Microbiome in TB treatment response and disease resolution

Treatment of TB is defined by two factors: the requirement for combination chemotherapy and extended duration of therapy. For antibiotic sensitive disease, the shortest duration of therapy that will cure >95% of treated subjects is 2 months of INH/RIF/PZA/ETH, followed by 4 months of INH/RIF (2HRZE/4HR). However, abundant clinical trial evidence indicates that the majority of treated subjects are cured with shorter durations of treatment, yet we lack any clinical or laboratory biomarkers that can identify these candidates for treatment shortening. The antimicrobials used to treat TB, both drug-sensitive and drug-resistant, are predominantly mycobacterial-specific and until recently, their effects on the gut microbiome were unknown. In the first award period, this Tri- I TBRU pioneered the analysis of the intestinal microbiome in TB infection and thereby advanced the idea that the intestinal microbiome is an unexplored cofactor in TB susceptibility and response to therapy. We found, in both cross sectional and longitudinal studies of human subjects with TB, that HRZE therapy has rapid, but long-lasting, effects on intestinal microbiome composition: Clostridiales are depleted, with relative preservation of other taxons. Clostridiales are critical components of the microbiota that interact with the host immune system through production of diverse chemical mediators including short chain fatty acids as well as other metabolites. Accordingly, we have also found, using new statistical modeling techniques developed during the prior award period, that the resolution of TB disease can be modeled as a combined effect of pathogen (Mtb) sterilization and the immune effects of antimycobacterial-induced microbiome perturbation. Our overriding hypothesis is that individual differences in microbiome composition and function, either pretreatment or induced by antimycobacterials during treatment, are associated with, and predictive of, different rates of pathogen clearance, resolution of inflammatory markers of active TB, and ultimately treatment success (both early sterilization and lack of relapse). We propose studies that will expand this concept to 1) validate microbiome derived biomarkers of TB treatment success; 2) develop predictive computational models that integrate microbiome, transcriptomic, and microbiologic data to predict treatment success; 3) yield mechanistic insight into the interaction of microbiome driven immunomodulation and TB disease. Coupled with the other projects and cores of this TBRU, this project will advance our understanding of the control of paucibacillary TB.