Decoding host-microbiome interactions through co-expression network analysis within the non-human primate intestine

The gut microbiome affects the health status of the host through complex interactions with the host's intestinal wall. These host-microbiome interactions may spatially vary along the physical and chemical environment of the intestine, but these changes remain unknown. This study investigated these intricate relationships through a gene co-expression network analysis based on dual transcriptome profiling of different intestinal sites-cecum, transverse colon, and rectum-of the primate common marmoset. We proposed a gene module extraction algorithm based on the graph theory to find tightly interacting gene modules of the host and the microbiome from a vast co-expression network. The 27 gene modules identified by this method, which include both host and microbiome genes, not only produced results consistent with previous studies regarding the host-microbiome relationships, but also provided new insights into microbiome genes acting as potential mediators in host-microbiome interplays. Specifically, we discovered associations between the host gene FBP1, a cancer marker, and polysaccharide degradation-related genes (pfkA and fucI) coded by Bacteroides vulgatus, as well as relationships between host B cell-specific genes (CD19, CD22, CD79B, and PTPN6) and a tryptophan synthesis gene (trpB) coded by Parabacteroides distasonis. Furthermore, our proposed module extraction algorithm surpassed existing approaches by successfully defining more functionally related gene modules, providing insights for understanding the complex relationship between the host and the microbiome.IMPORTANCEWe unveiled the intricate dynamics of the host-microbiome interactions along the colon by identifying closely interacting gene modules from a vast gene co-expression network, constructed based on simultaneous profiling of both host and microbiome transcriptomes. Our proposed gene module extraction algorithm, designed to interpret inter-species interactions, enabled the identification of functionally related gene modules encompassing both host and microbiome genes, which was challenging with conventional modularity maximization algorithms. Through these identified gene modules, we discerned previously unrecognized bacterial genes that potentially mediate in known relationships between host genes and specific bacterial species. Our findings underscore the spatial variations in host-microbiome interactions along the colon, rather than displaying a uniform pattern throughout the colon.