections can actually be promoted by the presence of gut bacteria (specifically by interactions with LPS) 13. The gut microbiota is also a hugely important source of immune-suppressive and anti-inflammatory stimuli, which promotes immune tolerance of gut microbes and restrains systemic immune activity (e.g. Treg).

Microbiota-immune interactions in disease
Given that different microbes stimulate difference responses, it is easy to see how deviations in microbiota balance could greatly influence local and systemic immunity. The balance of the gut microbiota is strongly influenced by many factors such as diet, stress, antibiotics, and drugs or conditions impacting upon basic gut secretions and motility. Changes to gut bacterial balance have been noted in many conditions where they may contribute to aberrant immune function 1–3. For example segmented filamentous bacteria (SFB) have been shown to induce Th17 responses and increase autoimmune responses in animal models of multiple sclerosis and rheumatoid arthritis. This may be augmented by a lower abundance of bacteria (e.g. Bifidobacteria and Bacteroides) which can stimulate Tregs and help moderate excessive inflammation and immune activation 2. Bacterial shifts which favour Th2 activity may predispose to IgE-mediated allergy 1,2,11. Excessive levels of gram-negative bacteria (e.g. E. coli) and the LPS they contain may promote a pro-inflammatory tone in the gut 3,14 and systemically upon translocation into peripheral blood 15. Loss of bacterial stimulation of systemic NK cell, neutrophil and general phagocytic activity may increase susceptibility to infection 10,16. These are just some examples.

While negative changes to the gut microbiota may promote disease, positive changes may ameliorate disease. This can be achieved mainly by prebiotics, probiotics and microbiota transplants. Probiotic immunomodulation may be mediated directly or indirectly (e.g. by antagonism of other bacteria or prevention of bacterial translocation). Current probiotics typically contain gram-positive Lactobacillus and Bifidobacteria spp., although in the future could contain many other genera, species and strains. Current research is hindered by the fact that bacteria vary at the strain level in their immune modulating effects. For instance 20 different Lactobacillus plantarum strains may have distinctly different immune modulating effects 17. This means that even probiotics with similar levels and types bacteria are not all equal. Often the most well-selected and studied strains become patented (e.g. Bifidobacteria infantis 35624) and are only available commercially from one brand (i.e. Align).

Microbiota-immune interactions in ME/CFS
To date the gut has received relatively little attention in ME/CFS research. However several studies have suggested that dysbiosis occurs in ME/CFS 18–20. This may relate to other changes in the gut reported in ME/CFS such as the presence of infections, immune cell infiltrate, and impaired barrier function 19,21,22. Systemic immune dysregulation is also a hallmark of ME/CFS. Changes in the expression of inflammatory cytokines and immune cells have been reported although vary between studies, patients and time points 23,24. Most consistently ME/CFS is associated with reduced NK cell activity which may increase susceptibility to infections 24. A recent cytokine network analysis also uncovered a Th2 biased immune response in ME/CFS 25. The suggestion that changes to the gut microbiota may relate to those in systemic immune function in CFS was initially proposed by Logan et al. 18. No study has yet tested this idea and it would be interesting to see if there are any significant correlations. For instance levels of several different bacteria were shown to relate to NK cell activity and phagocytosis in healthy elderly volunteers 16. The only correlation reported in CFS so far is between immune responses to the LPS of gram-negative bacteria and the expression of inflammatory cytokines and markers of cell-mediated immunity 22.

The importance of changes in the gut to systemic pathology in ME/CFS is further supported by related therapies. Different probiotic approaches have been shown to improve emotional symptoms 26 and cognition in CFS 27. Moreover bacteriotherapy was reported to result in long-term remission of CFS in subjects with comorbid IBS 28. The ability of gut bacteria to modulate systemic inflammatory signaling was recently demonstrated in CFS. Supplementation with B. infantis 35624 was shown to decrease blood levels of pro-inflammatory cytokines (i.e. IL-6 and TNFα) and C-reactive protein (CRP) 29. B. infantis 35624 likely achieves this effect through interactions with dendritic cells and promotion of anti-inflammatory Tregs 30. It is notable that Tregs have recently been found to be increased in ME/CFS, which may represent a compensatory response to limit chronic inflammation 23,31. Finally a Leaky gut type treatment has also been shown to improve symptoms and even result in remission in some cases of CFS 32,33.

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