Commensal antimicrobial resistance mediates microbiome resilience to antibiotic disruption.

Despite their therapeutic benefits, antibiotics exert collateral damage on the microbiome and promote antimicrobial resistance. However, the mechanisms governing microbiome recovery from antibiotics are poorly understood. Treatment of Mycobacterium tuberculosis, the world's most common infection, represents the longest antimicrobial exposure in humans. Here, we investigate gut microbiome dynamics over 20 months of multidrug-resistant tuberculosis (TB) and 6 months of drug-sensitive TB treatment in humans. We find that gut microbiome dynamics and TB clearance are shared predictive cofactors of the resolution of TB-driven inflammation. The initial severe taxonomic and functional microbiome disruption, pathobiont domination, and enhancement of antibiotic resistance that initially accompanied long-term antibiotics were countered by later recovery of commensals. This resilience was driven by the competing evolution of antimicrobial resistance mutations in pathobionts and commensals, with commensal strains with resistance mutations reestablishing dominance. Fecal-microbiota transplantation of the antibiotic-resistant commensal microbiome in mice recapitulated resistance to further antibiotic disruption. These findings demonstrate that antimicrobial resistance mutations in commensals can have paradoxically beneficial effects by promoting microbiome resilience to antimicrobials and identify microbiome dynamics as a predictor of disease resolution in antibiotic therapy of a chronic infection. Editor's summary: Antibiotic exposure is well known to disrupt the microbiome, but how microbiota recovery occurs is less well studied. Examining a clinical cohort, Bhattarai et al. longitudinally investigated the long-term impact of multidrug-resistant (MDR) tuberculosis (TB) antibiotic treatment on the gut microbiota. Although treatment severely destabilized patient gut microbiota, repopulation by nonpathogenic bacteria occurred by treatment completion at 6 to 24 months, a process that was promoted by the emergence of antibiotic resistance in commensal species. This study sheds light on the treatment and resolution of the most common infection worldwide. —Catherine Charneski [ABSTRACT FROM AUTHOR]

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