Multi-level aggregation analysis of microbiome composition and host gene expression reveals associations with systemic and local immunity
The human gut microbiome plays a critical role in immune regulation, yet the molecular links between microbial composition and host gene expression remain incompletely understood. We analyzed associations between host transcriptome profiles and microbiome composition in a cohort of 315 healthy individuals, integrating microarray-based gene expression data from three intestinal sites (ileum, transverse colon, rectum) and six blood cell types with microbiome sequencing data across three hypervariable regions. Using a hierarchical feature aggregation strategy combining PCA, clustering, and covariate correction, we discovered significant associations primarily related to immunity. While microbial profiles were similar across the three intestinal loci, the transverse colon yielded the most “microbiome-host transcriptome” associations. Among the blood cell types, CD8+ cells showed the highest number of associations. The first principal component of microbiome composition, reflecting a gradient from commensals (e.g., Ruminococcaceae, Christensenellaceae) to proinflammatory taxa ([Ruminococcus] gnavus, Lachnoclostridium), correlated with the expression of TNF-a–linked genes (HMOX1, CPI17, HSD3B2 and SLC5A1). Among individual genera, Catenibacterium abundance was associated with gene expression in both intestinal and immune cells, including negative associations with MRPS21 (related to mitochondrial function) in the transverse colon and with CD8+ gene programs related to T cell differentiation. These findings align with emerging evidence implicating mitochondrial dysfunction in intestinal inflammation. Our results identify multi-level associations between the gut microbiome and host gene expression, suggesting potential mechanisms by which microbiota shape local and systemic immunity and vice versa. The implicated genes and taxa represent candidates for experimental validation, to improve understanding of host-microbiome homeostasis and its disruption in disease.