Genetics-mediated regulation of intestinal gene expression on microbiome contributes to human disease heritability.

The gut microbiome plays fundamental roles in physiological and pathological processes, yet its interaction with host gene expression and contribution to disease remain underexplored. Here, we integrate the genetic regulatory maps of 116 microbial genera with gene expression quantitative trait loci (eQTLs) and DNA methylation QTLs (mQTLs) in three intestinal tissues to dissect host-microbiome interaction. We identify 6088, 5810, and 2398 gene-to-microbiome regulatory loci in the transverse colon, sigmoid colon, and ileum, respectively. Among these, 13.2% of genes show broad regulatory effects on multiple genera, with functional enrichments in developmental, metabolic, and immune-related pathways. Integrative analysis with genome-wide association studies (GWASs) reveals 283 microbiome-dependent disease loci. We observe pleiotropic effects mediated by the gene-to-microbiome regulation at both microbiome and disease layers. Notably, we predict and experimentally validate the suppressive effect of Allisonella on depression through regulating bile acid abundance, and the regulation of Parasutterella on short-chain fatty acid and its contribution to allergic rhinitis. The gene-microbiome-disease regulatory maps are available at our interactive database ( https://xiongxslab.github.io/microbiomeMR/ ).