Does the microbiome and virome contribute to myalgic encephalomyelitis/chronic fatigue syndrome?

Abstract

Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) (ME/CFS) is a disabling and debilitating disease of unknown aetiology. It is a heterogeneous disease characterized by various inflammatory, immune, viral, neurological and endocrine symptoms. Several microbiome studies have described alterations in the bacterial component of the microbiome (dysbiosis) consistent with a possible role in disease development. However, in focusing on the bacterial components of the microbiome, these studies have neglected the viral constituent known as the virome. Viruses, particularly those infecting bacteria (bacteriophages), have the potential to alter the function and structure of the microbiome via gene transfer and host lysis. Viral-induced microbiome changes can directly and indirectly influence host health and disease. The contribution of viruses towards disease pathogenesis is therefore an important area for research in ME/CFS. Recent advancements in sequencing technology and bioinformatics now allow more comprehensive and inclusive investigations of human microbiomes. However, as the number of microbiome studies increases, the need for greater consistency in study design and analysis also increases. Comparisons between different ME/CFS microbiome studies are difficult because of differences in patient selection and diagnosis criteria, sample processing, genome sequencing and downstream bioinformatics analysis. It is therefore important that microbiome studies adopt robust, reproducible and consistent study design to enable more reliable and valid comparisons and conclusions to be made between studies. This article provides a comprehensive review of the current evidence supporting microbiome alterations in ME/CFS patients. Additionally, the pitfalls and challenges associated with microbiome studies are discussed.

Keywords: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Virome; microbiome.

Graphical Abstract. The gut lumen contains large numbers of different bacteria which generate metabolites that together help maintain mucosal barrier function and reduce inflammation. The gut lining also contains enteroendocrine cells that secrete hormones which influence the enteric nervous system. These cells sense metabolites in the gut creating a microbiome–brain axis. Each bacterium can be infected by a bacteriophage and this can influence the microbiota. In this example, a blue bacteria is infected by a blue lytic phage and killed. The blue bacteria and its beneficial metabolites are lost from the microbiota. A second yellow bacteria is infected by a yellow prophage which integrates into the bacterial genome giving a selective advantage. Yellow bacteria and their harmful metabolites (red) predominate leading to dysbiosis, inflammation and altered enteric nervous system.

Figure 1. TEM images of Caudovirales from faecal water

(A–C) Myoviridae and (D,E) Siphoviridae. Imaging completed by S.-Y.H. and K.C.

Figure 2. VLP isolation protocol

Overview of VLP isolation protocol involving filtration (1,2) and centrifugation (3). Following isolation of concentration VLPs, DNA is extracted (4), sequencing and (5) bioinformatic tools applied to determine virome community composition.

Figure 3. Important considerations in designing ME microbiome studies

Recommendations for designing a microbiome study and important questions to consider