Pre- and post-treatment lung microbiota, metabolome and immune signatures at the site of disease in patients with active pulmonary tuberculosis - SUMMARY
The human microbiome is important for infectious disease pathogenesis. However, our understanding of the
microbiome’s role in tuberculosis (TB), which is arguably the most important lung disease in the world, is
extremely limited. In sub-Saharan Africa, TB is exacerbated by HIV which, even with antiretroviral therapy, results
in reduced pulmonary immunity. The site-of-disease in active TB (bronchoalveolar space) is a unique
environmental and immunological niche but its microbiota is surprisingly understudied. We do not know how
taxa, including those important for lung heath (oral anaerobic fermenters), correlate with bacterial fermentation
end-products like short chain fatty acids (SCFAs), which may influence immunological control of TB and tissue
repair. Furthermore, the TB regimen is comprised of thousands of doses of antibiotics yet its long-term effect on
the lung microbiota is hitherto uncharacterized. We hence lack key foundational knowledge that precludes
research on the lung microbiota as a potential diagnostic or therapeutic target to improve TB outcomes.
We will test our central hypothesis that site-of-disease oral anaerobic fermenters are associated with elevated
pulmonary SCFAs and impaired inflammation and tissue repair biomarkers in TB cases (n=50) and, at treatment
end, these taxa and biomarkers remain perturbed but improve a year later. We will recruit an equal number of
HIV-positive patients at our high TB-HIV burden site in Cape Town. We will test our central hypothesis using
three aims. Aim 1 will, using a modified bronchoalveolar lavage (BAL) procedure, compare the site-of-disease
microbiota to that in contralateral non-diseased lung tissue before treatment. Aim 2 will characterize, at each
lung site before treatment, the association between specific taxa, SCFAs, inflammation and tissue repair
biomarkers, and investigate whether SCFA addition to ex vivo stimulated BAL cells impairs immune marker
release in a dose-dependent manner. Aim 3 will re-sample patients by bronchoscopy at treatment end and a
year later, and repeat measurements of the microbiota, SCFAs, and host biomarkers at each lung site.
If the site-of-disease is associated with a perturbed microbiota, linked via SCFAs, to impaired pulmonary
immunity and tissue repair, including after treatment, it will justify study of the microbiota and long-term TB clinical
outcomes (e.g., progression, treatment failure, relapse), which requires large and expensive trials. It will enable
research on tests or therapeutic interventions (antibiotics, drugs, prebiotics, vaccines) that target the microbiota.
Key to achieving our aims are the transfer of the modified bronchoscopy and BAL microbiota sampling
procedure (required to minimize cross contamination in low microbial abundance lower airway specimens) and
leading-edge computational expertise (required to co-analyze sequence data in conjunction with biomarker and
clinical data) from New York University to Stellenbosch University (SU). South African clinicians and scientists
will train in each area by through research and training visits with the long-term aim of establishing a research
program on the lung microbiota and respiratory health at SU.
