Wallis, Amy (2017) Microbiota-Gut-Brain Interactions in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Focus on Neuropsychological Symptoms and Sex Comparisons. PhD thesis, Victoria University.

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, disabling condition with debilitating fatigue and neuroimmune symptoms. Consensus about diagnosis, pathogenesis and efficacious treatments for ME/CFS are yet to be elucidated. Advances in the understanding of microbiota-gut-brain interactions in healthy and disease states, combined with evidence of gastrointestinal symptoms and gut dysbiosis in individuals with ME/CFS has directed investigation towards the role of enteric microbiota in this condition. The body of work presented in this thesis includes five publications based on reviews and empirical research conducted over the past 3.5 years. The first review paper (Paper 1) found preliminary evidence to support the proposal that microbiota-gut-brain interactions may contribute to sleep, mood and cognitive symptoms but revealed gaps in knowledge with few empirical studies that have investigated commensal microbiota in patients with ME/CFS. Papers 2 and 3 describe the results of a correlational analyses between microbiota and ME/CFS symptoms in a cross-sectional, retrospective study of 274 ME/CFS patients. A notable finding from this study included sex-specific interactions between gut microbiota and symptom expression in ME/CFS, signaling possible sex differences in microbial function. The systematic review examining symptom and etiological overlap between D-lactic acidosis and ME/CFS in Paper 4, revealed preliminary support for the hypothesis that subclinical concentrations of D-lactate from bacterial dysbiosis may be a mechanism contributing to several ME/CFS symptoms (including fatigue, neurocognitive impairments, pain, sleep disturbances, motor disturbances, gastrointestinal abnormalities, cardiovascular, respiratory, thermostatic, and comorbid mood and behavioural disturbances). The review highlighted the gaps in knowledge without measurement of D-lactate concentrations in ME/CFS samples. Paper 5 presents the results of an open-label, repeated-measures trial examining the efficacy of a 4-week treatment (alternate weeks of Erythromycin and D-lactate free probiotic) for an overgrowth of commensal Streptococcus species in 44 adult patients with ME/CFS. Large time effects were shown including a reduction in Streptococcus count and improvement on several clinical outcomes (sleep, cognition and total symptoms) for the total sample at post intervention. Ancillary results highlighted individual variability in microbial changes and the importance of other genera with changes in Bacteroides, Bifidobacteria and Clostridium and associated with clinical changes in males. In combination, the analysis of literature and results from both cross-sectional and experimental studies substantiate the theoretical premise that microbiota and gut dysbiosis contribute to specific neuropsychological symptoms in some ME/CFS patients. Our mechanistic understanding of gut dysbiosis will be advanced by multidisciplinary investigations that include assessment of clinical symptoms, the microbiome (combined sequencing and culture techniques), metabolites, oxidative and inflammatory markers, and immune profiles that help identify possible factors contributing to, precipitating or perpetuating imbalances in microbial composition. These advances may help clarify diagnostic discrepancies and inform efficacious treatment alternatives that are responsive to individual variability.

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