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 microbiome dynamics over 20 months of multi-drug-resistant tuberculosis and 6 months of drug-sensitive TB treatment in humans. We find that 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 accompanies long-term antibiotics is countered by surprising later recovery of commensals. This resilience is driven by the competing evolution of antimicrobial resistance mutations in pathobionts and commensals, with commensal strains with resistance mutations reestablishing dominance. FMT of the antibiotic-resistant commensal microbiome in mice recapitulates 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.