The success of faecal microbiota transplant (FMT) to induce remission in ulcerative colitis cohorts highlights the gastrointestinal microbiome as a key target for therapeutic intervention in inflammatory bowel diseases (IBD). However, FMT is a broad-spectrum treatment, and a detailed model of the molecular mechanisms through which microbiome transplantation confers disease remission remains elusive. This undermines our ability to manipulate the gastrointestinal microbiome in a more targeted fashion. The technology we use to probe these communities is evolving; shotgun metagenomic sequencing enables high-throughput yield of microbial DNA, and increasing cultivation of hitherto ‘unculturable’ microbiota is revealing previously unappreciated diversity in microbial lifestyle and function. While taxonomy-guided metagenomics has played a crucial role in illuminating the importance of our intestinal microbes, improved characterisation of cultured bacterial isolates increasingly demonstrates incongruence between ecologically relevant microbial phenotypes and their taxonomic denomination. Instead, large databases of high-quality microbial genomes are ushering in a paradigm of genome-resolved metagenomics, that seeks to explain microbial function at a genetic and molecular, rather than taxonomic, level. We developed Expam for genome-guided analysis of shotgun metagenomic datasets, leveraging modern genomic techniques to quantify phylogenetic clades of bacteria in a taxonomy-agnostic manner. Applying Expam to a paediatric IBD cohort who underwent matched shotgun metagenomic sequencing and host transcriptional profiling from intestinal biopsy samples, revealed closely related phylogenetic clades of bacteria with distinct patterns of association to host transcriptional responses. This highlights the potential for genome-guided metagenomics to increase the resolution of compositional microbiome analyses, and foreshadows a mechanistic understanding of host-microbiome interactions in health and disease.