Longitudinal microbiome-host interactions and clinical outcomes in drug-resistant tuberculosis patients

项目总结

PROJECT SUMMARY The human microbiome is an essential mediator of health and influences important metabolic functions through production of short chain fatty acids (SCFAs). These compounds have been shown to independently predict risk for developing tuberculosis (TB) – a leading cause of death in South Africa. Antibiotics may profoundly impact the microbiome yet the impact of treatment on the microbiome remains completely uncharacterized in patients with rifampicin-resistant and multidrug-resistant tuberculosis (RR/MDR-TB; resistance to the two most effective TB drugs). In response to the RR/MDR-TB epidemic, the South African National Programme rolled-out an all- oral shorter course regimen (SCR) which is being investigated within the funded observational prospective cohort study (SHIFT-TB; PI: Dr Graeme Meintjes) that this proposal (NASCENT; PI: Dr Charissa Naidoo) will leverage. We hypothesize that the SCR, though comprising lifesaving antibiotics for TB, also contain others which could plausibly affect the commensal microbiota (≤540 broad-spectrum antibiotic doses given over 9 months). Using 16S rRNA gene sequencing, we will longitudinally characterize the sputum and stool microbiota in 260 RR/MDR- TB adults and adolescents (≥ 15 years) initiating the SCR at Nkqubela Hospital, Eastern Cape Province, South Africa, at five intervals before, during, and after treatment. We will correlate the microbiota with important clinical metadata measured in the parent study, including repeated pharmacokinetic (Pk) data and pre-defined clinical outcomes. This work will lay the foundation for future trials where the microbiome is monitored as a diagnostic tool for clinical outcomes or modulated (through dietary supplementation, host-directed therapies) to improve long-term health (i.e., post-TB lung sequalae). Specifically, Aim 1 will evaluate changes in the sputum and stool microbiota in patients receiving treatment for RR/MDR-TB. Aim 2 will, using targeted as chromatography-mass spectrometry in stool, longitudinally quantify microbially-produced SCFAs (butyrate, propionate, acetate) and correlate SCFAs with the microbiota in co- occurrence network analyses. Aim 3 will evaluate longitudinal associations between the microbiota and drug Pk (where we expect greater drug absorption to result in greater microbial shifts and loss of diversity), and whether distinct microbiomes reflect favorable vs. unfavorable outcomes. Together, the proposal will achieve the following: 1) promote an independently funded research career for the candidate at Stellenbosch University (through structured mentorship with scientific experts), 2) strengthen South African analytical capacity for microbiome research in a low-middle income country (LMIC) research priority (TB), 3) and enhance long term collaboration with leading US scientists.