Hybrid-metagenomics reveal off-target effects of albendazole, ivermectin-albendazole and moxidectin-albendazole on the human gut bacteria.

Abstract

The human whipworm parasite, Trichuris trichiura, poses a critical public health problem, affecting over 400 million people globally and responding poorly to the standard-of-care - benzimidazole chemotherapy. Recent efforts aimed at developing improved treatment options, the two macrolide-benzimidazole combination therapies ivermectin-albendazole and moxidectin-albendazole. Recent reports suggest that ivermectin and moxidectin possess antibacterial properties in vitro, hence there is a need to comprehensively characterize their off-target effects on the gut microbiome. In the framework of a randomized-controlled trial we collected stool samples of 204 T. trichiura-infected individuals in Cote dIvoire receiving albendazole (400mg), albendazole-ivermectin (400mg/200{micro}g/kg) and albendazole-moxidectin (400mg/8mg). Using a state-of-the-art hybrid sequencing approach that combines Illumina short read and Oxford Nanopore long read shotgun sequencing, we recovered over 800 high-quality metagenome-assembled genomes. Our analyses reveal that albendazole and albendazole-moxidectin induce taxonomic shifts in the gut microbiota with only mild functional consequences. In contrast, in individuals receiving higher quantities of albendazole-ivermectin (ivermectin > 12mg), based on their weight, we observed profoundly modulated taxonomic composition and microbial function, while the resistome was largely spared. These findings robustly confirm ivermectins antibacterial properties in the human gut, extending beyond previously reported in vitro effects. Given that ivermectin is a cornerstone in parasitic disease control, it is crucial to evaluate its broader impacts and considering more targeted, evidence-based treatment strategies.