Simon Isaiah

The primary hypothesis formulated for this investigative study is: ‘Can urinary metabolic profiles of paediatric cases of tuberculous meningitis (TBM) provide sufficient metabolic information to characterise and diagnose TBM, and monitor treatment response, thereafter?’ Secondly, if a brain–gut axis exists, then chronic central nervous system (CNS) bacterial infection(s) should theoretically be reflected in the urine. The premise here is that chronic CNS bacterial infection(s) will affect the gut microbiome and that altered metabolism in both the CNS and the gut will release metabolites into the blood that are filtered (kidneys) and excreted in the urine. Upon extensive deliberation and contemplation regarding the elucidation of the hypothesis, specific objectives became clear for this study:

(I) Characterise the urinary metabolic profile of the patient with TBM to comprehensively understand the aetiology, pathogenesis, clinical manifestations, epidemiology, and prognosis of the disease.
(II) Identify metabolite profiles that characterise the three stages of severity of TBM and potential biosignatures for early diagnosis of the disease, which may lead to a better outcome.
(III) Monitor the patients’ responses to treatment and identify possible prognostic markers to predict a successful treatment outcome.

The structure of this thesis follows. Chapter 1 is a literature overview of existing knowledge of Mycobacterium tuberculosis (M. tb), with a focus on the brain–gut axis exposed to chronic bacterial Infections in the central nervous system (CNS), underscoring the significance of the brain–gut axis within the realm of chronic bacterial infections in the CNS with concise step-by-step pathological aspects of M. tb in term of CNS infection. A brief description of the existing literature provides a complete overview of chronic bacterial infections of the CNS with a central focus on tuberculous meningitis (TBM), as well as the impact of bacterial infection on the gut microbiome and the potential application of urinary metabolic profiling for the diagnosis of M. tb infections. Infection with M. tb leads to perturbed metabolism in both the CNS and gut and will release metabolites into the blood that are filtered (by the kidneys) and excreted in the urine. Identifying the gap in the literature: no non-invasive (urinary) method of diagnosis of TBM (problem statement), showed that the association between the brain-intestinal connection and bacterial infections of the CNS is relatively scarce in the current literature. The intricate relationships with the gut microbiota are still inadequately elucidated. Metabolomics as a scientific method of choice was selected to fill this gap. But