Document text
Principal Investigator: Charissa Camille Naidoo
Organization: STELLENBOSCH UNIVERSITY
Fiscal Year: 2024
Award: $89,609
Funding agency: John E. Fogarty International Center for Advanced Study in the Health Sciences
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.
Terms: <16S gene sequencing><16S rRNA amplicon sequencing><16S rRNA gene amplicon sequencing><16S rRNA gene sequencing><16S rRNA genomic profiling><16S rRNA sequencing><16S ribosomal RNA gene sequencing><16S ribosomal RNA sequencing><16S sequencing><21+ years old><AIDS Virus><Acetates><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Adolescent><Adolescent Youth><Adult><Adult Human><Aerobacter><Affect><African><After Care><After-Treatment><Aftercare><Anaerobic Bacteria><Antibiotic Agents><Antibiotic Drug Combinations><Antibiotic Drugs><Antibiotic Therapy><Antibiotic Treatment><Antibiotics><Antibiotics against tuberculosis><Antitubercular Antibiotics><Antitubercular Drugs><Benemycin><Blood leukocyte><Butyrates><Calymmatobacterium><Causality><Cause of Death><Clinical><Clinical Trials><Coliform Bacilli><Collaborations><Combined Antibiotics><Computing Methodologies><Data><Dedications><Dietary Supplementation><Donovania><Dose><Drug Kinetics><Drug Resistance Tuberculosis><Drug Resistant TB><Drug Resistant Tuberculosis><Drug resistance in tuberculosis><Drugs><Enteric Bacteria><Enterobacter><Enterobacteria><Enterobacteriaceae><Epidemic><Ethambutol><Etiology><Feces><Foundations><Funding><Future><GC MS><GCMS><GI microbiota><Gas-Liquid-Mass Spectrometry Chromatography><Gastrointestinal microbiota><HIV><Health><Health Benefit><Hospitals><Human Immunodeficiency Viruses><Human Microbiome><Immune><Immunes><Immunomodulation><Inflammatory><Injections><Intervention><Intervention Strategies><Isonicotinic Acid Hydrazide><Klebsiella><Knowledge><LAV-HTLV-III><LMIC><Leukocytes><Leukocytes Reticuloendothelial System><Levaquin><Levofloxacin><Life><Linezolid><Lung TB><Lung Tuberculosis><Lymphadenopathy-Associated Virus><M tuberculosis infection><M. tb infection><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MDR Tuberculosis><MDR-TB><MTB infection><Marrow leukocyte><Mass Chromatography><Mass Fragmentographies><Mass Fragmentography><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mass-Gas Chromatography Spectrometry><Mass-Gas Chromatography Spectrum Analysis><Measures><Mediator><Medication><Mentors><Mentorship><Metabolic><Metadata><Mice><Mice Mammals><Microbiomics><Miscellaneous Antibiotic><Monitor><Multi-Drug Resistant Tuberculosis><MultiDrug Resistance Tuberculosis><Multidrug-Resistant Tuberculosis><Murine><Mus><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><Network Analysis><New York><Oral><Outcome><Pantoea><Parents><Pathogenesis><Pathway Analysis><Pathway interactions><Patients><Persons><Pharmaceutical Preparations><Pharmacokinetics><Physiologic><Physiological><Predicting Risk><Production><Propionates><Prospective, cohort study><Province><Pulmonary TB><Pulmonary Tuberculosis><Pyrazinamide><Pyrazinecarboxamide><Quixin><Regimen><Research><Research Priority><Research Support><Resistance><Rifadin><Rifampicin><Rifampicin resistance><Rifampicin resistant><Rifampin><Rifampin resistance><Rifampin resistant><Rimactane><Sampling><Scientist><Short-Chain Fatty Acids><South Africa><South African><Sputum><Structure><TB antibiotics><TB drug resistance><TB drugs><TB infection><TB therapy><TB treatment><Testing><Treatment outcome><Tuberculosis><Tuberculosis antibiotics><Uncertainty><Universities><Virus-HIV><Volatile Fatty Acids><White Blood Cells><White Cell><Withholding Treatment><Work><Zyvox><absorption><adulthood><anaerobe><analyzing longitudinal><anti-TB drugs><anti-tuberculosis drugs><antibiotic against TB><bacterial disease treatment><bacterial infectious disease treatment><career><career development><causation><cessation of treatment><cohort><combinatorial><commensal flora><commensal microbes><commensal microbiota><commensal microflora><community microbes><computational methodology><computational methods><computer based method><computer methods><computing method><design><designing><diagnostic tool><diet supplementation><disease causation><disseminated TB><disseminated tuberculosis><doubt><drug resistance in TB><drug resistant in tuberculosis><drug-sensitive><drug/agent><enteric microbial community><enteric microbiota><experiment><experimental research><experimental study><experiments><forecasting risk><gastrointestinal microbial flora><global health emergency><gut commensal><gut community><gut flora><gut microbe community><gut microbial community><gut microbial composition><gut microbial consortia><gut microbiota><gut microbiotic><gut microflora><host microbiome><human flora><human microbial communities><human microbiota><human microflora><human-associated microbial communities><human-associated microbiome><human-associated microbiota><immune modulation><immune regulation><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><improved><infection due to Mycobacterium tuberculosis><interventional strategy><intestinal flora><intestinal microbiota><intestinal microflora><intestinal tract microflora><ion trap mass spectrometry><isoniazid><juvenile><juvenile human><longitudinal analysis><low and middle-income countries><mass fragmentometry><medical college><medical schools><meta data><microbial><microbial community><microbial consortia><microbial flora><microbial host><microbiome><microbiome intervention><microbiome research><microbiome science><microbiome studies><microbiome therapeutics><microbiome therapy><microbiome treatment><microbiome-based intervention><microbiome-based therapeutic><microbiome-based therapy><microbiome-based treatment><microbiota><microbiota patterns><microbiota profiles><microbiota signature><microflora><mortality><multidisciplinary><multidrug-resistant TB><multispecies consortia><parent><pathway><polymicrobial community><post treatment><predict risk><predict risks><predicted risk><predicted risks><predicting risks><predictive risk><predicts risk><programs><resilience><resilient><resistance to rifampicin><resistance to rifampin><resistant><resistant to rifampicin><resistant to rifampin><response><response to therapy><response to treatment><risk prediction><risk predictions><school of medicine><stool><therapeutic response><therapy response><treat M. tuberculosis><treat Mtb><treat Mycobacterium tuberculosis><treat tb><treat tuberculosis><treatment cessation><treatment response><treatment responsiveness><tuberculosis drugs><tuberculosis infection><tuberculosis therapy><tuberculosis treatment><tuberculous spondyloarthropathy><white blood cell><white blood corpuscle>