Stress-Induced Transcriptomic Changes in Females with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Reveal Disrupted Immune Signatures

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, complex multi-organ illness characterized by unexplained debilitating fatigue and post-exertional malaise (PEM), which is defined as a worsening of symptoms following even minor physical or mental exertion. Our study aimed to evaluate transcriptomic changes in ME/CFS female patients undergoing an exercise challenge intended to precipitate PEM. Our time points (baseline before exercise challenge, the point of maximal exertion, and after an exercise challenge) allowed for the exploration of the transcriptomic response to exercise and recovery in female patients with ME/CFS, as compared to healthy controls (HCs). Under maximal exertion, ME/CFS patients did not show significant changes in gene expression, while HCs demonstrated altered functional gene networks related to signaling and integral functions of their immune cells. During the recovery period (commonly during onset of PEM), female ME/CFS patients showed dysregulated immune signaling pathways and dysfunctional cellular responses to stress. The unique functional pathways identified provide a foundation for future research efforts into the disease, as well as for potential targeted treatment options.

Keywords: chronic fatigue syndrome; dysregulated immune pathways; myalgic encephalomyelitis; post-exertional malaise; transcriptomics.

Figure 1

Metascape [29] express analysis of all 102 differentially expressed genes between HCs at T0 and T1. Each node represents an enriched term. These terms are colored by cluster ID to indicate which cluster they belong to. Cutoff values included a p-value of <0.01, a minimum count of 3, and an enrichment factor > 1.5. GO biological processes, KEGG pathways, Reactome gene sets, CORUM complexes, and canonical pathways from MSigDB were included in the search.

Figure 2

Metascape [29] express analysis of differentially expressed genes in ME/CFS patients and HCs between T1 and T2. (A) Each node represents an enriched term, and colors of the nodes are explained in (C). The larger the representation of the color the more differentially expressed in each cohort. Cutoff values included a p-value of <0.01, a minimum count of 3, and an enrichment factor of >1.5. GO biological processes, KEGG pathways, Reactome gene sets, CORUM complexes, and canonical pathways from MsigDB were included in the search. (B) Nodes are colored by rations ME/CFS to HC. The red color indicates functional pathways in ME/CFS patients while the blue color indicates functional pathways in HCs. (C) Heatmap of enriched terms across lists of DEGs between T2 and T1 in PBMC of ME/CFS patients and HCs.