ME/CFS – New review advocates a spotlight on both bacteria and viruses within the gut

Researchers on the Norwich Research Park have published a detailed review of evidence for a role of the gut microbiota and virome in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).  The review, published in The Journal of Clinical Medicine, examines mounting evidence pointing towards an infectious and autoimmune basis for ME/CFS, with emphasis placed on the impact of the bacterial and viral communities resident within our gut. The review was written by medical students Navena Navaneetharaja and Verity Griffiths, with Professor Simon Carding and Professor Tom Wileman from the University of East Anglia Norwich Medical School and Institute of Food Research, all based at the Norwich Research Park.  Below, Navena blogs about this recent publication:

Our recent review highlights current understanding of the role of infection in triggering Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We focus on the origin of persistent immune-related symptoms in the condition and describe mechanisms that may explain underlying immune impairment and potential autoimmune processes in ME/CFS, where B cell depletion therapy is of significant therapeutic benefit. We also provide focus for further research by exploring the potential impact of the intestinal microbiome and virome using sensitive study designs.

Numerous attempts have been made to identify viruses as a trigger of ME/CFS. We highlight discrepancies in research findings relating to difficulties in detecting active infections and discriminating them from reactivation of latent infection as well as inconsistencies in disease classifications, patient inclusion/exclusion criteria and the use of different analytical methodologies.

In addressing increasing interest in establishing the condition as an autoimmune disorder, we propose the gut as an attractive and important source of autoreactivity with the potential to cause chronic debilitating disease. We present the findings from culture-based studies and the one study that has utilised sensitive next-generation sequencing technology to profile the microbiota in ME/CFS. Again, we recognised that these studies lack apparent consistency, from patient-related issues such as inconsistent phenotypic classifications, small and often unpowered sample numbers and technical issues related to differences in the reliability, sensitivity and coverage of microbial sequence detection, different sequencing platforms and the reliance on single samples and time points of analysis that can only provide a snapshot of microbiota compositions. Despite demonstrations of altered diversity and stability of the intestinal microbiota in ME/CFS, it is not yet possible to say that a specific microbial signature exists in ME/CFS. Care must also be taken in attempting to establish such a disease microbiota signature in view of the heterogeneity in symptoms and subgroups presented in ME/CFS. Furthermore, the absence of a mouse model that faithfully reproduces the hallmark features of human ME/CFS is a constraint in determining if or how the microbiota contributes to the pathogenesis of ME/CFS.

Electron Microscopy Image of Virus-Like Particles from ME/CFS patient showing Filamentous Bacteriophages. Microscopy Image taken by Kathryn Cross. Virus Like Particle Purification by Nadine Davies.

Electron Microscopy Image of Virus-Like Particles from ME/CFS patient showing Filamentous Bacteriophages. Microscopy Image taken by Kathryn Cross. Virus Like Particle Purification by Nadine Davies.

Microbiome studies have to date almost exclusively focused on defining changes in bacterial population; recently however, the remit has broadened to assess the viral components of the microbiota. So far, the impact of the virome in healthy and disease states has received very little attention, but it is possible that bacteriophages specifically, can induce indirect changes to bacterial populations, or direct effects following stimulation of the immune system if they cross gut epithelial barriers. We stress that profiling bacterial communities will strengthen any association between virome composition and ME/CFS and propose that phages shape the bacterial microbiota through density-dependent predation, a mechanism by which actively replicating or reactivating phages lyse their bacterial hosts, change the abundance of specific bacterial species and induce dysbiosis.

We also briefly present expanding evidence of the role intestinal microbiota in influencing the brain and behaviour as part of the gut-microbiota-brain axis. The effect of the intestinal microbiota on the central nervous system and cognitive function represents exciting opportunities for elucidating the manifestation of the core ME/CFS symptoms. Further studies are required investigating the interactions between keystone bacterial species, phages and the mucosal immune responses that may provide a more complete picture of the intestinal environment in ME/CFS.

Overall, current studies have failed to identify a distinct microbial signature that establishes a pathogenic role of the intestinal microbiota in ME/CFS. The next steps in the Carding lab are to correlate phage populations in patients with severe disease compared to house-matched controls. This work has the potential to elucidate more distinct subpopulations within current ME/CFS classifications and of upmost importance, has the potential to influence therapeutics, providing much-needed approaches in preventing and managing a disease in need of confronting.

Written by Navena Navaneetharaja, June 2016.

Reference: Navaneetharaja N., Griffiths V., Wileman T., Carding S.R. (2016). A Role for the Intestinal Microbiota and Virome in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), J. Clin. Med. 5, 55; doi:10.3390/jcm5060055 [/box/

This research is supported by Invest in M.E.

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The programme receives funding from the BBSRC - Biotechnology and Biological Sciences Research Council and involves leading researchers from the Quadram Institute Bioscience, Imperial College, University of East Anglia and St. Mark's Hospital and Academic Institute

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