Multi-level aggregation analysis of microbiome composition and host gene expression reveals associations with systemic and local immunity
Lev I. Shagam, Anna Elizarova, Yukihide Momozawa, Julia Dmitrieva, Rob Mariman, Souad Rahmouni, Edouard Louis, Michel Georges, Alexander V. Tyakht, Natalia KlimenkoABSTRACT
The human gut microbiome plays a critical role in immune regulation, yet the molecular links between microbiome composition and host gene expression remain incompletely understood. We analyzed associations between host gene expression and microbiome composition in a cohort of 315 healthy individuals, integrating microarray-based gene expression data from three intestinal sites (ileum, transverse colon, and rectum) and six immune cell types with microbiome sequencing data. Using a hierarchical feature aggregation strategy combining principal component analysis, clustering, and covariate correction, we discovered significant associations primarily related to immunity. While microbial profiles were similar across the three intestinal sites, the transverse colon yielded the most “microbiome-host gene expression” associations. Among the immune cell types, CD8+ cells showed the highest number of associations. The first principal component of microbiome composition, reflecting a gradient from commensals (e.g.,
IMPORTANCE
The gut microbiome and immune system are engaged in a complex interplay throughout human life. While most associative studies focus on case-control comparisons—typically examining patients with conditions such as inflammatory bowel disease or metabolic diseases—less is known about the molecular links between the microbiome and immune system in healthy individuals. In this study of a large cohort of healthy individuals, we addressed this gap by applying multiscale modeling to tackle the high dimensionality of host-microbiome data. We identified multi-level associations between microbiome composition and host gene expression in both intestinal tissues and immune cells. These findings offer a valuable reference for understanding baseline host-microbiome communication and highlight molecular candidates—such as TNF-α-related genes and mitochondrial pathways—for future experimental validation.