B-S.B.44: TEMPEH: A Computational Framework for Linking Gut Microbiome Composition and Function in Disease
The human gut microbiome plays a vital role in host health, and alterations in microbial composition and function have been linked to diseases such as inflammatory bowel disease (IBD), colorectal cancer (CRC), and metabolic disorders. Metagenomic studies typically analyze microbiomes through either taxonomic profiling to identify species, or functional profiling to characterize gene families. However, these approaches are usually performed independently, limiting our ability to link specific microbial taxa to their functional contributions. Furthermore, current methods lack the capacity for large-scale, accurate functional copy number estimation directly from complex metagenomic samples.
Here, we present TEMPEH (Taxonomic and Enzymatic Metagenomic Profiling with Enhanced Hybrid Annotation), a computational pipeline designed to bridge this gap. By employing both k-mer and alignment-based annotation methods against a unified taxonomic-functional reference database, TEMPEH achieves coupled, read-level annotation. Crucially, it generates highly accurate matrices of species-function pairs, complete with precise copy number estimations, enabling the identification of combinatorial microbiome features that drive differences between case and control samples.
To interpret these high-resolution profiles, we generated genome-scale functional profiles for a large set of reference genomes to construct a comprehensive, low-dimensional functional embedding. By projecting TEMPEH-derived species profiles into this continuous reference space, we demonstrate the utility of this framework in distinguishing normal functional variation in healthy microbiomes from the metabolic deviations characteristic of dysbiosis.
Ultimately, TEMPEH provides a scalable computational framework to integrate taxonomic and functional dimensions, offering deeper insights into microbiome-mediated disease mechanisms and informing potential targeted therapeutic strategies.
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