Abstract
The composition of the gastrointestinal microbiota influences systemic immune responses, but how this affects infectious disease pathogenesis and antibiotic therapy outcome is poorly understood. This question is rarely examined in humans due to the difficulty in dissociating the immunologic effects of antibiotic-induced pathogen clearance and microbiome alteration. Here, we analyze data from two longitudinal studies of tuberculosis (TB) therapy (35 and 20 individuals) and a cross sectional study from 55 healthy controls, in which we collected fecal samples (for microbiome analysis), sputum (for determination of Mycobacterium tuberculosis (Mtb) bacterial load), and peripheral blood (for transcriptomic analysis). We decouple microbiome effects from pathogen sterilization by comparing standard TB therapy with an experimental TB treatment that did not reduce Mtb bacterial load. Random forest regression to the microbiome-transcriptome-sputum data from the two longitudinal datasets reveals that renormalization of the TB inflammatory state is associated with Mtb pathogen clearance, increased abundance of Clusters IV and XIVa Clostridia, and decreased abundance of Bacilli and Proteobacteria. We find similar associations when applying machine learning to peripheral gene expression and microbiota profiling in the independent cohort of healthy individuals. Our findings indicate that antibiotic-induced reduction in pathogen burden and changes in the microbiome are independently associated with treatment-induced changes of the inflammatory response of active TB, and the response to antibiotic therapy may be a combined effect of pathogen killing and microbiome driven immunomodulation.
Highlights
1234567890():,; The composition of the gastrointestinal microbiota influences systemic immune responses, but how this affects infectious disease pathogenesis and antibiotic therapy outcome is poorly understood
Since the advent of high-throughput microbiome characterization, it has become clear that antibiotics are one of the most common and severe perturbing influences on human microbiome composition, with both acute and longer lasting effects[56,57]
Significant prior data have documented the effects of antibiotics on microbiome composition and function and the consequent influence of these microbiome factors on immune cell populations[58], with the majority of these findings derived using in vivo mouse models
Summary
1234567890():,; The composition of the gastrointestinal microbiota influences systemic immune responses, but how this affects infectious disease pathogenesis and antibiotic therapy outcome is poorly understood. This question is rarely examined in humans due to the difficulty in dissociating the immunologic effects of antibiotic-induced pathogen clearance and microbiome alteration. A multitude of experiments in mice have allowed for the determination of mechanisms by which gastrointestinal mucosalassociated bacteria affect host physiology at the epithelial interface and systemically throughout their host[6,7] Despite these observations, it is unknown whether, and to what degree, microbiome changes are associated with systemic changes in inflammatory responses in humans. Individuals infected by Mycobacterium tuberculosis (Mtb) and having active TB disease (the 9th leading cause of death on Earth11)
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