Inflammatory bowel disease (IBD) is a complex pathology involving chronic inflammation of the gastrointestinal tract. It poses a significant risk to paediatric patients where early onset is associated with delayed growth and puberty. While the intestinal microbiome is thought to play a key role, its involvement is complex, and a better understanding is needed to improve the efficacy of IBD therapies targeting the microbiome. A key technology for investigating microbiome composition is shotgun metagenomic sequencing, a high-throughput approach that enables in-depth profiling of microbial community structure. It has proved an essential tool to address the challenge of identifying a robust microbial signature of IBD. Current approaches typically try to associate microbial species with disease, and these species are treated as entirely distinct biological entities. However, treating species as entirely distinct entities can obscure the similarities between communities; even distantly related species share genes. Leveraging this observation, we are developing an alternative approach for metagenomic analysis, called Expam. Expam measures the relative abundance of phylogenetic clades, rather than species, in shotgun metagenomic datasets. This increases our capacity to identify similarities between different microbiomes, because phylogenetic trees capture more genetic relationships than microbial taxonomy. This creates the capacity for a broader range of potential disease biomarkers, and more resolved insight into disease-associated microbial factors. 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. In particular, Enterococcus clades displayed differential association with expression of inflammatory gene sets in the host. We plan to extend the current implementation to identify genomic differences between members of these clades, utilising massive public databases of high-quality reference genomes, to provide novel insights into specific microbial pathways associated with IBD.