Jaa-Kwee, Amber Fung Yi Li (2024) Investigation of the Gut Microbiome and Host Metabolome in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. PhD thesis, Victoria University.

Abstract

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a devastating, complex chronic disease with ambiguous aetiology and pathophysiology. There are neither confirmed specific biomarker/s nor clearly defined biological mechanism/s currently available that enable routine, accurate, and efficient diagnosis. ME/CFS individuals suffer from a myriad of debilitating symptoms including profound fatigue and post-exertional malaise and are often affected by comorbid fibromyalgia (FM) and irritable bowel syndrome (IBS). The heterogeneous, multisystemic nature of the condition and numerous diverse comorbidities is a major point of confusion. It is unclear whether these varying presentations in ME/CFS are phenotypes of the same underlying mechanisms or a combination of different diseases and their pathophysiology. The challenge in distinguishing between ME/CFS cases and grappling with the variability in clinical practice and research often means that individuals are confronted with years without a proper diagnosis and adequate health care. To address these issues, this project focused on the gut microbiome, host metabolome, and its relationship (gut microbe-derived metabolites). Overall differences in the gut microbiome and host metabolome have been observed between ME/CFS and non-ME/CFS cohorts; however, not to the level of detail presented here. This thesis also sought to objectively address and explore the bearing of the FM and IBS comorbidities in ME/CFS within this framework. Material and Methods: 40 ME/CFS and 43 non-ME/CFS participants were recruited. All participants provided faecal and urine samples with questionnaire responses for Part One of the study. A selection of these participants (28 ME/CFS and 28 non-ME/CFS) provided a blood plasma and urine sample for Part Two. Participant metadata was used to form the comparative groups of interest described and discussed throughout this thesis: A) ME/CFS overall versus Control, B) ME/CFS with FM versus ME/CFS without FM, C) ME/CFS with IBS versus ME/CFS without IBS, and D) age-matched ME/CFS with IBS versus ME/CFS without IBS. All biological samples underwent a 1H-NMR and LC-MS/MS targeted metabolomic analytical workflow to characterise the host metabolome with polar metabolites. The faecal samples were used to provide insight into the gut microbiome with the usage of culture microbiology with MALDI-TOF MS, and 16S rRNA gene amplicon sequencing. PICRUSt2 and MiMeDB pipelines were used with the 16S rRNA sequences and culture data outcomes, respectively, to investigate the metabolic functionality and metabolite profiles of the gut microbiome. Across all datasets, univariate and multivariate statistics were used to evaluate the comparative groups. Results and Conclusions: Investigating the heterogeneity and intricate host-microbiome relationship in ME/CFS requires a multi-omic and multi-disciplinary approach. There is value in using complementary approaches and techniques including expanding coverage and data capabilities. The comparisons across the datasets indicate that due consideration needs to be given to the presence or absence of FM and IBS comorbidities in ME/CFS. Overall, there are nuanced and subtle differences and similarities in the patterns and features that emerge from the gut microbiome and host metabolome findings. This may have far-reaching implications for disease pathophysiology and mechanisms, and the downstream establishment of preventative and management options. While the findings from this project only display a snapshot in time and cannot prove causality or prognosis; it offers an objective framework and pragmatic workflow for approaching the multifaceted issues in ME/CFS.

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