# Microbiome in TB treatment response and disease resolution

> **NIH NIH U19** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $499,379

## Abstract

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.

## Key facts

- **NIH application ID:** 10430225
- **Project number:** 5U19AI162568-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** SABINE EHRT
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $499,379
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10430225

## Citation

> US National Institutes of Health, RePORTER application 10430225, Microbiome in TB treatment response and disease resolution (5U19AI162568-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10430225. Licensed CC0.

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