Time-dependent modulation of gut microbiome in response to systemic antifungal agents

Abstract

AbstractThe effects of antifungal agents on the human microbiome can be challenging to study due to confounding factors such as the underlying disease states and concomitant use of antibiotics and other therapies. We elucidated longitudinal modification of gut microbiome in response to a short course (5 days) of antifungal treatment in healthy male Sprague-Dawley (SD) rats by sequencing 16S rRNA V1–V3 and ITS2 hypervariable regions. SD rats were randomized into a control group and three antifungal treated (AT) groups including Amphotericin B (AmB), voriconazole and, our novel antifungal drug candidate SM21 once per day for 5 consecutive days. Fecal samples were collected at three different time points (day 0, day 1 and day 5). Microbial communities of both bacteria and fungi were compared between conditions. In silico analysis of differential microbial abundance and the predictive functional domains of microbial communities was further done by inferring metabarcoding profiles from 16S data. AT animals exhibited significant change in bacteriome alphadiversity although no divergence in community structure (beta-diversity) was observed compared with respective control groups (day 0). Specific bacterial clades and taxa were longitudinally and significantly modified in the AT animals. The AT bacterium of AmB and SM21 was particularly enriched in probiotic Lactobacillus strains including L. reuteri. The key pathways overrepresented in the bacteriome under AT animals were linked to cellular processes, environment information processing and metabolism. Moreover, AT treated mycobiome diversity decreased longitudinally with insignificant variations along the time course; different fungal taxa dominating at different timepoints in a wave-like fashion. However, acute antifungal treatments could not alter healthy gut microbial community structure. Hence, the healthy gut microbiome is capable of resisting a major dysbiotic shift during a short course of antifungal treatment.