Differential response to prolonged amoxicillin treatment: long-term resilience of the microbiome versus long-lasting perturbations in the gut resistome

Abstract

The collateral impact of antibiotics on the microbiome has attained increasing attention. However, the\necological consequences of long-term antibiotic exposure on the gut microbiome, including anti-\nbiotic resistance, are still limited. Here, we investigated long-term exposure effects to amoxicillin on\nthe human gut microbiome and resistome. Fecal samples were collected from 20 patients receiving\n3-months of amoxicillin or placebo treatment as part of a Norwegian multicenter clinical trial on\nchronic low back pain (AIM study). Samples were collected at baseline, last day of treatment, and\n9 months after antibiotic cessation. The abundance and diversity of microbial and resistome composi-\ntion were characterized using whole shotgun and functional metagenomic sequencing data. While\nthe microbiome profiles of placebo subjects were stable over time, discernible changes in diversity\nand overall microbiome composition were observed after amoxicillin treatment. In particular, health-\nassociated short-chain fatty acid producing species significantly decreased in proportion. However,\nthese changes were short-lived as the microbiome showed overall recovery 9 months post-treatment.\nOn the other hand, exposure to long-term amoxicillin was associated with an increase in total\nantimicrobial resistance gene load and diversity of antimicrobial resistance genes, with persistent\nchanges even at 9 months post-treatment. Additionally, beta-lactam resistance was the most affected\nantibiotic class, suggesting a targeted response to amoxicillin, although changes at the gene level\nvaried across individuals. Overall, our results suggest that the impact of prolonged amoxicillin\nexposure was more explicit and long-lasting in the fecal resistome than in microbiome composition.\nSuch information is relevant for designing rational administration guidelines for antibiotic therapies.