Combined high-quality metagenomics reveals off-target effects of albendazole, ivermectin-albendazole and moxidectin-albendazole on the human gut bacteria.

Human whipworm infections caused by Trichuris trichiura and Trichuris incognita remain a major public health problem, affecting over 400 million people globally and responding poorly to standard benzimidazole chemotherapy. Ivermectin-albendazole and moxidectin-albendazole have emerged as promising combination therapies, but recent in vitro evidence suggests that ivermectin and moxidectin may also affect gut bacteria. We therefore characterized their off-target effects on the gut microbiome in a randomized controlled trial including 204 Trichuris spp.-infected individuals in Côte d'Ivoire treated with albendazole (400 mg), ivermectin-albendazole (200 µg/kg/400 mg), or moxidectin-albendazole (8 mg/400 mg). By combining Illumina short reads and Nanopore long reads, we recovered over 800 high-quality metagenome-assembled genomes. Albendazole and moxidectin-albendazole induced taxonomic shifts with only mild functional consequences. In contrast, individuals receiving higher absolute ivermectin doses based on their bodyweight ( ≥ 15 mg) showed pronounced changes in taxonomic composition and microbial function, whereas the resistome remained largely stable. These findings confirm that ivermectin can exert antibacterial off-target effects in the human gut beyond those previously observed in vitro. Given its central role in parasite control, its broader microbiome effects warrant careful evaluation in future treatment strategies.