Gut microbial communities modulate efficacy of albendazole-ivermectin against soil-transmitted helminthiases

Abstract BackgroundSoil-transmitted helminth infections represent a large burden across the globe with over a quarter of the world’s population at risk. The outcome of available treatments is species-specific with a large proportion of unexplained treatment failure. Administration of albendazole is the standard of care, but because of low cure rates (CR) observed in treating Trichuris trichiura infections, a significantly more efficacious alternative therapy combining albendazole and ivermectin is being investigated. Methods80 patients from the village of Pak-Khan, in Laos, with confirmed STH infections (Trichuris trichiura and hookworms), received either albendazole (400 mg) or albendazole (400 mg) and ivermectin (200 μg/kg) together. A pre-treatment stool sample was collected as well as daily post-treatment stool samples for up to 28 days to measure treatment efficacy. Taxonomic profiling of pre-treatment stool samples was conducted using 16S rRNA gene sequencing, target-specific and total bacteria qPCR, as well as shotgun sequencing. ResultsThree bacterial communities, or enterotypes (ET) 1-3, were identified. No association with pre-treatment enterotype and treatment outcome of both Trichuris trichiura and hookworm were found in the monotherapy arm with overall cure rates (CR) of 7.5% and 50%, respectively. Pre-treatment enterotype was strongly associated with efficacy of the combination therapy for both, T. trichiura (CRoverall = 33.3%; CRET1 = 5.8%; CRET2 = 16.6%; CRET3 = 68.5%) and hookworm (CRoverall = 47.2%; CRET1 = 31.2%; CRET2 = 16.6%; CRET3 = 78.5%) infections. Daily post-treatment egg per gram of stool counts recapitulated these observations and faster and increased egg reduction was observed in ET3 when compared to failure-associated ET1 and ET2. Species-level comparisons of these enterotypes highlighted a set of ten differentially enriched bacterial species. ConclusionTaxonomically distinct gut microbiota communities were found in this setting in terms of both, relative and absolute abundances, of specific bacterial taxa. Pre-treatment enterotype was relevant for treatment outcome of the combination therapy, albendazole and ivermectin, for T. trichiura as well as for hookworm infections. These observations indicate that pre-treatment microbial composition of stool samples should be monitored to ensure evidence-based administration of albendazole-ivermectin to treat these diseases.