Divergent Relationships between Fecal Microbiota and Metabolome following Distinct Antibiotic-Induced Disruptions

Abstract

ABSTRACT The intestinal microbiome plays an essential role in regulating many aspects of host physiology, and its disruption through antibiotic exposure has been implicated in the development of a range of serious pathologies. The complex metabolic relationships that exist between members of the intestinal microbiota and the potential redundancy in functional pathways mean that an integrative analysis of changes in both structure and function are needed to understand the impact of antibiotic exposure. We used a combination of next-generation sequencing and nuclear magnetic resonance (NMR) metabolomics to characterize the effects of two clinically important antibiotic treatments, ciprofloxacin and vancomycin-imipenem, on the intestinal microbiomes of female C57BL/6 mice. This assessment was performed longitudinally and encompassed both antibiotic challenge and subsequent microbiome reestablishment. Both antibiotic treatments significantly altered the microbiota and metabolite compositions of fecal pellets during challenge and recovery. Spearman’s correlation analysis of microbiota and NMR data revealed that, while some metabolites could be correlated with individual operational taxonomic units (OTUs), frequently multiple OTUs were associated with a significant change in a given metabolite. Furthermore, one metabolite, arginine, can be associated with increases/decreases in different sets of OTUs under differing conditions. Taken together, these findings indicate that reliance on shifts in one data set alone will generate an incomplete picture of the functional effect of antibiotic intervention. A full mechanistic understanding will require knowledge of the baseline microbiota composition, combined with both a comparison and an integration of microbiota, metabolomics, and phenotypic data. IMPORTANCE Despite the fundamental importance of antibiotic therapies to human health, their functional impact on the intestinal microbiome and its subsequent ability to recover are poorly understood. Much research in this area has focused on changes in microbiota composition, despite the interdependency and overlapping functions of many members of the microbial community. These relationships make prediction of the functional impact of microbiota-level changes difficult, while analyses based on the metabolome alone provide relatively little insight into the taxon-level changes that underpin changes in metabolite levels. Here, we used combined microbiota and metabolome profiling to characterize changes associated with clinically important antibiotic combinations with distinct effects on the gut. Correlation analysis of changes in the metabolome and microbiota indicate that a combined approach will be essential for a mechanistic understanding of the functional impact of distinct antibiotic classes.

Keywords

• beta-lactam
• fluoroquinolone
• glycopeptide
• metabolic activity
• microbiota composition