Exploring the Role of Gut Microbial Tryptophan Metabolism in Patients with Myalgic Encephaloyelitis/Chronic Fatigue Syndrome

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease that affects patients’ immunologic and neurologic functioning. The primary symptom is post-exertional malaise, which is a disproportionate exacerbation of other symptoms and triggered by physical activity or psychological stress. The condition is often accompanied by comorbidities, including gastrointestinal conditions such as irritable bowel syndrome (IBS) and irritable bowel disease (IBD). Despite the substantial impact on patients’ quality of life, ME/CFS remains poorly understood, including the precise pathogenesis and identification of diagnostic signatures, which impedes diagnosis and therapy of ME/CFS. Increasing evidence suggests a potential role of chronic low-grade inflammation and microbiome dysbiosis in the pathophysiology of the disease. However, the functional metabolic contributions of the gut microbiome to ME/CFS remain largely unexplored. The gut microbiome has been demonstrated to possess the capacity to degrade tryptophan into a variety of bioactive molecules, including indoles. These metabolites have been shown to exert immunomodulatory and neuroactive effects, influencing inflammatory regulation and gut-brain signaling.
The objective of this project is to characterize ME/CFS by analyzing the degradation of tryptophan in the gastrointestinal tract. It is hypothesized that the altered gut microbial tryptophan metabolism contributes to the pathogenesis of ME/CFS by shifting the production of bioactive indole derivatives. Preliminary results from our previous research have shown altered relative pathway abundances for the production of several degradation products in patients of ME/CFS compared to healthy individuals. These metabolic changes may be indicative of a shift in the gut microbial composition and functioning of the gut microbiota, which could, in turn, contribute to immune dysregulation or neurological symptoms in individuals with ME/CFS.
The present project will utilize metagenomic data from the DMP cohort to perform in silico reconstruction of microbial networks using the command-line tool gapseq. To this end, genome-scale metabolic models will be constructed to estimate the relative abundance of tryptophan degradation pathways and to simulate interactions within the microbial communities. This methodological framework facilitates the identification of functionally relevant microbial signatures. The findings will contribute to the growing understanding of ME/CFS as a multi-system disorder with strong links to gut microbial function and host-microbe interactions.