Peripheral inflammatory response in human tuberculosis treatment is predicted by a combination of pathogen sterilization and microbiome dysbiosis

Abstract

Antibiotic therapy cures infection predominantly by killing the infecting pathogen, but for infections such as tuberculosis (TB), which are accompanied by chronic inflammation, the salutary effects of antibiotic therapy may reflect a combination of pathogen killing and microbiome alteration. This question has not been examined in humans due to the difficulty in dissociating the immunologic effects of antibiotic induced pathogen clearance and microbiome alteration. We analyzed sputum TB bacterial load, microbiome composition, and peripheral blood transcriptomics from a clinical trial (NCT02684240) comparing two antimicrobial therapies for tuberculosis, only one of which was clinically effective. We confirm that standard TB therapy (HRZE) rapidly depletes Clostridia from the intestinal microbiota. The antiparasitic drug nitazoxanide (NTZ), although ineffective in reducing Mycobacterium tuberculosis (Mtb) bacterial load in the sputum, caused profound alterations to host microbiome composition overlapping with alterations generated by HRZE. We then evaluated the effect of these two treatments on the TB driven inflammatory state and found that whereas HRZE normalized proinflammatory TB-associated gene sets, NTZ exacerbated these pathways. Using Random Forest Regression, we identify both pathogen sterilization and microbiome disruption as the top predictors of changes in TB-associated inflammatory transcriptomic markers. We then validate the observed microbiome-peripheral gene expression associations in an independent human cohort of healthy subjects in which the abundance of Clostridia was positively associated with homeostatic, and negatively associated with pro-inflammatory pathways, while the abundance of Bacilli and Proteobacteria species displayed the opposite trend. 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 more broadly indicate that response to antibiotic therapy may be a combined effect of pathogen killing and microbiome driven immunomodulation. Additionally, to our knowledge, this is the first analysis to directly test the hypothesis that the microbiome composition is associated with peripheral gene expression inflammatory profile in humans.

Proanthocyanidin-enriched cranberry extract induces resilient bacterial community dynamics in a gnotobiotic mouse model

“…Seminal studies in animal models have demonstrated that short-chain fatty acids, and in particular butyrate-producing Clostridia Cluster IV and XIVa promote the induction of regulatory T-cells and ameliorate symptoms of colitis [12]. Furthermore, these bacteria have been associated with dampening systemic inflammatory response in humans [13] and with promotion of neurological health and of related anti-inflammatory innate immune phenotypes [14]. Recent work has also shown that specific members of the Bacteroides, Parabacteroides and Fusobacterium genera robustly induce interferon-γ-producing CD8 T cells in the intestine and enhance therapeutic efficacy of immune checkpoint inhibitors in syngeneic tumor models [15].…”