UNLABELLED:Glycans form the primary nutritional source for microbes in the human gut, and understanding their metabolism is a critical yet understudied aspect of microbiome research. Here, we present a novel computational pipeline for modeling glycan degradation (GlyDeR) which predicts the glycan degradation potency of 10,000 reference glycans based on either genomic or metagenomic data. We first validated GlyDeR by comparing degradation profiles for genomes in the Human Microbiome Project against KEGG reaction annotations. Next, we applied GlyDeR to the analysis of human and mammalian gut microbial communities, which revealed that the glycan degradation potential of a community is strongly linked to host diet and can be used to predict diet with higher accuracy than sequence data alone. Finally, we show that a microbe's glycan degradation potential is significantly correlated (R = 0.46) with its abundance, with even higher correlations for potential pathogens such as the class Clostridia (R = 0.76). GlyDeR therefore represents an important tool for advancing our understanding of bacterial metabolism in the gut and for the future development of more effective prebiotics for microbial community manipulation. IMPORTANCE:The increased availability of high-throughput sequencing data has positioned the gut microbiota as a major new focal point for biomedical research. However, despite the expenditure of huge efforts and resources, sequencing-based analysis of the microbiome has uncovered mostly associative relationships between human health and diet, rather than a causal, mechanistic one. In order to utilize the full potential of systems biology approaches, one must first characterize the metabolic requirements of gut bacteria, specifically, the degradation of glycans, which are their primary nutritional source. We developed a computational framework called GlyDeR for integrating expert knowledge along with high-throughput data to uncover important new relationships within glycan metabolism. GlyDeR analyzes particular bacterial (meta)genomes and predicts the potency by which they degrade a variety of different glycans. Based on GlyDeR, we found a clear connection between microbial glycan degradation and human diet, and we suggest a method for the rational design of novel prebiotics.